miladalsh/processed_scinews_dataset · Datasets at Hugging Face

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The realization of controllable fermionic quantum systems via quantum simulation is instrumental for exploring many of the most intriguing effects in condensed-matter physics 1 , 2 , 3 . Semiconductor quantum dots are particularly promising for quantum simulation as they can be engineered to achieve strong quantum correlations. However, although simulation of the Fermi–Hubbard model 4 and Nagaoka ferromagnetism 5 have been reported before, the simplest one-dimensional model of strongly correlated topological matter, the many-body Su–Schrieffer–Heeger (SSH) model 6 , 7 , 8 , 9 , 10 , 11 , has so far remained elusive—mostly owing to the challenge of precisely engineering long-range interactions between electrons to reproduce the chosen Hamiltonian. Here we show that for precision-placed atoms in silicon with strong Coulomb confinement, we can engineer a minimum of six all-epitaxial in-plane gates to tune the energy levels across a linear array of ten quantum dots to realize both the trivial and the topological phases of the many-body SSH model. The strong on-site energies (about 25 millielectronvolts) and the ability to engineer gates with subnanometre precision in a unique staggered design allow us to tune the ratio between intercell and intracell electron transport to observe clear signatures of a topological phase with two conductance peaks at quarter-filling, compared with the ten conductance peaks of the trivial phase. The demonstration of the SSH model in a fermionic system isomorphic to qubits showcases our highly controllable quantum system and its usefulness for future simulations of strongly interacting electrons. Main Superconductivity, magnetism 12 , low-dimensional electron transport 13 , topological phases 14 and other exotic phases of matter arise owing to the presence of strongly interacting particles within crystals 15 . However, the complexity of simulating such large quantum systems becomes intractable using classical computing methods 16 . A promising solution is to build a physical system at the same scale so that we can simulate these interacting fermionic systems 17 , 18 directly, known as analogue quantum simulation 19 , 20 . The Su–Schrieffer–Heeger (SSH) model is the prototypical example of topological matter that describes a single electron hopping along a one-dimensional dimerized lattice with staggered tunnel couplings, v and w , as shown in Fig. 1a 21 . The SSH model has been experimentally simulated in physical systems of varying dimensions from Rydberg atoms (about 10 μm) to mechanical systems (about 10 mm) (Table 1 ). The coupling strengths of the various simulators lie in the nanoelectronvolt to microelectronvolt range, limiting their ability to reach the fully coherent regime. Importantly, these systems can be readily solved classically as they do not simulate many-body interactions. Only recently has the interacting many-body SSH model been observed using Rydberg atoms with an effective infinite on-site interaction (hardcore bosons) 10 . The ability to control the interaction strength, however, is critical for investigating fermionic systems 22 , 23 . Fig. 1: Realization of the SSH model in precision-engineered phosphorus donors in silicon. a , A dimerized one-dimensional lattice with staggered hopping amplitudes (tunnel couplings) v and w . The array consists of two sublattices where there exists a trivial phase, v > w (top) and a topological phase v < w (bottom). b , Single-particle energy spectrum of the SSH model for a linear array of ten quantum dots as a function of the interdot coupling ratio v / w . For v / w < 1, there exists zero-energy topological edge states, whereas the trivial case v / w > 1 exhibits an excitation gap. c , d , Calculated multi-electron energy spectrum in the trivial ( c ) and topological ( d ) phases for different electron numbers at quarter-filling. The trivial array exhibits a single ground state with five electrons about 3.85 meV below the four- and six-electron states, whereas the topological phase exhibits a nearly four-fold degeneracy involving four, five (two-fold degenerate) and six electrons. e , f , Scanning tunnelling micrograph for the trivial ( e ; device I) and topological ( f ; device II) phases. The lighter regions show the open lithographic hydrogen mask. The devices consist of an array of N = 10 Coulomb-confined quantum dots with staggered nearest-neighbour distances, tunnel-coupled to a source (drain) lead at the start (end) of the array outlined in white to perform bias spectroscopy. Device I is designed to be in the trivial phase with d v = 7.7 ± 0.1 nm and d w = 10.1 ± 0.2 nm, and device II is designed to be in the topological phase with d v = 9.6 ± 0.4 nm and d w = 7.8 ± 0.6 nm. Full size image Table 1 Experimental demonstrations of the SSH model to date Full size table Semiconductor quantum dots are an emerging platform for the quantum simulation of strongly correlated electron systems 4 , 5 , 20 . Interacting electrons confined to quantum dots have been described by the Hubbard model 16 involving Coulombic interactions that describe the energy required to add electrons to the same (on-site, U ) or neighbouring (intersite, V ) quantum dot 24 . Here intersite hopping is governed by the tunnel coupling, t , between quantum dots, and each dot can be tuned using electrostatic gates to raise or lower their energy levels, \${\\epsilon }\$ (ref. 4 ). Phosphorus donors in silicon in particular have been proposed as promising candidates for simulators as they are nanoscale in size with very strong on-site energies ( U ≈ 25 meV) and can be engineered to have strong intersite ( V ≈ 5 meV) and hopping ( t ≈ 5 meV) energies, while operating with a low thermal energy of k B T ≈ 0.02 meV (ref. 25 ), where k B is the Boltzmann constant and T is the temperature, reaching a range of U / t ≈ 1−100 while remaining in the low-temperature limit with t / k B T > 10 (ref. 23 ). The ability to reach the low-temperature, strongly interacting regime allows for a number", "role": "user" }, { "content": "A team of quantum computer physicists at UNSW Sydney has engineered a quantum processor at the atomic scale to simulate the behavior of a small organic molecule, solving a challenge set some 60 years ago by theoretical physicist Richard Feynman. The achievement, which occurred two years ahead of schedule, represents a major milestone in the race to build the world's first quantum computer, and demonstrates the team's ability to control the quantum states of electrons and atoms in silicon at an exquisite level not achieved before. In a paper published today in the journal Nature, the researchers described how they were able to mimic the structure and energy states of the organic compound polyacetylene—a repeating chain of carbon and hydrogen atoms distinguished by alternating single and double bonds of carbon. Lead researcher and former Australian of the Year, Scientia Professor Michelle Simmons, said the team at Silicon Quantum Computing, one of UNSW's most exciting start-ups, built a quantum integrated circuit comprising a chain of 10 quantum dots to simulate the precise location of atoms in the polyacetylene chain. \"If you go back to the 1950s, Richard Feynman said you can't understand how nature works unless you can build matter at the same length scale,\" Prof. Simmons said. \"And so that's what we're doing, we're literally building it from the bottom up, where we are mimicking the polyacetylene molecule by putting atoms in silicon with the exact distances that represent the single and double carbon-carbon bonds.\" Chain reaction The research relied on measuring the electric current through a deliberately engineered 10-quantum dot replica of the polyacetylene molecule as each new electron passed from the source outlet of the device to the drain—the other end of the circuit. To be doubly sure, they simulated two different strands of the polymer chains. In the first device they cut a snippet of the chain to leave double bonds at the end giving 10 peaks in the current. In the second device they cut a different snippet of the chain to leave single bonds at the end only giving rise to two peaks in the current. The current that passes through each chain was therefore dramatically different due to the different bond lengths of the atoms at the end of the chain. Not only did the measurements match the theoretical predictions, they matched perfectly. \"What it's showing is that you can literally mimic what actually happens in the real molecule. And that's why it's exciting because the signatures of the two chains are very different,\" Prof. Simmons said. \"Most of the other quantum computing architectures out there haven't got the ability to engineer atoms with sub-nanometer precision or allow the atoms to sit that close. \"And so that means that now we can start to understand more and more complicated molecules based on putting the atoms in place as if they're mimicking the real physical system.\" Standing at the edge According to Prof. Simmons, it was no accident that a carbon chain of 10 atoms was chosen because that sits within the size limit of what a classical computer is able to compute, with up to 1024 separate interactions of electrons in that system. Increasing it to a 20-dot chain would see the number of possible interactions rise exponentially, making it difficult for a classical computer to solve. \"We're near the limit of what classical computers can do, so it's like stepping off the edge into the unknown,\" she says. \"And this is the thing that's exciting, we can now make bigger devices that are beyond what a classical computer can model. So we can look at molecules that haven't been simulated before. We're going to be able to understand the world in a different way, addressing fundamental questions that we've never been able to solve before.\" One of the questions Prof. Simmons alluded to is about understanding and mimicking photosynthesis—how plants use light to create chemical energy for growth. Or understanding how to optimize the design of catalysts used for fertilizers, currently a high-energy, high-cost process. \"So there're huge implications for fundamentally understanding how nature works,\" she said. Future quantum computers Much has been written about quantum computers in the last three decades with the billion-dollar question always being \"but when can we see one?\" Prof. Simmons says that the development of quantum computers is on a comparable trajectory to how classical computers evolved—from a transistor in 1947 to an integrated circuit in 1958, and then small computing chips that went into commercial products like calculators approximately five years after that. \"And so we're now replicating that roadmap for quantum computers,\" Prof. Simmons says. \"We started with a single atom transistor in 2012. And this latest result, realized in 2021 is the equivalent of the atom-scale quantum integrated circuit, two years ahead of time. If we map it to the evolution of classical computing, we're predicting we should have some kind of commercial outcome from our technology five years from now.\" One of the advantages that the UNSW/SQC team's research brings is that the technology is scalable because it manages to use fewer components in the circuit to control the qubits—the basic bits of quantum information. \"In quantum systems, you need something that creates the qubits, some kind of structure in the device that allows you to form the quantum state,\" Prof. Simmons says. \"In our system, the atoms themselves create the qubits, requiring fewer elements in the circuits. We only needed six metallic gates to control the electrons in our 10-dot system—in other words, we have fewer gates than there are active device components. Whereas most quantum computing architectures need almost double the number or more of the control systems to move the electrons in the qubit architecture.\" Needing fewer components packed in tightly together minimizes the amount of any interference with the quantum states, allowing devices to be scaled up to make more complex and powerful quantum systems. \"So that very low physical gate density is also very exciting for us, because it shows that we've got this nice clean system that we can manipulate, keeping coherence across long distances with minimal overhead in the gates. That's why it's valuable for scalable quantum computing.\" Looking ahead, Prof. Simmons and her colleagues will explore larger compounds that may have been predicted theoretically, but have never been simulated and fully understood before, such as high temperature superconductors. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The realization of controllable fermionic quantum systems via quantum simulation is instrumental for exploring many of the most intriguing effects in condensed-matter physics 1 , 2 , 3 . Semiconductor quantum dots are particularly promising for quantum simulation as they can be engineered to achieve strong quantum correlations. However, although simulation of the Fermi–Hubbard model 4 and Nagaoka ferromagnetism 5 have been reported before, the simplest one-dimensional model of strongly correlated topological matter, the many-body Su–Schrieffer–Heeger (SSH) model 6 , 7 , 8 , 9 , 10 , 11 , has so far remained elusive—mostly owing to the challenge of precisely engineering long-range interactions between electrons to reproduce the chosen Hamiltonian. Here we show that for precision-placed atoms in silicon with strong Coulomb confinement, we can engineer a minimum of six all-epitaxial in-plane gates to tune the energy levels across a linear array of ten quantum dots to realize both the trivial and the topological phases of the many-body SSH model. The strong on-site energies (about 25 millielectronvolts) and the ability to engineer gates with subnanometre precision in a unique staggered design allow us to tune the ratio between intercell and intracell electron transport to observe clear signatures of a topological phase with two conductance peaks at quarter-filling, compared with the ten conductance peaks of the trivial phase. The demonstration of the SSH model in a fermionic system isomorphic to qubits showcases our highly controllable quantum system and its usefulness for future simulations of strongly interacting electrons. Main Superconductivity, magnetism 12 , low-dimensional electron transport 13 , topological phases 14 and other exotic phases of matter arise owing to the presence of strongly interacting particles within crystals 15 . However, the complexity of simulating such large quantum systems becomes intractable using classical computing methods 16 . A promising solution is to build a physical system at the same scale so that we can simulate these interacting fermionic systems 17 , 18 directly, known as analogue quantum simulation 19 , 20 . The Su–Schrieffer–Heeger (SSH) model is the prototypical example of topological matter that describes a single electron hopping along a one-dimensional dimerized lattice with staggered tunnel couplings, v and w , as shown in Fig. 1a 21 . The SSH model has been experimentally simulated in physical systems of varying dimensions from Rydberg atoms (about 10 μm) to mechanical systems (about 10 mm) (Table 1 ). The coupling strengths of the various simulators lie in the nanoelectronvolt to microelectronvolt range, limiting their ability to reach the fully coherent regime. Importantly, these systems can be readily solved classically as they do not simulate many-body interactions. Only recently has the interacting many-body SSH model been observed using Rydberg atoms with an effective infinite on-site interaction (hardcore bosons) 10 . The ability to control the interaction strength, however, is critical for investigating fermionic systems 22 , 23 . Fig. 1: Realization of the SSH model in precision-engineered phosphorus donors in silicon. a , A dimerized one-dimensional lattice with staggered hopping amplitudes (tunnel couplings) v and w . The array consists of two sublattices where there exists a trivial phase, v > w (top) and a topological phase v < w (bottom). b , Single-particle energy spectrum of the SSH model for a linear array of ten quantum dots as a function of the interdot coupling ratio v / w . For v / w < 1, there exists zero-energy topological edge states, whereas the trivial case v / w > 1 exhibits an excitation gap. c , d , Calculated multi-electron energy spectrum in the trivial ( c ) and topological ( d ) phases for different electron numbers at quarter-filling. The trivial array exhibits a single ground state with five electrons about 3.85 meV below the four- and six-electron states, whereas the topological phase exhibits a nearly four-fold degeneracy involving four, five (two-fold degenerate) and six electrons. e , f , Scanning tunnelling micrograph for the trivial ( e ; device I) and topological ( f ; device II) phases. The lighter regions show the open lithographic hydrogen mask. The devices consist of an array of N = 10 Coulomb-confined quantum dots with staggered nearest-neighbour distances, tunnel-coupled to a source (drain) lead at the start (end) of the array outlined in white to perform bias spectroscopy. Device I is designed to be in the trivial phase with d v = 7.7 ± 0.1 nm and d w = 10.1 ± 0.2 nm, and device II is designed to be in the topological phase with d v = 9.6 ± 0.4 nm and d w = 7.8 ± 0.6 nm. Full size image Table 1 Experimental demonstrations of the SSH model to date Full size table Semiconductor quantum dots are an emerging platform for the quantum simulation of strongly correlated electron systems 4 , 5 , 20 . Interacting electrons confined to quantum dots have been described by the Hubbard model 16 involving Coulombic interactions that describe the energy required to add electrons to the same (on-site, U ) or neighbouring (intersite, V ) quantum dot 24 . Here intersite hopping is governed by the tunnel coupling, t , between quantum dots, and each dot can be tuned using electrostatic gates to raise or lower their energy levels, ${\epsilon }$ (ref. 4 ). Phosphorus donors in silicon in particular have been proposed as promising candidates for simulators as they are nanoscale in size with very strong on-site energies ( U ≈ 25 meV) and can be engineered to have strong intersite ( V ≈ 5 meV) and hopping ( t ≈ 5 meV) energies, while operating with a low thermal energy of k B T ≈ 0.02 meV (ref. 25 ), where k B is the Boltzmann constant and T is the temperature, reaching a range of U / t ≈ 1−100 while remaining in the low-temperature limit with t / k B T > 10 (ref. 23 ). The ability to reach the low-temperature, strongly interacting regime allows for a number<|im_end|> <|im_start|>assistant A team of quantum computer physicists at UNSW Sydney has engineered a quantum processor at the atomic scale to simulate the behavior of a small organic molecule, solving a challenge set some 60 years ago by theoretical physicist Richard Feynman. The achievement, which occurred two years ahead of schedule, represents a major milestone in the race to build the world's first quantum computer, and demonstrates the team's ability to control the quantum states of electrons and atoms in silicon at an exquisite level not achieved before. In a paper published today in the journal Nature, the researchers described how they were able to mimic the structure and energy states of the organic compound polyacetylene—a repeating chain of carbon and hydrogen atoms distinguished by alternating single and double bonds of carbon. Lead researcher and former Australian of the Year, Scientia Professor Michelle Simmons, said the team at Silicon Quantum Computing, one of UNSW's most exciting start-ups, built a quantum integrated circuit comprising a chain of 10 quantum dots to simulate the precise location of atoms in the polyacetylene chain. "If you go back to the 1950s, Richard Feynman said you can't understand how nature works unless you can build matter at the same length scale," Prof. Simmons said. "And so that's what we're doing, we're literally building it from the bottom up, where we are mimicking the polyacetylene molecule by putting atoms in silicon with the exact distances that represent the single and double carbon-carbon bonds." Chain reaction The research relied on measuring the electric current through a deliberately engineered 10-quantum dot replica of the polyacetylene molecule as each new electron passed from the source outlet of the device to the drain—the other end of the circuit. To be doubly sure, they simulated two different strands of the polymer chains. In the first device they cut a snippet of the chain to leave double bonds at the end giving 10 peaks in the current. In the second device they cut a different snippet of the chain to leave single bonds at the end only giving rise to two peaks in the current. The current that passes through each chain was therefore dramatically different due to the different bond lengths of the atoms at the end of the chain. Not only did the measurements match the theoretical predictions, they matched perfectly. "What it's showing is that you can literally mimic what actually happens in the real molecule. And that's why it's exciting because the signatures of the two chains are very different," Prof. Simmons said. "Most of the other quantum computing architectures out there haven't got the ability to engineer atoms with sub-nanometer precision or allow the atoms to sit that close. "And so that means that now we can start to understand more and more complicated molecules based on putting the atoms in place as if they're mimicking the real physical system." Standing at the edge According to Prof. Simmons, it was no accident that a carbon chain of 10 atoms was chosen because that sits within the size limit of what a classical computer is able to compute, with up to 1024 separate interactions of electrons in that system. Increasing it to a 20-dot chain would see the number of possible interactions rise exponentially, making it difficult for a classical computer to solve. "We're near the limit of what classical computers can do, so it's like stepping off the edge into the unknown," she says. "And this is the thing that's exciting, we can now make bigger devices that are beyond what a classical computer can model. So we can look at molecules that haven't been simulated before. We're going to be able to understand the world in a different way, addressing fundamental questions that we've never been able to solve before." One of the questions Prof. Simmons alluded to is about understanding and mimicking photosynthesis—how plants use light to create chemical energy for growth. Or understanding how to optimize the design of catalysts used for fertilizers, currently a high-energy, high-cost process. "So there're huge implications for fundamentally understanding how nature works," she said. Future quantum computers Much has been written about quantum computers in the last three decades with the billion-dollar question always being "but when can we see one?" Prof. Simmons says that the development of quantum computers is on a comparable trajectory to how classical computers evolved—from a transistor in 1947 to an integrated circuit in 1958, and then small computing chips that went into commercial products like calculators approximately five years after that. "And so we're now replicating that roadmap for quantum computers," Prof. Simmons says. "We started with a single atom transistor in 2012. And this latest result, realized in 2021 is the equivalent of the atom-scale quantum integrated circuit, two years ahead of time. If we map it to the evolution of classical computing, we're predicting we should have some kind of commercial outcome from our technology five years from now." One of the advantages that the UNSW/SQC team's research brings is that the technology is scalable because it manages to use fewer components in the circuit to control the qubits—the basic bits of quantum information. "In quantum systems, you need something that creates the qubits, some kind of structure in the device that allows you to form the quantum state," Prof. Simmons says. "In our system, the atoms themselves create the qubits, requiring fewer elements in the circuits. We only needed six metallic gates to control the electrons in our 10-dot system—in other words, we have fewer gates than there are active device components. Whereas most quantum computing architectures need almost double the number or more of the control systems to move the electrons in the qubit architecture." Needing fewer components packed in tightly together minimizes the amount of any interference with the quantum states, allowing devices to be scaled up to make more complex and powerful quantum systems. "So that very low physical gate density is also very exciting for us, because it shows that we've got this nice clean system that we can manipulate, keeping coherence across long distances with minimal overhead in the gates. That's why it's valuable for scalable quantum computing." Looking ahead, Prof. Simmons and her colleagues will explore larger compounds that may have been predicted theoretically, but have never been simulated and fully understood before, such as high temperature superconductors. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections Cancer Biomarkers Cancer Causes, Screening and Diagnosis Cancer Drug Development Cancer Epidemiology and Prevention Cancer Immunology and Immunotherapy Cancer Informatics and Big Data Cancer Metastasis Cancer Pathophysiology Cancer Therapy Clinical Trials of Cancer Infectious Agents and Cancer Methods and Technologies Development Molecular Cancer Biology Pediatric Oncology Systematic Review or Meta-Analysis in Cancer Research Transplant Oncology and Cancer Nursing Care Tumor Microenvironment All Sections Special Issue All Special Issues \"The 10th International MDM2 Workshop\"—Opening Up New Avenues for MDM2 and p53 Research T Cells and Myeloid Cells in Cancer Immunotherapy Helicobacter pylori Associated Cancer TP53 in Solid Tumors and Hematological Malignancies How Does Obesity Cause Cancer? Methylation Changes in Early Stage Non-small Cell Lung Cancer: New Evidences, Methodological Approaches and Applications Cancer and Liposomes 10th Anniversary of Cancers—Targeted Therapies for Ovarian Cancer Treatment from Bench to Bedside 2nd Edition: Adolescent and Young Adult Oncology 2nd Edition: Advances in the Management of Thyroid Cancer 2nd Edition: Colorectal Cancers 2nd Edition: Combination and Innovative Therapies for Pancreatic Cancer 2nd Edition: Estrogen Receptor-Positive (ER+) Breast Cancers 2nd Edition: New Perspectives of Ocular Oncology 2nd Edition: Resistance Mechanisms in Malignant Brain Tumors 3rd Etnean Occupational Medicine Workshop—Breast Cancer and Work 3D Cell Culture Cancer Models: Development and Applications A Deeper Dive into Signaling Pathways in Cancers A Selection of Papers from the Cancer Therapy 2021 Virtual Scientific Meeting A Selection of Papers from the Meeting on Cancer Science and Targeted Therapy Conference A Special Issue on Tumor Stroma Actionable Mutations in Lung Cancer Acute Myeloid Leukemia Acute Myeloid Leukemia (AML) Acute Myeloid Leukemia: From Diagnosis to Treatment Acute Myeloid Leukemia: The Future Is Bright Acute Promyelocytic Leukemia Acute Promyelocytic Leukemia (APML) Adaptation Strategies of Circulating Tumor Cells Adhesion and Integrins Adjuvant Chemotherapy for Colorectal Cancer Adrenocortical Carcinoma Advance and New Insights in Bladder Cancer Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius Advance in Computational Methods in Cancer Research Advance in Morbidity and Survivorship of Breast Cancer Advance in Supportive and Palliative Care in Cancer Advance Research in Thrombosis and Hematologic Malignancies Advanced Cancer Nanotheranostics Advanced Neuroendocrine Tumors Advanced NSCLC with Oncogene Addiction: An Ongoing Revolution Advanced Ovarian Cancer Advanced Pancreatic Cancer Advanced Prostate Cancer: From Bench to Bedside Advanced Research in Cancer Initiation and Early Detection Advanced Research in Glycoproteins and Cancer Advanced Research in Oncology in 2022 Advanced Research in Oncology in 2023 Advanced Research in Organs-on-a-Chip and Cancer Advanced Research in Pancreatic Ductal Adenocarcinoma Advanced Therapies for Hematological Cancers Advances and Research Progress in Hepatocellular Carcinoma Advances in Adrenocortical Carcinoma Research: Diagnosis, Treatment and Prognosis Advances in Antitumor Molecular-Targeted Agents of Urological Cancers Advances in Bone Metastatic Cancer Research Advances in Breast Cancer Brain Metastases Advances in Breast Cancer: A Themed Issue in Honor of Prof. Fernando Schmitt Advances in Breast Cancer: From Pathogenesis to Therapy Advances in Cancer Chemoprevention Advances in Cancer Cachexia Advances in Cancer Data and Statistics Advances in Cancer Disparities Advances in Cancer Epigenetics Advances in Cancer Radiotherapy Advances in Cancer Stem Cell Research Advances in Chordoma Advances in Chronic Lymphocytic Leukaemia (CLL) Research Advances in Diagnosis and Treatment for Bone and Soft Tissue Sarcoma Advances in Diagnosis, Treatment and Management of Endocrine Neoplasms Advances in Diagnostics and Treatment of Head and Neck Cancer Advances in Endometrial Cancer: From Pathogenesis, Pathology Diagnosis and Molecular Classification to Targeted Therapy Advances in Experimental Radiotherapy Advances in Follicular Lymphoma Advances in Genetic and Molecular Approaches to Skin Cancer Advances in Genetics and Epigenetics of Bladder Cancer Advances in Gynecological Oncology: From Pathogenesis to Therapy Advances in Head and Neck Cancer Research Advances in Head and Neck Squamous Cell Carcinoma Advances in Hematological Neoplasms: A Wide Perspective on the 2022 WHO and International Consensus Classifications Advances in HPB/GI Imaging Advances in Human-Papillomavirus-Related Squamous Cell Carcinoma: From Pathogenesis to Treatment Advances in Integrins in Cancer Advances in Locally Advanced and Metastatic Kidney Cancer Advances in Lymphoma, Plasma Cell Myeloma, and Leukemia Diagnostics Advances in Modern Radiation Oncology Advances in Neuroendocrine Neoplasms Advances in NK/T-cell Lymphoma, Epidemiology, Biology and Therapy Advances in Oral Cancers and Precancers Advances in Our Understanding of ALK-Related Cancers: A Selection of Papers from the Joint Annual Meeting of the European Research Initiative for ALK-Related Malignancies (ERIA) and the European Union Marie Curie European Training Network ALKATRAS Advances in Pancreatic Cancer Research Advances in Pancreatic Ductal Adenocarcinoma Diagnosis and Treatment Advances in Papillary Thyroid Cancer Research Advances in Parathyroid Carcinoma: From Bench to Bedside Advances in Plasma Cell Dyscrasias Advances in Precision Medicine: Targeting Known and Emerging Oncogenic Targets in Lung Cancer Advances in Research, Diagnosis and Treatment of Brain Metastases Advances in Salivary Gland Carcinoma Advances in Soft Tissue and Bone Sarcoma Advances in Stimuli-Responsive Nanostructures for Cancer Therapy and Diagnosis Advances in Surgical Management of Colorectal Liver Metastases: Toward a Better Patient Selection, Lower Surgical Stress, and Multidisciplinary Approach Advances in the biological responses to radiation-induced DNA damage: A selection of papers from the Joint 43rd European Radiation Research Society (ERRS) and 20th German Society for Biological Radiation Research (GBS) Annual Meetings Advances in the Diagnosis, Prognosis and Treatment of Diffuse Large B-cell Lymphoma Advances in the Management of Hepatocellular Carcinoma Advances in the Management of Oligometastatic Disease in Non-colorectal Non-neuroendocrine Tumors Advances in the Management of Thyroid Cancer Advances in Thoracic Carcinoma and Translational Research Advances in Thoracic Oncology Advances in Thymic Tumors Advances in Translational Ovarian Cancer Research Advances in Translational Research for Soft Tissue Sarcomas Advances in Treatment for Hepatobiliary and Pancreatic Cancers: Multi-Disciplinary Strategies and Outcome Evaluation Advances in Treatment of Rare Tumors Advances in Triple-Negative Breast Cancer Advances in Tumor Angiogenesis Advances of Brain Mapping in Cancer Research Advances in Head and Neck Cancer Biology and Clinical Management Advances in In Vivo Quantitative and Qualitative Imaging Characterization of Gliomas", "role": "user" }, { "content": "Chemotherapy is one of the most used treatments against cancer, along with surgery and radiotherapy. In a chemotherapy treatment, one or several drugs are administered to the patient to remove or damage cancer cells. Nevertheless, the treatment has several drawbacks that are hard to overcome, particularly the side effects. In this case, the inherent toxicity of the drugs employed causes a variety of symptoms including weakness, nausea and hair loss. As a result, chemotherapy is far from an ideal approach. In this regard, scientists are trying to improve the efficacy and specificity of chemotherapy using carriers to deliver the drugs only where they are needed. Carriers based on gold nanostructures are excellent candidates for this objective because of their excellent stability, absence of toxicity and ease of modification with several chemical agents. Furthermore, some gold nanostructures, such as nanoclusters, are fluorescent, allowing their use for biotracking and imaging purposes. The group of NanoBiotechnology at IMDEA Nanociencia, led by Prof. Álvaro Somoza, has used gold nanoclusters coated with albumin to facilitate the attachment of two active molecules for the treatment of breast cancer. They used doxorubicin (D), a chemotherapeutic agent that intercalates in the DNA causing cell death, and camptothecin analog SN38 (S), a potent topoisomerase I inhibitor. The modified nanostructures were tested in vitro against breast cancer cells, where the release of chemotherapeutics took place in a controlled manner. Remarkably, the nanotherapy was able to reduce the size and number of mammospheres, a cancer stem cell model. This type of cell presents higher resistance to chemotherapy and is responsible for relapses and chemoresistance. What is more, the system combining both drugs presented excellent antitumor activity in different cancer models, thus confirming its promising nanotherapeutic potential. This is the first time that albumin-stabilized gold nanoclusters have been used to deliver more than one drug, with excellent antitumoral activity, in cancer and cancer stem cells. \"Our bifunctional nanostructure could be an excellent solution to overcome the solubility and biodistribution problems of different drugs,\" Somoza says. These nanomaterials could be the basis of a Trojan-horse strategy to get the chemotherapeutics effectively inside the tumors. The gold nanoclusters act as the vehicles for carrying the drugs where is needed and release them upon internal stimuli. Whereas chemotherapy research is developing new drugs for cancer treatment, emerging nanotherapies are about building smart vehicles for existing drugs, reducing costs and improving the efficiency of the treatments. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections Cancer Biomarkers Cancer Causes, Screening and Diagnosis Cancer Drug Development Cancer Epidemiology and Prevention Cancer Immunology and Immunotherapy Cancer Informatics and Big Data Cancer Metastasis Cancer Pathophysiology Cancer Therapy Clinical Trials of Cancer Infectious Agents and Cancer Methods and Technologies Development Molecular Cancer Biology Pediatric Oncology Systematic Review or Meta-Analysis in Cancer Research Transplant Oncology and Cancer Nursing Care Tumor Microenvironment All Sections Special Issue All Special Issues "The 10th International MDM2 Workshop"—Opening Up New Avenues for MDM2 and p53 Research T Cells and Myeloid Cells in Cancer Immunotherapy Helicobacter pylori Associated Cancer TP53 in Solid Tumors and Hematological Malignancies How Does Obesity Cause Cancer? Methylation Changes in Early Stage Non-small Cell Lung Cancer: New Evidences, Methodological Approaches and Applications Cancer and Liposomes 10th Anniversary of Cancers—Targeted Therapies for Ovarian Cancer Treatment from Bench to Bedside 2nd Edition: Adolescent and Young Adult Oncology 2nd Edition: Advances in the Management of Thyroid Cancer 2nd Edition: Colorectal Cancers 2nd Edition: Combination and Innovative Therapies for Pancreatic Cancer 2nd Edition: Estrogen Receptor-Positive (ER+) Breast Cancers 2nd Edition: New Perspectives of Ocular Oncology 2nd Edition: Resistance Mechanisms in Malignant Brain Tumors 3rd Etnean Occupational Medicine Workshop—Breast Cancer and Work 3D Cell Culture Cancer Models: Development and Applications A Deeper Dive into Signaling Pathways in Cancers A Selection of Papers from the Cancer Therapy 2021 Virtual Scientific Meeting A Selection of Papers from the Meeting on Cancer Science and Targeted Therapy Conference A Special Issue on Tumor Stroma Actionable Mutations in Lung Cancer Acute Myeloid Leukemia Acute Myeloid Leukemia (AML) Acute Myeloid Leukemia: From Diagnosis to Treatment Acute Myeloid Leukemia: The Future Is Bright Acute Promyelocytic Leukemia Acute Promyelocytic Leukemia (APML) Adaptation Strategies of Circulating Tumor Cells Adhesion and Integrins Adjuvant Chemotherapy for Colorectal Cancer Adrenocortical Carcinoma Advance and New Insights in Bladder Cancer Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius Advance in Computational Methods in Cancer Research Advance in Morbidity and Survivorship of Breast Cancer Advance in Supportive and Palliative Care in Cancer Advance Research in Thrombosis and Hematologic Malignancies Advanced Cancer Nanotheranostics Advanced Neuroendocrine Tumors Advanced NSCLC with Oncogene Addiction: An Ongoing Revolution Advanced Ovarian Cancer Advanced Pancreatic Cancer Advanced Prostate Cancer: From Bench to Bedside Advanced Research in Cancer Initiation and Early Detection Advanced Research in Glycoproteins and Cancer Advanced Research in Oncology in 2022 Advanced Research in Oncology in 2023 Advanced Research in Organs-on-a-Chip and Cancer Advanced Research in Pancreatic Ductal Adenocarcinoma Advanced Therapies for Hematological Cancers Advances and Research Progress in Hepatocellular Carcinoma Advances in Adrenocortical Carcinoma Research: Diagnosis, Treatment and Prognosis Advances in Antitumor Molecular-Targeted Agents of Urological Cancers Advances in Bone Metastatic Cancer Research Advances in Breast Cancer Brain Metastases Advances in Breast Cancer: A Themed Issue in Honor of Prof. Fernando Schmitt Advances in Breast Cancer: From Pathogenesis to Therapy Advances in Cancer Chemoprevention Advances in Cancer Cachexia Advances in Cancer Data and Statistics Advances in Cancer Disparities Advances in Cancer Epigenetics Advances in Cancer Radiotherapy Advances in Cancer Stem Cell Research Advances in Chordoma Advances in Chronic Lymphocytic Leukaemia (CLL) Research Advances in Diagnosis and Treatment for Bone and Soft Tissue Sarcoma Advances in Diagnosis, Treatment and Management of Endocrine Neoplasms Advances in Diagnostics and Treatment of Head and Neck Cancer Advances in Endometrial Cancer: From Pathogenesis, Pathology Diagnosis and Molecular Classification to Targeted Therapy Advances in Experimental Radiotherapy Advances in Follicular Lymphoma Advances in Genetic and Molecular Approaches to Skin Cancer Advances in Genetics and Epigenetics of Bladder Cancer Advances in Gynecological Oncology: From Pathogenesis to Therapy Advances in Head and Neck Cancer Research Advances in Head and Neck Squamous Cell Carcinoma Advances in Hematological Neoplasms: A Wide Perspective on the 2022 WHO and International Consensus Classifications Advances in HPB/GI Imaging Advances in Human-Papillomavirus-Related Squamous Cell Carcinoma: From Pathogenesis to Treatment Advances in Integrins in Cancer Advances in Locally Advanced and Metastatic Kidney Cancer Advances in Lymphoma, Plasma Cell Myeloma, and Leukemia Diagnostics Advances in Modern Radiation Oncology Advances in Neuroendocrine Neoplasms Advances in NK/T-cell Lymphoma, Epidemiology, Biology and Therapy Advances in Oral Cancers and Precancers Advances in Our Understanding of ALK-Related Cancers: A Selection of Papers from the Joint Annual Meeting of the European Research Initiative for ALK-Related Malignancies (ERIA) and the European Union Marie Curie European Training Network ALKATRAS Advances in Pancreatic Cancer Research Advances in Pancreatic Ductal Adenocarcinoma Diagnosis and Treatment Advances in Papillary Thyroid Cancer Research Advances in Parathyroid Carcinoma: From Bench to Bedside Advances in Plasma Cell Dyscrasias Advances in Precision Medicine: Targeting Known and Emerging Oncogenic Targets in Lung Cancer Advances in Research, Diagnosis and Treatment of Brain Metastases Advances in Salivary Gland Carcinoma Advances in Soft Tissue and Bone Sarcoma Advances in Stimuli-Responsive Nanostructures for Cancer Therapy and Diagnosis Advances in Surgical Management of Colorectal Liver Metastases: Toward a Better Patient Selection, Lower Surgical Stress, and Multidisciplinary Approach Advances in the biological responses to radiation-induced DNA damage: A selection of papers from the Joint 43rd European Radiation Research Society (ERRS) and 20th German Society for Biological Radiation Research (GBS) Annual Meetings Advances in the Diagnosis, Prognosis and Treatment of Diffuse Large B-cell Lymphoma Advances in the Management of Hepatocellular Carcinoma Advances in the Management of Oligometastatic Disease in Non-colorectal Non-neuroendocrine Tumors Advances in the Management of Thyroid Cancer Advances in Thoracic Carcinoma and Translational Research Advances in Thoracic Oncology Advances in Thymic Tumors Advances in Translational Ovarian Cancer Research Advances in Translational Research for Soft Tissue Sarcomas Advances in Treatment for Hepatobiliary and Pancreatic Cancers: Multi-Disciplinary Strategies and Outcome Evaluation Advances in Treatment of Rare Tumors Advances in Triple-Negative Breast Cancer Advances in Tumor Angiogenesis Advances of Brain Mapping in Cancer Research Advances in Head and Neck Cancer Biology and Clinical Management Advances in In Vivo Quantitative and Qualitative Imaging Characterization of Gliomas<|im_end|> <|im_start|>assistant Chemotherapy is one of the most used treatments against cancer, along with surgery and radiotherapy. In a chemotherapy treatment, one or several drugs are administered to the patient to remove or damage cancer cells. Nevertheless, the treatment has several drawbacks that are hard to overcome, particularly the side effects. In this case, the inherent toxicity of the drugs employed causes a variety of symptoms including weakness, nausea and hair loss. As a result, chemotherapy is far from an ideal approach. In this regard, scientists are trying to improve the efficacy and specificity of chemotherapy using carriers to deliver the drugs only where they are needed. Carriers based on gold nanostructures are excellent candidates for this objective because of their excellent stability, absence of toxicity and ease of modification with several chemical agents. Furthermore, some gold nanostructures, such as nanoclusters, are fluorescent, allowing their use for biotracking and imaging purposes. The group of NanoBiotechnology at IMDEA Nanociencia, led by Prof. Álvaro Somoza, has used gold nanoclusters coated with albumin to facilitate the attachment of two active molecules for the treatment of breast cancer. They used doxorubicin (D), a chemotherapeutic agent that intercalates in the DNA causing cell death, and camptothecin analog SN38 (S), a potent topoisomerase I inhibitor. The modified nanostructures were tested in vitro against breast cancer cells, where the release of chemotherapeutics took place in a controlled manner. Remarkably, the nanotherapy was able to reduce the size and number of mammospheres, a cancer stem cell model. This type of cell presents higher resistance to chemotherapy and is responsible for relapses and chemoresistance. What is more, the system combining both drugs presented excellent antitumor activity in different cancer models, thus confirming its promising nanotherapeutic potential. This is the first time that albumin-stabilized gold nanoclusters have been used to deliver more than one drug, with excellent antitumoral activity, in cancer and cancer stem cells. "Our bifunctional nanostructure could be an excellent solution to overcome the solubility and biodistribution problems of different drugs," Somoza says. These nanomaterials could be the basis of a Trojan-horse strategy to get the chemotherapeutics effectively inside the tumors. The gold nanoclusters act as the vehicles for carrying the drugs where is needed and release them upon internal stimuli. Whereas chemotherapy research is developing new drugs for cancer treatment, emerging nanotherapies are about building smart vehicles for existing drugs, reducing costs and improving the efficiency of the treatments. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Use of artificial at night (ALAN) exposes the world to continuously increasing levels and distribution of light pollution. Our understanding of the adverse effects of ALAN is based mostly on observational or laboratory studies, and its effects are probably underestimated. Demonstration of direct experimental fitness consequences of ALAN on mammals is missing. We studied the effects of chronic light pollution at different wavelengths on fitness and glucocorticoid hormone levels under semi-natural conditions in two closely related species: the nocturnal common spiny mouse ( Acomys cahirinus ) and the diurnal golden spiny mouse ( Acomys russatus ). Our results clearly demonstrate the adverse effects of ALAN exposure on the fitness of both nocturnal and diurnal species, manifested by changes in cortisol levels and reproductive timing, reduced reproductive output and reduced survival, which differed between species and wavelengths. In A. russatus exposure to blue ALAN had the strongest effect on fitness, followed by white and yellow ALAN exposure. In A. cahirinus the results are more complex and suggest it suffered from the combined effects of ALAN and competition. Our research shows that light pollution presents a real threat to both nocturnal and diurnal species, affecting the species fitness directly and through interspecific interactions. Worryingly, these effects are probably not limited to spiny mice. The clear adverse effects we documented, as well as the differences between wave lengths, contribute to our ability to present science-based recommendations to decision makers regarding the use of artificial light at night. Such information and guidelines are highly important nowadays when lighting systems are being replaced to promote energy efficiency. Introduction The extensive and increasing use of artificial at night (ALAN) exposes the world to continuously increasing levels and distribution of light pollution. The new world atlas of light pollution 1 portrays an unsettling reality, in which 99% of the US population and 80% of the world’s population live under light-polluted skies, and it is estimated that in areas where light pollution has not reached saturation, the increase in ALAN radiance and extent is 2–6% per year 2 – 4 . Light pollution has attracted increasing scientific attention over the last two decades. Though it was considered to have a limited spatial extent compared to more familiar anthropogenic interferences, such as climate change and plastic pollution, it is now accepted that ALAN effects are much more pervasive than previously considered, and that it is becoming a major threat to biodiversity 2 , 5 , 6 , 7 , 8 . ALAN affects all living organisms at the molecular, physiological, behavioral, and ecological level. For example, it was shown to disrupt foraging and feeding behavior, alter biological rhythms, cause mistimed reproductive behavior, and increase stress hormone levels (e.g. 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ), and it is clear that actions must be taken to mitigate its effects. However, to design effective mitigation measures we must better understand the adverse effects of light pollution, which are currently based mostly on observational field or laboratory studies, mainly focusing on changes in species behavior and physiology 5 , 8 , 20 , 21 . Length of photoperiod (day length) is a reliable indicator of time of year and serves as a cue for seasonal acclimation 18 , 22 . However, the extensive use of artificial light disrupts the clear delineation between day and night, and the reliability of photoperiod is compromised. As a result, seasonal acclimation and seasonal reproduction may be compromised, reducing both survival and reproductive success. Disruption of the natural light–dark cycle by ALAN may cause physiological and behavioral changes (reviewed by Bumgarner and Nelson 23 ). ALAN exposure changed the endocrine system, and glucocorticoid secretion in particular, in bird 9 , 24 , 25 and rodent species 26 , affected sexual behavior and fertilization success in common toads, Bufo bufo 27 , and advanced avian reproductive physiology 11 , and there is even an experimental field study on the effects of ALAN at different wavelength on physiology, behavior and ecology of species 9 , 28 , 29 . Yet, to the best of our knowledge, no study tested the effects of ALAN on survival and offspring number, which are the direct measures of fitness, and experimental fitness consequences of ALAN exposure on rodents have yet to be examined. Moreover, to promote science-based policies regarding the outdoor use of light at night, the effects of different wavelengths of ALAN at relevant intensities should be compared. To close this knowledge gap, we chose to study the effects of chronic light pollution on fitness (survival and reproduction) under semi-natural conditions in two closely-related, coexisting rodent species with opposite activity patterns: the nocturnal common spiny mouse ( Acomys cahirinus ) and the diurnal golden spiny mouse ( Acomys russatus ), which were chronically exposed to ALAN at different wavelengths with relevant intensity. Materials and methods Experimental design Experiments took place at the Zoological Research Garden at Tel Aviv University, were we used outdoor enclosures to test the long-term effects of ALAN under semi-natural conditions on two species of spiny mice; the diurnal Acomys russatus and the nocturnal A. cahirinus . Experiments were conducted for 6–8 months in two consecutive years: the first repetition started in November 2018 and ended in July 2019. The second repetition started on November 2019 and ended in June 2020. All experiments were carried out in accordance with the Israeli Ministry of Health guide for the care and use of laboratory animals and all experimental protocols were approved by the Tel-Aviv University Institutional Animal Care and Use Committee (IACUC protocol approval number 04-18-056, 04-19-031). Enclosures An enclosure complex of eight 3X3X3-meter metal mesh cages was built to prevent mice from escaping and protect them from predation, while allowing exposure of natural sunlight, moonlight and weather conditions. The rear part of the enclosures was covered with a tin roof to protect the mice from overheating and flooding. Enclosures were separated using", "role": "user" }, { "content": "An extensive study at Tel Aviv University's School of Zoology tested the impact of prolonged low-intensity light pollution on two species of desert rodents: the diurnal golden spiny mouse, and the nocturnal common spiny mouse. The findings were highly disturbing: on two different occasions, entire colonies exposed to ALAN (Artificial Light At Night) died within days, and reproduction also decreased significantly compared to control groups. \"Our results show clearly for the first time that light pollution can be extremely harmful to these species, and suggest they may be harmful to ecosystems, biodiversity, and even human health,\" say the researchers. The study was led by Prof. Noga Kronfeld-Schor, Chief Scientist of Israel's Ministry of Environmental Protection, and Ph.D. student Hagar Vardi-Naim, both from TAU's School of Zoology and the Steinhardt Museum of Natural History. The paper was published in Scientific Reports. Prof. Kronfeld-Schor explains, \"We have been studying these closely related rodent species for years. They both live in Israel's rocky deserts: the golden spiny mouse (Acomys russatus) is diurnal, and the common spiny mouse (A. cahirinus) in nocturnal. The two species share the same natural habitat but use it at different times to avoid competition. By comparing closely related species that differ in activity times, we gain new insights into the biological clock and its importance to the health of both animals and humans.\" Hagar Vardi-Naim says, \"In most species studied to date, including humans, the biological clock is synchronized by light. This mechanism evolved over millions of years in response to the daily and annual cycles of sunlight—day and night and their varying lengths that correspond to the change of seasons. Different species developed activity patterns that correspond to these changes in light intensity and daylength and developed anatomical, physiological and behavioral adaptations suitable for day or night activity and seasonality.\" \"However, over the last decades, humans have changed the rules by inventing and extensively using artificial light, which generates light pollution. According to latest studies, about 80% of the world's human population is exposed to ALAN, and the area affected by light pollution grows annually by 2-6%. In a small and overcrowded state like Israel, very few places remain free of light pollution. In our study we closely monitored the long-term effects of ALAN on individuals and populations under semi-natural conditions.\" In the study, the researchers placed 96 spiny mice of both species, males and females in equal numbers, in eight spacious outdoor enclosures at TAU's Zoological Research Garden. The enclosures simulated living conditions in the wild: all animals were exposed to natural environmental conditions, including the natural light/dark cycle, ambient temperatures, humidity, and precipitation. Each enclosure contained shelters, nesting materials and access to sufficient amounts of food. The experimental enclosures were exposed to low-intensity ALAN (similar to a streetlamp in urban areas) of different wavelengths (colors) for 10 months: two enclosures were exposed to cold white light, two to warm white (yellowish) light, and two to blue light, while two enclosures, remained dark at night and served as controls. All animals were marked to enable accurate monitoring of changes in behavior and physical condition. The experiment was conducted twice in two successive years. Prof. Kronfeld-Schor says, \"The average life expectancy of spiny mice is 4-5 years, and our original plan was to monitor the effects of ALAN on the same colonies, measuring the effects on reproductive output, well-being and longevity. But the dramatic results thwarted our plans: on two unrelated occasions, in two different enclosures exposed to white light, all animals died within several days.\" \"We had seen no preliminary signs, and autopsies at TAU's Faculty of Medicine and the Kimron Veterinary Institute in Beit Dagan revealed no abnormal findings in the dead spiny mice. We assume that exposure to ALAN had impaired the animals' immune response, leaving them with no protection against some unidentified pathogen. No abnormal mortality was recorded in any of the other enclosures, and as far as we are aware, no similar event has ever been documented by researchers before.\" Other findings also indicated that exposure to ALAN disrupts the reproductive success of spiny mice. Hagar Vardi-Naim says, \"In the wild both species of spiny mice breed mainly during summer, when temperatures are high, and the newborn pups are most likely to survive. Artificial light, however, seemed to confuse the animals. The common spiny mice began to breed year-round but produced a lower number of pups per year.\" \"Pups born during winter are not expected to survive in nature, which would further reduce the species' reproductive success in the wild. The reproduction of golden spiny mice was affected in a different way: colonies exposed to ALAN continued to breed in the summer, but the number of young was reduced by half compared to the control group, which continued to thrive and breed normally. These findings are in accordance with the fact that in seasonal long day breeders the cue for reproduction is day length.\" Additional tests revealed that exposure to ALAN caused physiological and hormonal changes—most significantly in the level of cortisol, an important stress hormone involved in the regulation and operation of many physiological pathways, including the regulation of the immune system. Lab tests indicated that exposure to blue light increased cortisol levels of golden spiny mice, while white light reduced cortisol levels of golden spiny mice males in winter. Prof. Kronfeld Schor says, \"Our findings show that light pollution, especially cold white and blue light, increases mortality and disrupts reproduction, and thus may be detrimental to the fitness and survival of species in the wild. This adverse effect can have far-reaching consequences at the current wide distribution of light pollution.\" \"Our clear results are an important step toward understanding the impact of light pollution on biodiversity and will help us promote science-based policies, specifically with regard to the use of artificial light in both built and open areas. In future studies we plan to investigate what caused the extensive deaths in the enclosures exposed to ALAN, focusing on the effect of light pollution exposure on the immune system.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Use of artificial at night (ALAN) exposes the world to continuously increasing levels and distribution of light pollution. Our understanding of the adverse effects of ALAN is based mostly on observational or laboratory studies, and its effects are probably underestimated. Demonstration of direct experimental fitness consequences of ALAN on mammals is missing. We studied the effects of chronic light pollution at different wavelengths on fitness and glucocorticoid hormone levels under semi-natural conditions in two closely related species: the nocturnal common spiny mouse ( Acomys cahirinus ) and the diurnal golden spiny mouse ( Acomys russatus ). Our results clearly demonstrate the adverse effects of ALAN exposure on the fitness of both nocturnal and diurnal species, manifested by changes in cortisol levels and reproductive timing, reduced reproductive output and reduced survival, which differed between species and wavelengths. In A. russatus exposure to blue ALAN had the strongest effect on fitness, followed by white and yellow ALAN exposure. In A. cahirinus the results are more complex and suggest it suffered from the combined effects of ALAN and competition. Our research shows that light pollution presents a real threat to both nocturnal and diurnal species, affecting the species fitness directly and through interspecific interactions. Worryingly, these effects are probably not limited to spiny mice. The clear adverse effects we documented, as well as the differences between wave lengths, contribute to our ability to present science-based recommendations to decision makers regarding the use of artificial light at night. Such information and guidelines are highly important nowadays when lighting systems are being replaced to promote energy efficiency. Introduction The extensive and increasing use of artificial at night (ALAN) exposes the world to continuously increasing levels and distribution of light pollution. The new world atlas of light pollution 1 portrays an unsettling reality, in which 99% of the US population and 80% of the world’s population live under light-polluted skies, and it is estimated that in areas where light pollution has not reached saturation, the increase in ALAN radiance and extent is 2–6% per year 2 – 4 . Light pollution has attracted increasing scientific attention over the last two decades. Though it was considered to have a limited spatial extent compared to more familiar anthropogenic interferences, such as climate change and plastic pollution, it is now accepted that ALAN effects are much more pervasive than previously considered, and that it is becoming a major threat to biodiversity 2 , 5 , 6 , 7 , 8 . ALAN affects all living organisms at the molecular, physiological, behavioral, and ecological level. For example, it was shown to disrupt foraging and feeding behavior, alter biological rhythms, cause mistimed reproductive behavior, and increase stress hormone levels (e.g. 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ), and it is clear that actions must be taken to mitigate its effects. However, to design effective mitigation measures we must better understand the adverse effects of light pollution, which are currently based mostly on observational field or laboratory studies, mainly focusing on changes in species behavior and physiology 5 , 8 , 20 , 21 . Length of photoperiod (day length) is a reliable indicator of time of year and serves as a cue for seasonal acclimation 18 , 22 . However, the extensive use of artificial light disrupts the clear delineation between day and night, and the reliability of photoperiod is compromised. As a result, seasonal acclimation and seasonal reproduction may be compromised, reducing both survival and reproductive success. Disruption of the natural light–dark cycle by ALAN may cause physiological and behavioral changes (reviewed by Bumgarner and Nelson 23 ). ALAN exposure changed the endocrine system, and glucocorticoid secretion in particular, in bird 9 , 24 , 25 and rodent species 26 , affected sexual behavior and fertilization success in common toads, Bufo bufo 27 , and advanced avian reproductive physiology 11 , and there is even an experimental field study on the effects of ALAN at different wavelength on physiology, behavior and ecology of species 9 , 28 , 29 . Yet, to the best of our knowledge, no study tested the effects of ALAN on survival and offspring number, which are the direct measures of fitness, and experimental fitness consequences of ALAN exposure on rodents have yet to be examined. Moreover, to promote science-based policies regarding the outdoor use of light at night, the effects of different wavelengths of ALAN at relevant intensities should be compared. To close this knowledge gap, we chose to study the effects of chronic light pollution on fitness (survival and reproduction) under semi-natural conditions in two closely-related, coexisting rodent species with opposite activity patterns: the nocturnal common spiny mouse ( Acomys cahirinus ) and the diurnal golden spiny mouse ( Acomys russatus ), which were chronically exposed to ALAN at different wavelengths with relevant intensity. Materials and methods Experimental design Experiments took place at the Zoological Research Garden at Tel Aviv University, were we used outdoor enclosures to test the long-term effects of ALAN under semi-natural conditions on two species of spiny mice; the diurnal Acomys russatus and the nocturnal A. cahirinus . Experiments were conducted for 6–8 months in two consecutive years: the first repetition started in November 2018 and ended in July 2019. The second repetition started on November 2019 and ended in June 2020. All experiments were carried out in accordance with the Israeli Ministry of Health guide for the care and use of laboratory animals and all experimental protocols were approved by the Tel-Aviv University Institutional Animal Care and Use Committee (IACUC protocol approval number 04-18-056, 04-19-031). Enclosures An enclosure complex of eight 3X3X3-meter metal mesh cages was built to prevent mice from escaping and protect them from predation, while allowing exposure of natural sunlight, moonlight and weather conditions. The rear part of the enclosures was covered with a tin roof to protect the mice from overheating and flooding. Enclosures were separated using<|im_end|> <|im_start|>assistant An extensive study at Tel Aviv University's School of Zoology tested the impact of prolonged low-intensity light pollution on two species of desert rodents: the diurnal golden spiny mouse, and the nocturnal common spiny mouse. The findings were highly disturbing: on two different occasions, entire colonies exposed to ALAN (Artificial Light At Night) died within days, and reproduction also decreased significantly compared to control groups. "Our results show clearly for the first time that light pollution can be extremely harmful to these species, and suggest they may be harmful to ecosystems, biodiversity, and even human health," say the researchers. The study was led by Prof. Noga Kronfeld-Schor, Chief Scientist of Israel's Ministry of Environmental Protection, and Ph.D. student Hagar Vardi-Naim, both from TAU's School of Zoology and the Steinhardt Museum of Natural History. The paper was published in Scientific Reports. Prof. Kronfeld-Schor explains, "We have been studying these closely related rodent species for years. They both live in Israel's rocky deserts: the golden spiny mouse (Acomys russatus) is diurnal, and the common spiny mouse (A. cahirinus) in nocturnal. The two species share the same natural habitat but use it at different times to avoid competition. By comparing closely related species that differ in activity times, we gain new insights into the biological clock and its importance to the health of both animals and humans." Hagar Vardi-Naim says, "In most species studied to date, including humans, the biological clock is synchronized by light. This mechanism evolved over millions of years in response to the daily and annual cycles of sunlight—day and night and their varying lengths that correspond to the change of seasons. Different species developed activity patterns that correspond to these changes in light intensity and daylength and developed anatomical, physiological and behavioral adaptations suitable for day or night activity and seasonality." "However, over the last decades, humans have changed the rules by inventing and extensively using artificial light, which generates light pollution. According to latest studies, about 80% of the world's human population is exposed to ALAN, and the area affected by light pollution grows annually by 2-6%. In a small and overcrowded state like Israel, very few places remain free of light pollution. In our study we closely monitored the long-term effects of ALAN on individuals and populations under semi-natural conditions." In the study, the researchers placed 96 spiny mice of both species, males and females in equal numbers, in eight spacious outdoor enclosures at TAU's Zoological Research Garden. The enclosures simulated living conditions in the wild: all animals were exposed to natural environmental conditions, including the natural light/dark cycle, ambient temperatures, humidity, and precipitation. Each enclosure contained shelters, nesting materials and access to sufficient amounts of food. The experimental enclosures were exposed to low-intensity ALAN (similar to a streetlamp in urban areas) of different wavelengths (colors) for 10 months: two enclosures were exposed to cold white light, two to warm white (yellowish) light, and two to blue light, while two enclosures, remained dark at night and served as controls. All animals were marked to enable accurate monitoring of changes in behavior and physical condition. The experiment was conducted twice in two successive years. Prof. Kronfeld-Schor says, "The average life expectancy of spiny mice is 4-5 years, and our original plan was to monitor the effects of ALAN on the same colonies, measuring the effects on reproductive output, well-being and longevity. But the dramatic results thwarted our plans: on two unrelated occasions, in two different enclosures exposed to white light, all animals died within several days." "We had seen no preliminary signs, and autopsies at TAU's Faculty of Medicine and the Kimron Veterinary Institute in Beit Dagan revealed no abnormal findings in the dead spiny mice. We assume that exposure to ALAN had impaired the animals' immune response, leaving them with no protection against some unidentified pathogen. No abnormal mortality was recorded in any of the other enclosures, and as far as we are aware, no similar event has ever been documented by researchers before." Other findings also indicated that exposure to ALAN disrupts the reproductive success of spiny mice. Hagar Vardi-Naim says, "In the wild both species of spiny mice breed mainly during summer, when temperatures are high, and the newborn pups are most likely to survive. Artificial light, however, seemed to confuse the animals. The common spiny mice began to breed year-round but produced a lower number of pups per year." "Pups born during winter are not expected to survive in nature, which would further reduce the species' reproductive success in the wild. The reproduction of golden spiny mice was affected in a different way: colonies exposed to ALAN continued to breed in the summer, but the number of young was reduced by half compared to the control group, which continued to thrive and breed normally. These findings are in accordance with the fact that in seasonal long day breeders the cue for reproduction is day length." Additional tests revealed that exposure to ALAN caused physiological and hormonal changes—most significantly in the level of cortisol, an important stress hormone involved in the regulation and operation of many physiological pathways, including the regulation of the immune system. Lab tests indicated that exposure to blue light increased cortisol levels of golden spiny mice, while white light reduced cortisol levels of golden spiny mice males in winter. Prof. Kronfeld Schor says, "Our findings show that light pollution, especially cold white and blue light, increases mortality and disrupts reproduction, and thus may be detrimental to the fitness and survival of species in the wild. This adverse effect can have far-reaching consequences at the current wide distribution of light pollution." "Our clear results are an important step toward understanding the impact of light pollution on biodiversity and will help us promote science-based policies, specifically with regard to the use of artificial light in both built and open areas. In future studies we plan to investigate what caused the extensive deaths in the enclosures exposed to ALAN, focusing on the effect of light pollution exposure on the immune system." <|im_end|>

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6577, 8814, 320, 362, 884, 1065, 64663, 1015, 7026, 902, 1051, 27076, 2740, 15246, 311, 8927, 1111, 520, 2204, 93959, 449, 9959, 21261, 13, 32009, 323, 5528, 57708, 2955, 1398, 50732, 3952, 2035, 520, 279, 45903, 5848, 8483, 19558, 520, 23683, 66947, 3907, 11, 1051, 584, 1511, 16166, 3289, 42306, 311, 1296, 279, 1317, 9860, 6372, 315, 8927, 1111, 1234, 18768, 5392, 4688, 4787, 389, 1403, 9606, 315, 993, 6577, 24548, 26, 279, 1891, 63550, 362, 884, 1065, 64663, 1015, 323, 279, 93101, 63550, 362, 13, 272, 52098, 71956, 662, 1398, 50732, 1051, 13375, 369, 220, 21, 4235, 23, 4038, 304, 1403, 24871, 1667, 25, 279, 1176, 54515, 3940, 304, 6841, 220, 679, 23, 323, 9670, 304, 5887, 220, 679, 24, 13, 578, 2132, 54515, 3940, 389, 6841, 220, 679, 24, 323, 9670, 304, 5651, 220, 2366, 15, 13, 2052, 21896, 1051, 11953, 704, 304, 18859, 449, 279, 16286, 20214, 315, 6401, 8641, 369, 279, 2512, 323, 1005, 315, 27692, 10099, 323, 682, 22772, 32885, 1051, 12054, 555, 279, 23683, 6830, 85, 344, 3907, 98984, 21995, 10852, 323, 5560, 10554, 320, 40, 1741, 5576, 11766, 14765, 1396, 220, 2371, 12, 972, 12, 25921, 11, 220, 2371, 12, 777, 12, 18887, 570, 10984, 42306, 1556, 58912, 6485, 315, 8223, 220, 18, 55, 18, 55, 18, 73601, 9501, 11546, 81947, 574, 5918, 311, 5471, 24548, 505, 53754, 323, 6144, 1124, 505, 4255, 367, 11, 1418, 10923, 14675, 315, 5933, 40120, 11, 18266, 4238, 323, 9282, 4787, 13, 578, 14981, 961, 315, 279, 3289, 42306, 574, 9960, 449, 264, 25826, 15485, 311, 6144, 279, 24548, 505, 72389, 1113, 323, 39262, 13, 10984, 42306, 1051, 19180, 1701, 128257, 198, 128256, 78191, 198, 2127, 16781, 4007, 520, 23683, 66947, 3907, 596, 6150, 315, 45903, 2508, 12793, 279, 5536, 315, 44387, 3428, 20653, 8127, 3177, 25793, 389, 1403, 9606, 315, 24521, 94209, 25, 279, 1891, 63550, 21411, 993, 6577, 8814, 11, 323, 279, 93101, 63550, 4279, 993, 6577, 8814, 13, 578, 14955, 1051, 7701, 34973, 25, 389, 1403, 2204, 25975, 11, 4553, 49028, 15246, 311, 8927, 1111, 320, 9470, 16895, 8828, 2468, 13120, 8, 8636, 2949, 2919, 11, 323, 39656, 1101, 25983, 12207, 7863, 311, 2585, 5315, 13, 330, 8140, 3135, 1501, 9539, 369, 279, 1176, 892, 430, 3177, 25793, 649, 387, 9193, 28856, 311, 1521, 9606, 11, 323, 4284, 814, 1253, 387, 28856, 311, 61951, 11, 73119, 11, 323, 1524, 3823, 2890, 1359, 2019, 279, 12074, 13, 578, 4007, 574, 6197, 555, 8626, 13, 452, 14361, 97660, 31202, 6354, 6279, 11, 14681, 68409, 315, 6921, 596, 20214, 315, 25027, 19721, 11, 323, 2405, 920, 13, 5575, 473, 38812, 650, 37489, 11500, 2706, 11, 2225, 505, 350, 36128, 596, 6150, 315, 45903, 2508, 323, 279, 35606, 60382, 16730, 315, 18955, 11346, 13, 578, 5684, 574, 4756, 304, 38130, 29140, 13, 8626, 13, 97660, 31202, 6354, 6279, 15100, 11, 330, 1687, 617, 1027, 21630, 1521, 15499, 5552, 21236, 306, 9606, 369, 1667, 13, 2435, 2225, 3974, 304, 6921, 596, 56617, 951, 15916, 25, 279, 21411, 993, 6577, 8814, 320, 32, 884, 1065, 64663, 1015, 8, 374, 1891, 63550, 11, 323, 279, 4279, 993, 6577, 8814, 320, 32, 13, 272, 52098, 71956, 8, 304, 93101, 63550, 13, 578, 1403, 9606, 4430, 279, 1890, 5933, 39646, 719, 1005, 433, 520, 2204, 3115, 311, 5766, 10937, 13, 3296, 27393, 15499, 5552, 9606, 430, 1782, 304, 5820, 3115, 11, 584, 8895, 502, 26793, 1139, 279, 24156, 9042, 323, 1202, 12939, 311, 279, 2890, 315, 2225, 10099, 323, 12966, 1210, 473, 38812, 650, 37489, 11500, 2706, 2795, 11, 330, 644, 1455, 9606, 20041, 311, 2457, 11, 2737, 12966, 11, 279, 24156, 9042, 374, 22183, 555, 3177, 13, 1115, 17383, 28995, 927, 11990, 315, 1667, 304, 2077, 311, 279, 7446, 323, 9974, 25492, 315, 40120, 2345, 1316, 323, 3814, 323, 872, 29865, 29416, 430, 8024, 311, 279, 2349, 315, 15956, 13, 34496, 9606, 8040, 5820, 12912, 430, 8024, 311, 1521, 4442, 304, 3177, 21261, 323, 1938, 4222, 323, 8040, 75893, 950, 11, 53194, 323, 36695, 77765, 14791, 369, 1938, 477, 3814, 5820, 323, 3280, 2786, 1210, 330, 11458, 11, 927, 279, 1566, 11026, 11, 12966, 617, 5614, 279, 5718, 555, 17459, 287, 323, 42817, 1701, 21075, 3177, 11, 902, 27983, 3177, 25793, 13, 10771, 311, 5652, 7978, 11, 922, 220, 1490, 4, 315, 279, 1917, 596, 3823, 7187, 374, 15246, 311, 8927, 1111, 11, 323, 279, 3158, 11754, 555, 3177, 25793, 28815, 30171, 555, 220, 17, 12, 21, 14697, 763, 264, 2678, 323, 88204, 9988, 1614, 1093, 6921, 11, 1633, 2478, 7634, 7293, 1949, 315, 3177, 25793, 13, 763, 1057, 4007, 584, 15499, 41223, 279, 1317, 9860, 6372, 315, 8927, 1111, 389, 7931, 323, 22673, 1234, 18768, 5392, 4688, 4787, 1210, 763, 279, 4007, 11, 279, 12074, 9277, 220, 4161, 993, 6577, 24548, 315, 2225, 9606, 11, 25000, 323, 28585, 304, 6273, 5219, 11, 304, 8223, 33236, 16166, 3289, 42306, 520, 350, 36128, 596, 45903, 5848, 8483, 19558, 13, 578, 3289, 42306, 46836, 5496, 4787, 304, 279, 8545, 25, 682, 10099, 1051, 15246, 311, 5933, 12434, 4787, 11, 2737, 279, 5933, 3177, 3529, 847, 11008, 11, 35288, 20472, 11, 38193, 11, 323, 61050, 13, 9062, 58912, 13282, 52888, 11, 67810, 7384, 323, 2680, 311, 14343, 15055, 315, 3691, 13, 578, 22772, 3289, 42306, 1051, 15246, 311, 3428, 20653, 8127, 8927, 1111, 320, 65387, 311, 264, 8761, 95857, 304, 16036, 5789, 8, 315, 2204, 93959, 320, 21712, 8, 369, 220, 605, 4038, 25, 1403, 3289, 42306, 1051, 15246, 311, 9439, 4251, 3177, 11, 1403, 311, 8369, 4251, 320, 28969, 819, 8, 3177, 11, 323, 1403, 311, 6437, 3177, 11, 1418, 1403, 3289, 42306, 11, 14958, 6453, 520, 3814, 323, 10434, 439, 11835, 13, 2052, 10099, 1051, 13160, 311, 7431, 13687, 16967, 315, 4442, 304, 7865, 323, 7106, 3044, 13, 578, 9526, 574, 13375, 11157, 304, 1403, 50024, 1667, 13, 8626, 13, 97660, 31202, 6354, 6279, 2795, 11, 330, 791, 5578, 2324, 66995, 315, 993, 6577, 24548, 374, 220, 19, 12, 20, 1667, 11, 323, 1057, 4113, 3197, 574, 311, 8891, 279, 6372, 315, 8927, 1111, 389, 279, 1890, 49028, 11, 30090, 279, 6372, 389, 42889, 2612, 11, 1664, 33851, 323, 58219, 13, 2030, 279, 22520, 3135, 64788, 291, 1057, 6787, 25, 389, 1403, 46305, 25975, 11, 304, 1403, 2204, 3289, 42306, 15246, 311, 4251, 3177, 11, 682, 10099, 8636, 2949, 3892, 2919, 1210, 330, 1687, 1047, 3970, 912, 33269, 12195, 11, 323, 3154, 3806, 552, 520, 350, 36128, 596, 42904, 315, 19152, 323, 279, 13818, 2298, 78103, 10181, 304, 76130, 423, 18851, 10675, 912, 35663, 14955, 304, 279, 5710, 993, 6577, 24548, 13, 1226, 9855, 430, 14675, 311, 8927, 1111, 1047, 50160, 279, 10099, 6, 22852, 2077, 11, 9564, 1124, 449, 912, 9313, 2403, 1063, 65578, 1853, 11968, 13, 2360, 35663, 29528, 574, 12715, 304, 904, 315, 279, 1023, 3289, 42306, 11, 323, 439, 3117, 439, 584, 527, 8010, 11, 912, 4528, 1567, 706, 3596, 1027, 27470, 555, 12074, 1603, 1210, 7089, 14955, 1101, 16717, 430, 14675, 311, 8927, 1111, 24927, 82, 279, 42889, 2450, 315, 993, 6577, 24548, 13, 473, 38812, 650, 37489, 11500, 2706, 2795, 11, 330, 644, 279, 8545, 2225, 9606, 315, 993, 6577, 24548, 28875, 14918, 2391, 7474, 11, 994, 20472, 527, 1579, 11, 323, 279, 46397, 90821, 527, 1455, 4461, 311, 18167, 13, 59294, 3177, 11, 4869, 11, 9508, 311, 59217, 279, 10099, 13, 578, 4279, 993, 6577, 24548, 6137, 311, 28875, 1060, 21691, 719, 9124, 264, 4827, 1396, 315, 90821, 824, 1060, 1210, 330, 47, 8772, 9405, 2391, 12688, 527, 539, 3685, 311, 18167, 304, 7138, 11, 902, 1053, 4726, 8108, 279, 9606, 6, 42889, 2450, 304, 279, 8545, 13, 578, 39656, 315, 21411, 993, 6577, 24548, 574, 11754, 304, 264, 2204, 1648, 25, 49028, 15246, 311, 8927, 1111, 8738, 311, 28875, 304, 279, 7474, 11, 719, 279, 1396, 315, 3995, 574, 11293, 555, 4376, 7863, 311, 279, 2585, 1912, 11, 902, 8738, 311, 41972, 323, 28875, 14614, 13, 4314, 14955, 527, 304, 18859, 449, 279, 2144, 430, 304, 36899, 1317, 1938, 28875, 388, 279, 50498, 369, 39656, 374, 1938, 3160, 1210, 24086, 7177, 10675, 430, 14675, 311, 8927, 1111, 9057, 53194, 323, 74218, 4442, 2345, 3646, 12207, 304, 279, 2237, 315, 89942, 11, 459, 3062, 8631, 36908, 6532, 304, 279, 19812, 323, 5784, 315, 1690, 53194, 44014, 11, 2737, 279, 19812, 315, 279, 22852, 1887, 13, 11868, 7177, 16717, 430, 14675, 311, 6437, 3177, 7319, 89942, 5990, 315, 21411, 993, 6577, 24548, 11, 1418, 4251, 3177, 11293, 89942, 5990, 315, 21411, 993, 6577, 24548, 25000, 304, 12688, 13, 8626, 13, 97660, 31202, 5124, 269, 2795, 11, 330, 8140, 14955, 1501, 430, 3177, 25793, 11, 5423, 9439, 4251, 323, 6437, 3177, 11, 12992, 29528, 323, 24927, 82, 39656, 11, 323, 8617, 1253, 387, 65069, 311, 279, 17479, 323, 20237, 315, 9606, 304, 279, 8545, 13, 1115, 31959, 2515, 649, 617, 3117, 87248, 16296, 520, 279, 1510, 7029, 8141, 315, 3177, 25793, 1210, 330, 8140, 2867, 3135, 527, 459, 3062, 3094, 9017, 8830, 279, 5536, 315, 3177, 25793, 389, 73119, 323, 690, 1520, 603, 12192, 8198, 6108, 10396, 11, 11951, 449, 5363, 311, 279, 1005, 315, 21075, 3177, 304, 2225, 5918, 323, 1825, 5789, 13, 763, 3938, 7978, 584, 3197, 311, 19874, 1148, 9057, 279, 16781, 16779, 304, 279, 3289, 42306, 15246, 311, 8927, 1111, 11, 21760, 389, 279, 2515, 315, 3177, 25793, 14675, 389, 279, 22852, 1887, 1210, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The impact of nutritional status during fetal life on the overall health of adults has been recognized 1 ; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed 2 , 3 . Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells 2 , 3 , 4 , 5 . Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero , which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring. Main Haematopoietic cells that initially colonize secondary lymphoid organ (SLO) sites include CD3 − c-Kit + IL-7Rα − α4β7 + CD11c + CD4 − lymphoid tissue initiator (LTin) cells and the prototypical member of type 3 ILCs, LTi cells 2 , 3 , 4 , 5 , 6 , 7 . Although most LTi cells express CD4, this is a late event in LTi differentiation and not all RORγt + LTi cells express this marker 5 , 6 , 8 , 9 . Thus, we proposed that CD3 − IL-7Rα + α4β7 + ID2 + c-Kit + CD11c − CD4 − ILCs (hereafter called ILC 4neg cells) receive local cues giving rise to ID2 + RORγt + CD4 + LTi cells (LTi 4 ) within developing SLOs. Notably, enteric ILC 4neg cells include mainly ID2 + RORγt + CD4 − LTi cells (LTi 0 ) but also a small fraction of ID2 + RORγt − CD4 − precursors with LTi cell potential (hereafter called pre-ILC cells) 9 . In contrast, nearly 100% of lymph node ILC 4neg cells are LTi 0 cells ( Extended Data Fig. 1a, b ). Analysis of embryonic day 12.5 (E12.5) guts revealed that ILC 4neg cells are the only appreciable IL-7Rα + colonizing cells ( Fig. 1a, b ). Accordingly, non-cycling mature Sca1 − LTi 4 cells increased throughout development, seemingly at the expense of Sca1 + ILC 4neg cells ( Fig. 1a–c and Extended Data Fig. 1c ). Further evidence that ILC 4neg cells differentiate locally was provided by organ cultures and transplantation of E12.5 intestines. Despite absence of fetal liver output in these settings, LTi 4 cells increased with time at the expense of local ILC 4neg cells ( Fig. 1d, e ). Furthermore, in E14.5 Rorgt −/− embryos, ILC 4neg cells were attracted to the intestine and lymph nodes, supporting initial anlagen colonization by these cells ( Extended Data Fig. 1d, e ). Notably, RA stimulation of E13.5 lymph node cells showed increased frequency of LTi 4 cells and reduction of ILC 4neg cells, indicating that differentiation of LTi 4 cells is regulated by RA ( Fig. 1f ). To confirm the effect of RA in LTi differentiation in vivo , pregnant mice received a RA-enriched diet starting at E10.5. Supplementation of RA increased the proportion of LTi 4 cells in the embryo, to the detriment of ILC 4neg cells ( Fig. 1f ). In agreement with this finding, provision of the RA signalling inhibitor BMS493 to pregnant female mice resulted in a decrease of fetal LTi 4 cells despite normal frequency of fetal liver progenitors and enteric haematopoietic cells ( Fig. 1f and Extended Data Fig. 1f ). Consequently, despite normal embryo size, BMS493 administration led to a reduction in lymph node dimensions and Peyer’s patch developmental failure ( Fig. 1g–i and Extended Data Fig. 1g ). Collectively, our data indicate that maternal retinoids control LTi cell differentiation within developing SLOs. Figure 1: Maternal RA controls LTi differentiation. a , Enteric fetal ILC 4neg and LTi 4 cells. b , Percentage of enteric fetal ILC 4neg and LTi 4 cells. E12.5, n = 8; E13.5, n = 3; E14.5, n = 6; E15.5, n = 3. c , Left: Sca1 - GFP lymph nodes. Right: E15.5 gut cells. d , e , Cultured or transplanted E12.5 guts. d , Day 0, n = 4; day 1, n = 6; day 2, n = 6. e , Day 0, n = 7; day 1, n = 3; day 2, n = 5. f , Left: E13.5 lymph node cells; n = 7. Centre: RA was provided to females. E13.5 lymph node cells; n = 8. Right: females received BMS493; n = 8. LTi 4 /ILC 4neg cell ratio is shown. g – i , hCD2 - GFP females received BMS493. E17.5 SLOs. g , Brachial (Bra) and inguinal (Ing) lymph nodes; n = 6. h , Arrowheads indicate Peyer’s patch. i , Peyer’s patch number per intestine: DMSO, n = 8; BMS, n = 22. Area: DMSO, n = 30; BMS, n = 25. Scale bars: 50 μm ( c ), 200 μm ( g , h right), 1 mm ( h , left). Error bars show s.e. * P < 0.05; ** P < 0.01; *** P < 0.001. NS, not significant. PowerPoint slide Full size image RA is a vitamin A metabolite that controls early vertebrate development, some immune processes in adulthood, and has been shown to mediate CXCL13 expression in fetal mesenchymal cells 10 , 11 , 12 , 13 , 14 , 15 , 16 . RA binds to heterodimers formed by the RA receptors (RARs)", "role": "user" }, { "content": "(Medical Xpress)—A team of researchers working in the Netherlands has found that the amount of vitamin A a woman consumes during pregnancy has a lifelong impact on the immune system of her offspring. In their paper published in the journal Nature, the team describes experiments they conducted with pregnant mice on vitamin A restricted diets and the impact it had on the development of offspring immunity. In a companion News & Views article Gérard Eberl, of the Pasteur Institute provides a history of vitamin A research and the various findings of several research efforts. Medical scientists have known for some time that vitamin A is important both for a developing fetus and for people of all ages, a lack of it has been linked to blindness, reproduction problems, bone metabolism and skin homeostasis. In this new effort the research team has found that it also plays a crucial role in the development of the immune system—specifically, in the development of lymph nodes and Peyer's patches. Lymph nodes are organs situated throughout the human body, most notably in the armpits. They are a garrison of several types of immunity cells—they serve as a form of net or trap for foreign elements that could potentially cause harm. Peyer's patches are structures similar to lymph nodes that exist in the intestine and serve much the same role in immunity. To find out whether a lack of vitamin A during pregnancy might have an impact on immunity in offspring later in life, the researchers fed pregnant mice a diet with little to no vitamin A and then tracked the development of the offspring as compared to the offspring of mice fed normal amounts of vitamin A. The researchers report that the vitamin A deprived offspring developed smaller lymph nodes and Peyer's patches than the control group, and as a result were more susceptible later in life to a virus that causes lung infections—it was introduced intentionally to demonstrate immune response. The researchers also noted that giving the newly born vitamin A deprived mice the vitamin didn't reverse the impact of the in vitro deficiency, nor did giving them a bone marrow transplant. The smaller lymph nodes and Peyer's patches remained smaller than normal throughout the entire life of the mice contributing to a weaker than normal immune system. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The impact of nutritional status during fetal life on the overall health of adults has been recognized 1 ; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed 2 , 3 . Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells 2 , 3 , 4 , 5 . Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero , which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring. Main Haematopoietic cells that initially colonize secondary lymphoid organ (SLO) sites include CD3 − c-Kit + IL-7Rα − α4β7 + CD11c + CD4 − lymphoid tissue initiator (LTin) cells and the prototypical member of type 3 ILCs, LTi cells 2 , 3 , 4 , 5 , 6 , 7 . Although most LTi cells express CD4, this is a late event in LTi differentiation and not all RORγt + LTi cells express this marker 5 , 6 , 8 , 9 . Thus, we proposed that CD3 − IL-7Rα + α4β7 + ID2 + c-Kit + CD11c − CD4 − ILCs (hereafter called ILC 4neg cells) receive local cues giving rise to ID2 + RORγt + CD4 + LTi cells (LTi 4 ) within developing SLOs. Notably, enteric ILC 4neg cells include mainly ID2 + RORγt + CD4 − LTi cells (LTi 0 ) but also a small fraction of ID2 + RORγt − CD4 − precursors with LTi cell potential (hereafter called pre-ILC cells) 9 . In contrast, nearly 100% of lymph node ILC 4neg cells are LTi 0 cells ( Extended Data Fig. 1a, b ). Analysis of embryonic day 12.5 (E12.5) guts revealed that ILC 4neg cells are the only appreciable IL-7Rα + colonizing cells ( Fig. 1a, b ). Accordingly, non-cycling mature Sca1 − LTi 4 cells increased throughout development, seemingly at the expense of Sca1 + ILC 4neg cells ( Fig. 1a–c and Extended Data Fig. 1c ). Further evidence that ILC 4neg cells differentiate locally was provided by organ cultures and transplantation of E12.5 intestines. Despite absence of fetal liver output in these settings, LTi 4 cells increased with time at the expense of local ILC 4neg cells ( Fig. 1d, e ). Furthermore, in E14.5 Rorgt −/− embryos, ILC 4neg cells were attracted to the intestine and lymph nodes, supporting initial anlagen colonization by these cells ( Extended Data Fig. 1d, e ). Notably, RA stimulation of E13.5 lymph node cells showed increased frequency of LTi 4 cells and reduction of ILC 4neg cells, indicating that differentiation of LTi 4 cells is regulated by RA ( Fig. 1f ). To confirm the effect of RA in LTi differentiation in vivo , pregnant mice received a RA-enriched diet starting at E10.5. Supplementation of RA increased the proportion of LTi 4 cells in the embryo, to the detriment of ILC 4neg cells ( Fig. 1f ). In agreement with this finding, provision of the RA signalling inhibitor BMS493 to pregnant female mice resulted in a decrease of fetal LTi 4 cells despite normal frequency of fetal liver progenitors and enteric haematopoietic cells ( Fig. 1f and Extended Data Fig. 1f ). Consequently, despite normal embryo size, BMS493 administration led to a reduction in lymph node dimensions and Peyer’s patch developmental failure ( Fig. 1g–i and Extended Data Fig. 1g ). Collectively, our data indicate that maternal retinoids control LTi cell differentiation within developing SLOs. Figure 1: Maternal RA controls LTi differentiation. a , Enteric fetal ILC 4neg and LTi 4 cells. b , Percentage of enteric fetal ILC 4neg and LTi 4 cells. E12.5, n = 8; E13.5, n = 3; E14.5, n = 6; E15.5, n = 3. c , Left: Sca1 - GFP lymph nodes. Right: E15.5 gut cells. d , e , Cultured or transplanted E12.5 guts. d , Day 0, n = 4; day 1, n = 6; day 2, n = 6. e , Day 0, n = 7; day 1, n = 3; day 2, n = 5. f , Left: E13.5 lymph node cells; n = 7. Centre: RA was provided to females. E13.5 lymph node cells; n = 8. Right: females received BMS493; n = 8. LTi 4 /ILC 4neg cell ratio is shown. g – i , hCD2 - GFP females received BMS493. E17.5 SLOs. g , Brachial (Bra) and inguinal (Ing) lymph nodes; n = 6. h , Arrowheads indicate Peyer’s patch. i , Peyer’s patch number per intestine: DMSO, n = 8; BMS, n = 22. Area: DMSO, n = 30; BMS, n = 25. Scale bars: 50 μm ( c ), 200 μm ( g , h right), 1 mm ( h , left). Error bars show s.e. * P < 0.05; ** P < 0.01; *** P < 0.001. NS, not significant. PowerPoint slide Full size image RA is a vitamin A metabolite that controls early vertebrate development, some immune processes in adulthood, and has been shown to mediate CXCL13 expression in fetal mesenchymal cells 10 , 11 , 12 , 13 , 14 , 15 , 16 . RA binds to heterodimers formed by the RA receptors (RARs)<|im_end|> <|im_start|>assistant (Medical Xpress)—A team of researchers working in the Netherlands has found that the amount of vitamin A a woman consumes during pregnancy has a lifelong impact on the immune system of her offspring. In their paper published in the journal Nature, the team describes experiments they conducted with pregnant mice on vitamin A restricted diets and the impact it had on the development of offspring immunity. In a companion News & Views article Gérard Eberl, of the Pasteur Institute provides a history of vitamin A research and the various findings of several research efforts. Medical scientists have known for some time that vitamin A is important both for a developing fetus and for people of all ages, a lack of it has been linked to blindness, reproduction problems, bone metabolism and skin homeostasis. In this new effort the research team has found that it also plays a crucial role in the development of the immune system—specifically, in the development of lymph nodes and Peyer's patches. Lymph nodes are organs situated throughout the human body, most notably in the armpits. They are a garrison of several types of immunity cells—they serve as a form of net or trap for foreign elements that could potentially cause harm. Peyer's patches are structures similar to lymph nodes that exist in the intestine and serve much the same role in immunity. To find out whether a lack of vitamin A during pregnancy might have an impact on immunity in offspring later in life, the researchers fed pregnant mice a diet with little to no vitamin A and then tracked the development of the offspring as compared to the offspring of mice fed normal amounts of vitamin A. The researchers report that the vitamin A deprived offspring developed smaller lymph nodes and Peyer's patches than the control group, and as a result were more susceptible later in life to a virus that causes lung infections—it was introduced intentionally to demonstrate immune response. The researchers also noted that giving the newly born vitamin A deprived mice the vitamin didn't reverse the impact of the in vitro deficiency, nor did giving them a bone marrow transplant. The smaller lymph nodes and Peyer's patches remained smaller than normal throughout the entire life of the mice contributing to a weaker than normal immune system. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Lysosomes have many roles, including degrading macromolecules and signalling to the nucleus 1 . Lysosomal dysfunction occurs in various human conditions, such as common neurodegenerative diseases and monogenic lysosomal storage disorders (LSDs) 2 , 3 , 4 . For most LSDs, the causal genes have been identified but, in some, the function of the implicated gene is unknown, in part because lysosomes occupy a small fraction of the cellular volume so that changes in lysosomal contents are difficult to detect. Here we develop the LysoTag mouse for the tissue-specific isolation of intact lysosomes that are compatible with the multimodal profiling of their contents. We used the LysoTag mouse to study CLN3, a lysosomal transmembrane protein with an unknown function. In children, the loss of CLN3 causes juvenile neuronal ceroid lipofuscinosis (Batten disease), a lethal neurodegenerative LSD. Untargeted metabolite profiling of lysosomes from the brains of mice lacking CLN3 revealed a massive accumulation of glycerophosphodiesters (GPDs)—the end products of glycerophospholipid catabolism. GPDs also accumulate in the lysosomes of CLN3-deficient cultured cells and we show that CLN3 is required for their lysosomal egress. Loss of CLN3 also disrupts glycerophospholipid catabolism in the lysosome. Finally, we found elevated levels of glycerophosphoinositol in the cerebrospinal fluid of patients with Batten disease, suggesting the potential use of glycerophosphoinositol as a disease biomarker. Our results show that CLN3 is required for the lysosomal clearance of GPDs and reveal Batten disease as a neurodegenerative LSD with a defect in glycerophospholipid metabolism. Main Lysosomes are membrane-bound organelles that degrade macromolecules and clear damaged organelles as well as regulate cellular signalling, such as the activation of the mTORC1 pathway by nutrients 1 , 5 , 6 . Mutations in genes encoding lysosomal proteins cause severe disorders that are collectively known as LSDs 2 , 3 , 7 , 8 , 9 . Many LSDs are associated with neurodegeneration, indicating a critical role for the lysosome in neuronal homeostasis 3 , 4 . Consistent with this, human genetic studies have implicated impaired lysosomal function in age-associated neurodegenerative diseases, including Alzheimer disease, Parkinson’s disease and frontotemporal dementia 2 , 10 , 11 . The function of several lysosomal proteins implicated in disease is incompletely understood, in part because lysosomes usually occupy only 1–3% of the cellular volume and changes in lysosomal contents can therefore be difficult to ascertain in whole cells or tissues 12 . The development of the LysoTag mouse Given this and the increasing interest in the roles of lysosomes in physiology and disease, we adapted our LysoIP method for the rapid purification of lysosomes from cultured cells 12 for use in mouse tissues. We generated a transgenic mouse line by integrating the cDNA encoding the lysosomally localized TMEM192–3×HA fusion protein into the Rosa26 locus downstream of a lox-stop-lox (LSL) cassette 13 (Fig. 1a ). By crossing these mice with those expressing a Cre recombinase driven by the CMV promoter, we generated LysoTag mice that constitutively express TMEM192–3×HA across tissues (Fig. 1a and Extended Data Fig. 1a ). TMEM192–3×HA marks lysosomes with a triple HA epitope, enabling their immunoisolation with anti-HA antibodies. Immunofluorescence-based analyses of liver and brain sections, two tissues examined in this study, confirmed that TMEM192–3×HA colocalizes with the lysosomal marker LAMP1 (Fig. 1b and Extended Data Fig. 2b ). Other than a 10–15% decrease in body weight, the constitutive LysoTag mice appear indistinguishable from their wild-type (WT) counterparts (Extended Data Fig. 1b ). Importantly, comprehensive characterizations confirm that LysoTag expression has no effect on lysosomal proteins, enzymatic activity or lysosomal ultrastructure (Extended Data Fig. 1a,c–f ). Fig. 1: LysoTag mouse for proteomic and metabolite profiling of tissue lysosomes. a , Schematic of the TMEM192-3×HA fusion gene (LysoTag) in the Rosa26 locus and the generation of the constitutive LysoTag line. b , Immunofluorescence analyses of TMEM192–3×HA (HA, green) and lysosomes (LAMP1, red) in the liver. Nuclei are shown in blue. Scale bars, 5 µm (main images) and 1 µm (insets). Micrographs are representative of three independent experiments. c , Immunoblot analyses of protein markers of subcellular compartments in whole tissues, purified lysosomes (immunoprecipitate: IP LysoTag + ), and control immunoprecipitates (IP LysoTag − ). Golgin-97, VDAC and calreticulin were used as markers for the Golgi, mitochondria and endoplasmic reticulum, respectively, and LAMP1 and cathepsin C for lysosomes. Immunoblots are representative of three independent experiments. d , e , Proteomic analyses of liver LysoIPs. d , PCA comparing the levels of the detected proteins. e , Volcano plot showing that previously annotated lysosomal proteins (orange dots) are enriched in lysosomes. Enriched unannotated proteins are shown in black. The vertical dashed lines indicate a log 2 -transformed fold change of >1.5 in LysoTag + immunoprecipitates either over control immunoprecipitates (left) or whole tissue (right). The horizontal dashed lines indicate q < 0.01. n = 3 male mice with an average age of 6.5 weeks. Statistical analysis was performed using paired t -tests, performed at the peptide precursor level; P values were corrected for multiple testing according to ref. 42 . Annot., annotation; sign., significant. f , The relative abundance of the indicated metabolites in whole tissue and immunoprecipitates. ND, not detected. Data are mean ± s.e.m. n = 4 (LysoTag + ) and n = 3 (LysoTag − ). g , Heat map of the mean of log 2 -transformed fold changes in metabolite levels after a 16 h fast (Supplementary Table 2 ). h , Fold changes in the levels of nucleosides after fasting. For g and h , data are mean and for h ± s.e.m. of n = 4 (ad libitum) or n = 3 (fasted). For f and h , statistical analysis was performed using two-tailed unpaired t -tests. For f – h , male mice with an average age of 5.5 weeks were used. Gel source data are provided in Supplementary Fig. 1 . The drawings in the schematics in a and c were created using Biorender. GlcNAc, N-acetylglucosamine; GSH, Glutathione; SAH, S-adenosylhomocysteine; SAM, S‐adenosylmethionine. Source data Full size image We modified our", "role": "user" }, { "content": "Small but mighty, lysosomes play a surprisingly important role in cells despite their diminutive size. Making up only 1-3% of the cell by volume, these small sacs are the cell's recycling centers, home to enzymes that break down unneeded molecules into small pieces that can then be reassembled to form new ones. Lysosomal dysfunction can lead to a variety of neurodegenerative or other diseases, but without ways to better study the inner contents of lysosomes, the exact molecules involved in diseases—and therefore new drugs to target them—remain elusive. A new method, reported in Nature on Sept. 21, allows scientists to determine all the molecules present in the lysosomes of any cell in mice. Studying the contents of these molecular recycling centers could help researchers learn how the improper degradation of cellular materials leads to certain diseases. Led by Stanford University's Monther Abu-Remaileh, institute scholar at Sarafan ChEM-H, the study's team also learned more about the cause for a currently untreatable neurodegenerative disease known as Batten disease, information that could lead to new therapies. \"Lysosomes are fascinating both fundamentally and clinically: they supply the rest of the cell with nutrients, but we don't always know how and when they supply them, and they are the places where many diseases, especially those that affect the brain, start,\" said Abu-Remaileh, who is an assistant professor of chemical engineering and of genetics. Some proteins that are usually located in lysosomes are linked to a number of diseases. Mutations in the genetic instructions for making those proteins lead to these \"lysosomal storage disorders,\" as they are collectively called, but the functions of some of these proteins have long puzzled scientists. Information about how these proteins work could help scientists develop better ways to diagnose, monitor, or treat these diseases. If scientists want to study the role a particular protein plays in the cell, they might either block or stimulate its function and see if certain molecules appear or disappear in response. But studying the contents of lysosomes is a problem of scale. \"If something happens and a molecule grows in abundance 200-fold in the lysosome, you would see only a two-fold increase if you look at the whole cell,\" said Nouf Laqtom, first author on the study. The revealing results get buried in the noise. To quiet the noise, the researchers would have to separate lysosomes from everything else in the cell. They had previously developed a method to do just that in cells grown in labs, but they wanted to develop a way to do the same thing in mice. Fishing for magnets The first step in their quest to isolate lysosomes was making a small change in the genes of the mice to install a little molecular tag on the surface of every lysosome in the entire animal. At any point when they want to stop and check on the molecules in the mouse lysosomes, like after fasting or feeding them a specific food, they turn on the tag in the cells they want to examine, and then remove the tissue and carefully grind it up to break open the cells without disrupting the lysosomes inside. To fish lysosomes from the cellular sludge, the team relies on magnets. To their slurry they add tiny magnetic beads that are each decorated with molecular clamps that grab ahold of the lysosomal tag they had previously installed. They can selectively collect all the lysosomes using a second magnet, and then break apart the lysosomes to reveal the molecules that had been safely tucked inside. Mass spectrometry, a set of tools that determines the weights of different molecules in a mixture, then helps the researchers identify the individuals in their lysosomal molecular potpourri. Those that grow or decrease would point scientists to certain pathways or functions. Except for the little extra tag on each lysosome, these \"LysoTag\" mice are otherwise normal laboratory mice. Now, almost any researcher can use these mice to study the role of lysosomes in different diseases. \"These mice are freely available for anyone in the research community to use, and people are already starting to use them,\" said Abu-Remaileh. \"We hope that this will become the gold standard.\" Knowing where to look The team was eager to apply their method to study the lysosomes found in brain cells to better understand the neurodegenerative lysosomal storage diseases, starting with CLN3 disease or juvenile Batten disease. \"We really see this as one of the most urgent problems we can help solve,\" said Abu-Remaileh. Caused by a mutation in the gene that codes for a protein called CLN3, juvenile Batten disease is fatal and leads to vision loss, seizures, and progressive motor and mental deterioration in children and young adults. The CLN3 protein is found on the membrane of the lysosome, but no one has ever determined its function in the cell or how its dysfunction leads to the observed symptoms. Using their LysoTag mice, the researchers collaborated with experts in both the Sarafan ChEM-H Metabolomics Knowledge Center and the Whitehead Institute Metabolomics Core Facility and found a dramatic increase in the amount of a kind of molecule called a glycerophosphodiester, or GPD for short, in mice with the CLN3 disease mutation. These GPDs are temporarily formed during the degradation of the fatty molecules that make up the membranes of every cell in our body. In healthy cells, the GPDs do not accumulate in the lysosome; they get exported to a different part of the cell, where they are then degraded into smaller pieces. The researchers now believe that the CLN3 protein plays an important role in that export, either by directly shuttling out the molecules or by helping another protein do that job. They found GPD molecules in the cerebral spinal fluid of patients with CLN3 disease, which suggests that clinicians could potentially monitor GPD levels to measure the success of future treatments. The team is now determining which of the GPD molecules might be toxic and how the proteins involved in making and exporting GPDs could be targeted with new drugs. They also are applying their method to look at other diseases that involve mutations in lysosomal genes, like Parkinson's disease. \"You can't develop new ways to diagnose or treat diseases if you don't know what is changing in the lysosomes,\" said Laqtom, a former postdoctoral scholar in the Abu-Remaileh lab. \"This method helps you make sure you're looking in the right direction. It points you down the right path and keeps you from getting lost.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Lysosomes have many roles, including degrading macromolecules and signalling to the nucleus 1 . Lysosomal dysfunction occurs in various human conditions, such as common neurodegenerative diseases and monogenic lysosomal storage disorders (LSDs) 2 , 3 , 4 . For most LSDs, the causal genes have been identified but, in some, the function of the implicated gene is unknown, in part because lysosomes occupy a small fraction of the cellular volume so that changes in lysosomal contents are difficult to detect. Here we develop the LysoTag mouse for the tissue-specific isolation of intact lysosomes that are compatible with the multimodal profiling of their contents. We used the LysoTag mouse to study CLN3, a lysosomal transmembrane protein with an unknown function. In children, the loss of CLN3 causes juvenile neuronal ceroid lipofuscinosis (Batten disease), a lethal neurodegenerative LSD. Untargeted metabolite profiling of lysosomes from the brains of mice lacking CLN3 revealed a massive accumulation of glycerophosphodiesters (GPDs)—the end products of glycerophospholipid catabolism. GPDs also accumulate in the lysosomes of CLN3-deficient cultured cells and we show that CLN3 is required for their lysosomal egress. Loss of CLN3 also disrupts glycerophospholipid catabolism in the lysosome. Finally, we found elevated levels of glycerophosphoinositol in the cerebrospinal fluid of patients with Batten disease, suggesting the potential use of glycerophosphoinositol as a disease biomarker. Our results show that CLN3 is required for the lysosomal clearance of GPDs and reveal Batten disease as a neurodegenerative LSD with a defect in glycerophospholipid metabolism. Main Lysosomes are membrane-bound organelles that degrade macromolecules and clear damaged organelles as well as regulate cellular signalling, such as the activation of the mTORC1 pathway by nutrients 1 , 5 , 6 . Mutations in genes encoding lysosomal proteins cause severe disorders that are collectively known as LSDs 2 , 3 , 7 , 8 , 9 . Many LSDs are associated with neurodegeneration, indicating a critical role for the lysosome in neuronal homeostasis 3 , 4 . Consistent with this, human genetic studies have implicated impaired lysosomal function in age-associated neurodegenerative diseases, including Alzheimer disease, Parkinson’s disease and frontotemporal dementia 2 , 10 , 11 . The function of several lysosomal proteins implicated in disease is incompletely understood, in part because lysosomes usually occupy only 1–3% of the cellular volume and changes in lysosomal contents can therefore be difficult to ascertain in whole cells or tissues 12 . The development of the LysoTag mouse Given this and the increasing interest in the roles of lysosomes in physiology and disease, we adapted our LysoIP method for the rapid purification of lysosomes from cultured cells 12 for use in mouse tissues. We generated a transgenic mouse line by integrating the cDNA encoding the lysosomally localized TMEM192–3×HA fusion protein into the Rosa26 locus downstream of a lox-stop-lox (LSL) cassette 13 (Fig. 1a ). By crossing these mice with those expressing a Cre recombinase driven by the CMV promoter, we generated LysoTag mice that constitutively express TMEM192–3×HA across tissues (Fig. 1a and Extended Data Fig. 1a ). TMEM192–3×HA marks lysosomes with a triple HA epitope, enabling their immunoisolation with anti-HA antibodies. Immunofluorescence-based analyses of liver and brain sections, two tissues examined in this study, confirmed that TMEM192–3×HA colocalizes with the lysosomal marker LAMP1 (Fig. 1b and Extended Data Fig. 2b ). Other than a 10–15% decrease in body weight, the constitutive LysoTag mice appear indistinguishable from their wild-type (WT) counterparts (Extended Data Fig. 1b ). Importantly, comprehensive characterizations confirm that LysoTag expression has no effect on lysosomal proteins, enzymatic activity or lysosomal ultrastructure (Extended Data Fig. 1a,c–f ). Fig. 1: LysoTag mouse for proteomic and metabolite profiling of tissue lysosomes. a , Schematic of the TMEM192-3×HA fusion gene (LysoTag) in the Rosa26 locus and the generation of the constitutive LysoTag line. b , Immunofluorescence analyses of TMEM192–3×HA (HA, green) and lysosomes (LAMP1, red) in the liver. Nuclei are shown in blue. Scale bars, 5 µm (main images) and 1 µm (insets). Micrographs are representative of three independent experiments. c , Immunoblot analyses of protein markers of subcellular compartments in whole tissues, purified lysosomes (immunoprecipitate: IP LysoTag + ), and control immunoprecipitates (IP LysoTag − ). Golgin-97, VDAC and calreticulin were used as markers for the Golgi, mitochondria and endoplasmic reticulum, respectively, and LAMP1 and cathepsin C for lysosomes. Immunoblots are representative of three independent experiments. d , e , Proteomic analyses of liver LysoIPs. d , PCA comparing the levels of the detected proteins. e , Volcano plot showing that previously annotated lysosomal proteins (orange dots) are enriched in lysosomes. Enriched unannotated proteins are shown in black. The vertical dashed lines indicate a log 2 -transformed fold change of >1.5 in LysoTag + immunoprecipitates either over control immunoprecipitates (left) or whole tissue (right). The horizontal dashed lines indicate q < 0.01. n = 3 male mice with an average age of 6.5 weeks. Statistical analysis was performed using paired t -tests, performed at the peptide precursor level; P values were corrected for multiple testing according to ref. 42 . Annot., annotation; sign., significant. f , The relative abundance of the indicated metabolites in whole tissue and immunoprecipitates. ND, not detected. Data are mean ± s.e.m. n = 4 (LysoTag + ) and n = 3 (LysoTag − ). g , Heat map of the mean of log 2 -transformed fold changes in metabolite levels after a 16 h fast (Supplementary Table 2 ). h , Fold changes in the levels of nucleosides after fasting. For g and h , data are mean and for h ± s.e.m. of n = 4 (ad libitum) or n = 3 (fasted). For f and h , statistical analysis was performed using two-tailed unpaired t -tests. For f – h , male mice with an average age of 5.5 weeks were used. Gel source data are provided in Supplementary Fig. 1 . The drawings in the schematics in a and c were created using Biorender. GlcNAc, N-acetylglucosamine; GSH, Glutathione; SAH, S-adenosylhomocysteine; SAM, S‐adenosylmethionine. Source data Full size image We modified our<|im_end|> <|im_start|>assistant Small but mighty, lysosomes play a surprisingly important role in cells despite their diminutive size. Making up only 1-3% of the cell by volume, these small sacs are the cell's recycling centers, home to enzymes that break down unneeded molecules into small pieces that can then be reassembled to form new ones. Lysosomal dysfunction can lead to a variety of neurodegenerative or other diseases, but without ways to better study the inner contents of lysosomes, the exact molecules involved in diseases—and therefore new drugs to target them—remain elusive. A new method, reported in Nature on Sept. 21, allows scientists to determine all the molecules present in the lysosomes of any cell in mice. Studying the contents of these molecular recycling centers could help researchers learn how the improper degradation of cellular materials leads to certain diseases. Led by Stanford University's Monther Abu-Remaileh, institute scholar at Sarafan ChEM-H, the study's team also learned more about the cause for a currently untreatable neurodegenerative disease known as Batten disease, information that could lead to new therapies. "Lysosomes are fascinating both fundamentally and clinically: they supply the rest of the cell with nutrients, but we don't always know how and when they supply them, and they are the places where many diseases, especially those that affect the brain, start," said Abu-Remaileh, who is an assistant professor of chemical engineering and of genetics. Some proteins that are usually located in lysosomes are linked to a number of diseases. Mutations in the genetic instructions for making those proteins lead to these "lysosomal storage disorders," as they are collectively called, but the functions of some of these proteins have long puzzled scientists. Information about how these proteins work could help scientists develop better ways to diagnose, monitor, or treat these diseases. If scientists want to study the role a particular protein plays in the cell, they might either block or stimulate its function and see if certain molecules appear or disappear in response. But studying the contents of lysosomes is a problem of scale. "If something happens and a molecule grows in abundance 200-fold in the lysosome, you would see only a two-fold increase if you look at the whole cell," said Nouf Laqtom, first author on the study. The revealing results get buried in the noise. To quiet the noise, the researchers would have to separate lysosomes from everything else in the cell. They had previously developed a method to do just that in cells grown in labs, but they wanted to develop a way to do the same thing in mice. Fishing for magnets The first step in their quest to isolate lysosomes was making a small change in the genes of the mice to install a little molecular tag on the surface of every lysosome in the entire animal. At any point when they want to stop and check on the molecules in the mouse lysosomes, like after fasting or feeding them a specific food, they turn on the tag in the cells they want to examine, and then remove the tissue and carefully grind it up to break open the cells without disrupting the lysosomes inside. To fish lysosomes from the cellular sludge, the team relies on magnets. To their slurry they add tiny magnetic beads that are each decorated with molecular clamps that grab ahold of the lysosomal tag they had previously installed. They can selectively collect all the lysosomes using a second magnet, and then break apart the lysosomes to reveal the molecules that had been safely tucked inside. Mass spectrometry, a set of tools that determines the weights of different molecules in a mixture, then helps the researchers identify the individuals in their lysosomal molecular potpourri. Those that grow or decrease would point scientists to certain pathways or functions. Except for the little extra tag on each lysosome, these "LysoTag" mice are otherwise normal laboratory mice. Now, almost any researcher can use these mice to study the role of lysosomes in different diseases. "These mice are freely available for anyone in the research community to use, and people are already starting to use them," said Abu-Remaileh. "We hope that this will become the gold standard." Knowing where to look The team was eager to apply their method to study the lysosomes found in brain cells to better understand the neurodegenerative lysosomal storage diseases, starting with CLN3 disease or juvenile Batten disease. "We really see this as one of the most urgent problems we can help solve," said Abu-Remaileh. Caused by a mutation in the gene that codes for a protein called CLN3, juvenile Batten disease is fatal and leads to vision loss, seizures, and progressive motor and mental deterioration in children and young adults. The CLN3 protein is found on the membrane of the lysosome, but no one has ever determined its function in the cell or how its dysfunction leads to the observed symptoms. Using their LysoTag mice, the researchers collaborated with experts in both the Sarafan ChEM-H Metabolomics Knowledge Center and the Whitehead Institute Metabolomics Core Facility and found a dramatic increase in the amount of a kind of molecule called a glycerophosphodiester, or GPD for short, in mice with the CLN3 disease mutation. These GPDs are temporarily formed during the degradation of the fatty molecules that make up the membranes of every cell in our body. In healthy cells, the GPDs do not accumulate in the lysosome; they get exported to a different part of the cell, where they are then degraded into smaller pieces. The researchers now believe that the CLN3 protein plays an important role in that export, either by directly shuttling out the molecules or by helping another protein do that job. They found GPD molecules in the cerebral spinal fluid of patients with CLN3 disease, which suggests that clinicians could potentially monitor GPD levels to measure the success of future treatments. The team is now determining which of the GPD molecules might be toxic and how the proteins involved in making and exporting GPDs could be targeted with new drugs. They also are applying their method to look at other diseases that involve mutations in lysosomal genes, like Parkinson's disease. "You can't develop new ways to diagnose or treat diseases if you don't know what is changing in the lysosomes," said Laqtom, a former postdoctoral scholar in the Abu-Remaileh lab. "This method helps you make sure you're looking in the right direction. It points you down the right path and keeps you from getting lost." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract With a growing body of research highlighting the therapeutic potential of experiential phenomenology which diminishes egoic identity and increases one’s sense of connectedness, there is significant interest in how to elicit such ‘self-transcendent experiences’ (STEs) in laboratory contexts. Psychedelic drugs (YDs) have proven particularly effective in this respect, producing subjective phenomenology which reliably elicits intense STEs. With virtual reality (VR) emerging as a powerful tool for constructing new perceptual environments, we describe a VR framework called ‘Isness-distributed’ (Isness-D) which harnesses the unique affordances of distributed multi-person VR to blur conventional self-other boundaries. Within Isness-D, groups of participants co-habit a shared virtual space, collectively experiencing their bodies as luminous energetic essences with diffuse spatial boundaries. It enables moments of ‘energetic coalescence’, a new class of embodied intersubjective experience where bodies can fluidly merge, enabling participants to include multiple others within their self-representation. To evaluate Isness-D, we adopted a citizen science approach, coordinating an international network of Isness-D 'nodes'. We analyzed the results (N = 58) using 4 different self-report scales previously applied to analyze subjective YD phenomenology (the inclusion of community in self scale, ego-dissolution inventory, communitas scale, and the MEQ30 mystical experience questionnaire). Despite the complexities associated with a distributed experiment like this, the Isness-D scores on all 4 scales were statistically indistinguishable from recently published YD studies, demonstrating that distributed VR can be used to design intersubjective STEs where people dissolve their sense of self in the connection to others. Introduction Describing the sensations that arose immediately following a left-hemisphere stroke, brain scientist Jill Bolte Taylor recounted: I could no longer define the boundaries of my body. I can’t define where I begin and where I end, because the atoms and molecules of my arm blend with the atoms and molecules of the wall, and all I could detect was this energy… I was immediately captivated by the magnificence of the energy around me. And because I could no longer identify the boundaries of my body, I felt enormous and expansive. I felt at one with all the energy that was, and it was beautiful 1 . Recounting the sensations that arose after seeing the Earth from space, astronaut Edgar Mitchell said: And suddenly I realized that the molecules of my body, the spacecraft, the body of my partners, were all manufactured in some ancient generation of stars. I felt an overwhelming sense of oneness, or connectedness… an insight, an epiphany 2 . During a particularly potent meditation session Zen master Sokei-an Sasaki described how: I lost the boundary of my physical body. I had my skin, of course, but I felt I was standing in the center of the cosmos… I saw people coming towards me, but all were… myself! 3 Recounting the sensations which arose from a high dose of the psychedelic drug (YD) psilocybin, a participant in a 2008 Griffiths et al. study recounted a feeling of no boundaries, where I didn’t know where I ended and where my surroundings began. Somehow I was able to comprehend what oneness is 4 . These accounts, which express a profound sense of unity with other beings and other objects, stand in contrast to our typical day-to-day perspective, in which we often default to conceptual representations of ourselves (and others) as separate objects rather than coupled interdependent subjects. Yaden et al. have coined the term ‘self-transcendent experiences’ (STEs) to describe transient mental states in which the subjective sense of one’s self as an isolated entity can temporarily fade into an experience of unity with other people or one’s surroundings, involving the dissolution of boundaries between the sense of self and ‘other’ 5 . Research across psychology, neuroscience, philosophy, pharmacology, and theology has drawn attention to the meaning and insight attributed to STEs by those who undergo them. Because they have been studied across so many different knowledge domains, they are described using different terminology, conceptual frameworks, and theoretical lenses, which makes it complicated to perform a comprehensive analysis of their subjective qualities, behavioral effects, and therapeutic potential. In an attempt to draw conceptual links across these various domains, Yaden et al. have identified a number of states as STEs, including for example Flow states 6 ; Mindfulness states 7 ; Awe 8 ; Peak Experiences 9 ; and Mystical-Type Experiences 10 . The phenomenology associated with different classes of STEs varies in saliency and visceral potency. As such, STEs have a broad range of intensities, some of which are more memorable, and thereby more significant for the person undergoing the experience. For example, “losing oneself” whilst reading a book or writing computer code may represent a relatively weak STE; whereas the deep sense of interdependence with the cosmos that arises from a spiritual ‘God-encounter’ experience represents a considerably more intense form of STE 11 . Analysis by Yaden et al. suggests that STEs involve at least two interrelated phenomenological ingredients: (1) an ‘annihilation’ of the sense of self, accomplished by dissolving self-boundaries and self-salience; and (2) a ‘relational’ sense of unity with something beyond the self (e.g., others or the natural world). The intensity of an STE is associated with the degree to which the participant experiences these interrelated phenomenological ingredients. While the precise sense of ‘self’ is difficult to define here, several different studies have nevertheless demonstrated the effectiveness of the so-called Inclusion of Other in the Self (IOS) Scale 12 for assessing the degree to which an individual feels a sense of connectedness to others or to their environment. As shown in Fig. 1 , this scale represents individuals and others as distinct circles. During weak unitive experiences, overlap between the circles is small; during particularly intense unitive experiences the overlap is more significant, representing an individual’s sense that ‘the other’ forms a significant part of the self. Figure 1 The Inclusion of Other in the Self Scale, which offers a continuum for expressing the sense of unitive feelings. Full size image William James suggested that particularly intense classes of STEs—namely ‘mystical type experiences’ (MTEs), where", "role": "user" }, { "content": "A paper published in the journal Scientific Reports demonstrates how virtual reality group experiences can produce responses similar to those triggered by psychoactive drugs, such as hallucinogenic mushrooms or LSD. Describing the sensations that arose immediately following a left-hemisphere stroke, brain scientist Jill Bolte Taylor recounted, \"I could no longer define the boundaries of my body. I can't define where I begin and where I end, because the atoms and molecules of my arm blend with the atoms and molecules of the wall, and all I could detect was this energy… I was immediately captivated by the magnificence of the energy around me. And because I could no longer identify the boundaries of my body, I felt enormous and expansive. I felt at one with all the energy that was, and it was beautiful.\" The neuroanatomist's account is one of many well-known examples of \"self-transcendent\" experiences: a term coined to describe transient mental states in which the subjective sense of oneself as an isolated entity can temporarily fade into an experience of oneness with other people or the environment, involving the dissolution of boundaries between the sense of \"self\" and \"others.\" \"Getting lost while reading a book, or during the writing of a computer code, are everyday examples of a relatively weak self-transcendent experience,\" says David Glowacki, an expert in virtual reality and researcher at CiTIUS (Singular Center for Research in Intelligent Technologies at the University of Santiago de Compostela, Spain). \"However, the profound sense of interdependence with the cosmos that arises from a mystical experience, or 'encounter with God,' represents a considerably more intense form of this type of experience,\" continues the scientist, who also leads the NanoVR project, in which new forms of nanoscale design will be developed through virtual reality. Video of the Isness-D technology. Credit: David Glowacki Recent research published in various fields of study (psychology, neuroscience, philosophy, pharmacology or theology) has drawn attention to the meaning and perception attributed to these experiences by people who have undergone them. Thus, there is now a growing scientific interest in investigating the therapeutic potential of this type of experiential phenomenology, which diminishes ego identity, increases the sense of connectedness and is associated with lasting therapeutic benefit in the treatment of depression, addiction and anxiety at the end of life. The aim is to unravel how such \"experiences of self-transcendence\" might be induced in laboratory contexts, in order to harness their potential mental health benefits. Glowacki, founder and head of the Intangible Realities Laboratory (IRL), says that the controlled use of psychedelic drugs (chemical compounds such as psilocybin, found in hallucinogenic mushrooms, or LSD) represents a particularly promising approach: \"For example, a study published in 2006 showed that 67% of participants who had these subjective experiences while taking psilocybin as part of a 'psychedelic psychotherapy' program considered the experience to be among the most meaningful of their lives.\" Nevertheless, these therapies face a number of taboos and practical challenges to their widespread administration: their intense phenomenology sometimes provoke fear or panic and associated physiological responses, the onset and duration of which are often beyond the therapist's control, making it difficult for the therapist to positively direct the patient's experience. In addition, many questions remain about how best to determine an appropriate target dose that reliably elicits therapeutic effects and minimizes risks. Distributed version of Isness (Isness-D), with four participants simultaneously joining a session from different nodes around the world. Credit: David Glowacki Given the complications associated with the administration of psychedelics, there is already alternative research exploring non-pharmacological technologies to safely and reliably elicit these states. \"Of these, virtual reality has emerged as a particularly interesting candidate, given its ability to create strong alterations in perceptual phenomenology,\" says David Glowacki. Together with his colleagues at the IRL, he has been working for years on a multi-person virtual reality experience, which they have called Isness. In this environment, groups of up to five participants experience together the collective emergence, fluctuation and dissipation of their own bodies: Isness creates an abstraction of the human body as a luminous and diffuse energetic essence, an aesthetic representation which is associated with \"spirit\" in various wisdom and meditation traditions. In their recent study published in Scientific Reports, the researchers went a step further in the design of these intersubjective group spaces, allowing participants located in different parts of the world to cohabit the same virtual space in order to have a remote experience of corporeal overlap. \"We continue to improve our technology to safely generate these experiences of self-transcendence from virtual reality and thus contribute to the development of therapeutic alternatives,\" says the group. Dissolving into energy and merging with others. An animated sample of the Isness-D technology. Credit: David Glowacki Specifically, Glowacki's lab has built a cloud-based, multi-person virtual reality experience called Isness-D (Isness-distributed), which blurs the conventional boundaries of personal space that humans usually keep between themselves. Isness-D participants have accessed this virtual space from a network of nodes in different countries around the world (U.S., Germany, U.K.), in which they are represented just as luminous energy essences, whose radiance is concentrated around their hearts. Glowacki says, \"The new technology [provides] moments of 'energetic coalescence,' a new kind of intersubjective experience in which bodies can fluidly merge, allowing participants to include other individuals in their self-representation.\" The bodily boundaries of Isness-D are fuzzy, blurred and soft: they extend beyond the limits of the physical body, making it difficult to clearly specify where one body ends, and another begins. To compare the therapeutic effects of this new technology with pharmacological treatments, Glowacki and his colleagues adopted a citizen science approach, coordinating an international network of Isness-D nodes. The team writes, \"We analyzed the results using four key scales applied in previous studies with psychedelics to assess the subjective phenomenology of Isness-D.... In fact, and to the best of our knowledge, this work represents the first attempt to analyze a virtual reality experience using these measurement scales. Despite the complexities associated with such a distributed experiment, Isness-D scores on all four scales were statistically indistinguishable from those of recently published psychedelic drug studies.\" The authors note that these results \"demonstrate that distributed virtual reality can be used to design intersubjective self-transcendent experiences in which people dissolve their sense of self in connection with others, and may therefore offer similar therapeutic benefits that these techniques can have in the treatment of various pathologies.\" Participants also expressed positive emotions, as well as an \"overwhelming sense of calm and relaxation\" at the end of their Isness-D experience. This was reflected in their responses in the subsequent questionnaire provided by the research team, with eloquent phrases confirming their level of enjoyment: \"I feel remarkably happy. There's something very happiness-inducing about this whole practice.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract With a growing body of research highlighting the therapeutic potential of experiential phenomenology which diminishes egoic identity and increases one’s sense of connectedness, there is significant interest in how to elicit such ‘self-transcendent experiences’ (STEs) in laboratory contexts. Psychedelic drugs (YDs) have proven particularly effective in this respect, producing subjective phenomenology which reliably elicits intense STEs. With virtual reality (VR) emerging as a powerful tool for constructing new perceptual environments, we describe a VR framework called ‘Isness-distributed’ (Isness-D) which harnesses the unique affordances of distributed multi-person VR to blur conventional self-other boundaries. Within Isness-D, groups of participants co-habit a shared virtual space, collectively experiencing their bodies as luminous energetic essences with diffuse spatial boundaries. It enables moments of ‘energetic coalescence’, a new class of embodied intersubjective experience where bodies can fluidly merge, enabling participants to include multiple others within their self-representation. To evaluate Isness-D, we adopted a citizen science approach, coordinating an international network of Isness-D 'nodes'. We analyzed the results (N = 58) using 4 different self-report scales previously applied to analyze subjective YD phenomenology (the inclusion of community in self scale, ego-dissolution inventory, communitas scale, and the MEQ30 mystical experience questionnaire). Despite the complexities associated with a distributed experiment like this, the Isness-D scores on all 4 scales were statistically indistinguishable from recently published YD studies, demonstrating that distributed VR can be used to design intersubjective STEs where people dissolve their sense of self in the connection to others. Introduction Describing the sensations that arose immediately following a left-hemisphere stroke, brain scientist Jill Bolte Taylor recounted: I could no longer define the boundaries of my body. I can’t define where I begin and where I end, because the atoms and molecules of my arm blend with the atoms and molecules of the wall, and all I could detect was this energy… I was immediately captivated by the magnificence of the energy around me. And because I could no longer identify the boundaries of my body, I felt enormous and expansive. I felt at one with all the energy that was, and it was beautiful 1 . Recounting the sensations that arose after seeing the Earth from space, astronaut Edgar Mitchell said: And suddenly I realized that the molecules of my body, the spacecraft, the body of my partners, were all manufactured in some ancient generation of stars. I felt an overwhelming sense of oneness, or connectedness… an insight, an epiphany 2 . During a particularly potent meditation session Zen master Sokei-an Sasaki described how: I lost the boundary of my physical body. I had my skin, of course, but I felt I was standing in the center of the cosmos… I saw people coming towards me, but all were… myself! 3 Recounting the sensations which arose from a high dose of the psychedelic drug (YD) psilocybin, a participant in a 2008 Griffiths et al. study recounted a feeling of no boundaries, where I didn’t know where I ended and where my surroundings began. Somehow I was able to comprehend what oneness is 4 . These accounts, which express a profound sense of unity with other beings and other objects, stand in contrast to our typical day-to-day perspective, in which we often default to conceptual representations of ourselves (and others) as separate objects rather than coupled interdependent subjects. Yaden et al. have coined the term ‘self-transcendent experiences’ (STEs) to describe transient mental states in which the subjective sense of one’s self as an isolated entity can temporarily fade into an experience of unity with other people or one’s surroundings, involving the dissolution of boundaries between the sense of self and ‘other’ 5 . Research across psychology, neuroscience, philosophy, pharmacology, and theology has drawn attention to the meaning and insight attributed to STEs by those who undergo them. Because they have been studied across so many different knowledge domains, they are described using different terminology, conceptual frameworks, and theoretical lenses, which makes it complicated to perform a comprehensive analysis of their subjective qualities, behavioral effects, and therapeutic potential. In an attempt to draw conceptual links across these various domains, Yaden et al. have identified a number of states as STEs, including for example Flow states 6 ; Mindfulness states 7 ; Awe 8 ; Peak Experiences 9 ; and Mystical-Type Experiences 10 . The phenomenology associated with different classes of STEs varies in saliency and visceral potency. As such, STEs have a broad range of intensities, some of which are more memorable, and thereby more significant for the person undergoing the experience. For example, “losing oneself” whilst reading a book or writing computer code may represent a relatively weak STE; whereas the deep sense of interdependence with the cosmos that arises from a spiritual ‘God-encounter’ experience represents a considerably more intense form of STE 11 . Analysis by Yaden et al. suggests that STEs involve at least two interrelated phenomenological ingredients: (1) an ‘annihilation’ of the sense of self, accomplished by dissolving self-boundaries and self-salience; and (2) a ‘relational’ sense of unity with something beyond the self (e.g., others or the natural world). The intensity of an STE is associated with the degree to which the participant experiences these interrelated phenomenological ingredients. While the precise sense of ‘self’ is difficult to define here, several different studies have nevertheless demonstrated the effectiveness of the so-called Inclusion of Other in the Self (IOS) Scale 12 for assessing the degree to which an individual feels a sense of connectedness to others or to their environment. As shown in Fig. 1 , this scale represents individuals and others as distinct circles. During weak unitive experiences, overlap between the circles is small; during particularly intense unitive experiences the overlap is more significant, representing an individual’s sense that ‘the other’ forms a significant part of the self. Figure 1 The Inclusion of Other in the Self Scale, which offers a continuum for expressing the sense of unitive feelings. Full size image William James suggested that particularly intense classes of STEs—namely ‘mystical type experiences’ (MTEs), where<|im_end|> <|im_start|>assistant A paper published in the journal Scientific Reports demonstrates how virtual reality group experiences can produce responses similar to those triggered by psychoactive drugs, such as hallucinogenic mushrooms or LSD. Describing the sensations that arose immediately following a left-hemisphere stroke, brain scientist Jill Bolte Taylor recounted, "I could no longer define the boundaries of my body. I can't define where I begin and where I end, because the atoms and molecules of my arm blend with the atoms and molecules of the wall, and all I could detect was this energy… I was immediately captivated by the magnificence of the energy around me. And because I could no longer identify the boundaries of my body, I felt enormous and expansive. I felt at one with all the energy that was, and it was beautiful." The neuroanatomist's account is one of many well-known examples of "self-transcendent" experiences: a term coined to describe transient mental states in which the subjective sense of oneself as an isolated entity can temporarily fade into an experience of oneness with other people or the environment, involving the dissolution of boundaries between the sense of "self" and "others." "Getting lost while reading a book, or during the writing of a computer code, are everyday examples of a relatively weak self-transcendent experience," says David Glowacki, an expert in virtual reality and researcher at CiTIUS (Singular Center for Research in Intelligent Technologies at the University of Santiago de Compostela, Spain). "However, the profound sense of interdependence with the cosmos that arises from a mystical experience, or 'encounter with God,' represents a considerably more intense form of this type of experience," continues the scientist, who also leads the NanoVR project, in which new forms of nanoscale design will be developed through virtual reality. Video of the Isness-D technology. Credit: David Glowacki Recent research published in various fields of study (psychology, neuroscience, philosophy, pharmacology or theology) has drawn attention to the meaning and perception attributed to these experiences by people who have undergone them. Thus, there is now a growing scientific interest in investigating the therapeutic potential of this type of experiential phenomenology, which diminishes ego identity, increases the sense of connectedness and is associated with lasting therapeutic benefit in the treatment of depression, addiction and anxiety at the end of life. The aim is to unravel how such "experiences of self-transcendence" might be induced in laboratory contexts, in order to harness their potential mental health benefits. Glowacki, founder and head of the Intangible Realities Laboratory (IRL), says that the controlled use of psychedelic drugs (chemical compounds such as psilocybin, found in hallucinogenic mushrooms, or LSD) represents a particularly promising approach: "For example, a study published in 2006 showed that 67% of participants who had these subjective experiences while taking psilocybin as part of a 'psychedelic psychotherapy' program considered the experience to be among the most meaningful of their lives." Nevertheless, these therapies face a number of taboos and practical challenges to their widespread administration: their intense phenomenology sometimes provoke fear or panic and associated physiological responses, the onset and duration of which are often beyond the therapist's control, making it difficult for the therapist to positively direct the patient's experience. In addition, many questions remain about how best to determine an appropriate target dose that reliably elicits therapeutic effects and minimizes risks. Distributed version of Isness (Isness-D), with four participants simultaneously joining a session from different nodes around the world. Credit: David Glowacki Given the complications associated with the administration of psychedelics, there is already alternative research exploring non-pharmacological technologies to safely and reliably elicit these states. "Of these, virtual reality has emerged as a particularly interesting candidate, given its ability to create strong alterations in perceptual phenomenology," says David Glowacki. Together with his colleagues at the IRL, he has been working for years on a multi-person virtual reality experience, which they have called Isness. In this environment, groups of up to five participants experience together the collective emergence, fluctuation and dissipation of their own bodies: Isness creates an abstraction of the human body as a luminous and diffuse energetic essence, an aesthetic representation which is associated with "spirit" in various wisdom and meditation traditions. In their recent study published in Scientific Reports, the researchers went a step further in the design of these intersubjective group spaces, allowing participants located in different parts of the world to cohabit the same virtual space in order to have a remote experience of corporeal overlap. "We continue to improve our technology to safely generate these experiences of self-transcendence from virtual reality and thus contribute to the development of therapeutic alternatives," says the group. Dissolving into energy and merging with others. An animated sample of the Isness-D technology. Credit: David Glowacki Specifically, Glowacki's lab has built a cloud-based, multi-person virtual reality experience called Isness-D (Isness-distributed), which blurs the conventional boundaries of personal space that humans usually keep between themselves. Isness-D participants have accessed this virtual space from a network of nodes in different countries around the world (U.S., Germany, U.K.), in which they are represented just as luminous energy essences, whose radiance is concentrated around their hearts. Glowacki says, "The new technology [provides] moments of 'energetic coalescence,' a new kind of intersubjective experience in which bodies can fluidly merge, allowing participants to include other individuals in their self-representation." The bodily boundaries of Isness-D are fuzzy, blurred and soft: they extend beyond the limits of the physical body, making it difficult to clearly specify where one body ends, and another begins. To compare the therapeutic effects of this new technology with pharmacological treatments, Glowacki and his colleagues adopted a citizen science approach, coordinating an international network of Isness-D nodes. The team writes, "We analyzed the results using four key scales applied in previous studies with psychedelics to assess the subjective phenomenology of Isness-D.... In fact, and to the best of our knowledge, this work represents the first attempt to analyze a virtual reality experience using these measurement scales. Despite the complexities associated with such a distributed experiment, Isness-D scores on all four scales were statistically indistinguishable from those of recently published psychedelic drug studies." The authors note that these results "demonstrate that distributed virtual reality can be used to design intersubjective self-transcendent experiences in which people dissolve their sense of self in connection with others, and may therefore offer similar therapeutic benefits that these techniques can have in the treatment of various pathologies." Participants also expressed positive emotions, as well as an "overwhelming sense of calm and relaxation" at the end of their Isness-D experience. This was reflected in their responses in the subsequent questionnaire provided by the research team, with eloquent phrases confirming their level of enjoyment: "I feel remarkably happy. There's something very happiness-inducing about this whole practice." <|im_end|>

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330, 59961, 1210, 330, 29755, 5675, 1418, 5403, 264, 2363, 11, 477, 2391, 279, 4477, 315, 264, 6500, 2082, 11, 527, 18254, 10507, 315, 264, 12309, 7621, 659, 39160, 66, 29293, 3217, 1359, 2795, 6941, 88448, 474, 72, 11, 459, 6335, 304, 4200, 8903, 323, 32185, 520, 32744, 27712, 2078, 320, 50, 42980, 5955, 369, 8483, 304, 78188, 25579, 520, 279, 3907, 315, 55678, 409, 1219, 2252, 8458, 11, 18157, 570, 330, 11458, 11, 279, 28254, 5647, 315, 958, 91746, 449, 279, 83645, 430, 48282, 505, 264, 69532, 3217, 11, 477, 364, 967, 41014, 449, 4359, 2965, 11105, 264, 33452, 810, 19428, 1376, 315, 420, 955, 315, 3217, 1359, 9731, 279, 28568, 11, 889, 1101, 11767, 279, 64051, 19330, 2447, 11, 304, 902, 502, 7739, 315, 20622, 437, 2296, 2955, 690, 387, 8040, 1555, 4200, 8903, 13, 8519, 315, 279, 2209, 2136, 9607, 5557, 13, 16666, 25, 6941, 88448, 474, 72, 35390, 3495, 4756, 304, 5370, 5151, 315, 4007, 320, 92109, 2508, 11, 93048, 11, 19675, 11, 36449, 2508, 477, 54641, 8, 706, 15107, 6666, 311, 279, 7438, 323, 21063, 30706, 311, 1521, 11704, 555, 1274, 889, 617, 64238, 1124, 13, 14636, 11, 1070, 374, 1457, 264, 7982, 12624, 2802, 304, 24834, 279, 37471, 4754, 315, 420, 955, 315, 2183, 1188, 532, 17151, 2508, 11, 902, 57160, 288, 37374, 9764, 11, 12992, 279, 5647, 315, 8599, 2136, 323, 374, 5938, 449, 29869, 37471, 8935, 304, 279, 6514, 315, 18710, 11, 27471, 323, 18547, 520, 279, 842, 315, 2324, 13, 578, 9395, 374, 311, 75073, 1268, 1778, 330, 327, 69597, 315, 659, 39160, 66, 408, 768, 1, 2643, 387, 36572, 304, 27692, 38697, 11, 304, 2015, 311, 33508, 872, 4754, 10723, 2890, 7720, 13, 88448, 474, 72, 11, 19533, 323, 2010, 315, 279, 1357, 61186, 8976, 1385, 32184, 320, 2871, 43, 705, 2795, 430, 279, 14400, 1005, 315, 82082, 11217, 320, 32056, 32246, 1778, 439, 4831, 27043, 88, 7006, 11, 1766, 304, 59123, 258, 29569, 48251, 11, 477, 72170, 8, 11105, 264, 8104, 26455, 5603, 25, 330, 2520, 3187, 11, 264, 4007, 4756, 304, 220, 1049, 21, 8710, 430, 220, 3080, 4, 315, 13324, 889, 1047, 1521, 44122, 11704, 1418, 4737, 4831, 27043, 88, 7006, 439, 961, 315, 264, 364, 46246, 2454, 43723, 42111, 46755, 6, 2068, 6646, 279, 3217, 311, 387, 4315, 279, 1455, 23222, 315, 872, 6439, 1210, 35053, 11, 1521, 52312, 3663, 264, 1396, 315, 5769, 78, 437, 323, 15325, 11774, 311, 872, 24716, 8735, 25, 872, 19428, 17151, 2508, 7170, 73093, 8850, 477, 22743, 323, 5938, 53194, 14847, 11, 279, 42080, 323, 8250, 315, 902, 527, 3629, 7953, 279, 42863, 596, 2585, 11, 3339, 433, 5107, 369, 279, 42863, 311, 40646, 2167, 279, 8893, 596, 3217, 13, 763, 5369, 11, 1690, 4860, 7293, 922, 1268, 1888, 311, 8417, 459, 8475, 2218, 19660, 430, 57482, 658, 51650, 37471, 6372, 323, 21877, 4861, 15635, 13, 45055, 2373, 315, 2209, 2136, 320, 3957, 2136, 9607, 705, 449, 3116, 13324, 25291, 18667, 264, 3882, 505, 2204, 7954, 2212, 279, 1917, 13, 16666, 25, 6941, 88448, 474, 72, 16644, 279, 36505, 5938, 449, 279, 8735, 315, 61833, 301, 1233, 11, 1070, 374, 2736, 10778, 3495, 24919, 2536, 63837, 72482, 5848, 14645, 311, 21676, 323, 57482, 658, 19195, 1521, 5415, 13, 330, 2173, 1521, 11, 4200, 8903, 706, 22763, 439, 264, 8104, 7185, 9322, 11, 2728, 1202, 5845, 311, 1893, 3831, 61086, 304, 78632, 940, 17151, 2508, 1359, 2795, 6941, 88448, 474, 72, 13, 32255, 449, 813, 18105, 520, 279, 358, 4833, 11, 568, 706, 1027, 3318, 369, 1667, 389, 264, 7447, 29145, 4200, 8903, 3217, 11, 902, 814, 617, 2663, 2209, 2136, 13, 763, 420, 4676, 11, 5315, 315, 709, 311, 4330, 13324, 3217, 3871, 279, 22498, 49179, 11, 39388, 4090, 323, 14091, 49686, 315, 872, 1866, 13162, 25, 2209, 2136, 11705, 459, 59851, 315, 279, 3823, 2547, 439, 264, 46058, 788, 323, 55517, 45955, 28591, 11, 459, 37637, 13340, 902, 374, 5938, 449, 330, 86390, 1, 304, 5370, 24278, 323, 33862, 32006, 13, 763, 872, 3293, 4007, 4756, 304, 38130, 29140, 11, 279, 12074, 4024, 264, 3094, 4726, 304, 279, 2955, 315, 1521, 82019, 392, 51591, 1912, 12908, 11, 10923, 13324, 7559, 304, 2204, 5596, 315, 279, 1917, 311, 1080, 97802, 279, 1890, 4200, 3634, 304, 2015, 311, 617, 264, 8870, 3217, 315, 37566, 90868, 28347, 13, 330, 1687, 3136, 311, 7417, 1057, 5557, 311, 21676, 7068, 1521, 11704, 315, 659, 39160, 66, 408, 768, 505, 4200, 8903, 323, 8617, 17210, 311, 279, 4500, 315, 37471, 27548, 1359, 2795, 279, 1912, 13, 52132, 20222, 1139, 4907, 323, 54477, 449, 3885, 13, 1556, 11625, 6205, 315, 279, 2209, 2136, 9607, 5557, 13, 16666, 25, 6941, 88448, 474, 72, 45863, 11, 88448, 474, 72, 596, 10278, 706, 5918, 264, 9624, 6108, 11, 7447, 29145, 4200, 8903, 3217, 2663, 2209, 2136, 9607, 320, 3957, 2136, 1773, 26204, 705, 902, 1529, 1759, 279, 21349, 23546, 315, 4443, 3634, 430, 12966, 6118, 2567, 1990, 5694, 13, 2209, 2136, 9607, 13324, 617, 25790, 420, 4200, 3634, 505, 264, 4009, 315, 7954, 304, 2204, 5961, 2212, 279, 1917, 320, 52, 815, 2637, 10057, 11, 549, 11606, 25390, 304, 902, 814, 527, 15609, 1120, 439, 46058, 788, 4907, 4043, 2436, 11, 6832, 12164, 685, 374, 38626, 2212, 872, 23492, 13, 88448, 474, 72, 2795, 11, 330, 791, 502, 5557, 510, 782, 68254, 60, 14269, 315, 364, 804, 36324, 1080, 3916, 36634, 2965, 264, 502, 3169, 315, 82019, 392, 51591, 3217, 304, 902, 13162, 649, 15962, 398, 11117, 11, 10923, 13324, 311, 2997, 1023, 7931, 304, 872, 659, 5621, 45025, 1210, 578, 48131, 23546, 315, 2209, 2136, 9607, 527, 53833, 11, 73500, 323, 8579, 25, 814, 13334, 7953, 279, 13693, 315, 279, 7106, 2547, 11, 3339, 433, 5107, 311, 9539, 14158, 1405, 832, 2547, 10548, 11, 323, 2500, 12302, 13, 2057, 9616, 279, 37471, 6372, 315, 420, 502, 5557, 449, 36449, 5848, 22972, 11, 88448, 474, 72, 323, 813, 18105, 18306, 264, 22618, 8198, 5603, 11, 66515, 459, 6625, 4009, 315, 2209, 2136, 9607, 7954, 13, 578, 2128, 14238, 11, 330, 1687, 30239, 279, 3135, 1701, 3116, 1401, 29505, 9435, 304, 3766, 7978, 449, 61833, 301, 1233, 311, 8720, 279, 44122, 17151, 2508, 315, 2209, 2136, 9607, 1975, 763, 2144, 11, 323, 311, 279, 1888, 315, 1057, 6677, 11, 420, 990, 11105, 279, 1176, 4879, 311, 24564, 264, 4200, 8903, 3217, 1701, 1521, 19179, 29505, 13, 18185, 279, 84140, 5938, 449, 1778, 264, 4332, 9526, 11, 2209, 2136, 9607, 12483, 389, 682, 3116, 29505, 1051, 47952, 1280, 89747, 481, 505, 1884, 315, 6051, 4756, 82082, 5623, 7978, 1210, 578, 12283, 5296, 430, 1521, 3135, 330, 67, 7439, 71015, 430, 4332, 4200, 8903, 649, 387, 1511, 311, 2955, 82019, 392, 51591, 659, 39160, 66, 29293, 11704, 304, 902, 1274, 73739, 872, 5647, 315, 659, 304, 3717, 449, 3885, 11, 323, 1253, 9093, 3085, 4528, 37471, 7720, 430, 1521, 12823, 649, 617, 304, 279, 6514, 315, 5370, 1853, 9268, 1210, 52878, 1101, 13605, 6928, 21958, 11, 439, 1664, 439, 459, 330, 2017, 94179, 5647, 315, 19858, 323, 43685, 1, 520, 279, 842, 315, 872, 2209, 2136, 9607, 3217, 13, 1115, 574, 27000, 304, 872, 14847, 304, 279, 17876, 48964, 3984, 555, 279, 3495, 2128, 11, 449, 64235, 17187, 32847, 50096, 872, 2237, 315, 45278, 25, 330, 40, 2733, 49723, 6380, 13, 2684, 596, 2555, 1633, 23871, 18251, 59144, 922, 420, 4459, 6725, 1210, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Identifying biological mechanisms through which the experience of adversity emerges as individual risk for mental illness is an important step toward developing strategies for personalized treatment and, ultimately, prevention. Preclinical studies have identified epigenetic modification of gene expression as one such mechanism. Recent clinical studies have suggested that epigenetic modification, particularly methylation of gene regulatory regions, also acts to shape human brain function associated with risk for mental illness. However, it is not yet clear whether differential gene methylation as a function of adversity contributes to the emergence of individual risk for mental illness. Using prospective longitudinal epigenetic, neuroimaging and behavioral data from 132 adolescents, we demonstrate that changes in gene methylation associated with lower socioeconomic status (SES) predict changes in risk-related brain function. Specifically, we find that lower SES during adolescence is associated with an increase in methylation of the proximal promoter of the serotonin transporter gene, which predicts greater increases in threat-related amygdala reactivity. We subsequently demonstrate that greater increases in amygdala reactivity moderate the association between a positive family history for depression and the later manifestation of depressive symptoms. These initial results suggest a specific biological mechanism through which adversity contributes to altered brain function, which in turn moderates the emergence of general liability as individual risk for mental illness. If replicated, this prospective pathway may represent a novel target biomarker for intervention and prevention among high-risk individuals. Introduction Although specific stressors including exposure to traumatic events or the experience of childhood maltreatment and neglect have been associated with increased risk for mental illness, 1 non-specific, relatively common risk factors, such as low socioeconomic status (SES), account for a large proportion of psychiatric morbidity in the population. 2 Low SES may confer risk through a variety of mechanisms, including higher levels of perceived and objective stress and cumulative environmental risk such as poor housing quality, noise pollution and exposure to violence. 3 Lower SES has been associated with a host of negative outcomes including poorer general health and increased risk for mental illness including depression, anxiety and addiction. 2 , 4 , 5 Given the insidious nature of low SES, it is at best difficult to directly mitigate these associated risks. An alternative strategy is to identify specific biological processes mediating the association between lower SES and individual risk thereby creating possible targets through which risk may be buffered. One candidate biological process through which the environment may be exerting its influence is epigenetics, which encompasses molecular mechanisms mediating the effects of extrinsic factors on intrinsic functions through the modulation of gene expression. 6 In particular, experience-dependent methylation of gene regulatory regions such as proximal promoter sites has been proposed as one epigenetic mechanism through which stress may drive risk for future mental illness. 6 Generally, relatively increased DNA methylation of gene promoters, which is most often associated with decreased gene expression, has been associated with exposure to both specific 7 and non-specific stressors including lower SES. 8 These epigenetic changes in gene expression subsequently impact risk-related brain function and behavior. 9 Recent clinical studies have specifically implicated DNA methylation of the proximal promoter region of the serotonin transporter gene ( SLC6A4 ) as a potential epigenetic mechanism of increased risk for mental illness. For example, the experience of specific (that is, child abuse) 10 and non-specific (that is, lower SES) 11 stressors is associated with increased methylation of multiple CpG sites within SLC6A4, including the proximal promoter, and these patterns of methylation have been associated with higher depressive symptoms. 12 Moreover, we have demonstrated that relatively increased SLC6A4 proximal promoter methylation is associated with increased threat-related amygdala reactivity, which not only has a central role in stress responsiveness but also is implicated in the etiology and pathophysiology of stress-related disorders including depression. 13 , 14 Collectively, these epigenetic findings are consistent with the important modulatory role of the serotonin transporter on stress physiology, amygdala function and mood. 15 Despite these findings, cross-sectional data collected at one point in time do not allow for examination of dynamic changes in DNA methylation. Thus, it is unclear whether the experience of stress is associated with a change in SLC6A4 methylation and, if so, how this manifests as a change in risk-related brain function. Here, we use longitudinal epigenetic, neuroimaging and behavioral data to construct a prospective indirect effects model examining whether lower SES predicts increased future risk for depression via increased SLC6A4 proximal promoter methylation and resulting sensitization of threat-related amygdala reactivity. We test this model in adolescents at high and low risk for depression due to presence or absence of a family history of depression, respectively. In prior analyses of this cohort, we have found that either a positive family history of depression or exposure to stressful life events predicts greater increases in the reactivity of the left amygdala to fearful facial expressions from Wave 1 to Wave 2. 16 Thus, we first examined whether adversity-related changes in SLC6A4 proximal promoter methylation may, in part, explain this sensitization of amygdala reactivity. We modeled the effect of three types of stressors previously associated with risk for depression, including childhood maltreatment, stressful life events, and low SES, on changes in methylation. We hypothesized that exposure to these stressors would be associated with an increase in SLC6A4 proximal promoter methylation from Wave 1 to Wave 2, and that this increase would be associated with sensitized amygdala reactivity to threat over the same time period. Although a positive family history is one of the strongest predictors of the future development of depression, not all individuals with this risk factor will become depressed. 17 , 18 Thus, we next examined the extent to which greater increases in threat-related amygdala reactivity associated with differential SLC6A4 methylation predicted individual risk for depression in adolescents and whether this risk was specific for youth with a positive family history of depression. Prior studies have found that threat-related amygdala reactivity predicts greater psychological vulnerability to future trauma, 19 , 20 and we recently demonstrated in a large", "role": "user" }, { "content": "A long line of research links poverty and depression. Now, a study by Duke University scientists shows how biology might underlie the depression experienced by high-risk adolescents whose families are socio-economically disadvantaged. The study, published May 24, 2016 in the journal Molecular Psychiatry, combined genetics, brain imaging and behavioral data gathered as adolescents were followed for more than three years as part of a larger study. The results are part of a growing body of work that may lead to biological predictors that could guide individualized depression-prevention strategies. Adolescents growing up in households with lower socioeconomic status were shown to accumulate greater quantities of a chemical tag on a depression-linked gene over the course of two years. These \"epigenetic\" tags work by altering the activity of genes. The more chemical tags an individual had near a gene called SLC6A4, the more responsive was their amygdala—a brain area that coordinates the body's reactions to threat—to photographs of fearful faces as they underwent functional MRI brain scans. Participants with a more active amygdala were more likely to later report symptoms of depression. \"This is some of the first research to demonstrating that low socioeconomic status can lead to changes in the way genes are expressed, and it maps this out through brain development to the future experience of depression symptoms,\" said the study's first author Johnna Swartz, a Duke postdoctoral researcher in the lab of Ahmad Hariri, a Duke professor of psychology and neuroscience. Adolescence is rarely an easy time for anyone. But growing up in a family with low socioeconomic status or SES—a metric that incorporates parents' income and education levels—can add chronic stressors such as family discord and chaos, and environmental risks such as poor nutrition and smoking. \"These small daily hassles of scraping by are evident in changes that build up and affect children's development,\" Swartz said. The study included 132 non-Hispanic Caucasian adolescents in the Teen Alcohol Outcomes Study (TAOS) who were between 11 and 15 years old at the outset of the study and came from households that ranged from low to high SES. About half of the participants had a family history of depression. \"The biggest risk factor we have currently for depression is a family history of the disorder,\" said study co-author Douglas Williamson, principal investigator of TAOS and professor of psychiatry and behavioral sciences at Duke. \"Our new work reveals one of the mechanisms by which such familial risk may be manifested or expressed in a particular group of vulnerable individuals during adolescence.\" The group's previous work, published last year in the journal Neuron, had shown that fMRI scan activity of the amygdala could signal who is more likely to experience depression and anxiety in response to stress several years later. That study included healthy college-aged participants of Hariri's ongoing Duke Neurogenetics Study (DNS), which aims to link genes, brain activity, and other biological markers to a risk for mental illness. This study asked whether higher activity in the same brain area could predict depression in the younger, at-risk TAOS participants. Indeed, about one year later, these individuals (now between 14 and 19 years of age) were more likely to report symptoms of depression, especially if they had a family history of the disorder. Swartz said the new study examined a range of socioeconomic status and did not focus specifically on families affected by extreme poverty or neglect. She said the findings suggest that even modestly lower socioeconomic status is associated with biological differences that elevate adolescents' risk for depression. Most of the team's work so far has focused on epigenetic chemical tags near the SLC6A4 gene because it helps control the brain's levels of serotonin, a neurochemical involved in clinical depression and other mood disorders. The more marks present just upstream of this gene, the less likely it is to be active. In 2014, Williamson and Hariri first showed that the presence of marks near the SLC6A4 gene can predict the way a person's amygdala responds to threat. That study included both Williamson's TAOS and Hariri's DNS participants, but had looked at the chemical tags at a single point in time. Looking at the changes in these markers over an extended time is a more powerful way to understand an individual's risk for depression, said Hariri, who is also a member of the Duke Institute for Brain Sciences. The team is now searching the genome for new markers that would predict depression. Ultimately, a panel of markers used in combination will lead to more accurate predictions, Swartz said. They also hope to expand the age ranges of the study to include younger individuals and to continue following the TAOS participants into young adulthood. \"As they enter into young adulthood they are going to be experiencing more problems with depression or anxiety—or maybe substance abuse,\" Hariri said. \"The extent to which our measures of their genomes and brains earlier in their lives continue to predict their relative health is something that's very important to know and very exciting for us to study.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Identifying biological mechanisms through which the experience of adversity emerges as individual risk for mental illness is an important step toward developing strategies for personalized treatment and, ultimately, prevention. Preclinical studies have identified epigenetic modification of gene expression as one such mechanism. Recent clinical studies have suggested that epigenetic modification, particularly methylation of gene regulatory regions, also acts to shape human brain function associated with risk for mental illness. However, it is not yet clear whether differential gene methylation as a function of adversity contributes to the emergence of individual risk for mental illness. Using prospective longitudinal epigenetic, neuroimaging and behavioral data from 132 adolescents, we demonstrate that changes in gene methylation associated with lower socioeconomic status (SES) predict changes in risk-related brain function. Specifically, we find that lower SES during adolescence is associated with an increase in methylation of the proximal promoter of the serotonin transporter gene, which predicts greater increases in threat-related amygdala reactivity. We subsequently demonstrate that greater increases in amygdala reactivity moderate the association between a positive family history for depression and the later manifestation of depressive symptoms. These initial results suggest a specific biological mechanism through which adversity contributes to altered brain function, which in turn moderates the emergence of general liability as individual risk for mental illness. If replicated, this prospective pathway may represent a novel target biomarker for intervention and prevention among high-risk individuals. Introduction Although specific stressors including exposure to traumatic events or the experience of childhood maltreatment and neglect have been associated with increased risk for mental illness, 1 non-specific, relatively common risk factors, such as low socioeconomic status (SES), account for a large proportion of psychiatric morbidity in the population. 2 Low SES may confer risk through a variety of mechanisms, including higher levels of perceived and objective stress and cumulative environmental risk such as poor housing quality, noise pollution and exposure to violence. 3 Lower SES has been associated with a host of negative outcomes including poorer general health and increased risk for mental illness including depression, anxiety and addiction. 2 , 4 , 5 Given the insidious nature of low SES, it is at best difficult to directly mitigate these associated risks. An alternative strategy is to identify specific biological processes mediating the association between lower SES and individual risk thereby creating possible targets through which risk may be buffered. One candidate biological process through which the environment may be exerting its influence is epigenetics, which encompasses molecular mechanisms mediating the effects of extrinsic factors on intrinsic functions through the modulation of gene expression. 6 In particular, experience-dependent methylation of gene regulatory regions such as proximal promoter sites has been proposed as one epigenetic mechanism through which stress may drive risk for future mental illness. 6 Generally, relatively increased DNA methylation of gene promoters, which is most often associated with decreased gene expression, has been associated with exposure to both specific 7 and non-specific stressors including lower SES. 8 These epigenetic changes in gene expression subsequently impact risk-related brain function and behavior. 9 Recent clinical studies have specifically implicated DNA methylation of the proximal promoter region of the serotonin transporter gene ( SLC6A4 ) as a potential epigenetic mechanism of increased risk for mental illness. For example, the experience of specific (that is, child abuse) 10 and non-specific (that is, lower SES) 11 stressors is associated with increased methylation of multiple CpG sites within SLC6A4, including the proximal promoter, and these patterns of methylation have been associated with higher depressive symptoms. 12 Moreover, we have demonstrated that relatively increased SLC6A4 proximal promoter methylation is associated with increased threat-related amygdala reactivity, which not only has a central role in stress responsiveness but also is implicated in the etiology and pathophysiology of stress-related disorders including depression. 13 , 14 Collectively, these epigenetic findings are consistent with the important modulatory role of the serotonin transporter on stress physiology, amygdala function and mood. 15 Despite these findings, cross-sectional data collected at one point in time do not allow for examination of dynamic changes in DNA methylation. Thus, it is unclear whether the experience of stress is associated with a change in SLC6A4 methylation and, if so, how this manifests as a change in risk-related brain function. Here, we use longitudinal epigenetic, neuroimaging and behavioral data to construct a prospective indirect effects model examining whether lower SES predicts increased future risk for depression via increased SLC6A4 proximal promoter methylation and resulting sensitization of threat-related amygdala reactivity. We test this model in adolescents at high and low risk for depression due to presence or absence of a family history of depression, respectively. In prior analyses of this cohort, we have found that either a positive family history of depression or exposure to stressful life events predicts greater increases in the reactivity of the left amygdala to fearful facial expressions from Wave 1 to Wave 2. 16 Thus, we first examined whether adversity-related changes in SLC6A4 proximal promoter methylation may, in part, explain this sensitization of amygdala reactivity. We modeled the effect of three types of stressors previously associated with risk for depression, including childhood maltreatment, stressful life events, and low SES, on changes in methylation. We hypothesized that exposure to these stressors would be associated with an increase in SLC6A4 proximal promoter methylation from Wave 1 to Wave 2, and that this increase would be associated with sensitized amygdala reactivity to threat over the same time period. Although a positive family history is one of the strongest predictors of the future development of depression, not all individuals with this risk factor will become depressed. 17 , 18 Thus, we next examined the extent to which greater increases in threat-related amygdala reactivity associated with differential SLC6A4 methylation predicted individual risk for depression in adolescents and whether this risk was specific for youth with a positive family history of depression. Prior studies have found that threat-related amygdala reactivity predicts greater psychological vulnerability to future trauma, 19 , 20 and we recently demonstrated in a large<|im_end|> <|im_start|>assistant A long line of research links poverty and depression. Now, a study by Duke University scientists shows how biology might underlie the depression experienced by high-risk adolescents whose families are socio-economically disadvantaged. The study, published May 24, 2016 in the journal Molecular Psychiatry, combined genetics, brain imaging and behavioral data gathered as adolescents were followed for more than three years as part of a larger study. The results are part of a growing body of work that may lead to biological predictors that could guide individualized depression-prevention strategies. Adolescents growing up in households with lower socioeconomic status were shown to accumulate greater quantities of a chemical tag on a depression-linked gene over the course of two years. These "epigenetic" tags work by altering the activity of genes. The more chemical tags an individual had near a gene called SLC6A4, the more responsive was their amygdala—a brain area that coordinates the body's reactions to threat—to photographs of fearful faces as they underwent functional MRI brain scans. Participants with a more active amygdala were more likely to later report symptoms of depression. "This is some of the first research to demonstrating that low socioeconomic status can lead to changes in the way genes are expressed, and it maps this out through brain development to the future experience of depression symptoms," said the study's first author Johnna Swartz, a Duke postdoctoral researcher in the lab of Ahmad Hariri, a Duke professor of psychology and neuroscience. Adolescence is rarely an easy time for anyone. But growing up in a family with low socioeconomic status or SES—a metric that incorporates parents' income and education levels—can add chronic stressors such as family discord and chaos, and environmental risks such as poor nutrition and smoking. "These small daily hassles of scraping by are evident in changes that build up and affect children's development," Swartz said. The study included 132 non-Hispanic Caucasian adolescents in the Teen Alcohol Outcomes Study (TAOS) who were between 11 and 15 years old at the outset of the study and came from households that ranged from low to high SES. About half of the participants had a family history of depression. "The biggest risk factor we have currently for depression is a family history of the disorder," said study co-author Douglas Williamson, principal investigator of TAOS and professor of psychiatry and behavioral sciences at Duke. "Our new work reveals one of the mechanisms by which such familial risk may be manifested or expressed in a particular group of vulnerable individuals during adolescence." The group's previous work, published last year in the journal Neuron, had shown that fMRI scan activity of the amygdala could signal who is more likely to experience depression and anxiety in response to stress several years later. That study included healthy college-aged participants of Hariri's ongoing Duke Neurogenetics Study (DNS), which aims to link genes, brain activity, and other biological markers to a risk for mental illness. This study asked whether higher activity in the same brain area could predict depression in the younger, at-risk TAOS participants. Indeed, about one year later, these individuals (now between 14 and 19 years of age) were more likely to report symptoms of depression, especially if they had a family history of the disorder. Swartz said the new study examined a range of socioeconomic status and did not focus specifically on families affected by extreme poverty or neglect. She said the findings suggest that even modestly lower socioeconomic status is associated with biological differences that elevate adolescents' risk for depression. Most of the team's work so far has focused on epigenetic chemical tags near the SLC6A4 gene because it helps control the brain's levels of serotonin, a neurochemical involved in clinical depression and other mood disorders. The more marks present just upstream of this gene, the less likely it is to be active. In 2014, Williamson and Hariri first showed that the presence of marks near the SLC6A4 gene can predict the way a person's amygdala responds to threat. That study included both Williamson's TAOS and Hariri's DNS participants, but had looked at the chemical tags at a single point in time. Looking at the changes in these markers over an extended time is a more powerful way to understand an individual's risk for depression, said Hariri, who is also a member of the Duke Institute for Brain Sciences. The team is now searching the genome for new markers that would predict depression. Ultimately, a panel of markers used in combination will lead to more accurate predictions, Swartz said. They also hope to expand the age ranges of the study to include younger individuals and to continue following the TAOS participants into young adulthood. "As they enter into young adulthood they are going to be experiencing more problems with depression or anxiety—or maybe substance abuse," Hariri said. "The extent to which our measures of their genomes and brains earlier in their lives continue to predict their relative health is something that's very important to know and very exciting for us to study." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We propose a new approach in device architecture to realize bias-selectable three-color shortwave-midwave-longwave infrared photodetectors based on InAs/GaSb/AlSb type-II superlattices. The effect of conduction band off-set and different doping levels between two absorption layers are employed to control the turn-on voltage for individual channels. The optimization of these parameters leads to a successful separation of operation regimes; we demonstrate experimentally three-color photodiodes without using additional terminal contacts. As the applied bias voltage varies, the photodiodes exhibit sequentially the behavior of three different colors, corresponding to the bandgap of three absorbers. Well defined cut-offs and high quantum efficiency in each channel are achieved. Such all-in-one devices also provide the versatility of working as single or dual-band photodetectors at high operating temperature. With this design, by retaining the simplicity in device fabrication, this demonstration opens the prospect for three-color infrared imaging. Introduction Multispectral detection or simultaneous collection of signal from different infrared bands provides enhanced target discrimination and identification. The shortwave infrared (SWIR) wave band enables detecting reflected light which produces more intuitive and visible-like images. Meanwhile, longer wavelength regimes provide thermographic images. The mid-wave infrared (MWIR) detection is capable of detecting hot plumes while long-wave infrared (LWIR) as the peak of the radiation spectrum for room temperature objects can detect cooler bodies. Providing this new dimension of contrast, when coupling with powerful signal processing algorithms, multispectral detectors offer important advantages over single band detectors under a wide range of applications 1 , 2 . Third generation infrared imagers have considered multispectral detection as one of the key requirements 3 . While two-color detection (SW-MW, MW-LW, LW-LW) becomes increasingly popular 4 , there are several attempts in incorporating one more band to make three-color photodetectors 5 , 6 . Recent trends in multispectral focal plane array (FPA) development has leaned toward integrating multicolor functionality into single pixels 4 . This approach removes the external parts such as beam splitters, filters, thus significantly reduces the size, weight and power requirements. However, integrated pixel collocating multiband photodetectors face different kinds of challenges. The first major obstacle is the choice of material systems that have the ability to perform over a broad range of infrared spectrum. Due to the limit of available substrates, semiconductor materials are often limited to a particular detection window near the semiconductors’ bandgap. There are currently only a few material systems that are suitable for multispectral detection. The current state-of-the-art HgCdTe and quantum well infrared photodetectors (QWIPs) are commercially available for infrared dual-band detection 4 . However, HgCdTe technology is reported to suffer from high cost and low producibility yield while QWIPs have drawbacks of low quantum efficiency and lower operating temperature 4 . In that context, the 6.1 Angstroms family based Type-II InAs/GaSb/AlSb superlattices 7 have proved to be an excellent alternative. Controlling the electronic structure by the layer thicknesses that are grown on GaSb substrate, Type-II superlattice (T2SL) offers the capability of tuning from SWIR 8 to VLWIR 9 , covers the whole infrared spectrum. In recent years, T2SL material has not only matured in the improvement of single color detector performance but also witnessed a new phase of development for multi-band detection 10 and imaging 11 . Two-color SWIR-MWIR 12 , MWIR-MWIR 13 , MWIR-LWIR 14 and LWIR-LWIR 15 focal plane arrays have been demonstrated with high performance. The second major challenge resides in integrating a stack of absorbers into a single pixel. The incorporation of new channel usually needs additional terminal contacts, which will lead to more complicated fabrication process and thus, low yield. On the other hand, by defining additional metal contact, a portion of material must be etched away; the optical fill factor of stacked absorption channels in the pixels is therefore severely reduced 3 . This is particularly critical for applications which need high resolutions, namely detectors with smaller pitches. In order to mitigate these issues, two-terminal photodetectors with only a top and a common ground contact are more favorable. Besides providing a near unity optical fill factor, a single contact pixel has the advantage of simplicity on sharing the same fabrication process as single color or bias-selectable two-color arrays. In this matter, read out integrated circuits (ROICs) with one Indium bump could also be used for later Focal Plane Array (FPA) application. In this article, we present our novel device design using only two terminals and report the experimental demonstration for the high performance triple-band T2SL-based SWIR/MWIR/LWIR photodetector based on this architecture. The core idea is to demonstrate devices that can perform sequentially as three individual single color photodetectors according to the magnitude variation of applied bias. Results and Discussion The schematic diagram of top-side illumination device structure is shown in Fig. 1 . Each layer absorbs radiation up to its cut-off and passes through longer wavelengths, which are then collected in subsequent layers. The SWIR channel is grown on the MWIR channel which is on top of the LWIR absorption layer. Using empirical tight binding model (ETBM) 16 , the design for SWIR absorber is 7.5/1/5/1 monolayers (MLs) of InAs/GaSb/AlSb/GaSb, aiming for 50% cut-off wavelength of 2.0 μm at 77 K. MWIR channel is designed with 7.5/10 MLs of InAs/GaSb with 50% cut-off wavelength of 4.5 μm and the LWIR absorber is made of 11/7 MLs of InAs/GaSb, aiming for 9 μm cut-off at 77 K. Figure 1 Schematic diagram of a triple-band SWIR-MWIR-LWIR photodiode structure with two terminal contacts and schematic band alignment of superlattices in three absorption layers. The colored rectangles in the insets represent the forbidden gap of component materials. Dotted lines represent the effective band gaps of superlattices. Full size image With only two contacts, the extraction of each color photocurrent therefore must be determined not only by the polarity of the applied bias but also by its magnitude. The design philosophy behind this device structure is to be able to control the distribution of electric potential along the device as function of applied bias, hence divide the applied bias into three separate intervals which will turn", "role": "user" }, { "content": "While infrared waves are available in short, mid, and long lengths, most detection devices are unable to harness all three at the same time. Now Northwestern University's Manijeh Razeghi and her team have developed a new approach in device design to realize a three-color, shortwave-midwave-longwave infrared photodetector. With the new design, the devices can detect different infrared wavebands by simply varying the applied bias voltage. This could open up a range of potential applications, including infrared color televisions and three-color infrared imaging. \"A device capable of detecting different infrared wavebands is highly desirable in the next generation infrared imaging systems,\" said Razeghi, Walter P. Murphy Professor of Electrical Engineering and Computer Science in Northwestern's McCormick School of Engineering. Supported by DARPA, the Army Research Laboratory, Air Force Research Laboratory, and NASA, the team's finding were published on April 7 in Nature's Scientific Reports. Led by Razeghi, the researchers invented and investigated the new design for three-color photodiodes without using additional terminal contacts. The resulting photodetector is based on indium-arsenide/gallium-antimonide/aluminum-antimonide type-II superlattices. As the applied bias voltage varies, the photodetector sequentially exhibits the behavior of three different colors, corresponding to the bandgap of three absorbers, and achieves well-defined cut-off wavelengths and high-quantum efficiency in each channel. This new research builds on the Razeghi group's many years of work in Northwestern's Center for Quantum Devices, including the development of the first single-color, short-wavelength infrared photodetector and two-color, shortwave-midwave infrared photodetector based on type-II superlattices. \"I am fascinated by these results,\" Razeghi said. \"The initial success in this demonstration will drive us to the new frontier of infrared detection and imaging technology.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract We propose a new approach in device architecture to realize bias-selectable three-color shortwave-midwave-longwave infrared photodetectors based on InAs/GaSb/AlSb type-II superlattices. The effect of conduction band off-set and different doping levels between two absorption layers are employed to control the turn-on voltage for individual channels. The optimization of these parameters leads to a successful separation of operation regimes; we demonstrate experimentally three-color photodiodes without using additional terminal contacts. As the applied bias voltage varies, the photodiodes exhibit sequentially the behavior of three different colors, corresponding to the bandgap of three absorbers. Well defined cut-offs and high quantum efficiency in each channel are achieved. Such all-in-one devices also provide the versatility of working as single or dual-band photodetectors at high operating temperature. With this design, by retaining the simplicity in device fabrication, this demonstration opens the prospect for three-color infrared imaging. Introduction Multispectral detection or simultaneous collection of signal from different infrared bands provides enhanced target discrimination and identification. The shortwave infrared (SWIR) wave band enables detecting reflected light which produces more intuitive and visible-like images. Meanwhile, longer wavelength regimes provide thermographic images. The mid-wave infrared (MWIR) detection is capable of detecting hot plumes while long-wave infrared (LWIR) as the peak of the radiation spectrum for room temperature objects can detect cooler bodies. Providing this new dimension of contrast, when coupling with powerful signal processing algorithms, multispectral detectors offer important advantages over single band detectors under a wide range of applications 1 , 2 . Third generation infrared imagers have considered multispectral detection as one of the key requirements 3 . While two-color detection (SW-MW, MW-LW, LW-LW) becomes increasingly popular 4 , there are several attempts in incorporating one more band to make three-color photodetectors 5 , 6 . Recent trends in multispectral focal plane array (FPA) development has leaned toward integrating multicolor functionality into single pixels 4 . This approach removes the external parts such as beam splitters, filters, thus significantly reduces the size, weight and power requirements. However, integrated pixel collocating multiband photodetectors face different kinds of challenges. The first major obstacle is the choice of material systems that have the ability to perform over a broad range of infrared spectrum. Due to the limit of available substrates, semiconductor materials are often limited to a particular detection window near the semiconductors’ bandgap. There are currently only a few material systems that are suitable for multispectral detection. The current state-of-the-art HgCdTe and quantum well infrared photodetectors (QWIPs) are commercially available for infrared dual-band detection 4 . However, HgCdTe technology is reported to suffer from high cost and low producibility yield while QWIPs have drawbacks of low quantum efficiency and lower operating temperature 4 . In that context, the 6.1 Angstroms family based Type-II InAs/GaSb/AlSb superlattices 7 have proved to be an excellent alternative. Controlling the electronic structure by the layer thicknesses that are grown on GaSb substrate, Type-II superlattice (T2SL) offers the capability of tuning from SWIR 8 to VLWIR 9 , covers the whole infrared spectrum. In recent years, T2SL material has not only matured in the improvement of single color detector performance but also witnessed a new phase of development for multi-band detection 10 and imaging 11 . Two-color SWIR-MWIR 12 , MWIR-MWIR 13 , MWIR-LWIR 14 and LWIR-LWIR 15 focal plane arrays have been demonstrated with high performance. The second major challenge resides in integrating a stack of absorbers into a single pixel. The incorporation of new channel usually needs additional terminal contacts, which will lead to more complicated fabrication process and thus, low yield. On the other hand, by defining additional metal contact, a portion of material must be etched away; the optical fill factor of stacked absorption channels in the pixels is therefore severely reduced 3 . This is particularly critical for applications which need high resolutions, namely detectors with smaller pitches. In order to mitigate these issues, two-terminal photodetectors with only a top and a common ground contact are more favorable. Besides providing a near unity optical fill factor, a single contact pixel has the advantage of simplicity on sharing the same fabrication process as single color or bias-selectable two-color arrays. In this matter, read out integrated circuits (ROICs) with one Indium bump could also be used for later Focal Plane Array (FPA) application. In this article, we present our novel device design using only two terminals and report the experimental demonstration for the high performance triple-band T2SL-based SWIR/MWIR/LWIR photodetector based on this architecture. The core idea is to demonstrate devices that can perform sequentially as three individual single color photodetectors according to the magnitude variation of applied bias. Results and Discussion The schematic diagram of top-side illumination device structure is shown in Fig. 1 . Each layer absorbs radiation up to its cut-off and passes through longer wavelengths, which are then collected in subsequent layers. The SWIR channel is grown on the MWIR channel which is on top of the LWIR absorption layer. Using empirical tight binding model (ETBM) 16 , the design for SWIR absorber is 7.5/1/5/1 monolayers (MLs) of InAs/GaSb/AlSb/GaSb, aiming for 50% cut-off wavelength of 2.0 μm at 77 K. MWIR channel is designed with 7.5/10 MLs of InAs/GaSb with 50% cut-off wavelength of 4.5 μm and the LWIR absorber is made of 11/7 MLs of InAs/GaSb, aiming for 9 μm cut-off at 77 K. Figure 1 Schematic diagram of a triple-band SWIR-MWIR-LWIR photodiode structure with two terminal contacts and schematic band alignment of superlattices in three absorption layers. The colored rectangles in the insets represent the forbidden gap of component materials. Dotted lines represent the effective band gaps of superlattices. Full size image With only two contacts, the extraction of each color photocurrent therefore must be determined not only by the polarity of the applied bias but also by its magnitude. The design philosophy behind this device structure is to be able to control the distribution of electric potential along the device as function of applied bias, hence divide the applied bias into three separate intervals which will turn<|im_end|> <|im_start|>assistant While infrared waves are available in short, mid, and long lengths, most detection devices are unable to harness all three at the same time. Now Northwestern University's Manijeh Razeghi and her team have developed a new approach in device design to realize a three-color, shortwave-midwave-longwave infrared photodetector. With the new design, the devices can detect different infrared wavebands by simply varying the applied bias voltage. This could open up a range of potential applications, including infrared color televisions and three-color infrared imaging. "A device capable of detecting different infrared wavebands is highly desirable in the next generation infrared imaging systems," said Razeghi, Walter P. Murphy Professor of Electrical Engineering and Computer Science in Northwestern's McCormick School of Engineering. Supported by DARPA, the Army Research Laboratory, Air Force Research Laboratory, and NASA, the team's finding were published on April 7 in Nature's Scientific Reports. Led by Razeghi, the researchers invented and investigated the new design for three-color photodiodes without using additional terminal contacts. The resulting photodetector is based on indium-arsenide/gallium-antimonide/aluminum-antimonide type-II superlattices. As the applied bias voltage varies, the photodetector sequentially exhibits the behavior of three different colors, corresponding to the bandgap of three absorbers, and achieves well-defined cut-off wavelengths and high-quantum efficiency in each channel. This new research builds on the Razeghi group's many years of work in Northwestern's Center for Quantum Devices, including the development of the first single-color, short-wavelength infrared photodetector and two-color, shortwave-midwave infrared photodetector based on type-II superlattices. "I am fascinated by these results," Razeghi said. "The initial success in this demonstration will drive us to the new frontier of infrared detection and imaging technology." <|im_end|>

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1,835

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Wildfires in the Pacific Northwest (Washington, Oregon, Idaho, and western Montana, USA) have been immense in recent years, capturing the attention of resource managers, fire scientists, and the general public. This paper synthesizes understanding of the potential effects of changing climate and fire regimes on Pacific Northwest forests, including effects on disturbance and stress interactions, forest structure and composition, and post-fire ecological processes. We frame this information in a risk assessment context, and conclude with management implications and future research needs. Results Large and severe fires in the Pacific Northwest are associated with warm and dry conditions, and such conditions will likely occur with increasing frequency in a warming climate. According to projections based on historical records, current trends, and simulation modeling, protracted warmer and drier conditions will drive lower fuel moisture and longer fire seasons in the future, likely increasing the frequency and extent of fires compared to the twentieth century. Interactions between fire and other disturbances, such as drought and insect outbreaks, are likely to be the primary drivers of ecosystem change in a warming climate. Reburns are also likely to occur more frequently with warming and drought, with potential effects on tree regeneration and species composition. Hotter, drier sites may be particularly at risk for regeneration failures. Conclusion Resource managers will likely be unable to affect the total area burned by fire, as this trend is driven strongly by climate. However, fuel treatments, when implemented in a spatially strategic manner, can help to decrease fire intensity and severity and improve forest resilience to fire, insects, and drought. Where fuel treatments are less effective (wetter, high-elevation, and coastal forests), managers may consider implementing fuel breaks around high-value resources. When and where post-fire planting is an option, planting different genetic stock than has been used in the past may increase seedling survival. Planting seedlings on cooler, wetter microsites may also help to increase survival. In the driest topographic locations, managers may need to consider where they will try to forestall change and where they will allow conversions to vegetation other than what is currently dominant. Resumen Antecedentes Los incendios de vegetación en el Noroeste del pacífico (Washington, Oregon, Idaho, y el oeste de Montana, EEUU), han sido inmensos en años recientes, capturando la atención de los gestores de recursos, de científicos dedicados a los incendios, y del público en general. Este trabajo sintetiza el conocimiento de los efectos potenciales del cambio climático y de los regímenes de fuego en bosques del noroeste del Pacífico, incluyendo los efectos sobre las interacciones entre disturbios y distintos estreses, la estructura y composición de los bosques, y los procesos ecológicos posteriores. Encuadramos esta información en el contexto de la determinación del riesgo, y concluimos con implicancias en el manejo y la necesidad de futuras investigaciones. Resultados Los incendios grandes y severos en el Noroeste del Pacífico están asociados con condiciones calurosas y secas, y tales condiciones muy probablemente ocurran con el incremento en la frecuencia del calentamiento global. De acuerdo a proyecciones basadas en registros históricos, tendencias actuales y modelos de simulación, condiciones prolongadas de aumento de temperaturas y sequías conducirán a menores niveles de humedad, incrementando probablemente la frecuencia y extensión de fuegos en el futuro, en comparación con lo ocurrido durante el siglo XX. Las interacciones entre el fuego y otros disturbios, son probablemente los principales conductores de cambios en los ecosistemas en el marco del calentamiento global. Los incendios recurrentes podrían ocurrir más frecuentemente con aumentos de temperatura y sequías, con efectos potenciales en la regeneración de especies forestales y en la composición de especies. Los sitios más cálidos y secos, pueden estar particularmente en riesgo por fallas en la regeneración. Conclusiones Los gestores de recursos no podrían tener ningún efecto sobre el área quemada, ya que esta tendencia está fuertemente influenciada por el clima. Sin embargo, el tratamiento de combustibles, cuando está implementado de una manera espacialmente estratégica, puede ayudar a reducir la intensidad y severidad de los incendios, y mejorar la resiliencia de los bosques al fuego, insectos, y sequías. En lugares en los que el tratamiento de combustibles es menos efectivo (áreas más húmedas, elevadas, y bosques costeros) los gestores deberían considerar implementar barreras de combustible alrededor de valores a proteger. Cuando y donde la plantación post fuego sea una opción, plántulas provenientes de diferentes stocks genéticos de aquellos que han sido usados en el pasado pueden incrementar su supervivencia. La plantación de plántulas en micrositios más húmedos y fríos podría ayudar también a incrementar la supervivencia de plántulas. En ubicaciones topográficas más secas, los gestores deberían considerar evitar cambios y donde estos sean posibles, permitir conversiones a tipos de vegetación diferentes a las actualmente dominantes. Abbreviations ENSO: El Niño-Southern Oscillation MPB: Mountain Pine Beetle PDO: Pacific Decadal Oscillation Introduction Large fires are becoming a near-annual occurrence in many regions globally as fire regimes are changing with warming temperatures and shifting precipitation patterns. The US Pacific Northwest (states of Washington, Oregon, Idaho, and western Montana, USA; hereafter the Northwest) is no exception. In 2014, the largest wildfire in recorded history for Washington State occurred, the 103 640 ha Carlton Complex Fire (Fig. 1 ). In 2015, an extreme drought year with very low snowpack across the Northwest (Marlier et al. 2017 ), 688 000 ha burned in Oregon and Washington (Fig. 2 ), with over 3.6 million ha burned in the western United States. Several fires in 2015 occurred in conifer forests on the west ( i.e. , wet) side of the Cascade Range, including a rare fire event in coastal temperate rainforest on the Olympic Peninsula. In some locations, short-interval reburns have occurred. For example, one location on Mount Adams in southwestern Washington burned three times between 2008 and 2015 (Fig. 3 ). Similarly, during the summer of 2017 in southwestern Oregon, the 77 000 ha Chetco Bar Fire burned over 40 000 ha of the 2002 Biscuit Fire, including a portion of the Biscuit Fire that had burned over part of the 1987", "role": "user" }, { "content": "Recent years have brought unusually large and damaging wildfires to the Pacific Northwest—from the Carlton Complex Fire in 2014 that was the largest in Washington's history, to the 2017 fire season in Oregon, to the 2018 Maple Fire, when normally sodden rainforests on the Olympic Peninsula were ablaze. Many people have wondered what this means for our region's future. A University of Washington study, published this winter in Fire Ecology, takes a big-picture look at what climate change could mean for wildfires in the Northwest, considering Washington, Oregon, Idaho and western Montana. \"We can't predict the exact location of wildfires, because we don't know where ignitions will occur. But based on historical and contemporary fire records, we know some forests are much more likely to burn frequently, and models can help us determine where climate change will likely increase the frequency of fire,\" said lead author Jessica Halofsky, a research scientist at the UW School of Environmental and Forest Sciences and with the U.S. Forest Service. The review was done in response to a survey of stakeholder needs by the Northwest Climate Adaptation Science Center, a UW-hosted federal–university partnership. State, federal and tribal resource managers wanted more information on the available science about fire and climate change. \"We're on the cusp of some big changes. We expect that droughts will become more common, and the interaction of climate and fire could look very different by the mid-21st century,\" said David Peterson, professor at the UW School of Environmental and Forest Sciences. \"Starting the process of adapting to those changes now will give us a better chance of protecting forest resources in the future.\" The greatest increased risk was found for low-elevation ponderosa pine forests, of the type found at lower elevations on the east side of the Cascade Range in Washington, Oregon, Montana and Idaho. This ecosystem has the highest fire risk today and also has the highest increase in risk due to climate change. The authors predict with high confidence that wildfires in this region will become larger and more frequent. \"We can't attribute single fire events to climate change. But the trends in large fire events that have been occurring in the region are consistent with expected trends in a warming climate,\" said co-author Brian Harvey, assistant professor at the UW School of Environmental and Forest Sciences. His UW research group studies forests and fires in the Pacific Northwest and Northern Rockies. The authors also summarize how other Northwest ecosystems might experience the combined threats of drought, warmer temperatures and insect outbreaks. Moist, coniferous forests—found on the Olympic Peninsula, in Western Washington and in Northern Idaho—will likely burn more often, but fires won't be significantly larger than they were historically. Fires in subalpine, high-elevation forests, found in mountainous terrain, will similarly become more frequent but only slightly larger or more severe. After describing the threats, the authors evaluate potential strategies to prepare. Land managers could remove dry organic material, or fuels, and maintain forest densities at lower levels to reduce the severity of fires, since the severity of wildfire is more controllable than the frequency or total area burned. Thinning would also help the remaining trees to withstand drought. Planting genetically diverse seedlings could also help with regeneration after fires—an important step for long-term survival of forests. Rural landowners can also play a role, the authors write. \"Individual landowners can reduce hazardous fuels, promote species that can survive fire and drought, and increase diversity of species and structures across the landscape,\" Peterson said. Historically the Northwest has had lower risk of wildfire than other states, such as California, but that may be changing. \"In general, the climate in the Northwest is cooler and wetter than in most low-elevation areas of California,\" Halofsky said. But the Northwest summers are dry and warm. \"Climate change will accentuate dry summers, and Northwest climate will become more similar to current-day California climate, leading to more and bigger fires.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Wildfires in the Pacific Northwest (Washington, Oregon, Idaho, and western Montana, USA) have been immense in recent years, capturing the attention of resource managers, fire scientists, and the general public. This paper synthesizes understanding of the potential effects of changing climate and fire regimes on Pacific Northwest forests, including effects on disturbance and stress interactions, forest structure and composition, and post-fire ecological processes. We frame this information in a risk assessment context, and conclude with management implications and future research needs. Results Large and severe fires in the Pacific Northwest are associated with warm and dry conditions, and such conditions will likely occur with increasing frequency in a warming climate. According to projections based on historical records, current trends, and simulation modeling, protracted warmer and drier conditions will drive lower fuel moisture and longer fire seasons in the future, likely increasing the frequency and extent of fires compared to the twentieth century. Interactions between fire and other disturbances, such as drought and insect outbreaks, are likely to be the primary drivers of ecosystem change in a warming climate. Reburns are also likely to occur more frequently with warming and drought, with potential effects on tree regeneration and species composition. Hotter, drier sites may be particularly at risk for regeneration failures. Conclusion Resource managers will likely be unable to affect the total area burned by fire, as this trend is driven strongly by climate. However, fuel treatments, when implemented in a spatially strategic manner, can help to decrease fire intensity and severity and improve forest resilience to fire, insects, and drought. Where fuel treatments are less effective (wetter, high-elevation, and coastal forests), managers may consider implementing fuel breaks around high-value resources. When and where post-fire planting is an option, planting different genetic stock than has been used in the past may increase seedling survival. Planting seedlings on cooler, wetter microsites may also help to increase survival. In the driest topographic locations, managers may need to consider where they will try to forestall change and where they will allow conversions to vegetation other than what is currently dominant. Resumen Antecedentes Los incendios de vegetación en el Noroeste del pacífico (Washington, Oregon, Idaho, y el oeste de Montana, EEUU), han sido inmensos en años recientes, capturando la atención de los gestores de recursos, de científicos dedicados a los incendios, y del público en general. Este trabajo sintetiza el conocimiento de los efectos potenciales del cambio climático y de los regímenes de fuego en bosques del noroeste del Pacífico, incluyendo los efectos sobre las interacciones entre disturbios y distintos estreses, la estructura y composición de los bosques, y los procesos ecológicos posteriores. Encuadramos esta información en el contexto de la determinación del riesgo, y concluimos con implicancias en el manejo y la necesidad de futuras investigaciones. Resultados Los incendios grandes y severos en el Noroeste del Pacífico están asociados con condiciones calurosas y secas, y tales condiciones muy probablemente ocurran con el incremento en la frecuencia del calentamiento global. De acuerdo a proyecciones basadas en registros históricos, tendencias actuales y modelos de simulación, condiciones prolongadas de aumento de temperaturas y sequías conducirán a menores niveles de humedad, incrementando probablemente la frecuencia y extensión de fuegos en el futuro, en comparación con lo ocurrido durante el siglo XX. Las interacciones entre el fuego y otros disturbios, son probablemente los principales conductores de cambios en los ecosistemas en el marco del calentamiento global. Los incendios recurrentes podrían ocurrir más frecuentemente con aumentos de temperatura y sequías, con efectos potenciales en la regeneración de especies forestales y en la composición de especies. Los sitios más cálidos y secos, pueden estar particularmente en riesgo por fallas en la regeneración. Conclusiones Los gestores de recursos no podrían tener ningún efecto sobre el área quemada, ya que esta tendencia está fuertemente influenciada por el clima. Sin embargo, el tratamiento de combustibles, cuando está implementado de una manera espacialmente estratégica, puede ayudar a reducir la intensidad y severidad de los incendios, y mejorar la resiliencia de los bosques al fuego, insectos, y sequías. En lugares en los que el tratamiento de combustibles es menos efectivo (áreas más húmedas, elevadas, y bosques costeros) los gestores deberían considerar implementar barreras de combustible alrededor de valores a proteger. Cuando y donde la plantación post fuego sea una opción, plántulas provenientes de diferentes stocks genéticos de aquellos que han sido usados en el pasado pueden incrementar su supervivencia. La plantación de plántulas en micrositios más húmedos y fríos podría ayudar también a incrementar la supervivencia de plántulas. En ubicaciones topográficas más secas, los gestores deberían considerar evitar cambios y donde estos sean posibles, permitir conversiones a tipos de vegetación diferentes a las actualmente dominantes. Abbreviations ENSO: El Niño-Southern Oscillation MPB: Mountain Pine Beetle PDO: Pacific Decadal Oscillation Introduction Large fires are becoming a near-annual occurrence in many regions globally as fire regimes are changing with warming temperatures and shifting precipitation patterns. The US Pacific Northwest (states of Washington, Oregon, Idaho, and western Montana, USA; hereafter the Northwest) is no exception. In 2014, the largest wildfire in recorded history for Washington State occurred, the 103 640 ha Carlton Complex Fire (Fig. 1 ). In 2015, an extreme drought year with very low snowpack across the Northwest (Marlier et al. 2017 ), 688 000 ha burned in Oregon and Washington (Fig. 2 ), with over 3.6 million ha burned in the western United States. Several fires in 2015 occurred in conifer forests on the west ( i.e. , wet) side of the Cascade Range, including a rare fire event in coastal temperate rainforest on the Olympic Peninsula. In some locations, short-interval reburns have occurred. For example, one location on Mount Adams in southwestern Washington burned three times between 2008 and 2015 (Fig. 3 ). Similarly, during the summer of 2017 in southwestern Oregon, the 77 000 ha Chetco Bar Fire burned over 40 000 ha of the 2002 Biscuit Fire, including a portion of the Biscuit Fire that had burned over part of the 1987<|im_end|> <|im_start|>assistant Recent years have brought unusually large and damaging wildfires to the Pacific Northwest—from the Carlton Complex Fire in 2014 that was the largest in Washington's history, to the 2017 fire season in Oregon, to the 2018 Maple Fire, when normally sodden rainforests on the Olympic Peninsula were ablaze. Many people have wondered what this means for our region's future. A University of Washington study, published this winter in Fire Ecology, takes a big-picture look at what climate change could mean for wildfires in the Northwest, considering Washington, Oregon, Idaho and western Montana. "We can't predict the exact location of wildfires, because we don't know where ignitions will occur. But based on historical and contemporary fire records, we know some forests are much more likely to burn frequently, and models can help us determine where climate change will likely increase the frequency of fire," said lead author Jessica Halofsky, a research scientist at the UW School of Environmental and Forest Sciences and with the U.S. Forest Service. The review was done in response to a survey of stakeholder needs by the Northwest Climate Adaptation Science Center, a UW-hosted federal–university partnership. State, federal and tribal resource managers wanted more information on the available science about fire and climate change. "We're on the cusp of some big changes. We expect that droughts will become more common, and the interaction of climate and fire could look very different by the mid-21st century," said David Peterson, professor at the UW School of Environmental and Forest Sciences. "Starting the process of adapting to those changes now will give us a better chance of protecting forest resources in the future." The greatest increased risk was found for low-elevation ponderosa pine forests, of the type found at lower elevations on the east side of the Cascade Range in Washington, Oregon, Montana and Idaho. This ecosystem has the highest fire risk today and also has the highest increase in risk due to climate change. The authors predict with high confidence that wildfires in this region will become larger and more frequent. "We can't attribute single fire events to climate change. But the trends in large fire events that have been occurring in the region are consistent with expected trends in a warming climate," said co-author Brian Harvey, assistant professor at the UW School of Environmental and Forest Sciences. His UW research group studies forests and fires in the Pacific Northwest and Northern Rockies. The authors also summarize how other Northwest ecosystems might experience the combined threats of drought, warmer temperatures and insect outbreaks. Moist, coniferous forests—found on the Olympic Peninsula, in Western Washington and in Northern Idaho—will likely burn more often, but fires won't be significantly larger than they were historically. Fires in subalpine, high-elevation forests, found in mountainous terrain, will similarly become more frequent but only slightly larger or more severe. After describing the threats, the authors evaluate potential strategies to prepare. Land managers could remove dry organic material, or fuels, and maintain forest densities at lower levels to reduce the severity of fires, since the severity of wildfire is more controllable than the frequency or total area burned. Thinning would also help the remaining trees to withstand drought. Planting genetically diverse seedlings could also help with regeneration after fires—an important step for long-term survival of forests. Rural landowners can also play a role, the authors write. "Individual landowners can reduce hazardous fuels, promote species that can survive fire and drought, and increase diversity of species and structures across the landscape," Peterson said. Historically the Northwest has had lower risk of wildfire than other states, such as California, but that may be changing. "In general, the climate in the Northwest is cooler and wetter than in most low-elevation areas of California," Halofsky said. But the Northwest summers are dry and warm. "Climate change will accentuate dry summers, and Northwest climate will become more similar to current-day California climate, leading to more and bigger fires." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy. Introduction Abnormal aggregation and spreading of the microtubule-associated protein tau is the key defining feature of a group of heterogeneous neurodegenerative diseases known as tauopathies 1 . Alzheimer’s disease (AD) is the most common tauopathy, with a hallmark of neurofibrillary tangles (NFTs) composed of insoluble tau fibrils. Tau pathology correlates more closely with synaptic loss, neurodegeneration, and cognitive decline than does amyloid pathology 2 , 3 , 4 . Understanding the pathogenic mechanism induced by pathological tau is critical for developing effective therapeutics for AD and other tauopathies. Neuroinflammation, the immune response in the central nervous system (CNS) characterized by reactive gliosis and increased inflammatory molecules, is one of the early and sustained pathological features of tauopathies 5 . Microglia, the resident innate immune cells in the CNS, are key players in neuroinflammation. Recent genetic and gene network analysis of late-onset AD (LOAD) identified several risk variants predominantly expressed in microglia, implicating a pivotal role of microglia in AD pathogenesis 6 . Reactive microglia have been observed to associate with NFTs in AD 7 , primary tauopathies 8 , 9 , and tau transgenic models 10 , 11 . In vitro studies confirm that tau directly activates microglia and triggers a proinflammatory profile 12 . Accumulated evidence also suggests that microglia are involved in tau-mediated pathobiology, including tau phagocytosis 13 , 14 , post-translational modification and aggregation 15 , 16 , spreading 17 , and tau-induced synaptic loss 18 . Blockade of microglia proliferation attenuates tau-induced neurodegeneration and functional deficits 19 . However, the molecular pathways underlying microglia-mediated tau toxicity remain poorly defined. NF-κB is a transcription factor known to modulate many target genes that are associated with neuroinflammation, glial activation, oxidative stress, cell proliferation, and apoptosis in the central nervous system. IκB kinase (IKK) activates NF-κB via phosphorylation and subsequent degradation of IκBα, an inhibitor of NF-κB 20 . Genetic manipulations of IκB and IKK using the Cre-lox system enable conditional activation or inactivation of NF-κB and the dissection of functions of NF-κB in specific cell types 21 . Such studies have shown that neuronal NF-κB plays an essential role in synaptic plasticity and regulating learning and memory behaviors in basal conditions 22 , 23 , whereas in pathological conditions, the anti-apoptotic role of neuronal NF-κB is associated with neuroprotective effects 24 , 25 . Microglial NF-κB also regulates synaptic plasticity 26 . Dysregulation of NF-κB has been implicated in AD pathogenesis 27 , 28 . Indeed, in a meta-analysis, NF-κB signaling was found to be among the most perturbed pathways in LOAD brains 29 . NF-κB is known to be activated by amyloid β (Aβ) and to contribute to Aβ production 30 , 31 . We previously showed that specific inhibition of microglial NF-κB activation via deacetylation of p65 protected against Aβ toxicity in glial-neuron co-cultures 32 . However, very little is known about the role of microglial NF-κB activation in tauopathy. Our current study establishes NF-κB signaling as a central transcription factor driving tau responses in vitro and in vivo models of tauopathy. By genetically deleting or activating IKKβ kinase selectively in microglia, we investigated how microglial NF-κB signaling contributes to tau processing, seeding, and spreading, as well as tau toxicity using behavioral studies. Using bulk and single-nuclei RNA-sequencing (RNA-seq), we dissected how microglial NF-κB activation and inactivation modify overall transcriptomic changes, tau-associated microglial states, and underlying pathways in microglia. Our findings uncover mechanisms by which microglial NF-κB activation drives disease progression in tauopathy. Results Tau activates NF-κB pathway in microglia To determine tau-induced transcriptome changes in microglia, we treated primary mouse microglia with synthetic 0N4R full-length wild-type (FL_WT) tau fibrils for 24 h and analyzed them by RNA-seq. Synthetic recombinant tau monomers and fibrils contained negligible endotoxin (Supplementary Data 1 ). Out of 2975 differentially expressed genes (DEGs, False Discovery Rate (FDR) < 0.05) (Fig. 1a and Supplementary Data 2 ), Ingenuity Pathway Analysis (IPA) revealed that the top affected canonical pathways were associated with cellular immune responses, morphological changes, cell movement, survival, and proliferation (Fig. 1b , Supplementary Data 3 ). NF-κB signaling, which is involved in the upstream or downstream regulation of many other canonical pathways, such as Tumor Necrosis Factor Receptor 2 (TNFR2), toll-like receptor (TLR), interferon, and interleukin 12 (IL-12) signaling, was among the top altered cellular immune response pathways. Many NF-κB target genes were upregulated, including chemokines and receptors, such as C–C Motif Chemokine Ligand 5 ( Ccl5 ), C–X–C Motif Chemokine Ligand 9 (Cxcl9) , complement component C3 , proinflammatory cytokines interleukin 1 beta ( Il1b) , Interleukin 12b ( Il12b) , and Tumor Necrosis Factor ( Tnf ), Fc fragment of IgG receptors involved in phagocytosis such as Fc receptor, IgG, high affinity I ( Fcgr1) , and the NF-κB pathway component NF-κB Inhibitor Alpha ( Nfkbia) (Fig. 1a ). Fig. 1: Tau activates NF-κB pathway in microglia. a Volcano plot of significant DEGs between full-length wild-type tau fibril-treated and vehicle-treated primary mouse microglia. Colored points represent FDR < 0.05 (−log (FDR) ≥ 1.3, dashed line), log 2 FC > 0 upregulated genes (red) and log 2 FC < 0", "role": "user" }, { "content": "Inhibiting an important signaling pathway in brain-resident immune cells may calm brain inflammation and thereby slow the disease process in Alzheimer's and some other neurodegenerative diseases, suggests a study by Weill Cornell Medicine investigators. The findings point to the possibility of new therapeutic strategies against neurodegenerative diseases, which are relatively common in older adults and so far have no effective, disease-modifying treatments. Brain inflammation, especially via the activation of immune cells in the brain called microglia, has long been noted as a common feature of neurodegenerative diseases. The spread of abnormal, thread-like aggregates—\"tangles\"—of a neuronal protein called tau is another frequent feature of these disorders. In the study, which appeared April 12 in Nature Communications, the researchers showed that the tau tangles help trigger the inflammatory activation of microglia, via a multifunctional signaling pathway called the NF-κB pathway. Inhibiting microglial NF-κB signaling in a tau-based Alzheimer's mouse model largely pulled the immune cells out of their inflammatory state and reversed the animals' learning and memory problems. \"Our findings suggest restraining overactive NF-κB may be a good therapeutic strategy in Alzheimer's and other tau-mediated neurodegenerative diseases,\" said senior author Dr. Li Gan, director of the Helen and Robert Appel Alzheimer's Disease Research Institute and the Burton P. and the Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. Tau tangles are found inside neurons in affected brain areas in Alzheimer's, Parkinson's, Pick disease, progressive supranuclear palsy, frontotemporal dementia and other neurodegenerative diseases. Experiments have shown that tangles, when injected into animal brains, can seed the formation of new tangles, creating a chain-reaction in which the tangles spread to other brain regions. Autopsy studies in Alzheimer's and other \"tauopathies\" indicate that this spread of tangles often tracks closely the progress of disease. The tangles' precise role in harming brain cells has never been fully understood. However, prior studies have suggested that tau tangles can interact with microglia, in a way that drives the microglia into an inflammatory, disease-associated state. In this inflamed state, the microglia, which normally try to consume the tau tangles, become relatively inefficient at doing so. Much of the tau ends up being not digested, but rather disgorged from the microglia, in forms that tend to seed new tangles. In the new study, Dr. Gan and her team found evidence from cell culture and mouse experiments that tau tangles push microglia into this disease-linked inflammatory state mainly by activating the NF-κB signaling pathway within them. In a Alzheimer's mouse model with tau-tangle mainly driven by seeded tau, they showed that keeping the NF-κB pathway overactive in microglia enhanced the seeding and spread of tangles, which propel further NF-κB activation. By contrast, shutting off NF-κB blocked this vicious cycle, and markedly lessened the spread of the tangles. In another tau mouse model, with tau tangles formed in aged neurons, the researchers showed that the inactivation of microglial NF-κB shifted the microglia almost entirely out of their inflammatory, disease-associated state, restoring a much more normal cell appearance and pattern of gene activity. This shift, which suppresses microglia from disgorging toxic tau seeds, strikingly, prevented key cognitive/memory deficits the mice normally develop in this model. \"Taken together, our experiments suggest that tau's toxic effects on cognition require microglial NF-κB signaling,\" said co-senior author Dr. Wenjie Luo, associate professor of research in neuroscience in the Appel Alzheimer's Disease Research Institute and the Feil Family Brain and Mind Research Institute at Weill Cornell. Over the past two decades, many experimental Alzheimer's treatments have aimed to slow or stop the disease process by targeting amyloid plaques, and more recently tau tangles. So far, all these efforts have failed in large-scale clinical trials. The new findings suggest that future drugs taming overactive microglial NF-κB signaling might fare better, Dr. Gan said. Her lab is now following up with further research to detail more precisely how microglial NF-κB signaling, which affects the activities of at least hundreds of other microglial genes, impairs neurons and leads to cognitive and memory deficits. The researchers will investigate how to restrain specific aspects of overactive NF-κB signaling without affecting the normal function of brain's immune cells. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy. Introduction Abnormal aggregation and spreading of the microtubule-associated protein tau is the key defining feature of a group of heterogeneous neurodegenerative diseases known as tauopathies 1 . Alzheimer’s disease (AD) is the most common tauopathy, with a hallmark of neurofibrillary tangles (NFTs) composed of insoluble tau fibrils. Tau pathology correlates more closely with synaptic loss, neurodegeneration, and cognitive decline than does amyloid pathology 2 , 3 , 4 . Understanding the pathogenic mechanism induced by pathological tau is critical for developing effective therapeutics for AD and other tauopathies. Neuroinflammation, the immune response in the central nervous system (CNS) characterized by reactive gliosis and increased inflammatory molecules, is one of the early and sustained pathological features of tauopathies 5 . Microglia, the resident innate immune cells in the CNS, are key players in neuroinflammation. Recent genetic and gene network analysis of late-onset AD (LOAD) identified several risk variants predominantly expressed in microglia, implicating a pivotal role of microglia in AD pathogenesis 6 . Reactive microglia have been observed to associate with NFTs in AD 7 , primary tauopathies 8 , 9 , and tau transgenic models 10 , 11 . In vitro studies confirm that tau directly activates microglia and triggers a proinflammatory profile 12 . Accumulated evidence also suggests that microglia are involved in tau-mediated pathobiology, including tau phagocytosis 13 , 14 , post-translational modification and aggregation 15 , 16 , spreading 17 , and tau-induced synaptic loss 18 . Blockade of microglia proliferation attenuates tau-induced neurodegeneration and functional deficits 19 . However, the molecular pathways underlying microglia-mediated tau toxicity remain poorly defined. NF-κB is a transcription factor known to modulate many target genes that are associated with neuroinflammation, glial activation, oxidative stress, cell proliferation, and apoptosis in the central nervous system. IκB kinase (IKK) activates NF-κB via phosphorylation and subsequent degradation of IκBα, an inhibitor of NF-κB 20 . Genetic manipulations of IκB and IKK using the Cre-lox system enable conditional activation or inactivation of NF-κB and the dissection of functions of NF-κB in specific cell types 21 . Such studies have shown that neuronal NF-κB plays an essential role in synaptic plasticity and regulating learning and memory behaviors in basal conditions 22 , 23 , whereas in pathological conditions, the anti-apoptotic role of neuronal NF-κB is associated with neuroprotective effects 24 , 25 . Microglial NF-κB also regulates synaptic plasticity 26 . Dysregulation of NF-κB has been implicated in AD pathogenesis 27 , 28 . Indeed, in a meta-analysis, NF-κB signaling was found to be among the most perturbed pathways in LOAD brains 29 . NF-κB is known to be activated by amyloid β (Aβ) and to contribute to Aβ production 30 , 31 . We previously showed that specific inhibition of microglial NF-κB activation via deacetylation of p65 protected against Aβ toxicity in glial-neuron co-cultures 32 . However, very little is known about the role of microglial NF-κB activation in tauopathy. Our current study establishes NF-κB signaling as a central transcription factor driving tau responses in vitro and in vivo models of tauopathy. By genetically deleting or activating IKKβ kinase selectively in microglia, we investigated how microglial NF-κB signaling contributes to tau processing, seeding, and spreading, as well as tau toxicity using behavioral studies. Using bulk and single-nuclei RNA-sequencing (RNA-seq), we dissected how microglial NF-κB activation and inactivation modify overall transcriptomic changes, tau-associated microglial states, and underlying pathways in microglia. Our findings uncover mechanisms by which microglial NF-κB activation drives disease progression in tauopathy. Results Tau activates NF-κB pathway in microglia To determine tau-induced transcriptome changes in microglia, we treated primary mouse microglia with synthetic 0N4R full-length wild-type (FL_WT) tau fibrils for 24 h and analyzed them by RNA-seq. Synthetic recombinant tau monomers and fibrils contained negligible endotoxin (Supplementary Data 1 ). Out of 2975 differentially expressed genes (DEGs, False Discovery Rate (FDR) < 0.05) (Fig. 1a and Supplementary Data 2 ), Ingenuity Pathway Analysis (IPA) revealed that the top affected canonical pathways were associated with cellular immune responses, morphological changes, cell movement, survival, and proliferation (Fig. 1b , Supplementary Data 3 ). NF-κB signaling, which is involved in the upstream or downstream regulation of many other canonical pathways, such as Tumor Necrosis Factor Receptor 2 (TNFR2), toll-like receptor (TLR), interferon, and interleukin 12 (IL-12) signaling, was among the top altered cellular immune response pathways. Many NF-κB target genes were upregulated, including chemokines and receptors, such as C–C Motif Chemokine Ligand 5 ( Ccl5 ), C–X–C Motif Chemokine Ligand 9 (Cxcl9) , complement component C3 , proinflammatory cytokines interleukin 1 beta ( Il1b) , Interleukin 12b ( Il12b) , and Tumor Necrosis Factor ( Tnf ), Fc fragment of IgG receptors involved in phagocytosis such as Fc receptor, IgG, high affinity I ( Fcgr1) , and the NF-κB pathway component NF-κB Inhibitor Alpha ( Nfkbia) (Fig. 1a ). Fig. 1: Tau activates NF-κB pathway in microglia. a Volcano plot of significant DEGs between full-length wild-type tau fibril-treated and vehicle-treated primary mouse microglia. Colored points represent FDR < 0.05 (−log (FDR) ≥ 1.3, dashed line), log 2 FC > 0 upregulated genes (red) and log 2 FC < 0<|im_end|> <|im_start|>assistant Inhibiting an important signaling pathway in brain-resident immune cells may calm brain inflammation and thereby slow the disease process in Alzheimer's and some other neurodegenerative diseases, suggests a study by Weill Cornell Medicine investigators. The findings point to the possibility of new therapeutic strategies against neurodegenerative diseases, which are relatively common in older adults and so far have no effective, disease-modifying treatments. Brain inflammation, especially via the activation of immune cells in the brain called microglia, has long been noted as a common feature of neurodegenerative diseases. The spread of abnormal, thread-like aggregates—"tangles"—of a neuronal protein called tau is another frequent feature of these disorders. In the study, which appeared April 12 in Nature Communications, the researchers showed that the tau tangles help trigger the inflammatory activation of microglia, via a multifunctional signaling pathway called the NF-κB pathway. Inhibiting microglial NF-κB signaling in a tau-based Alzheimer's mouse model largely pulled the immune cells out of their inflammatory state and reversed the animals' learning and memory problems. "Our findings suggest restraining overactive NF-κB may be a good therapeutic strategy in Alzheimer's and other tau-mediated neurodegenerative diseases," said senior author Dr. Li Gan, director of the Helen and Robert Appel Alzheimer's Disease Research Institute and the Burton P. and the Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. Tau tangles are found inside neurons in affected brain areas in Alzheimer's, Parkinson's, Pick disease, progressive supranuclear palsy, frontotemporal dementia and other neurodegenerative diseases. Experiments have shown that tangles, when injected into animal brains, can seed the formation of new tangles, creating a chain-reaction in which the tangles spread to other brain regions. Autopsy studies in Alzheimer's and other "tauopathies" indicate that this spread of tangles often tracks closely the progress of disease. The tangles' precise role in harming brain cells has never been fully understood. However, prior studies have suggested that tau tangles can interact with microglia, in a way that drives the microglia into an inflammatory, disease-associated state. In this inflamed state, the microglia, which normally try to consume the tau tangles, become relatively inefficient at doing so. Much of the tau ends up being not digested, but rather disgorged from the microglia, in forms that tend to seed new tangles. In the new study, Dr. Gan and her team found evidence from cell culture and mouse experiments that tau tangles push microglia into this disease-linked inflammatory state mainly by activating the NF-κB signaling pathway within them. In a Alzheimer's mouse model with tau-tangle mainly driven by seeded tau, they showed that keeping the NF-κB pathway overactive in microglia enhanced the seeding and spread of tangles, which propel further NF-κB activation. By contrast, shutting off NF-κB blocked this vicious cycle, and markedly lessened the spread of the tangles. In another tau mouse model, with tau tangles formed in aged neurons, the researchers showed that the inactivation of microglial NF-κB shifted the microglia almost entirely out of their inflammatory, disease-associated state, restoring a much more normal cell appearance and pattern of gene activity. This shift, which suppresses microglia from disgorging toxic tau seeds, strikingly, prevented key cognitive/memory deficits the mice normally develop in this model. "Taken together, our experiments suggest that tau's toxic effects on cognition require microglial NF-κB signaling," said co-senior author Dr. Wenjie Luo, associate professor of research in neuroscience in the Appel Alzheimer's Disease Research Institute and the Feil Family Brain and Mind Research Institute at Weill Cornell. Over the past two decades, many experimental Alzheimer's treatments have aimed to slow or stop the disease process by targeting amyloid plaques, and more recently tau tangles. So far, all these efforts have failed in large-scale clinical trials. The new findings suggest that future drugs taming overactive microglial NF-κB signaling might fare better, Dr. Gan said. Her lab is now following up with further research to detail more precisely how microglial NF-κB signaling, which affects the activities of at least hundreds of other microglial genes, impairs neurons and leads to cognitive and memory deficits. The researchers will investigate how to restrain specific aspects of overactive NF-κB signaling without affecting the normal function of brain's immune cells. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Intestinal stem cells (ISCs) are located at the crypt base and fine-tune the balance of their self-renewal and differentiation 1 , 2 , but the physiological mechanism involved in regulating that balance remains unknown. Here we describe a transcriptional regulator that preserves the stemness of ISCs by restricting their differentiation into secretory-cell lineages. Interferon regulatory factor 2 (IRF2) negatively regulates interferon signalling 3 , and mice completely lacking Irf2 4 or with a selective Irf2 deletion in their intestinal epithelial cells have significantly fewer crypt Lgr5 hi ISCs than control mice. Although the integrity of intestinal epithelial cells was unimpaired at steady state in Irf2- deficient mice, regeneration of their intestinal epithelia after 5-fluorouracil-induced damage was severely impaired. Similarly, extended treatment with low-dose poly(I:C) or chronic infection of lymphocytic choriomeningitis virus clone 13 (LCMV C13) 5 caused a functional decline of ISCs in wild-type mice. In contrast, massive accumulations of immature Paneth cells were found at the crypt base of Irf2 −/− as well as LCMV C13-infected wild-type mice, indicating that excess interferon signalling directs ISCs towards a secretory-cell fate. Collectively, our findings indicate that regulated interferon signalling preserves ISC stemness by restricting secretory-cell differentiation. Main Interferons (IFNs) are the most important cytokines that induce host antiviral and antibacterial responses 6 . Following viral infection, the type I IFN pathway is activated, in which the ISGF3 complex binds to the ISRE motif to induce the expression of IFN-stimulated genes (ISGs) 7 . After that, interferon regulatory factor 2 (IRF2) competitively binds to the same motif to repress the expression of ISGs as a negative feedback system 3 , 4 , 7 . Even under non-infectious basal conditions, such as in mice in specific-pathogen-free conditions, type I IFNs are constitutively produced at low levels by various cell types and tissues (sterile IFN), and those IFNs amplify the host immune responses 8 . We previously reported that the transcription factor IRF2 is critical for preserving the stemness of haematopoietic stem cells by regulating sterile IFN signalling 9 . Here we examined the role of IRF2 in intestinal-stem-cell (ISC) functions. Irf2 messenger RNA is expressed throughout the intestinal epithelium, including ISCs (EpCAM hi Lgr5 hi Olfm4 hi ) and, to a lesser extent, Paneth cells (EpCAM hi UEA1 hi CD24 hi Lyz1 hi ; Extended Data Fig. 1a–e ). Irf2 −/− mice had a normal crypt-villus structure in the small intestine at steady state, suggesting that IRF2 is dispensable for the basal homeostasis of gut epithelium (Fig. 1a,b ). We next tested the effect of an IRF2 deficiency in the regeneration capacity of intestinal epithelium. Control Irf2 +/− and Irf2 −/− mice were administered 5-fluorouracil (5-FU), a well-known inducer of intestinal mucositis and the death of ISCs and other proliferating crypt epithelial cells 10 . The crypt in the small intestine was shrunken in size due to the apoptosis of epithelial cells at 2 d after 5-FU administration (Extended Data Fig. 1f ) and it occurred similarly in Irf2 +/− and Irf2 −/− mice, indicating the comparable 5-FU sensitivity of the intestinal epithelium in those mice. The villi-crypt structure of the small intestine was completely restored in Irf2 +/− mice 6 d after the administration of 5-FU but was impaired in Irf2 −/− mice, which had blunted short villi and a severe reduction in regenerating crypts, defined as those containing more than ten adjacent Ki67 + cells within a crypt-like structure (Fig. 1c–f ). Notably, the expression of Olfm4 mRNA, a representative ISC marker, in the jejunum was substantially lower in Irf2 −/− than Irf2 +/− mice at 6 d (Extended Data Fig. 1g ), suggesting a loss of the ISC pool in Irf2 −/− mice after epithelial injury. However, apoptotic cells were absent and Wnt/Notch signalling, represented by Ascl2 and Hes1 expression (Extended Data Fig. 1h,i ), was comparable or enhanced in the jejunum in Irf2 +/− and Irf2 −/− mice at day 6, suggesting that the impaired regeneration in Irf2 −/− mice is independent of sustained apoptosis and defective niche function. Fig. 1: An IRF2 deficiency attenuates crypt regeneration after injury. a , b , Sections of the jejunum of naive Irf2 +/− (left) and Irf2 −/− (right) mice were stained with haematoxylin and eosin ( a ), and Ki67 ( b ). c , d , Sections of the jejunum of Irf2 +/− (left) and Irf2 −/− (right) mice, treated with 5-FU and observed 6 d after treatment, were stained with haematoxylin and eosin ( c ) and Ki67 ( d ). a – d , Images are representative of three ( a , b ) and five ( c , d ) mice per group. e – h , Number of viable regenerating crypts per intestinal circumference in the jejunum of Irf2 +/− ( n = 18 sections from 3 mice) and Irf2 −/− ( n = 18 sections from 3 mice; e , f ) mice as well as Irf2 fl/fl ( n = 10 sections from 3 mice) and Irf2 ΔIEC ( n = 17 sections from 4 mice; g , h ) mice that were treated with 5-FU and observed by Ki67 staining 6 d after treatment. Data represent the mean ± s.d. Statistical significance was determined using a two-tailed Mann–Whitney test. Scale bars, 100 μm ( a – d ) and 500 μm ( e , g ). Source data Full size image To explore how the loss of IRF2 affects specific cell types, we generated mice harbouring a conditional Irf2 allele by flanking exons 3–5 of the Irf2 gene with loxP sites ( Irf2 fl/fl mice; Extended Data Fig. 2a,b ) and crossed those mice with Villin-cre mice 11 to generate mice selectively lacking Irf2 in the intestinal epithelial cells (IECs; Irf2 ΔIEC mice). The Irf2 allele was floxed out in the jejunum, ileum, crypt and colon but not the spleen, liver, lungs, kidneys or mesenteric lymph nodes of the Irf2 ΔIEC mice (Extended Data Fig. 2c,d ). Irf2 ΔIEC mice had a", "role": "user" }, { "content": "Intestinal stem cells hold a fine balance between two potential forms: remaining as stem cells, or developing into intestinal epithelial cells. In a new study, researchers from Tokyo Medical and Dental University (TMDU) discovered a novel molecular mechanism that regulates this balance and preserves the stemness of intestinal stem cells—that is, their ability to develop into any intestinal epithelial cell type. The inner lining of intestines, the intestinal epithelium, ensures adequate digestion and adsorption of nutrients. It is made up of several different cell types, all of which fulfill a specific function. Intestinal stem cells ensure proper functioning of the intestines, which requires constantly replacing old and damaged cells with young cells, by developing, or differentiating, into one of the different intestinal epithelial cell types when needed. Because there is a constant demand for new cells, intestinal stem cells have the ability to self-renew, thereby providing a constant supply of stem cells as well. However, little is known about the mechanisms that regulate this balance between self-renewal and differentiation. \"Just like any other type of stem cell, intestinal stem cells have the ability to differentiate into any cell within their lineage,\" says corresponding author of the study Professor Toshiaki Ohteki. \"But they have to do it in a regulated manner, only differentiating when needed. The goal of our study was to understand the regulatory mechanism that preserves the stemness of intestinal stem cells.\" A. ISCs undergo self-renewal and have the capacity to produce more differentiated epithelial cells, such as immature secretory epithelial cells. The balance between self-renewal and differentiation is strictly maintained in ISCs. B. In Irf2-/- mice, augmented IFN signaling causes aberrant differentiation of ISCs into immature secretory epithelial cells, that causes ISC reduction. Credit: Department of Biodefense Research,TMDU To achieve their goal, Taku Sato, a main contributor of this project, and collaborators focused on a molecular signaling pathway that they had previously shown to preserve the stemness of hematopoietic stem cells (HSCs) that give rise to blood cells. Interferons are molecules that are produced especially during viral and bacterial infections, but more recently it was also shown that they are present even in the absence of infections to regulate various biological processes. In either case, interferons induce the expression of certain genes, a process that is regulated by the protein interferon regulatory factor-2 (IRF2) to ensure that the actions of interferons are balanced. In the case of HSCs, IRF2 turned out to be a critical factor for their stemness. In the current study, the researchers found that IRF2 is produced throughout the intestinal epithelium and that IRF2-deficient mice had normal anatomical structure during homeostasis (the absence of an infection or any other damaging factor). However, in the presence of 5-fluorouracil, which is known to damage the intestinal epithelium, normal mice were able to regenerate completely, but IRF2-deficient mice showed a blunted regenerative response, indicating that intestinal stem cells were not able to function properly in the absence of IRF2. Interestingly, immature Paneth cells, which are specialized secretory cells, were highly abundant in IRF2-deficient mice. The researchers had the same finding in normal mice exposed to lymphocytic choriomeningitis virus (LCMV), which causes chronic infection. \"These are striking results that show how excess interferon signaling in the absence of IRF2 impairs the ability to self-renew and directs intestinal stem cells towards the secretory cell lineage. Our findings provide new insight into the biology of intestinal stem cells and show that regulated interferon signaling is a means to preserve the stemness of intestinal stem cells,\" says Professor Ohteki. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Intestinal stem cells (ISCs) are located at the crypt base and fine-tune the balance of their self-renewal and differentiation 1 , 2 , but the physiological mechanism involved in regulating that balance remains unknown. Here we describe a transcriptional regulator that preserves the stemness of ISCs by restricting their differentiation into secretory-cell lineages. Interferon regulatory factor 2 (IRF2) negatively regulates interferon signalling 3 , and mice completely lacking Irf2 4 or with a selective Irf2 deletion in their intestinal epithelial cells have significantly fewer crypt Lgr5 hi ISCs than control mice. Although the integrity of intestinal epithelial cells was unimpaired at steady state in Irf2- deficient mice, regeneration of their intestinal epithelia after 5-fluorouracil-induced damage was severely impaired. Similarly, extended treatment with low-dose poly(I:C) or chronic infection of lymphocytic choriomeningitis virus clone 13 (LCMV C13) 5 caused a functional decline of ISCs in wild-type mice. In contrast, massive accumulations of immature Paneth cells were found at the crypt base of Irf2 −/− as well as LCMV C13-infected wild-type mice, indicating that excess interferon signalling directs ISCs towards a secretory-cell fate. Collectively, our findings indicate that regulated interferon signalling preserves ISC stemness by restricting secretory-cell differentiation. Main Interferons (IFNs) are the most important cytokines that induce host antiviral and antibacterial responses 6 . Following viral infection, the type I IFN pathway is activated, in which the ISGF3 complex binds to the ISRE motif to induce the expression of IFN-stimulated genes (ISGs) 7 . After that, interferon regulatory factor 2 (IRF2) competitively binds to the same motif to repress the expression of ISGs as a negative feedback system 3 , 4 , 7 . Even under non-infectious basal conditions, such as in mice in specific-pathogen-free conditions, type I IFNs are constitutively produced at low levels by various cell types and tissues (sterile IFN), and those IFNs amplify the host immune responses 8 . We previously reported that the transcription factor IRF2 is critical for preserving the stemness of haematopoietic stem cells by regulating sterile IFN signalling 9 . Here we examined the role of IRF2 in intestinal-stem-cell (ISC) functions. Irf2 messenger RNA is expressed throughout the intestinal epithelium, including ISCs (EpCAM hi Lgr5 hi Olfm4 hi ) and, to a lesser extent, Paneth cells (EpCAM hi UEA1 hi CD24 hi Lyz1 hi ; Extended Data Fig. 1a–e ). Irf2 −/− mice had a normal crypt-villus structure in the small intestine at steady state, suggesting that IRF2 is dispensable for the basal homeostasis of gut epithelium (Fig. 1a,b ). We next tested the effect of an IRF2 deficiency in the regeneration capacity of intestinal epithelium. Control Irf2 +/− and Irf2 −/− mice were administered 5-fluorouracil (5-FU), a well-known inducer of intestinal mucositis and the death of ISCs and other proliferating crypt epithelial cells 10 . The crypt in the small intestine was shrunken in size due to the apoptosis of epithelial cells at 2 d after 5-FU administration (Extended Data Fig. 1f ) and it occurred similarly in Irf2 +/− and Irf2 −/− mice, indicating the comparable 5-FU sensitivity of the intestinal epithelium in those mice. The villi-crypt structure of the small intestine was completely restored in Irf2 +/− mice 6 d after the administration of 5-FU but was impaired in Irf2 −/− mice, which had blunted short villi and a severe reduction in regenerating crypts, defined as those containing more than ten adjacent Ki67 + cells within a crypt-like structure (Fig. 1c–f ). Notably, the expression of Olfm4 mRNA, a representative ISC marker, in the jejunum was substantially lower in Irf2 −/− than Irf2 +/− mice at 6 d (Extended Data Fig. 1g ), suggesting a loss of the ISC pool in Irf2 −/− mice after epithelial injury. However, apoptotic cells were absent and Wnt/Notch signalling, represented by Ascl2 and Hes1 expression (Extended Data Fig. 1h,i ), was comparable or enhanced in the jejunum in Irf2 +/− and Irf2 −/− mice at day 6, suggesting that the impaired regeneration in Irf2 −/− mice is independent of sustained apoptosis and defective niche function. Fig. 1: An IRF2 deficiency attenuates crypt regeneration after injury. a , b , Sections of the jejunum of naive Irf2 +/− (left) and Irf2 −/− (right) mice were stained with haematoxylin and eosin ( a ), and Ki67 ( b ). c , d , Sections of the jejunum of Irf2 +/− (left) and Irf2 −/− (right) mice, treated with 5-FU and observed 6 d after treatment, were stained with haematoxylin and eosin ( c ) and Ki67 ( d ). a – d , Images are representative of three ( a , b ) and five ( c , d ) mice per group. e – h , Number of viable regenerating crypts per intestinal circumference in the jejunum of Irf2 +/− ( n = 18 sections from 3 mice) and Irf2 −/− ( n = 18 sections from 3 mice; e , f ) mice as well as Irf2 fl/fl ( n = 10 sections from 3 mice) and Irf2 ΔIEC ( n = 17 sections from 4 mice; g , h ) mice that were treated with 5-FU and observed by Ki67 staining 6 d after treatment. Data represent the mean ± s.d. Statistical significance was determined using a two-tailed Mann–Whitney test. Scale bars, 100 μm ( a – d ) and 500 μm ( e , g ). Source data Full size image To explore how the loss of IRF2 affects specific cell types, we generated mice harbouring a conditional Irf2 allele by flanking exons 3–5 of the Irf2 gene with loxP sites ( Irf2 fl/fl mice; Extended Data Fig. 2a,b ) and crossed those mice with Villin-cre mice 11 to generate mice selectively lacking Irf2 in the intestinal epithelial cells (IECs; Irf2 ΔIEC mice). The Irf2 allele was floxed out in the jejunum, ileum, crypt and colon but not the spleen, liver, lungs, kidneys or mesenteric lymph nodes of the Irf2 ΔIEC mice (Extended Data Fig. 2c,d ). Irf2 ΔIEC mice had a<|im_end|> <|im_start|>assistant Intestinal stem cells hold a fine balance between two potential forms: remaining as stem cells, or developing into intestinal epithelial cells. In a new study, researchers from Tokyo Medical and Dental University (TMDU) discovered a novel molecular mechanism that regulates this balance and preserves the stemness of intestinal stem cells—that is, their ability to develop into any intestinal epithelial cell type. The inner lining of intestines, the intestinal epithelium, ensures adequate digestion and adsorption of nutrients. It is made up of several different cell types, all of which fulfill a specific function. Intestinal stem cells ensure proper functioning of the intestines, which requires constantly replacing old and damaged cells with young cells, by developing, or differentiating, into one of the different intestinal epithelial cell types when needed. Because there is a constant demand for new cells, intestinal stem cells have the ability to self-renew, thereby providing a constant supply of stem cells as well. However, little is known about the mechanisms that regulate this balance between self-renewal and differentiation. "Just like any other type of stem cell, intestinal stem cells have the ability to differentiate into any cell within their lineage," says corresponding author of the study Professor Toshiaki Ohteki. "But they have to do it in a regulated manner, only differentiating when needed. The goal of our study was to understand the regulatory mechanism that preserves the stemness of intestinal stem cells." A. ISCs undergo self-renewal and have the capacity to produce more differentiated epithelial cells, such as immature secretory epithelial cells. The balance between self-renewal and differentiation is strictly maintained in ISCs. B. In Irf2-/- mice, augmented IFN signaling causes aberrant differentiation of ISCs into immature secretory epithelial cells, that causes ISC reduction. Credit: Department of Biodefense Research,TMDU To achieve their goal, Taku Sato, a main contributor of this project, and collaborators focused on a molecular signaling pathway that they had previously shown to preserve the stemness of hematopoietic stem cells (HSCs) that give rise to blood cells. Interferons are molecules that are produced especially during viral and bacterial infections, but more recently it was also shown that they are present even in the absence of infections to regulate various biological processes. In either case, interferons induce the expression of certain genes, a process that is regulated by the protein interferon regulatory factor-2 (IRF2) to ensure that the actions of interferons are balanced. In the case of HSCs, IRF2 turned out to be a critical factor for their stemness. In the current study, the researchers found that IRF2 is produced throughout the intestinal epithelium and that IRF2-deficient mice had normal anatomical structure during homeostasis (the absence of an infection or any other damaging factor). However, in the presence of 5-fluorouracil, which is known to damage the intestinal epithelium, normal mice were able to regenerate completely, but IRF2-deficient mice showed a blunted regenerative response, indicating that intestinal stem cells were not able to function properly in the absence of IRF2. Interestingly, immature Paneth cells, which are specialized secretory cells, were highly abundant in IRF2-deficient mice. The researchers had the same finding in normal mice exposed to lymphocytic choriomeningitis virus (LCMV), which causes chronic infection. "These are striking results that show how excess interferon signaling in the absence of IRF2 impairs the ability to self-renew and directs intestinal stem cells towards the secretory cell lineage. Our findings provide new insight into the biology of intestinal stem cells and show that regulated interferon signaling is a means to preserve the stemness of intestinal stem cells," says Professor Ohteki. <|im_end|>

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922, 279, 24717, 430, 37377, 420, 8335, 1990, 659, 5621, 943, 278, 323, 60038, 13, 330, 10156, 1093, 904, 1023, 955, 315, 19646, 2849, 11, 63900, 19646, 7917, 617, 279, 5845, 311, 54263, 1139, 904, 2849, 2949, 872, 65009, 1359, 2795, 12435, 3229, 315, 279, 4007, 17054, 350, 32945, 14966, 507, 427, 79853, 13, 330, 4071, 814, 617, 311, 656, 433, 304, 264, 35319, 11827, 11, 1193, 2204, 23747, 994, 4460, 13, 578, 5915, 315, 1057, 4007, 574, 311, 3619, 279, 23331, 17383, 430, 75998, 279, 19646, 2136, 315, 63900, 19646, 7917, 1210, 362, 13, 3507, 34645, 37771, 659, 5621, 943, 278, 323, 617, 279, 8824, 311, 8356, 810, 89142, 64779, 59544, 7917, 11, 1778, 439, 86525, 6367, 683, 64779, 59544, 7917, 13, 578, 8335, 1990, 659, 5621, 943, 278, 323, 60038, 374, 26549, 18908, 304, 3507, 34645, 13, 426, 13, 763, 358, 8212, 17, 12, 24572, 24548, 11, 57088, 11812, 45, 43080, 11384, 82102, 519, 60038, 315, 3507, 34645, 1139, 86525, 6367, 683, 64779, 59544, 7917, 11, 430, 11384, 97281, 14278, 13, 16666, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R’s functional features in the control of specific motor behaviors. Introduction The striatum is the gateway to the basal ganglia, an ensemble of subcortical structures involved in motor planning and action selection 1 . Striatal dysfunction has been associated with multiple neurological and psychiatric disorders, including Parkinson’s and Huntington’s disease, Tourette’s syndrome, schizophrenia, autism, and addiction 2 , 3 . In the striatum, dopamine D2 receptors (D2R) have been tightly linked to a wide variety of motor- and reward/aversion-related behaviors. Pharmacological and genetic studies have demonstrated a direct involvement of D2R neurons in a wide range of functions including motor control 4 , 5 , 6 , aversive learning 7 , addiction 8 , compulsive food-intake 9 , motivational aspects of chronic pain 10 , and risky decision-making 11 . However, many of these studies used optogenetic or chemogenetic approaches to manipulate D2R neurons, but they did not assess the function of D2R itself in these neurons. Imaging studies in humans and rats have shown a significant reduction in striatal D2R availability in subjects addicted to drugs such as cocaine, alcohol, heroin, nicotine, and methamphetamine as well as in obesity 12 . However, the widespread expression of striatal D2R—which are present in indirect pathway striatal projection neurons (iSPNs), cholinergic interneurons (CINs), and presynaptically in both dopaminergic and glutamatergic afferents—have impeded the interpretation of many pharmacological and behavioral experiments. Our understanding of the complexity of striatal D2R expression pattern and its associated function has recently increased with a study reporting a relative heterogeneity of iSPN subpopulations 13 . In addition, the majority of studies that aimed to uncover the role of D2R, by using either global or conditional D2R knockout mice, could not rule out developmental compensatory adaptations from deleting D2R early in life, since their genetic approaches were not temporally controlled. Given that the rodent striatum is divided into two regions, the dorsal striatum (DS) and the nucleus accumbens (Acb), which have distinct input–output organization and play different roles in behavior 1 , 14 , we first aimed to identify DS- and Acb-specific molecular markers, which may serve as tools to assess the role of D2R in striatal subpopulations in adult mice. Therefore, we performed RNAseq in DS and Acb D2R neurons separately followed by histological analyses and revealed hundreds of region-specific markers. As a proof of concept, we focused on a cell subpopulation, identified by the expression of Wolfram syndrome 1 ( Wfs1 ), displaying a specific expression pattern within the Acb. Following the characterization of the molecular identity of WFS1 neurons, we evaluated the behavioral effect of temporally controlled deletion of D2R from this neuronal subpopulation ( Wfs1-CreERT2:Drd2 loxP/loxP mice, hereafter named D2R-cKO). We found that D2R-cKO mice displayed altered digging behavior and an exacerbated hyperlocomotor response to amphetamine. Together, our cell type- and region-specific high-throughput analyses uncover previously unknown molecularly and functionally defined subpopulations of D2R neurons and hence reveal novel striatal subcircuits. As a proof of principle, the deletion of D2R from one of these subpopulations identified, WFS1 SPNs, revealed a novel D2R’s role in an innate behavior as well as in response to a drug of abuse. Results Uncovering region-specific molecular markers of striatal D2R neurons To identify genes that are preferentially expressed in DS and Acb D2R neurons, we generated D2-RiboTag mice 15 , which express the Cre-dependent ribosomal protein rpl22 tagged with the hemagglutinin (HA) epitope exclusively in D2R cells (Fig. 1a, b ). HA expression —which was selective to iSPNs and CINs 16 , and homogeneously spread in both DS and Acb (Fig. 1a, b and Supplementary Fig. 1 a)— enabled the immunoprecipitation of ribosome-bound associated mRNAs selectively from D2R cells. To validate the specificity of the mouse line, we used quantitative reverse transcription PCR (qRT-PCR) to compare the relative abundance of transcripts after HA-immunoprecipitation on whole striatal extracts and the input fraction that contains transcripts from all cell types (Supplementary Fig. 1 b). As expected, expression of iSPN markers ( Drd2 , Adora2 , Penk1 ) was enriched after HA-immunoprecipitation (Fig. 1b ). By contrast, gene expression of markers for direct pathway SPNs (dSPNs) ( Drd1 , Pdyn , Tac1 ), astrocytes ( Gfap ), microglia ( Aif1 ), oligodendrocytes ( Cnp ), as well as GABAergic interneuron-specific markers ( Sst , Calb2 , Pvalb , Npy ) were all decreased. No differences were observed for Chat (only a fraction of CINs express D2R, see below) and Th transcripts (Fig. 1b ). Fig. 1: Translatome profile of DS and Acb D2R neurons using D2-Ribotag mice. a Coronal striatal section of D2-RiboTag mice stained with HA (cyan) and DARPP-32 (orange), PV (parvalbumin), CR (calretinin), NPY (neuropeptide Y), or SOM (somatostatin). Note the selective HA expression in ~50% of SPNs (DARPP-32-positive) corresponding to iSPNs and in CINs (arrowhead). b Drawing summarizing HA expression (cyan) among the distinct striatal cell types and validation by qRT-PCR (ΔΔCT) of the enrichment of iSPN markers and de-enrichment of dSPNs, interneurons, and glial cells markers after HA-immunoprecipitation on whole striatal extract (DS and Acb) compared with the input fraction (containing the mRNAs from all cellular types) ( n = 4 mice/group). Data are presented as mean values", "role": "user" }, { "content": "An international collaboration, which included the involvement of the research team from the Institut de Neurociències of the UAB (INC-UAB), has shown that neurons expressing dopamine D2 receptors have different molecular features and functions, depending on their anatomical localization within the striatum. This research, conducted with mouse models and published in Nature Communications, opens the door to develop better treatments for diseases in which dopamine is altered, such as schizophrenia, addictions and Parkinson's disease. The striatum is a brain region involved in motor control, habit formation, decision-making, motivation and reinforcement, among other aspects, and its dysfunction has been associated with many neurological and psychiatric disorders. One of the most important neurotransmitters in the striatum is dopamine, which exerts different functions depending on the kind of receptor it binds to. This study has focused on D2 receptors, and has shown that, contrary to paradigm, not all D2 neurons within the striatum have the same molecular identify or function, but that their neuro-anatomical localization is key. Researchers identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. \"These results show that there is significant molecular and functional heterogeneity of neuronal populations in the striatum. If we know them better, we will be able to be more selective in the design of treatments for diseases in which dopamine levels are altered, such as in schizophrenia or Parkinson's disease,\" says Emma Puighermanal-Puigvert, first author of the article. \"The more specific we are with our therapeutic target, the less secondary effects will appear.\" The work was conducted by an international collaboration of researchers in which Albert Quintana and Elisenda Sanz, from the INC-UAB, also participated. Using cutting-edge technologies, they analyzed mouse models to see what genes are expressed in D2 neurons from the two main areas of the striatum: the ventral striatum, consisting mainly of the nucleus accumbens, and the dorsal striatum, and revealed overwhelming differences among them. Thus, depending on their precise anatomical location, they express different kinds of proteins, changing neurons' features and functions. In this research, scientists also focused on a group of neurons mainly located in the accumbens, which express the protein WFS1, and studied the effects of deleting their D2 receptors. What they observed was a significant reduction in digging, an innate behavior used in many species to seek or hoard food, as shelter, or to hide away from predators, whose underlying neuronal mechanisms were still unknown. Additionally, the authors found that these animals present an exacerbated hyperlocomotor response when their dopamine levels are increased through amphetamine administration, suggesting a key role of D2 receptors from WFS1 neurons in the response to psychostimulants. Overall, this study demonstrates that there is a huge complexity and functional specificity among D2 neuron subpopulations, and reveals the possibility to manipulate them specifically to better understand their functions, in both physiological and pathological contexts. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R’s functional features in the control of specific motor behaviors. Introduction The striatum is the gateway to the basal ganglia, an ensemble of subcortical structures involved in motor planning and action selection 1 . Striatal dysfunction has been associated with multiple neurological and psychiatric disorders, including Parkinson’s and Huntington’s disease, Tourette’s syndrome, schizophrenia, autism, and addiction 2 , 3 . In the striatum, dopamine D2 receptors (D2R) have been tightly linked to a wide variety of motor- and reward/aversion-related behaviors. Pharmacological and genetic studies have demonstrated a direct involvement of D2R neurons in a wide range of functions including motor control 4 , 5 , 6 , aversive learning 7 , addiction 8 , compulsive food-intake 9 , motivational aspects of chronic pain 10 , and risky decision-making 11 . However, many of these studies used optogenetic or chemogenetic approaches to manipulate D2R neurons, but they did not assess the function of D2R itself in these neurons. Imaging studies in humans and rats have shown a significant reduction in striatal D2R availability in subjects addicted to drugs such as cocaine, alcohol, heroin, nicotine, and methamphetamine as well as in obesity 12 . However, the widespread expression of striatal D2R—which are present in indirect pathway striatal projection neurons (iSPNs), cholinergic interneurons (CINs), and presynaptically in both dopaminergic and glutamatergic afferents—have impeded the interpretation of many pharmacological and behavioral experiments. Our understanding of the complexity of striatal D2R expression pattern and its associated function has recently increased with a study reporting a relative heterogeneity of iSPN subpopulations 13 . In addition, the majority of studies that aimed to uncover the role of D2R, by using either global or conditional D2R knockout mice, could not rule out developmental compensatory adaptations from deleting D2R early in life, since their genetic approaches were not temporally controlled. Given that the rodent striatum is divided into two regions, the dorsal striatum (DS) and the nucleus accumbens (Acb), which have distinct input–output organization and play different roles in behavior 1 , 14 , we first aimed to identify DS- and Acb-specific molecular markers, which may serve as tools to assess the role of D2R in striatal subpopulations in adult mice. Therefore, we performed RNAseq in DS and Acb D2R neurons separately followed by histological analyses and revealed hundreds of region-specific markers. As a proof of concept, we focused on a cell subpopulation, identified by the expression of Wolfram syndrome 1 ( Wfs1 ), displaying a specific expression pattern within the Acb. Following the characterization of the molecular identity of WFS1 neurons, we evaluated the behavioral effect of temporally controlled deletion of D2R from this neuronal subpopulation ( Wfs1-CreERT2:Drd2 loxP/loxP mice, hereafter named D2R-cKO). We found that D2R-cKO mice displayed altered digging behavior and an exacerbated hyperlocomotor response to amphetamine. Together, our cell type- and region-specific high-throughput analyses uncover previously unknown molecularly and functionally defined subpopulations of D2R neurons and hence reveal novel striatal subcircuits. As a proof of principle, the deletion of D2R from one of these subpopulations identified, WFS1 SPNs, revealed a novel D2R’s role in an innate behavior as well as in response to a drug of abuse. Results Uncovering region-specific molecular markers of striatal D2R neurons To identify genes that are preferentially expressed in DS and Acb D2R neurons, we generated D2-RiboTag mice 15 , which express the Cre-dependent ribosomal protein rpl22 tagged with the hemagglutinin (HA) epitope exclusively in D2R cells (Fig. 1a, b ). HA expression —which was selective to iSPNs and CINs 16 , and homogeneously spread in both DS and Acb (Fig. 1a, b and Supplementary Fig. 1 a)— enabled the immunoprecipitation of ribosome-bound associated mRNAs selectively from D2R cells. To validate the specificity of the mouse line, we used quantitative reverse transcription PCR (qRT-PCR) to compare the relative abundance of transcripts after HA-immunoprecipitation on whole striatal extracts and the input fraction that contains transcripts from all cell types (Supplementary Fig. 1 b). As expected, expression of iSPN markers ( Drd2 , Adora2 , Penk1 ) was enriched after HA-immunoprecipitation (Fig. 1b ). By contrast, gene expression of markers for direct pathway SPNs (dSPNs) ( Drd1 , Pdyn , Tac1 ), astrocytes ( Gfap ), microglia ( Aif1 ), oligodendrocytes ( Cnp ), as well as GABAergic interneuron-specific markers ( Sst , Calb2 , Pvalb , Npy ) were all decreased. No differences were observed for Chat (only a fraction of CINs express D2R, see below) and Th transcripts (Fig. 1b ). Fig. 1: Translatome profile of DS and Acb D2R neurons using D2-Ribotag mice. a Coronal striatal section of D2-RiboTag mice stained with HA (cyan) and DARPP-32 (orange), PV (parvalbumin), CR (calretinin), NPY (neuropeptide Y), or SOM (somatostatin). Note the selective HA expression in ~50% of SPNs (DARPP-32-positive) corresponding to iSPNs and in CINs (arrowhead). b Drawing summarizing HA expression (cyan) among the distinct striatal cell types and validation by qRT-PCR (ΔΔCT) of the enrichment of iSPN markers and de-enrichment of dSPNs, interneurons, and glial cells markers after HA-immunoprecipitation on whole striatal extract (DS and Acb) compared with the input fraction (containing the mRNAs from all cellular types) ( n = 4 mice/group). Data are presented as mean values<|im_end|> <|im_start|>assistant An international collaboration, which included the involvement of the research team from the Institut de Neurociències of the UAB (INC-UAB), has shown that neurons expressing dopamine D2 receptors have different molecular features and functions, depending on their anatomical localization within the striatum. This research, conducted with mouse models and published in Nature Communications, opens the door to develop better treatments for diseases in which dopamine is altered, such as schizophrenia, addictions and Parkinson's disease. The striatum is a brain region involved in motor control, habit formation, decision-making, motivation and reinforcement, among other aspects, and its dysfunction has been associated with many neurological and psychiatric disorders. One of the most important neurotransmitters in the striatum is dopamine, which exerts different functions depending on the kind of receptor it binds to. This study has focused on D2 receptors, and has shown that, contrary to paradigm, not all D2 neurons within the striatum have the same molecular identify or function, but that their neuro-anatomical localization is key. Researchers identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. "These results show that there is significant molecular and functional heterogeneity of neuronal populations in the striatum. If we know them better, we will be able to be more selective in the design of treatments for diseases in which dopamine levels are altered, such as in schizophrenia or Parkinson's disease," says Emma Puighermanal-Puigvert, first author of the article. "The more specific we are with our therapeutic target, the less secondary effects will appear." The work was conducted by an international collaboration of researchers in which Albert Quintana and Elisenda Sanz, from the INC-UAB, also participated. Using cutting-edge technologies, they analyzed mouse models to see what genes are expressed in D2 neurons from the two main areas of the striatum: the ventral striatum, consisting mainly of the nucleus accumbens, and the dorsal striatum, and revealed overwhelming differences among them. Thus, depending on their precise anatomical location, they express different kinds of proteins, changing neurons' features and functions. In this research, scientists also focused on a group of neurons mainly located in the accumbens, which express the protein WFS1, and studied the effects of deleting their D2 receptors. What they observed was a significant reduction in digging, an innate behavior used in many species to seek or hoard food, as shelter, or to hide away from predators, whose underlying neuronal mechanisms were still unknown. Additionally, the authors found that these animals present an exacerbated hyperlocomotor response when their dopamine levels are increased through amphetamine administration, suggesting a key role of D2 receptors from WFS1 neurons in the response to psychostimulants. Overall, this study demonstrates that there is a huge complexity and functional specificity among D2 neuron subpopulations, and reveals the possibility to manipulate them specifically to better understand their functions, in both physiological and pathological contexts. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Two-dimensional (2D) materials have emerged as promising candidates for next-generation electronic and optoelectronic applications. Yet, only a few dozen 2D materials have been successfully synthesized or exfoliated. Here, we search for 2D materials that can be easily exfoliated from their parent compounds. Starting from 108,423 unique, experimentally known 3D compounds, we identify a subset of 5,619 compounds that appear layered according to robust geometric and bonding criteria. High-throughput calculations using van der Waals density functional theory, validated against experimental structural data and calculated random phase approximation binding energies, further allowed the identification of 1,825 compounds that are either easily or potentially exfoliable. In particular, the subset of 1,036 easily exfoliable cases provides novel structural prototypes and simple ternary compounds as well as a large portfolio of materials to search from for optimal properties. For a subset of 258 compounds, we explore vibrational, electronic, magnetic and topological properties, identifying 56 ferromagnetic and antiferromagnetic systems, including half-metals and half-semiconductors. Main Two-dimensional (2D) materials provide opportunities to venture into largely unexplored regions of the materials space. On the one hand, their ultimate thinness makes them extremely promising for applications in electronics 1 , 2 . On the other, the physical properties of monolayers often change dramatically from those of their parent 3D materials, providing a new degree of freedom 3 for applications while also unveiling novel physics (for example, the valley Hall effect and composite excitations such as trions). Moreover, van der Waals (vdW) heterostructures 4 have recently emerged as an additional avenue to engineer new properties by stacking 2D materials in a desired fashion. Progress in this area would be strongly accelerated by the availability of a broad portfolio of 2D candidate materials. To illustrate this point, we can compare the current situation for known 3D crystals, for which the knowledge accumulated in the past century (both crystal structures and measured physical properties) has been collected in databases such as the Pauling file 5 , the Inorganic Crystal Structure Database 6 (ICSD) or the Crystallographic Open Database 7 (COD) (the latter two combined contain, to date, over half a million entries). In comparison, 2D materials databases are still scarce and limited in size: a first scan of the ICSD identified 92 2D compounds 8 (including Cu 2 S, subsequently synthesized 9 ). This was followed by 103 compounds selected among specific classes 10 , while a recent study focused on transition-metal dichalcogenides and oxides, identifying 51 of them as stable 11 . More extensive efforts 12 , 13 have also been put forward to expand the set of prospective 2D materials by screening crystal structures from the Materials Project 14 . In fact, high-throughput computational methods represent a powerful tool 15 for exploring materials space and for screening materials without having to synthesize them first 16 , 17 , 18 , 19 , 20 . For instance, these techniques have been successfully employed in the search for materials for Li–air and Li-ion batteries 21 , 22 , for hydrogen storage 23 , scintillators 24 , electrocatalysts 25 , or to accelerate the discovery of light-absorbing materials 26 . Here, we systematically explore experimentally known compounds for possible exfoliation, paying particular attention to the mechanical stability of the exfoliated layers and the changes in the electronic structure that take place in reducing dimensionality—from the emergence of magnetic order to charge-density-wave instabilities. We perform this search starting from the inorganic compounds recorded in the ICSD and the COD, and then use vdW density functional theory (DFT) simulations to test these 3D parents for possible exfoliation. In particular, we compute the binding energy of 2,662 prospective layered structures and identify those that are held together by weak interactions and are ready for mechanical 27 or liquid-phase 28 exfoliation. This results in a portfolio of 1,825 materials that can be exfoliated in monolayers or multilayers. To showcase their potential, we explore the electronic, vibrational, magnetic and topological properties of 258 of the most promising systems, disclosing a number of functional materials that can be studied experimentally, notably including 56 magnetically ordered monolayers. The reproducibility of all results is ensured by the deployment of the AiiDA 29 materials’ informatics infrastructure, which keeps track of the full provenance of each calculation and result. Identification of layered compounds The search protocol starts from a comprehensive initial set of bulk 3D crystal structures extracted from the ICSD 6 and COD 7 databases, containing, respectively, 177,343 (ICSD 2015.1) and 351,589 entries (COD revision 171462). Entries containing at most 6 different species are retrieved in the form of Crystallographic Information Files (CIF), correcting typical syntax errors 30 . We exclude structures with partial occupancies in the unit cell, those that are incompletely defined or are obviously incorrect, as well as theoretical structures that do not have an experimental counterpart. We then parse the CIF files using pymatgen 31 , refine the atomic positions in the primitive cell with the spglib library 32 , and finally remove duplicate structures (see Methods ). This procedure provides a starting point of 108,423 unique 3D crystal structures (set A, see Table 1 ), that can then be analysed to find promising candidates for exfoliation, that is, composed of chemically bonded manifolds held together by weak vdW interactions. Generalizing the pioneering effort of Lebègue and co-authors 8 , we implement a protocol shown schematically in Fig. 1a and detailed in the Methods . Chemically bonded subunits are identified heuristically by comparing interatomic distances to the vdW radii 33 of the atoms involved. The dimensionality of each connected manifold is then obtained from the rank of the 3D lattice vectors embedded into the manifold (see Methods ). Table 1 Database statistics Full size table Fig. 1: Screening for low-dimensional manifolds in a parent 3D crystal. a , Schematic showing the fundamental steps needed to find low-dimensional subunits of a parent 3D crystal (here MgPS 3 ). From left to right: a 3 × 3 × 3 supercell of the bulk primitive cell is constructed, chemical bonds are", "role": "user" }, { "content": "A team from EPFL and NCCR Marvel has identified more than 1,000 materials with a particularly interesting 2-D structure. Their research, published in Nature Nanotechnlogy, paves the way for groundbreaking technological applications. 2-D materials, which consist of a few layers of atoms, are considered the future of nanotechnology. They offer potential new applications and could be used in small, higher-performance and more energy-efficient devices. Two-dimensional materials were first discovered almost 15 years ago, but only a few dozen of them have been synthesized so far. Now, thanks to an approach developed by researchers from EPFL's Theory and Simulation of Materials Laboratory (THEOS) and from NCCR-MARVEL for Computational Design and Discovey of Novel Materials, many more promising 2-D materials may be identified. Their work was recently published in the journal Nature Nanotechnology. The first 2-D material isolated was graphene, in 2004, earning its discoverers a Nobel Prize in 2010. This marked the start of a whole new era in electronics, as graphene is light, transparent and resilient and, above all, a good conductor of electricity. It paved the way to new applications in such fields as photovoltaics and optoelectronics. \"To find other materials with similar properties, we focused on the feasibility of exfoliation,\" explains Nicolas Mounet, a researcher in the THEOS lab and lead author of the study. \"But instead of placing adhesive strips on graphite to see if the layers peeled off, like the Nobel Prize winners did, we used a digital method.\" The researchers developed an algorithm to review and carefully analyze the structure of more than 100,000 3-D materials recorded in external databases. From this, they created a database of around 5,600 potential 2-D materials, including more than 1,000 with particularly promising properties. In other words, they've created a treasure trove for nanotechnology experts. To build their database, the researchers used a step-by-step process of elimination. First, they identified all of the materials that are made up of separate layers. \"We then studied the chemistry of these materials in greater detail and calculated the energy that would be needed to separate the layers, focusing primarily on materials where interactions between atoms of different layers are weak, something known as Van der Waals bonding,\" says Marco Gibertini, a researcher at THEOS and the second author of the study. Of the 5,600 materials initially identified, the researchers singled out 1,800 structures that could potentially be exfoliated, including 1,036 that looked especially easy to exfoliate. This represents a considerable increase in the number of possible 2-D materials known today. They then selected the 258 most promising materials, categorizing them according to their magnetic, electronic, mechanical, thermal and topological properties. \"Our study demonstrates that digital techniques can really boost discoveries of new materials,\" says Nicola Marzari, the director of NCCR-MARVEL and a professor at THEOS. \"In the past, chemists had to start from scratch and just keep trying different things, which required hours of lab work and a certain amount of luck. With our approach, we can avoid this long, frustrating process because we have a tool that can single out the materials that are worth studying further, allowing us to conduct more focused research.\" It is also possible to reproduce the researchers' calculations thanks to their software AiiDA, which describes the calculation process for each material discovered in the form of workflows and stores the full provenance of each stage of the calculation. \"Without AiiDA, it would have been very difficult to combine and process different types of data,\" explains Giovanni Pizzi, a senior researcher at THEOS and co-author of the study. \"Our workflows are available to the public, so anyone in the world can reproduce our calculations and apply them to any material to find out if it can be exfoliated.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Two-dimensional (2D) materials have emerged as promising candidates for next-generation electronic and optoelectronic applications. Yet, only a few dozen 2D materials have been successfully synthesized or exfoliated. Here, we search for 2D materials that can be easily exfoliated from their parent compounds. Starting from 108,423 unique, experimentally known 3D compounds, we identify a subset of 5,619 compounds that appear layered according to robust geometric and bonding criteria. High-throughput calculations using van der Waals density functional theory, validated against experimental structural data and calculated random phase approximation binding energies, further allowed the identification of 1,825 compounds that are either easily or potentially exfoliable. In particular, the subset of 1,036 easily exfoliable cases provides novel structural prototypes and simple ternary compounds as well as a large portfolio of materials to search from for optimal properties. For a subset of 258 compounds, we explore vibrational, electronic, magnetic and topological properties, identifying 56 ferromagnetic and antiferromagnetic systems, including half-metals and half-semiconductors. Main Two-dimensional (2D) materials provide opportunities to venture into largely unexplored regions of the materials space. On the one hand, their ultimate thinness makes them extremely promising for applications in electronics 1 , 2 . On the other, the physical properties of monolayers often change dramatically from those of their parent 3D materials, providing a new degree of freedom 3 for applications while also unveiling novel physics (for example, the valley Hall effect and composite excitations such as trions). Moreover, van der Waals (vdW) heterostructures 4 have recently emerged as an additional avenue to engineer new properties by stacking 2D materials in a desired fashion. Progress in this area would be strongly accelerated by the availability of a broad portfolio of 2D candidate materials. To illustrate this point, we can compare the current situation for known 3D crystals, for which the knowledge accumulated in the past century (both crystal structures and measured physical properties) has been collected in databases such as the Pauling file 5 , the Inorganic Crystal Structure Database 6 (ICSD) or the Crystallographic Open Database 7 (COD) (the latter two combined contain, to date, over half a million entries). In comparison, 2D materials databases are still scarce and limited in size: a first scan of the ICSD identified 92 2D compounds 8 (including Cu 2 S, subsequently synthesized 9 ). This was followed by 103 compounds selected among specific classes 10 , while a recent study focused on transition-metal dichalcogenides and oxides, identifying 51 of them as stable 11 . More extensive efforts 12 , 13 have also been put forward to expand the set of prospective 2D materials by screening crystal structures from the Materials Project 14 . In fact, high-throughput computational methods represent a powerful tool 15 for exploring materials space and for screening materials without having to synthesize them first 16 , 17 , 18 , 19 , 20 . For instance, these techniques have been successfully employed in the search for materials for Li–air and Li-ion batteries 21 , 22 , for hydrogen storage 23 , scintillators 24 , electrocatalysts 25 , or to accelerate the discovery of light-absorbing materials 26 . Here, we systematically explore experimentally known compounds for possible exfoliation, paying particular attention to the mechanical stability of the exfoliated layers and the changes in the electronic structure that take place in reducing dimensionality—from the emergence of magnetic order to charge-density-wave instabilities. We perform this search starting from the inorganic compounds recorded in the ICSD and the COD, and then use vdW density functional theory (DFT) simulations to test these 3D parents for possible exfoliation. In particular, we compute the binding energy of 2,662 prospective layered structures and identify those that are held together by weak interactions and are ready for mechanical 27 or liquid-phase 28 exfoliation. This results in a portfolio of 1,825 materials that can be exfoliated in monolayers or multilayers. To showcase their potential, we explore the electronic, vibrational, magnetic and topological properties of 258 of the most promising systems, disclosing a number of functional materials that can be studied experimentally, notably including 56 magnetically ordered monolayers. The reproducibility of all results is ensured by the deployment of the AiiDA 29 materials’ informatics infrastructure, which keeps track of the full provenance of each calculation and result. Identification of layered compounds The search protocol starts from a comprehensive initial set of bulk 3D crystal structures extracted from the ICSD 6 and COD 7 databases, containing, respectively, 177,343 (ICSD 2015.1) and 351,589 entries (COD revision 171462). Entries containing at most 6 different species are retrieved in the form of Crystallographic Information Files (CIF), correcting typical syntax errors 30 . We exclude structures with partial occupancies in the unit cell, those that are incompletely defined or are obviously incorrect, as well as theoretical structures that do not have an experimental counterpart. We then parse the CIF files using pymatgen 31 , refine the atomic positions in the primitive cell with the spglib library 32 , and finally remove duplicate structures (see Methods ). This procedure provides a starting point of 108,423 unique 3D crystal structures (set A, see Table 1 ), that can then be analysed to find promising candidates for exfoliation, that is, composed of chemically bonded manifolds held together by weak vdW interactions. Generalizing the pioneering effort of Lebègue and co-authors 8 , we implement a protocol shown schematically in Fig. 1a and detailed in the Methods . Chemically bonded subunits are identified heuristically by comparing interatomic distances to the vdW radii 33 of the atoms involved. The dimensionality of each connected manifold is then obtained from the rank of the 3D lattice vectors embedded into the manifold (see Methods ). Table 1 Database statistics Full size table Fig. 1: Screening for low-dimensional manifolds in a parent 3D crystal. a , Schematic showing the fundamental steps needed to find low-dimensional subunits of a parent 3D crystal (here MgPS 3 ). From left to right: a 3 × 3 × 3 supercell of the bulk primitive cell is constructed, chemical bonds are<|im_end|> <|im_start|>assistant A team from EPFL and NCCR Marvel has identified more than 1,000 materials with a particularly interesting 2-D structure. Their research, published in Nature Nanotechnlogy, paves the way for groundbreaking technological applications. 2-D materials, which consist of a few layers of atoms, are considered the future of nanotechnology. They offer potential new applications and could be used in small, higher-performance and more energy-efficient devices. Two-dimensional materials were first discovered almost 15 years ago, but only a few dozen of them have been synthesized so far. Now, thanks to an approach developed by researchers from EPFL's Theory and Simulation of Materials Laboratory (THEOS) and from NCCR-MARVEL for Computational Design and Discovey of Novel Materials, many more promising 2-D materials may be identified. Their work was recently published in the journal Nature Nanotechnology. The first 2-D material isolated was graphene, in 2004, earning its discoverers a Nobel Prize in 2010. This marked the start of a whole new era in electronics, as graphene is light, transparent and resilient and, above all, a good conductor of electricity. It paved the way to new applications in such fields as photovoltaics and optoelectronics. "To find other materials with similar properties, we focused on the feasibility of exfoliation," explains Nicolas Mounet, a researcher in the THEOS lab and lead author of the study. "But instead of placing adhesive strips on graphite to see if the layers peeled off, like the Nobel Prize winners did, we used a digital method." The researchers developed an algorithm to review and carefully analyze the structure of more than 100,000 3-D materials recorded in external databases. From this, they created a database of around 5,600 potential 2-D materials, including more than 1,000 with particularly promising properties. In other words, they've created a treasure trove for nanotechnology experts. To build their database, the researchers used a step-by-step process of elimination. First, they identified all of the materials that are made up of separate layers. "We then studied the chemistry of these materials in greater detail and calculated the energy that would be needed to separate the layers, focusing primarily on materials where interactions between atoms of different layers are weak, something known as Van der Waals bonding," says Marco Gibertini, a researcher at THEOS and the second author of the study. Of the 5,600 materials initially identified, the researchers singled out 1,800 structures that could potentially be exfoliated, including 1,036 that looked especially easy to exfoliate. This represents a considerable increase in the number of possible 2-D materials known today. They then selected the 258 most promising materials, categorizing them according to their magnetic, electronic, mechanical, thermal and topological properties. "Our study demonstrates that digital techniques can really boost discoveries of new materials," says Nicola Marzari, the director of NCCR-MARVEL and a professor at THEOS. "In the past, chemists had to start from scratch and just keep trying different things, which required hours of lab work and a certain amount of luck. With our approach, we can avoid this long, frustrating process because we have a tool that can single out the materials that are worth studying further, allowing us to conduct more focused research." It is also possible to reproduce the researchers' calculations thanks to their software AiiDA, which describes the calculation process for each material discovered in the form of workflows and stores the full provenance of each stage of the calculation. "Without AiiDA, it would have been very difficult to combine and process different types of data," explains Giovanni Pizzi, a senior researcher at THEOS and co-author of the study. "Our workflows are available to the public, so anyone in the world can reproduce our calculations and apply them to any material to find out if it can be exfoliated." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Advanced oxidation processes that utilize highly oxidative radicals are widely used in water reuse treatment. In recent years, the application of sulfate radical (SO 4 ˙ − ) as a promising oxidant for water treatment has gained increasing attention. To understand the efficiency of SO 4 ˙ − in the degradation of organic contaminants in wastewater effluent, it is important to be able to predict the reaction kinetics of various SO 4 ˙ − -driven oxidation reactions. In this study, we utilize density functional theory (DFT) and high-level wavefunction-based methods (including computationally-intensive coupled cluster methods), to explore the activation energies of SO 4 ˙ − -driven oxidation reactions on a series of benzene-derived contaminants. These high-level calculations encompass a wide set of reactions including 110 forward/reverse reactions and 5 different computational methods in total. Based on the high-level coupled-cluster quantum calculations, we find that the popular M06-2X DFT functional is significantly more accurate for OH − additions than for SO 4 ˙ − reactions. Most importantly, we highlight some of the limitations and deficiencies of other computational methods, and we recommend the use of high-level quantum calculations to spot-check environmental chemistry reactions that may lie outside the training set of the M06-2X functional, particularly for water oxidation reactions that involve SO 4 ˙ − and other inorganic species. This article is part of the themed collection: QSARs and computational chemistry methods in environmental chemical sciences Environmental impact Sulfate radical (SO 4 ˙ − ) is a promising oxidant for water treatment that has gained increasing attention in environmental chemistry; however, our understanding of the fundamental reaction kinetics and activation energies of SO 4 ˙ − -driven oxidation processes on trace organic contaminants is still severely limited. Predictive quantum chemical methods provide a rational path forward to explore these complex reactions, but the accuracy of commonly used density functional theory (DFT) methods on SO 4 ˙-driven oxidation, in particular, is not well understood. This work demonstrates that widely-used DFT methods perform quite accurately for conventional reactions of benzene-based contaminants, but we recommend the use of high-level quantum calculations to spot-check environmental chemistry reactions that may lie outside the training set of some DFT functionals, particularly for oxidation reactions that involve SO 4 ˙ − and other inorganic compounds. Introduction Water scarcity has become a global crisis. This situation is exacerbated – and will continue to be dominated – by the global shrinkage of surface water sources and notably sharp decreases caused by extreme climate conditions. 1,2 Municipal wastewater reuse offers the potential to significantly increase a nation's total available water resources. Approximately 12 billion gallons of municipal wastewater effluent are discharged each day in the U.S., which is equivalent to 27% of the total public water supply. 3 However, only about 10% of the wastewater effluent is actively reused nationwide. 3 One major challenge to recycling is the development of efficient and cost-effective purification processes. Wastewater effluent is widely compromised by sewage produced from growing populations, industries, and agriculture. Trace organic chemicals including petroleum hydrocarbons, pharmaceuticals, personal care products, and industrial solvents are often present in the effluent. 4–13 To minimize the presence of trace organic chemicals, different advanced oxidation processes (AOPs) have been employed. 14–19 The most widely applied approach is based on the photolysis of hydrogen peroxide (H 2 O 2 ) to produce hydroxyl radical (HO˙). In recent years, sulfate radical (SO 4 ˙ − ) has garnered much attention as an alternative oxidant for AOP. 20–22 In these processes, SO 4 ˙ − is typically generated via UV photolysis of persulfate (S 2 O 8 2− ) for water reuse applications. 23–26 SO 4 ˙ − has a similar oxidizing power to HO˙, yet possesses selectively higher reaction rates with electron-rich contaminants that are typically observed in wastewater effluent. 27–30 Due to a higher quantum yield, the rate of S 2 O 8 2− photolysis is 40% higher than that of H 2 O 2 under UV irradiation at 254 nm (a typical wavelength used in UV lamps). 31 Furthermore, the scavenging effect of S 2 O 8 2− on SO 4 ˙ − is two orders of magnitude lower than the scavenging effect of H 2 O 2 on HO˙, 32,33 which leads to a higher yield of SO 4 ˙ − from S 2 O 8 2− than that of HO˙ from H 2 O 2 . These chemical features make SO 4 ˙ − -based AOP an attractive option for water reuse. Considering these prospective applications of SO 4 ˙ − -based oxidation processes for water reuse, it is important to predict the reaction kinetics of SO 4 ˙ − -driven oxidation reactions with organic contaminants that are present in wastewater effluent. Although some of the radical-driven rate constants can be measured using experimental techniques, e.g. , electron pulse radiolysis and γ radiation, 34,35 it is logistically unrealistic to experimentally measure the rates of every contaminant with short-lived radical species. In addition, the activation energies of SO 4 ˙ − with different benzene-derived contaminants are largely unknown, and understanding the activation energies in possible degradation pathways of organic contaminants on a fundamental level are required for predicting byproduct formation in SO 4 ˙ − -based oxidative water treatment. Recently, density functional theory (DFT) calculations have started to become commonplace as computational tools for predicting reaction mechanisms and activation energies in redox reactions of environmental significance. There has been recent work using quantum chemical techniques to estimate reaction barriers and thermodynamic relations in the degradation of trace organic contaminants, especially via the oxidation of HO˙ or ozone (O 3 ). 36–41 Due to the complexity of the chemical species examined, these prior studies largely used popular computationally-efficient DFT methods to systematically explore and assess the reactivities of contaminants in the aqueous phase. However, most DFT methods are heavily parameterized against a training set of benchmark molecules, i.e. , typically organic compounds containing only hydrogen, carbon, nitrogen, and oxygen. 42–44 Specifically, these DFT methods were", "role": "user" }, { "content": "Turning on the faucet and not getting clean water, or any water at all, is a global issue. Cleaning wastewater could help make more water available. In delving into the nuances of wastewater purification, scientists often use computational chemistry approaches. Which is best? Researchers examined five options using 110 reactions associated with a highly reactive sulfate radical breaking apart a contaminant (benzene). They suggest using high-level quantum calculations to spot-check reactions involving the sulfate radical and other inorganic species. Scientists often use computational chemistry methods to predict reactions of major contaminants in water. They want to understand how new water purification methods, such as using sulfate radicals, work. This study helps scientists pick the most accurate method. The availability of fresh water is a global issue that's driving interest in ways to turn wastewater into clean water. Purifying wastewater that contains traces of benzene and other chemicals could make more water available. The challenge is cleaning it. In certain approaches, highly reactive chemicals, called radicals, are used. Scientists are interested in using a highly reactive, highly efficient sulfate radical. It can break down, or oxidize, trace amounts of certain contaminants, but scientists want to know exactly how the sulfate radical works. Computational chemistry provides a predictive path to probe and assess oxidation reactions, but what are the benefits and limitations of each approach? Now, a team analyzed five computational methods, including density functional theory (DFT). They did the analysis with a wide set of reactions (110 in total) that play a key role in sulfate-based oxidation processes. They showed that the DFT methods perform quite accurately for conventional reactions of benzene-based contaminants. However, sulfate radical research benefits from high-level quantum calculations to spot check reactions and ensure that the kinetic and thermodynamic data accurately predict the reactions involving the sulfate radical and other inorganic compounds. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Advanced oxidation processes that utilize highly oxidative radicals are widely used in water reuse treatment. In recent years, the application of sulfate radical (SO 4 ˙ − ) as a promising oxidant for water treatment has gained increasing attention. To understand the efficiency of SO 4 ˙ − in the degradation of organic contaminants in wastewater effluent, it is important to be able to predict the reaction kinetics of various SO 4 ˙ − -driven oxidation reactions. In this study, we utilize density functional theory (DFT) and high-level wavefunction-based methods (including computationally-intensive coupled cluster methods), to explore the activation energies of SO 4 ˙ − -driven oxidation reactions on a series of benzene-derived contaminants. These high-level calculations encompass a wide set of reactions including 110 forward/reverse reactions and 5 different computational methods in total. Based on the high-level coupled-cluster quantum calculations, we find that the popular M06-2X DFT functional is significantly more accurate for OH − additions than for SO 4 ˙ − reactions. Most importantly, we highlight some of the limitations and deficiencies of other computational methods, and we recommend the use of high-level quantum calculations to spot-check environmental chemistry reactions that may lie outside the training set of the M06-2X functional, particularly for water oxidation reactions that involve SO 4 ˙ − and other inorganic species. This article is part of the themed collection: QSARs and computational chemistry methods in environmental chemical sciences Environmental impact Sulfate radical (SO 4 ˙ − ) is a promising oxidant for water treatment that has gained increasing attention in environmental chemistry; however, our understanding of the fundamental reaction kinetics and activation energies of SO 4 ˙ − -driven oxidation processes on trace organic contaminants is still severely limited. Predictive quantum chemical methods provide a rational path forward to explore these complex reactions, but the accuracy of commonly used density functional theory (DFT) methods on SO 4 ˙-driven oxidation, in particular, is not well understood. This work demonstrates that widely-used DFT methods perform quite accurately for conventional reactions of benzene-based contaminants, but we recommend the use of high-level quantum calculations to spot-check environmental chemistry reactions that may lie outside the training set of some DFT functionals, particularly for oxidation reactions that involve SO 4 ˙ − and other inorganic compounds. Introduction Water scarcity has become a global crisis. This situation is exacerbated – and will continue to be dominated – by the global shrinkage of surface water sources and notably sharp decreases caused by extreme climate conditions. 1,2 Municipal wastewater reuse offers the potential to significantly increase a nation's total available water resources. Approximately 12 billion gallons of municipal wastewater effluent are discharged each day in the U.S., which is equivalent to 27% of the total public water supply. 3 However, only about 10% of the wastewater effluent is actively reused nationwide. 3 One major challenge to recycling is the development of efficient and cost-effective purification processes. Wastewater effluent is widely compromised by sewage produced from growing populations, industries, and agriculture. Trace organic chemicals including petroleum hydrocarbons, pharmaceuticals, personal care products, and industrial solvents are often present in the effluent. 4–13 To minimize the presence of trace organic chemicals, different advanced oxidation processes (AOPs) have been employed. 14–19 The most widely applied approach is based on the photolysis of hydrogen peroxide (H 2 O 2 ) to produce hydroxyl radical (HO˙). In recent years, sulfate radical (SO 4 ˙ − ) has garnered much attention as an alternative oxidant for AOP. 20–22 In these processes, SO 4 ˙ − is typically generated via UV photolysis of persulfate (S 2 O 8 2− ) for water reuse applications. 23–26 SO 4 ˙ − has a similar oxidizing power to HO˙, yet possesses selectively higher reaction rates with electron-rich contaminants that are typically observed in wastewater effluent. 27–30 Due to a higher quantum yield, the rate of S 2 O 8 2− photolysis is 40% higher than that of H 2 O 2 under UV irradiation at 254 nm (a typical wavelength used in UV lamps). 31 Furthermore, the scavenging effect of S 2 O 8 2− on SO 4 ˙ − is two orders of magnitude lower than the scavenging effect of H 2 O 2 on HO˙, 32,33 which leads to a higher yield of SO 4 ˙ − from S 2 O 8 2− than that of HO˙ from H 2 O 2 . These chemical features make SO 4 ˙ − -based AOP an attractive option for water reuse. Considering these prospective applications of SO 4 ˙ − -based oxidation processes for water reuse, it is important to predict the reaction kinetics of SO 4 ˙ − -driven oxidation reactions with organic contaminants that are present in wastewater effluent. Although some of the radical-driven rate constants can be measured using experimental techniques, e.g. , electron pulse radiolysis and γ radiation, 34,35 it is logistically unrealistic to experimentally measure the rates of every contaminant with short-lived radical species. In addition, the activation energies of SO 4 ˙ − with different benzene-derived contaminants are largely unknown, and understanding the activation energies in possible degradation pathways of organic contaminants on a fundamental level are required for predicting byproduct formation in SO 4 ˙ − -based oxidative water treatment. Recently, density functional theory (DFT) calculations have started to become commonplace as computational tools for predicting reaction mechanisms and activation energies in redox reactions of environmental significance. There has been recent work using quantum chemical techniques to estimate reaction barriers and thermodynamic relations in the degradation of trace organic contaminants, especially via the oxidation of HO˙ or ozone (O 3 ). 36–41 Due to the complexity of the chemical species examined, these prior studies largely used popular computationally-efficient DFT methods to systematically explore and assess the reactivities of contaminants in the aqueous phase. However, most DFT methods are heavily parameterized against a training set of benchmark molecules, i.e. , typically organic compounds containing only hydrogen, carbon, nitrogen, and oxygen. 42–44 Specifically, these DFT methods were<|im_end|> <|im_start|>assistant Turning on the faucet and not getting clean water, or any water at all, is a global issue. Cleaning wastewater could help make more water available. In delving into the nuances of wastewater purification, scientists often use computational chemistry approaches. Which is best? Researchers examined five options using 110 reactions associated with a highly reactive sulfate radical breaking apart a contaminant (benzene). They suggest using high-level quantum calculations to spot-check reactions involving the sulfate radical and other inorganic species. Scientists often use computational chemistry methods to predict reactions of major contaminants in water. They want to understand how new water purification methods, such as using sulfate radicals, work. This study helps scientists pick the most accurate method. The availability of fresh water is a global issue that's driving interest in ways to turn wastewater into clean water. Purifying wastewater that contains traces of benzene and other chemicals could make more water available. The challenge is cleaning it. In certain approaches, highly reactive chemicals, called radicals, are used. Scientists are interested in using a highly reactive, highly efficient sulfate radical. It can break down, or oxidize, trace amounts of certain contaminants, but scientists want to know exactly how the sulfate radical works. Computational chemistry provides a predictive path to probe and assess oxidation reactions, but what are the benefits and limitations of each approach? Now, a team analyzed five computational methods, including density functional theory (DFT). They did the analysis with a wide set of reactions (110 in total) that play a key role in sulfate-based oxidation processes. They showed that the DFT methods perform quite accurately for conventional reactions of benzene-based contaminants. However, sulfate radical research benefits from high-level quantum calculations to spot check reactions and ensure that the kinetic and thermodynamic data accurately predict the reactions involving the sulfate radical and other inorganic compounds. <|im_end|>

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247, 25173, 323, 1023, 304, 61694, 32246, 13, 29438, 10164, 82484, 706, 3719, 264, 3728, 11501, 13, 1115, 6671, 374, 92541, 1389, 323, 690, 3136, 311, 387, 30801, 1389, 555, 279, 3728, 30000, 425, 315, 7479, 3090, 8336, 323, 35146, 17676, 43154, 9057, 555, 14560, 10182, 4787, 13, 220, 16, 11, 17, 45340, 77681, 27068, 6209, 279, 4754, 311, 12207, 5376, 264, 7140, 596, 2860, 2561, 3090, 5070, 13, 79904, 220, 717, 7239, 51222, 315, 27512, 77681, 3369, 57167, 527, 57191, 1855, 1938, 304, 279, 549, 815, 2637, 902, 374, 13890, 311, 220, 1544, 4, 315, 279, 2860, 586, 3090, 8312, 13, 220, 18, 4452, 11, 1193, 922, 220, 605, 4, 315, 279, 77681, 3369, 57167, 374, 22815, 69843, 29054, 13, 220, 18, 3861, 3682, 8815, 311, 34978, 374, 279, 4500, 315, 11297, 323, 2853, 53421, 94536, 11618, 13, 468, 561, 48544, 3369, 57167, 374, 13882, 44500, 555, 72217, 9124, 505, 7982, 22673, 11, 19647, 11, 323, 30029, 13, 28262, 17808, 26333, 2737, 60063, 17055, 7063, 47620, 11, 35410, 82, 11, 4443, 2512, 3956, 11, 323, 13076, 2092, 48764, 527, 3629, 3118, 304, 279, 3369, 57167, 13, 220, 19, 4235, 1032, 2057, 30437, 279, 9546, 315, 11917, 17808, 26333, 11, 2204, 11084, 71162, 11618, 320, 32, 3143, 82, 8, 617, 1027, 20011, 13, 220, 975, 4235, 777, 578, 1455, 13882, 9435, 5603, 374, 3196, 389, 279, 4604, 337, 4548, 315, 35784, 824, 55189, 320, 39, 220, 17, 507, 220, 17, 883, 311, 8356, 17055, 87, 4010, 18336, 320, 24755, 135, 247, 570, 763, 3293, 1667, 11, 89418, 18336, 320, 14202, 220, 19, 220, 135, 247, 25173, 883, 706, 68390, 1790, 6666, 439, 459, 10778, 36172, 519, 369, 362, 3143, 13, 220, 508, 4235, 1313, 763, 1521, 11618, 11, 5745, 220, 19, 220, 135, 247, 25173, 374, 11383, 8066, 4669, 30136, 4604, 337, 4548, 315, 7565, 14643, 349, 320, 50, 220, 17, 507, 220, 23, 220, 17, 34363, 883, 369, 3090, 27068, 8522, 13, 220, 1419, 4235, 1627, 5745, 220, 19, 220, 135, 247, 25173, 706, 264, 4528, 36172, 4954, 2410, 311, 31350, 135, 247, 11, 3686, 50326, 82775, 5190, 13010, 7969, 449, 17130, 41947, 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8522, 315, 5745, 220, 19, 220, 135, 247, 25173, 482, 31039, 71162, 11618, 369, 3090, 27068, 11, 433, 374, 3062, 311, 7168, 279, 13010, 91468, 315, 5745, 220, 19, 220, 135, 247, 25173, 482, 3696, 2116, 71162, 25481, 449, 17808, 88959, 430, 527, 3118, 304, 77681, 3369, 57167, 13, 10541, 1063, 315, 279, 18336, 32505, 4478, 18508, 649, 387, 17303, 1701, 22772, 12823, 11, 384, 1326, 13, 1174, 17130, 28334, 12164, 337, 4548, 323, 63127, 25407, 11, 220, 1958, 11, 1758, 433, 374, 1515, 38210, 71985, 311, 9526, 750, 6767, 279, 7969, 315, 1475, 35522, 519, 449, 2875, 62954, 18336, 9606, 13, 763, 5369, 11, 279, 15449, 49969, 315, 5745, 220, 19, 220, 135, 247, 25173, 449, 2204, 72046, 1994, 72286, 88959, 527, 14090, 9987, 11, 323, 8830, 279, 15449, 49969, 304, 3284, 53568, 44014, 315, 17808, 88959, 389, 264, 16188, 2237, 527, 2631, 369, 52997, 555, 3107, 18488, 304, 5745, 220, 19, 220, 135, 247, 25173, 482, 31039, 79401, 3090, 6514, 13, 42096, 11, 17915, 16003, 10334, 320, 35, 4082, 8, 29217, 617, 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11, 374, 264, 3728, 4360, 13, 47755, 77681, 1436, 1520, 1304, 810, 3090, 2561, 13, 763, 1624, 4504, 1139, 279, 84889, 315, 77681, 94536, 11, 14248, 3629, 1005, 55580, 30903, 20414, 13, 16299, 374, 1888, 30, 59250, 25078, 4330, 2671, 1701, 220, 5120, 25481, 5938, 449, 264, 7701, 56563, 89418, 18336, 15061, 10980, 264, 35522, 519, 320, 8123, 89, 1994, 570, 2435, 4284, 1701, 1579, 11852, 31228, 29217, 311, 7858, 16313, 25481, 16239, 279, 89418, 18336, 323, 1023, 304, 61694, 9606, 13, 57116, 3629, 1005, 55580, 30903, 5528, 311, 7168, 25481, 315, 3682, 88959, 304, 3090, 13, 2435, 1390, 311, 3619, 1268, 502, 3090, 94536, 5528, 11, 1778, 439, 1701, 89418, 74356, 11, 990, 13, 1115, 4007, 8779, 14248, 3820, 279, 1455, 13687, 1749, 13, 578, 18539, 315, 7878, 3090, 374, 264, 3728, 4360, 430, 596, 10043, 2802, 304, 5627, 311, 2543, 77681, 1139, 4335, 3090, 13, 14874, 7922, 77681, 430, 5727, 35483, 315, 72046, 1994, 323, 1023, 26333, 1436, 1304, 810, 3090, 2561, 13, 578, 8815, 374, 16204, 433, 13, 763, 3738, 20414, 11, 7701, 56563, 26333, 11, 2663, 74356, 11, 527, 1511, 13, 57116, 527, 8173, 304, 1701, 264, 7701, 56563, 11, 7701, 11297, 89418, 18336, 13, 1102, 649, 1464, 1523, 11, 477, 36172, 553, 11, 11917, 15055, 315, 3738, 88959, 11, 719, 14248, 1390, 311, 1440, 7041, 1268, 279, 89418, 18336, 4375, 13, 93028, 30903, 5825, 264, 60336, 1853, 311, 22477, 323, 8720, 71162, 25481, 11, 719, 1148, 527, 279, 7720, 323, 9669, 315, 1855, 5603, 30, 4800, 11, 264, 2128, 30239, 4330, 55580, 5528, 11, 2737, 17915, 16003, 10334, 320, 35, 4082, 570, 2435, 1550, 279, 6492, 449, 264, 7029, 743, 315, 25481, 320, 5120, 304, 2860, 8, 430, 1514, 264, 1401, 3560, 304, 89418, 6108, 71162, 11618, 13, 2435, 8710, 430, 279, 423, 4082, 5528, 2804, 5115, 30357, 369, 21349, 25481, 315, 72046, 1994, 6108, 88959, 13, 4452, 11, 89418, 18336, 3495, 7720, 505, 1579, 11852, 31228, 29217, 311, 7858, 1817, 25481, 323, 6106, 430, 279, 71423, 323, 30945, 61002, 828, 30357, 7168, 279, 25481, 16239, 279, 89418, 18336, 323, 1023, 304, 61694, 32246, 13, 220, 128257, 198 ]

1,757

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The large number of spatial modes supported by standard multimode fibers is a promising platform for boosting the channel capacity of quantum and classical communications by orders of magnitude. However, the practical use of long multimode fibers is severely hampered by modal crosstalk and polarization mixing. To overcome these challenges, we develop and experimentally demonstrate a vectorial time reversal technique, which is accomplished by digitally pre-shaping the wavefront and polarization of the forward-propagating signal beam to be the phase conjugate of an auxiliary, backward-propagating probe beam. Here, we report an average modal fidelity above 80% for 210 Laguerre-Gauss and Hermite-Gauss modes by using vectorial time reversal over an unstabilized 1-km-long fiber. We also propose a practical and scalable spatial-mode-multiplexed quantum communication protocol over long multimode fibers to illustrate potential applications that can be enabled by our technique. Introduction Quantum cryptography 1 , 2 is a maturing technology that can guarantee the security of communication based on the fundamental laws of physics. The secure key rate of quantum key distribution (QKD) systems is many orders of magnitude lower than the data transfer rate of classical communication systems, inhibiting the widespread adoption of QKD in practical scenarios. Numerous methods have been proposed to increase the secure key rate in QKD, such as the development of new protocols 3 , use of high-performance detectors 4 , and wavelength-division multiplexing 5 . The spatial degree of freedom in a multimode fiber (MMF) has long been recognized as an additional resource to further increase the communication rate by either mode-division multiplexing 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 or high-dimensional encoding 14 , 15 , 16 , 17 , 18 . It is compatible with other multiplexing methods such as wavelength-division multiplexing and can be also used to enhance quantum teleportation 19 and entanglement distribution 20 , 21 . However, the inevitable mode crosstalk in standard MMFs is a persistent obstacle to practical applications of spatial modes for QKD. Tremendous efforts have been devoted to attempts to mitigate the effects of spatial-mode crosstalk during the past decades. Transfer matrix inversion is a standard method that has been successfully used to transmit spatial modes through MMFs 22 , 23 , 24 , 25 , 26 , 27 , 28 . However, standard MMFs can support between tens and hundreds of modes depending on the wavelength, and thus the number of complex-valued elements in the transfer matrix is typically between 10 3 and 10 5 . As a consequence, all transfer matrix inversion experiments reported in the literature have used a short MMF (≈1 m) 22 , 23 , 24 , 25 , 26 , 27 , 28 because the fiber has to be carefully stabilized during the slow characterization process (see Supplementary Note 1 for a summary of the fiber length used in previously reported experiments). When applying this method to a long fiber, it is foreseeable that instability will severely impede long-distance communication outside the laboratory. By contrast, mode-group excitation 29 , 30 , 31 has been applied to long fibers due to the relatively low inter-modal-group crosstalk. However, for a fiber supporting N spatial modes, only approximately \$\\sqrt{N}\$ mode groups are supported. Thus the number of usable mode groups is intrinsically limited in this method (see Supplementary Note 1 ). Multiple-input-multiple-output (MIMO) algorithm is another standard method for classical crosstalk mitigation 32 . However, it requires a high signal-to-noise ratio for digital signal processing and thus is unsuitable for quantum applications. Hence, none of these existing methods can be used to support a large number (>100) of modes for high-dimensional or spatial-mode-multiplexed QKD over long, unstabilized, standard MMFs outside the laboratory. Optical time reversal, which is also referred to as phase conjugation 33 , is an alternative method for modal crosstalk suppression. The concept of time reversal is illustrated in Fig. 1 a. The wavefront of an optical beam transmitted by Bob is distorted by an aberrating medium as shown in the left panel. Reflecting the beam by an ordinary mirror at Alice’s side is not helpful as the wavefront becomes distorted even more severely (see the middle panel). In contrast, a time-reversing mirror flips the sign of phase of the reflected beam, and consequently wavefront distortion can be exactly corrected after propagating through the same aberrating medium 33 as illustrated in the right panel. Although we use a simple plane wave to illustrate the concept, it should be noted that time reversal is applicable to an arbitrary spatial mode. Optical time reversal has been investigated for biological tissues 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 and MMFs 41 , 42 , 43 , 44 , 45 , 46 . The textbook description of time reversal 33 assumes a scalar incident field \${{\\bf{E}}}_{\\text{scalar}}({\\bf{r}})=\\hat{\\epsilon }A({\\bf{r}}){{\\rm{e}}}^{{\\rm{i}}{\\bf{k}}\\cdot {\\bf{r}}}\$ , where \$\\hat{\\epsilon }\$ is the polarization unit vector, A ( r ) is the complex field amplitude, r is the position vector, and k is the wavevector of the incident field. It can be seen that the polarization \$\\hat{\\epsilon }\$ and the complex field amplitude A ( r ) are separable from each other. The scalar time reversal of the incident field can be expressed as 33 $${{\\bf{E}}}_{\\,\\text{scalar}\\,}^{* }({\\bf{r}})={\\hat{\\epsilon }}^{* }{A}^{* }({\\bf{r}}){{\\rm{e}}}^{-{\\rm{i}}{\\bf{k}}\\cdot {\\bf{r}}},$$ (1) where * in the superscript denotes the complex conjugate. Here we generalize the scalar time reversal and propose the vectorial time reversal. Assume a vectorial incident field given by \${{\\bf{E}}}_{\\text{vector}}({\\bf{r}})=\\hat{x}{A}_{1}({\\bf{r}}){{\\rm{e}}}^{{\\rm{i}}{{\\bf{k}}}_{1}\\cdot {\\bf{r}}}+\\hat{y}{A}_{2}({\\bf{r}}){{\\rm{e}}}^{{\\rm{i}}{{\\bf{k}}}_{2}\\cdot {\\bf{r}}}\$ , where A 1 ( r ) and A 2 ( r ) ( k 1 and k 2 ) denote the respective complex field amplitude (wavevector) of the horizontally and vertically polarized field, and \$\\hat{x}\$ ( \$\\hat{y}\$ ) denotes the horizontal (vertical) unit vector. Its vectorial time reversal can be written as $${{\\bf{E}}}_{\\,\\text{vector}\\,}^{* }({\\bf{r}})=\\hat{x}{A}_{1}^{* }({\\bf{r}}){{\\rm{e}}}^{-{\\rm{i}}{{\\bf{k}}}_{1}\\cdot {\\bf{r}}}+\\hat{y}{A}_{2}^{* }({\\bf{r}}){{\\rm{e}}}^{-{\\rm{i}}{{\\bf{k}}}_{2}\\cdot {\\bf{r}}}.$$ (2) Here, the incident vectorial field is described by a non-separable state, which is a more general form than a", "role": "user" }, { "content": "The use of multimode optical fibers to boost the information capacity of the Internet is severely hampered by distortions that occur during the transmission of images because of a phenomenon called modal crosstalk. However, University of Rochester researchers at the Institute of Optics have devised a novel technique, described in a paper in Nature Communications, to \"flip\" the optical wavefront of an image for both polarizations simultaneously, so that it can be transmitted through a multimode fiber without distortion. Researchers at the University of South Florida and at the University of Southern California collaborated on the project. Lead author Yiyu Zhou, a Ph.D. candidate in the Rochester lab of Robert Boyd, professor of optics, draws an analogy to a multilane highway in describing the challenge the researchers confronted. \"Obviously, a multiple lane highway is faster than a single lane,\" Zhou says. \"But if a courier is forced to change from lane A to lane B, the package will be delivered to the wrong destination. When this happens in a multimode fiber—when one spatial mode is coupled to another during the propagation through the fiber—it's what we call modal crosstalk. And we want to suppress that.\" The solution the researchers devised involves digitally pre-shaping the wavefront and polarization of a forward-propagating signal beam to be the phase conjugate of an auxiliary, backward-propagating probe beam—in an experimental realization of vectorial time reversal. \"When an optical beam with perfect wavefronts passes through the multimode fiber, it comes out badly distorted,\" explains Boyd, who is also the Canada Excellence Research Chair in Quantum Nonlinear Optics at the University of Ottawa. \"If we use a mirror to send the wavefront back, it will become even more distorted. But if we instead reflect it off a mirror, and also flip the wavefront from front to back, the distortion becomes undone as the waves go back through that distorting medium. In particular, we need perform this procedure for both polarizations simultaneously when the distorting medium is a long multimode fiber.\" The researchers demonstrate that this technology can enhance the channel capacity in a 1-km-long multimode fiber. \"Our technique can be used to realize mode-division multiplexing over long, standard multimode fibers to significantly enhance the channel capacity of optical communication links,\" Zhou says. \"It can potentially be used to increase the Internet speed by one or two orders of magnitude.\" The technique could also be potentially used to improve endoscopy imaging of the brain and other biological tissues, Zhou says. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The large number of spatial modes supported by standard multimode fibers is a promising platform for boosting the channel capacity of quantum and classical communications by orders of magnitude. However, the practical use of long multimode fibers is severely hampered by modal crosstalk and polarization mixing. To overcome these challenges, we develop and experimentally demonstrate a vectorial time reversal technique, which is accomplished by digitally pre-shaping the wavefront and polarization of the forward-propagating signal beam to be the phase conjugate of an auxiliary, backward-propagating probe beam. Here, we report an average modal fidelity above 80% for 210 Laguerre-Gauss and Hermite-Gauss modes by using vectorial time reversal over an unstabilized 1-km-long fiber. We also propose a practical and scalable spatial-mode-multiplexed quantum communication protocol over long multimode fibers to illustrate potential applications that can be enabled by our technique. Introduction Quantum cryptography 1 , 2 is a maturing technology that can guarantee the security of communication based on the fundamental laws of physics. The secure key rate of quantum key distribution (QKD) systems is many orders of magnitude lower than the data transfer rate of classical communication systems, inhibiting the widespread adoption of QKD in practical scenarios. Numerous methods have been proposed to increase the secure key rate in QKD, such as the development of new protocols 3 , use of high-performance detectors 4 , and wavelength-division multiplexing 5 . The spatial degree of freedom in a multimode fiber (MMF) has long been recognized as an additional resource to further increase the communication rate by either mode-division multiplexing 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 or high-dimensional encoding 14 , 15 , 16 , 17 , 18 . It is compatible with other multiplexing methods such as wavelength-division multiplexing and can be also used to enhance quantum teleportation 19 and entanglement distribution 20 , 21 . However, the inevitable mode crosstalk in standard MMFs is a persistent obstacle to practical applications of spatial modes for QKD. Tremendous efforts have been devoted to attempts to mitigate the effects of spatial-mode crosstalk during the past decades. Transfer matrix inversion is a standard method that has been successfully used to transmit spatial modes through MMFs 22 , 23 , 24 , 25 , 26 , 27 , 28 . However, standard MMFs can support between tens and hundreds of modes depending on the wavelength, and thus the number of complex-valued elements in the transfer matrix is typically between 10 3 and 10 5 . As a consequence, all transfer matrix inversion experiments reported in the literature have used a short MMF (≈1 m) 22 , 23 , 24 , 25 , 26 , 27 , 28 because the fiber has to be carefully stabilized during the slow characterization process (see Supplementary Note 1 for a summary of the fiber length used in previously reported experiments). When applying this method to a long fiber, it is foreseeable that instability will severely impede long-distance communication outside the laboratory. By contrast, mode-group excitation 29 , 30 , 31 has been applied to long fibers due to the relatively low inter-modal-group crosstalk. However, for a fiber supporting N spatial modes, only approximately $\sqrt{N}$ mode groups are supported. Thus the number of usable mode groups is intrinsically limited in this method (see Supplementary Note 1 ). Multiple-input-multiple-output (MIMO) algorithm is another standard method for classical crosstalk mitigation 32 . However, it requires a high signal-to-noise ratio for digital signal processing and thus is unsuitable for quantum applications. Hence, none of these existing methods can be used to support a large number (>100) of modes for high-dimensional or spatial-mode-multiplexed QKD over long, unstabilized, standard MMFs outside the laboratory. Optical time reversal, which is also referred to as phase conjugation 33 , is an alternative method for modal crosstalk suppression. The concept of time reversal is illustrated in Fig. 1 a. The wavefront of an optical beam transmitted by Bob is distorted by an aberrating medium as shown in the left panel. Reflecting the beam by an ordinary mirror at Alice’s side is not helpful as the wavefront becomes distorted even more severely (see the middle panel). In contrast, a time-reversing mirror flips the sign of phase of the reflected beam, and consequently wavefront distortion can be exactly corrected after propagating through the same aberrating medium 33 as illustrated in the right panel. Although we use a simple plane wave to illustrate the concept, it should be noted that time reversal is applicable to an arbitrary spatial mode. Optical time reversal has been investigated for biological tissues 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 and MMFs 41 , 42 , 43 , 44 , 45 , 46 . The textbook description of time reversal 33 assumes a scalar incident field ${{\bf{E}}}_{\text{scalar}}({\bf{r}})=\hat{\epsilon }A({\bf{r}}){{\rm{e}}}^{{\rm{i}}{\bf{k}}\cdot {\bf{r}}}$ , where $\hat{\epsilon }$ is the polarization unit vector, A ( r ) is the complex field amplitude, r is the position vector, and k is the wavevector of the incident field. It can be seen that the polarization $\hat{\epsilon }$ and the complex field amplitude A ( r ) are separable from each other. The scalar time reversal of the incident field can be expressed as 33 $${{\bf{E}}}_{\,\text{scalar}\,}^{* }({\bf{r}})={\hat{\epsilon }}^{* }{A}^{* }({\bf{r}}){{\rm{e}}}^{-{\rm{i}}{\bf{k}}\cdot {\bf{r}}},$$ (1) where * in the superscript denotes the complex conjugate. Here we generalize the scalar time reversal and propose the vectorial time reversal. Assume a vectorial incident field given by ${{\bf{E}}}_{\text{vector}}({\bf{r}})=\hat{x}{A}_{1}({\bf{r}}){{\rm{e}}}^{{\rm{i}}{{\bf{k}}}_{1}\cdot {\bf{r}}}+\hat{y}{A}_{2}({\bf{r}}){{\rm{e}}}^{{\rm{i}}{{\bf{k}}}_{2}\cdot {\bf{r}}}$ , where A 1 ( r ) and A 2 ( r ) ( k 1 and k 2 ) denote the respective complex field amplitude (wavevector) of the horizontally and vertically polarized field, and $\hat{x}$ ( $\hat{y}$ ) denotes the horizontal (vertical) unit vector. Its vectorial time reversal can be written as $${{\bf{E}}}_{\,\text{vector}\,}^{* }({\bf{r}})=\hat{x}{A}_{1}^{* }({\bf{r}}){{\rm{e}}}^{-{\rm{i}}{{\bf{k}}}_{1}\cdot {\bf{r}}}+\hat{y}{A}_{2}^{* }({\bf{r}}){{\rm{e}}}^{-{\rm{i}}{{\bf{k}}}_{2}\cdot {\bf{r}}}.$$ (2) Here, the incident vectorial field is described by a non-separable state, which is a more general form than a<|im_end|> <|im_start|>assistant The use of multimode optical fibers to boost the information capacity of the Internet is severely hampered by distortions that occur during the transmission of images because of a phenomenon called modal crosstalk. However, University of Rochester researchers at the Institute of Optics have devised a novel technique, described in a paper in Nature Communications, to "flip" the optical wavefront of an image for both polarizations simultaneously, so that it can be transmitted through a multimode fiber without distortion. Researchers at the University of South Florida and at the University of Southern California collaborated on the project. Lead author Yiyu Zhou, a Ph.D. candidate in the Rochester lab of Robert Boyd, professor of optics, draws an analogy to a multilane highway in describing the challenge the researchers confronted. "Obviously, a multiple lane highway is faster than a single lane," Zhou says. "But if a courier is forced to change from lane A to lane B, the package will be delivered to the wrong destination. When this happens in a multimode fiber—when one spatial mode is coupled to another during the propagation through the fiber—it's what we call modal crosstalk. And we want to suppress that." The solution the researchers devised involves digitally pre-shaping the wavefront and polarization of a forward-propagating signal beam to be the phase conjugate of an auxiliary, backward-propagating probe beam—in an experimental realization of vectorial time reversal. "When an optical beam with perfect wavefronts passes through the multimode fiber, it comes out badly distorted," explains Boyd, who is also the Canada Excellence Research Chair in Quantum Nonlinear Optics at the University of Ottawa. "If we use a mirror to send the wavefront back, it will become even more distorted. But if we instead reflect it off a mirror, and also flip the wavefront from front to back, the distortion becomes undone as the waves go back through that distorting medium. In particular, we need perform this procedure for both polarizations simultaneously when the distorting medium is a long multimode fiber." The researchers demonstrate that this technology can enhance the channel capacity in a 1-km-long multimode fiber. "Our technique can be used to realize mode-division multiplexing over long, standard multimode fibers to significantly enhance the channel capacity of optical communication links," Zhou says. "It can potentially be used to increase the Internet speed by one or two orders of magnitude." The technique could also be potentially used to improve endoscopy imaging of the brain and other biological tissues, Zhou says. <|im_end|>

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2,198

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The ideal form of semiconducting-single-walled carbon nanotubes (sem-SWNTs) for science and technology is long, defect-free, chirality pure and chemically pure isolated narrow diameter tubes. While various techniques to solubilize and purify sem-SWNTs have been developed, many of them targeted only the chiral- or chemically-purity while sacrificing the sem-SWNT intrinsic structural identities by applying strong ultra-sonication and/or chemical modifications. Toward the ultimate purification of the sem-SWNTs, here we report a mild-conditioned extraction of the sem-SWNTs using removable supramolecular hydrogen-bonding polymers ( HBP s) that are composed of dicarboxylic- or diaminopyridyl-fluorenes with ~70%-(8,6)SWNT selective extraction. Replacing conventional strong sonication techniques by a simple shaking using HPB s was found to provide long sem-SWNTs (>2.0 μm) with a very high D/G ratio, which was determined by atomic force microscopy observations. The HBP s were readily removed from the nanotube surfaces by an outer stimulus, such as a change in the solvent polarities, to provide chemically pure (8,6)-enriched sem-SWNTs. We also describe molecular mechanics calculations to propose possible structures for the HBP -wrapped sem-SWNTs, furthermore, the mechanism of the chiral selectivity for the sorted sem-SWNTs is well explained by the relationship between the molecular surface area and mass of the HBP /SWNT composites. Introduction SWNTs have attracted special interests as materials with remarkable electronic, mechanical, thermal and photophysical properties due to their unique one-dimensional structures 1 , 2 , 3 , 4 . Their characteristic quantum-confined structures due to their chiral indices (n,m) provide unique opto-nanoelectronic behaviors 5 , 6 , 7 , 8 , 9 . Therefore, the separation/purification of the sem-SWNTs based on their chiralities is one of the most important issues in the science and applications of carbon nanotubes 10 , 11 . However, to achieve chiral- and chemical-purifications at the same time is still challenging because most of the commercially supplied as-produced SWNTs contains both sem-SWNTs and metallic-SWNTs as well as metal catalysts and other carbon forms. A typical purification requires solution-phase processes using surfactants 12 , which also chemically contaminate the sem-SWNTs by changing the surrounding environments that alter the intrinsic properties of the sem-SWNTs 13 , 14 , 15 . Many attempts toward the goal of selective sem-SWNT sorting have been reported and the typical methods include polymer-wrapping 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , density gradient ultracentrifugation 25 , 26 and gel chromatography 27 , 28 , 29 . Such methods are powerful for the selective chirality sorting; however, complete removal of the used adsorbents from the sorted SWNT surfaces is difficult 30 , 31 . Even after the suitable adsorbent removal procedures, adsorbent molecules still remain on the sorted SWNTs 32 , 33 , 34 , 35 . We previously reported an efficient SWNT sorting using a supramolecular coordination polymers ( CP s) 36 followed by complete removal of the CP s based on dynamic supramolecular coordination chemistry 37 , which was the first report to utilize a supramolecular system for the selective sorting of the sem-SWNTs not containing the used adsorbent. In contrast, other reported polymers for the chemical purification of SWNTs usually lack a chirality sorting ability and/or adsorbent-removal process 30 , 31 , 32 , 33 , 37 , 38 . Furthermore, in order to maintain the original sem-SWNT properties after the sorting processes, structural identities of the sem-SWNTs, such as the length and crystallinity of the graphitic surface structure, must be preserved 39 , 40 , which is very difficult under conventional solubilizing/sorting experimental conditions using strong sonication 25 , 41 , 42 , 43 , which is a destructive process for the SWNTs. This issue is especially important for the sem-SWNTs with smaller diameters, such as chemical vapor deposition-produced HiPco- and CoMoCAT-SWNTs having much larger band gaps than those of the SWNTs with large diameters synthesized by the arc-discharged or laser-ablation method 44 . Such small diameter SWNTs are promising materials for use in optoelectronic device applications, such as thin film transistors, transistors, sensors, etc. Here, we report a mild and highly chirality-selective extracting method for the chemically pure smaller diameter sem-SWNT sorting using newly-designed and synthesized supramolecular hydrogen-bond polymers ( HBP s) as shown in Fig. 1 together with the concept of this study. The sem-SWNT selectivity is programmed in the HBP s by introducing fluorene moieties, which features molecular recognition of the sem-SWNTs 16 , 17 , 18 , 20 , 21 , 22 , 34 , 35 , 36 and the formation of a linear polymer conformation achieved by the combination of a carboxylic acid and 4-aminopyridine on both ends of the fluorene is designed for the selective sorting of smaller diameter SWNTs. As a HBP , we designed and synthesized two building blocks, 2,7-bis-4-aminopyridyl-9,9'-dioctylfluorene ( 1 ) and 2,7-dicarboxyl-9,9'-dioctylfluorene ( 2 ). Furthermore, the simplicity of the HBP conformations aided in determining the mechanism of the chiral-selectivity of the HBP by considering the molecular surface area and the molecular weight of the composite with sem-SWNTs, which is the first trial to evaluate the selectivity extracting specific chiral sem-SWNTs based on the dynamic supramolecular chemistry. In this study, our goal is to extract long sem-SWNTs with smaller tube diameters while retaining their structural properties. During this study, using a concept that is similar to our previous report based on dynamic supramolecular chemistry 36 , Pochorovski et al. 44 focused on the extraction of large-diameter SWNTs and reported the extraction of arc-discharge-produced SWNTs with diameters in the range of 1.28–1.39 nm using an HBP with a wide zigzag polymer structure as well as the removal of the used polymer adsorbent. The dispersion of such larger-diameter tubes using the reported HBP with sheet- or ribbon-structures needed sonication by a tip-sonicator with a higher-power 38 , 44 . The SWNTs with small tube diameters have highly tensioned graphitic surfaces and for the dispersion of such tubes, sheet-shaped solubilizers and high power sonication are not suitable. Instead, our designed and synthesized linear HBP dispersed the SWNTs with small diameters under", "role": "user" }, { "content": "Manufacture of longer, thinner, and uncontaminated carbon nanotubes, and successfully isolating them, have been ongoing challenges for researchers. A newly developed method has opened up new possibilities in carbon nanotube development. As recently reported in an article published online at Scientific Reports, researchers at Kyushu University's Department of Applied Chemistry have developed a method for obtaining high-quality single-walled carbon nanotubes. The relatively mild process uses an outer stimulus to yield undamaged carbon nanotubes that are purer and longer, and even gives researchers the ability to sort nanotubes according to their structure and length. Previous approaches for isolating or sorting nanotubes have required use of more aggressive techniques. These can contaminate the nanotubes and are difficult to completely remove. They also involve processes that could damage the nanotubes and impair their functionality. \"Our approach involves introducing supramolecular hydrogen-bonding polymers, followed by simply shaking the mixture and changing the polarity of the solvent, rather than applying potentially destructive sonication or chemical modification,\" says coauthor Naotoshi Nakashima. \"In this way, we can obtain single-walled carbon nanotubes over two microns long that do a fine job maintaining structural integrity.\" The new technique is particularly useful because of the mildness and selectivity of the newly designed hydrogen-bonding polymers used. The presence of fluorene moieties within them enables the specific recognition of and binding to single-walled carbon nanotubes, and specific sorting of tubes with a small diameter. This is particularly beneficial because small-diameter nanotubes are exceedingly useful for optoelectronic devices, such as thin-film transistors and sensors. \"The nanotubes we can obtain using this method can be expected to have superior characteristics to those isolated by previous procedures,\" says coauthor Fumiyuki Toshimitsu (Visiting Assistant Professor). \"For example, by limiting contamination, their electrical and mechanical properties can be optimized. And by being able to sort nanotubes by length or chirality, we can more precisely customize those used for a particular application.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The ideal form of semiconducting-single-walled carbon nanotubes (sem-SWNTs) for science and technology is long, defect-free, chirality pure and chemically pure isolated narrow diameter tubes. While various techniques to solubilize and purify sem-SWNTs have been developed, many of them targeted only the chiral- or chemically-purity while sacrificing the sem-SWNT intrinsic structural identities by applying strong ultra-sonication and/or chemical modifications. Toward the ultimate purification of the sem-SWNTs, here we report a mild-conditioned extraction of the sem-SWNTs using removable supramolecular hydrogen-bonding polymers ( HBP s) that are composed of dicarboxylic- or diaminopyridyl-fluorenes with ~70%-(8,6)SWNT selective extraction. Replacing conventional strong sonication techniques by a simple shaking using HPB s was found to provide long sem-SWNTs (>2.0 μm) with a very high D/G ratio, which was determined by atomic force microscopy observations. The HBP s were readily removed from the nanotube surfaces by an outer stimulus, such as a change in the solvent polarities, to provide chemically pure (8,6)-enriched sem-SWNTs. We also describe molecular mechanics calculations to propose possible structures for the HBP -wrapped sem-SWNTs, furthermore, the mechanism of the chiral selectivity for the sorted sem-SWNTs is well explained by the relationship between the molecular surface area and mass of the HBP /SWNT composites. Introduction SWNTs have attracted special interests as materials with remarkable electronic, mechanical, thermal and photophysical properties due to their unique one-dimensional structures 1 , 2 , 3 , 4 . Their characteristic quantum-confined structures due to their chiral indices (n,m) provide unique opto-nanoelectronic behaviors 5 , 6 , 7 , 8 , 9 . Therefore, the separation/purification of the sem-SWNTs based on their chiralities is one of the most important issues in the science and applications of carbon nanotubes 10 , 11 . However, to achieve chiral- and chemical-purifications at the same time is still challenging because most of the commercially supplied as-produced SWNTs contains both sem-SWNTs and metallic-SWNTs as well as metal catalysts and other carbon forms. A typical purification requires solution-phase processes using surfactants 12 , which also chemically contaminate the sem-SWNTs by changing the surrounding environments that alter the intrinsic properties of the sem-SWNTs 13 , 14 , 15 . Many attempts toward the goal of selective sem-SWNT sorting have been reported and the typical methods include polymer-wrapping 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , density gradient ultracentrifugation 25 , 26 and gel chromatography 27 , 28 , 29 . Such methods are powerful for the selective chirality sorting; however, complete removal of the used adsorbents from the sorted SWNT surfaces is difficult 30 , 31 . Even after the suitable adsorbent removal procedures, adsorbent molecules still remain on the sorted SWNTs 32 , 33 , 34 , 35 . We previously reported an efficient SWNT sorting using a supramolecular coordination polymers ( CP s) 36 followed by complete removal of the CP s based on dynamic supramolecular coordination chemistry 37 , which was the first report to utilize a supramolecular system for the selective sorting of the sem-SWNTs not containing the used adsorbent. In contrast, other reported polymers for the chemical purification of SWNTs usually lack a chirality sorting ability and/or adsorbent-removal process 30 , 31 , 32 , 33 , 37 , 38 . Furthermore, in order to maintain the original sem-SWNT properties after the sorting processes, structural identities of the sem-SWNTs, such as the length and crystallinity of the graphitic surface structure, must be preserved 39 , 40 , which is very difficult under conventional solubilizing/sorting experimental conditions using strong sonication 25 , 41 , 42 , 43 , which is a destructive process for the SWNTs. This issue is especially important for the sem-SWNTs with smaller diameters, such as chemical vapor deposition-produced HiPco- and CoMoCAT-SWNTs having much larger band gaps than those of the SWNTs with large diameters synthesized by the arc-discharged or laser-ablation method 44 . Such small diameter SWNTs are promising materials for use in optoelectronic device applications, such as thin film transistors, transistors, sensors, etc. Here, we report a mild and highly chirality-selective extracting method for the chemically pure smaller diameter sem-SWNT sorting using newly-designed and synthesized supramolecular hydrogen-bond polymers ( HBP s) as shown in Fig. 1 together with the concept of this study. The sem-SWNT selectivity is programmed in the HBP s by introducing fluorene moieties, which features molecular recognition of the sem-SWNTs 16 , 17 , 18 , 20 , 21 , 22 , 34 , 35 , 36 and the formation of a linear polymer conformation achieved by the combination of a carboxylic acid and 4-aminopyridine on both ends of the fluorene is designed for the selective sorting of smaller diameter SWNTs. As a HBP , we designed and synthesized two building blocks, 2,7-bis-4-aminopyridyl-9,9'-dioctylfluorene ( 1 ) and 2,7-dicarboxyl-9,9'-dioctylfluorene ( 2 ). Furthermore, the simplicity of the HBP conformations aided in determining the mechanism of the chiral-selectivity of the HBP by considering the molecular surface area and the molecular weight of the composite with sem-SWNTs, which is the first trial to evaluate the selectivity extracting specific chiral sem-SWNTs based on the dynamic supramolecular chemistry. In this study, our goal is to extract long sem-SWNTs with smaller tube diameters while retaining their structural properties. During this study, using a concept that is similar to our previous report based on dynamic supramolecular chemistry 36 , Pochorovski et al. 44 focused on the extraction of large-diameter SWNTs and reported the extraction of arc-discharge-produced SWNTs with diameters in the range of 1.28–1.39 nm using an HBP with a wide zigzag polymer structure as well as the removal of the used polymer adsorbent. The dispersion of such larger-diameter tubes using the reported HBP with sheet- or ribbon-structures needed sonication by a tip-sonicator with a higher-power 38 , 44 . The SWNTs with small tube diameters have highly tensioned graphitic surfaces and for the dispersion of such tubes, sheet-shaped solubilizers and high power sonication are not suitable. Instead, our designed and synthesized linear HBP dispersed the SWNTs with small diameters under<|im_end|> <|im_start|>assistant Manufacture of longer, thinner, and uncontaminated carbon nanotubes, and successfully isolating them, have been ongoing challenges for researchers. A newly developed method has opened up new possibilities in carbon nanotube development. As recently reported in an article published online at Scientific Reports, researchers at Kyushu University's Department of Applied Chemistry have developed a method for obtaining high-quality single-walled carbon nanotubes. The relatively mild process uses an outer stimulus to yield undamaged carbon nanotubes that are purer and longer, and even gives researchers the ability to sort nanotubes according to their structure and length. Previous approaches for isolating or sorting nanotubes have required use of more aggressive techniques. These can contaminate the nanotubes and are difficult to completely remove. They also involve processes that could damage the nanotubes and impair their functionality. "Our approach involves introducing supramolecular hydrogen-bonding polymers, followed by simply shaking the mixture and changing the polarity of the solvent, rather than applying potentially destructive sonication or chemical modification," says coauthor Naotoshi Nakashima. "In this way, we can obtain single-walled carbon nanotubes over two microns long that do a fine job maintaining structural integrity." The new technique is particularly useful because of the mildness and selectivity of the newly designed hydrogen-bonding polymers used. The presence of fluorene moieties within them enables the specific recognition of and binding to single-walled carbon nanotubes, and specific sorting of tubes with a small diameter. This is particularly beneficial because small-diameter nanotubes are exceedingly useful for optoelectronic devices, such as thin-film transistors and sensors. "The nanotubes we can obtain using this method can be expected to have superior characteristics to those isolated by previous procedures," says coauthor Fumiyuki Toshimitsu (Visiting Assistant Professor). "For example, by limiting contamination, their electrical and mechanical properties can be optimized. And by being able to sort nanotubes by length or chirality, we can more precisely customize those used for a particular application." <|im_end|>

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2,028

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Elastomers such as silicone are common in medical devices (catheters, prosthetic implants, endoscopes), but they remain prone to microbial colonization and biofilm infections. For the first time, our work shows that rates of microbial surface attachment to polydimethylsiloxane (PDMS) silicone can be significantly affected by mechanical deformation. For a section of bent commercial catheter tubing, bacteria ( P. aeruginosa ) show a strong preference for the ‘convex’ side compared to the ‘concave’ side, by a factor of 4.2. Further testing of cast PDMS materials in bending only showed a significant difference for samples that were manually wiped (damaged) beforehand (1.75 × 10 4 and 6.02 × 10 3 cells/mm 2 on the convex and concave sides, respectively). We demonstrate that surface microcracks in elastomers are opened under tensile stress (convex bending) to become ‘activated’ as sites for microbial colonization. This work demonstrates that the high elastic limit of elastomers enables these microcracks to reversibly open and close, as ‘dynamic defects’. Commercial catheters have relatively high surface roughness inherent to manufacturing, but we show that even manual wiping of newly-cast PDMS is sufficient to generate surface microcracks. We consider the implication for medical devices that feature sustained, surgical, or cyclic deformation, in which localized tensile conditions may expose these surface defects to opportunistic microbes. As a result, our work showcases serious potential problems in the widespread usage and development of elastomers in medical devices. Introduction Elastomers such as silicones, polyurethanes and polyvinylchloride (PVC) were first used in medical devices in the 1950s and are now in widespread use. Examples include polydimethylsiloxane (PDMS) urinary catheters, polyurethane PICC catheters, endoscope sheaths, and a wide range of reconstructive plastic surgery products, such as silicone prosthetic breast or facial implants 1 , 2 . Recently silicones have been the basis for a new generation of artificial heart and prosthetic heart valves as silicones have low thrombogenicity, good chemical stability and versatile manufacturability 3 . In addition to implanted devices, elastomers are common in extracorporeal medical devices such as pumps and tubing in dialysis systems. Despite their widespread use, the microbial colonization of elastomeric devices, and subsequent development to biofilm-based infections, remain a persistent problem both for implanted and reusable devices. Device associated infections are responsible for 50–70% of the nearly 2 million healthcare-associated infections (HAIs) in the US 4 , 5 . HAIs significantly increase adverse health risks, length of hospital stays for patients and treatment costs. The majority of device-associated infections are a result of bacterial colonization on catheters, including central-line associated bloodstream infections (CLABSI), catheter-associated urinary tract infections (CAUTI), and ventilator-associated pneumonia (VAP) 6 , 7 . Of the more than 5 million central line catheters inserted per year in the US, 3–5% of these patients suffered from CLABSIs, increasing treatment costs significantly 8 . A recent comparative analysis of patients requiring intravenous catheterization showed infection caused an average of 2 additional days hospital stay 9 . Device-associated infections begin with the initial colonization of the surface by microbial pathogens and subsequent development into a biofilm 10 , 11 , 12 . Cells in a biofilm produce extracellular polymeric substances, which protect them from disinfectants, antibiotics and host defense mechanisms and as a result biofilms are persistent and difficult to eradicate 5 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . Various gram-positive bacteria ( Enterococcus faecalis , Staphylococcus aureus, S. epidermidis ), gram-negative bacteria ( Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Pseudomonas aeruginosa ), and fungi ( Candida albicans ) are commonly isolated from explanted medical devices 12 . These pathogens are known to develop multidrug resistance and once they form biofilms the use of systemic, broad-spectrum antibiotics is often ineffective. If infected, the removal and replacement of device is often a necessity, which can be a highly traumatic and medically risky option with a high likelihood for re-infection 12 . The material factors that determine when and where these bacterial colonies initially attach on devices are not well understood. Certainly, there are known risks (probabilities) of contamination events, such as central venous catheters (CVC) picking up flora from skin during insertion or blood-borne pathogens colonizing implant surfaces (in the ‘race to the surface’) 20 , 21 . However, device-associated infection events remain difficult to predict. Thus, we aim to better understand the initial stages of microbial surface colonization. In this work we uncover an entirely new mechanism for microbial colonization associated with surface defects and the mechanical deformation of elastomer biomaterials. We begin with a preliminary observation that bending deformation of elastomer devices influences bacterial colonization. Sections of a commercial silicone Foley catheter (Rusch OD 4.7 mm, 5 mL) (Fig. 1 a) were cut and exposed to a P. aeruginosa (PAO1) culture within the wells of a standard 6-well plate (Fig. 1 b). The catheter sections were either kept straight (unbent), or were cut slightly long, to cause them to bend within the wells (mid-point displacement of 4 mm, and 1.9 cm radius of curvature). The samples (n = 5) were suspended at the mid-point of wells, so that cells had free access to all surfaces. After 4 h (25 °C), the samples were fixed with glutaraldehyde (GDA) and Tween-20 and stained with Sytox green (30 min). Figure 1 Bending deformation of elastomer devices influences bacterial colonization. ( a ) Commercial silicone Foley urinary catheter (Rusch, OD 4.7 mm, 5 mL); ( b ) Culture of P. aeruginosa (25 °C, static culture, LB media) with catheter sections in a straight (unbent) or bent condition; ( c ) Representative fluorescence microscopy images of P. aeruginosa (Sytox-stained) on the convex and concave outer surfaces of the catheter tubing, after 4 h growth, showing significantly higher growth on the convex side. Full size image In fluorescence imaging (Fig. 1 c), the bent sections of catheter tubing showed a significantly higher density of cells on the convex (tensile) side (2.11 ± 0.19 × 10 4 cells/mm 2 ), compared to the concave (compressive) side (4.94", "role": "user" }, { "content": "A study by researchers at the University of Toronto's Faculty of Applied Science and Engineering shows that mechanical deformation of medically implantable materials—such as bending or twisting—can have a big impact on the formation of potentially harmful biofilms. The study, described in a paper published in Scientific Reports, shows that even slight bending of elastomeric materials such as polydimethylsiloxane (PDMS)—also known as silicone—opens up microscopic cracks that are perfect environments for colonizing bacteria. \"These kinds of materials are used in all kinds of biomedical applications, from catheters to tracheal tubes and prosthetic breast implants,\" says Ben Hatton, associate professor in the faculty's department of materials science and engineering, and senior author of the new study. \"The formation of microbial biofilms on these materials is common, but we were surprised by the degree to which bending silicone, and other rubber materials, causes these cracks to reversibly open and close—and how big a difference they make in terms of biofilm formation.\" Biofilms are complex communities of organisms that grow on surfaces. While individual microbial cells are susceptible both to antibiotics and the body's natural defensive systems, the biofilm environment can shield them from these interventions, which can lead to persistent infections. Infections associated with medical-device biofilms, which sometimes develop after surgery, can be serious health risks—lengthening hospital stays or causing patients who have been discharged to be readmitted. Hatton and his team are among many groups around the world developing new materials, coatings and other approaches to prevent the formation of biofilms that can lead to such infections. But in their latest work, they chose to study something more fundamental: How do these colonizing microbial organisms gain a toehold in the first place? \"In part, this comes out of the multidisciplinary approach we take in our group,\" Hatton says. \"We're combining microbiology and materials science, but also mechanical engineering, because we're talking about mechanical stress, strain and deformation. This bending effect is something that had not been noticed before.\" The team tested various samples of silicone, including some they synthesized themselves as well as commercial-grade medical tubing used for urinary catheters. They then subjected these samples to mechanical forces to create surface damage. Their experiments showed that the microcracks can be formed very easily. Associate Professor Ben Hatton, left, and PhD candidate Desmond van den Berg examine bacteria samples in the lab. Credit: Neil Ta \"One thing we did was simply wipe them a bunch of times with an ordinary laboratory tissue,\" says Desmond van den Berg, a Ph.D. candidate in the Institute of Biomedical Engineering and lead author on the paper, which was co-authored by fellow Hatton Lab researchers Dalal Asker and Tarek Awad. \"Even this wiping was enough to create surface damage. By eye it still looks fine, but under the microscope, we could already see microcracks of the size that bacteria could get into. Bacteria are only a few micrometers big, so it doesn't take much.\" Other samples were pressed with a rough, ridged pattern to create a series of regularly-spaced microcracks. All the samples were then placed in a bacterial culture plate and seeded with Pseudomonas aeruginosa, a biofilm-forming bacterium commonly used as a model organism in these types of studies. After growth, the samples were treated with a fluorescent dye, causing any attached bacteria to glow green under an optical microscope. \"What we saw was that the bacteria very clearly preferred to attach in these microscopic cracks,\" van den Berg says. \"In the bent samples, there were four to five times as many bacteria on the side that was in tension versus the side that was in compression. These cells have full choice about where to grow, but they clearly love the side where all these microcracks are opened up.\" The only samples that remained relatively free of bacteria were the ones that had been synthesized in the team's own lab, and therefore remained extremely smooth, van den Berg notes. \"Even the commercially produced ones that we didn't damage in any way already had microcracks in them, straight out of the package,\" he says. \"We suspect that these are introduced via the manufacturing process, arising from the way the plastic is formed into tubes or other shapes by extrusion or injection molding.\" Hatton says that the study underlines just how easy it is to introduce surface features that encourage microbial attachment. For surgeons, one implication is that they should be looking out for situations where silicone devices—such as tubing or prosthetic implants—are being bent during use, and paying particular attention to the side under tension, as this is where infections might be starting. \"Obviously it's difficult to simply not bend a rubber tube that is meant to be bent—otherwise, why would you make it out of rubber in the first place?\" Hatton says. \"But perhaps we can learn more about how to control or hide these surface cracks, so that bending is not a problem. That's what we're working on now—researching methods to reduce surface damage, or modifying the silicone surface to reduce the formation of such cracks.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Elastomers such as silicone are common in medical devices (catheters, prosthetic implants, endoscopes), but they remain prone to microbial colonization and biofilm infections. For the first time, our work shows that rates of microbial surface attachment to polydimethylsiloxane (PDMS) silicone can be significantly affected by mechanical deformation. For a section of bent commercial catheter tubing, bacteria ( P. aeruginosa ) show a strong preference for the ‘convex’ side compared to the ‘concave’ side, by a factor of 4.2. Further testing of cast PDMS materials in bending only showed a significant difference for samples that were manually wiped (damaged) beforehand (1.75 × 10 4 and 6.02 × 10 3 cells/mm 2 on the convex and concave sides, respectively). We demonstrate that surface microcracks in elastomers are opened under tensile stress (convex bending) to become ‘activated’ as sites for microbial colonization. This work demonstrates that the high elastic limit of elastomers enables these microcracks to reversibly open and close, as ‘dynamic defects’. Commercial catheters have relatively high surface roughness inherent to manufacturing, but we show that even manual wiping of newly-cast PDMS is sufficient to generate surface microcracks. We consider the implication for medical devices that feature sustained, surgical, or cyclic deformation, in which localized tensile conditions may expose these surface defects to opportunistic microbes. As a result, our work showcases serious potential problems in the widespread usage and development of elastomers in medical devices. Introduction Elastomers such as silicones, polyurethanes and polyvinylchloride (PVC) were first used in medical devices in the 1950s and are now in widespread use. Examples include polydimethylsiloxane (PDMS) urinary catheters, polyurethane PICC catheters, endoscope sheaths, and a wide range of reconstructive plastic surgery products, such as silicone prosthetic breast or facial implants 1 , 2 . Recently silicones have been the basis for a new generation of artificial heart and prosthetic heart valves as silicones have low thrombogenicity, good chemical stability and versatile manufacturability 3 . In addition to implanted devices, elastomers are common in extracorporeal medical devices such as pumps and tubing in dialysis systems. Despite their widespread use, the microbial colonization of elastomeric devices, and subsequent development to biofilm-based infections, remain a persistent problem both for implanted and reusable devices. Device associated infections are responsible for 50–70% of the nearly 2 million healthcare-associated infections (HAIs) in the US 4 , 5 . HAIs significantly increase adverse health risks, length of hospital stays for patients and treatment costs. The majority of device-associated infections are a result of bacterial colonization on catheters, including central-line associated bloodstream infections (CLABSI), catheter-associated urinary tract infections (CAUTI), and ventilator-associated pneumonia (VAP) 6 , 7 . Of the more than 5 million central line catheters inserted per year in the US, 3–5% of these patients suffered from CLABSIs, increasing treatment costs significantly 8 . A recent comparative analysis of patients requiring intravenous catheterization showed infection caused an average of 2 additional days hospital stay 9 . Device-associated infections begin with the initial colonization of the surface by microbial pathogens and subsequent development into a biofilm 10 , 11 , 12 . Cells in a biofilm produce extracellular polymeric substances, which protect them from disinfectants, antibiotics and host defense mechanisms and as a result biofilms are persistent and difficult to eradicate 5 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . Various gram-positive bacteria ( Enterococcus faecalis , Staphylococcus aureus, S. epidermidis ), gram-negative bacteria ( Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Pseudomonas aeruginosa ), and fungi ( Candida albicans ) are commonly isolated from explanted medical devices 12 . These pathogens are known to develop multidrug resistance and once they form biofilms the use of systemic, broad-spectrum antibiotics is often ineffective. If infected, the removal and replacement of device is often a necessity, which can be a highly traumatic and medically risky option with a high likelihood for re-infection 12 . The material factors that determine when and where these bacterial colonies initially attach on devices are not well understood. Certainly, there are known risks (probabilities) of contamination events, such as central venous catheters (CVC) picking up flora from skin during insertion or blood-borne pathogens colonizing implant surfaces (in the ‘race to the surface’) 20 , 21 . However, device-associated infection events remain difficult to predict. Thus, we aim to better understand the initial stages of microbial surface colonization. In this work we uncover an entirely new mechanism for microbial colonization associated with surface defects and the mechanical deformation of elastomer biomaterials. We begin with a preliminary observation that bending deformation of elastomer devices influences bacterial colonization. Sections of a commercial silicone Foley catheter (Rusch OD 4.7 mm, 5 mL) (Fig. 1 a) were cut and exposed to a P. aeruginosa (PAO1) culture within the wells of a standard 6-well plate (Fig. 1 b). The catheter sections were either kept straight (unbent), or were cut slightly long, to cause them to bend within the wells (mid-point displacement of 4 mm, and 1.9 cm radius of curvature). The samples (n = 5) were suspended at the mid-point of wells, so that cells had free access to all surfaces. After 4 h (25 °C), the samples were fixed with glutaraldehyde (GDA) and Tween-20 and stained with Sytox green (30 min). Figure 1 Bending deformation of elastomer devices influences bacterial colonization. ( a ) Commercial silicone Foley urinary catheter (Rusch, OD 4.7 mm, 5 mL); ( b ) Culture of P. aeruginosa (25 °C, static culture, LB media) with catheter sections in a straight (unbent) or bent condition; ( c ) Representative fluorescence microscopy images of P. aeruginosa (Sytox-stained) on the convex and concave outer surfaces of the catheter tubing, after 4 h growth, showing significantly higher growth on the convex side. Full size image In fluorescence imaging (Fig. 1 c), the bent sections of catheter tubing showed a significantly higher density of cells on the convex (tensile) side (2.11 ± 0.19 × 10 4 cells/mm 2 ), compared to the concave (compressive) side (4.94<|im_end|> <|im_start|>assistant A study by researchers at the University of Toronto's Faculty of Applied Science and Engineering shows that mechanical deformation of medically implantable materials—such as bending or twisting—can have a big impact on the formation of potentially harmful biofilms. The study, described in a paper published in Scientific Reports, shows that even slight bending of elastomeric materials such as polydimethylsiloxane (PDMS)—also known as silicone—opens up microscopic cracks that are perfect environments for colonizing bacteria. "These kinds of materials are used in all kinds of biomedical applications, from catheters to tracheal tubes and prosthetic breast implants," says Ben Hatton, associate professor in the faculty's department of materials science and engineering, and senior author of the new study. "The formation of microbial biofilms on these materials is common, but we were surprised by the degree to which bending silicone, and other rubber materials, causes these cracks to reversibly open and close—and how big a difference they make in terms of biofilm formation." Biofilms are complex communities of organisms that grow on surfaces. While individual microbial cells are susceptible both to antibiotics and the body's natural defensive systems, the biofilm environment can shield them from these interventions, which can lead to persistent infections. Infections associated with medical-device biofilms, which sometimes develop after surgery, can be serious health risks—lengthening hospital stays or causing patients who have been discharged to be readmitted. Hatton and his team are among many groups around the world developing new materials, coatings and other approaches to prevent the formation of biofilms that can lead to such infections. But in their latest work, they chose to study something more fundamental: How do these colonizing microbial organisms gain a toehold in the first place? "In part, this comes out of the multidisciplinary approach we take in our group," Hatton says. "We're combining microbiology and materials science, but also mechanical engineering, because we're talking about mechanical stress, strain and deformation. This bending effect is something that had not been noticed before." The team tested various samples of silicone, including some they synthesized themselves as well as commercial-grade medical tubing used for urinary catheters. They then subjected these samples to mechanical forces to create surface damage. Their experiments showed that the microcracks can be formed very easily. Associate Professor Ben Hatton, left, and PhD candidate Desmond van den Berg examine bacteria samples in the lab. Credit: Neil Ta "One thing we did was simply wipe them a bunch of times with an ordinary laboratory tissue," says Desmond van den Berg, a Ph.D. candidate in the Institute of Biomedical Engineering and lead author on the paper, which was co-authored by fellow Hatton Lab researchers Dalal Asker and Tarek Awad. "Even this wiping was enough to create surface damage. By eye it still looks fine, but under the microscope, we could already see microcracks of the size that bacteria could get into. Bacteria are only a few micrometers big, so it doesn't take much." Other samples were pressed with a rough, ridged pattern to create a series of regularly-spaced microcracks. All the samples were then placed in a bacterial culture plate and seeded with Pseudomonas aeruginosa, a biofilm-forming bacterium commonly used as a model organism in these types of studies. After growth, the samples were treated with a fluorescent dye, causing any attached bacteria to glow green under an optical microscope. "What we saw was that the bacteria very clearly preferred to attach in these microscopic cracks," van den Berg says. "In the bent samples, there were four to five times as many bacteria on the side that was in tension versus the side that was in compression. These cells have full choice about where to grow, but they clearly love the side where all these microcracks are opened up." The only samples that remained relatively free of bacteria were the ones that had been synthesized in the team's own lab, and therefore remained extremely smooth, van den Berg notes. "Even the commercially produced ones that we didn't damage in any way already had microcracks in them, straight out of the package," he says. "We suspect that these are introduced via the manufacturing process, arising from the way the plastic is formed into tubes or other shapes by extrusion or injection molding." Hatton says that the study underlines just how easy it is to introduce surface features that encourage microbial attachment. For surgeons, one implication is that they should be looking out for situations where silicone devices—such as tubing or prosthetic implants—are being bent during use, and paying particular attention to the side under tension, as this is where infections might be starting. "Obviously it's difficult to simply not bend a rubber tube that is meant to be bent—otherwise, why would you make it out of rubber in the first place?" Hatton says. "But perhaps we can learn more about how to control or hide these surface cracks, so that bending is not a problem. That's what we're working on now—researching methods to reduce surface damage, or modifying the silicone surface to reduce the formation of such cracks." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract With the increasing availability of single-cell transcriptomes, RNA signatures offer a promising basis for targeting living cells. Molecular RNA sensors would enable the study of and therapeutic interventions for specific cell types/states in diverse contexts, particularly in human patients and non-model organisms. Here we describe a modular, programmable system for live RNA sensing using adenosine deaminases acting on RNA (RADAR). We validate, and then expand, our basic design, characterize its performance, and analyze its compatibility with human and mouse transcriptomes. We identify strategies to boost output levels and improve the dynamic range. Additionally, we show that RADAR enables compact AND logic. In addition to responding to transcript levels, RADAR can distinguish disease-relevant sequence alterations of transcript identities, such as point mutations and fusions. Finally, we demonstrate that RADAR is a self-contained system with the potential to function in diverse organisms. Main Single-cell transcriptomics often serve as the de facto way to define cell types and states 1 , but targeting cells on the basis of their RNA profile has remained challenging. RNA sense–response systems would enable the identification and destruction of harmful cells (for example, in the contexts of cancer and autoimmune disorders), or the experimental manipulation of specific cells in a complex ensemble (for example, the nervous and the immune systems). Available RNA-sensing technologies are limited to micro RNAs (miRNAs) 2 , 3 , 4 , or require careful design around functional RNA structures such as ribozymes, guide RNAs 5 , 6 , 7 , 8 or internal ribosome entry sites 9 . For the latter, an additional confounding factor is the natural response of the cell to double-stranded RNA (dsRNA) 10 . We postulate that we could build novel RNA sensors by leveraging such natural responses instead, specifically dsRNA editing by adenosine deaminases acting on RNA (ADARs) 11 , 12 , 13 . ADAR enzymes bind dsRNA in a largely sequence-agnostic way and edit A nucleotides to G-like I nucleotides, which we leverage to edit away UAG stop codons gating translation of a protein payload to form RNA-responsive, protein-outputting sensors. We demonstrate that RNA sensors using ADAR (RADAR sensors) are modular and programmable, have multiplexing and logic capabilities, discriminate disease-relevant variations, and can potentially function in many organisms. Results Proof-of-principle with synthetic trigger–sensor pairs A RADAR sensor is inspired by recent advances in RNA editing 14 , 15 , 16 , 17 , 18 , and consists of three parts (Fig. 1a ): an optional marker coding sequence; a sensor sequence reverse complementary to the target RNA of interest (‘trigger’), but with an editing-enhancing C:A mismatch at a central UAG stop codon (alternative pairings could be used); and an output coding sequence. The stop codon prevents the translation of the output coding sequence (CDS) so that only the marker (for example, mCherry) is expressed. In the presence of the trigger, dsRNA is formed, which recruits ADAR to edit the adenosine (A) in the UAG to an inosine (I), enabling the translation of the downstream CDS (for example, EGFP). ‘Self-cleaving’ 2A sequences 19 insulate the flanking CDS’s from the variable sensing sequence. We focused our initial efforts on identifying potential trigger sequences in 3′ untranslated regions (UTRs) for two reasons. First, ADAR editing is more efficient in 3′ UTR than CDS 20 , likely because translating ribosomes may destabilize dsRNA. Second, RADAR is less likely to interfere with the production of the protein encoded by the trigger, because dsRNA formation in the 3′ UTR rather than the CDS will not affect the translation ribosome, and because any bystander editing that occur in the 3′ UTR of the trigger is less likely to cause detrimental outcomes. Most human (57%) and mouse (73%) genes have a 90-bp trigger candidate for at least one reported 3′ UTR variant. Fig. 1: Characterizing RADAR. a , RADAR expresses an output protein once an input RNA has bound the sensor sequence, triggering an edit of an upstream stop codon by ADAR. b , Sensor 1 detects transfected trigger 1 (T1), but not the non-matching trigger 2 (T2) in human cells and is enhanced by ADAR1 p150 as assayed by flow cytometry. ‘Pos. ctrl’ replaces UAG by UGG (tryptophan), mimicking 100% editing efficiency. c , Linear relation between RADAR output and the amount of trigger 1 plasmid. Comparison to no-input case by Bonferroni-corrected two-tailed Student’s t -test (all significant comparisons P < 0.0014). n.s., not significant. d , Cre recombinase as an alternative output. The reporter is turned on by Cre-mediated inversion. e , A matched sensor (+ ✓ ) increases signal when the expression of a genomically integrated trigger is induced by doxycycline. A mismatched sensor (+ × ) was used as a negative control. f , RADAR sensor for mouse Bdnf detects a subsequence within the natural 3′ UTR of Bdnf . g , The output from a RADAR sensor for GAPDH is affected by siRNA against GAPDH. Top, RADAR output; bottom, qPCR quantification normalized to the no-knockdown condition. Bonferroni-corrected one-tailed Student t -test. h , A sensor (+ ✓ ) reports an endogenous transcript induced by heat shock whereas a negative control mismatched sensor (+ × ) does not. Left, RADAR output, with linear regression on a full factorial experimental design (intercept coefficient 1.96; heat-shock effect size 0.518, P = 0.017; three-way interaction effect size 1.94, P < 0.001; two-tailed P values from t -statistics; no multiple hypothesis correction); right, qPCR quantification of DNAJB1 expression normalized to GAPDH. For g and h , flow cytometry and RNA extraction were of the same samples. In all figures, unless otherwise noted, sensors and triggers were expressed from transiently transfected plasmids and we report the mean output fluorescence intensity in cells gated for high transfection efficiency (relative within the given experiment). Each dot represents one biological replicate, horizontal lines indicate the mean of data in each group ( n = 3). Significance determined by Bonferroni-corrected two-tailed Student’s t -test. **** P < 0.0001, *** P < 0.001, ** P < 0.01, * P < 0.05.", "role": "user" }, { "content": "Thanks to new RNA vaccines, we humans have been able to protect ourselves incredibly quickly from new viruses like SARS-CoV-2, the virus that causes COVID-19. These vaccines insert a piece of ephemeral genetic material into the body's cells, which then read its code and churn out a specific protein—in this case, telltale \"spikes\" that stud the outside of the coronavirus—priming the immune system to fight future invaders. The technique is effective, and has promise for all sorts of therapies, says Eerik Kaseniit, Ph.D. student in bioengineering at Stanford. At the moment, though, these sorts of RNA therapies can't focus on specific cells. Once injected into the body, they indiscriminately make the encoded protein in every cell they enter. If you want to use them to treat only one kind of cell—like those inside a cancerous tumor—you'll need something more precise. Kaseniit and his advisor, assistant professor of chemical engineering Xiaojing Gao, may have found a way to make this possible. They've created a new tool called an RNA \"sensor\"—a strand of lab-made RNA that reveals its contents only when it enters particular tissues within the body. The method is so exact that it can home in on both cell types and cell states, activating only when its target cell is creating a certain RNA, says Gao. The pair published their findings Oct. 5 in the journal Nature Biotechnology. \"For the first time, you can directly make only the cells of interest produce a protein under very specific circumstances,\" Gao adds. \"That kind of accuracy just wasn't previously possible.\" The protein produced could be an antigen—a foreign substance that elicits an immune response—like in the case of vaccines, an enzyme that restores function to a broken cell, a fluorescent protein that can be used to track specific cells in a research study, or a protein that triggers cell death to remove pathogenic or otherwise unwanted cells, among other possibilities. Leveraging the immune system The pair's new system, dubbed RADAR, is essentially made up of two sections: a \"sensor\" region that latches onto specific RNAs within the body, and a \"payload\" region that a cell will read and convert into a protein. The two sections are separated by a stop codon, an RNA sequence portion that makes a chunk of RADAR's genetic code inaccessible. If RADAR's sensor region successfully latches onto its target, the stop codon will disappear, making the remaining region—its \"payload\"—suddenly readable. In theory, this payload could hold instructions to make any protein, in any type of cell, at any time. The process takes place thanks to an existing set of enzymes called ADAR (Adenosine Deaminases Acting on RNA)—a byproduct of an ongoing viral arms race that has raged within in the human body for millennia, Gao says. Some viruses, like SARS-CoV-2, flu, and norovirus, are just a protein shell with RNA nestled inside. In the process of replicating, these viruses create very long stretches of double-stranded RNA. Since the viruses can have devastating effects on the body, our immune system has gradually learned to see those double-stranded RNAs as a threat and will quickly shut them down. \"It's a kind of danger signal—if a cell sees double-stranded RNA, it's immediately freaked out about it,\" Kaseniit says. In a strange twist of evolution, though, our own bodies also make double-stranded RNA. As viruses have attacked us over millennia, burrowing into our cells and toying with our genetic machinery, some of their genes have been absorbed and incorporated into our DNA. (That's not a fluke: It has happened so many times in the past that today the human genome is almost 8% virus.) To solve this problem, ADAR evolved as a sort of \"test\" system—a way for the body to tell if a piece of double-stranded RNA is friend or foe. If it finds one created by our own genome, ADAR edits it slightly to make it appear less threatening, causing holes or gaps to open up between the two strands, like removing a few stitches in the middle of a seam of fabric. The immune system, which has bigger fish to fry, promptly ignores this raggedy-looking RNA and goes on to fight the real enemy. RADAR takes advantage of that mechanism. When its \"sensor\" module latches onto a specific target molecule (another piece of RNA), ADAR sees the resulting double-stranded pair as a friendly, harmless variety and faithfully edits it so the immune system will ignore it. In the process, it erases the tiny molecular \"stop\" sign that the researchers built into the middle of the RNA strand. Once removed, the payload section of RADAR is visible to the cell, and the code it contains is turned into a protein. Potential for new programmable therapies Right now, Kaseniit, Gao, and their collaborators are still testing RADAR in a variety of settings, but the results look promising. With co-authors associate professor of chemical engineering Elizabeth Sattely and postdocs Diego Wengier and Will Cody, they've even tried it in plants, which don't naturally have ADAR systems—but after adding ADAR enzymes into the mix, they were able to get same results. In the future, they say, the flexibility and precision of RADAR could offer a valuable tool in both research and medicine, giving scientists a way to home in on specific cells in the lab or deliver therapies within the body. \"That's the hope and dream of RNA as a platform, because you can just encode whatever protein you want onto a piece of RNA and cells will make it. Now with these control elements, we can specify which target cell it will be activated in. That's very powerful,\" Kaseniit says. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract With the increasing availability of single-cell transcriptomes, RNA signatures offer a promising basis for targeting living cells. Molecular RNA sensors would enable the study of and therapeutic interventions for specific cell types/states in diverse contexts, particularly in human patients and non-model organisms. Here we describe a modular, programmable system for live RNA sensing using adenosine deaminases acting on RNA (RADAR). We validate, and then expand, our basic design, characterize its performance, and analyze its compatibility with human and mouse transcriptomes. We identify strategies to boost output levels and improve the dynamic range. Additionally, we show that RADAR enables compact AND logic. In addition to responding to transcript levels, RADAR can distinguish disease-relevant sequence alterations of transcript identities, such as point mutations and fusions. Finally, we demonstrate that RADAR is a self-contained system with the potential to function in diverse organisms. Main Single-cell transcriptomics often serve as the de facto way to define cell types and states 1 , but targeting cells on the basis of their RNA profile has remained challenging. RNA sense–response systems would enable the identification and destruction of harmful cells (for example, in the contexts of cancer and autoimmune disorders), or the experimental manipulation of specific cells in a complex ensemble (for example, the nervous and the immune systems). Available RNA-sensing technologies are limited to micro RNAs (miRNAs) 2 , 3 , 4 , or require careful design around functional RNA structures such as ribozymes, guide RNAs 5 , 6 , 7 , 8 or internal ribosome entry sites 9 . For the latter, an additional confounding factor is the natural response of the cell to double-stranded RNA (dsRNA) 10 . We postulate that we could build novel RNA sensors by leveraging such natural responses instead, specifically dsRNA editing by adenosine deaminases acting on RNA (ADARs) 11 , 12 , 13 . ADAR enzymes bind dsRNA in a largely sequence-agnostic way and edit A nucleotides to G-like I nucleotides, which we leverage to edit away UAG stop codons gating translation of a protein payload to form RNA-responsive, protein-outputting sensors. We demonstrate that RNA sensors using ADAR (RADAR sensors) are modular and programmable, have multiplexing and logic capabilities, discriminate disease-relevant variations, and can potentially function in many organisms. Results Proof-of-principle with synthetic trigger–sensor pairs A RADAR sensor is inspired by recent advances in RNA editing 14 , 15 , 16 , 17 , 18 , and consists of three parts (Fig. 1a ): an optional marker coding sequence; a sensor sequence reverse complementary to the target RNA of interest (‘trigger’), but with an editing-enhancing C:A mismatch at a central UAG stop codon (alternative pairings could be used); and an output coding sequence. The stop codon prevents the translation of the output coding sequence (CDS) so that only the marker (for example, mCherry) is expressed. In the presence of the trigger, dsRNA is formed, which recruits ADAR to edit the adenosine (A) in the UAG to an inosine (I), enabling the translation of the downstream CDS (for example, EGFP). ‘Self-cleaving’ 2A sequences 19 insulate the flanking CDS’s from the variable sensing sequence. We focused our initial efforts on identifying potential trigger sequences in 3′ untranslated regions (UTRs) for two reasons. First, ADAR editing is more efficient in 3′ UTR than CDS 20 , likely because translating ribosomes may destabilize dsRNA. Second, RADAR is less likely to interfere with the production of the protein encoded by the trigger, because dsRNA formation in the 3′ UTR rather than the CDS will not affect the translation ribosome, and because any bystander editing that occur in the 3′ UTR of the trigger is less likely to cause detrimental outcomes. Most human (57%) and mouse (73%) genes have a 90-bp trigger candidate for at least one reported 3′ UTR variant. Fig. 1: Characterizing RADAR. a , RADAR expresses an output protein once an input RNA has bound the sensor sequence, triggering an edit of an upstream stop codon by ADAR. b , Sensor 1 detects transfected trigger 1 (T1), but not the non-matching trigger 2 (T2) in human cells and is enhanced by ADAR1 p150 as assayed by flow cytometry. ‘Pos. ctrl’ replaces UAG by UGG (tryptophan), mimicking 100% editing efficiency. c , Linear relation between RADAR output and the amount of trigger 1 plasmid. Comparison to no-input case by Bonferroni-corrected two-tailed Student’s t -test (all significant comparisons P < 0.0014). n.s., not significant. d , Cre recombinase as an alternative output. The reporter is turned on by Cre-mediated inversion. e , A matched sensor (+ ✓ ) increases signal when the expression of a genomically integrated trigger is induced by doxycycline. A mismatched sensor (+ × ) was used as a negative control. f , RADAR sensor for mouse Bdnf detects a subsequence within the natural 3′ UTR of Bdnf . g , The output from a RADAR sensor for GAPDH is affected by siRNA against GAPDH. Top, RADAR output; bottom, qPCR quantification normalized to the no-knockdown condition. Bonferroni-corrected one-tailed Student t -test. h , A sensor (+ ✓ ) reports an endogenous transcript induced by heat shock whereas a negative control mismatched sensor (+ × ) does not. Left, RADAR output, with linear regression on a full factorial experimental design (intercept coefficient 1.96; heat-shock effect size 0.518, P = 0.017; three-way interaction effect size 1.94, P < 0.001; two-tailed P values from t -statistics; no multiple hypothesis correction); right, qPCR quantification of DNAJB1 expression normalized to GAPDH. For g and h , flow cytometry and RNA extraction were of the same samples. In all figures, unless otherwise noted, sensors and triggers were expressed from transiently transfected plasmids and we report the mean output fluorescence intensity in cells gated for high transfection efficiency (relative within the given experiment). Each dot represents one biological replicate, horizontal lines indicate the mean of data in each group ( n = 3). Significance determined by Bonferroni-corrected two-tailed Student’s t -test. **** P < 0.0001, *** P < 0.001, ** P < 0.01, * P < 0.05.<|im_end|> <|im_start|>assistant Thanks to new RNA vaccines, we humans have been able to protect ourselves incredibly quickly from new viruses like SARS-CoV-2, the virus that causes COVID-19. These vaccines insert a piece of ephemeral genetic material into the body's cells, which then read its code and churn out a specific protein—in this case, telltale "spikes" that stud the outside of the coronavirus—priming the immune system to fight future invaders. The technique is effective, and has promise for all sorts of therapies, says Eerik Kaseniit, Ph.D. student in bioengineering at Stanford. At the moment, though, these sorts of RNA therapies can't focus on specific cells. Once injected into the body, they indiscriminately make the encoded protein in every cell they enter. If you want to use them to treat only one kind of cell—like those inside a cancerous tumor—you'll need something more precise. Kaseniit and his advisor, assistant professor of chemical engineering Xiaojing Gao, may have found a way to make this possible. They've created a new tool called an RNA "sensor"—a strand of lab-made RNA that reveals its contents only when it enters particular tissues within the body. The method is so exact that it can home in on both cell types and cell states, activating only when its target cell is creating a certain RNA, says Gao. The pair published their findings Oct. 5 in the journal Nature Biotechnology. "For the first time, you can directly make only the cells of interest produce a protein under very specific circumstances," Gao adds. "That kind of accuracy just wasn't previously possible." The protein produced could be an antigen—a foreign substance that elicits an immune response—like in the case of vaccines, an enzyme that restores function to a broken cell, a fluorescent protein that can be used to track specific cells in a research study, or a protein that triggers cell death to remove pathogenic or otherwise unwanted cells, among other possibilities. Leveraging the immune system The pair's new system, dubbed RADAR, is essentially made up of two sections: a "sensor" region that latches onto specific RNAs within the body, and a "payload" region that a cell will read and convert into a protein. The two sections are separated by a stop codon, an RNA sequence portion that makes a chunk of RADAR's genetic code inaccessible. If RADAR's sensor region successfully latches onto its target, the stop codon will disappear, making the remaining region—its "payload"—suddenly readable. In theory, this payload could hold instructions to make any protein, in any type of cell, at any time. The process takes place thanks to an existing set of enzymes called ADAR (Adenosine Deaminases Acting on RNA)—a byproduct of an ongoing viral arms race that has raged within in the human body for millennia, Gao says. Some viruses, like SARS-CoV-2, flu, and norovirus, are just a protein shell with RNA nestled inside. In the process of replicating, these viruses create very long stretches of double-stranded RNA. Since the viruses can have devastating effects on the body, our immune system has gradually learned to see those double-stranded RNAs as a threat and will quickly shut them down. "It's a kind of danger signal—if a cell sees double-stranded RNA, it's immediately freaked out about it," Kaseniit says. In a strange twist of evolution, though, our own bodies also make double-stranded RNA. As viruses have attacked us over millennia, burrowing into our cells and toying with our genetic machinery, some of their genes have been absorbed and incorporated into our DNA. (That's not a fluke: It has happened so many times in the past that today the human genome is almost 8% virus.) To solve this problem, ADAR evolved as a sort of "test" system—a way for the body to tell if a piece of double-stranded RNA is friend or foe. If it finds one created by our own genome, ADAR edits it slightly to make it appear less threatening, causing holes or gaps to open up between the two strands, like removing a few stitches in the middle of a seam of fabric. The immune system, which has bigger fish to fry, promptly ignores this raggedy-looking RNA and goes on to fight the real enemy. RADAR takes advantage of that mechanism. When its "sensor" module latches onto a specific target molecule (another piece of RNA), ADAR sees the resulting double-stranded pair as a friendly, harmless variety and faithfully edits it so the immune system will ignore it. In the process, it erases the tiny molecular "stop" sign that the researchers built into the middle of the RNA strand. Once removed, the payload section of RADAR is visible to the cell, and the code it contains is turned into a protein. Potential for new programmable therapies Right now, Kaseniit, Gao, and their collaborators are still testing RADAR in a variety of settings, but the results look promising. With co-authors associate professor of chemical engineering Elizabeth Sattely and postdocs Diego Wengier and Will Cody, they've even tried it in plants, which don't naturally have ADAR systems—but after adding ADAR enzymes into the mix, they were able to get same results. In the future, they say, the flexibility and precision of RADAR could offer a valuable tool in both research and medicine, giving scientists a way to home in on specific cells in the lab or deliver therapies within the body. "That's the hope and dream of RNA as a platform, because you can just encode whatever protein you want onto a piece of RNA and cells will make it. Now with these control elements, we can specify which target cell it will be activated in. That's very powerful," Kaseniit says. <|im_end|>

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3524, 13, 578, 6857, 4756, 872, 14955, 5020, 13, 220, 20, 304, 279, 8486, 22037, 12371, 52536, 13, 330, 2520, 279, 1176, 892, 11, 499, 649, 6089, 1304, 1193, 279, 7917, 315, 2802, 8356, 264, 13128, 1234, 1633, 3230, 13463, 1359, 480, 3524, 11621, 13, 330, 4897, 3169, 315, 13708, 1120, 5828, 956, 8767, 3284, 1210, 578, 13128, 9124, 1436, 387, 459, 83089, 29096, 7362, 20278, 430, 658, 51650, 459, 22852, 2077, 2345, 4908, 304, 279, 1162, 315, 40300, 11, 459, 49242, 430, 88855, 734, 311, 264, 11102, 2849, 11, 264, 74864, 13128, 430, 649, 387, 1511, 311, 3839, 3230, 7917, 304, 264, 3495, 4007, 11, 477, 264, 13128, 430, 31854, 2849, 4648, 311, 4148, 1853, 29569, 477, 6062, 36021, 7917, 11, 4315, 1023, 24525, 13, 79679, 4210, 279, 22852, 1887, 578, 6857, 596, 502, 1887, 11, 42160, 75250, 946, 11, 374, 16168, 1903, 709, 315, 1403, 14491, 25, 264, 330, 30611, 1, 5654, 430, 326, 9296, 8800, 3230, 46916, 2170, 2949, 279, 2547, 11, 323, 264, 330, 19992, 1, 5654, 430, 264, 2849, 690, 1373, 323, 5625, 1139, 264, 13128, 13, 578, 1403, 14491, 527, 19180, 555, 264, 3009, 20950, 263, 11, 459, 41214, 8668, 13651, 430, 3727, 264, 12143, 315, 75250, 946, 596, 19465, 2082, 82828, 13, 1442, 75250, 946, 596, 12271, 5654, 7946, 326, 9296, 8800, 1202, 2218, 11, 279, 3009, 20950, 263, 690, 32153, 11, 3339, 279, 9861, 5654, 2345, 1220, 330, 19992, 66101, 82, 44806, 34898, 13, 763, 10334, 11, 420, 7885, 1436, 3412, 11470, 311, 1304, 904, 13128, 11, 304, 904, 955, 315, 2849, 11, 520, 904, 892, 13, 578, 1920, 5097, 2035, 9523, 311, 459, 6484, 743, 315, 56067, 2663, 9827, 946, 320, 2654, 71970, 483, 1611, 8778, 2315, 73789, 389, 41214, 68850, 64, 555, 3107, 315, 459, 14529, 29962, 11977, 7102, 430, 706, 436, 3359, 2949, 304, 279, 3823, 2547, 369, 96731, 11, 480, 3524, 2795, 13, 4427, 42068, 11, 1093, 328, 17485, 87271, 53, 12, 17, 11, 20236, 11, 323, 6463, 869, 17402, 11, 527, 1120, 264, 13128, 12811, 449, 41214, 89777, 4871, 13, 763, 279, 1920, 315, 29641, 1113, 11, 1521, 42068, 1893, 1633, 1317, 50699, 315, 2033, 42728, 6601, 41214, 13, 8876, 279, 42068, 649, 617, 33318, 6372, 389, 279, 2547, 11, 1057, 22852, 1887, 706, 27115, 9687, 311, 1518, 1884, 2033, 42728, 6601, 46916, 2170, 439, 264, 6023, 323, 690, 6288, 9495, 1124, 1523, 13, 330, 2181, 596, 264, 3169, 315, 8137, 8450, 90863, 264, 2849, 16008, 2033, 42728, 6601, 41214, 11, 433, 596, 7214, 30305, 291, 704, 922, 433, 1359, 38642, 34229, 275, 2795, 13, 763, 264, 15234, 27744, 315, 15740, 11, 3582, 11, 1057, 1866, 13162, 1101, 1304, 2033, 42728, 6601, 41214, 13, 1666, 42068, 617, 18855, 603, 927, 96731, 11, 7951, 25156, 1139, 1057, 7917, 323, 311, 7169, 449, 1057, 19465, 26953, 11, 1063, 315, 872, 21389, 617, 1027, 42101, 323, 32762, 1139, 1057, 15922, 13, 320, 4897, 596, 539, 264, 1344, 10647, 25, 1102, 706, 7077, 779, 1690, 3115, 304, 279, 3347, 430, 3432, 279, 3823, 33869, 374, 4661, 220, 23, 4, 17188, 6266, 2057, 11886, 420, 3575, 11, 9827, 946, 28995, 439, 264, 3460, 315, 330, 1985, 1, 1887, 29096, 1648, 369, 279, 2547, 311, 3371, 422, 264, 6710, 315, 2033, 42728, 6601, 41214, 374, 4333, 477, 53077, 13, 1442, 433, 14035, 832, 3549, 555, 1057, 1866, 33869, 11, 9827, 946, 51944, 433, 10284, 311, 1304, 433, 5101, 2753, 27903, 11, 14718, 20349, 477, 33251, 311, 1825, 709, 1990, 279, 1403, 69864, 11, 1093, 18054, 264, 2478, 63036, 304, 279, 6278, 315, 264, 27494, 315, 13354, 13, 578, 22852, 1887, 11, 902, 706, 11493, 7795, 311, 53646, 11, 40522, 49378, 420, 21108, 3640, 88, 31348, 41214, 323, 5900, 389, 311, 4465, 279, 1972, 9354, 13, 75250, 946, 5097, 9610, 315, 430, 17383, 13, 3277, 1202, 330, 30611, 1, 4793, 326, 9296, 8800, 264, 3230, 2218, 43030, 320, 43063, 6710, 315, 41214, 705, 9827, 946, 16008, 279, 13239, 2033, 42728, 6601, 6857, 439, 264, 11919, 11, 53997, 8205, 323, 94176, 51944, 433, 779, 279, 22852, 1887, 690, 10240, 433, 13, 763, 279, 1920, 11, 433, 2781, 2315, 279, 13987, 31206, 330, 9684, 1, 1879, 430, 279, 12074, 5918, 1139, 279, 6278, 315, 279, 41214, 42589, 13, 9843, 7108, 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2,687

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections AI Remote Sensing Atmospheric Remote Sensing Biogeosciences Remote Sensing Coral Reefs Remote Sensing Discoveries in Remote Sensing Earth Observation Data Earth Observation for Emergency Management Ecological Remote Sensing Engineering Remote Sensing Environmental Remote Sensing Forest Remote Sensing Ocean Remote Sensing Remote Sensing and Geo-Spatial Science Remote Sensing Communications Remote Sensing Image Processing Remote Sensing in Agriculture and Vegetation Remote Sensing in Geology, Geomorphology and Hydrology Remote Sensing of the Water Cycle Satellite Missions for Earth and Planetary Exploration Urban Remote Sensing All Sections Special Issue All Special Issues Remote Sensing: 15th Anniversary 100 Years ISPRS - Advancing Remote Sensing Science 2nd Edition Advances in Remote Sensing for Archaeological Heritage 3D Point Clouds in Rock Mechanics Applications Accuracy Assessment of UAS Lidar Active-Passive Microwave Sensing for Earth System Parameters Advanced Communication and Networking Techniques for Remote Sensing Advanced Machine Learning and Big Data Analytics in Remote Sensing for Natural Hazards Management Advanced Machine Learning Approaches for Hyperspectral Data Analysis Advanced Radar Signal Processing and Applications Advanced Remote Sensing Methods for 3D Vegetation Mapping and Characterization Advanced Satellite-Terrestrial Networks Advanced Topics in Remote Sensing Advancement of Remote Sensing and UAS in Cartography and Visualisation Advancements in Remote Sensing and GIS in Mobile Computing and Location-Based Services Advances and Innovative Applications of Unmanned Aerial Vehicles Advances in Applications of Volunteered Geographic Information Advances in Climate and Geophysics Advances in Geographic Object-Based Image Analysis (GEOBIA) Advances in Mobile Laser Scanning and Mobile Mapping Advances in Object and Activity Detection in Remote Sensing Imagery Advances in Object and Activity Detection in Remote Sensing Imagery II Advances in Object-Based Image Analysis—Linking with Computer Vision and Machine Learning Advances in Quantitative Remote Sensing in China – In Memory of Prof. Xiaowen Li Advances in Real Aperture and Synthetic Aperture Ground-Based Interferometry Advances in Remote Sensing and Geographic Information Science and Their Uses in Geointelligence Advances in Remote Sensing Applications for the Detection of Biological Invasions Advances in Remote Sensing for Archaeological Heritage Advances in Remote Sensing in Coastal Geomorphology Advances in Remote Sensing of Agriculture Advances in Remote Sensing of Crop Water Use Estimation Advances in Remote Sensing of Forestry Advances in Remote Sensing of Wildland Fires Advances in Remote Sensing-based Disaster Monitoring and Assessment Advances in SAR: Sensors, Methodologies, and Applications Advances in Satellite Altimetry Advances in Satellite Altimetry and Its Application Advances in Synthetic Aperture Radar Remote Sensing Advances in the Remote Sensing of Terrestrial Evaporation Advances in VIIRS Data Advances of Remote Sensing in Environmental Geoscience Aerosol and Cloud Remote Sensing Airborne Laser Scanning Analysis of Remote Sensing Image Data Application of Machine Learning in Volcano Monitoring Application of Multi-Sensor Fusion Technology in Target Detection and Recognition Application of Remote Sensing in Hydrological Modeling and Watershed Management Applications and New Trends in Metrology for Radar/LiDAR-Based Systems Applications of Deep Learning in Smart Agriculture Applications of Full Waveform Lidar Applications of GNSS Reflectometry for Earth Observation Applications of Micro- and Nano-Satellites for Earth Observation Applications of Remote Sensing in Landscape Ecology in Latin America Applications of Remote Sensing in Rangelands Research Applications of Synthetic Aperture Radar (SAR) for Land Cover Analysis Approaches for Monitoring Land Degradation with Remote Sensing Archaeological Prospecting and Remote Sensing Artifacts in Remote Sensing Data Analysis: An Ecological Perspective Artificial Intelligence and Automation in Sustainable Smart Farming Artificial Neural Networks and Evolutionary Computation in Remote Sensing Assessment of Renewable Energy Resources with Remote Sensing Assimilation of Remote Sensing Data into Earth System Models Atmospheric Remote Sensing Baltic Sea Remote Sensing Big Data Analytics for Secure and Smart Environmental Services Big Earth Observation Data: From Cloud Technologies to Insights and Foresight Bistatic HF Radar Calibration and Validation of Synthetic Aperture Radar Calibration and Verification of Remote Sensing Instruments and Observations Carbon Cycle, Global Change, and Multi-Sensor Remote Sensing Cartography of the Solar System: Remote Sensing beyond Earth Celebrating the 50th Anniversary of the Moon Landing with Views of Earth from Satellite and Apollo Missions Citizen Science and Earth Observation Climate Modelling and Monitoring Using GNSS Close Range Remote Sensing Close-Range Remote Sensing by Ground Penetrating Radar Compact Polarimetric SAR Concurrent Positioning, Mapping and Perception of Multi-source Data Fusion for Smart Applications Contemporary Microwave and Radar Techniques in Remote Sensing—MIKON 2022, IRS 2022 CORINE Land Cover System: Limits and Challenges for Territorial Studies and Planning Cross-Calibration and Interoperability of Remote Sensing Instruments Cryospheric Remote Sensing Data Mining in Multi-Platform Remote Sensing Data Science in Remote Sensing Data Science, Artificial Intelligence and Remote Sensing Deep Learning for Intelligent Synthetic Aperture Radar Systems Deep Learning for Target Object Detection and Identification in Remote Sensing Data Deep Learning in Remote Sensing: Sample Datasets, Algorithms and Applications Dense Image Time Series Analysis for Ecosystem Monitoring Design and Calibration of Microwave Radiometers and Scatterometers for Remote Sensing of the Earth Designing and Managing the Next Generation of Transportation Infrastructure Digital Forest Resource Monitoring and Uncertainty Analysis Discovering A More Diverse Remote Sensing Discipline Drone-Based Ecological Conservation Earth Environment Monitoring with Advanced Spaceborne Synthetic Aperture Radar: New Architectures, Operational Modes, and Processing Techniques Earth Monitoring from A New Generation of Geostationary Satellites Earth Observation and Sustainable Development in Marine and Freshwater Systems Earth Observation for Ecosystems Monitoring in Space and Time Earth Observation for Water Resource Management in Africa Earth Observation in Planning for Sustainable Urban Development Earth Observation Technology Cluster: Innovative Sensor Systems for Advanced Land Surface Studies Earth Observation to Support Disaster Preparedness and Disaster Risk Management Earth Observation with AVHRR Data and Interconsistency Earth Observations for a Better Future Earth Earth Observations for Addressing Global Challenges Earth Observations for Geohazards Earth Observations for the Sustainable Development Ecogeomorphological Research Using Satellite Images Ecological Status and Change by Remote Sensing Environmental Research with Global Navigation Satellite System (GNSS) EO Solutions to Support Countries Implementing the SDGs ESA - NRSCC", "role": "user" }, { "content": "An analysis of thousands of water and oil wells in the Houston metro area has uncovered significant rates of subsidence, or gradual sinking of the ground, in some of the region's fast-growing suburbs that have not been previously reported. Shuhab Khan, professor of geology at the University of Houston, led the study published in Remote Sensing. His team found substantial subsidence in Katy, Spring, The Woodlands, Fresno and Mont Belvieu with groundwater and oil and gas withdrawal identified as the primary cause. \"Subsidence used to be a rare phenomenon. Now, it is all over the world,\" Khan said. \"There are 200 locations in 34 countries where there's known subsidence. Cities in the northern Gulf of Mexico, such as Houston, have experienced one of the fastest rates of subsidence.\" Severe subsidence not only raises the possibility of flooding homes and businesses, but it also produces a negative feedback loop, the study authors write. The weight of floodwater from severe flooding can compress the sediments in the subsurface and could exacerbate the already compacted soil to potentially drive subsidence further. The researchers used interferometric synthetic aperture radar (InSAR) data obtained from a European Space Agency satellite, which showed total subsidence of up to 9 cm to the north, northwest and west of Houston from 2016 to 2020. The subsidence rate was 2 cm a year. Khan and his team applied optimized hot spot analysis, a statistical tool, to groundwater level data collected over the past 31 years from more than 71,000 water wells to consider how much groundwater pumping contributed to subsidence. Similarly, they used the same analysis on more than 5,000 oil and gas wells to evaluate their impact on subsidence. \"It is thanks to the latest advances in geospatial analysis that we were able to investigate subsidence across the Houston area in unprecedented detail,\" said Otto Gadea, a graduate student from Khan's team. \"By analyzing comprehensive datasets from recent years, we determined for the suburbs, excessive groundwater extraction appears to be the primary driver of subsidence. Meanwhile for other areas such as Mont Belvieu, subsidence can be attributed to the heavy withdrawal of local oil and natural gas reserves.\" With population growth, groundwater extraction has become more prevalent in the Houston area. Khan points out downtown Houston, suburbs to Houston's southeast and parts of Spring Branch previously experienced subsidence, but because of groundwater regulation, the subsidence is no longer substantial. His team also studied natural causes for the sinking, like the expansion and shrinking of Houston's clay, silty and sandy soil sediments, and the impact of flooding. Sinking may also be causing fault movement in the area. \"If current ground pumping trends continue, faults in Katy and The Woodlands will likely become reactivated and increase in activity over time,\" the authors write. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections AI Remote Sensing Atmospheric Remote Sensing Biogeosciences Remote Sensing Coral Reefs Remote Sensing Discoveries in Remote Sensing Earth Observation Data Earth Observation for Emergency Management Ecological Remote Sensing Engineering Remote Sensing Environmental Remote Sensing Forest Remote Sensing Ocean Remote Sensing Remote Sensing and Geo-Spatial Science Remote Sensing Communications Remote Sensing Image Processing Remote Sensing in Agriculture and Vegetation Remote Sensing in Geology, Geomorphology and Hydrology Remote Sensing of the Water Cycle Satellite Missions for Earth and Planetary Exploration Urban Remote Sensing All Sections Special Issue All Special Issues Remote Sensing: 15th Anniversary 100 Years ISPRS - Advancing Remote Sensing Science 2nd Edition Advances in Remote Sensing for Archaeological Heritage 3D Point Clouds in Rock Mechanics Applications Accuracy Assessment of UAS Lidar Active-Passive Microwave Sensing for Earth System Parameters Advanced Communication and Networking Techniques for Remote Sensing Advanced Machine Learning and Big Data Analytics in Remote Sensing for Natural Hazards Management Advanced Machine Learning Approaches for Hyperspectral Data Analysis Advanced Radar Signal Processing and Applications Advanced Remote Sensing Methods for 3D Vegetation Mapping and Characterization Advanced Satellite-Terrestrial Networks Advanced Topics in Remote Sensing Advancement of Remote Sensing and UAS in Cartography and Visualisation Advancements in Remote Sensing and GIS in Mobile Computing and Location-Based Services Advances and Innovative Applications of Unmanned Aerial Vehicles Advances in Applications of Volunteered Geographic Information Advances in Climate and Geophysics Advances in Geographic Object-Based Image Analysis (GEOBIA) Advances in Mobile Laser Scanning and Mobile Mapping Advances in Object and Activity Detection in Remote Sensing Imagery Advances in Object and Activity Detection in Remote Sensing Imagery II Advances in Object-Based Image Analysis—Linking with Computer Vision and Machine Learning Advances in Quantitative Remote Sensing in China – In Memory of Prof. Xiaowen Li Advances in Real Aperture and Synthetic Aperture Ground-Based Interferometry Advances in Remote Sensing and Geographic Information Science and Their Uses in Geointelligence Advances in Remote Sensing Applications for the Detection of Biological Invasions Advances in Remote Sensing for Archaeological Heritage Advances in Remote Sensing in Coastal Geomorphology Advances in Remote Sensing of Agriculture Advances in Remote Sensing of Crop Water Use Estimation Advances in Remote Sensing of Forestry Advances in Remote Sensing of Wildland Fires Advances in Remote Sensing-based Disaster Monitoring and Assessment Advances in SAR: Sensors, Methodologies, and Applications Advances in Satellite Altimetry Advances in Satellite Altimetry and Its Application Advances in Synthetic Aperture Radar Remote Sensing Advances in the Remote Sensing of Terrestrial Evaporation Advances in VIIRS Data Advances of Remote Sensing in Environmental Geoscience Aerosol and Cloud Remote Sensing Airborne Laser Scanning Analysis of Remote Sensing Image Data Application of Machine Learning in Volcano Monitoring Application of Multi-Sensor Fusion Technology in Target Detection and Recognition Application of Remote Sensing in Hydrological Modeling and Watershed Management Applications and New Trends in Metrology for Radar/LiDAR-Based Systems Applications of Deep Learning in Smart Agriculture Applications of Full Waveform Lidar Applications of GNSS Reflectometry for Earth Observation Applications of Micro- and Nano-Satellites for Earth Observation Applications of Remote Sensing in Landscape Ecology in Latin America Applications of Remote Sensing in Rangelands Research Applications of Synthetic Aperture Radar (SAR) for Land Cover Analysis Approaches for Monitoring Land Degradation with Remote Sensing Archaeological Prospecting and Remote Sensing Artifacts in Remote Sensing Data Analysis: An Ecological Perspective Artificial Intelligence and Automation in Sustainable Smart Farming Artificial Neural Networks and Evolutionary Computation in Remote Sensing Assessment of Renewable Energy Resources with Remote Sensing Assimilation of Remote Sensing Data into Earth System Models Atmospheric Remote Sensing Baltic Sea Remote Sensing Big Data Analytics for Secure and Smart Environmental Services Big Earth Observation Data: From Cloud Technologies to Insights and Foresight Bistatic HF Radar Calibration and Validation of Synthetic Aperture Radar Calibration and Verification of Remote Sensing Instruments and Observations Carbon Cycle, Global Change, and Multi-Sensor Remote Sensing Cartography of the Solar System: Remote Sensing beyond Earth Celebrating the 50th Anniversary of the Moon Landing with Views of Earth from Satellite and Apollo Missions Citizen Science and Earth Observation Climate Modelling and Monitoring Using GNSS Close Range Remote Sensing Close-Range Remote Sensing by Ground Penetrating Radar Compact Polarimetric SAR Concurrent Positioning, Mapping and Perception of Multi-source Data Fusion for Smart Applications Contemporary Microwave and Radar Techniques in Remote Sensing—MIKON 2022, IRS 2022 CORINE Land Cover System: Limits and Challenges for Territorial Studies and Planning Cross-Calibration and Interoperability of Remote Sensing Instruments Cryospheric Remote Sensing Data Mining in Multi-Platform Remote Sensing Data Science in Remote Sensing Data Science, Artificial Intelligence and Remote Sensing Deep Learning for Intelligent Synthetic Aperture Radar Systems Deep Learning for Target Object Detection and Identification in Remote Sensing Data Deep Learning in Remote Sensing: Sample Datasets, Algorithms and Applications Dense Image Time Series Analysis for Ecosystem Monitoring Design and Calibration of Microwave Radiometers and Scatterometers for Remote Sensing of the Earth Designing and Managing the Next Generation of Transportation Infrastructure Digital Forest Resource Monitoring and Uncertainty Analysis Discovering A More Diverse Remote Sensing Discipline Drone-Based Ecological Conservation Earth Environment Monitoring with Advanced Spaceborne Synthetic Aperture Radar: New Architectures, Operational Modes, and Processing Techniques Earth Monitoring from A New Generation of Geostationary Satellites Earth Observation and Sustainable Development in Marine and Freshwater Systems Earth Observation for Ecosystems Monitoring in Space and Time Earth Observation for Water Resource Management in Africa Earth Observation in Planning for Sustainable Urban Development Earth Observation Technology Cluster: Innovative Sensor Systems for Advanced Land Surface Studies Earth Observation to Support Disaster Preparedness and Disaster Risk Management Earth Observation with AVHRR Data and Interconsistency Earth Observations for a Better Future Earth Earth Observations for Addressing Global Challenges Earth Observations for Geohazards Earth Observations for the Sustainable Development Ecogeomorphological Research Using Satellite Images Ecological Status and Change by Remote Sensing Environmental Research with Global Navigation Satellite System (GNSS) EO Solutions to Support Countries Implementing the SDGs ESA - NRSCC<|im_end|> <|im_start|>assistant An analysis of thousands of water and oil wells in the Houston metro area has uncovered significant rates of subsidence, or gradual sinking of the ground, in some of the region's fast-growing suburbs that have not been previously reported. Shuhab Khan, professor of geology at the University of Houston, led the study published in Remote Sensing. His team found substantial subsidence in Katy, Spring, The Woodlands, Fresno and Mont Belvieu with groundwater and oil and gas withdrawal identified as the primary cause. "Subsidence used to be a rare phenomenon. Now, it is all over the world," Khan said. "There are 200 locations in 34 countries where there's known subsidence. Cities in the northern Gulf of Mexico, such as Houston, have experienced one of the fastest rates of subsidence." Severe subsidence not only raises the possibility of flooding homes and businesses, but it also produces a negative feedback loop, the study authors write. The weight of floodwater from severe flooding can compress the sediments in the subsurface and could exacerbate the already compacted soil to potentially drive subsidence further. The researchers used interferometric synthetic aperture radar (InSAR) data obtained from a European Space Agency satellite, which showed total subsidence of up to 9 cm to the north, northwest and west of Houston from 2016 to 2020. The subsidence rate was 2 cm a year. Khan and his team applied optimized hot spot analysis, a statistical tool, to groundwater level data collected over the past 31 years from more than 71,000 water wells to consider how much groundwater pumping contributed to subsidence. Similarly, they used the same analysis on more than 5,000 oil and gas wells to evaluate their impact on subsidence. "It is thanks to the latest advances in geospatial analysis that we were able to investigate subsidence across the Houston area in unprecedented detail," said Otto Gadea, a graduate student from Khan's team. "By analyzing comprehensive datasets from recent years, we determined for the suburbs, excessive groundwater extraction appears to be the primary driver of subsidence. Meanwhile for other areas such as Mont Belvieu, subsidence can be attributed to the heavy withdrawal of local oil and natural gas reserves." With population growth, groundwater extraction has become more prevalent in the Houston area. Khan points out downtown Houston, suburbs to Houston's southeast and parts of Spring Branch previously experienced subsidence, but because of groundwater regulation, the subsidence is no longer substantial. His team also studied natural causes for the sinking, like the expansion and shrinking of Houston's clay, silty and sandy soil sediments, and the impact of flooding. Sinking may also be causing fault movement in the area. "If current ground pumping trends continue, faults in Katy and The Woodlands will likely become reactivated and increase in activity over time," the authors write. <|im_end|>

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1,956

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract RNA polymerase I (Pol I) specifically synthesizes ribosomal RNA. Pol I upregulation is linked to cancer, while mutations in the Pol I machinery lead to developmental disorders. Here we report the cryo-EM structure of elongating human Pol I at 2.7 Å resolution. In the exit tunnel, we observe a double-stranded RNA helix that may support Pol I processivity. Our structure confirms that human Pol I consists of 13 subunits with only one subunit forming the Pol I stalk. Additionally, the structure of human Pol I in complex with the initiation factor RRN3 at 3.1 Å resolution reveals stalk flipping upon RRN3 binding. We also observe an inactivated state of human Pol I bound to an open DNA scaffold at 3.3 Å resolution. Lastly, the high-resolution structure of human Pol I allows mapping of disease-related mutations that can aid understanding of disease etiology. Main RNA polymerase I (Pol I) is one of three eukaryotic RNA polymerases and is specialized in the transcription of ribosomal RNA (rRNA) 1 . rRNA constitutes 80–90% of the total RNA mass in mammalian cells 2 . Owing to the high-energy expense imposed by rRNA transcription, Pol I activity needs to be tightly regulated. Pol I transcription is the first step in ribosome biogenesis and thus plays a key role in cellular homeostasis 3 . Upregulation of Pol I activity is required for cancer cells to proliferate. Therefore, Pol I transcription is a promising drug target for a range of cancer types 4 . Several drugs acting on Pol I cofactors are already in clinical use, while other small molecules directly targeting Pol I are in clinical trials 3 . Transcriptional activity at the rDNA loci may compromise gene integrity, which promotes ageing 5 . Concomitantly, partial inhibition of Pol I has been associated with increasing longevity 6 . High rates of rRNA transcription are also observed in pluripotent stem cells 5 and any misregulation in the function of the Pol I machinery during development can lead to diseases resulting from impaired ribosome biogenesis and function, collectively named ribosomopathies 7 . Mutations causing acrofacial dysostosis (AD) and some mutations causing Treacher Collins syndrome (TCS) have been mapped to the Pol I core 8 , 9 . Other mutations causing TCS, as well as many mutations associated with hypomyelinating leukodystrophy (HLD), are also found in the subunits shared between Pol I and Pol III, making it difficult to distinguish whether functional impairment of Pol I or Pol III is causing the diseases 10 , 11 , 12 . A detailed understanding of Pol I structure and function in humans is therefore required to better understand its role in development, aging, and the etiology of diseases. Pol I shares its general architecture with other eukaryotic DNA-dependent RNA polymerases 13 , which comprise of a homologous core bound by the stalk subcomplex 13 . In addition, Pol I and Pol III have stably integrated subunits homologous to general transcription factors of Pol II, namely TFIIE and TFIIF 14 . Pol I is the second largest eukaryotic RNA polymerase. While yeast Pol I comprises 14 subunits 14 , 15 , in humans only homologs of 13 subunits have been identified 16 . For transcription to take place, Pol I needs to bind to the promoter sequence in the context of a preinitiation complex (PIC). Pol I bound by RRN3 associates with the five-subunit selectivity factor 1 (SL1) containing the TATA-box binding protein (TBP), which is activated by the upstream binding factor (UBF) to allow specific rRNA transcription initiation 16 . All components of the human Pol I PIC are regulated by post-translational modifications to regulate the rate of rRNA production in response to the cell cycle, growth factors, nutrient availability, and stress 17 , 18 , 19 , 20 , 21 , 22 . While we have a detailed understanding of the structure and transcription cycle of yeast Pol I 14 , 15 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , structural insights into human Pol I have been lacking. Here we report cryo-electron microscopy (cryo-EM) structures of human Pol I bound to different nucleic acid scaffolds as well as in complex with initiation factor RRN3 at 2.7 to 3.3 Å resolution. Obtained insights expand our understanding of human Pol I function and lay the ground for further studies of its regulation and role in disease. Results Structure of elongating human Pol I For cryo-EM structure determination, we purified human Pol I from HEK293T suspension cells where subunit RPAC1 was endogenously tagged by CRISPR–Cas9 (ref. 33 ). The introduced tag carries the mCherry fluorescent protein, allowing us to confirm the correct localization of Pol I to the nucleoli in the engineered cell line (Fig. 1a ). The quality of purified Pol I was assessed by SDS–PAGE, and the identity of all subunits was confirmed by mass spectrometry (Fig. 1b and Supplementary Table 1 ). Additionally, we confirmed the transcriptional activity of the obtained human Pol I through an in vitro RNA primer extension assay (Fig. 1c ). Subsequently, we used the DNA–RNA scaffold, mimicking the elongation transcription bubble, for the cryo-EM structure determination of the Pol I elongating complex (Pol I EC). The human Pol I EC was resolved at 2.7 Å resolution (Extended Data Fig. 1 ). To resolve the more flexible, peripheral parts of the complex, we used focused classification and multibody refinement, which yielded three additional partial cryo-EM maps (Extended Data Fig. 1 and Table 1 ). Fig. 1: Structure of human Pol I. a , Confocal images of the HEK293T cell line with endogenously tagged subunit RPAC1, showing localization to the nucleolus. Overlay of the transmission image with the mCherry signal (red, middle) and live Hoechst dye staining the DNA (cyan, right). Scale bars, 5 μm; n = 1. b , Coomassie-stained SDS–PAGE of the purified human Pol I; representative gel of 15 independent purifications. Identities of the labeled bands were confirmed by", "role": "user" }, { "content": "Using state-of-the-art technology and techniques, EMBL's Müller group has provided the most detailed structure to date of human RNA polymerase I (Pol I), offering fundamental information about cellular function for those studying rare diseases and cancers. RNA Pol I has been implicated in certain disorders and cancers. Their findings, published in Nature Structural and Molecular Biology, illuminate the structure and function of human Pol I in different functional states. This marks the latest research chapter on this enzyme that began with prior Pol I research in yeast in 2013. It's only fairly recently that the researchers moved from studying RNA Pol I in yeast to human Pol I. In collaboration with Aleix Lafita, a computational biologist formerly at EMBL's European Bioinformatics Institute (EMBL-EBI) in Hinxton, UK, the team was able to shed light on how this human version of the enzyme and some of its regulatory cofactors evolutionarily differ. \"When I started working on this project, we didn't even know exactly how many subunits comprised human Pol I,\" said Agata Misiaszek, the paper's lead author. In yeast, Pol I has 14 units, but in humans that number is just 13. As it turns out, most species have only 13 subunits to RNA Pol I—except for yeast and some other fungi—and the difference could be important. \"So, scientists have been studying an outlier for a long time,\" said Mathias Girbig, one of the paper's co-authors. \"Interestingly, the place where this subunit is 'missing' is an important interaction site. The contrast to earlier work raises important questions that could help in understanding the regulation of Pol I's function.\" Human RNA Pol I can only be obtained in small amounts, preventing the use of classical structural biology techniques, such as X-ray crystallography. However, with the advent of cryo-electron microscopy (cryo-EM) and CRISPR–Cas9 genome editing, EMBL researchers—along with others in the field—have begun making progress in understanding what Pol I looks like and how it works in human cells. The group's findings, along with their other recent work with human RNA polymerase III, complete the gallery of human RNA polymerases. This research lends insights into machineries that produce different types of RNA: from short ribosomal RNAs and transfer RNAs (Pol III) to long ribosomal RNAs (Pol I). \"Both Pol I and III are vital for the cell to function, but we now see some differences in key areas where mutations occur,\" Misiaszek explained, \"So, for example, in a rare disease like Treacher Collins syndrome, both polymerases are affected, but Pol I may be more so. Consequently, this begs the question of why this happens and what it means in patients.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract RNA polymerase I (Pol I) specifically synthesizes ribosomal RNA. Pol I upregulation is linked to cancer, while mutations in the Pol I machinery lead to developmental disorders. Here we report the cryo-EM structure of elongating human Pol I at 2.7 Å resolution. In the exit tunnel, we observe a double-stranded RNA helix that may support Pol I processivity. Our structure confirms that human Pol I consists of 13 subunits with only one subunit forming the Pol I stalk. Additionally, the structure of human Pol I in complex with the initiation factor RRN3 at 3.1 Å resolution reveals stalk flipping upon RRN3 binding. We also observe an inactivated state of human Pol I bound to an open DNA scaffold at 3.3 Å resolution. Lastly, the high-resolution structure of human Pol I allows mapping of disease-related mutations that can aid understanding of disease etiology. Main RNA polymerase I (Pol I) is one of three eukaryotic RNA polymerases and is specialized in the transcription of ribosomal RNA (rRNA) 1 . rRNA constitutes 80–90% of the total RNA mass in mammalian cells 2 . Owing to the high-energy expense imposed by rRNA transcription, Pol I activity needs to be tightly regulated. Pol I transcription is the first step in ribosome biogenesis and thus plays a key role in cellular homeostasis 3 . Upregulation of Pol I activity is required for cancer cells to proliferate. Therefore, Pol I transcription is a promising drug target for a range of cancer types 4 . Several drugs acting on Pol I cofactors are already in clinical use, while other small molecules directly targeting Pol I are in clinical trials 3 . Transcriptional activity at the rDNA loci may compromise gene integrity, which promotes ageing 5 . Concomitantly, partial inhibition of Pol I has been associated with increasing longevity 6 . High rates of rRNA transcription are also observed in pluripotent stem cells 5 and any misregulation in the function of the Pol I machinery during development can lead to diseases resulting from impaired ribosome biogenesis and function, collectively named ribosomopathies 7 . Mutations causing acrofacial dysostosis (AD) and some mutations causing Treacher Collins syndrome (TCS) have been mapped to the Pol I core 8 , 9 . Other mutations causing TCS, as well as many mutations associated with hypomyelinating leukodystrophy (HLD), are also found in the subunits shared between Pol I and Pol III, making it difficult to distinguish whether functional impairment of Pol I or Pol III is causing the diseases 10 , 11 , 12 . A detailed understanding of Pol I structure and function in humans is therefore required to better understand its role in development, aging, and the etiology of diseases. Pol I shares its general architecture with other eukaryotic DNA-dependent RNA polymerases 13 , which comprise of a homologous core bound by the stalk subcomplex 13 . In addition, Pol I and Pol III have stably integrated subunits homologous to general transcription factors of Pol II, namely TFIIE and TFIIF 14 . Pol I is the second largest eukaryotic RNA polymerase. While yeast Pol I comprises 14 subunits 14 , 15 , in humans only homologs of 13 subunits have been identified 16 . For transcription to take place, Pol I needs to bind to the promoter sequence in the context of a preinitiation complex (PIC). Pol I bound by RRN3 associates with the five-subunit selectivity factor 1 (SL1) containing the TATA-box binding protein (TBP), which is activated by the upstream binding factor (UBF) to allow specific rRNA transcription initiation 16 . All components of the human Pol I PIC are regulated by post-translational modifications to regulate the rate of rRNA production in response to the cell cycle, growth factors, nutrient availability, and stress 17 , 18 , 19 , 20 , 21 , 22 . While we have a detailed understanding of the structure and transcription cycle of yeast Pol I 14 , 15 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , structural insights into human Pol I have been lacking. Here we report cryo-electron microscopy (cryo-EM) structures of human Pol I bound to different nucleic acid scaffolds as well as in complex with initiation factor RRN3 at 2.7 to 3.3 Å resolution. Obtained insights expand our understanding of human Pol I function and lay the ground for further studies of its regulation and role in disease. Results Structure of elongating human Pol I For cryo-EM structure determination, we purified human Pol I from HEK293T suspension cells where subunit RPAC1 was endogenously tagged by CRISPR–Cas9 (ref. 33 ). The introduced tag carries the mCherry fluorescent protein, allowing us to confirm the correct localization of Pol I to the nucleoli in the engineered cell line (Fig. 1a ). The quality of purified Pol I was assessed by SDS–PAGE, and the identity of all subunits was confirmed by mass spectrometry (Fig. 1b and Supplementary Table 1 ). Additionally, we confirmed the transcriptional activity of the obtained human Pol I through an in vitro RNA primer extension assay (Fig. 1c ). Subsequently, we used the DNA–RNA scaffold, mimicking the elongation transcription bubble, for the cryo-EM structure determination of the Pol I elongating complex (Pol I EC). The human Pol I EC was resolved at 2.7 Å resolution (Extended Data Fig. 1 ). To resolve the more flexible, peripheral parts of the complex, we used focused classification and multibody refinement, which yielded three additional partial cryo-EM maps (Extended Data Fig. 1 and Table 1 ). Fig. 1: Structure of human Pol I. a , Confocal images of the HEK293T cell line with endogenously tagged subunit RPAC1, showing localization to the nucleolus. Overlay of the transmission image with the mCherry signal (red, middle) and live Hoechst dye staining the DNA (cyan, right). Scale bars, 5 μm; n = 1. b , Coomassie-stained SDS–PAGE of the purified human Pol I; representative gel of 15 independent purifications. Identities of the labeled bands were confirmed by<|im_end|> <|im_start|>assistant Using state-of-the-art technology and techniques, EMBL's Müller group has provided the most detailed structure to date of human RNA polymerase I (Pol I), offering fundamental information about cellular function for those studying rare diseases and cancers. RNA Pol I has been implicated in certain disorders and cancers. Their findings, published in Nature Structural and Molecular Biology, illuminate the structure and function of human Pol I in different functional states. This marks the latest research chapter on this enzyme that began with prior Pol I research in yeast in 2013. It's only fairly recently that the researchers moved from studying RNA Pol I in yeast to human Pol I. In collaboration with Aleix Lafita, a computational biologist formerly at EMBL's European Bioinformatics Institute (EMBL-EBI) in Hinxton, UK, the team was able to shed light on how this human version of the enzyme and some of its regulatory cofactors evolutionarily differ. "When I started working on this project, we didn't even know exactly how many subunits comprised human Pol I," said Agata Misiaszek, the paper's lead author. In yeast, Pol I has 14 units, but in humans that number is just 13. As it turns out, most species have only 13 subunits to RNA Pol I—except for yeast and some other fungi—and the difference could be important. "So, scientists have been studying an outlier for a long time," said Mathias Girbig, one of the paper's co-authors. "Interestingly, the place where this subunit is 'missing' is an important interaction site. The contrast to earlier work raises important questions that could help in understanding the regulation of Pol I's function." Human RNA Pol I can only be obtained in small amounts, preventing the use of classical structural biology techniques, such as X-ray crystallography. However, with the advent of cryo-electron microscopy (cryo-EM) and CRISPR–Cas9 genome editing, EMBL researchers—along with others in the field—have begun making progress in understanding what Pol I looks like and how it works in human cells. The group's findings, along with their other recent work with human RNA polymerase III, complete the gallery of human RNA polymerases. This research lends insights into machineries that produce different types of RNA: from short ribosomal RNAs and transfer RNAs (Pol III) to long ribosomal RNAs (Pol I). "Both Pol I and III are vital for the cell to function, but we now see some differences in key areas where mutations occur," Misiaszek explained, "So, for example, in a rare disease like Treacher Collins syndrome, both polymerases are affected, but Pol I may be more so. Consequently, this begs the question of why this happens and what it means in patients." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The growing body of literature on the recognition of sexual orientation from voice (“auditory gaydar”) is silent on the cognitive and social consequences of having a gay-/lesbian- versus heterosexual-sounding voice. We investigated this issue in four studies (overall N = 276), conducted in Italian language, in which heterosexual listeners were exposed to single-sentence voice samples of gay/lesbian and heterosexual speakers. In all four studies, listeners were found to make gender-typical inferences about traits and preferences of heterosexual speakers, but gender-atypical inferences about those of gay or lesbian speakers. Behavioral intention measures showed that listeners considered lesbian and gay speakers as less suitable for a leadership position, and male (but not female) listeners took distance from gay speakers. Together, this research demonstrates that having a gay/lesbian rather than heterosexual-sounding voice has tangible consequences for stereotyping and discrimination. Working on a manuscript? Avoid the common mistakes Introduction Sexual orientation is a social category that, differently from many others that are signaled by clear visual features such as skin color, is not ascertained until the person self-discloses. Yet, people categorize individuals as gay or heterosexual on the basis of indirect cues, including their physical appearance, their body language, and their vocal characteristics (Rieger, Linsenmeier, Gygax, Garcia, & Bailey, 2010 ; Rule, 2017 ; Shelp, 2002 ). Whereas people may find it relatively easy to monitor their appearance and body language, voice may be less controllable than other cues (Fasoli, Maass, & Sulpizio, 2016 ). Although a growing number of studies have investigated how people use voice to infer sexual orientation (Gaudio, 1994 ; Munson, 2007 ; Munson, McDonald, DeBoe, & White, 2006 ; Rieger et al., 2010 ; Smyth, Jacobs, & Rogers, 2003 ; Sulpizio et al., 2015 ), less is known about the role of auditory information in stereotyping, namely the attribution of traits or characteristics to a person on the basis of shared beliefs regarding the social groups they belong to (Locksley, Hepburn, & Ortiz, 1982 ). The few studies that have analyzed the consequences of inferred sexual orientation have mainly focused on visual rather than vocal information (Knöfler & Imhof, 2007 ; Lick & Johnson, 2014 ). The present work aims to extend this literature by investigating how people react to vocal cues of sexual orientation in terms of stereotypical inferences, social avoidance, and discriminatory behaviors. At a theoretical level, we argue that vocal cues affect stereotyping and discrimination in much the same ways as do visual cues. Paralleling current theorizing on social vision (for a recent overview, see Johnson, Lick, & Carpinella, 2015 ), we believe that there are two pathways through which social hearing may affect inferences, judgments, and behaviors toward speakers: a category- and a feature-based process (Blair, Judd, Sadler, & Jenkins, 2002 ). As happens for visual perception (Blair et al., 2002 ), on one side auditory cues may trigger a social categorization (gay vs. heterosexual), which in turn activates corresponding stereotypes and behavioral responses. On the other side, it may activate stereotypes directly, in the absence of categorization, only based on people’s vocal features (see Ko, Judd, & Blair, 2006 ; Ko, Judd, & Stapel, 2009 ). Concretely, speakers may be stereotyped and/or discriminated either because they are categorized as gay (category-based process) or simply because they sound feminine (feature-based process). In our work, we address these issues by investigating how listeners react to vocal cues when no explicit mention of sexual orientation is made. Detection of Sexual Orientation The above distinction between category- and feature-based processes is important, as research on categorization of sexual orientation has provided mixed results with regard to people’s ability to detect sexual identity (so called “gaydar”). Studies have shown that people are quite accurate in judging whether a person is gay or heterosexual on the basis of nonverbal behavior, including mannerisms, gestures, and gait (Ambady, Hallahan, & Conner, 1999 ). Observers also seem, to some degree, able to guess a person’s sexual orientation from facial features even when peripheral cues such as hairstyle are removed (e.g., Rule & Ambady, 2008 , 2009 ; Tskhay, Feriozzo, & Rule, 2013 ). Studies conducted on voice, mostly done in English, have at times provided evidence that people are accurate in detecting sexual orientation from vocal cues (Gaudio, 1994 ; Rieger et al., 2010 ; Valentova & Havlíček, 2013 ). However, other studies have often disproven this claim and suggested that people distinguish between gay and heterosexual individuals on the basis of the stereotypical idea of how gays appear or sound (Smyth et al., 2003 ; Sulpizio et al., 2015 ). According to gender inversion theory (Kite & Deaux, 1987 ), gay/lesbian individuals are expected to be similar, even in terms of face and voice, to opposite-sex heterosexuals. This assumption of gender-atypicality may in part reflect actual differences in personality (Lippa, 2005 , 2008 ). Different lines of research concur that observers tend to rely on gender-typicality versus gender-atypicality when categorizing and drawing conclusions about a person’s sexual orientation, independent of the actual diagnosticity of such cues (Cox, Devine, Bischmann, & Hyde, 2016 ; Freeman, Johnson, Ambady, & Rule, 2010 ; Lick & Johnson, 2014 ; Lyons, Lynch, Brewer, & Bruno, 2014 ; Rule, Johnson, & Freeman, 2016 ; see also D’Augelli, Grossman, & Starks, 2008 ; Dunne, Bailey, Kirk, & Martin, 2000 ). Also, listeners’ voice-based categorization often reflects their expectations of how heterosexual (vs. gay) people are likely to speak. Listeners make reliable and consensually shared distinctions between gay- and heterosexual-sounding speech that do not necessarily correspond with the speakers’ self-definition (Smyth et al., 2003 ; Sulpizio et al., 2015 ; Zimman, 2010 ). Interestingly, the degree to which people use gender-stereotypical or gender-atypical cues (female features in men and male features in women) to infer sexual orientation depends greatly on people’s beliefs of how diagnostic such cues are (Cox et al., 2016 ; Freeman et al., 2010 ; Lick & Johnson, 2014 ; Stern, West, Jost, & Rule, 2013 ). Together, these lines of research suggest that people rely", "role": "user" }, { "content": "Gay men and lesbian women face discrimination when seeking leadership positions due to the sound of their voice, a new study in the Archives of Sexual Behaviour has found. The study, carried out by researchers at the University of Surrey, also found that people thought gay men should be paid less than their heterosexual counterparts. During this study researchers presented voice samples of gay and heterosexual speakers and pictures, devoid of any background features and other characteristics, to a heterosexual sample group. Participants were not informed of the sexual orientation of the person but allowed to freely guess from the voice or face of the individual. The sample group were asked to form impressions about applicants for the fake position of CEO and evaluate the employability of candidates by responding to five statements (which were rated on a scale of one to five) and to report the amount of monthly salary they considered adequate. The process was then repeated with lesbian candidates. Researchers discovered that participants perceived men and women who they considered to be gay or lesbian, as inadequate for a leadership position. For male candidates, auditory and not facial features impacted on whether they were deemed suitable for the role. Researchers discovered that having a heterosexual- rather than a 'gay- sounding' voice created the impression that the speaker had typically masculine traits, which in turn increased their perceived suitability for the role and the chance of receiving a higher salary. Lesbian candidates were associated with a lack of femininity and identified as gender non-conforming and received less positive evaluation than heterosexual counterparts. Dr Fabio Fasoli said: \"These results demonstrate that the mere sound of a voice is sufficient to trigger stereotyping denying gay- and lesbian-sounding speakers the qualities that are considered typical of their gender. \"It is revealing, that despite all the work to lessen discrimination against the LGBT community, people subconsciously type cast an individual before getting to know them. This study highlights that it can be a real problem in the workplace and for people's career prospects.\" In another study participants were also asked to listen to the voices of two different speakers who pronounced a single sentence of neutral content and then requested to evaluate the speakers' likely personality traits and personal interests (i.e. sports and fields of study). The traits and interests were manipulated in order to be recast characteristics/interests perceived to be \"typically masculine\" (e.g., football) and \"typically feminine\" (e.g., dance). In addition, participants were asked which of the speakers they would choose as an acquaintance. Similarly to the first study this was repeated with lesbian candidates. Researchers discovered that participants attributed more feminine traits to the gay than to the heterosexual speakers and lesbian speakers were more likely to be associated with masculine than to feminine characteristics. Interestingly, this happened without any mention of sexual orientation of the speakers demonstrating that vocal cues can lead to unfair stereotyping. When asked which of the speakers' participants would choose as an acquaintance for an interaction, researchers found that male participants were more likely to avoid male gay-sounding speakers, suggesting a subtle impact of voice on social exclusion of gay individuals. Dr Fasoli added: \"What is most concerning about this study is the subconscious behaviour intention of participants, where heterosexual male participants avoided choosing a gay male as an acquaintance. \"This study demonstrates that unacceptable levels of discrimination, be they subconscious or conscious, still exists in our society, and we need to do more to tackle the discrimination faced by the LGBT community.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The growing body of literature on the recognition of sexual orientation from voice (“auditory gaydar”) is silent on the cognitive and social consequences of having a gay-/lesbian- versus heterosexual-sounding voice. We investigated this issue in four studies (overall N = 276), conducted in Italian language, in which heterosexual listeners were exposed to single-sentence voice samples of gay/lesbian and heterosexual speakers. In all four studies, listeners were found to make gender-typical inferences about traits and preferences of heterosexual speakers, but gender-atypical inferences about those of gay or lesbian speakers. Behavioral intention measures showed that listeners considered lesbian and gay speakers as less suitable for a leadership position, and male (but not female) listeners took distance from gay speakers. Together, this research demonstrates that having a gay/lesbian rather than heterosexual-sounding voice has tangible consequences for stereotyping and discrimination. Working on a manuscript? Avoid the common mistakes Introduction Sexual orientation is a social category that, differently from many others that are signaled by clear visual features such as skin color, is not ascertained until the person self-discloses. Yet, people categorize individuals as gay or heterosexual on the basis of indirect cues, including their physical appearance, their body language, and their vocal characteristics (Rieger, Linsenmeier, Gygax, Garcia, & Bailey, 2010 ; Rule, 2017 ; Shelp, 2002 ). Whereas people may find it relatively easy to monitor their appearance and body language, voice may be less controllable than other cues (Fasoli, Maass, & Sulpizio, 2016 ). Although a growing number of studies have investigated how people use voice to infer sexual orientation (Gaudio, 1994 ; Munson, 2007 ; Munson, McDonald, DeBoe, & White, 2006 ; Rieger et al., 2010 ; Smyth, Jacobs, & Rogers, 2003 ; Sulpizio et al., 2015 ), less is known about the role of auditory information in stereotyping, namely the attribution of traits or characteristics to a person on the basis of shared beliefs regarding the social groups they belong to (Locksley, Hepburn, & Ortiz, 1982 ). The few studies that have analyzed the consequences of inferred sexual orientation have mainly focused on visual rather than vocal information (Knöfler & Imhof, 2007 ; Lick & Johnson, 2014 ). The present work aims to extend this literature by investigating how people react to vocal cues of sexual orientation in terms of stereotypical inferences, social avoidance, and discriminatory behaviors. At a theoretical level, we argue that vocal cues affect stereotyping and discrimination in much the same ways as do visual cues. Paralleling current theorizing on social vision (for a recent overview, see Johnson, Lick, & Carpinella, 2015 ), we believe that there are two pathways through which social hearing may affect inferences, judgments, and behaviors toward speakers: a category- and a feature-based process (Blair, Judd, Sadler, & Jenkins, 2002 ). As happens for visual perception (Blair et al., 2002 ), on one side auditory cues may trigger a social categorization (gay vs. heterosexual), which in turn activates corresponding stereotypes and behavioral responses. On the other side, it may activate stereotypes directly, in the absence of categorization, only based on people’s vocal features (see Ko, Judd, & Blair, 2006 ; Ko, Judd, & Stapel, 2009 ). Concretely, speakers may be stereotyped and/or discriminated either because they are categorized as gay (category-based process) or simply because they sound feminine (feature-based process). In our work, we address these issues by investigating how listeners react to vocal cues when no explicit mention of sexual orientation is made. Detection of Sexual Orientation The above distinction between category- and feature-based processes is important, as research on categorization of sexual orientation has provided mixed results with regard to people’s ability to detect sexual identity (so called “gaydar”). Studies have shown that people are quite accurate in judging whether a person is gay or heterosexual on the basis of nonverbal behavior, including mannerisms, gestures, and gait (Ambady, Hallahan, & Conner, 1999 ). Observers also seem, to some degree, able to guess a person’s sexual orientation from facial features even when peripheral cues such as hairstyle are removed (e.g., Rule & Ambady, 2008 , 2009 ; Tskhay, Feriozzo, & Rule, 2013 ). Studies conducted on voice, mostly done in English, have at times provided evidence that people are accurate in detecting sexual orientation from vocal cues (Gaudio, 1994 ; Rieger et al., 2010 ; Valentova & Havlíček, 2013 ). However, other studies have often disproven this claim and suggested that people distinguish between gay and heterosexual individuals on the basis of the stereotypical idea of how gays appear or sound (Smyth et al., 2003 ; Sulpizio et al., 2015 ). According to gender inversion theory (Kite & Deaux, 1987 ), gay/lesbian individuals are expected to be similar, even in terms of face and voice, to opposite-sex heterosexuals. This assumption of gender-atypicality may in part reflect actual differences in personality (Lippa, 2005 , 2008 ). Different lines of research concur that observers tend to rely on gender-typicality versus gender-atypicality when categorizing and drawing conclusions about a person’s sexual orientation, independent of the actual diagnosticity of such cues (Cox, Devine, Bischmann, & Hyde, 2016 ; Freeman, Johnson, Ambady, & Rule, 2010 ; Lick & Johnson, 2014 ; Lyons, Lynch, Brewer, & Bruno, 2014 ; Rule, Johnson, & Freeman, 2016 ; see also D’Augelli, Grossman, & Starks, 2008 ; Dunne, Bailey, Kirk, & Martin, 2000 ). Also, listeners’ voice-based categorization often reflects their expectations of how heterosexual (vs. gay) people are likely to speak. Listeners make reliable and consensually shared distinctions between gay- and heterosexual-sounding speech that do not necessarily correspond with the speakers’ self-definition (Smyth et al., 2003 ; Sulpizio et al., 2015 ; Zimman, 2010 ). Interestingly, the degree to which people use gender-stereotypical or gender-atypical cues (female features in men and male features in women) to infer sexual orientation depends greatly on people’s beliefs of how diagnostic such cues are (Cox et al., 2016 ; Freeman et al., 2010 ; Lick & Johnson, 2014 ; Stern, West, Jost, & Rule, 2013 ). Together, these lines of research suggest that people rely<|im_end|> <|im_start|>assistant Gay men and lesbian women face discrimination when seeking leadership positions due to the sound of their voice, a new study in the Archives of Sexual Behaviour has found. The study, carried out by researchers at the University of Surrey, also found that people thought gay men should be paid less than their heterosexual counterparts. During this study researchers presented voice samples of gay and heterosexual speakers and pictures, devoid of any background features and other characteristics, to a heterosexual sample group. Participants were not informed of the sexual orientation of the person but allowed to freely guess from the voice or face of the individual. The sample group were asked to form impressions about applicants for the fake position of CEO and evaluate the employability of candidates by responding to five statements (which were rated on a scale of one to five) and to report the amount of monthly salary they considered adequate. The process was then repeated with lesbian candidates. Researchers discovered that participants perceived men and women who they considered to be gay or lesbian, as inadequate for a leadership position. For male candidates, auditory and not facial features impacted on whether they were deemed suitable for the role. Researchers discovered that having a heterosexual- rather than a 'gay- sounding' voice created the impression that the speaker had typically masculine traits, which in turn increased their perceived suitability for the role and the chance of receiving a higher salary. Lesbian candidates were associated with a lack of femininity and identified as gender non-conforming and received less positive evaluation than heterosexual counterparts. Dr Fabio Fasoli said: "These results demonstrate that the mere sound of a voice is sufficient to trigger stereotyping denying gay- and lesbian-sounding speakers the qualities that are considered typical of their gender. "It is revealing, that despite all the work to lessen discrimination against the LGBT community, people subconsciously type cast an individual before getting to know them. This study highlights that it can be a real problem in the workplace and for people's career prospects." In another study participants were also asked to listen to the voices of two different speakers who pronounced a single sentence of neutral content and then requested to evaluate the speakers' likely personality traits and personal interests (i.e. sports and fields of study). The traits and interests were manipulated in order to be recast characteristics/interests perceived to be "typically masculine" (e.g., football) and "typically feminine" (e.g., dance). In addition, participants were asked which of the speakers they would choose as an acquaintance. Similarly to the first study this was repeated with lesbian candidates. Researchers discovered that participants attributed more feminine traits to the gay than to the heterosexual speakers and lesbian speakers were more likely to be associated with masculine than to feminine characteristics. Interestingly, this happened without any mention of sexual orientation of the speakers demonstrating that vocal cues can lead to unfair stereotyping. When asked which of the speakers' participants would choose as an acquaintance for an interaction, researchers found that male participants were more likely to avoid male gay-sounding speakers, suggesting a subtle impact of voice on social exclusion of gay individuals. Dr Fasoli added: "What is most concerning about this study is the subconscious behaviour intention of participants, where heterosexual male participants avoided choosing a gay male as an acquaintance. "This study demonstrates that unacceptable levels of discrimination, be they subconscious or conscious, still exists in our society, and we need to do more to tackle the discrimination faced by the LGBT community." <|im_end|>

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2,175

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Sympathetic cooling of trapped ions through collisions with neutral buffer gases is critical to a variety of modern scientific fields, including fundamental chemistry, mass spectrometry, nuclear and particle physics, and atomic and molecular physics. Despite its widespread use over four decades, there remain open questions regarding its fundamental limitations. To probe these limits, here we examine the steady-state evolution of up to 10 barium ions immersed in a gas of three-million laser-cooled calcium atoms. We observe and explain the emergence of nonequilibrium behaviour as evidenced by bifurcations in the ion steady-state temperature, parameterized by ion number. We show that this behaviour leads to the limitations in creating and maintaining translationally cold samples of trapped ions using neutral-gas sympathetic cooling. These results may provide a route to studying non-equilibrium thermodynamics at the atomic level. Introduction The concept of using a background gas to facilitate the loading of metallic particles into early ion traps was first demonstrated in 1959 (ref. 1 ). Since then, using collisions with cold, chemically inert gases to sympathetically cool trapped ions has become a general technique in many areas of scientific research. Today, the sympathetic cooling of ions with neutral buffer gases is routinely used to control the energy scales of chemical reactions 2 , to improve the performance of commercial mass spectrometers 3 , and to prepare short-lived exotic nuclei for tests of the Standard Model 4 . It has also been proposed as a method to initialize qubits in future quantum computation architecture 5 . Despite the widespread use of sympathetic cooling in ion traps, its kinetics have not yet been completely described and, likewise, its limitations are still not fully understood. The complexity of the cooling process derives from the fact that a system of trapped ions immersed in a cold buffer gas is not an isolated system. Instead, due to the presence of the time-dependent trapping potential, energy is injected and removed from the system over a single trapping cycle. Thus, as it is not a true representation of the canonical ensemble, the trapped ions do not tend to thermal equilibrium with the cold buffer gas as one might expect. As a result, collisions in the ion trap lead to fundamentally nonequilibrium processes that have made it difficult to establish a complete kinetic description of the technique and, as later explained, limits its ability to create and maintain translationally cold temperatures. To probe this nonequilibrium behaviour, we characterize the collisional processes between trapped ions and a buffer gas of laser-cooled atoms in a hybrid atom–ion trap. In our conception of this apparatus (shown in Fig. 1a ), laser-cooled barium ions confined by a linear quadrupole trap (LQT) are immersed in a 4 mK gas of magneto-optically trapped calcium atoms. Thus far, relatively little work has been done to fully understand the complex statistical mechanics of these hybrid systems 6 , 7 , 8 , 9 , 10 , 11 , despite being critical to current applications such as observing atom–ion collisions and reactions at cold temperatures 7 , 12 , 13 , 14 , 15 , 16 and producing cold molecular ions 17 , 18 . Through a more complete understanding of the collisional processes and nonequilibrium phenomena in these systems, which offer precise experimental control, we can establish the general limits of sympathetic cooling in ion traps. Figure 1: Emergence of nonequilbrium dynamics in a hybrid atom–ion trap. ( a ) A 3D rendering of the hybrid trap used to create an ensemble of trapped ions immersed in a laser-cooled buffer gas, as shown in the inset composite photograph. ( b ) Analytical heating and cooling rates for ions in a hybrid atom–ion trap. Three characteristic regimes exist for different relative heating and cooling strengths as parameterized by N i and are characterized by the number and type of fixed points they exhibit. ( c ) Steady-state evolution of ion temperatures for different N i and initializations as calculated by the MD simulation and analytical model. The left (right) pairs convey this evolution near the opening (closing) of the bifurcation at N i =3 ( N i =26), where the number of steady-state temperatures go from one (two) to two (one). ( d ) Steady-state temperatures for different N i and initializations as calculated by the MD simulation and analytical model. Error bars represent s.e. Red (blue)-shaded regions represent the ranges of ion temperatures before immersion for the hot (cold) initialization. Regimes I, II, and III are observed and indicated by differently shaded regions. The transitions between these regimes are marked by blue-sky bifurcations. Full size image In what follows, we first present a full description of the sympathetic collisional processes in a hybrid trap and how they lead to the emergence of nonequilibrium behaviour. Second, we provide the results of a molecular dynamics (MD) simulation that confirms the emergence of nonequilibrium dynamics of small numbers of trapped ions in a laser-cooled buffer gas under idealized conditions. Third, we describe an experiment in which we immerse laser-cooled barium ions in a gas of ultracold calcium atoms and observe the hallmark of this nonequilibrium behaviour: bifurcation of the ion steady-state temperature as parameterized by trapped ion number. Last, we remark on what these findings entail regarding the limits of sympathetic cooling of trapped ions with neutral buffer gases, we discuss the implications of the results on current hybrid trap experiments, and we expound on ways to engineer future hybrid traps to tailor more diverse sources of heating and cooling to model a variety of non-equilibrium systems. Results Analytical model of the sympathetic cooling process Since the work of Major and Dehmelt 19 , it has been known that even a single trapped ion immersed in a buffer gas does not equilibrate to the temperature of the buffer gas. Recent work has explained that this is due to a phenomenon, termed ‘micromotion interruption’ 10 , 11 , 20 , whereby collisions with buffer gas particles disrupt the ion micromotion and couple energy from", "role": "user" }, { "content": "According to the basic laws of thermodynamics, if you leave a warm apple pie in a winter window eventually the pie would cool down to the same temperature as the surrounding air. For chemists and physicists, cooling samples of charged particles, also called ions, makes them easier to control and study. So they use a similar approach—called buffer gas cooling—to lower the temperature of ions by trapping them and then immersing them in clouds of cold atoms. Collisions with the atoms cool the originally hot ions by transferring energy from the ions to the atoms—much the same way a warm pie is cooled next to the cold window, said Eric Hudson, associate professor of physics at UCLA. But new research by Hudson and his team, published in the journal Nature Communications, demonstrates that ions never truly cool to the temperature of the surrounding gas. Also, very surprisingly, they discovered that under certain conditions, two final temperatures exist, and the temperature that the ions choose depends on their starting temperature. \"This apparent departure from the familiar laws of thermodynamics is akin to our warm apple pie either cooling as expected or spontaneously bursting into flames, depending on the pie's exact temperature when it is placed in the window,\" said Hudson, the senior author of the study. The UCLA researchers have, for the first time, placed fundamental limits on the use of buffer gas cooling in \"ion traps.\" To perform their experiment, the researchers prepared a microscopic sample of laser cooled ions of the chemical element barium and immersed them in clouds of roughly 3 million laser-cooled calcium atoms. The researchers make molecules extremely cold under highly controlled conditions to reveal the quantum mechanical properties that are normally hidden. The ions were trapped in an apparatus that levitates charged particles by using electric fields that oscillate millions of times per second, confining the ions to a region smaller than the width of a human hair. Both the atomic and ionic samples were brought to ultra-cold temperatures —just one-thousandth of a degree above absolute zero—via a technique in which the momentum of light in a laser is used to slow particle motion. After allowing collisions between the atoms and ions to occur and the system to reach its final temperature, the physicists removed the calcium atoms and measured the temperature of the barium ions. The results, which show the existence of multiple final temperatures based on ion number and initial temperature, suggest that subtle non-equilibrium physics is at play. The researchers trace these strange features to the heating and cooling rates which exist in the system—the peculiar temperature dependence of the interaction among multiple ions in an ion trap. Both simulation and theory support their experimental findings, and paint the buffer-gas cooling process as a fundamentally nuanced, non-equilibrium process rather than the straightforward equilibrium process it was originally understood to be. Lead author Steven Schowalter, a graduate student researcher in Hudson's laboratory and now a staff scientist at NASA's Jet Propulsion Laboratory, said, \"Our results demonstrate that you can't just throw any buffer gas into your device—no matter how cold it is—and expect it to work as an effective coolant.\" Buffer gas cooling is crucial in fields ranging from forensics to the production of antimatter. Hudson's research group has discovered important nuances that revise the current understanding of the cooling process, explain the difficulties encountered in previous cooling experiments and show a new path forward for creating ultra-cold ion samples. With this framework the researchers showed how troublesome effects can be overcome and even exploited to study the mechanisms at play in molecular motors and single-atom heat engines in a precisely controlled manner. \"Of course, this work does not violate the laws of thermodynamics, but it does demonstrate there are still some interesting, potentially useful things to learn about buffer gas cooling,\" said John Gillaspy, a physics division program director at the National Science Foundation, which funds the research. \"This is the sort of fundamental research that can really guide a wide range of more applied research efforts, helping other scientists and engineers to avoid going down dead-end paths and illuminating more fruitful directions they might take instead.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Sympathetic cooling of trapped ions through collisions with neutral buffer gases is critical to a variety of modern scientific fields, including fundamental chemistry, mass spectrometry, nuclear and particle physics, and atomic and molecular physics. Despite its widespread use over four decades, there remain open questions regarding its fundamental limitations. To probe these limits, here we examine the steady-state evolution of up to 10 barium ions immersed in a gas of three-million laser-cooled calcium atoms. We observe and explain the emergence of nonequilibrium behaviour as evidenced by bifurcations in the ion steady-state temperature, parameterized by ion number. We show that this behaviour leads to the limitations in creating and maintaining translationally cold samples of trapped ions using neutral-gas sympathetic cooling. These results may provide a route to studying non-equilibrium thermodynamics at the atomic level. Introduction The concept of using a background gas to facilitate the loading of metallic particles into early ion traps was first demonstrated in 1959 (ref. 1 ). Since then, using collisions with cold, chemically inert gases to sympathetically cool trapped ions has become a general technique in many areas of scientific research. Today, the sympathetic cooling of ions with neutral buffer gases is routinely used to control the energy scales of chemical reactions 2 , to improve the performance of commercial mass spectrometers 3 , and to prepare short-lived exotic nuclei for tests of the Standard Model 4 . It has also been proposed as a method to initialize qubits in future quantum computation architecture 5 . Despite the widespread use of sympathetic cooling in ion traps, its kinetics have not yet been completely described and, likewise, its limitations are still not fully understood. The complexity of the cooling process derives from the fact that a system of trapped ions immersed in a cold buffer gas is not an isolated system. Instead, due to the presence of the time-dependent trapping potential, energy is injected and removed from the system over a single trapping cycle. Thus, as it is not a true representation of the canonical ensemble, the trapped ions do not tend to thermal equilibrium with the cold buffer gas as one might expect. As a result, collisions in the ion trap lead to fundamentally nonequilibrium processes that have made it difficult to establish a complete kinetic description of the technique and, as later explained, limits its ability to create and maintain translationally cold temperatures. To probe this nonequilibrium behaviour, we characterize the collisional processes between trapped ions and a buffer gas of laser-cooled atoms in a hybrid atom–ion trap. In our conception of this apparatus (shown in Fig. 1a ), laser-cooled barium ions confined by a linear quadrupole trap (LQT) are immersed in a 4 mK gas of magneto-optically trapped calcium atoms. Thus far, relatively little work has been done to fully understand the complex statistical mechanics of these hybrid systems 6 , 7 , 8 , 9 , 10 , 11 , despite being critical to current applications such as observing atom–ion collisions and reactions at cold temperatures 7 , 12 , 13 , 14 , 15 , 16 and producing cold molecular ions 17 , 18 . Through a more complete understanding of the collisional processes and nonequilibrium phenomena in these systems, which offer precise experimental control, we can establish the general limits of sympathetic cooling in ion traps. Figure 1: Emergence of nonequilbrium dynamics in a hybrid atom–ion trap. ( a ) A 3D rendering of the hybrid trap used to create an ensemble of trapped ions immersed in a laser-cooled buffer gas, as shown in the inset composite photograph. ( b ) Analytical heating and cooling rates for ions in a hybrid atom–ion trap. Three characteristic regimes exist for different relative heating and cooling strengths as parameterized by N i and are characterized by the number and type of fixed points they exhibit. ( c ) Steady-state evolution of ion temperatures for different N i and initializations as calculated by the MD simulation and analytical model. The left (right) pairs convey this evolution near the opening (closing) of the bifurcation at N i =3 ( N i =26), where the number of steady-state temperatures go from one (two) to two (one). ( d ) Steady-state temperatures for different N i and initializations as calculated by the MD simulation and analytical model. Error bars represent s.e. Red (blue)-shaded regions represent the ranges of ion temperatures before immersion for the hot (cold) initialization. Regimes I, II, and III are observed and indicated by differently shaded regions. The transitions between these regimes are marked by blue-sky bifurcations. Full size image In what follows, we first present a full description of the sympathetic collisional processes in a hybrid trap and how they lead to the emergence of nonequilibrium behaviour. Second, we provide the results of a molecular dynamics (MD) simulation that confirms the emergence of nonequilibrium dynamics of small numbers of trapped ions in a laser-cooled buffer gas under idealized conditions. Third, we describe an experiment in which we immerse laser-cooled barium ions in a gas of ultracold calcium atoms and observe the hallmark of this nonequilibrium behaviour: bifurcation of the ion steady-state temperature as parameterized by trapped ion number. Last, we remark on what these findings entail regarding the limits of sympathetic cooling of trapped ions with neutral buffer gases, we discuss the implications of the results on current hybrid trap experiments, and we expound on ways to engineer future hybrid traps to tailor more diverse sources of heating and cooling to model a variety of non-equilibrium systems. Results Analytical model of the sympathetic cooling process Since the work of Major and Dehmelt 19 , it has been known that even a single trapped ion immersed in a buffer gas does not equilibrate to the temperature of the buffer gas. Recent work has explained that this is due to a phenomenon, termed ‘micromotion interruption’ 10 , 11 , 20 , whereby collisions with buffer gas particles disrupt the ion micromotion and couple energy from<|im_end|> <|im_start|>assistant According to the basic laws of thermodynamics, if you leave a warm apple pie in a winter window eventually the pie would cool down to the same temperature as the surrounding air. For chemists and physicists, cooling samples of charged particles, also called ions, makes them easier to control and study. So they use a similar approach—called buffer gas cooling—to lower the temperature of ions by trapping them and then immersing them in clouds of cold atoms. Collisions with the atoms cool the originally hot ions by transferring energy from the ions to the atoms—much the same way a warm pie is cooled next to the cold window, said Eric Hudson, associate professor of physics at UCLA. But new research by Hudson and his team, published in the journal Nature Communications, demonstrates that ions never truly cool to the temperature of the surrounding gas. Also, very surprisingly, they discovered that under certain conditions, two final temperatures exist, and the temperature that the ions choose depends on their starting temperature. "This apparent departure from the familiar laws of thermodynamics is akin to our warm apple pie either cooling as expected or spontaneously bursting into flames, depending on the pie's exact temperature when it is placed in the window," said Hudson, the senior author of the study. The UCLA researchers have, for the first time, placed fundamental limits on the use of buffer gas cooling in "ion traps." To perform their experiment, the researchers prepared a microscopic sample of laser cooled ions of the chemical element barium and immersed them in clouds of roughly 3 million laser-cooled calcium atoms. The researchers make molecules extremely cold under highly controlled conditions to reveal the quantum mechanical properties that are normally hidden. The ions were trapped in an apparatus that levitates charged particles by using electric fields that oscillate millions of times per second, confining the ions to a region smaller than the width of a human hair. Both the atomic and ionic samples were brought to ultra-cold temperatures —just one-thousandth of a degree above absolute zero—via a technique in which the momentum of light in a laser is used to slow particle motion. After allowing collisions between the atoms and ions to occur and the system to reach its final temperature, the physicists removed the calcium atoms and measured the temperature of the barium ions. The results, which show the existence of multiple final temperatures based on ion number and initial temperature, suggest that subtle non-equilibrium physics is at play. The researchers trace these strange features to the heating and cooling rates which exist in the system—the peculiar temperature dependence of the interaction among multiple ions in an ion trap. Both simulation and theory support their experimental findings, and paint the buffer-gas cooling process as a fundamentally nuanced, non-equilibrium process rather than the straightforward equilibrium process it was originally understood to be. Lead author Steven Schowalter, a graduate student researcher in Hudson's laboratory and now a staff scientist at NASA's Jet Propulsion Laboratory, said, "Our results demonstrate that you can't just throw any buffer gas into your device—no matter how cold it is—and expect it to work as an effective coolant." Buffer gas cooling is crucial in fields ranging from forensics to the production of antimatter. Hudson's research group has discovered important nuances that revise the current understanding of the cooling process, explain the difficulties encountered in previous cooling experiments and show a new path forward for creating ultra-cold ion samples. With this framework the researchers showed how troublesome effects can be overcome and even exploited to study the mechanisms at play in molecular motors and single-atom heat engines in a precisely controlled manner. "Of course, this work does not violate the laws of thermodynamics, but it does demonstrate there are still some interesting, potentially useful things to learn about buffer gas cooling," said John Gillaspy, a physics division program director at the National Science Foundation, which funds the research. "This is the sort of fundamental research that can really guide a wide range of more applied research efforts, helping other scientists and engineers to avoid going down dead-end paths and illuminating more fruitful directions they might take instead." <|im_end|>

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2,096

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We present a quantum chemistry benchmark for noisy intermediate-scale quantum computers that leverages the variational quantum eigensolver, active-space reduction, a reduced unitary coupled cluster ansatz, and reduced density purification as error mitigation. We demonstrate this benchmark using 4 of the available qubits on the 20-qubit IBM Tokyo and 16-qubit Rigetti Aspen processors via the simulation of alkali metal hydrides (NaH, KH, RbH), with accuracy of the computed ground state energy serving as the primary benchmark metric. We further parameterize this benchmark suite on the trial circuit type, the level of symmetry reduction, and error mitigation strategies. Our results demonstrate the characteristically high noise level present in near-term superconducting hardware, but provide a relevant baseline for future improvement of the underlying hardware, and a means for comparison across near-term hardware types. We also demonstrate how to reduce the noise in post processing with specific error mitigation techniques. Particularly, the adaptation of McWeeny purification of noisy density matrices dramatically improves accuracy of quantum computations, which, along with adjustable active space, significantly extends the range of accessible molecular systems. We demonstrate that for specific benchmark settings and a selected range of problems, the accuracy metric can reach chemical accuracy when computing over the cloud on certain quantum computers. Introduction Noisy intermediate-scale quantum (NISQ) devices have been used recently to demonstrate a variety of different small-scale quantum computations. 1 , 2 , 3 , 4 , 5 These demonstrations underscore the progress in developing programmable quantum processing units (QPUs) as well as advances in how to use these devices for scientifically meaningful computations. However, evaluating the impact of these demonstrations is complicated by the interplay of unique features available from different quantum computing technologies (superconducting electronics, trapped ions, etc.) and the multitude of programming choices that influence observed performance. Several properties quantify the intrinsic utility of a QPU including the capacity of the quantum register, the fidelity of the available instructions, the connectivity between register elements, etc. While these hardware-specific parameters characterize progress in quantum hardware development, they do not directly benchmark the performance of a quantum computer for a given computational task. Benchmarks for application-specific metrics are needed to evaluate the efficiency and applicability of quantum computing for scientific applications. In particular, comparing the benchmark performance of quantum computation to alternative computational approaches should rely on definitions that are meaningful across computational paradigms. Application-specific performance metrics have been used recently to evaluate the utility of near-term QPUs with respect to computational accuracy, including examples from machine learning 6 and nuclear physics. 4 However, the design and demonstration of an application-specific benchmark to evaluate QPU performance across scalable problem instances has been absent from the literature up to now. We present a quantum chemistry simulation benchmark to evaluate the performance of quantum computing by defining a series of electronic structure calculation instances that can be realized on current hardware. We outline and investigate an array of parameter choices that influence quantum computational performance. Our approach uses multiple techniques including density matrix purification and active-space reduction via frozen-core approximation and truncation of the virtual space to accommodate hardware limitations such as a limited number of noisy qubits (low circuit width) and a limited achievable circuit depth (the number of parallel gate executions), while staying within the well-known hierarchy of quantum chemistry methods. For calculations on small molecular systems, such as alkali metal hydride molecules with multiple electrons presented here, the complexity of the quantum computation can be reduced to two valence electrons and the equivalent of a hydrogen molecule in minimal basis set. These approximations can be gradually lifted as the quality of quantum devices improves to provide a flexible benchmarking model. The quantum algorithmic primitive at the center of this benchmark is the state preparation circuit—the unitary coupled cluster (UCC) ansatz 7 or hardware-efficient (HWE) ansatz, 3 , 8 , 9 for example—used in the variational quantum eigensolver (VQE), 1 , 10 a noise-resilient algorithm which has been implemented on current noisy QPUs. This hybrid algorithm uses a classical search for the lowest eigenvalue of a given observable using the variational principle and the chosen ansatz, which is prepared and measured on the quantum computer. The utility of this algorithm has been demonstrated in a number of fields, including high-energy and nuclear physics 4 , 11 in addition to quantum chemistry. 8 Its success is primarily due to the reliance on finite classical computing resources in tandem with invocations of the quantum computer for exponentially scaling aspects of the problem. We use multiple variations of the state-preparation primitives noted above in order to illustrates its effect on performance and accuracy of quantum computations. The benchmark assesses accuracy of VQE for recovering the ground state energy for a series of molecules when using different parameterized trial circuits and error mitigation strategies. The alkali metal hydrides currently included in the benchmark are NaH, KH, and RbH. We implemented calculations of the ground state energies of each of these molecules using four qubits on the 20-qubit IBM Tokyo and 16-qubit Rigetti Aspen superconducting circuit devices. The variational quantum eigensolver (VQE) has been used previously to calculate ground state energy, 1 , 12 and it has become a leading example of quantum-classical computing. Several groups have demonstrated VQE applications using a variety of QPUs and trial circuits to target small molecular systems. 1 , 4 , 5 , 8 , 9 , 13 , 14 , 15 VQE recovers the ground state energy of a Hamiltonian by searching for the quantum state that minimizes the observed energy expectation value. The complexity of this classical search through the parameter space depends strongly on the form of the underlying trial circuit. Optimization of the energy expectation value uses preparation and measurement of the parameterized quantum circuit to drive the classical search method executed on a conventional computer. Existing demonstrations of VQE have revealed that despite the algorithm’s noise resilience, error mitigation is required to overcome the extensive noise present in current platforms. 16 , 17 , 18 For chemistry", "role": "user" }, { "content": "Researchers at the Department of Energy's Oak Ridge National Laboratory have developed a quantum chemistry simulation benchmark to evaluate the performance of quantum devices and guide the development of applications for future quantum computers. Their findings were published in npj Quantum Information. Quantum computers use the laws of quantum mechanics and units known as qubits to greatly increase the threshold at which information can be transmitted and processed. Whereas traditional \"bits\" have a value of either 0 or 1, qubits are encoded with values of both 0 and 1, or any combination thereof, allowing for a vast number of possibilities for storing data. While still in their early stages, quantum systems have the potential to be exponentially more powerful than today's leading classical computing systems and promise to revolutionize research in materials, chemistry, high-energy physics, and across the scientific spectrum. But because these systems are in their relative infancy, understanding what applications are well suited to their unique architectures is considered an important field of research. \"We are currently running fairly simple scientific problems that represent the sort of problems we believe these systems will help us to solve in the future,\" said ORNL's Raphael Pooser, principal investigator of the Quantum Testbed Pathfinder project. \"These benchmarks give us an idea of how future quantum systems will perform when tackling similar, though exponentially more complex, simulations.\" Pooser and his colleagues calculated the bound state energy of alkali hydride molecules on 20-qubit IBM Tokyo and 16-qubit Rigetti Aspen processors. These molecules are simple and their energies well understood, allowing them to effectively test the performance of the quantum computer. By tuning the quantum computer as a function of a few parameters, the team calculated these molecules' bound states with chemical accuracy, which was obtained using simulations on a classical computer. Of equal importance is the fact that the quantum calculations also included systematic error mitigation, illuminating the shortcomings in current quantum hardware. Systematic error occurs when the \"noise\" inherent in current quantum architectures affects their operation. Because quantum computers are extremely delicate (for instance, the qubits used by the ORNL team are kept in a dilution refrigerator at around 20 millikelvin (or more than -450 degrees Fahrenheit), temperatures and vibrations from their surrounding environments can create instabilities that throw off their accuracy. For instance, such noise may cause a qubit to rotate 21 degrees instead of the desired 20, greatly affecting a calculation's outcome. \"This new benchmark characterizes the 'mixed state,' or how the environment and machine interact, very well,\" Pooser said. \"This work is a critical step toward a universal benchmark to measure the performance of quantum computers, much like the LINPACK metric is used to judge the fastest classical computers in the world.\" While the calculations were fairly simple compared to what is possible on leading classical systems such as ORNL's Summit, currently ranked as the world's most powerful computer, quantum chemistry, along with nuclear physics and quantum field theory, is considered a quantum \"killer app.\" In other words, it is believed that as they evolve quantum computers will be able to more accurately and more efficiently perform a wide swathe of chemistry-related calculations better than any classical computer currently in operation, including Summit. \"The current benchmark is a first step towards a comprehensive suite of benchmarks and metrics that govern the performance of quantum processors for different science domains,\" said ORNL quantum chemist Jacek Jakowski. \"We expect it to evolve with time as the quantum computing hardware improves. ORNL's vast expertise in domain sciences, computer science and high-performance computing make it the perfect venue for the creation of this benchmark suite.\" ORNL has been planning for paradigm-shifting platforms such as quantum for more than a decade via dedicated research programs in quantum computing, networking, sensing and quantum materials. These efforts aim to accelerate the understanding of how near-term quantum computing resources can help tackle today's most daunting scientific challenges and support the recently announced National Quantum Initiative, a federal effort to ensure American leadership in quantum sciences, particularly computing. Such leadership will require systems like Summit to ensure the steady march from devices such as those used by the ORNL team to larger-scale quantum systems exponentially more powerful than anything in operation today. Access to the IBM and Rigetti processors was provided by the Quantum Computing User Program at the Oak Ridge Leadership Computing Facility, which provides early access to existing, commercial quantum computing systems while supporting the development of future quantum programmers through educational outreach and internship programs. Support for the research came from DOE's Office of Science Advanced Scientific Computing Research program. \"This project helps DOE better understand what will work and what won't work as they forge ahead in their mission to realize the potential of quantum computing in solving today's biggest science and national security challenges,\" Pooser said. Next, the team plans to calculate the exponentially more complex excited states of these molecules, which will help them devise further novel error mitigation schemes and bring the possibility of practical quantum computing one step closer to reality. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract We present a quantum chemistry benchmark for noisy intermediate-scale quantum computers that leverages the variational quantum eigensolver, active-space reduction, a reduced unitary coupled cluster ansatz, and reduced density purification as error mitigation. We demonstrate this benchmark using 4 of the available qubits on the 20-qubit IBM Tokyo and 16-qubit Rigetti Aspen processors via the simulation of alkali metal hydrides (NaH, KH, RbH), with accuracy of the computed ground state energy serving as the primary benchmark metric. We further parameterize this benchmark suite on the trial circuit type, the level of symmetry reduction, and error mitigation strategies. Our results demonstrate the characteristically high noise level present in near-term superconducting hardware, but provide a relevant baseline for future improvement of the underlying hardware, and a means for comparison across near-term hardware types. We also demonstrate how to reduce the noise in post processing with specific error mitigation techniques. Particularly, the adaptation of McWeeny purification of noisy density matrices dramatically improves accuracy of quantum computations, which, along with adjustable active space, significantly extends the range of accessible molecular systems. We demonstrate that for specific benchmark settings and a selected range of problems, the accuracy metric can reach chemical accuracy when computing over the cloud on certain quantum computers. Introduction Noisy intermediate-scale quantum (NISQ) devices have been used recently to demonstrate a variety of different small-scale quantum computations. 1 , 2 , 3 , 4 , 5 These demonstrations underscore the progress in developing programmable quantum processing units (QPUs) as well as advances in how to use these devices for scientifically meaningful computations. However, evaluating the impact of these demonstrations is complicated by the interplay of unique features available from different quantum computing technologies (superconducting electronics, trapped ions, etc.) and the multitude of programming choices that influence observed performance. Several properties quantify the intrinsic utility of a QPU including the capacity of the quantum register, the fidelity of the available instructions, the connectivity between register elements, etc. While these hardware-specific parameters characterize progress in quantum hardware development, they do not directly benchmark the performance of a quantum computer for a given computational task. Benchmarks for application-specific metrics are needed to evaluate the efficiency and applicability of quantum computing for scientific applications. In particular, comparing the benchmark performance of quantum computation to alternative computational approaches should rely on definitions that are meaningful across computational paradigms. Application-specific performance metrics have been used recently to evaluate the utility of near-term QPUs with respect to computational accuracy, including examples from machine learning 6 and nuclear physics. 4 However, the design and demonstration of an application-specific benchmark to evaluate QPU performance across scalable problem instances has been absent from the literature up to now. We present a quantum chemistry simulation benchmark to evaluate the performance of quantum computing by defining a series of electronic structure calculation instances that can be realized on current hardware. We outline and investigate an array of parameter choices that influence quantum computational performance. Our approach uses multiple techniques including density matrix purification and active-space reduction via frozen-core approximation and truncation of the virtual space to accommodate hardware limitations such as a limited number of noisy qubits (low circuit width) and a limited achievable circuit depth (the number of parallel gate executions), while staying within the well-known hierarchy of quantum chemistry methods. For calculations on small molecular systems, such as alkali metal hydride molecules with multiple electrons presented here, the complexity of the quantum computation can be reduced to two valence electrons and the equivalent of a hydrogen molecule in minimal basis set. These approximations can be gradually lifted as the quality of quantum devices improves to provide a flexible benchmarking model. The quantum algorithmic primitive at the center of this benchmark is the state preparation circuit—the unitary coupled cluster (UCC) ansatz 7 or hardware-efficient (HWE) ansatz, 3 , 8 , 9 for example—used in the variational quantum eigensolver (VQE), 1 , 10 a noise-resilient algorithm which has been implemented on current noisy QPUs. This hybrid algorithm uses a classical search for the lowest eigenvalue of a given observable using the variational principle and the chosen ansatz, which is prepared and measured on the quantum computer. The utility of this algorithm has been demonstrated in a number of fields, including high-energy and nuclear physics 4 , 11 in addition to quantum chemistry. 8 Its success is primarily due to the reliance on finite classical computing resources in tandem with invocations of the quantum computer for exponentially scaling aspects of the problem. We use multiple variations of the state-preparation primitives noted above in order to illustrates its effect on performance and accuracy of quantum computations. The benchmark assesses accuracy of VQE for recovering the ground state energy for a series of molecules when using different parameterized trial circuits and error mitigation strategies. The alkali metal hydrides currently included in the benchmark are NaH, KH, and RbH. We implemented calculations of the ground state energies of each of these molecules using four qubits on the 20-qubit IBM Tokyo and 16-qubit Rigetti Aspen superconducting circuit devices. The variational quantum eigensolver (VQE) has been used previously to calculate ground state energy, 1 , 12 and it has become a leading example of quantum-classical computing. Several groups have demonstrated VQE applications using a variety of QPUs and trial circuits to target small molecular systems. 1 , 4 , 5 , 8 , 9 , 13 , 14 , 15 VQE recovers the ground state energy of a Hamiltonian by searching for the quantum state that minimizes the observed energy expectation value. The complexity of this classical search through the parameter space depends strongly on the form of the underlying trial circuit. Optimization of the energy expectation value uses preparation and measurement of the parameterized quantum circuit to drive the classical search method executed on a conventional computer. Existing demonstrations of VQE have revealed that despite the algorithm’s noise resilience, error mitigation is required to overcome the extensive noise present in current platforms. 16 , 17 , 18 For chemistry<|im_end|> <|im_start|>assistant Researchers at the Department of Energy's Oak Ridge National Laboratory have developed a quantum chemistry simulation benchmark to evaluate the performance of quantum devices and guide the development of applications for future quantum computers. Their findings were published in npj Quantum Information. Quantum computers use the laws of quantum mechanics and units known as qubits to greatly increase the threshold at which information can be transmitted and processed. Whereas traditional "bits" have a value of either 0 or 1, qubits are encoded with values of both 0 and 1, or any combination thereof, allowing for a vast number of possibilities for storing data. While still in their early stages, quantum systems have the potential to be exponentially more powerful than today's leading classical computing systems and promise to revolutionize research in materials, chemistry, high-energy physics, and across the scientific spectrum. But because these systems are in their relative infancy, understanding what applications are well suited to their unique architectures is considered an important field of research. "We are currently running fairly simple scientific problems that represent the sort of problems we believe these systems will help us to solve in the future," said ORNL's Raphael Pooser, principal investigator of the Quantum Testbed Pathfinder project. "These benchmarks give us an idea of how future quantum systems will perform when tackling similar, though exponentially more complex, simulations." Pooser and his colleagues calculated the bound state energy of alkali hydride molecules on 20-qubit IBM Tokyo and 16-qubit Rigetti Aspen processors. These molecules are simple and their energies well understood, allowing them to effectively test the performance of the quantum computer. By tuning the quantum computer as a function of a few parameters, the team calculated these molecules' bound states with chemical accuracy, which was obtained using simulations on a classical computer. Of equal importance is the fact that the quantum calculations also included systematic error mitigation, illuminating the shortcomings in current quantum hardware. Systematic error occurs when the "noise" inherent in current quantum architectures affects their operation. Because quantum computers are extremely delicate (for instance, the qubits used by the ORNL team are kept in a dilution refrigerator at around 20 millikelvin (or more than -450 degrees Fahrenheit), temperatures and vibrations from their surrounding environments can create instabilities that throw off their accuracy. For instance, such noise may cause a qubit to rotate 21 degrees instead of the desired 20, greatly affecting a calculation's outcome. "This new benchmark characterizes the 'mixed state,' or how the environment and machine interact, very well," Pooser said. "This work is a critical step toward a universal benchmark to measure the performance of quantum computers, much like the LINPACK metric is used to judge the fastest classical computers in the world." While the calculations were fairly simple compared to what is possible on leading classical systems such as ORNL's Summit, currently ranked as the world's most powerful computer, quantum chemistry, along with nuclear physics and quantum field theory, is considered a quantum "killer app." In other words, it is believed that as they evolve quantum computers will be able to more accurately and more efficiently perform a wide swathe of chemistry-related calculations better than any classical computer currently in operation, including Summit. "The current benchmark is a first step towards a comprehensive suite of benchmarks and metrics that govern the performance of quantum processors for different science domains," said ORNL quantum chemist Jacek Jakowski. "We expect it to evolve with time as the quantum computing hardware improves. ORNL's vast expertise in domain sciences, computer science and high-performance computing make it the perfect venue for the creation of this benchmark suite." ORNL has been planning for paradigm-shifting platforms such as quantum for more than a decade via dedicated research programs in quantum computing, networking, sensing and quantum materials. These efforts aim to accelerate the understanding of how near-term quantum computing resources can help tackle today's most daunting scientific challenges and support the recently announced National Quantum Initiative, a federal effort to ensure American leadership in quantum sciences, particularly computing. Such leadership will require systems like Summit to ensure the steady march from devices such as those used by the ORNL team to larger-scale quantum systems exponentially more powerful than anything in operation today. Access to the IBM and Rigetti processors was provided by the Quantum Computing User Program at the Oak Ridge Leadership Computing Facility, which provides early access to existing, commercial quantum computing systems while supporting the development of future quantum programmers through educational outreach and internship programs. Support for the research came from DOE's Office of Science Advanced Scientific Computing Research program. "This project helps DOE better understand what will work and what won't work as they forge ahead in their mission to realize the potential of quantum computing in solving today's biggest science and national security challenges," Pooser said. Next, the team plans to calculate the exponentially more complex excited states of these molecules, which will help them devise further novel error mitigation schemes and bring the possibility of practical quantum computing one step closer to reality. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Scaling down the size of field-effect transistors in integrated circuits leads to higher speed, lower power consumption and increased integration density, but also results in short-channel effects. Transistors made using high-mobility two-dimensional (2D) semiconductor channels and ultrathin high- κ dielectrics can suppress this effect. However, it is difficult to integrate 2D semiconductors with dielectric layers that have an equivalent oxide thickness below 0.5 nm and low leakage current. Here we report the wafer-scale synthesis of β-Bi 2 SeO 5 —a single-crystalline native oxide with a dielectric constant of around 22—via the lithography-compatible ultraviolet-assisted intercalative oxidation of the high-mobility 2D semiconductor Bi 2 O 2 Se. We use the approach to create top-gated 2D transistors with sub-0.5-nm-equivalent-oxide-thickness dielectrics that exhibit leakage current below the low-power limit of 0.015 A cm −2 at a gate voltage of 1 V. Main The scaling of silicon-based integrated circuits improves the switching frequency, power consumption and integration density 1 . However, the switch-off behaviour of devices with scaled channel lengths ( L ch ) is degraded due to the short-channel effect, leading to a reduced frequency and higher power consumption 2 . The short-channel effect can be suppressed by scaling the characteristic length λ = \$\\sqrt {\\varepsilon _{\\mathrm{b}}t_{\\mathrm{b}}t_{{\\mathrm{ox}}}/n\\varepsilon _{{\\mathrm{ox}}}}\$ , where n is the effective gate number, and t b ( ε b ) and t ox ( ε ox ) are the thicknesses (dielectric constants) of the semiconductor body and oxide dielectric, respectively 3 , 4 . Two-dimensional (2D) semiconductors could thus be used to provide a channel material with atomically thin thickness 1 as high carrier mobility is maintained 3 , 5 , 6 , 7 , 8 . Such 2D devices also require high-quality dielectrics with a low equivalent oxide thickness (EOT = 3.9 t ox / ε ox )—the thickness of a layer of SiO 2 ( ε r = 3.9) that would give an equivalent electrical performance as the higher constant dielectric layer being used—and a low leakage current 1 , 9 , 10 . However, the integration of 2D semiconductors and sub-0.5-nm-EOT dielectrics 1 , 10 —with a well-defined high-quality interface and leakage current below the low-power limit of 1.5 × 10 − 2 A cm − 2 at 1 V gate voltage 11 —remains challenging 12 , 13 . In silicon-based field-effect transistors (FETs), the atomic layer deposition (ALD) of ultrathin amorphous high- κ dielectric hafnium oxide (HfO 2 ) has been used to scale the gate dielectric 1 , 14 , but it is difficult to directly deposit HfO 2 on the dangling-bond-free surface of 2D semiconductors due to heterogeneous nucleation and island formation 13 . Using a molecular seeding layer with a thickness of around 0.3 nm, uniform HfO 2 dielectrics as thin as 1.5 nm have been synthesized on 2D semiconductors via ALD 13 . However, the low- κ molecular seeding layer ( κ ≈ 1.9) can also lead to an additional EOT of around 0.6 nm (ref. 13 ), making it unsuitable for sub-0.5-nm-EOT scaled dielectrics. The transfer of single-crystalline layered hexagonal boron nitride (hBN) onto 2D semiconductors provides a high-quality dangling-bond-free interface with interfacial trap density below 10 10 cm − 2 eV − 1 (ref. 12 ), but due to the inefficient transfer process, relatively low κ (~5.0) and high leakage current, hBN is not competitive for sub-1-nm-EOT dielectric in integrated electronics 12 , 15 , 16 , 17 . Single-crystalline ionic crystal calcium fluoride (CaF 2 ) has a dielectric constant of around 8.4 and good insulativity, and has been used as a dielectric layer in back-gated 2D devices with an EOT of around 0.9 nm (refs. 9 , 18 ). However, the fabrication of top-gated FET devices and optimization of interface quality remain challenging 9 , 12 . The conformal synthesis of native oxide dielectrics on semiconductors is a promising route for the fabrication of advanced devices 17 , 19 , 20 . The native oxides of most 2D semiconductors—including molybdenum disulfide (MoS 2 ) 21 , 22 , 23 , tungsten diselenide (WSe 2 ) 24 , hafnium disulfide (HfS 2 ) 25 , 26 , tantalum disulfide (TaS 2 ) 27 , hafnium diselenide (HfSe 2 ) 28 and zirconium diselenide (ZrSe 2 ) 28 —cannot be used as sub-1-nm-EOT gate dielectrics in 2D transistors due to their poor insulativity and interface quality. However, amorphous and polycrystalline native oxide dielectrics, Bi 2 SeO 5 ( κ ≈ 21), have been synthesized from the high-mobility 2D semiconductor Bi 2 O 2 Se via oxygen plasma treatment or thermal oxidation 19 , 29 . A minimum EOT of 0.9 nm was achieved in top-gated Bi 2 O 2 Se/Bi 2 SeO 5 FETs, but the leakage current exceeds the low-power limit 19 . In this Article, we report the conformal synthesis of a single-crystalline native oxide dielectric, β-Bi 2 SeO 5 , via the ultraviolet (UV)-assisted intercalative oxidation of 2D Bi 2 O 2 Se. Selenium layers in 2D Bi 2 O 2 Se are intercalatively oxidized and the planar [Bi 2 O 2 ] frameworks remain intact; therefore, the native oxide maintains the single-crystalline nature and has an atomically flat lattice-matched interface. The UV-assisted oxidation is compatible with advanced UV lithography and we achieve wafer-scale polymer-free area-selective oxidation of 2D Bi 2 O 2 Se with a photolithography mask. Single-crystalline β-Bi 2 SeO 5 exhibits high insulativity and a thickness-independent κ of around 22, which allows us to fabricate sub-0.5-nm-EOT dielectrics in top-gated 2D FETs. Our best device has a 0.41-nm-EOT dielectric and leakage current below 0.015 A cm − 2 at 1 V gate voltage, meeting the requirements of sub-0.5-nm-EOT and low-power limit in the 2021 International Roadmap for Devices and Systems (IRDS). Intercalative oxidation for single-crystalline native oxide The body-centred tetragonal lattice of high-mobility 2D semiconductor Bi 2 O 2 Se with I 4/ mmm space group (no. 139, a = b = 3.88 Å, c = 12.16 Å, Z = 2.00 Å) consists of positively", "role": "user" }, { "content": "Field-effect transistors (FETs) are transistors in which the resistance of most of the electrical current can be controlled by a transverse electric field. Over the past decade or so, these devices have proved to be very valuable solutions for controlling the flow of current in semiconductors. To further develop FETs, electronics engineers worldwide have recently been trying to reduce their size. While these down-scaling efforts have been found to increase the device's speed and lower the power consumption, they are also associated with short-channel effects (i.e., unfavorable effects that occur when an FET's channel length is approximately equal to the space charge regions of source and drain junctions within its substrate). These undesirable effects, which include barrier lowering and velocity saturation, could be suppressed by using 2D semiconductor channels with high carrier mobilities and ultrathin high-k dielectrics (i.e., materials with high dielectric constants). Integrating 2D semiconductors with dielectrics with similar oxide thicknesses has been found to be highly challenging. Researchers at Peking University and University of Texas at Austin have recently demonstrated the successful integration of a sub-0.5nm dielectric layer with 2D semiconductor-based transistors. Their design, introduced in a paper published in Nature Electronics, could ultimately pave the way towards the development of smaller, faster, and more efficient FETs. \"Previously we have synthesized a poly-crystalline high-κ (dielectric constant) native oxide dielectric of 2D Bi2O2Se and found that its equivalent oxide thickness (EOT) can be scaled down to 0.9 nm, but the leakage current exceeds the low-power limit,\" Hailin Peng, one of the researchers who carried out the study, told TechXplore. \"Inspired by the layered crystal structure of 2D Bi2O2Se and the intercalation of 2D materials, we designed an intercalative oxidation process to retain the lattice framework of the precursor, to obtain a single-crystalline native oxide with better insulativity for further downscaling.\" To integrate their dielectric with 2D semiconductors, Peng and his colleagues used a process called UV-assisted intercalative oxidation. Firstly, they decomposed oxygen molecules contained in the air into atomic oxygen using 185 nm ultraviolet (UV) rays emitted from a low-pressure mercury lamp. Subsequently, they used the atomic oxygen to oxidize the Se2- layer in the 2D semiconductor Bi2O2Se between the two [Bi2O2]n2n+ layers, without affecting the properties of the [Bi2O2]n2n+ layers. This process led to the formation of a new 'layered phase,\" which inherited the single-crystalline [Bi2O2]n2n+ structure of the original Bi2O2Se sample. \"The as-synthesized oxide is further confirmed to be a single-crystalline native dielectric and named β-Bi2SeO5,\" Peng explained. \"The single-crystalline native oxide β-Bi2SeO5 has a thickness-independent high dielectric constant of about 22, ultraflat lattice-matched interface, and excellent insulativity. Even when scaled down to 2.3 nm and the EOT (equivalent oxide thickness, 3.9×thickness/dielectric constant) is as low as 0.41 nm, the leakage current at 1 V gate voltage is still below the low-power limit (0.015 A/cm2), meeting the industrial requirements of dielectrics in next-generation transistors.\" The initial tests carried out by Peng and his colleagues yielded interesting results. Overall, their findings suggest β-Bi2SeO5, the material they created, could be promising for developing an ultrathin high-κ (dielectric constant) gate dielectric in 2D transistors. \"The most notable achievement of our study was the successful integration of sub-0.5-nm-EOT dielectrics in top-gated 2D transistors, which meets the benchmarks of dielectric in the 2021 International Roadmap for Devices and Systems,\" Peng said. \"Thus, one of the challenges for 2D electronics, the integration with sub-0.5-nm-EOT ultrathin high-κ dielectric, has been overcome.\" This team of researchers demonstrated the possibility of integrating 2D semiconductors with high-k dielectrics. In the future, the material that they created and the method introduced in their paper could be used to create smaller and highly-performing FETs that are not adversely impacted by short-channel effects. \"We will now further investigate the compatibility of β-Bi2SeO5 with other common 2D materials and metal electrodes,\" Peng added. \"In addition, a large-scale transfer process of Bi2SeO5 or its precursor Bi2O2Se is also desired for the integration of this ultrathin high-κ dielectric with a broad range of 2D materials.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Scaling down the size of field-effect transistors in integrated circuits leads to higher speed, lower power consumption and increased integration density, but also results in short-channel effects. Transistors made using high-mobility two-dimensional (2D) semiconductor channels and ultrathin high- κ dielectrics can suppress this effect. However, it is difficult to integrate 2D semiconductors with dielectric layers that have an equivalent oxide thickness below 0.5 nm and low leakage current. Here we report the wafer-scale synthesis of β-Bi 2 SeO 5 —a single-crystalline native oxide with a dielectric constant of around 22—via the lithography-compatible ultraviolet-assisted intercalative oxidation of the high-mobility 2D semiconductor Bi 2 O 2 Se. We use the approach to create top-gated 2D transistors with sub-0.5-nm-equivalent-oxide-thickness dielectrics that exhibit leakage current below the low-power limit of 0.015 A cm −2 at a gate voltage of 1 V. Main The scaling of silicon-based integrated circuits improves the switching frequency, power consumption and integration density 1 . However, the switch-off behaviour of devices with scaled channel lengths ( L ch ) is degraded due to the short-channel effect, leading to a reduced frequency and higher power consumption 2 . The short-channel effect can be suppressed by scaling the characteristic length λ = $\sqrt {\varepsilon _{\mathrm{b}}t_{\mathrm{b}}t_{{\mathrm{ox}}}/n\varepsilon _{{\mathrm{ox}}}}$ , where n is the effective gate number, and t b ( ε b ) and t ox ( ε ox ) are the thicknesses (dielectric constants) of the semiconductor body and oxide dielectric, respectively 3 , 4 . Two-dimensional (2D) semiconductors could thus be used to provide a channel material with atomically thin thickness 1 as high carrier mobility is maintained 3 , 5 , 6 , 7 , 8 . Such 2D devices also require high-quality dielectrics with a low equivalent oxide thickness (EOT = 3.9 t ox / ε ox )—the thickness of a layer of SiO 2 ( ε r = 3.9) that would give an equivalent electrical performance as the higher constant dielectric layer being used—and a low leakage current 1 , 9 , 10 . However, the integration of 2D semiconductors and sub-0.5-nm-EOT dielectrics 1 , 10 —with a well-defined high-quality interface and leakage current below the low-power limit of 1.5 × 10 − 2 A cm − 2 at 1 V gate voltage 11 —remains challenging 12 , 13 . In silicon-based field-effect transistors (FETs), the atomic layer deposition (ALD) of ultrathin amorphous high- κ dielectric hafnium oxide (HfO 2 ) has been used to scale the gate dielectric 1 , 14 , but it is difficult to directly deposit HfO 2 on the dangling-bond-free surface of 2D semiconductors due to heterogeneous nucleation and island formation 13 . Using a molecular seeding layer with a thickness of around 0.3 nm, uniform HfO 2 dielectrics as thin as 1.5 nm have been synthesized on 2D semiconductors via ALD 13 . However, the low- κ molecular seeding layer ( κ ≈ 1.9) can also lead to an additional EOT of around 0.6 nm (ref. 13 ), making it unsuitable for sub-0.5-nm-EOT scaled dielectrics. The transfer of single-crystalline layered hexagonal boron nitride (hBN) onto 2D semiconductors provides a high-quality dangling-bond-free interface with interfacial trap density below 10 10 cm − 2 eV − 1 (ref. 12 ), but due to the inefficient transfer process, relatively low κ (~5.0) and high leakage current, hBN is not competitive for sub-1-nm-EOT dielectric in integrated electronics 12 , 15 , 16 , 17 . Single-crystalline ionic crystal calcium fluoride (CaF 2 ) has a dielectric constant of around 8.4 and good insulativity, and has been used as a dielectric layer in back-gated 2D devices with an EOT of around 0.9 nm (refs. 9 , 18 ). However, the fabrication of top-gated FET devices and optimization of interface quality remain challenging 9 , 12 . The conformal synthesis of native oxide dielectrics on semiconductors is a promising route for the fabrication of advanced devices 17 , 19 , 20 . The native oxides of most 2D semiconductors—including molybdenum disulfide (MoS 2 ) 21 , 22 , 23 , tungsten diselenide (WSe 2 ) 24 , hafnium disulfide (HfS 2 ) 25 , 26 , tantalum disulfide (TaS 2 ) 27 , hafnium diselenide (HfSe 2 ) 28 and zirconium diselenide (ZrSe 2 ) 28 —cannot be used as sub-1-nm-EOT gate dielectrics in 2D transistors due to their poor insulativity and interface quality. However, amorphous and polycrystalline native oxide dielectrics, Bi 2 SeO 5 ( κ ≈ 21), have been synthesized from the high-mobility 2D semiconductor Bi 2 O 2 Se via oxygen plasma treatment or thermal oxidation 19 , 29 . A minimum EOT of 0.9 nm was achieved in top-gated Bi 2 O 2 Se/Bi 2 SeO 5 FETs, but the leakage current exceeds the low-power limit 19 . In this Article, we report the conformal synthesis of a single-crystalline native oxide dielectric, β-Bi 2 SeO 5 , via the ultraviolet (UV)-assisted intercalative oxidation of 2D Bi 2 O 2 Se. Selenium layers in 2D Bi 2 O 2 Se are intercalatively oxidized and the planar [Bi 2 O 2 ] frameworks remain intact; therefore, the native oxide maintains the single-crystalline nature and has an atomically flat lattice-matched interface. The UV-assisted oxidation is compatible with advanced UV lithography and we achieve wafer-scale polymer-free area-selective oxidation of 2D Bi 2 O 2 Se with a photolithography mask. Single-crystalline β-Bi 2 SeO 5 exhibits high insulativity and a thickness-independent κ of around 22, which allows us to fabricate sub-0.5-nm-EOT dielectrics in top-gated 2D FETs. Our best device has a 0.41-nm-EOT dielectric and leakage current below 0.015 A cm − 2 at 1 V gate voltage, meeting the requirements of sub-0.5-nm-EOT and low-power limit in the 2021 International Roadmap for Devices and Systems (IRDS). Intercalative oxidation for single-crystalline native oxide The body-centred tetragonal lattice of high-mobility 2D semiconductor Bi 2 O 2 Se with I 4/ mmm space group (no. 139, a = b = 3.88 Å, c = 12.16 Å, Z = 2.00 Å) consists of positively<|im_end|> <|im_start|>assistant Field-effect transistors (FETs) are transistors in which the resistance of most of the electrical current can be controlled by a transverse electric field. Over the past decade or so, these devices have proved to be very valuable solutions for controlling the flow of current in semiconductors. To further develop FETs, electronics engineers worldwide have recently been trying to reduce their size. While these down-scaling efforts have been found to increase the device's speed and lower the power consumption, they are also associated with short-channel effects (i.e., unfavorable effects that occur when an FET's channel length is approximately equal to the space charge regions of source and drain junctions within its substrate). These undesirable effects, which include barrier lowering and velocity saturation, could be suppressed by using 2D semiconductor channels with high carrier mobilities and ultrathin high-k dielectrics (i.e., materials with high dielectric constants). Integrating 2D semiconductors with dielectrics with similar oxide thicknesses has been found to be highly challenging. Researchers at Peking University and University of Texas at Austin have recently demonstrated the successful integration of a sub-0.5nm dielectric layer with 2D semiconductor-based transistors. Their design, introduced in a paper published in Nature Electronics, could ultimately pave the way towards the development of smaller, faster, and more efficient FETs. "Previously we have synthesized a poly-crystalline high-κ (dielectric constant) native oxide dielectric of 2D Bi2O2Se and found that its equivalent oxide thickness (EOT) can be scaled down to 0.9 nm, but the leakage current exceeds the low-power limit," Hailin Peng, one of the researchers who carried out the study, told TechXplore. "Inspired by the layered crystal structure of 2D Bi2O2Se and the intercalation of 2D materials, we designed an intercalative oxidation process to retain the lattice framework of the precursor, to obtain a single-crystalline native oxide with better insulativity for further downscaling." To integrate their dielectric with 2D semiconductors, Peng and his colleagues used a process called UV-assisted intercalative oxidation. Firstly, they decomposed oxygen molecules contained in the air into atomic oxygen using 185 nm ultraviolet (UV) rays emitted from a low-pressure mercury lamp. Subsequently, they used the atomic oxygen to oxidize the Se2- layer in the 2D semiconductor Bi2O2Se between the two [Bi2O2]n2n+ layers, without affecting the properties of the [Bi2O2]n2n+ layers. This process led to the formation of a new 'layered phase," which inherited the single-crystalline [Bi2O2]n2n+ structure of the original Bi2O2Se sample. "The as-synthesized oxide is further confirmed to be a single-crystalline native dielectric and named β-Bi2SeO5," Peng explained. "The single-crystalline native oxide β-Bi2SeO5 has a thickness-independent high dielectric constant of about 22, ultraflat lattice-matched interface, and excellent insulativity. Even when scaled down to 2.3 nm and the EOT (equivalent oxide thickness, 3.9×thickness/dielectric constant) is as low as 0.41 nm, the leakage current at 1 V gate voltage is still below the low-power limit (0.015 A/cm2), meeting the industrial requirements of dielectrics in next-generation transistors." The initial tests carried out by Peng and his colleagues yielded interesting results. Overall, their findings suggest β-Bi2SeO5, the material they created, could be promising for developing an ultrathin high-κ (dielectric constant) gate dielectric in 2D transistors. "The most notable achievement of our study was the successful integration of sub-0.5-nm-EOT dielectrics in top-gated 2D transistors, which meets the benchmarks of dielectric in the 2021 International Roadmap for Devices and Systems," Peng said. "Thus, one of the challenges for 2D electronics, the integration with sub-0.5-nm-EOT ultrathin high-κ dielectric, has been overcome." This team of researchers demonstrated the possibility of integrating 2D semiconductors with high-k dielectrics. In the future, the material that they created and the method introduced in their paper could be used to create smaller and highly-performing FETs that are not adversely impacted by short-channel effects. "We will now further investigate the compatibility of β-Bi2SeO5 with other common 2D materials and metal electrodes," Peng added. "In addition, a large-scale transfer process of Bi2SeO5 or its precursor Bi2O2Se is also desired for the integration of this ultrathin high-κ dielectric with a broad range of 2D materials." <|im_end|>

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10068, 19488, 3422, 315, 1455, 220, 17, 35, 5347, 1965, 1076, 1105, 76070, 296, 5849, 65, 5294, 372, 834, 14643, 579, 320, 26694, 50, 220, 17, 883, 220, 1691, 1174, 220, 1313, 1174, 220, 1419, 1174, 85307, 16172, 834, 8564, 579, 320, 54, 1542, 220, 17, 883, 220, 1187, 1174, 105539, 77, 2411, 834, 14643, 579, 320, 39, 69, 50, 220, 17, 883, 220, 914, 1174, 220, 1627, 1174, 95685, 372, 834, 14643, 579, 320, 57099, 50, 220, 17, 883, 220, 1544, 1174, 105539, 77, 2411, 834, 8564, 579, 320, 39, 69, 1542, 220, 17, 883, 220, 1591, 323, 1167, 89376, 2411, 834, 8564, 579, 320, 57, 81, 1542, 220, 17, 883, 220, 1591, 2001, 34360, 387, 1511, 439, 1207, 12, 16, 5392, 76, 13737, 1831, 18618, 2815, 772, 6329, 304, 220, 17, 35, 1380, 380, 1105, 4245, 311, 872, 8009, 1672, 360, 44515, 323, 3834, 4367, 13, 4452, 11, 1097, 16751, 788, 323, 1499, 3418, 81, 599, 543, 483, 10068, 51180, 2815, 772, 6329, 11, 12371, 220, 17, 1369, 46, 220, 20, 320, 72738, 118792, 220, 1691, 705, 617, 1027, 92106, 505, 279, 1579, 1474, 677, 1429, 220, 17, 35, 87836, 12371, 220, 17, 507, 220, 17, 1369, 4669, 24463, 32426, 6514, 477, 29487, 71162, 220, 777, 1174, 220, 1682, 662, 362, 8187, 469, 1831, 315, 220, 15, 13, 24, 26807, 574, 17427, 304, 1948, 2427, 660, 12371, 220, 17, 507, 220, 17, 1369, 16675, 72, 220, 17, 1369, 46, 220, 20, 435, 1372, 82, 11, 719, 279, 81373, 1510, 36375, 279, 3428, 27624, 4017, 220, 777, 662, 763, 420, 13659, 11, 584, 1934, 279, 26965, 278, 39975, 315, 264, 3254, 48689, 599, 543, 483, 10068, 51180, 2815, 47262, 11, 34318, 7826, 72, 220, 17, 1369, 46, 220, 20, 1174, 4669, 279, 37232, 85311, 320, 23042, 7435, 395, 13539, 958, 5531, 1413, 71162, 315, 220, 17, 35, 12371, 220, 17, 507, 220, 17, 1369, 13, 86817, 13931, 304, 220, 17, 35, 12371, 220, 17, 507, 220, 17, 1369, 527, 958, 5531, 8046, 36172, 1534, 323, 279, 3197, 277, 510, 37196, 220, 17, 507, 220, 17, 2331, 49125, 7293, 35539, 26, 9093, 11, 279, 10068, 51180, 33095, 279, 3254, 48689, 599, 543, 483, 7138, 323, 706, 459, 19670, 2740, 10269, 55372, 1474, 35344, 3834, 13, 578, 30136, 35915, 13539, 71162, 374, 18641, 449, 11084, 30136, 46282, 5814, 323, 584, 11322, 10667, 809, 13230, 47393, 12862, 3158, 21090, 535, 71162, 315, 220, 17, 35, 12371, 220, 17, 507, 220, 17, 1369, 449, 264, 4604, 48218, 5814, 7056, 13, 11579, 48689, 599, 543, 483, 34318, 7826, 72, 220, 17, 1369, 46, 220, 20, 50829, 1579, 1672, 360, 44515, 323, 264, 26839, 98885, 72738, 315, 2212, 220, 1313, 11, 902, 6276, 603, 311, 13354, 349, 1207, 12, 15, 13, 20, 5392, 76, 13737, 1831, 2815, 772, 6329, 304, 1948, 2427, 660, 220, 17, 35, 435, 1372, 82, 13, 5751, 1888, 3756, 706, 264, 220, 15, 13, 3174, 5392, 76, 13737, 1831, 2815, 47262, 323, 81373, 1510, 3770, 220, 15, 13, 16037, 362, 10166, 25173, 220, 17, 520, 220, 16, 650, 18618, 22465, 11, 6574, 279, 8670, 315, 1207, 12, 15, 13, 20, 5392, 76, 13737, 1831, 323, 3428, 27624, 4017, 304, 279, 220, 2366, 16, 7327, 9728, 2235, 369, 41477, 323, 15264, 320, 2871, 6061, 570, 1357, 3035, 278, 1413, 71162, 369, 3254, 48689, 599, 543, 483, 10068, 51180, 578, 2547, 21911, 1171, 28953, 4193, 25180, 55372, 315, 1579, 1474, 677, 1429, 220, 17, 35, 87836, 12371, 220, 17, 507, 220, 17, 1369, 449, 358, 220, 19, 14, 296, 3906, 3634, 1912, 320, 2201, 13, 220, 10125, 11, 264, 284, 293, 284, 220, 18, 13, 2421, 80352, 11, 272, 284, 220, 717, 13, 845, 80352, 11, 1901, 284, 220, 17, 13, 410, 80352, 8, 17610, 315, 40646, 128257, 198, 128256, 78191, 198, 1915, 23937, 1380, 380, 1105, 320, 37, 1372, 82, 8, 527, 1380, 380, 1105, 304, 902, 279, 13957, 315, 1455, 315, 279, 20314, 1510, 649, 387, 14400, 555, 264, 1380, 4550, 9249, 2115, 13, 6193, 279, 3347, 13515, 477, 779, 11, 1521, 7766, 617, 19168, 311, 387, 1633, 15525, 10105, 369, 26991, 279, 6530, 315, 1510, 304, 5347, 1965, 1076, 1105, 13, 2057, 4726, 2274, 435, 1372, 82, 11, 31591, 25175, 15603, 617, 6051, 1027, 4560, 311, 8108, 872, 1404, 13, 6104, 1521, 1523, 62987, 287, 9045, 617, 1027, 1766, 311, 5376, 279, 3756, 596, 4732, 323, 4827, 279, 2410, 15652, 11, 814, 527, 1101, 5938, 449, 2875, 54968, 6372, 320, 72, 1770, 2637, 93071, 6372, 430, 12446, 994, 459, 435, 1372, 596, 5613, 3160, 374, 13489, 6273, 311, 279, 3634, 6900, 13918, 315, 2592, 323, 24659, 49341, 82, 2949, 1202, 54057, 570, 4314, 77344, 6372, 11, 902, 2997, 22881, 46301, 323, 15798, 50843, 11, 1436, 387, 56089, 555, 1701, 220, 17, 35, 87836, 12006, 449, 1579, 19115, 12881, 4396, 323, 37232, 589, 258, 1579, 12934, 2815, 772, 6329, 320, 72, 1770, 2637, 7384, 449, 1579, 2815, 47262, 18508, 570, 30101, 1113, 220, 17, 35, 5347, 1965, 1076, 1105, 449, 2815, 772, 6329, 449, 4528, 51180, 26839, 288, 706, 1027, 1766, 311, 387, 7701, 17436, 13, 59250, 520, 393, 59952, 3907, 323, 3907, 315, 8421, 520, 19816, 617, 6051, 21091, 279, 6992, 18052, 315, 264, 1207, 12, 15, 13, 20, 20211, 2815, 47262, 6324, 449, 220, 17, 35, 87836, 6108, 1380, 380, 1105, 13, 11205, 2955, 11, 11784, 304, 264, 5684, 4756, 304, 22037, 38784, 11, 1436, 13967, 94123, 279, 1648, 7119, 279, 4500, 315, 9333, 11, 10819, 11, 323, 810, 11297, 435, 1372, 82, 13, 330, 83039, 584, 617, 92106, 264, 10062, 48689, 599, 543, 483, 1579, 12, 68437, 320, 27591, 47262, 6926, 8, 10068, 51180, 2815, 47262, 315, 220, 17, 35, 12371, 17, 46, 17, 1542, 323, 1766, 430, 1202, 13890, 51180, 26839, 320, 36, 1831, 8, 649, 387, 31790, 1523, 311, 220, 15, 13, 24, 26807, 11, 719, 279, 81373, 1510, 36375, 279, 3428, 27624, 4017, 1359, 473, 607, 258, 52150, 11, 832, 315, 279, 12074, 889, 11953, 704, 279, 4007, 11, 3309, 17829, 55, 79, 20763, 13, 330, 74640, 2757, 555, 279, 64241, 26110, 6070, 315, 220, 17, 35, 12371, 17, 46, 17, 1542, 323, 279, 958, 5531, 367, 315, 220, 17, 35, 7384, 11, 584, 6319, 459, 958, 5531, 1413, 71162, 1920, 311, 14389, 279, 55372, 12914, 315, 279, 71261, 11, 311, 6994, 264, 3254, 48689, 599, 543, 483, 10068, 51180, 449, 2731, 1672, 360, 44515, 369, 4726, 1523, 94152, 1210, 2057, 32172, 872, 2815, 47262, 449, 220, 17, 35, 5347, 1965, 1076, 1105, 11, 52150, 323, 813, 18105, 1511, 264, 1920, 2663, 30136, 35915, 13539, 958, 5531, 1413, 71162, 13, 77795, 11, 814, 29602, 3950, 24463, 35715, 13282, 304, 279, 3805, 1139, 25524, 24463, 1701, 220, 9741, 26807, 37232, 85311, 320, 23042, 8, 45220, 48042, 505, 264, 3428, 89561, 51852, 29062, 13, 3804, 39742, 11, 814, 1511, 279, 25524, 24463, 311, 36172, 553, 279, 1369, 17, 12, 6324, 304, 279, 220, 17, 35, 87836, 12371, 17, 46, 17, 1542, 1990, 279, 1403, 510, 37196, 17, 46, 17, 60, 77, 17, 77, 10, 13931, 11, 2085, 28987, 279, 6012, 315, 279, 510, 37196, 17, 46, 17, 60, 77, 17, 77, 10, 13931, 13, 1115, 1920, 6197, 311, 279, 18488, 315, 264, 502, 364, 10546, 291, 10474, 1359, 902, 28088, 279, 3254, 48689, 599, 543, 483, 510, 37196, 17, 46, 17, 60, 77, 17, 77, 10, 6070, 315, 279, 4113, 12371, 17, 46, 17, 1542, 6205, 13, 330, 791, 439, 1355, 1910, 83979, 51180, 374, 4726, 11007, 311, 387, 264, 3254, 48689, 599, 543, 483, 10068, 2815, 47262, 323, 7086, 34318, 7826, 72, 17, 1542, 46, 20, 1359, 52150, 11497, 13, 330, 791, 3254, 48689, 599, 543, 483, 10068, 51180, 34318, 7826, 72, 17, 1542, 46, 20, 706, 264, 26839, 98885, 1579, 2815, 47262, 6926, 315, 922, 220, 1313, 11, 24955, 27323, 55372, 1474, 35344, 3834, 11, 323, 9250, 1672, 360, 44515, 13, 7570, 994, 31790, 1523, 311, 220, 17, 13, 18, 26807, 323, 279, 469, 1831, 320, 26378, 12031, 51180, 26839, 11, 220, 18, 13, 24, 18028, 92067, 3529, 648, 47262, 6926, 8, 374, 439, 3428, 439, 220, 15, 13, 3174, 26807, 11, 279, 81373, 1510, 520, 220, 16, 650, 18618, 22465, 374, 2103, 3770, 279, 3428, 27624, 4017, 320, 15, 13, 16037, 362, 70298, 17, 705, 6574, 279, 13076, 8670, 315, 2815, 772, 6329, 304, 1828, 43927, 1380, 380, 1105, 1210, 578, 2926, 7177, 11953, 704, 555, 52150, 323, 813, 18105, 58487, 7185, 3135, 13, 28993, 11, 872, 14955, 4284, 34318, 7826, 72, 17, 1542, 46, 20, 11, 279, 3769, 814, 3549, 11, 1436, 387, 26455, 369, 11469, 459, 37232, 589, 258, 1579, 12, 68437, 320, 27591, 47262, 6926, 8, 18618, 2815, 47262, 304, 220, 17, 35, 1380, 380, 1105, 13, 330, 791, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Human immunodeficiency virus 1 (HIV-1) is a retrovirus with a ten-kilobase single-stranded RNA genome. HIV-1 must express all of its gene products from a single primary transcript, which undergoes alternative splicing to produce diverse protein products that include structural proteins and regulatory factors 1 , 2 . Despite the critical role of alternative splicing, the mechanisms that drive the choice of splice site are poorly understood. Synonymous RNA mutations that lead to severe defects in splicing and viral replication indicate the presence of unknown cis -regulatory elements 3 . Here we use dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) to investigate the structure of HIV-1 RNA in cells, and develop an algorithm that we name ‘detection of RNA folding ensembles using expectation–maximization’ (DREEM), which reveals the alternative conformations that are assumed by the same RNA sequence. Contrary to previous models that have analysed population averages 4 , our results reveal heterogeneous regions of RNA structure across the entire HIV-1 genome. In addition to confirming that in vitro characterized 5 alternative structures for the HIV-1 Rev responsive element also exist in cells, we discover alternative conformations at critical splice sites that influence the ratio of transcript isoforms. Our simultaneous measurement of splicing and intracellular RNA structure provides evidence for the long-standing hypothesis 6 , 7 , 8 that heterogeneity in RNA conformation regulates splice-site use and viral gene expression. Main Previous work 4 on the genome-wide RNA structure of HIV-1 in vitro and in virion has provided a population-average model, with the underlying assumption that every molecule within the population assumes the same conformation. However, previous in vitro studies 5 , 9 , 10 have identified alternative conformations for the HIV-1 Rev responsive element (RRE) and 5′ untranslated region (UTR), which raises the possibility that alternative structures have roles in the export of viral RNA from the nucleus and packaging in virions. To resolve the fundamental question of whether RNA structure affects splicing, it is necessary to distinguish multiple conformations for the same sequence in cells. We developed the clustering algorithm DREEM, and here we demonstrate that we can quantitatively detect alternative RNA structures. DREEM starts with single-molecule chemical probing data—in our case, derived from DMS-MaPseq 11 . Dimethyl sulfate (DMS) adds methyl groups to the unpaired adenines and cytosines of RNA molecules (Fig. 1 ). The presence of a methyl adduct is read during reverse transcription using TGIRT-III, which marks these sites by incorporating random mutations in the complementary (c)DNA. PCR amplifies the cDNA product and attaches sequencing adapters to the DNA, followed by massively parallel sequencing. Each of the resulting reads is represented as a binary readout of mutations and matches, which is the input for DREEM (Extended Data Fig. 1a ). As DMS-MaPseq has a negligible background error 11 , the mutations observed on a single DNA molecule correspond to the DMS-accessible bases on the parent RNA molecule. The two key challenges for detecting heterogeneity are: (1) that DMS modification rates are relatively low (for example, an open base has a probability of about 2–10% of being modified); and (2) that the rate of DMS modification per open base is sensitive to the local chemical environment, such that not all open bases are equally reactive to DMS. Traditional approaches to determining RNA structure combine chemical probing data into a population-average signal per base, which obscures any underlying heterogeneity. By contrast, the DREEM algorithm groups sequencing reads issued from each structure into distinct clusters, by exploiting information contained in the observation of multiple modifications on single molecules. Theoretically, if two individual bases are DMS-reactive in the population average but are never both mutated on a single read, it follows that at least two conformations are present. DREEM identifies patterns of DMS-induced mutations on reads and clusters in a mathematically rigorous manner using an expectation–maximization algorithm (Fig. 1a , Extended Data Fig. 1a ). The DMS modification rate per base for each cluster (or structure) is determined by iteratively maximizing a log-likelihood function to find and quantify the abundance of alternative structures directly from the dataset. The binary nature of the readouts enables the use of a multivariate Bernoulli mixture model to compute the log-likelihood function 12 . The DMS modification pattern from each cluster is used to create a secondary structure model. Fig. 1: Development and validation of DREEM algorithm for analysis of alternative RNA structures. a , Schematic of combining DMS-MaPseq data with the DREEM algorithm to detect alternative RNA structures. EM, expectation–maximization. b , Structural model of in vitro-transcribed and folded structure 1 and structure 2, as determined by DMS-MaPseq. Nucleotides are colour-coded by normalized DMS signal. c , DMS mutational fraction per nucleotide and quantification of structure 1 and structure 2, determined by DREEM clustering for a mixing ratio of 25% (structure 1) to 75% (structure 2) before DMS modification. d , Proportion of structure 1 and structure 2 measured by DREEM clustering after in vitro transcription, mixing and DMS-MaPseq. The expected (E) and observed (O) ratios are shown from n = 1 experiment for each mixing proportion. Full size image Our control experiments on denatured RNA indicated that TGIRT-III is unable to read-through mismatches located within three nucleotides (nt) of each other (Extended Data Fig. 1b ). To account for this observation, we modified the log-likelihood function of the standard multivariate Bernoulli mixture model (Extended Data Fig. 1a ). Upon convergence of the clustering, the DMS signal from each cluster was used as a constraint in the program RNAstructure 13 . To our knowledge, DREEM is unique among algorithms for RNA folding ensembles 14 because DREEM directly clusters the experimental data. Clustering before the generation of a secondary structure model enables the discovery of new RNA structures, in contrast to previous work 15 , 16 . Purely computational algorithms rely on suboptimal folding to create variation that is not captured by minimum free energy calculations. However, using experimentally derived constraints is preferable to using randomly generated constraints 17 , 18 . Moreover, DREEM does", "role": "user" }, { "content": "Australian and US researchers have made a breakthrough in understanding the structure of a key genetic molecule, called RNA, and revealing for the first time how these changes impact RNA's function. Publishing in the journal Nature, the research team developed a bioinformatics technique to resolve separate structures of RNA rather than viewing them as a 'blur' that averaged multiple structures. This underpinned their discovery that the structure of RNA can influence how cells function. RNA is a DNA-like molecule that encodes genetic information. Certain viruses—including HIV and SARS-CoV2—use RNA as their genetic material. The team were able to apply the techniques they developed to reveal how the structure of HIV's RNA genome influences which proteins the virus produces. The international collaborative team was led by Walter and Eliza Hall Institute researcher Dr. Vincent Corbin together with Mr Phil Tomezsko and Professor Silvi Rouskin at the Whitehead Institute for Biomedical Research, Boston (US). The research team also included the Institute's Computational Biology Theme Leader Professor Tony Papenfuss and mathematician and Ph.D. student Mr Lachlan McIntosh. RNA's shifting shapes RNA is a molecule found in all living things that carries genetic information. RNA is an important regulator of how cells function, directly controlling which proteins are produced in cells, and can also switch genes on and off. RNA molecules have a two-dimensional structure which influences how the genetic information contained within them can be accessed, said Dr. Corbin, who led the project's bioinformatics research. \"The big question in RNA biology has been whether RNA molecules have a single, constant structure, or whether they can shift between different structures—and what this means for the function of a particular RNA molecule,\" he said. \"Our collaborators, led by Professor Silvi Rouskin, developed a technique for deciphering the structure of RNA molecules. We wanted to understand whether what we were detecting was a single structure of RNA, or an 'average' structure that blurs multiple different structures together. \"It's a bit like seeing red and yellow stripes, or blurring them together and thinking you can see orange,\" he said. By developing a computational algorithm, the team were able to detect and measure the amount of different RNA structures. \"We could detect these both in a test tube and in living cells, so we next looked at whether these structures influenced how RNA functioned,\" Dr. Corbin said. Changing RNA function When RNA is produced in cells, it starts in a longer form that is 'spliced' or trimmed to remove unwanted parts. \"RNA splicing can influence how it encodes proteins,\" Dr. Corbin said. \"There are many examples of how altered RNA splicing influences how a cell functions—and in some cases, changes in RNA splicing have been associated with cancer or neurodegenerative diseases.\" Certain viruses use RNA for their genome, including HIV and SARS-CoV2 (the coronavirus that causes COVID-19). In the case of HIV, RNA splicing influences which protein the virus produces—which changes at different stages of the virus's lifecycle. \"Using the HIV genome as a model system, we looked at whether RNA structure influences how HIV's RNA is spliced. We discovered that RNA structure was a critical determinant of RNA splicing in HIV, and influenced which viral proteins were produced,\" Dr. Corbin said. \"This is the first clear evidence of how RNA structure can control RNA function. The techniques we have developed have opened up a new field of research into the role of RNA structure in regulating the function of cells.\" Professor Papenfuss said the research showed how finely tuned biological systems are. \"This study how very subtle changes in one tiny molecule can have big implications for the function of a virus. By using computational biology to unravel these changes, we've made a significant discovery about how viruses—and potentially human cells—function, which may underpin future discoveries about health and disease.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Human immunodeficiency virus 1 (HIV-1) is a retrovirus with a ten-kilobase single-stranded RNA genome. HIV-1 must express all of its gene products from a single primary transcript, which undergoes alternative splicing to produce diverse protein products that include structural proteins and regulatory factors 1 , 2 . Despite the critical role of alternative splicing, the mechanisms that drive the choice of splice site are poorly understood. Synonymous RNA mutations that lead to severe defects in splicing and viral replication indicate the presence of unknown cis -regulatory elements 3 . Here we use dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) to investigate the structure of HIV-1 RNA in cells, and develop an algorithm that we name ‘detection of RNA folding ensembles using expectation–maximization’ (DREEM), which reveals the alternative conformations that are assumed by the same RNA sequence. Contrary to previous models that have analysed population averages 4 , our results reveal heterogeneous regions of RNA structure across the entire HIV-1 genome. In addition to confirming that in vitro characterized 5 alternative structures for the HIV-1 Rev responsive element also exist in cells, we discover alternative conformations at critical splice sites that influence the ratio of transcript isoforms. Our simultaneous measurement of splicing and intracellular RNA structure provides evidence for the long-standing hypothesis 6 , 7 , 8 that heterogeneity in RNA conformation regulates splice-site use and viral gene expression. Main Previous work 4 on the genome-wide RNA structure of HIV-1 in vitro and in virion has provided a population-average model, with the underlying assumption that every molecule within the population assumes the same conformation. However, previous in vitro studies 5 , 9 , 10 have identified alternative conformations for the HIV-1 Rev responsive element (RRE) and 5′ untranslated region (UTR), which raises the possibility that alternative structures have roles in the export of viral RNA from the nucleus and packaging in virions. To resolve the fundamental question of whether RNA structure affects splicing, it is necessary to distinguish multiple conformations for the same sequence in cells. We developed the clustering algorithm DREEM, and here we demonstrate that we can quantitatively detect alternative RNA structures. DREEM starts with single-molecule chemical probing data—in our case, derived from DMS-MaPseq 11 . Dimethyl sulfate (DMS) adds methyl groups to the unpaired adenines and cytosines of RNA molecules (Fig. 1 ). The presence of a methyl adduct is read during reverse transcription using TGIRT-III, which marks these sites by incorporating random mutations in the complementary (c)DNA. PCR amplifies the cDNA product and attaches sequencing adapters to the DNA, followed by massively parallel sequencing. Each of the resulting reads is represented as a binary readout of mutations and matches, which is the input for DREEM (Extended Data Fig. 1a ). As DMS-MaPseq has a negligible background error 11 , the mutations observed on a single DNA molecule correspond to the DMS-accessible bases on the parent RNA molecule. The two key challenges for detecting heterogeneity are: (1) that DMS modification rates are relatively low (for example, an open base has a probability of about 2–10% of being modified); and (2) that the rate of DMS modification per open base is sensitive to the local chemical environment, such that not all open bases are equally reactive to DMS. Traditional approaches to determining RNA structure combine chemical probing data into a population-average signal per base, which obscures any underlying heterogeneity. By contrast, the DREEM algorithm groups sequencing reads issued from each structure into distinct clusters, by exploiting information contained in the observation of multiple modifications on single molecules. Theoretically, if two individual bases are DMS-reactive in the population average but are never both mutated on a single read, it follows that at least two conformations are present. DREEM identifies patterns of DMS-induced mutations on reads and clusters in a mathematically rigorous manner using an expectation–maximization algorithm (Fig. 1a , Extended Data Fig. 1a ). The DMS modification rate per base for each cluster (or structure) is determined by iteratively maximizing a log-likelihood function to find and quantify the abundance of alternative structures directly from the dataset. The binary nature of the readouts enables the use of a multivariate Bernoulli mixture model to compute the log-likelihood function 12 . The DMS modification pattern from each cluster is used to create a secondary structure model. Fig. 1: Development and validation of DREEM algorithm for analysis of alternative RNA structures. a , Schematic of combining DMS-MaPseq data with the DREEM algorithm to detect alternative RNA structures. EM, expectation–maximization. b , Structural model of in vitro-transcribed and folded structure 1 and structure 2, as determined by DMS-MaPseq. Nucleotides are colour-coded by normalized DMS signal. c , DMS mutational fraction per nucleotide and quantification of structure 1 and structure 2, determined by DREEM clustering for a mixing ratio of 25% (structure 1) to 75% (structure 2) before DMS modification. d , Proportion of structure 1 and structure 2 measured by DREEM clustering after in vitro transcription, mixing and DMS-MaPseq. The expected (E) and observed (O) ratios are shown from n = 1 experiment for each mixing proportion. Full size image Our control experiments on denatured RNA indicated that TGIRT-III is unable to read-through mismatches located within three nucleotides (nt) of each other (Extended Data Fig. 1b ). To account for this observation, we modified the log-likelihood function of the standard multivariate Bernoulli mixture model (Extended Data Fig. 1a ). Upon convergence of the clustering, the DMS signal from each cluster was used as a constraint in the program RNAstructure 13 . To our knowledge, DREEM is unique among algorithms for RNA folding ensembles 14 because DREEM directly clusters the experimental data. Clustering before the generation of a secondary structure model enables the discovery of new RNA structures, in contrast to previous work 15 , 16 . Purely computational algorithms rely on suboptimal folding to create variation that is not captured by minimum free energy calculations. However, using experimentally derived constraints is preferable to using randomly generated constraints 17 , 18 . Moreover, DREEM does<|im_end|> <|im_start|>assistant Australian and US researchers have made a breakthrough in understanding the structure of a key genetic molecule, called RNA, and revealing for the first time how these changes impact RNA's function. Publishing in the journal Nature, the research team developed a bioinformatics technique to resolve separate structures of RNA rather than viewing them as a 'blur' that averaged multiple structures. This underpinned their discovery that the structure of RNA can influence how cells function. RNA is a DNA-like molecule that encodes genetic information. Certain viruses—including HIV and SARS-CoV2—use RNA as their genetic material. The team were able to apply the techniques they developed to reveal how the structure of HIV's RNA genome influences which proteins the virus produces. The international collaborative team was led by Walter and Eliza Hall Institute researcher Dr. Vincent Corbin together with Mr Phil Tomezsko and Professor Silvi Rouskin at the Whitehead Institute for Biomedical Research, Boston (US). The research team also included the Institute's Computational Biology Theme Leader Professor Tony Papenfuss and mathematician and Ph.D. student Mr Lachlan McIntosh. RNA's shifting shapes RNA is a molecule found in all living things that carries genetic information. RNA is an important regulator of how cells function, directly controlling which proteins are produced in cells, and can also switch genes on and off. RNA molecules have a two-dimensional structure which influences how the genetic information contained within them can be accessed, said Dr. Corbin, who led the project's bioinformatics research. "The big question in RNA biology has been whether RNA molecules have a single, constant structure, or whether they can shift between different structures—and what this means for the function of a particular RNA molecule," he said. "Our collaborators, led by Professor Silvi Rouskin, developed a technique for deciphering the structure of RNA molecules. We wanted to understand whether what we were detecting was a single structure of RNA, or an 'average' structure that blurs multiple different structures together. "It's a bit like seeing red and yellow stripes, or blurring them together and thinking you can see orange," he said. By developing a computational algorithm, the team were able to detect and measure the amount of different RNA structures. "We could detect these both in a test tube and in living cells, so we next looked at whether these structures influenced how RNA functioned," Dr. Corbin said. Changing RNA function When RNA is produced in cells, it starts in a longer form that is 'spliced' or trimmed to remove unwanted parts. "RNA splicing can influence how it encodes proteins," Dr. Corbin said. "There are many examples of how altered RNA splicing influences how a cell functions—and in some cases, changes in RNA splicing have been associated with cancer or neurodegenerative diseases." Certain viruses use RNA for their genome, including HIV and SARS-CoV2 (the coronavirus that causes COVID-19). In the case of HIV, RNA splicing influences which protein the virus produces—which changes at different stages of the virus's lifecycle. "Using the HIV genome as a model system, we looked at whether RNA structure influences how HIV's RNA is spliced. We discovered that RNA structure was a critical determinant of RNA splicing in HIV, and influenced which viral proteins were produced," Dr. Corbin said. "This is the first clear evidence of how RNA structure can control RNA function. The techniques we have developed have opened up a new field of research into the role of RNA structure in regulating the function of cells." Professor Papenfuss said the research showed how finely tuned biological systems are. "This study how very subtle changes in one tiny molecule can have big implications for the function of a virus. By using computational biology to unravel these changes, we've made a significant discovery about how viruses—and potentially human cells—function, which may underpin future discoveries about health and disease." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Thermally activated ion channels are known to detect the entire thermal range from extreme heat (TRPV2), painful heat (TRPV1, TRPM3 and ANO1), non-painful warmth (TRPV3 and TRPV4) and non-painful coolness (TRPM8) through to painful cold (TRPA1) 1 , 2 , 3 , 4 , 5 , 6 , 7 . Genetic deletion of each of these ion channels, however, has only modest effects on thermal behaviour in mice 6 , 7 , 8 , 9 , 10 , 11 , 12 , with the exception of TRPM8, the deletion of which has marked effects on the perception of moderate coolness in the range 10–25 °C 13 . The molecular mechanism responsible for detecting non-painful warmth, in particular, is unresolved. Here we used calcium imaging to identify a population of thermally sensitive somatosensory neurons which do not express any of the known thermally activated TRP channels. We then used a combination of calcium imaging, electrophysiology and RNA sequencing to show that the ion channel generating heat sensitivity in these neurons is TRPM2. Autonomic neurons, usually thought of as exclusively motor, also express TRPM2 and respond directly to heat. Mice in which TRPM2 had been genetically deleted showed a striking deficit in their sensation of non-noxious warm temperatures, consistent with the idea that TRPM2 initiates a ‘warm’ signal which drives cool-seeking behaviour. Main Previous studies have described novel heat-sensitive neurons not activated by agonists for any of the known heat-sensitive ion channels 5 , 14 , 15 , 16 . We identified these neurons in cultures from dorsal root ganglia (DRG) by using calcium imaging and selective agonists for known thermo-TRP ion channels. We found that around 10% of neurons responded to heat, but were not activated by any of the agonists for known TRP channels ( Fig. 1a–c and Supplementary Video 1 ). Changing the order of application of agonists or using a lower starting temperature had little effect on this proportion ( Extended Data Figs 1 and 2 ). Novel heat-sensitive neurons were found to be activated over a wide range of temperatures, with a subset activated in the range of warm temperatures between 34 °C and 42 °C, suggesting a possible role in warmth sensation, and a second group activated only at higher temperatures ( Fig. 1d, e ). Novel heat-sensitive neurons were significantly larger than either TRPV1-expressing or TRPM3-expressing neurons ( Extended Data Fig. 3 ). We investigated the possibility that the novel heat-sensitivity may be co-expressed with TRPV1 and TRPM3 by blocking these channels with antagonists before applying heat; the higher proportion of neurons responding (46% in Extended Data Fig. 4a , compared to <10% expressing only the novel heat-sensitive mechanism, see Fig. 1 and Extended Data Figs 1 , 2 and 4b ) shows that there is significant co-expression of the novel heat-sensitive mechanism with TRPV1 and TRPM3. The phenotype of neurons expressing the novel heat-sensitive mechanism was investigated by identifying novel heat-sensitive neurons in the presence of TRP channel blockers ( Extended Data Fig. 5a , red) and then exposing them to IB4, which marks a non-peptidergic neuronal population ( Extended Data Fig. 5b , green). These results show that the novel heat-sensitive mechanism is predominantly expressed in IB4 + neurons (74% IB4 + ). Figure 1: Around 10% of somatosensory neurons demonstrate a novel heat-sensitive response. a , Examples of increases of [Ca 2+ ] i measured with fura-2 (F 340/380 ratio, ordinate) in response to known TRP channel agonists and to heat. From top: TRPV1-expressing neuron responding to capsaicin (caps, red); TRPM3-expressing neuron responding to pregenolone sulphate (PS, blue); TRPV1-and TRPM3-co-expressing neuron (brown); neuron unresponsive to TRP channel agonists but showing a response to heat (bottom trace). See Supplementary Information Video 1 . b , Percentages of neurons expressing TRPV1, TRPM3 and the novel heat-sensitive mechanism in DRG neurons from wild-type (WT) (top) and Trpm2 −/− knockout (KO) mice (bottom). Green: neurons responding to 2-APB but not to other agonists. c , Histogram of maximal F 340/380 ratio increase in neurons insensitive to TRP agonists. Black, wild-type neurons; red, Trpm2 −/− neurons. Vertical dashed lines: thresholds discriminating between heat-sensitive and insensitive neurons (see Extended Data Fig. 1 ). d , Thermal thresholds of novel heat-sensitive DRG neurons. Increases of F 340/380 ratio (top) in response to slowly rising heat ramp (bottom). e , Temperature thresholds of novel heat-sensitive neurons from wild-type (black) and Trpm2 −/− mice (red). Proportion in range 34–42 °C reduced from 4.4% in wild type to 0.9% in Trpm2 −/− ( P ≤ 0.0001; Fisher’s exact test), and in range 42–48 °C from 15% in wild type (290/1,890) to 3% in Trpm2 −/− (55/1,800) ( P ≤ 0.0001; Fisher’s exact test). Cell numbers and replicates for a – c were 1,324 DRG neurons from one wild-type mouse on 4 coverslips and 981 DRG neurons from one Trpm2 −/− mouse on 4 coverslips were imaged. Similar results obtained using 52 additional coverslips from 9 additional wild-type mice and 10 coverslips from 3 additional Trpm2 −/− mice; some of these results are shown in Extended Data Figs 1 , 2 and 4 . Cell numbers and replicates for d and e were 1,890 DRG neurons from one wild-type mouse on 8 coverslips and 1,800 DRG neurons from one Trpm2 −/− mouse on 8 coverslips were imaged. Similar results obtained using 10 coverslips from one additional wild-type mouse. PowerPoint slide Full size image We next sought to identify a source of neurons which expresses a less-complex set of heat-sensitive ion channels than are present in DRG neurons. In isolated sympathetic neurons from the superior cervical ganglion (SCG) we found that no neuron showed an increase in intracellular calcium concentration ([Ca 2+ ] i ) in response to agonists of known thermo-TRP channels, but that 58% showed a significant response to heat ( Fig. 2a and Extended Data Fig. 6 ). Similar results were obtained in parasympathetic neurons isolated from the pterygopalatine ganglion (PPG), in which 49% of neurons showed novel heat sensitivity", "role": "user" }, { "content": "With temperatures soaring across the UK, our ability to detect and avoid places that are too warm is vital for regulating our body temperature. However, until now, little was known about the molecular mechanisms responsible for detecting warmth in the sensory neurons of our skin. A new King's College London study, published today in Nature, reveals that a gene called TRPM2 initiates a 'warm' signal in mice that drives them to seek cooler environments. When this gene is removed, the mice are unable to distinguish between cool and warm temperatures. Some 'TRP' (Transient Receptor Potential) proteins were already known to be activated by painful levels of heat. These proteins can conduct positively charged ions across the cell membrane, and so can change the internal voltage of a nerve cell. This change in voltage in turn triggers nerve activity, and so signals the painful sensation of heat, such as from touching a hot kettle. However, previous research had not revealed ion channels which may be activated by milder levels of non-painful warmth. Dr Chun-Hsiang Tan and Professor Peter McNaughton from King's College London identified an ion channel called TRPM2, which had not previously been linked to the sensation of warmth. Having isolated this novel sensory channel, they removed the TRPM2 gene in a group of mice and compared their behaviour to normal mice when walking across warmed surfaces at 33°C or 38°C. The researchers found that normal mice preferred a cooler temperature of 33°C and avoided the warmer temperature of 38°C, while the mice in which the TRPM2 gene had been deleted were unable to distinguish between the two. Dr Chun-Hsiang Tan, a postdoctoral worker at King's College London, said: 'The removal of TRPM2 in these mice eliminated their ability to detect non-painful warmth, yet the capacity to detect painful levels of heat using other known receptors was unaffected. This reveals how we are able to detect environments that are too warm at a sensory level.' Professor Peter McNaughton, also of King's College London, said: 'The temperatures we examined are certainly comparable to those you might find on a London bus or tube carriage in the height of summer. At 38°C a busy tube carriage would be quite suffocating, so sensory neurons in our skin allow us to detect that the environment is too warm and drive us to take action - whether that be removing an article of clothing or alighting the tube and seeking a cooler environment.' Professor McNaughton added: 'We have shown that TRPM2 is important for the conscious detection of warmth, but does it also play a role in the unconscious regulation of body temperature? In future studies it would be interesting to explore whether TRPM2 also plays an unconscious role in controlling our body temperature, by regulating sweating and the constriction of blood vessels in the skin.' ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Thermally activated ion channels are known to detect the entire thermal range from extreme heat (TRPV2), painful heat (TRPV1, TRPM3 and ANO1), non-painful warmth (TRPV3 and TRPV4) and non-painful coolness (TRPM8) through to painful cold (TRPA1) 1 , 2 , 3 , 4 , 5 , 6 , 7 . Genetic deletion of each of these ion channels, however, has only modest effects on thermal behaviour in mice 6 , 7 , 8 , 9 , 10 , 11 , 12 , with the exception of TRPM8, the deletion of which has marked effects on the perception of moderate coolness in the range 10–25 °C 13 . The molecular mechanism responsible for detecting non-painful warmth, in particular, is unresolved. Here we used calcium imaging to identify a population of thermally sensitive somatosensory neurons which do not express any of the known thermally activated TRP channels. We then used a combination of calcium imaging, electrophysiology and RNA sequencing to show that the ion channel generating heat sensitivity in these neurons is TRPM2. Autonomic neurons, usually thought of as exclusively motor, also express TRPM2 and respond directly to heat. Mice in which TRPM2 had been genetically deleted showed a striking deficit in their sensation of non-noxious warm temperatures, consistent with the idea that TRPM2 initiates a ‘warm’ signal which drives cool-seeking behaviour. Main Previous studies have described novel heat-sensitive neurons not activated by agonists for any of the known heat-sensitive ion channels 5 , 14 , 15 , 16 . We identified these neurons in cultures from dorsal root ganglia (DRG) by using calcium imaging and selective agonists for known thermo-TRP ion channels. We found that around 10% of neurons responded to heat, but were not activated by any of the agonists for known TRP channels ( Fig. 1a–c and Supplementary Video 1 ). Changing the order of application of agonists or using a lower starting temperature had little effect on this proportion ( Extended Data Figs 1 and 2 ). Novel heat-sensitive neurons were found to be activated over a wide range of temperatures, with a subset activated in the range of warm temperatures between 34 °C and 42 °C, suggesting a possible role in warmth sensation, and a second group activated only at higher temperatures ( Fig. 1d, e ). Novel heat-sensitive neurons were significantly larger than either TRPV1-expressing or TRPM3-expressing neurons ( Extended Data Fig. 3 ). We investigated the possibility that the novel heat-sensitivity may be co-expressed with TRPV1 and TRPM3 by blocking these channels with antagonists before applying heat; the higher proportion of neurons responding (46% in Extended Data Fig. 4a , compared to <10% expressing only the novel heat-sensitive mechanism, see Fig. 1 and Extended Data Figs 1 , 2 and 4b ) shows that there is significant co-expression of the novel heat-sensitive mechanism with TRPV1 and TRPM3. The phenotype of neurons expressing the novel heat-sensitive mechanism was investigated by identifying novel heat-sensitive neurons in the presence of TRP channel blockers ( Extended Data Fig. 5a , red) and then exposing them to IB4, which marks a non-peptidergic neuronal population ( Extended Data Fig. 5b , green). These results show that the novel heat-sensitive mechanism is predominantly expressed in IB4 + neurons (74% IB4 + ). Figure 1: Around 10% of somatosensory neurons demonstrate a novel heat-sensitive response. a , Examples of increases of [Ca 2+ ] i measured with fura-2 (F 340/380 ratio, ordinate) in response to known TRP channel agonists and to heat. From top: TRPV1-expressing neuron responding to capsaicin (caps, red); TRPM3-expressing neuron responding to pregenolone sulphate (PS, blue); TRPV1-and TRPM3-co-expressing neuron (brown); neuron unresponsive to TRP channel agonists but showing a response to heat (bottom trace). See Supplementary Information Video 1 . b , Percentages of neurons expressing TRPV1, TRPM3 and the novel heat-sensitive mechanism in DRG neurons from wild-type (WT) (top) and Trpm2 −/− knockout (KO) mice (bottom). Green: neurons responding to 2-APB but not to other agonists. c , Histogram of maximal F 340/380 ratio increase in neurons insensitive to TRP agonists. Black, wild-type neurons; red, Trpm2 −/− neurons. Vertical dashed lines: thresholds discriminating between heat-sensitive and insensitive neurons (see Extended Data Fig. 1 ). d , Thermal thresholds of novel heat-sensitive DRG neurons. Increases of F 340/380 ratio (top) in response to slowly rising heat ramp (bottom). e , Temperature thresholds of novel heat-sensitive neurons from wild-type (black) and Trpm2 −/− mice (red). Proportion in range 34–42 °C reduced from 4.4% in wild type to 0.9% in Trpm2 −/− ( P ≤ 0.0001; Fisher’s exact test), and in range 42–48 °C from 15% in wild type (290/1,890) to 3% in Trpm2 −/− (55/1,800) ( P ≤ 0.0001; Fisher’s exact test). Cell numbers and replicates for a – c were 1,324 DRG neurons from one wild-type mouse on 4 coverslips and 981 DRG neurons from one Trpm2 −/− mouse on 4 coverslips were imaged. Similar results obtained using 52 additional coverslips from 9 additional wild-type mice and 10 coverslips from 3 additional Trpm2 −/− mice; some of these results are shown in Extended Data Figs 1 , 2 and 4 . Cell numbers and replicates for d and e were 1,890 DRG neurons from one wild-type mouse on 8 coverslips and 1,800 DRG neurons from one Trpm2 −/− mouse on 8 coverslips were imaged. Similar results obtained using 10 coverslips from one additional wild-type mouse. PowerPoint slide Full size image We next sought to identify a source of neurons which expresses a less-complex set of heat-sensitive ion channels than are present in DRG neurons. In isolated sympathetic neurons from the superior cervical ganglion (SCG) we found that no neuron showed an increase in intracellular calcium concentration ([Ca 2+ ] i ) in response to agonists of known thermo-TRP channels, but that 58% showed a significant response to heat ( Fig. 2a and Extended Data Fig. 6 ). Similar results were obtained in parasympathetic neurons isolated from the pterygopalatine ganglion (PPG), in which 49% of neurons showed novel heat sensitivity<|im_end|> <|im_start|>assistant With temperatures soaring across the UK, our ability to detect and avoid places that are too warm is vital for regulating our body temperature. However, until now, little was known about the molecular mechanisms responsible for detecting warmth in the sensory neurons of our skin. A new King's College London study, published today in Nature, reveals that a gene called TRPM2 initiates a 'warm' signal in mice that drives them to seek cooler environments. When this gene is removed, the mice are unable to distinguish between cool and warm temperatures. Some 'TRP' (Transient Receptor Potential) proteins were already known to be activated by painful levels of heat. These proteins can conduct positively charged ions across the cell membrane, and so can change the internal voltage of a nerve cell. This change in voltage in turn triggers nerve activity, and so signals the painful sensation of heat, such as from touching a hot kettle. However, previous research had not revealed ion channels which may be activated by milder levels of non-painful warmth. Dr Chun-Hsiang Tan and Professor Peter McNaughton from King's College London identified an ion channel called TRPM2, which had not previously been linked to the sensation of warmth. Having isolated this novel sensory channel, they removed the TRPM2 gene in a group of mice and compared their behaviour to normal mice when walking across warmed surfaces at 33°C or 38°C. The researchers found that normal mice preferred a cooler temperature of 33°C and avoided the warmer temperature of 38°C, while the mice in which the TRPM2 gene had been deleted were unable to distinguish between the two. Dr Chun-Hsiang Tan, a postdoctoral worker at King's College London, said: 'The removal of TRPM2 in these mice eliminated their ability to detect non-painful warmth, yet the capacity to detect painful levels of heat using other known receptors was unaffected. This reveals how we are able to detect environments that are too warm at a sensory level.' Professor Peter McNaughton, also of King's College London, said: 'The temperatures we examined are certainly comparable to those you might find on a London bus or tube carriage in the height of summer. At 38°C a busy tube carriage would be quite suffocating, so sensory neurons in our skin allow us to detect that the environment is too warm and drive us to take action - whether that be removing an article of clothing or alighting the tube and seeking a cooler environment.' Professor McNaughton added: 'We have shown that TRPM2 is important for the conscious detection of warmth, but does it also play a role in the unconscious regulation of body temperature? In future studies it would be interesting to explore whether TRPM2 also plays an unconscious role in controlling our body temperature, by regulating sweating and the constriction of blood vessels in the skin.' <|im_end|>

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2,127

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Many marine Precambrian iron formations (IF) record deep anoxic seawater enriched in Fe(II) (i.e. ferruginous) overlain by mildly oxygenated surface water. This is reflected by iron-rich sediments forming in deep basins, and relatively iron-poor sediments forming in shallow, sunlit waters. Such an iron gradient is often interpreted as a redox interface where dissolved Fe(II) was oxidized and precipitated as Fe(III)-bearing minerals. As such, sedimentary iron enrichments are proxy to the progressive oxidation of the oceans through geological time. However, this interpretation is founded on the assumption that Fe(II) could not persist within an oxygenated water column. Here, we cultivated cyanobacteria in an illuminated column supplied with Fe(II)-rich seawater medium in a laboratory-scale analog of a continental margin supporting IF deposition. We first observed Fe(II) oxidation with oxygen, then biologically-mediated reduction of Fe(III) (oxyhydr)oxides, which maintained a pool of Fe(II) in the presence of oxygen. Such steady-state iron redox cycling may have maintained dissolved, and hence mobile Fe(II) in oxygenated seawater above ferruginous deep basins such as those inferred for many Precambrian IF. Introduction Interfaces between deep, anoxic and Fe(II)-containing (i.e. ferruginous) seawater and overlying oxygenated surface water existed for billions of years on Earth 1 , 2 , 3 , 4 . Due to the low redox potential of Fe 2+ /Fe 3+ (E°′ = +0.36 V), non-diagenetic sedimentary enrichments indicative of Fe(II) in seawater should indicate the absence of oxygen in that same water. This delineation between oxic and ferruginous water masses manifests itself as a sharp redoxcline between Fe(II) and oxygen-containing layers of water in modern anoxic basins and lakes, or in sediment cores, such that Fe(II) and oxygen are generally not observed to coexist in stratified systems 5 , 6 . After Fe(II) is oxidized and precipitated, generally as Fe(III) (oxyhydr)oxide minerals under circumneutral pH conditions, it can be reduced back to Fe(II) by the activity of dissimilatory Fe(III)-reducing bacteria within anoxic sediments containing organic carbon, regenerating Fe(II). Alternatively, Fe(III) minerals can be reductively dissolved by hydrogen sulfide 7 , formed after microbial sulfate reduction in anoxic sediments supplied with sufficient organic carbon. However, if oxygenated waters are present over anoxic and/or sulfidic sediments, remobilized Fe(II) should not re-enter the water column, as it will be rapidly re-oxidized at the oxic-anoxic interface 5 , effectively immobilizing iron in oxygenated settings. There are, however, photochemical and enzymatic pathways for Fe(III) reduction that occur in the presence of oxygen, and are known to generate steady-state pools of Fe(II) within the modern ocean 8 , 9 . One such pathway is photochemical Fe(III) reduction, which abiotically transfers electrons from Fe(III)-binding organic ligands bound to Fe(III), forming Fe(II) in a process termed ligand-to-metal charge transfer (LMCT) 10 . Complexation to organic ligands changes the stability of Fe(III) and thus its accessibility to redox transformations 11 . Light also induces the production of reactive oxygen species (ROS) from organics or from the splitting of water. ROS react with iron, and can result in Fe(III) reduction and Fe(II) oxidation 11 , 12 . Cyanobacteria, the lineage of modern bacteria thought to be related to Earth’s earliest photosynthetic oxygen-producers, have been shown to enzymatically reduce Fe(III) directly 13 , as well as via enzymatic production of ROS 14 , which then reduce Fe(III), with both processes occurring under oxic conditions. Thus, within sunlit water, shallow microbial mats, or sediments there is the possibility for oxic Fe(III) reduction by processes that are distinct from dissimilatory microbial Fe(III) reduction or reductive dissolution occurring in anoxic sediments. Furthermore, these processes for Fe(III) reduction may have been favored by the higher concentrations of organic material available to complex and solubilize Fe(III) in the upper water column of Precambrian seawater 15 . It is unclear from studies of oxic Fe(III) reduction in modern systems, however, whether such processes could occur under the range of Fe(II) and oxygen concentrations relevant for Precambrian IF depositional settings. Furthermore, can oxic Fe(III) reduction generate Fe(II) in high enough abundance to be recorded in the sedimentary iron record? This would require steady-state reduction of Fe(III) to Fe(II), such that the Fe(II) is continually produced and persists despite rapid re-oxidation with oxygen. Finally, can oxic Fe(III) reduction permit transport of dissolved Fe(II) within suboxic or oxic environments, such that sediments might record the presence of Fe(II) in oxygenated seawater? To address these questions, we utilized a flow-through column where a marine planktonic cyanobacterium was grown in a gradient of Fe(II)-rich seawater medium advectively supplied from the bottom, and light provided from the top 16 . This column is a laboratory-scale analogue to both the water column and shallow microbial mat environments that would have been present along a Precambrian continental margin exposed to upwelling Fe(II)-rich waters (Fig. 1 ). Over 4 weeks of column deployment, we tracked depth-dependent Fe(II), Fe(III), and oxygen concentrations in the presence of a marine cyanobacterium, Synechococcus PCC 7002. The results are used to address the possibility of a dynamic iron redox cycle within an oxygenated surface ocean above an anoxic and ferruginous deep basin, such as those from which Precambrian IF were deposited. Figure 1 ( a ) Schematic cross-section and dimensions of the column. Small darker grey squares are optodes, labeled with the depth in the column. Dark grey sampling ports show the arrangement of fixed needles used to take aqueous samples at different depths in the center of the column. White ports show where medium was pumped in (bottom), pumped out (top), and an additional port used for flushing the headspace. ( b ) Schematic cross-section of a Precambrian continental margin overlying a deep, ferruginous basin, simulated in one dimension (vertically) by the column experiment. Insets show that oxic Fe(III) reduction described here could take place in the water column and/or in a benthic setting, simulated by glass beads in the column. Full size image Methods Extensive details of column design, setup, and operation have been published 16 , and so are described only briefly here. The column was a modified 1 L glass graduated cylinder (Fig.", "role": "user" }, { "content": "A new experiment by Iowa State University's Elizabeth Swanner that evaluates the reduction of iron in prehistoric oceans may reinterpret the conditions under which iron-rich sedimentary rock is formed. Swanner, an assistant professor of geological and atmospheric sciences, was part of an international research team including researchers from the University of Tuebingen in Germany and the Chinese Academy of Sciences in Beijing. The team modeled the prehistoric ocean, similar to that of the Archean Era 2.5 billion years ago within a graduated cylinder. \"We really only wanted to simulate it in the vertical dimension, so we used a graduated cylinder and modified it,\" Swanner said. In a previous experiment, the researchers had modified the cylinder to simulate an Archean ocean with large amounts of iron and no oxygen except for what was made by cyanobacteria. Ports along the cylinder's side allowed for sampling at various levels. \"We were studying cyanobacteria because these are the organisms which we think put all of the oxygen in the atmosphere originally,\" she said. The research, recently published by Scientific Reports, showed that despite the oxygenation by the cyanobacteria, much of the iron did not remain oxidized but was reduced again into its dissolved form. This unexpected result may be explained by an enzyme on cyanobacteria which reduces iron. In the modern ocean, which contains at least 1,000 times less iron, cyanobacteria reduce a small amount of iron, but the experiment showed a larger amount of iron reduction than the researchers anticipated. Another possible explanation is that the iron is reduced by a photochemical reaction occurring when the iron is hit by light. The implications of this finding could change the conditions under which iron-rich sedimentary rocks are thought to be formed from the ancient oceans. \"Traditionally if you see iron enriched in sediments from the ocean you tend to think it was deposited under anoxic conditions,\" Swanner said. \"But potentially we have a way to still deposit a lot of iron but have it be deposited under fully oxygenated conditions.\" The initial results in the laboratory prompt new questions for Swanner, including whether she will find evidence of this process in the Midwestern lakes that her research group is now studying. These lakes have iron at the bottom and oxygen only in the top of the water column, and also contain cyanobacteria. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Many marine Precambrian iron formations (IF) record deep anoxic seawater enriched in Fe(II) (i.e. ferruginous) overlain by mildly oxygenated surface water. This is reflected by iron-rich sediments forming in deep basins, and relatively iron-poor sediments forming in shallow, sunlit waters. Such an iron gradient is often interpreted as a redox interface where dissolved Fe(II) was oxidized and precipitated as Fe(III)-bearing minerals. As such, sedimentary iron enrichments are proxy to the progressive oxidation of the oceans through geological time. However, this interpretation is founded on the assumption that Fe(II) could not persist within an oxygenated water column. Here, we cultivated cyanobacteria in an illuminated column supplied with Fe(II)-rich seawater medium in a laboratory-scale analog of a continental margin supporting IF deposition. We first observed Fe(II) oxidation with oxygen, then biologically-mediated reduction of Fe(III) (oxyhydr)oxides, which maintained a pool of Fe(II) in the presence of oxygen. Such steady-state iron redox cycling may have maintained dissolved, and hence mobile Fe(II) in oxygenated seawater above ferruginous deep basins such as those inferred for many Precambrian IF. Introduction Interfaces between deep, anoxic and Fe(II)-containing (i.e. ferruginous) seawater and overlying oxygenated surface water existed for billions of years on Earth 1 , 2 , 3 , 4 . Due to the low redox potential of Fe 2+ /Fe 3+ (E°′ = +0.36 V), non-diagenetic sedimentary enrichments indicative of Fe(II) in seawater should indicate the absence of oxygen in that same water. This delineation between oxic and ferruginous water masses manifests itself as a sharp redoxcline between Fe(II) and oxygen-containing layers of water in modern anoxic basins and lakes, or in sediment cores, such that Fe(II) and oxygen are generally not observed to coexist in stratified systems 5 , 6 . After Fe(II) is oxidized and precipitated, generally as Fe(III) (oxyhydr)oxide minerals under circumneutral pH conditions, it can be reduced back to Fe(II) by the activity of dissimilatory Fe(III)-reducing bacteria within anoxic sediments containing organic carbon, regenerating Fe(II). Alternatively, Fe(III) minerals can be reductively dissolved by hydrogen sulfide 7 , formed after microbial sulfate reduction in anoxic sediments supplied with sufficient organic carbon. However, if oxygenated waters are present over anoxic and/or sulfidic sediments, remobilized Fe(II) should not re-enter the water column, as it will be rapidly re-oxidized at the oxic-anoxic interface 5 , effectively immobilizing iron in oxygenated settings. There are, however, photochemical and enzymatic pathways for Fe(III) reduction that occur in the presence of oxygen, and are known to generate steady-state pools of Fe(II) within the modern ocean 8 , 9 . One such pathway is photochemical Fe(III) reduction, which abiotically transfers electrons from Fe(III)-binding organic ligands bound to Fe(III), forming Fe(II) in a process termed ligand-to-metal charge transfer (LMCT) 10 . Complexation to organic ligands changes the stability of Fe(III) and thus its accessibility to redox transformations 11 . Light also induces the production of reactive oxygen species (ROS) from organics or from the splitting of water. ROS react with iron, and can result in Fe(III) reduction and Fe(II) oxidation 11 , 12 . Cyanobacteria, the lineage of modern bacteria thought to be related to Earth’s earliest photosynthetic oxygen-producers, have been shown to enzymatically reduce Fe(III) directly 13 , as well as via enzymatic production of ROS 14 , which then reduce Fe(III), with both processes occurring under oxic conditions. Thus, within sunlit water, shallow microbial mats, or sediments there is the possibility for oxic Fe(III) reduction by processes that are distinct from dissimilatory microbial Fe(III) reduction or reductive dissolution occurring in anoxic sediments. Furthermore, these processes for Fe(III) reduction may have been favored by the higher concentrations of organic material available to complex and solubilize Fe(III) in the upper water column of Precambrian seawater 15 . It is unclear from studies of oxic Fe(III) reduction in modern systems, however, whether such processes could occur under the range of Fe(II) and oxygen concentrations relevant for Precambrian IF depositional settings. Furthermore, can oxic Fe(III) reduction generate Fe(II) in high enough abundance to be recorded in the sedimentary iron record? This would require steady-state reduction of Fe(III) to Fe(II), such that the Fe(II) is continually produced and persists despite rapid re-oxidation with oxygen. Finally, can oxic Fe(III) reduction permit transport of dissolved Fe(II) within suboxic or oxic environments, such that sediments might record the presence of Fe(II) in oxygenated seawater? To address these questions, we utilized a flow-through column where a marine planktonic cyanobacterium was grown in a gradient of Fe(II)-rich seawater medium advectively supplied from the bottom, and light provided from the top 16 . This column is a laboratory-scale analogue to both the water column and shallow microbial mat environments that would have been present along a Precambrian continental margin exposed to upwelling Fe(II)-rich waters (Fig. 1 ). Over 4 weeks of column deployment, we tracked depth-dependent Fe(II), Fe(III), and oxygen concentrations in the presence of a marine cyanobacterium, Synechococcus PCC 7002. The results are used to address the possibility of a dynamic iron redox cycle within an oxygenated surface ocean above an anoxic and ferruginous deep basin, such as those from which Precambrian IF were deposited. Figure 1 ( a ) Schematic cross-section and dimensions of the column. Small darker grey squares are optodes, labeled with the depth in the column. Dark grey sampling ports show the arrangement of fixed needles used to take aqueous samples at different depths in the center of the column. White ports show where medium was pumped in (bottom), pumped out (top), and an additional port used for flushing the headspace. ( b ) Schematic cross-section of a Precambrian continental margin overlying a deep, ferruginous basin, simulated in one dimension (vertically) by the column experiment. Insets show that oxic Fe(III) reduction described here could take place in the water column and/or in a benthic setting, simulated by glass beads in the column. Full size image Methods Extensive details of column design, setup, and operation have been published 16 , and so are described only briefly here. The column was a modified 1 L glass graduated cylinder (Fig.<|im_end|> <|im_start|>assistant A new experiment by Iowa State University's Elizabeth Swanner that evaluates the reduction of iron in prehistoric oceans may reinterpret the conditions under which iron-rich sedimentary rock is formed. Swanner, an assistant professor of geological and atmospheric sciences, was part of an international research team including researchers from the University of Tuebingen in Germany and the Chinese Academy of Sciences in Beijing. The team modeled the prehistoric ocean, similar to that of the Archean Era 2.5 billion years ago within a graduated cylinder. "We really only wanted to simulate it in the vertical dimension, so we used a graduated cylinder and modified it," Swanner said. In a previous experiment, the researchers had modified the cylinder to simulate an Archean ocean with large amounts of iron and no oxygen except for what was made by cyanobacteria. Ports along the cylinder's side allowed for sampling at various levels. "We were studying cyanobacteria because these are the organisms which we think put all of the oxygen in the atmosphere originally," she said. The research, recently published by Scientific Reports, showed that despite the oxygenation by the cyanobacteria, much of the iron did not remain oxidized but was reduced again into its dissolved form. This unexpected result may be explained by an enzyme on cyanobacteria which reduces iron. In the modern ocean, which contains at least 1,000 times less iron, cyanobacteria reduce a small amount of iron, but the experiment showed a larger amount of iron reduction than the researchers anticipated. Another possible explanation is that the iron is reduced by a photochemical reaction occurring when the iron is hit by light. The implications of this finding could change the conditions under which iron-rich sedimentary rocks are thought to be formed from the ancient oceans. "Traditionally if you see iron enriched in sediments from the ocean you tend to think it was deposited under anoxic conditions," Swanner said. "But potentially we have a way to still deposit a lot of iron but have it be deposited under fully oxygenated conditions." The initial results in the laboratory prompt new questions for Swanner, including whether she will find evidence of this process in the Midwestern lakes that her research group is now studying. These lakes have iron at the bottom and oxygen only in the top of the water column, and also contain cyanobacteria. <|im_end|>

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2,006

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The spread of multidrug-resistance in Gram-negative bacterial pathogens presents a major clinical challenge, and new approaches are required to combat these organisms. Nitric oxide (NO) is a well-known antimicrobial that is produced by the immune system in response to infection, and numerous studies have demonstrated that NO is a respiratory inhibitor with both bacteriostatic and bactericidal properties. However, given that loss of aerobic respiratory complexes is known to diminish antibiotic efficacy, it was hypothesised that the potent respiratory inhibitor NO would elicit similar effects. Indeed, the current work demonstrates that pre-exposure to NO-releasers elicits a > tenfold increase in IC 50 for gentamicin against pathogenic E. coli (i.e. a huge decrease in lethality). It was therefore hypothesised that hyper-sensitivity to NO may have arisen in bacterial pathogens and that this trait could promote the acquisition of antibiotic-resistance mechanisms through enabling cells to persist in the presence of toxic levels of antibiotic. To test this hypothesis, genomics and microbiological approaches were used to screen a collection of E. coli clinical isolates for antibiotic susceptibility and NO tolerance, although the data did not support a correlation between increased carriage of antibiotic resistance genes and NO tolerance. However, the current work has important implications for how antibiotic susceptibility might be measured in future (i.e. ± NO) and underlines the evolutionary advantage for bacterial pathogens to maintain tolerance to toxic levels of NO. Working on a manuscript? Avoid the common mistakes Introduction For the last eight decades, antibiotics have been used to combat infectious diseases. However, their widespread use has led to the emergence of bacterial pathogens with increased resistance to antimicrobial agents, leading to an increase in mortality and morbidity. Recently, the emergence of multidrug-resistance (i.e. to three or more antibiotic classes) in Gram-negative pathogens has become a cause for concern, with several Gram-negative bacteria, including E. coli , found to be NDM-1 β-lactamase-producing (Walsh et al. 2011 ). These strains often carry many other resistant determinants resulting in extreme multidrug-resistant phenotypes (Yong et al. 2009 ). Of particular concern is bacteraemia caused by E. coli , where there are approximately 40,000 annual cases in England. Over one-third of these are caused by drug-resistant strains causing close to 5,000 deaths each year (Public Health England). An over-represented clonal group is E. coli ST131, a uropathogen first identified in 2008 (Nicolas-Chanoine et al. 2008 ) that is now globally disseminated in both hospital and community settings and has a high incidence of CTX-M-15 extended-spectrum β-lactamase (ESBL)-producing isolates (Croxall et al. 2011 ; Nicolas-Chanoine et al. 2014 ). Given the apparent ease with which multidrug-resistant E. coli are able to spread throughout the human population, it is important to understand elements of the host environment and bacterial physiology that could potentially subvert the efficacy of antibiotics. Indeed, the ability of a bacterium to respire has a profound impact upon antibiotic function and is, therefore, a major focus of the current study. A recent study has shown that the abolition of aerobic respiration (reviewed in (Stokes et al. 2019 )), dramatically reduces the toxic effects of bactericidal antibiotics (Lobritz et al. 2015 ). It, therefore, seems reasonable that a potent respiratory inhibitor such as a nitric oxide (NO), which is produced by the host immune system during infection, would also impair antibiotic efficacy. It is well-known that bactericidal antibiotics can induce cell death via activation of pathways that result in oxidative damage via elevation of aerobic respiratory rates (Dwyer et al. 2007 , 2014 ; Foti et al. 2012 ), with superoxide production implicated as a key intermediate: superoxide causes destabilisation of iron-sulphur complexes (Imlay and Fridovich 1991 ; Keyer and Imlay 1996 ) which causes iron dysregulation and, more importantly, leaching of ferrous iron. Subsequent reactions of leached ferrous iron reduce hydrogen peroxide to toxic hydroxyl radicals via the Fenton reaction (Imlay et al. 1988 ). Although different bactericidal antibiotics have different modes of action, Kohanski and colleagues (Kohanski et al. 2007 , 2010 ) identified that most are able to induce the formation of hydroxyl radicals which is thought to be linked to the aerobic respiratory chain. However, for aminoglycosides, there is significant evidence to support a link between the proton motive force and antibiotic toxicity that is independent of ROS formation: uptake of positively charged aminoglycosides is linked to the electrical component of the proton motive force, as transport into the cell is thermodynamically favourable as the charge component of the PMF will be dissipated upon antibiotic entry (Taber et al. 1987 ; Farha et al. 2018 ). Aside from the potential role in disrupting the potency of antibiotics, the primary function of NO in the immune response is to act as a toxic antimicrobial to combat infection. Cellular targets for NO include thiols, metal centres, haem cofactors, and cysteine residues of proteins that are susceptible to S -nitrosylation (Fang 1997 ; Keszler et al. 2010 ). Bacteria have encountered NO in the gut and at the local site of infection for millennia, and have predictably evolved a variety of mechanisms to circumvent this toxicity (Shepherd et al. 2016 ), including detoxification systems to convert NO to less toxic substances, NO-tolerant respiratory oxidases, and mechanisms to repair damaged iron sulphur clusters. Hence, an assumption made in the current study is that bacterial exposure to NO and the evolution of resistance to this toxic molecule pre-dates the widespread exposure to antibiotics and the resultant emergence of antibiotic resistance. Given that loss of aerobic respiratory complexes had previously been shown to diminish the efficacy of various antibiotics (Lobritz et al. 2015 ), it was anticipated that the respiratory inhibitor NO would also diminish antibiotic susceptibility. If this could be demonstrated, we hypothesised that hyper-sensitivity to NO may have arisen in bacterial pathogens as a mechanism to promote the acquisition of antibiotic-resistance through enabling cells to persist in the presence of toxic levels of antibiotic (Fig. 1 ). Hence, the current work sought to investigate the relationship between NO tolerance/sensitivity and carriage of antibiotic resistance", "role": "user" }, { "content": "Research from the School of Biosciences has revealed that a molecule produced by the human immune system can severely diminish the potency of certain antibiotics. This may explain why antibiotics effective in laboratory settings can be less effective at clearing infections in humans. The research findings, which have been published in the journal Archives of Microbiology, reveal that nitric oxide, a molecule produced by our immune systems, can render aminoglycoside antibiotics ineffective when used against E. coli strains isolated from human infections. E. coli causes life-threatening infections including sepsis, bladder infections, kidney failure, and dysentery. Whilst the human immune system produces nitric oxide to kill invading bacteria, this study reports that nitric oxide can also undermine the function of antibiotics that are used as first-line agents to treat infections caused by drug-resistant E. coli. It is expected that these findings will greatly influence the choice and dose of antibiotic treatments prescribed by medical professionals. Corresponding author Dr. Mark Shepherd, Senior Lecturer in Microbial Biochemistry at Kent, said: \"This work highlights the urgent need for a better understanding of how the human immune system can profoundly affect the activity of antibiotics, which is of great importance for future therapies to treat multidrug-resistant bacterial infections.\" The paper \"Nitric oxide (NO) elicits aminoglycoside tolerance in Escherichia coli but antibiotic resistance gene carriage and NO sensitivity have not co-evolved,\" is published in the Archives of Microbiology. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The spread of multidrug-resistance in Gram-negative bacterial pathogens presents a major clinical challenge, and new approaches are required to combat these organisms. Nitric oxide (NO) is a well-known antimicrobial that is produced by the immune system in response to infection, and numerous studies have demonstrated that NO is a respiratory inhibitor with both bacteriostatic and bactericidal properties. However, given that loss of aerobic respiratory complexes is known to diminish antibiotic efficacy, it was hypothesised that the potent respiratory inhibitor NO would elicit similar effects. Indeed, the current work demonstrates that pre-exposure to NO-releasers elicits a > tenfold increase in IC 50 for gentamicin against pathogenic E. coli (i.e. a huge decrease in lethality). It was therefore hypothesised that hyper-sensitivity to NO may have arisen in bacterial pathogens and that this trait could promote the acquisition of antibiotic-resistance mechanisms through enabling cells to persist in the presence of toxic levels of antibiotic. To test this hypothesis, genomics and microbiological approaches were used to screen a collection of E. coli clinical isolates for antibiotic susceptibility and NO tolerance, although the data did not support a correlation between increased carriage of antibiotic resistance genes and NO tolerance. However, the current work has important implications for how antibiotic susceptibility might be measured in future (i.e. ± NO) and underlines the evolutionary advantage for bacterial pathogens to maintain tolerance to toxic levels of NO. Working on a manuscript? Avoid the common mistakes Introduction For the last eight decades, antibiotics have been used to combat infectious diseases. However, their widespread use has led to the emergence of bacterial pathogens with increased resistance to antimicrobial agents, leading to an increase in mortality and morbidity. Recently, the emergence of multidrug-resistance (i.e. to three or more antibiotic classes) in Gram-negative pathogens has become a cause for concern, with several Gram-negative bacteria, including E. coli , found to be NDM-1 β-lactamase-producing (Walsh et al. 2011 ). These strains often carry many other resistant determinants resulting in extreme multidrug-resistant phenotypes (Yong et al. 2009 ). Of particular concern is bacteraemia caused by E. coli , where there are approximately 40,000 annual cases in England. Over one-third of these are caused by drug-resistant strains causing close to 5,000 deaths each year (Public Health England). An over-represented clonal group is E. coli ST131, a uropathogen first identified in 2008 (Nicolas-Chanoine et al. 2008 ) that is now globally disseminated in both hospital and community settings and has a high incidence of CTX-M-15 extended-spectrum β-lactamase (ESBL)-producing isolates (Croxall et al. 2011 ; Nicolas-Chanoine et al. 2014 ). Given the apparent ease with which multidrug-resistant E. coli are able to spread throughout the human population, it is important to understand elements of the host environment and bacterial physiology that could potentially subvert the efficacy of antibiotics. Indeed, the ability of a bacterium to respire has a profound impact upon antibiotic function and is, therefore, a major focus of the current study. A recent study has shown that the abolition of aerobic respiration (reviewed in (Stokes et al. 2019 )), dramatically reduces the toxic effects of bactericidal antibiotics (Lobritz et al. 2015 ). It, therefore, seems reasonable that a potent respiratory inhibitor such as a nitric oxide (NO), which is produced by the host immune system during infection, would also impair antibiotic efficacy. It is well-known that bactericidal antibiotics can induce cell death via activation of pathways that result in oxidative damage via elevation of aerobic respiratory rates (Dwyer et al. 2007 , 2014 ; Foti et al. 2012 ), with superoxide production implicated as a key intermediate: superoxide causes destabilisation of iron-sulphur complexes (Imlay and Fridovich 1991 ; Keyer and Imlay 1996 ) which causes iron dysregulation and, more importantly, leaching of ferrous iron. Subsequent reactions of leached ferrous iron reduce hydrogen peroxide to toxic hydroxyl radicals via the Fenton reaction (Imlay et al. 1988 ). Although different bactericidal antibiotics have different modes of action, Kohanski and colleagues (Kohanski et al. 2007 , 2010 ) identified that most are able to induce the formation of hydroxyl radicals which is thought to be linked to the aerobic respiratory chain. However, for aminoglycosides, there is significant evidence to support a link between the proton motive force and antibiotic toxicity that is independent of ROS formation: uptake of positively charged aminoglycosides is linked to the electrical component of the proton motive force, as transport into the cell is thermodynamically favourable as the charge component of the PMF will be dissipated upon antibiotic entry (Taber et al. 1987 ; Farha et al. 2018 ). Aside from the potential role in disrupting the potency of antibiotics, the primary function of NO in the immune response is to act as a toxic antimicrobial to combat infection. Cellular targets for NO include thiols, metal centres, haem cofactors, and cysteine residues of proteins that are susceptible to S -nitrosylation (Fang 1997 ; Keszler et al. 2010 ). Bacteria have encountered NO in the gut and at the local site of infection for millennia, and have predictably evolved a variety of mechanisms to circumvent this toxicity (Shepherd et al. 2016 ), including detoxification systems to convert NO to less toxic substances, NO-tolerant respiratory oxidases, and mechanisms to repair damaged iron sulphur clusters. Hence, an assumption made in the current study is that bacterial exposure to NO and the evolution of resistance to this toxic molecule pre-dates the widespread exposure to antibiotics and the resultant emergence of antibiotic resistance. Given that loss of aerobic respiratory complexes had previously been shown to diminish the efficacy of various antibiotics (Lobritz et al. 2015 ), it was anticipated that the respiratory inhibitor NO would also diminish antibiotic susceptibility. If this could be demonstrated, we hypothesised that hyper-sensitivity to NO may have arisen in bacterial pathogens as a mechanism to promote the acquisition of antibiotic-resistance through enabling cells to persist in the presence of toxic levels of antibiotic (Fig. 1 ). Hence, the current work sought to investigate the relationship between NO tolerance/sensitivity and carriage of antibiotic resistance<|im_end|> <|im_start|>assistant Research from the School of Biosciences has revealed that a molecule produced by the human immune system can severely diminish the potency of certain antibiotics. This may explain why antibiotics effective in laboratory settings can be less effective at clearing infections in humans. The research findings, which have been published in the journal Archives of Microbiology, reveal that nitric oxide, a molecule produced by our immune systems, can render aminoglycoside antibiotics ineffective when used against E. coli strains isolated from human infections. E. coli causes life-threatening infections including sepsis, bladder infections, kidney failure, and dysentery. Whilst the human immune system produces nitric oxide to kill invading bacteria, this study reports that nitric oxide can also undermine the function of antibiotics that are used as first-line agents to treat infections caused by drug-resistant E. coli. It is expected that these findings will greatly influence the choice and dose of antibiotic treatments prescribed by medical professionals. Corresponding author Dr. Mark Shepherd, Senior Lecturer in Microbial Biochemistry at Kent, said: "This work highlights the urgent need for a better understanding of how the human immune system can profoundly affect the activity of antibiotics, which is of great importance for future therapies to treat multidrug-resistant bacterial infections." The paper "Nitric oxide (NO) elicits aminoglycoside tolerance in Escherichia coli but antibiotic resistance gene carriage and NO sensitivity have not co-evolved," is published in the Archives of Microbiology. <|im_end|>

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1,708

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Drugs that target histone deacetylase (HDAC) entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a quantitative chemical proteomics assay using immobilized HDAC inhibitors and mass spectrometry that we deployed to establish the target landscape of 53 drugs. The assay covers 9 of the 11 human zinc-dependent HDACs, questions the reported selectivity of some widely-used molecules (notably for HDAC6) and delineates how the composition of HDAC complexes influences drug potency. Unexpectedly, metallo-β-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent off-target of hydroxamate drugs. This poorly characterized palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nanomolar potency. MBLAC2 enzymatic inhibition and knockdown led to the accumulation of extracellular vesicles. Given the importance of extracellular vesicle biology in neurological diseases and cancer, this HDAC-independent drug effect may qualify MBLAC2 as a target for drug discovery. Main HDAC inhibition has emerged as a promising therapeutic option in oncology, as well as for other conditions such as Duchenne muscular dystrophy 1 . The United States Food and Drug Administration (FDA) approval of the first-in-class HDAC inhibitor (HDACi) vorinostat in 2006 for the treatment of cutaneous T-cell lymphoma marked the start of a series of drug approvals for cancerous diseases. Notably, most clinical HDACis engage several targets across the four classes of human zinc-dependent HDACs (I, IIa, IIb and IV). Such pan-HDACis and their polypharmacological mechanisms of action might be beneficial particularly in oncology, in which several disease-relevant class I and II HDACs are inhibited simultaneously 2 . However, conditions such as amyotrophic lateral sclerosis or Huntington’s disease would require class II isoform-selective inhibitors that precisely interfere with the pathological mechanism 3 , 4 but bypass the toxicity that arises from the inhibition of epigenetic class I HDACs 2 . Therefore, the delineation of the target spectrum of HDACis appears to be essential for the understanding of their mechanisms of action and for the development of more tailored therapies. HDAC activity highly depends on molecular context such as post-translational modifications 5 , allosteric factors 6 or participation in gene regulatory protein complexes 7 . These factors have been shown to affect drug affinity, but are not recapitulated in traditional enzyme activity assays 8 , 9 . To address this challenge, a landmark study 8 reported a chemoproteomic assay that probes HDACi target engagement in lysates that contains natively folded proteins with their cofactors and that maintains the biomolecular interactions. The immobilization of vorinostat allowed for the pulldown of HDAC complexes, and competitive drug binding enabled the selectivity profiling of 16 HDACis against 6 of the 11 HDACs, particularly those in classes I and IIb. These chemoproteomic experiments led to the discovery of the mitotic deacetylase complex (MiDAC), which was later shown to be relevant for correct mitotic chromosome alignment 10 . Moreover, the study revealed that aminoanilide-based HDACis exhibit reduced affinity for the Sin3–HDAC complex and slow binding kinetics 8 , 9 . So far, however, affinity matrices designed to profile HDAC drugs do not address class IIa HDACs 11 , which are targets of increasing interest 12 . Here, we substantially extended the existing profiling technology by creating an affinity matrix that enriches 9 out of 11 zinc (Zn 2+ )-dependent HDACs, including class IIa HDACs, and mapped the target landscape of 53 HDAC and metallohydrolase drugs. The results highlight HDACis with unexpected target profiles and low selectivity. However, we also identify drugs with unparalleled selectivity for class IIb HDAC6 and HDAC10. Moreover, the quantitative data revealed that drugs interacting with HDAC1 as part of gene regulatory REST corepressor (CoREST) complexes 13 containing either RCOR1 or RCOR3 show a >10-fold difference in HDAC1 binding affinity. Surprisingly, about half of the HDACis, including clinically advanced molecules, inhibit the acyl-CoA hydrolase MBLAC2 (ref. 14 ) at nanomolar concentrations. We further demonstrate that pharmacological inhibition or knockdown of MBLAC2 triggers the accumulation of extracellular vesicles in cell culture, placing this poorly characterized protein into the context of extracellular vesicle biology. Results Optimized chemoproteomics assay for HDAC drugs profiling Inspired by previous chemoproteomic studies of HDAC drugs 11 , we embarked on the development of a general affinity matrix to comprehensively enrich the HDAC protein family. We synthesized 15 chemical probes ( 1 – 15 ) (Extended Data Fig. 1a ) that represented different chemotypes, including different zinc-binding groups, and immobilized them on beads. Then, we evaluated the obtained affinity matrices for their suitability in pulling down HDACs from lysates of ten cell lines with different HDAC expression profiles, akin to the Kinobeads technology or other similar chemical proteomics approaches 15 . This led to the identification of a combination of three probes (iC, iQ and iA) (Fig. 1a ) and lysates of two cell lines (MV4-11 and SW620) that together covered the widest range of targets (Fig. 1a and Extended Data Figs. 1 and 2 ). Specifically, iC robustly enriched seven HDACs, including class IIa HDAC4, HDAC5 and HDAC7, as well as MBLAC2. The addition of iQ improved the enrichment of HDAC3 and HDAC8, extending the coverage of the affinity matrix to 9 of the 11 zinc-dependent HDACs. We also included iA, as we observed that it enriched many metalloenzymes, including iron–sulfur cluster proteins (Extended Data Fig. 2 and Fig. 1a ), as well as GATD3A, ALDH2, ISOC1 and ISOC2 that turned out to be common HDACi off-targets (see the section ‘The target landscape of HDAC drugs’ and Fig. 2a ). Fig. 1: Chemical proteomics assay for HDACis. a , Contribution of each of the three selected affinity probes to the enrichment of zinc-dependent HDACs and off-targets from mixed SW620 and MV4-11 cell lysates. b , Temperature dependence of aminoanilide (entinostat) and hydroxamate (CHDI00465983) drugs on target engagement over time (up to 25 h). When binding equilibrium is reached, maximal occupancy of the target binding sites is obtained and minimal enrichment by the affinity matrix ensues (minimal residual binding is synonymous with maximal competition). c , Exemplary dose–response curves for romidepsin binding to HDACs using the", "role": "user" }, { "content": "Mass-spectrometry based proteomics is the big-data science of proteins that allows the monitoring of the abundance of thousands of proteins in a sample at once. Therefore, it is a particularly well-suited readout for discovering which proteins are targeted by any small molecule. An international research team has investigated this using chemical proteomics. Histone deacetylase (HDAC) inhibitors are a class of drugs used in oncology. An international research team involving scientists at the Technical University of Munich (TUM), Cornell University in Ithaca (U.S.), the German Cancer Research Center (DKFZ) in Heidelberg and Martin Luther University of Halle-Wittenberg has now investigated the effects of some HDAC drugs in more detail. The scientists researched whether those epidrugs affect proteins other than the HDACs which they are designed to inhibit. \"To do so, target deconvolution by chemical proteomics is the method of choice. Hence, we first made new chemical tools—the so called affinity matrices—that would allow us to systematically profile the HDACs,\" explains Dr. Guillaume Médard, group leader for chemical proteomics at the TUM chair of Proteomics and Bioanalytics led by Prof. Bernhard Küster. Profiling HDAC drugs by chemical proteomics \"I profiled 53 drugs and most of them, but not all, hit their intended HDAC target,\" stated Severin Lechner, a doctoral candidate at the TUM School of Life Sciences. \"There were, however, some surprises. Drugs used in hundreds of scientific studies were not as selective as it had been assumed. Many had additional targets that were not previously known.\" These results highlight the power of proteomic approaches, as they can probe the binding to thousands of proteins at once. Finally, the team identified several molecules with outstanding selectivity, making them the inhibitors of choice for future scientific studies. The target landscape of HDAC drugs \"The most unexpected finding was that MBLAC2 is off-target for half of the profiled molecules,\" Lechner continues. This protein is not well characterized. Coincidentally, the team of Prof. Maurine Linder in Cornell researched on it at the same time. The two groups collaborated and confirmed that the protein is indeed hindered in performing its function in presence of the drugs. Working with the group of Prof. Michael Pfaffl at TUM, Lechner examined the hinted unexplained phenotypic effects of some drugs and proved that MBLAC2 inhibition or knock-down leads to an accumulation of extracellular vesicles in the extracellular space. Extracellular vesicles are small membrane-bounded particles secreted by cells and transported through the whole body to transmit biomolecules and information between cells and tissues. Fundamental research to make tomorrow's epidrugs \"We are excited because we have uncovered a new player in this field of biology that notably encompasses exosomes, which play crucial roles in neurology, immunology and oncology,\" explains Médard. \"We are now designing molecules that only hit MBLAC2 so that we can probe this obscure protein in a range of model systems.\" This study will be useful to those who want to use HDAC inhibitors for probing biology or for therapeutic use. It helps in choosing the right chemical tool. It is also a valuable set of data for medicinal chemists who need to understand how chemical structures relate to potency and selectivity to make tomorrow's epidrugs. The research was published in Nature Chemical Biology. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Drugs that target histone deacetylase (HDAC) entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a quantitative chemical proteomics assay using immobilized HDAC inhibitors and mass spectrometry that we deployed to establish the target landscape of 53 drugs. The assay covers 9 of the 11 human zinc-dependent HDACs, questions the reported selectivity of some widely-used molecules (notably for HDAC6) and delineates how the composition of HDAC complexes influences drug potency. Unexpectedly, metallo-β-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent off-target of hydroxamate drugs. This poorly characterized palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nanomolar potency. MBLAC2 enzymatic inhibition and knockdown led to the accumulation of extracellular vesicles. Given the importance of extracellular vesicle biology in neurological diseases and cancer, this HDAC-independent drug effect may qualify MBLAC2 as a target for drug discovery. Main HDAC inhibition has emerged as a promising therapeutic option in oncology, as well as for other conditions such as Duchenne muscular dystrophy 1 . The United States Food and Drug Administration (FDA) approval of the first-in-class HDAC inhibitor (HDACi) vorinostat in 2006 for the treatment of cutaneous T-cell lymphoma marked the start of a series of drug approvals for cancerous diseases. Notably, most clinical HDACis engage several targets across the four classes of human zinc-dependent HDACs (I, IIa, IIb and IV). Such pan-HDACis and their polypharmacological mechanisms of action might be beneficial particularly in oncology, in which several disease-relevant class I and II HDACs are inhibited simultaneously 2 . However, conditions such as amyotrophic lateral sclerosis or Huntington’s disease would require class II isoform-selective inhibitors that precisely interfere with the pathological mechanism 3 , 4 but bypass the toxicity that arises from the inhibition of epigenetic class I HDACs 2 . Therefore, the delineation of the target spectrum of HDACis appears to be essential for the understanding of their mechanisms of action and for the development of more tailored therapies. HDAC activity highly depends on molecular context such as post-translational modifications 5 , allosteric factors 6 or participation in gene regulatory protein complexes 7 . These factors have been shown to affect drug affinity, but are not recapitulated in traditional enzyme activity assays 8 , 9 . To address this challenge, a landmark study 8 reported a chemoproteomic assay that probes HDACi target engagement in lysates that contains natively folded proteins with their cofactors and that maintains the biomolecular interactions. The immobilization of vorinostat allowed for the pulldown of HDAC complexes, and competitive drug binding enabled the selectivity profiling of 16 HDACis against 6 of the 11 HDACs, particularly those in classes I and IIb. These chemoproteomic experiments led to the discovery of the mitotic deacetylase complex (MiDAC), which was later shown to be relevant for correct mitotic chromosome alignment 10 . Moreover, the study revealed that aminoanilide-based HDACis exhibit reduced affinity for the Sin3–HDAC complex and slow binding kinetics 8 , 9 . So far, however, affinity matrices designed to profile HDAC drugs do not address class IIa HDACs 11 , which are targets of increasing interest 12 . Here, we substantially extended the existing profiling technology by creating an affinity matrix that enriches 9 out of 11 zinc (Zn 2+ )-dependent HDACs, including class IIa HDACs, and mapped the target landscape of 53 HDAC and metallohydrolase drugs. The results highlight HDACis with unexpected target profiles and low selectivity. However, we also identify drugs with unparalleled selectivity for class IIb HDAC6 and HDAC10. Moreover, the quantitative data revealed that drugs interacting with HDAC1 as part of gene regulatory REST corepressor (CoREST) complexes 13 containing either RCOR1 or RCOR3 show a >10-fold difference in HDAC1 binding affinity. Surprisingly, about half of the HDACis, including clinically advanced molecules, inhibit the acyl-CoA hydrolase MBLAC2 (ref. 14 ) at nanomolar concentrations. We further demonstrate that pharmacological inhibition or knockdown of MBLAC2 triggers the accumulation of extracellular vesicles in cell culture, placing this poorly characterized protein into the context of extracellular vesicle biology. Results Optimized chemoproteomics assay for HDAC drugs profiling Inspired by previous chemoproteomic studies of HDAC drugs 11 , we embarked on the development of a general affinity matrix to comprehensively enrich the HDAC protein family. We synthesized 15 chemical probes ( 1 – 15 ) (Extended Data Fig. 1a ) that represented different chemotypes, including different zinc-binding groups, and immobilized them on beads. Then, we evaluated the obtained affinity matrices for their suitability in pulling down HDACs from lysates of ten cell lines with different HDAC expression profiles, akin to the Kinobeads technology or other similar chemical proteomics approaches 15 . This led to the identification of a combination of three probes (iC, iQ and iA) (Fig. 1a ) and lysates of two cell lines (MV4-11 and SW620) that together covered the widest range of targets (Fig. 1a and Extended Data Figs. 1 and 2 ). Specifically, iC robustly enriched seven HDACs, including class IIa HDAC4, HDAC5 and HDAC7, as well as MBLAC2. The addition of iQ improved the enrichment of HDAC3 and HDAC8, extending the coverage of the affinity matrix to 9 of the 11 zinc-dependent HDACs. We also included iA, as we observed that it enriched many metalloenzymes, including iron–sulfur cluster proteins (Extended Data Fig. 2 and Fig. 1a ), as well as GATD3A, ALDH2, ISOC1 and ISOC2 that turned out to be common HDACi off-targets (see the section ‘The target landscape of HDAC drugs’ and Fig. 2a ). Fig. 1: Chemical proteomics assay for HDACis. a , Contribution of each of the three selected affinity probes to the enrichment of zinc-dependent HDACs and off-targets from mixed SW620 and MV4-11 cell lysates. b , Temperature dependence of aminoanilide (entinostat) and hydroxamate (CHDI00465983) drugs on target engagement over time (up to 25 h). When binding equilibrium is reached, maximal occupancy of the target binding sites is obtained and minimal enrichment by the affinity matrix ensues (minimal residual binding is synonymous with maximal competition). c , Exemplary dose–response curves for romidepsin binding to HDACs using the<|im_end|> <|im_start|>assistant Mass-spectrometry based proteomics is the big-data science of proteins that allows the monitoring of the abundance of thousands of proteins in a sample at once. Therefore, it is a particularly well-suited readout for discovering which proteins are targeted by any small molecule. An international research team has investigated this using chemical proteomics. Histone deacetylase (HDAC) inhibitors are a class of drugs used in oncology. An international research team involving scientists at the Technical University of Munich (TUM), Cornell University in Ithaca (U.S.), the German Cancer Research Center (DKFZ) in Heidelberg and Martin Luther University of Halle-Wittenberg has now investigated the effects of some HDAC drugs in more detail. The scientists researched whether those epidrugs affect proteins other than the HDACs which they are designed to inhibit. "To do so, target deconvolution by chemical proteomics is the method of choice. Hence, we first made new chemical tools—the so called affinity matrices—that would allow us to systematically profile the HDACs," explains Dr. Guillaume Médard, group leader for chemical proteomics at the TUM chair of Proteomics and Bioanalytics led by Prof. Bernhard Küster. Profiling HDAC drugs by chemical proteomics "I profiled 53 drugs and most of them, but not all, hit their intended HDAC target," stated Severin Lechner, a doctoral candidate at the TUM School of Life Sciences. "There were, however, some surprises. Drugs used in hundreds of scientific studies were not as selective as it had been assumed. Many had additional targets that were not previously known." These results highlight the power of proteomic approaches, as they can probe the binding to thousands of proteins at once. Finally, the team identified several molecules with outstanding selectivity, making them the inhibitors of choice for future scientific studies. The target landscape of HDAC drugs "The most unexpected finding was that MBLAC2 is off-target for half of the profiled molecules," Lechner continues. This protein is not well characterized. Coincidentally, the team of Prof. Maurine Linder in Cornell researched on it at the same time. The two groups collaborated and confirmed that the protein is indeed hindered in performing its function in presence of the drugs. Working with the group of Prof. Michael Pfaffl at TUM, Lechner examined the hinted unexplained phenotypic effects of some drugs and proved that MBLAC2 inhibition or knock-down leads to an accumulation of extracellular vesicles in the extracellular space. Extracellular vesicles are small membrane-bounded particles secreted by cells and transported through the whole body to transmit biomolecules and information between cells and tissues. Fundamental research to make tomorrow's epidrugs "We are excited because we have uncovered a new player in this field of biology that notably encompasses exosomes, which play crucial roles in neurology, immunology and oncology," explains Médard. "We are now designing molecules that only hit MBLAC2 so that we can probe this obscure protein in a range of model systems." This study will be useful to those who want to use HDAC inhibitors for probing biology or for therapeutic use. It helps in choosing the right chemical tool. It is also a valuable set of data for medicinal chemists who need to understand how chemical structures relate to potency and selectivity to make tomorrow's epidrugs. The research was published in Nature Chemical Biology. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In the barley β- d -glucan glucohydrolase, a glycoside hydrolase family 3 (GH3) enzyme, the Trp286/Trp434 clamp ensures β- d -glucosides binding, which is fundamental for substrate hydrolysis during plant growth and development. We employ mutagenesis, high-resolution X-ray crystallography, and multi-scale molecular modelling methods to examine the binding and conformational behaviour of isomeric β- d -glucosides during substrate-product assisted processive catalysis that operates in GH3 hydrolases. Enzyme kinetics reveals that the W434H mutant retains broad specificity, while W434A behaves as a strict (1,3)-β- d -glucosidase. Investigations of reactant movements on the nanoscale reveal that processivity is sensitive to mutation-specific alterations of the tryptophan clamp. While wild-type and W434H utilise a lateral cavity for glucose displacement and sliding of (1,3)-linked hydrolytic products through the catalytic site without dissociation, consistent with their high hydrolytic rates, W434A does not adopt processive catalysis. Phylogenomic analyses of GH3 hydrolases disclose the evolutionary advantage of the tryptophan clamp that confers broad specificity, high catalytic efficiency, and processivity. Introduction The barley ( Hordeum vulgare L.) β- d -glucan glucohydrolase HvExoI is the only plant family 3 glycoside hydrolase (GH3) for which the atomic structure is available 1 , 2 , 3 , although the Carbohydrate-Active Enzymes CAZy database 4 lists nearly 48,400 GH3 entries (August 2022) from archaea, bacteria, fungi, and eukaryotes, including economically important plants Triticum , Oryza, Glycine, Zea , Brassica , Medicago , Phaseolus , and Solanum . HvExoI folds into a two-domain structure consisting of an (α/β) 8 barrel (domain 1) and an (α/β) 6 sandwich (domain 2) with a 13 Å-deep active site pocket embracing the subsites −1 and +1, positioned at the interface between the two domains. At the −1 subsite, the pocket contains the catalytic nucleophile Asp285 and the acid/base catalyst Glu491, while the +1 subsite is shaped in a clamp with a coin slot formed by the Trp286 and Trp434 residues that hold β- d -glucosides entering the active site in a productive mode for hydrolysis 1 , 2 , 3 , 5 (Fig. 1a, b ). HvExoI catalyses the hydrolytic removal of nonreducing glucose (Glc) moiety from a broad spectrum of poly- and oligomeric β- d -glucosides. This hydrolytic reaction underpins a vital role of HvExoI during plant growth and development, to participate during e.g . primary root extension and the recycling of mixed-linkage (1,4;1,3)-β- d -glucans during germination and root elongation 1 , 3 , 6 . The capacity of HvExoI to hydrolyse a panel of β- d -glucosides was rationalised from the observation that non-reducing Glc at the −1 subsite is locked into a fixed position through a network of hydrogen bonds (H-bonds), while the reducing Glc moiety at the +1 subsite is constrained through stacking interactions, and thus the flexibility of attached substrates and their projection is unencumbered allowing HvExoI to accommodate isomeric (1,2)-, (1,3)-, (1,4)- and (1,6)-linked β- d -glucosides 2 , 3 . It was estimated that the strength of binding through aromatic residues could be in the range of 2-5 kcal/mol 7 . Fig. 1: Exo-hydrolytic enzymes of the GH3 family with an entrapped Glc molecule and a ligand-free form, and their phylogeny. a Hordeum vulgare HvExoI with entrapped Glc (PDB 3WLH; atomic colours), Bacteroides ovatus β-glucosidase with perfused Glc (PDB 5JP0; green cpk), and a ligand-free form of Pseudoalteromonas sp. exo-(1,4;1,3)-β-glucanase (PDB 3UT0; yellow cpk). Distances ached of HvExoI residues to Glc in the −1 subsite (black dashes) are within 3.3 Å. HvExoI and structurally equivalent residues in 3UT0 and 5JP0 superpose with respective RMSD values of 0.7 Å and 1.2 Å. b Surface morphology of the active site pocket of HvExoI coloured by an electrostatic potential: white, neutral; red, −5 kT·e −1 . Separations (dashed lines) between Glc and key interacting residues are within 3.3 Å. The positions of the −1 subsites in panels a and b are indicated. c Unrooted phylogenetic tree of representative GH3 family members (accession numbers listed in Supplementary Table 1 ) revealed the presence of four major clades with five activities [β -d -glucan glucohydrolases (EC 3.2.1.-), β -d -glucosidases (EC 3.2.1.21), β-N-acetylhexosaminidases (EC 3.2.1.52), β -d -xylosidases (EC 3.2.1.37), and α- l -arabinofuranosidases (EC 3.2.1.55)]. In β -d -glucan glucohydrolases, three subclades were identified with residue variability in the aromatic clamp (residue numbering corresponding to HvExoI; PDB 1EX1). The percentage of replicate trees with taxa clustering together in the bootstrap test (1000 replicates) are shown at node bipartitions. Full size image Since the HvExoI structure was elucidated 1 , 2 , 3 , many prokaryotic, fungal and unclassified metagenome GH3 structures have become available but provided little information on the substrate specificity of this class of enzymes. These include two-domain bacterial β-N-acetylglucosaminidases, for example, from Bacillus subtilis 8 , and a β-N-acetylhexosaminidase from Salmonella typhimurium 9 , while a β-hexosaminidase from Burkholderia cenocepacia 10 folds into a single-domain (α/β) 8 sandwich structure. Several three-domain architectures consisting of an (α/β) 8 barrel, an (α/β) 6 sandwich, and another β-sandwich domain were revealed in β-glucosidases from Thermotoga neapolitana 11 , Hypocrea jecorina 12 and Aspergillus aculeatus 13 , in a β-N-acetylglucosaminidase from Thermotoga neapolitana 14 , in a (1,4;1,3)-β-exo-glucanase from Pseudoalteromonas sp. BB1 15 , and in a β-glucosidase JMB19063 isolated from metagenome 16 . These additional β-sandwich domains are described as fibronectin type III or Ig-like β-sandwich folds and have similar architectures. Four-domains structures consisting of (α/β) 8 barrel, an (α/β) 6 sandwich, and two β-sandwich domain folds (PA14 and fibronectin type III) were identified in the β-glucosidases from Kluyveromyces marxianus 17 , Aspergillus fumigatus, A. oryzae 18 and Streptomyces venezuelae 19 . The precise roles of these additional β-sandwich domains have not been fully clarified. However, in some GH3 enzymes these domains are thought to be linked to substrate binding and specificity 17 , protein structure stability 14 , 20 , and oligomerisation, meaning that dimerisation is required for catalytic activity 16 . Although the details of the catalytic mechanism in HvExoI were reported 1 , 2 , 3 , 21 , the", "role": "user" }, { "content": "Researchers from the University of Adelaide have uncovered previously unknown properties in a plant enzyme that could lead to advances in cereal production, medical and pharmaceutical industries. The research—published in Nature Communications—also has the potential to be applied to the design of chemicals, drugs, herbicides and pesticides where enzymes are an environmentally friendly and cost-effective alternative to current methods. \"We discovered these enzymes are not rigid, as often seen in crystal structures, but are flexible and prone to remarkable changes in shape,\" said project leader Emerita Professor Maria Hrmova, from The University of Adelaide's School of Agriculture, Food and Wine, and the Waite Research Institute. \"This was achieved by examining the binding behavior of sugars in the enzyme at ultra-fast time scales. \"We solved 25 new crystal structures and combined the structural data with powerful multi-scale modeling, which revealed unexpected dynamic processes in a plant enzyme. \"Our study provides a blueprint on enzyme dynamics, which was inaccessible before. \"This means we could potentially improve the properties of the enzyme that are critical to germination and the way the roots grow, leading to higher barley yields, which is crucial in cereal production. \"There are also a variety of other fields that this research could apply across multiple industries and products. \"This work is the result of eight years of research, not only from the School of Agriculture, Food and Wine and the Waite Research Institute, but other institutions in Australia, and also in China, France, Spain and Thailand. \"It has truly been a collaborative effort and one we are extremely proud of, especially when food scarcity is such a critical and important issue around the world. The possibilities that stem from this work are endless.\" Enzymes are essential to life. They significantly increase the rate of a chemical reaction without undergoing any permanent chemical change to themselves. But when enzymes convert, the substances with which an enzyme operates move in and out from the enzyme at high speed. This process inhibits the investigation of these interactions using standard experimental techniques—a problem that brought to light using this multidisciplinary approach. \"This work could lead to significant improvements in catalytic rates, stability, and product inhibition in these enzymes,\" said Emerita Professor Hrmova. \"The new findings are applicable for developing or manufacturing products through new forms of bioengineered enzymes that could be applied outside of biological systems through the chemical and biotechnology industries.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In the barley β- d -glucan glucohydrolase, a glycoside hydrolase family 3 (GH3) enzyme, the Trp286/Trp434 clamp ensures β- d -glucosides binding, which is fundamental for substrate hydrolysis during plant growth and development. We employ mutagenesis, high-resolution X-ray crystallography, and multi-scale molecular modelling methods to examine the binding and conformational behaviour of isomeric β- d -glucosides during substrate-product assisted processive catalysis that operates in GH3 hydrolases. Enzyme kinetics reveals that the W434H mutant retains broad specificity, while W434A behaves as a strict (1,3)-β- d -glucosidase. Investigations of reactant movements on the nanoscale reveal that processivity is sensitive to mutation-specific alterations of the tryptophan clamp. While wild-type and W434H utilise a lateral cavity for glucose displacement and sliding of (1,3)-linked hydrolytic products through the catalytic site without dissociation, consistent with their high hydrolytic rates, W434A does not adopt processive catalysis. Phylogenomic analyses of GH3 hydrolases disclose the evolutionary advantage of the tryptophan clamp that confers broad specificity, high catalytic efficiency, and processivity. Introduction The barley ( Hordeum vulgare L.) β- d -glucan glucohydrolase HvExoI is the only plant family 3 glycoside hydrolase (GH3) for which the atomic structure is available 1 , 2 , 3 , although the Carbohydrate-Active Enzymes CAZy database 4 lists nearly 48,400 GH3 entries (August 2022) from archaea, bacteria, fungi, and eukaryotes, including economically important plants Triticum , Oryza, Glycine, Zea , Brassica , Medicago , Phaseolus , and Solanum . HvExoI folds into a two-domain structure consisting of an (α/β) 8 barrel (domain 1) and an (α/β) 6 sandwich (domain 2) with a 13 Å-deep active site pocket embracing the subsites −1 and +1, positioned at the interface between the two domains. At the −1 subsite, the pocket contains the catalytic nucleophile Asp285 and the acid/base catalyst Glu491, while the +1 subsite is shaped in a clamp with a coin slot formed by the Trp286 and Trp434 residues that hold β- d -glucosides entering the active site in a productive mode for hydrolysis 1 , 2 , 3 , 5 (Fig. 1a, b ). HvExoI catalyses the hydrolytic removal of nonreducing glucose (Glc) moiety from a broad spectrum of poly- and oligomeric β- d -glucosides. This hydrolytic reaction underpins a vital role of HvExoI during plant growth and development, to participate during e.g . primary root extension and the recycling of mixed-linkage (1,4;1,3)-β- d -glucans during germination and root elongation 1 , 3 , 6 . The capacity of HvExoI to hydrolyse a panel of β- d -glucosides was rationalised from the observation that non-reducing Glc at the −1 subsite is locked into a fixed position through a network of hydrogen bonds (H-bonds), while the reducing Glc moiety at the +1 subsite is constrained through stacking interactions, and thus the flexibility of attached substrates and their projection is unencumbered allowing HvExoI to accommodate isomeric (1,2)-, (1,3)-, (1,4)- and (1,6)-linked β- d -glucosides 2 , 3 . It was estimated that the strength of binding through aromatic residues could be in the range of 2-5 kcal/mol 7 . Fig. 1: Exo-hydrolytic enzymes of the GH3 family with an entrapped Glc molecule and a ligand-free form, and their phylogeny. a Hordeum vulgare HvExoI with entrapped Glc (PDB 3WLH; atomic colours), Bacteroides ovatus β-glucosidase with perfused Glc (PDB 5JP0; green cpk), and a ligand-free form of Pseudoalteromonas sp. exo-(1,4;1,3)-β-glucanase (PDB 3UT0; yellow cpk). Distances ached of HvExoI residues to Glc in the −1 subsite (black dashes) are within 3.3 Å. HvExoI and structurally equivalent residues in 3UT0 and 5JP0 superpose with respective RMSD values of 0.7 Å and 1.2 Å. b Surface morphology of the active site pocket of HvExoI coloured by an electrostatic potential: white, neutral; red, −5 kT·e −1 . Separations (dashed lines) between Glc and key interacting residues are within 3.3 Å. The positions of the −1 subsites in panels a and b are indicated. c Unrooted phylogenetic tree of representative GH3 family members (accession numbers listed in Supplementary Table 1 ) revealed the presence of four major clades with five activities [β -d -glucan glucohydrolases (EC 3.2.1.-), β -d -glucosidases (EC 3.2.1.21), β-N-acetylhexosaminidases (EC 3.2.1.52), β -d -xylosidases (EC 3.2.1.37), and α- l -arabinofuranosidases (EC 3.2.1.55)]. In β -d -glucan glucohydrolases, three subclades were identified with residue variability in the aromatic clamp (residue numbering corresponding to HvExoI; PDB 1EX1). The percentage of replicate trees with taxa clustering together in the bootstrap test (1000 replicates) are shown at node bipartitions. Full size image Since the HvExoI structure was elucidated 1 , 2 , 3 , many prokaryotic, fungal and unclassified metagenome GH3 structures have become available but provided little information on the substrate specificity of this class of enzymes. These include two-domain bacterial β-N-acetylglucosaminidases, for example, from Bacillus subtilis 8 , and a β-N-acetylhexosaminidase from Salmonella typhimurium 9 , while a β-hexosaminidase from Burkholderia cenocepacia 10 folds into a single-domain (α/β) 8 sandwich structure. Several three-domain architectures consisting of an (α/β) 8 barrel, an (α/β) 6 sandwich, and another β-sandwich domain were revealed in β-glucosidases from Thermotoga neapolitana 11 , Hypocrea jecorina 12 and Aspergillus aculeatus 13 , in a β-N-acetylglucosaminidase from Thermotoga neapolitana 14 , in a (1,4;1,3)-β-exo-glucanase from Pseudoalteromonas sp. BB1 15 , and in a β-glucosidase JMB19063 isolated from metagenome 16 . These additional β-sandwich domains are described as fibronectin type III or Ig-like β-sandwich folds and have similar architectures. Four-domains structures consisting of (α/β) 8 barrel, an (α/β) 6 sandwich, and two β-sandwich domain folds (PA14 and fibronectin type III) were identified in the β-glucosidases from Kluyveromyces marxianus 17 , Aspergillus fumigatus, A. oryzae 18 and Streptomyces venezuelae 19 . The precise roles of these additional β-sandwich domains have not been fully clarified. However, in some GH3 enzymes these domains are thought to be linked to substrate binding and specificity 17 , protein structure stability 14 , 20 , and oligomerisation, meaning that dimerisation is required for catalytic activity 16 . Although the details of the catalytic mechanism in HvExoI were reported 1 , 2 , 3 , 21 , the<|im_end|> <|im_start|>assistant Researchers from the University of Adelaide have uncovered previously unknown properties in a plant enzyme that could lead to advances in cereal production, medical and pharmaceutical industries. The research—published in Nature Communications—also has the potential to be applied to the design of chemicals, drugs, herbicides and pesticides where enzymes are an environmentally friendly and cost-effective alternative to current methods. "We discovered these enzymes are not rigid, as often seen in crystal structures, but are flexible and prone to remarkable changes in shape," said project leader Emerita Professor Maria Hrmova, from The University of Adelaide's School of Agriculture, Food and Wine, and the Waite Research Institute. "This was achieved by examining the binding behavior of sugars in the enzyme at ultra-fast time scales. "We solved 25 new crystal structures and combined the structural data with powerful multi-scale modeling, which revealed unexpected dynamic processes in a plant enzyme. "Our study provides a blueprint on enzyme dynamics, which was inaccessible before. "This means we could potentially improve the properties of the enzyme that are critical to germination and the way the roots grow, leading to higher barley yields, which is crucial in cereal production. "There are also a variety of other fields that this research could apply across multiple industries and products. "This work is the result of eight years of research, not only from the School of Agriculture, Food and Wine and the Waite Research Institute, but other institutions in Australia, and also in China, France, Spain and Thailand. "It has truly been a collaborative effort and one we are extremely proud of, especially when food scarcity is such a critical and important issue around the world. The possibilities that stem from this work are endless." Enzymes are essential to life. They significantly increase the rate of a chemical reaction without undergoing any permanent chemical change to themselves. But when enzymes convert, the substances with which an enzyme operates move in and out from the enzyme at high speed. This process inhibits the investigation of these interactions using standard experimental techniques—a problem that brought to light using this multidisciplinary approach. "This work could lead to significant improvements in catalytic rates, stability, and product inhibition in these enzymes," said Emerita Professor Hrmova. "The new findings are applicable for developing or manufacturing products through new forms of bioengineered enzymes that could be applied outside of biological systems through the chemical and biotechnology industries." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Lantibiotics are a class of peptide antibiotics that contain one or more thioether bonds. The lantibiotic nisin is an antimicrobial peptide that is widely used as a food preservative to combat food-borne pathogens 1 . Nisin contains dehydroalanine and dehydrobutyrine residues that are formed by the dehydration of Ser/Thr by the lantibiotic dehydratase NisB (ref. 2 ). Recent biochemical studies revealed that NisB glutamylates Ser/Thr side chains as part of the dehydration process 3 . However, the molecular mechanism by which NisB uses glutamate to catalyse dehydration remains unresolved. Here we show that this process involves glutamyl-tRNA Glu to activate Ser/Thr residues. In addition, the 2.9-Å crystal structure of NisB in complex with its substrate peptide NisA reveals the presence of two separate domains that catalyse the Ser/Thr glutamylation and glutamate elimination steps. The co-crystal structure also provides insights into substrate recognition by lantibiotic dehydratases. Our findings demonstrate an unexpected role for aminoacyl-tRNA in the formation of dehydroamino acids in lantibiotics, and serve as a basis for the functional characterization of the many lantibiotic-like dehydratases involved in the biosynthesis of other classes of natural products. Main Bacterial resistance to currently used antibiotics is a growing health threat. A potential solution to this emerging problem is the development of new antibiotics with multiple modes of action that would challenge bacterial resistance mechanisms. For instance, the lantibiotic nisin has been used worldwide in the food industry for more than 40 years without substantial development of resistance 1 , 4 . This unique property is thought to be a consequence of nisin’s dual mode of action: pore formation in bacterial cell membranes and stalling of peptidoglycan biosynthesis by sequestering the cell-wall precursor lipid II 5 , 6 , 7 . Lantibiotics are lanthionine-containing antimicrobial peptides 8 . Nisin is generated from a ribosomally synthesized linear precursor peptide termed NisA 9 . The dehydratase NisB then dehydrates eight serines and threonines in the NisA core region, yielding dehydroalanine (Dha) and dehydrobutyrine (Dhb) residues, respectively ( Fig. 1a ) 2 . The cyclase NisC subsequently catalyses the formation of five lanthionine and methyllanthionine crosslinks by the nucleophilic addition of cysteinyl thiols to Dha and Dhb, respectively ( Fig. 1a ) 10 . In the final maturation step, the lantibiotic protease NisP removes a leader peptide, which is important for recognition by NisB and NisC, to yield the mature lantibiotic 11 . Figure 1: Biosynthesis of the lantibiotic nisin. a , Post-translational modifications involved in nisin biosynthesis. b , NisB dehydrates Ser/Thr residues in NisA by glutamylation, forming Dha and Dhb, respectively. NisC catalyses the formation of lanthionines (red) and methyllanthionines (blue). NisP removes the leader peptide. Negative numbers represent the position of an amino acid in the leader peptide with respect to the core region. c – g , MALDI–TOF MS analysis of His 6 –NisA incubated with Glu, ATP and His 6 –NisB in the presence of E. coli cell extract ( c ), His 6 –GluRS and tRNA Glu ( d ), tRNA Glu ( e ), His 6 –GluRS ( f ) or GluRS and tRNA Glu in the absence of His 6 –NisB ( g ). M, unmodified His 6 –NisA ( m / z 7,993, calc. m / z 7,996); 7, sevenfold dehydrated His 6 –NisA ( m / z 7,870, calc. m / z 7,870); 8, eightfold dehydrated His 6 –NisA ( m / z 7,853, calc. m / z 7,852). The asterisk indicates a peak resulting from laser-induced deamination ( Extended Data Fig. 6 ). PowerPoint slide Full size image During the 26 years since the characterization of the first lantibiotic gene cluster 12 , the mechanism by which lantibiotic dehydratases (LanB) introduce dehydroamino acids into class I lantibiotics such as nisin has remained enigmatic. Recently, NisB was shown to dehydrate NisA via an unprecedented glutamylation mechanism ( Fig. 1b ) 3 . However, NisB was only active in the presence of an unknown component within Escherichia coli cell extract 3 . Here we identify glutamyl-tRNA Glu as the key component needed to catalyse the formation of dehydroamino acids in class I lantibiotics. In addition we report the co-crystal structure of NisA bound to NisB, which provides key information on the glutamyl-tRNA Glu -dependent esterification of Ser/Thr residues in NisA and offers the first insights into leader peptide binding and substrate recognition by lantibiotic dehydratases. In the previously proposed dehydration mechanism 3 , glutamate needs to be activated before the formation of an ester linkage with the side chain of Ser/Thr residues in NisA. To identify the required component for activation, anion-exchange chromatographic fractions of E. coli cell extracts were analysed for supporting NisB-catalysed dehydration of NisA by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI–TOF MS) ( Extended Data Fig. 1 ). The A 260 / A 280 ratio for the fraction supporting NisB activity was 1.7, suggesting the presence of nucleic acids. Treatment of E. coli cell extract with DNase did not prevent the NisB-catalysed dehydration of NisA, but treatment with RNase abolished activity ( Extended Data Fig. 1 ). The requirements for glutamate and RNA suggested the possibility of a glutamyl-tRNA Glu -dependent dehydration process. We therefore cloned, expressed and purified glutamyl-tRNA synthetase (GluRS) and tRNA Glu from E. coli. MALDI–TOF MS analysis of NisA after incubation with NisB, Glu, ATP, GluRS and tRNA Glu revealed up to eight dehydrations in NisA ( Fig. 1c, d ). No activity was observed when GluRS, tRNA Glu or NisB was omitted from the reaction assay ( Fig. 1e–g ). The inability of NisB to dehydrate NisA in the absence of GluRS ( Fig. 1e ) demonstrates that NisB does not aminoacylate tRNA Glu but instead uses the glutamyl-tRNA Glu synthesized in situ by GluRS. Dehydration assays with purified glutamyl-tRNA Glu and subsequent MALDI–TOF MS analysis confirmed this conclusion and also showed that ATP was not required for activity ( Extended Data Fig. 2 ). This observation suggests that dehydration of Ser/Thr residues located at different positions", "role": "user" }, { "content": "Researchers report in the journal Nature that they have made a breakthrough in understanding how a powerful antibiotic agent is made in nature. Their discovery solves a decades-old mystery, and opens up new avenues of research into thousands of similar molecules, many of which are likely to be medically useful. The team focused on a class of compounds that includes dozens with antibiotic properties. The most famous of these is nisin, a natural product in milk that can be synthesized in the lab and is added to foods as a preservative. Nisin has been used to combat food-borne pathogens since the late 1960s. Researchers have long known the sequence of the nisin gene, and they can assemble the chain of amino acids (called a peptide) that are encoded by this gene. But the peptide undergoes several modifications in the cell after it is made, changes that give it its final form and function. Researchers have tried for more than 25 years to understand how these changes occur. \"Peptides are a little bit like spaghetti; they're too flexible to do their jobs,\" said University of Illinois chemistry professor Wilfred van der Donk, who led the research with biochemistry professor Satish K. Nair. \"So what nature does is it starts putting knobs in, or starts making the peptide cyclical.\" Special enzymes do this work. For nisin, an enzyme called a dehydratase removes water to help give the antibiotic its final, three-dimensional shape. This is the first step in converting the spaghetti-like peptide into a five-ringed structure, van der Donk said. The rings are essential to nisin's antibiotic function: Two of them disrupt the construction of bacterial cell walls, while the other three punch holes in bacterial membranes. This dual action is especially effective, making it much more difficult for microbes to evolve resistance to the antibiotic. Previous studies showed that the dehydratase was involved in making these modifications, but researchers have been unable to determine how it did so. This lack of insight has prevented the discovery, production and study of dozens of similar compounds that also could be useful in fighting food-borne diseases or dangerous microbial infections, van der Donk said. Through a painstaking process of elimination, Manuel Ortega, a graduate student in van der Donk's lab, established that the amino acid glutamate was essential to nisin's transformation. \"They discovered that the dehydratase did two things,\" Nair said. \"One is that it added glutamate (to the nisin peptide), and the second thing it did was it eliminated glutamate. But how does one enzyme have two different activities?\" To help answer this question, Yue Hao, a graduate student in Nair's lab, used X-ray crystallography to visualize how the dehydratase bound to the nisin peptide. She found that the enzyme interacted with the peptide in two ways: It grasped one part of the peptide and held it fast, while a different part of the dehydratase helped install the ring structures. \"There's a part of the nisin precursor peptide that is held steady, and there's a part that is flexible. And the flexible part is actually where the chemistry is carried out,\" Nair said. Ortega also made another a surprising discovery: transfer-RNA, a molecule best known for its role in protein production, supplies the glutamate that allows the dehydratase to help shape the nisin into its final, active form. \"In this study, we solve a lot of questions that people have had about how dehydration works on a chemical level,\" van der Donk said. \"And it turns out that in nature a fairly large number of natural products – many of them with therapeutic potential – are made in a similar fashion. This really is like turning on a light where it was dark before, and now we and other labs can do all kinds of things that we couldn't do previously.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Lantibiotics are a class of peptide antibiotics that contain one or more thioether bonds. The lantibiotic nisin is an antimicrobial peptide that is widely used as a food preservative to combat food-borne pathogens 1 . Nisin contains dehydroalanine and dehydrobutyrine residues that are formed by the dehydration of Ser/Thr by the lantibiotic dehydratase NisB (ref. 2 ). Recent biochemical studies revealed that NisB glutamylates Ser/Thr side chains as part of the dehydration process 3 . However, the molecular mechanism by which NisB uses glutamate to catalyse dehydration remains unresolved. Here we show that this process involves glutamyl-tRNA Glu to activate Ser/Thr residues. In addition, the 2.9-Å crystal structure of NisB in complex with its substrate peptide NisA reveals the presence of two separate domains that catalyse the Ser/Thr glutamylation and glutamate elimination steps. The co-crystal structure also provides insights into substrate recognition by lantibiotic dehydratases. Our findings demonstrate an unexpected role for aminoacyl-tRNA in the formation of dehydroamino acids in lantibiotics, and serve as a basis for the functional characterization of the many lantibiotic-like dehydratases involved in the biosynthesis of other classes of natural products. Main Bacterial resistance to currently used antibiotics is a growing health threat. A potential solution to this emerging problem is the development of new antibiotics with multiple modes of action that would challenge bacterial resistance mechanisms. For instance, the lantibiotic nisin has been used worldwide in the food industry for more than 40 years without substantial development of resistance 1 , 4 . This unique property is thought to be a consequence of nisin’s dual mode of action: pore formation in bacterial cell membranes and stalling of peptidoglycan biosynthesis by sequestering the cell-wall precursor lipid II 5 , 6 , 7 . Lantibiotics are lanthionine-containing antimicrobial peptides 8 . Nisin is generated from a ribosomally synthesized linear precursor peptide termed NisA 9 . The dehydratase NisB then dehydrates eight serines and threonines in the NisA core region, yielding dehydroalanine (Dha) and dehydrobutyrine (Dhb) residues, respectively ( Fig. 1a ) 2 . The cyclase NisC subsequently catalyses the formation of five lanthionine and methyllanthionine crosslinks by the nucleophilic addition of cysteinyl thiols to Dha and Dhb, respectively ( Fig. 1a ) 10 . In the final maturation step, the lantibiotic protease NisP removes a leader peptide, which is important for recognition by NisB and NisC, to yield the mature lantibiotic 11 . Figure 1: Biosynthesis of the lantibiotic nisin. a , Post-translational modifications involved in nisin biosynthesis. b , NisB dehydrates Ser/Thr residues in NisA by glutamylation, forming Dha and Dhb, respectively. NisC catalyses the formation of lanthionines (red) and methyllanthionines (blue). NisP removes the leader peptide. Negative numbers represent the position of an amino acid in the leader peptide with respect to the core region. c – g , MALDI–TOF MS analysis of His 6 –NisA incubated with Glu, ATP and His 6 –NisB in the presence of E. coli cell extract ( c ), His 6 –GluRS and tRNA Glu ( d ), tRNA Glu ( e ), His 6 –GluRS ( f ) or GluRS and tRNA Glu in the absence of His 6 –NisB ( g ). M, unmodified His 6 –NisA ( m / z 7,993, calc. m / z 7,996); 7, sevenfold dehydrated His 6 –NisA ( m / z 7,870, calc. m / z 7,870); 8, eightfold dehydrated His 6 –NisA ( m / z 7,853, calc. m / z 7,852). The asterisk indicates a peak resulting from laser-induced deamination ( Extended Data Fig. 6 ). PowerPoint slide Full size image During the 26 years since the characterization of the first lantibiotic gene cluster 12 , the mechanism by which lantibiotic dehydratases (LanB) introduce dehydroamino acids into class I lantibiotics such as nisin has remained enigmatic. Recently, NisB was shown to dehydrate NisA via an unprecedented glutamylation mechanism ( Fig. 1b ) 3 . However, NisB was only active in the presence of an unknown component within Escherichia coli cell extract 3 . Here we identify glutamyl-tRNA Glu as the key component needed to catalyse the formation of dehydroamino acids in class I lantibiotics. In addition we report the co-crystal structure of NisA bound to NisB, which provides key information on the glutamyl-tRNA Glu -dependent esterification of Ser/Thr residues in NisA and offers the first insights into leader peptide binding and substrate recognition by lantibiotic dehydratases. In the previously proposed dehydration mechanism 3 , glutamate needs to be activated before the formation of an ester linkage with the side chain of Ser/Thr residues in NisA. To identify the required component for activation, anion-exchange chromatographic fractions of E. coli cell extracts were analysed for supporting NisB-catalysed dehydration of NisA by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI–TOF MS) ( Extended Data Fig. 1 ). The A 260 / A 280 ratio for the fraction supporting NisB activity was 1.7, suggesting the presence of nucleic acids. Treatment of E. coli cell extract with DNase did not prevent the NisB-catalysed dehydration of NisA, but treatment with RNase abolished activity ( Extended Data Fig. 1 ). The requirements for glutamate and RNA suggested the possibility of a glutamyl-tRNA Glu -dependent dehydration process. We therefore cloned, expressed and purified glutamyl-tRNA synthetase (GluRS) and tRNA Glu from E. coli. MALDI–TOF MS analysis of NisA after incubation with NisB, Glu, ATP, GluRS and tRNA Glu revealed up to eight dehydrations in NisA ( Fig. 1c, d ). No activity was observed when GluRS, tRNA Glu or NisB was omitted from the reaction assay ( Fig. 1e–g ). The inability of NisB to dehydrate NisA in the absence of GluRS ( Fig. 1e ) demonstrates that NisB does not aminoacylate tRNA Glu but instead uses the glutamyl-tRNA Glu synthesized in situ by GluRS. Dehydration assays with purified glutamyl-tRNA Glu and subsequent MALDI–TOF MS analysis confirmed this conclusion and also showed that ATP was not required for activity ( Extended Data Fig. 2 ). This observation suggests that dehydration of Ser/Thr residues located at different positions<|im_end|> <|im_start|>assistant Researchers report in the journal Nature that they have made a breakthrough in understanding how a powerful antibiotic agent is made in nature. Their discovery solves a decades-old mystery, and opens up new avenues of research into thousands of similar molecules, many of which are likely to be medically useful. The team focused on a class of compounds that includes dozens with antibiotic properties. The most famous of these is nisin, a natural product in milk that can be synthesized in the lab and is added to foods as a preservative. Nisin has been used to combat food-borne pathogens since the late 1960s. Researchers have long known the sequence of the nisin gene, and they can assemble the chain of amino acids (called a peptide) that are encoded by this gene. But the peptide undergoes several modifications in the cell after it is made, changes that give it its final form and function. Researchers have tried for more than 25 years to understand how these changes occur. "Peptides are a little bit like spaghetti; they're too flexible to do their jobs," said University of Illinois chemistry professor Wilfred van der Donk, who led the research with biochemistry professor Satish K. Nair. "So what nature does is it starts putting knobs in, or starts making the peptide cyclical." Special enzymes do this work. For nisin, an enzyme called a dehydratase removes water to help give the antibiotic its final, three-dimensional shape. This is the first step in converting the spaghetti-like peptide into a five-ringed structure, van der Donk said. The rings are essential to nisin's antibiotic function: Two of them disrupt the construction of bacterial cell walls, while the other three punch holes in bacterial membranes. This dual action is especially effective, making it much more difficult for microbes to evolve resistance to the antibiotic. Previous studies showed that the dehydratase was involved in making these modifications, but researchers have been unable to determine how it did so. This lack of insight has prevented the discovery, production and study of dozens of similar compounds that also could be useful in fighting food-borne diseases or dangerous microbial infections, van der Donk said. Through a painstaking process of elimination, Manuel Ortega, a graduate student in van der Donk's lab, established that the amino acid glutamate was essential to nisin's transformation. "They discovered that the dehydratase did two things," Nair said. "One is that it added glutamate (to the nisin peptide), and the second thing it did was it eliminated glutamate. But how does one enzyme have two different activities?" To help answer this question, Yue Hao, a graduate student in Nair's lab, used X-ray crystallography to visualize how the dehydratase bound to the nisin peptide. She found that the enzyme interacted with the peptide in two ways: It grasped one part of the peptide and held it fast, while a different part of the dehydratase helped install the ring structures. "There's a part of the nisin precursor peptide that is held steady, and there's a part that is flexible. And the flexible part is actually where the chemistry is carried out," Nair said. Ortega also made another a surprising discovery: transfer-RNA, a molecule best known for its role in protein production, supplies the glutamate that allows the dehydratase to help shape the nisin into its final, active form. "In this study, we solve a lot of questions that people have had about how dehydration works on a chemical level," van der Donk said. "And it turns out that in nature a fairly large number of natural products – many of them with therapeutic potential – are made in a similar fashion. This really is like turning on a light where it was dark before, and now we and other labs can do all kinds of things that we couldn't do previously." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Non-volatile magnetic random-access memories (MRAMs), such as spin-transfer torque MRAM and next-generation spin–orbit torque MRAM, are emerging as key to enabling low-power technologies, which are expected to spread over large markets from embedded memories to the Internet of Things. Concurrently, the development and performances of devices based on two-dimensional van der Waals heterostructures bring ultracompact multilayer compounds with unprecedented material-engineering capabilities. Here we provide an overview of the current developments and challenges in regard to MRAM, and then outline the opportunities that can arise by incorporating two-dimensional material technologies. We highlight the fundamental properties of atomically smooth interfaces, the reduced material intermixing, the crystal symmetries and the proximity effects as the key drivers for possible disruptive improvements for MRAM at advanced technology nodes. Main Emerging technologies generally follow a hype cycle before reaching the mature production stage. When NAND flash memory was first commercialized in 1989, it competed against conventional non-volatile memories such as electrically erasable programmable read-only memory 1 . Even when its market size reached over US$1.8 billion in 1995, the semiconductor industry was still uncertain about the full potential of this technology. However, new applications such as MP3 players and smart phones, which rapidly increased end-use demands, fuelled NAND flash development to reduce the cost per bit, resulting in three-dimensional (3D) NAND flash innovation 2 . Mobility and miniaturization trends in consumer electronics have continuously driven the NAND flash market, which reached over US$50 billion in 2020 3 . In contrast, although the potential of spintronic memories in terms of low power and speed is proven, they are still emerging in terms of market size. The most advanced emerging generation of magnetic random-access memory (MRAM), based on the spin-transfer-torque mechanism (Fig. 1 ), is already addressing a few market segments. However, it is envisioned that, in the near future, the MRAM market will expand significantly by addressing the power and data-transfer (memory-wall bottleneck) challenges in a variety of embedded applications, including neural networks and in-memory computing 4 , 5 . Considering that the embedded emerging non-volatile memory market is forecasted to grow from US$20 million in 2019 to US$2.5 billion by 2025 6 , it could well drive MRAM growth, like mobile consumer electronics has driven NAND flash growth in the past. To achieve such growth, MRAM technology must meet a variety of challenges that require material and device integration breakthroughs, in which two-dimensional materials (2DMs) could play a key role. Fig. 1: State-of-the-art MRAM technologies. a , b , Schematics of STT-MRAM ( a ) and SOT-MRAM ( b ) cells with PMA. c , Bottom-pinned STT-MTJ sketch and transmission electron microscopy (TEM) cross-section of a 45-nm-diameter STT-MTJ consisting of a CoFeB free layer (FL), a MgO tunnel barrier and a CoFeB/spacer/Co/Ru/[Co/Pt] reference layer (RL). Inset: TEM cross-section of an STT-MRAM array (top dashed box) controlled by CMOS (bottom dashed box). d , Top-pinned SOT-MTJ sketch and TEM cross-section of a 60-nm SOT-MTJ. Inset: a typical SOT-MRAM cell where the write current is injected from bottom electrode BE1 to BE2, and the read current from the top electrode (TE) to BE2. Full size image Indeed, since the discovery of graphene, followed by an ever-growing family of related materials 7 , 2DMs have emerged as potential enablers for potentially ultracompact device architectures or radically new concepts for spin information processing 8 , 9 . Scientific advances of 2DM-based spintronic devices, as well as recent progress in large-scale co-integration of 2DMs with conventional microelectronics materials 10 , 11 , have opened a promising perspective for developing innovative MRAM technology. Here we provide an overview of the most recent developments, identify challenges and opportunities brought by 2DMs for MRAM, and give a vision of how progress in 2DMs research could morph into a game-changing solution for future generations of spintronic-memory technologies. We first describe fundamental MRAM concepts and the prospects for MRAM commercialization, including the main roadblocks for broader deployment. We then highlight the unique opportunities brought by 2DMs and van der Waals (vdW) heterostructures to overcome some of the technological challenges. Afterwards, we analyse the requirements and challenges for further advances concerning growth, processing and integration of 2DMs to enable an impact in next-generation spintronic-memory development. Finally, an outlook provides a vision of 2DM-MRAM technologies. STT-MRAM and next-generation SOT-MRAM Non-volatile MRAM technologies are built on magnetic tunnel junctions (MTJs) composed of two ferromagnetic (FM) layers separated by a thin insulator. One of the FM layers, known as the free layer (FL), stores information, whereas the other layer, the reference layer (RL), provides a stable reference for reading the FL information. Two main technologies relying on electrically generated spin currents have emerged to control the FL magnetization: spin-transfer torque (STT) 12 and spin–orbit torque (SOT) 13 . The STT concept was first introduced in 1996 14 , 15 and implemented at STT-MRAM chip level in 2005 16 . STT is observed in a two-terminal geometry, in which a vertical current is injected through the MTJ (Fig. 1a ). The current tunnelling through the barrier is spin-polarized, leading to the FL magnetization reversal for large enough currents, owing to the transfer of angular momentum. The relative magnetization orientation of the FL and RL layers determines the resistance of the device, which is monitored by the tunnelling magnetoresistance (TMR). SOT-MRAM is based on three-terminal devices, where an additional conducting path is added adjacent to the FL (Fig. 1b ). A charge current flowing through this path results in the injection of a spin-polarized current into the FL in virtue of the spin-Hall and/or Rashba–Edelstein effect 13 , 17 , 18 , 19 . In such devices, SOT can switch the FL magnetization without passing a current through the MTJ tunnel barrier. At the expense of adding another terminal, the decoupling of the write and read current paths prevents write errors during read operation and reduces the risk of voltage breakdown. It further enables versatile cell designs by allowing the spin torque direction to be set independently of the anisotropy direction", "role": "user" }, { "content": "Non-volatile memories—which are able to retain information even when power is removed—are largely employed in computers, tablets, pen drives and many other electronic devices. Among the various existing technologies, magnetoresistive random-access memories (MRAM), currently used only in specific applications, are expected to expand considerably on the market in the decade to come. The newest MRAMs based on spintronic mechanisms—i.e., phenomena related to the spin, which is an intrinsic property of electrons and other particles—can offer faster operations, lower power consumption and long retention time, with potential applications in wearable devices, automotive industry, and the Internet of Things, among others. In this context, graphene and other 2D materials, which are as thin as one or very few atomic layers, may play a disruptive role. In fact, their peculiar and remarkable characteristics can provide solutions to current technological challenges and performance limitations that prevent further efficient deployment of MRAMs; therefore, they can have a strong impact on the design of next-generation spintronic devices. The expected enhancement and new opportunities that can arise from the introduction of 2D materials into spin-based memory technologies are presented in a perspective article, published last week in Nature. This work, led by the Catalan Institute of Nanoscience and Nanotechnology (ICN2) at the Universitat Autònoma de Barcelona (UAB) campus, and the National University of Singapore, provides an overview of the state of the art of the field and of the current challenges being faced in the development of non-volatile memories in general, and specifically, of those employing spintronic mechanisms such as spin-transfer torque (STT) and spin-orbit torque (SOT). The authors discuss the advantages that the co-integration of 2D materials in these technologies introduces, giving a panoramic of the improvements already achieved as well as a prospect of the many advances that further research can produce. A possible timeline of progress during the next decade is also traced. \"As thoroughly discussed in the paper,\" comments ICREA professor Stephan Roche, group leader at the ICN2 and leader of the Graphene Flagship Work Package dedicated to Spintronics, \"the fundamental properties of 2D materials such as atomically smooth interfaces, reduced material intermixing, crystal symmetries, and proximity effects are the drivers for possible disruptive improvements for spin-based MRAMs. These are emerging as key enabling low-power technologies and are expected to spread over large markets from embedded memories to the Internet of Things.\" This research was coordinated by ICN2 group leaders and ICREA professors Prof. Stephan Roche and Prof. Sergio O. Valenzuela, and by Prof. Hyunsoo Yang from the National University of Singapore. It was carried out by a collaboration of various members of the Graphene Flagship project consortium, including various institutes of the Centre national de la recherche scientifique (CNRS, France), Imec (Belgium), Thales Research and Technology (France), and the French Atomic Energy Commission (CEA), as well as key industries such as Samsung Electronics (South Korea) and Global Foundries (Singapore), which bring the vision of future market integration. \"It is impressive to observe the scientific results achieved by the spintronics work package and the technology activities carried out in the Imec environment, together with SMEs (Singulus Technologies, GRAPHENEA), which pave the way towards future impact on market applications,\" states Prof. Jari Kinaret, Director of the Graphene Flagship. \"There are still challenges to be overcome to fully deploy the potential of 2D materials in real-life applications, but the expected industrial and economic benefits are very high.\" \"Funding efforts made by the European Commission to support the Graphene Flagship activities could position Europe at the lead of innovation spintronic technologies in a decade timescale,\" adds Prof. Andrea Ferrari, Science and Technology Officer of the Graphene Flagship. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Non-volatile magnetic random-access memories (MRAMs), such as spin-transfer torque MRAM and next-generation spin–orbit torque MRAM, are emerging as key to enabling low-power technologies, which are expected to spread over large markets from embedded memories to the Internet of Things. Concurrently, the development and performances of devices based on two-dimensional van der Waals heterostructures bring ultracompact multilayer compounds with unprecedented material-engineering capabilities. Here we provide an overview of the current developments and challenges in regard to MRAM, and then outline the opportunities that can arise by incorporating two-dimensional material technologies. We highlight the fundamental properties of atomically smooth interfaces, the reduced material intermixing, the crystal symmetries and the proximity effects as the key drivers for possible disruptive improvements for MRAM at advanced technology nodes. Main Emerging technologies generally follow a hype cycle before reaching the mature production stage. When NAND flash memory was first commercialized in 1989, it competed against conventional non-volatile memories such as electrically erasable programmable read-only memory 1 . Even when its market size reached over US$1.8 billion in 1995, the semiconductor industry was still uncertain about the full potential of this technology. However, new applications such as MP3 players and smart phones, which rapidly increased end-use demands, fuelled NAND flash development to reduce the cost per bit, resulting in three-dimensional (3D) NAND flash innovation 2 . Mobility and miniaturization trends in consumer electronics have continuously driven the NAND flash market, which reached over US$50 billion in 2020 3 . In contrast, although the potential of spintronic memories in terms of low power and speed is proven, they are still emerging in terms of market size. The most advanced emerging generation of magnetic random-access memory (MRAM), based on the spin-transfer-torque mechanism (Fig. 1 ), is already addressing a few market segments. However, it is envisioned that, in the near future, the MRAM market will expand significantly by addressing the power and data-transfer (memory-wall bottleneck) challenges in a variety of embedded applications, including neural networks and in-memory computing 4 , 5 . Considering that the embedded emerging non-volatile memory market is forecasted to grow from US$20 million in 2019 to US$2.5 billion by 2025 6 , it could well drive MRAM growth, like mobile consumer electronics has driven NAND flash growth in the past. To achieve such growth, MRAM technology must meet a variety of challenges that require material and device integration breakthroughs, in which two-dimensional materials (2DMs) could play a key role. Fig. 1: State-of-the-art MRAM technologies. a , b , Schematics of STT-MRAM ( a ) and SOT-MRAM ( b ) cells with PMA. c , Bottom-pinned STT-MTJ sketch and transmission electron microscopy (TEM) cross-section of a 45-nm-diameter STT-MTJ consisting of a CoFeB free layer (FL), a MgO tunnel barrier and a CoFeB/spacer/Co/Ru/[Co/Pt] reference layer (RL). Inset: TEM cross-section of an STT-MRAM array (top dashed box) controlled by CMOS (bottom dashed box). d , Top-pinned SOT-MTJ sketch and TEM cross-section of a 60-nm SOT-MTJ. Inset: a typical SOT-MRAM cell where the write current is injected from bottom electrode BE1 to BE2, and the read current from the top electrode (TE) to BE2. Full size image Indeed, since the discovery of graphene, followed by an ever-growing family of related materials 7 , 2DMs have emerged as potential enablers for potentially ultracompact device architectures or radically new concepts for spin information processing 8 , 9 . Scientific advances of 2DM-based spintronic devices, as well as recent progress in large-scale co-integration of 2DMs with conventional microelectronics materials 10 , 11 , have opened a promising perspective for developing innovative MRAM technology. Here we provide an overview of the most recent developments, identify challenges and opportunities brought by 2DMs for MRAM, and give a vision of how progress in 2DMs research could morph into a game-changing solution for future generations of spintronic-memory technologies. We first describe fundamental MRAM concepts and the prospects for MRAM commercialization, including the main roadblocks for broader deployment. We then highlight the unique opportunities brought by 2DMs and van der Waals (vdW) heterostructures to overcome some of the technological challenges. Afterwards, we analyse the requirements and challenges for further advances concerning growth, processing and integration of 2DMs to enable an impact in next-generation spintronic-memory development. Finally, an outlook provides a vision of 2DM-MRAM technologies. STT-MRAM and next-generation SOT-MRAM Non-volatile MRAM technologies are built on magnetic tunnel junctions (MTJs) composed of two ferromagnetic (FM) layers separated by a thin insulator. One of the FM layers, known as the free layer (FL), stores information, whereas the other layer, the reference layer (RL), provides a stable reference for reading the FL information. Two main technologies relying on electrically generated spin currents have emerged to control the FL magnetization: spin-transfer torque (STT) 12 and spin–orbit torque (SOT) 13 . The STT concept was first introduced in 1996 14 , 15 and implemented at STT-MRAM chip level in 2005 16 . STT is observed in a two-terminal geometry, in which a vertical current is injected through the MTJ (Fig. 1a ). The current tunnelling through the barrier is spin-polarized, leading to the FL magnetization reversal for large enough currents, owing to the transfer of angular momentum. The relative magnetization orientation of the FL and RL layers determines the resistance of the device, which is monitored by the tunnelling magnetoresistance (TMR). SOT-MRAM is based on three-terminal devices, where an additional conducting path is added adjacent to the FL (Fig. 1b ). A charge current flowing through this path results in the injection of a spin-polarized current into the FL in virtue of the spin-Hall and/or Rashba–Edelstein effect 13 , 17 , 18 , 19 . In such devices, SOT can switch the FL magnetization without passing a current through the MTJ tunnel barrier. At the expense of adding another terminal, the decoupling of the write and read current paths prevents write errors during read operation and reduces the risk of voltage breakdown. It further enables versatile cell designs by allowing the spin torque direction to be set independently of the anisotropy direction<|im_end|> <|im_start|>assistant Non-volatile memories—which are able to retain information even when power is removed—are largely employed in computers, tablets, pen drives and many other electronic devices. Among the various existing technologies, magnetoresistive random-access memories (MRAM), currently used only in specific applications, are expected to expand considerably on the market in the decade to come. The newest MRAMs based on spintronic mechanisms—i.e., phenomena related to the spin, which is an intrinsic property of electrons and other particles—can offer faster operations, lower power consumption and long retention time, with potential applications in wearable devices, automotive industry, and the Internet of Things, among others. In this context, graphene and other 2D materials, which are as thin as one or very few atomic layers, may play a disruptive role. In fact, their peculiar and remarkable characteristics can provide solutions to current technological challenges and performance limitations that prevent further efficient deployment of MRAMs; therefore, they can have a strong impact on the design of next-generation spintronic devices. The expected enhancement and new opportunities that can arise from the introduction of 2D materials into spin-based memory technologies are presented in a perspective article, published last week in Nature. This work, led by the Catalan Institute of Nanoscience and Nanotechnology (ICN2) at the Universitat Autònoma de Barcelona (UAB) campus, and the National University of Singapore, provides an overview of the state of the art of the field and of the current challenges being faced in the development of non-volatile memories in general, and specifically, of those employing spintronic mechanisms such as spin-transfer torque (STT) and spin-orbit torque (SOT). The authors discuss the advantages that the co-integration of 2D materials in these technologies introduces, giving a panoramic of the improvements already achieved as well as a prospect of the many advances that further research can produce. A possible timeline of progress during the next decade is also traced. "As thoroughly discussed in the paper," comments ICREA professor Stephan Roche, group leader at the ICN2 and leader of the Graphene Flagship Work Package dedicated to Spintronics, "the fundamental properties of 2D materials such as atomically smooth interfaces, reduced material intermixing, crystal symmetries, and proximity effects are the drivers for possible disruptive improvements for spin-based MRAMs. These are emerging as key enabling low-power technologies and are expected to spread over large markets from embedded memories to the Internet of Things." This research was coordinated by ICN2 group leaders and ICREA professors Prof. Stephan Roche and Prof. Sergio O. Valenzuela, and by Prof. Hyunsoo Yang from the National University of Singapore. It was carried out by a collaboration of various members of the Graphene Flagship project consortium, including various institutes of the Centre national de la recherche scientifique (CNRS, France), Imec (Belgium), Thales Research and Technology (France), and the French Atomic Energy Commission (CEA), as well as key industries such as Samsung Electronics (South Korea) and Global Foundries (Singapore), which bring the vision of future market integration. "It is impressive to observe the scientific results achieved by the spintronics work package and the technology activities carried out in the Imec environment, together with SMEs (Singulus Technologies, GRAPHENEA), which pave the way towards future impact on market applications," states Prof. Jari Kinaret, Director of the Graphene Flagship. "There are still challenges to be overcome to fully deploy the potential of 2D materials in real-life applications, but the expected industrial and economic benefits are very high." "Funding efforts made by the European Commission to support the Graphene Flagship activities could position Europe at the lead of innovation spintronic technologies in a decade timescale," adds Prof. Andrea Ferrari, Science and Technology Officer of the Graphene Flagship. <|im_end|>

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323, 37843, 6372, 527, 279, 12050, 369, 3284, 62642, 18637, 369, 12903, 6108, 29433, 1428, 82, 13, 4314, 527, 24084, 439, 1401, 28462, 3428, 27624, 14645, 323, 527, 3685, 311, 9041, 927, 3544, 11987, 505, 23711, 19459, 311, 279, 8191, 315, 20695, 1210, 1115, 3495, 574, 47672, 555, 19845, 45, 17, 1912, 6164, 323, 358, 9614, 32, 45724, 8626, 13, 39464, 12093, 1557, 323, 8626, 13, 66294, 507, 13, 4196, 17007, 24669, 11, 323, 555, 8626, 13, 10320, 359, 708, 78, 25482, 505, 279, 5165, 3907, 315, 21181, 13, 1102, 574, 11953, 704, 555, 264, 20632, 315, 5370, 3697, 315, 279, 12441, 1994, 23497, 5383, 2447, 75094, 11, 2737, 5370, 94812, 315, 279, 14821, 5426, 409, 1208, 38317, 7330, 52760, 320, 29768, 11706, 11, 9822, 705, 2417, 762, 320, 22404, 90339, 705, 666, 3916, 8483, 323, 12053, 320, 50100, 705, 323, 279, 8753, 31416, 12634, 9849, 320, 2152, 32, 705, 439, 1664, 439, 1401, 19647, 1778, 439, 18907, 38784, 320, 26070, 12126, 8, 323, 8121, 12595, 4108, 320, 92928, 705, 902, 4546, 279, 11376, 315, 3938, 3157, 18052, 13, 330, 2181, 374, 16358, 311, 23846, 279, 12624, 3135, 17427, 555, 279, 12903, 35785, 1233, 990, 6462, 323, 279, 5557, 7640, 11953, 704, 304, 279, 2417, 762, 4676, 11, 3871, 449, 79867, 82, 320, 60300, 19990, 25579, 11, 69736, 965, 19657, 705, 902, 94123, 279, 1648, 7119, 3938, 5536, 389, 3157, 8522, 1359, 5415, 8626, 13, 622, 2850, 31991, 11554, 11, 10783, 315, 279, 12441, 1994, 23497, 5383, 13, 330, 3947, 527, 2103, 11774, 311, 387, 23075, 311, 7373, 10739, 279, 4754, 315, 220, 17, 35, 7384, 304, 1972, 26928, 8522, 11, 719, 279, 3685, 13076, 323, 7100, 7720, 527, 1633, 1579, 1210, 330, 37, 38289, 9045, 1903, 555, 279, 7665, 9849, 311, 1862, 279, 12441, 1994, 23497, 5383, 7640, 1436, 2361, 4606, 520, 279, 3063, 315, 19297, 12903, 376, 14338, 14645, 304, 264, 13515, 3115, 2296, 1359, 11621, 8626, 13, 41184, 46853, 11, 10170, 323, 12053, 20148, 315, 279, 12441, 1994, 23497, 5383, 13, 220, 128257, 198 ]

2,265

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objective To forecast dementia prevalence with a dynamic modelling approach that integrates calendar trends in dementia incidence with those for mortality and cardiovascular disease. Design Modelling study. Setting General adult population of England and Wales. Participants The English Longitudinal Study of Ageing (ELSA) is a representative panel study with six waves of data across 2002-13. Men and women aged 50 or more years, selected randomly, and their cohabiting partners were recruited to the first wave of ELSA (2002-03). 11392 adults participated (response rate 67%). To maintain representativeness, refreshment participants were recruited to the study at subsequent waves. The total analytical sample constituted 17 906 people. Constant objective criteria based on cognitive and functional impairment were used to ascertain dementia cases at each wave. Main outcome measures To estimate calendar trends in dementia incidence, correcting for bias due to loss to follow-up of study participants, a joint model of longitudinal and time-to-event data was fitted to ELSA data. To forecast future dementia prevalence, the probabilistic Markov model IMPACT-BAM (IMPACT-Better Ageing Model) was developed. IMPACT-BAM models transitions of the population aged 35 or more years through states of cardiovascular disease, cognitive and functional impairment, and dementia, to death. It enables prediction of dementia prevalence while accounting for the growing pool of susceptible people as a result of increased life expectancy and the competing effects due to changes in mortality, and incidence of cardiovascular disease. Results In ELSA, dementia incidence was estimated at 14.3 per 1000 person years in men and 17.0/1000 person years in women aged 50 or more in 2010. Dementia incidence declined at a relative rate of 2.7% (95% confidence interval 2.4% to 2.9%) for each year during 2002-13. Using IMPACT-BAM, we estimated there were approximately 767 000 (95% uncertainty interval 735 000 to 797 000) people with dementia in England and Wales in 2016. Despite the decrease in incidence and age specific prevalence, the number of people with dementia is projected to increase to 872 000, 1 092 000, and 1 205 000 in 2020, 2030, and 2040, respectively. A sensitivity analysis without the incidence decline gave a much larger projected growth, of more than 1.9 million people with dementia in 2040. Conclusions Age specific dementia incidence is declining. The number of people with dementia in England and Wales is likely to increase by 57% from 2016 to 2040. This increase is mainly driven by improved life expectancy. Introduction It has been predicted that by 2050 well in excess of 100 million people worldwide will have dementia. 1 Current costs of dementia to the UK economy are estimated at £23bn ($29bn; €26bn) annually. 2 Burden of disability and years of life lost due to dementia in the UK increased by 76% between 1990 and 2010. 3 Accurate projections for burden of dementia is a key step for planning to meet future needs. Projections of dementia burden based on constant prevalence or incidence rates may not be precise, 4 5 6 as they will only reflect population aging. Accurate predictions rely on accounting for changes in dementia incidence as well as changes in mortality rates. The competing effect of cardiovascular risk on future projections of dementia is also important. Alzheimer’s disease, vascular dementia, and cardiovascular disease share risk factors. 7 8 Thus, vascular risk reduction is likely to drive down age specific dementia incidence while, in contrast, leading to increased life expectancy and larger numbers susceptible to dementia. 9 Given the opposing effects, simultaneous modelling of cardiovascular disease, dementia, and mortality is likely to enhance the accuracy of projections. Addressing shared determinants of disease follow recommendations from the National Institute for Health and Care Excellence, 10 Public Health England, and the World Health Organization in the Blackfriars consensus. 11 Such modelling approaches are, however, currently lacking. 4 A key determinant of the future burden of dementia will be the underlying incidence trend. Although the balance of evidence suggests dementia incidence is declining, 12 13 14 15 16 17 18 the magnitude of the decline is less certain. The ideal approach to determine time trends in dementia incidence would be based on continuous monitoring of a defined and representative population using a standard approach for case identification. 13 19 20 In large epidemiological studies, changes in clinical criteria 21 22 and poor diagnostic agreement among clinicians 23 are sources of variation in measured dementia incidence over time. Another challenge in establishing time trends is higher dropout among cohort study participants affected by, or in the preclinical stages of, dementia, 24 25 which leads to inaccurate estimates of dementia incidence and calendar trends. In the present study, we developed a novel probabilistic Markov method (IMPACT-Better Ageing Model) to simultaneously model the transitions of the population through states of health, cardiovascular disease, cognitive and functional impairment, and dementia, to death, to obtain projections for the prevalence of dementia in England and Wales up to 2040. To account for the effect of selective dropout of study participants and to obtain unbiased estimates for dementia incidence over the past 15 years, with which to inform the model, we applied a robust joint modelling technique 26 to data from the English Longitudinal Study of Ageing. Methods Study population and sample The English Longitudinal Study of Ageing (ELSA) sample was recruited in 2002-03 from participants of the 1998-2001 health surveys for England. 27 28 The sample was drawn by postcode sector, stratified by health authority and proportion of households in non-manual socioeconomic groups. A total of 12 099 men and women participated (response rate 67%), including 11 392 people aged 50 or more selected through the random sampling and 707 cohabiting partners. Survey weights were applied to ensure study participants formed a representative sample. Comparison of sociodemographic characteristics against national census indicated the ELSA sample was broadly representative of the population of England. 27 To maintain representativeness of the study sample, refreshment participants were recruited to the study at wave 3 (2006-07; ages 50-55), wave 4 (2008-09; ages 50-74), and wave 6 (2012-13; ages 50-55) all", "role": "user" }, { "content": "By 2040, there will be over 1.2 million people living with dementia in England and Wales (an increase of 57% from 2016), largely due to increased life expectancy, say researchers in The BMJ today. Their results show that, although the incidence (number of newly diagnosed cases) of dementia is falling, the overall prevalence (number of people living with the condition) is set to increase substantially as people live longer and deaths from other causes, such as heart disease, continue to decline. With current costs of dementia to the UK economy estimated at £23 billion a year, accurate projections are vital in defining future needs. But existing forecasts may not be precise as they assume that rates of dementia remain constant. So an international team of researchers, based at University College London and the University of Liverpool, set out to predict the future burden of dementia with more certainty by developing a mathematical model (IMPACT - Better Ageing Model) that takes account of disease trends and death rates alongside the effects of increasing life expectancy. They used data from 18,000 men and women from the English Longitudinal Study of Ageing (ELSA) - a study which began in 2002 to track the health of a representative sample of the population in England aged 50 and older. Participants were selected randomly in six waves from 2002 to 2013. At each wave, tests were carried out to assess memory, verbal fluency and numeracy function, and basic activities of daily living (e.g. getting in or out of bed, dressing and eating). Dementia was identified by these assessments, complemented by interviews with carers, or by diagnosis by a doctor. After accounting for the effect of dropout from the study, the team found the rate of dementia incidence goes down by 2.7% per year between 2002 and 2013. Despite this decline in incidence, the model shows that overall prevalence of dementia is set to increase substantially - mainly due to increased life expectancy. Based on these calculations, the researchers estimate there are currently 800,000 people living with dementia in England and Wales and the number will increase to over 1.2 million by 2040. Dr Sara Ahmadi-Abhari, lead author from University College London, says: \"The risk of developing dementia at any given age is going down over time, shifting dementia to later years in life. This decline is mainly because of improvements in healthcare and adopting healthier lifestyles. Our estimate of 1.2 million people with dementia by 2040 is based on the assumption that the decline in risk of developing dementia continues to the future. If public health efforts fail and the risk of developing dementia does not continue to decline, the growth in numbers of people living with dementia will be much larger, reaching 1.9 million by 2040.\" The authors outline some study limitations which could have introduced bias, but Professor Eric Brunner, the senior investigator, says: \"our results have significant policy implications in terms of care needs and public spending\" and \"act as a benchmark to measure the impact of possible dementia prevention initiatives.\" In a linked editorial, Emiliano Albanese at the University of Geneva says, although these results should be interpreted cautiously, they do confirm that \"the absolute number of people with dementia will increase substantially in the coming years in England and Wales, as a result of an aging population, and it is these numbers that matter most to policy makers planning future care and services.\" The study also confirms that high quality epidemiological studies are still needed to monitor actual changes in dementia prevalence, incidence, and associated mortality over time, he adds. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objective To forecast dementia prevalence with a dynamic modelling approach that integrates calendar trends in dementia incidence with those for mortality and cardiovascular disease. Design Modelling study. Setting General adult population of England and Wales. Participants The English Longitudinal Study of Ageing (ELSA) is a representative panel study with six waves of data across 2002-13. Men and women aged 50 or more years, selected randomly, and their cohabiting partners were recruited to the first wave of ELSA (2002-03). 11392 adults participated (response rate 67%). To maintain representativeness, refreshment participants were recruited to the study at subsequent waves. The total analytical sample constituted 17 906 people. Constant objective criteria based on cognitive and functional impairment were used to ascertain dementia cases at each wave. Main outcome measures To estimate calendar trends in dementia incidence, correcting for bias due to loss to follow-up of study participants, a joint model of longitudinal and time-to-event data was fitted to ELSA data. To forecast future dementia prevalence, the probabilistic Markov model IMPACT-BAM (IMPACT-Better Ageing Model) was developed. IMPACT-BAM models transitions of the population aged 35 or more years through states of cardiovascular disease, cognitive and functional impairment, and dementia, to death. It enables prediction of dementia prevalence while accounting for the growing pool of susceptible people as a result of increased life expectancy and the competing effects due to changes in mortality, and incidence of cardiovascular disease. Results In ELSA, dementia incidence was estimated at 14.3 per 1000 person years in men and 17.0/1000 person years in women aged 50 or more in 2010. Dementia incidence declined at a relative rate of 2.7% (95% confidence interval 2.4% to 2.9%) for each year during 2002-13. Using IMPACT-BAM, we estimated there were approximately 767 000 (95% uncertainty interval 735 000 to 797 000) people with dementia in England and Wales in 2016. Despite the decrease in incidence and age specific prevalence, the number of people with dementia is projected to increase to 872 000, 1 092 000, and 1 205 000 in 2020, 2030, and 2040, respectively. A sensitivity analysis without the incidence decline gave a much larger projected growth, of more than 1.9 million people with dementia in 2040. Conclusions Age specific dementia incidence is declining. The number of people with dementia in England and Wales is likely to increase by 57% from 2016 to 2040. This increase is mainly driven by improved life expectancy. Introduction It has been predicted that by 2050 well in excess of 100 million people worldwide will have dementia. 1 Current costs of dementia to the UK economy are estimated at £23bn ($29bn; €26bn) annually. 2 Burden of disability and years of life lost due to dementia in the UK increased by 76% between 1990 and 2010. 3 Accurate projections for burden of dementia is a key step for planning to meet future needs. Projections of dementia burden based on constant prevalence or incidence rates may not be precise, 4 5 6 as they will only reflect population aging. Accurate predictions rely on accounting for changes in dementia incidence as well as changes in mortality rates. The competing effect of cardiovascular risk on future projections of dementia is also important. Alzheimer’s disease, vascular dementia, and cardiovascular disease share risk factors. 7 8 Thus, vascular risk reduction is likely to drive down age specific dementia incidence while, in contrast, leading to increased life expectancy and larger numbers susceptible to dementia. 9 Given the opposing effects, simultaneous modelling of cardiovascular disease, dementia, and mortality is likely to enhance the accuracy of projections. Addressing shared determinants of disease follow recommendations from the National Institute for Health and Care Excellence, 10 Public Health England, and the World Health Organization in the Blackfriars consensus. 11 Such modelling approaches are, however, currently lacking. 4 A key determinant of the future burden of dementia will be the underlying incidence trend. Although the balance of evidence suggests dementia incidence is declining, 12 13 14 15 16 17 18 the magnitude of the decline is less certain. The ideal approach to determine time trends in dementia incidence would be based on continuous monitoring of a defined and representative population using a standard approach for case identification. 13 19 20 In large epidemiological studies, changes in clinical criteria 21 22 and poor diagnostic agreement among clinicians 23 are sources of variation in measured dementia incidence over time. Another challenge in establishing time trends is higher dropout among cohort study participants affected by, or in the preclinical stages of, dementia, 24 25 which leads to inaccurate estimates of dementia incidence and calendar trends. In the present study, we developed a novel probabilistic Markov method (IMPACT-Better Ageing Model) to simultaneously model the transitions of the population through states of health, cardiovascular disease, cognitive and functional impairment, and dementia, to death, to obtain projections for the prevalence of dementia in England and Wales up to 2040. To account for the effect of selective dropout of study participants and to obtain unbiased estimates for dementia incidence over the past 15 years, with which to inform the model, we applied a robust joint modelling technique 26 to data from the English Longitudinal Study of Ageing. Methods Study population and sample The English Longitudinal Study of Ageing (ELSA) sample was recruited in 2002-03 from participants of the 1998-2001 health surveys for England. 27 28 The sample was drawn by postcode sector, stratified by health authority and proportion of households in non-manual socioeconomic groups. A total of 12 099 men and women participated (response rate 67%), including 11 392 people aged 50 or more selected through the random sampling and 707 cohabiting partners. Survey weights were applied to ensure study participants formed a representative sample. Comparison of sociodemographic characteristics against national census indicated the ELSA sample was broadly representative of the population of England. 27 To maintain representativeness of the study sample, refreshment participants were recruited to the study at wave 3 (2006-07; ages 50-55), wave 4 (2008-09; ages 50-74), and wave 6 (2012-13; ages 50-55) all<|im_end|> <|im_start|>assistant By 2040, there will be over 1.2 million people living with dementia in England and Wales (an increase of 57% from 2016), largely due to increased life expectancy, say researchers in The BMJ today. Their results show that, although the incidence (number of newly diagnosed cases) of dementia is falling, the overall prevalence (number of people living with the condition) is set to increase substantially as people live longer and deaths from other causes, such as heart disease, continue to decline. With current costs of dementia to the UK economy estimated at £23 billion a year, accurate projections are vital in defining future needs. But existing forecasts may not be precise as they assume that rates of dementia remain constant. So an international team of researchers, based at University College London and the University of Liverpool, set out to predict the future burden of dementia with more certainty by developing a mathematical model (IMPACT - Better Ageing Model) that takes account of disease trends and death rates alongside the effects of increasing life expectancy. They used data from 18,000 men and women from the English Longitudinal Study of Ageing (ELSA) - a study which began in 2002 to track the health of a representative sample of the population in England aged 50 and older. Participants were selected randomly in six waves from 2002 to 2013. At each wave, tests were carried out to assess memory, verbal fluency and numeracy function, and basic activities of daily living (e.g. getting in or out of bed, dressing and eating). Dementia was identified by these assessments, complemented by interviews with carers, or by diagnosis by a doctor. After accounting for the effect of dropout from the study, the team found the rate of dementia incidence goes down by 2.7% per year between 2002 and 2013. Despite this decline in incidence, the model shows that overall prevalence of dementia is set to increase substantially - mainly due to increased life expectancy. Based on these calculations, the researchers estimate there are currently 800,000 people living with dementia in England and Wales and the number will increase to over 1.2 million by 2040. Dr Sara Ahmadi-Abhari, lead author from University College London, says: "The risk of developing dementia at any given age is going down over time, shifting dementia to later years in life. This decline is mainly because of improvements in healthcare and adopting healthier lifestyles. Our estimate of 1.2 million people with dementia by 2040 is based on the assumption that the decline in risk of developing dementia continues to the future. If public health efforts fail and the risk of developing dementia does not continue to decline, the growth in numbers of people living with dementia will be much larger, reaching 1.9 million by 2040." The authors outline some study limitations which could have introduced bias, but Professor Eric Brunner, the senior investigator, says: "our results have significant policy implications in terms of care needs and public spending" and "act as a benchmark to measure the impact of possible dementia prevention initiatives." In a linked editorial, Emiliano Albanese at the University of Geneva says, although these results should be interpreted cautiously, they do confirm that "the absolute number of people with dementia will increase substantially in the coming years in England and Wales, as a result of an aging population, and it is these numbers that matter most to policy makers planning future care and services." The study also confirms that high quality epidemiological studies are still needed to monitor actual changes in dementia prevalence, incidence, and associated mortality over time, he adds. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Arctic coasts are vulnerable to the effects of climate change, including rising sea levels and the loss of permafrost, sea ice and glaciers. Assessing the influence of anthropogenic warming on Arctic coastal dynamics, however, is challenged by the limited availability of observational, oceanographic and environmental data. Yet, with the majority of permafrost coasts being erosive, coupled with projected intensification of erosion and flooding, understanding these changes is critical. In this Review, we describe the morphological diversity of Arctic coasts, discuss important drivers of coastal change, explain the specific sensitivity of Arctic coasts to climate change and provide an overview of pan-Arctic shoreline change and its multifaceted impacts. Arctic coastal changes impact the human environment by threatening coastal settlements, infrastructure, cultural sites and archaeological remains. Changing sediment fluxes also impact the natural environment through carbon, nutrient and pollutant release on a magnitude that remains difficult to predict. Increasing transdisciplinary and interdisciplinary collaboration efforts will build the foundation for identifying sustainable solutions and adaptation strategies to reduce future risks for those living on, working at and visiting the rapidly changing Arctic coast. Key points Arctic coasts are some of the most rapidly changing coasts on Earth. Most change occurs during the sea-ice-free period, which can be up to 3 months. The erosion of permafrost coasts has increased since the early 2000s when compared with the late twentieth century (1960s–1990s), coinciding with an intensification of environmental drivers linked to anthropogenic warming. Mean annual erosion rates along stretches of unlithified permafrost coasts in Alaska, Canada and Siberia have more than doubled since the early 2000s compared with the latter half of the twentieth century. Coastal erosion along permafrost coasts is expected to continue at high rates or even accelerate in response to further climate warming. Rapid environmental and social change in the Arctic highlights the need for coordinated interdisciplinary and transdisciplinary efforts of scientists, stakeholders and policymakers, together with the local coastal population, to develop adaptive strategies around Arctic coasts in transition. Introduction Arctic coasts are influenced by the presence of sea ice, permafrost and ground ice 1 , 2 , 3 . The presence of ice onshore and offshore makes Arctic coasts particularly sensitive to the effects of climate warming. The most visible changes are to shoreline position, predominantly by shoreline retreat through erosion 4 , 5 . To a lesser extent, shoreline progradation through accumulation also shapes Arctic coasts 4 , 5 . The interplay and combined effects of oceanographic, terrestrial, periglacial and paraglacial processes lead to changes in shoreline position and cause the redistribution of sediments, carbon, nutrients and contaminants within the coastal zone and into the offshore marine environment 6 , 7 , 8 . Permafrost coasts are particularly vulnerable to rising air temperatures; warm air acts upon the soil column from the top down and laterally inwards from the bluff face . This combination leads to rapid ground-ice melt and permafrost thaw, making the coast more susceptible to erosion 2 , 9 . Climate warming is amplified in the Arctic. For example, between 1971 and 2017, Arctic surface air temperatures rose 2.4 times faster than the Northern Hemisphere average 10 , with mean annual, cold season and warm season Arctic air temperatures increasing by 2.7 °C, 3.1 °C and 1.8 °C, respectively 10 . Furthermore, 9 of the years between 2010 and 2020, recorded average surface air temperature anomalies of more than 1 °C, making them the warmest years since 1900 (ref. 11 ). In the same time period, numerous sites along permafrost coasts recorded an increase of erosion rates 4 . Rising air temperature also influences the extent and spatiotemporal distribution of sea ice. The ten lowest sea-ice extents since the beginning of satellite-based observations in 1979 were recorded between 2010 and 2021, with the exception of 2014 (ref. 12 ). Consequently, the effects of climate-change-induced stressors on the terrestrial and marine environments are leading to more rapid landscape and coastal morphological changes along Arctic coasts, compared with historical rates of change 13 , 14 ; however, for much of the Arctic, only limited data exist. In 1999, the Arctic Coastal Dynamics project was launched as an initiative of the International Permafrost Association and the International Arctic Science Committee to provide an international platform for Arctic coastal researchers. The release of the Arctic Coastal Dynamics (ACD) database 15 and corresponding publication 5 in 2011 marked a turning point in Arctic coastal research. The ACD database contains a pan-Arctic assessment of shoreline change rates, backshore elevation and coastal ground-ice distribution. Entries largely rely on expert estimates and, currently, this is the only dataset that allows for a pan-Arctic comparison of shoreline change rates. Further development of the ACD database will help in understanding how climate warming influences Arctic coastal dynamics . To date, only a very limited number of reviews have focused on Arctic coastal dynamics 16 , 17 . Past reviews primarily addressed differences in geomorphology among Arctic coasts and the evolution of rates of shoreline change 16 , 17 . Notably, the State of the Arctic coast 2010 report provided a comprehensive integration of physical, ecological and socio-economical aspects related to coastal change, and explored factors that influence the capability of Arctic coastal communities to respond to coastal changes 18 . However, since 2010, the lowest sea-ice extents and warmest air temperatures on record within the Arctic have been observed 19 . In addition, considerable research has been conducted to better understand how Arctic coastal dynamics have changed over the past two decades 4 and what implications arise from these changes to the natural and human environment 20 . In this Review, we illustrate how the morphologic diversity and evolution of Arctic coasts describe the interplay between environmental drivers and the local coastal setting, and discuss how both are changing as an effect of a warming climate. We provide an overview of shoreline change evolution, with a particular focus on research developments since the early 2000s, and lay out the multifarious impacts that coastal dynamics have", "role": "user" }, { "content": "Arctic coasts are characterized by sea ice, permafrost and ground ice. This makes them particularly vulnerable to the effects of climate change, which is already accelerating rapid coastal erosion. The increasing warming is affecting coast stability, sediments, carbon storage, and nutrient mobilization. Understanding the correlation of these changes is essential to improve forecasts and adaptation strategies for Arctic coasts. In a special issue of the journal Nature Reviews Earth & Environment, researchers from the Alfred Wegener Institute describe the sensitivity of Arctic coasts to climate change and the challenges for humans and nature. \"The pace of changes in the Arctic is increasing, leading to accelerated coastal retreat,\" says Dr. Anna Irrgang of the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI). \"This affects both the natural and human environment, for example, by releasing carbon from the soil into the sea and atmosphere, or losing the land that supports communities and infrastructure.\" Exactly how and how much coasts are changing depends on the interplay of the local coastal settings, like the presence of permafrost, and environmental factors such as air and water temperature. \"Predictions about this are often subject to large uncertainties because reliable oceanographic and environmental data for remote coastal zones are limited,\" Irrgang says. To improve understanding and thus predictions of future developments, the AWI permafrost researcher has compiled the most important factors and drivers that affect Arctic coasts and that are important for developing adaptation strategies to climate change along Arctic coasts. Environmental factors and local settings drive coastal change Arctic coasts have different structures depending on the region. In Alaska, Canada or Siberia, for example, they are particularly rich in ground ice with permafrost bluffs that range in height up to 40 meters. In Greenland, Svalbard and the Canadian Archipelago, on the other hand, the coasts usually contain little to no ground ice but, instead, large volumes of coarse, glacially derived sediment, or even solid rock. These regional geomorphological differences influence how other environmental variables affect coasts. For example, if air and water temperatures change, it affects the entire coastal system. Ice-rich permafrost bluffs, for example, some of which are up to 80 percent ice, are quite resilient to mechanical wave action. However, when they thaw due to increased air and water temperatures, they become particularly vulnerable to destruction by waves, which manifests itself in rapid coastal erosion. Arctic coasts are thus particularly sensitive to climate: Global warming is causing large areas of permafrost to thaw, ground ice to melt and land surfaces to collapse. This in turn affects the availability and quality of water, the growth of plants, and increases soil stripping (erosion) and coastal flooding. In addition, sea surface temperatures rise in most parts of the Arctic, which can extend the sea ice-free period. Coasts are then exposed to strong waves for much longer, especially during the stormy fall season. Arctic shoreline changes Comparing the rates of change of Arctic coastlines shows that the overwhelming majority of permafrost coasts are receding due to erosion. Northern Canada's Herschel Island, for example, loses up to 22 meters of bluff per year. When permafrost thaws, it allows organic carbon, nutrients and pollutants to be released into the nearshore environment and the atmosphere. Experts estimate that coastal erosion releases about 14 megatons of organic carbon into the Arctic Ocean each year—which is higher than the amount of particulate organic carbon provided by Arctic rivers. The thawing of previously solid soils is also affecting local people. Around 4.3 million of them will be confronted with the consequences: they will lose buildings and roads, traditional hunting grounds and also cultural sites. In Alaska, already entire settlements need to be abandoned and people have to relocate. The erosion of frozen areas increases the risks of permafrost thaws and currently incalculable environmental pollution from industrial infrastructures. Only in the long term, new opportunities could open up as a result of the changes, due to access to resources in previously inaccessible regions, new agricultural areas and shipping routes for trade and tourism. Accurate data for good living conditions at Arctic coasts \"Our current understanding of Arctic coastal dynamics is fragmented, with too few data with high spatial and temporal resolution on environmental factors and shoreline changes,\" says Anna Irrgang. \"While such datasets already exist for some regions such as northern Alaska, most of the Arctic coast is poorly mapped.\" Yet Arctic-wide observations of environmental factors and coastal changes are urgently needed to reduce uncertainties in forecasts. These would help local communities to deal with new socio-ecological developments. \"For this, we need to develop adaptation methods that enable good and sustainable living conditions in Arctic coastal settlements. Close cooperation with local people is central to this,\" says Anna Irrgang. The analysis of Arctic coastal change is part of the special issue \"Permafrost\" of the journal Nature Reviews Earth & Environment. The AWI Permafrost Section is also involved with two additional contributions: In a review, researchers show how millions of dew lakes and drained lake basins have formed and grown in Arctic and boreal lowland areas as a result of the melting of ice-rich permafrost. These processes influence landscape and ecosystem processes as well as human livelihoods in the vast Arctic lowland regions. A third article presents the \"Permafrost Comics\" project, which uses cartoons to make knowledge about permafrost more easily accessible to a broad and especially young audience. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Arctic coasts are vulnerable to the effects of climate change, including rising sea levels and the loss of permafrost, sea ice and glaciers. Assessing the influence of anthropogenic warming on Arctic coastal dynamics, however, is challenged by the limited availability of observational, oceanographic and environmental data. Yet, with the majority of permafrost coasts being erosive, coupled with projected intensification of erosion and flooding, understanding these changes is critical. In this Review, we describe the morphological diversity of Arctic coasts, discuss important drivers of coastal change, explain the specific sensitivity of Arctic coasts to climate change and provide an overview of pan-Arctic shoreline change and its multifaceted impacts. Arctic coastal changes impact the human environment by threatening coastal settlements, infrastructure, cultural sites and archaeological remains. Changing sediment fluxes also impact the natural environment through carbon, nutrient and pollutant release on a magnitude that remains difficult to predict. Increasing transdisciplinary and interdisciplinary collaboration efforts will build the foundation for identifying sustainable solutions and adaptation strategies to reduce future risks for those living on, working at and visiting the rapidly changing Arctic coast. Key points Arctic coasts are some of the most rapidly changing coasts on Earth. Most change occurs during the sea-ice-free period, which can be up to 3 months. The erosion of permafrost coasts has increased since the early 2000s when compared with the late twentieth century (1960s–1990s), coinciding with an intensification of environmental drivers linked to anthropogenic warming. Mean annual erosion rates along stretches of unlithified permafrost coasts in Alaska, Canada and Siberia have more than doubled since the early 2000s compared with the latter half of the twentieth century. Coastal erosion along permafrost coasts is expected to continue at high rates or even accelerate in response to further climate warming. Rapid environmental and social change in the Arctic highlights the need for coordinated interdisciplinary and transdisciplinary efforts of scientists, stakeholders and policymakers, together with the local coastal population, to develop adaptive strategies around Arctic coasts in transition. Introduction Arctic coasts are influenced by the presence of sea ice, permafrost and ground ice 1 , 2 , 3 . The presence of ice onshore and offshore makes Arctic coasts particularly sensitive to the effects of climate warming. The most visible changes are to shoreline position, predominantly by shoreline retreat through erosion 4 , 5 . To a lesser extent, shoreline progradation through accumulation also shapes Arctic coasts 4 , 5 . The interplay and combined effects of oceanographic, terrestrial, periglacial and paraglacial processes lead to changes in shoreline position and cause the redistribution of sediments, carbon, nutrients and contaminants within the coastal zone and into the offshore marine environment 6 , 7 , 8 . Permafrost coasts are particularly vulnerable to rising air temperatures; warm air acts upon the soil column from the top down and laterally inwards from the bluff face . This combination leads to rapid ground-ice melt and permafrost thaw, making the coast more susceptible to erosion 2 , 9 . Climate warming is amplified in the Arctic. For example, between 1971 and 2017, Arctic surface air temperatures rose 2.4 times faster than the Northern Hemisphere average 10 , with mean annual, cold season and warm season Arctic air temperatures increasing by 2.7 °C, 3.1 °C and 1.8 °C, respectively 10 . Furthermore, 9 of the years between 2010 and 2020, recorded average surface air temperature anomalies of more than 1 °C, making them the warmest years since 1900 (ref. 11 ). In the same time period, numerous sites along permafrost coasts recorded an increase of erosion rates 4 . Rising air temperature also influences the extent and spatiotemporal distribution of sea ice. The ten lowest sea-ice extents since the beginning of satellite-based observations in 1979 were recorded between 2010 and 2021, with the exception of 2014 (ref. 12 ). Consequently, the effects of climate-change-induced stressors on the terrestrial and marine environments are leading to more rapid landscape and coastal morphological changes along Arctic coasts, compared with historical rates of change 13 , 14 ; however, for much of the Arctic, only limited data exist. In 1999, the Arctic Coastal Dynamics project was launched as an initiative of the International Permafrost Association and the International Arctic Science Committee to provide an international platform for Arctic coastal researchers. The release of the Arctic Coastal Dynamics (ACD) database 15 and corresponding publication 5 in 2011 marked a turning point in Arctic coastal research. The ACD database contains a pan-Arctic assessment of shoreline change rates, backshore elevation and coastal ground-ice distribution. Entries largely rely on expert estimates and, currently, this is the only dataset that allows for a pan-Arctic comparison of shoreline change rates. Further development of the ACD database will help in understanding how climate warming influences Arctic coastal dynamics . To date, only a very limited number of reviews have focused on Arctic coastal dynamics 16 , 17 . Past reviews primarily addressed differences in geomorphology among Arctic coasts and the evolution of rates of shoreline change 16 , 17 . Notably, the State of the Arctic coast 2010 report provided a comprehensive integration of physical, ecological and socio-economical aspects related to coastal change, and explored factors that influence the capability of Arctic coastal communities to respond to coastal changes 18 . However, since 2010, the lowest sea-ice extents and warmest air temperatures on record within the Arctic have been observed 19 . In addition, considerable research has been conducted to better understand how Arctic coastal dynamics have changed over the past two decades 4 and what implications arise from these changes to the natural and human environment 20 . In this Review, we illustrate how the morphologic diversity and evolution of Arctic coasts describe the interplay between environmental drivers and the local coastal setting, and discuss how both are changing as an effect of a warming climate. We provide an overview of shoreline change evolution, with a particular focus on research developments since the early 2000s, and lay out the multifarious impacts that coastal dynamics have<|im_end|> <|im_start|>assistant Arctic coasts are characterized by sea ice, permafrost and ground ice. This makes them particularly vulnerable to the effects of climate change, which is already accelerating rapid coastal erosion. The increasing warming is affecting coast stability, sediments, carbon storage, and nutrient mobilization. Understanding the correlation of these changes is essential to improve forecasts and adaptation strategies for Arctic coasts. In a special issue of the journal Nature Reviews Earth & Environment, researchers from the Alfred Wegener Institute describe the sensitivity of Arctic coasts to climate change and the challenges for humans and nature. "The pace of changes in the Arctic is increasing, leading to accelerated coastal retreat," says Dr. Anna Irrgang of the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI). "This affects both the natural and human environment, for example, by releasing carbon from the soil into the sea and atmosphere, or losing the land that supports communities and infrastructure." Exactly how and how much coasts are changing depends on the interplay of the local coastal settings, like the presence of permafrost, and environmental factors such as air and water temperature. "Predictions about this are often subject to large uncertainties because reliable oceanographic and environmental data for remote coastal zones are limited," Irrgang says. To improve understanding and thus predictions of future developments, the AWI permafrost researcher has compiled the most important factors and drivers that affect Arctic coasts and that are important for developing adaptation strategies to climate change along Arctic coasts. Environmental factors and local settings drive coastal change Arctic coasts have different structures depending on the region. In Alaska, Canada or Siberia, for example, they are particularly rich in ground ice with permafrost bluffs that range in height up to 40 meters. In Greenland, Svalbard and the Canadian Archipelago, on the other hand, the coasts usually contain little to no ground ice but, instead, large volumes of coarse, glacially derived sediment, or even solid rock. These regional geomorphological differences influence how other environmental variables affect coasts. For example, if air and water temperatures change, it affects the entire coastal system. Ice-rich permafrost bluffs, for example, some of which are up to 80 percent ice, are quite resilient to mechanical wave action. However, when they thaw due to increased air and water temperatures, they become particularly vulnerable to destruction by waves, which manifests itself in rapid coastal erosion. Arctic coasts are thus particularly sensitive to climate: Global warming is causing large areas of permafrost to thaw, ground ice to melt and land surfaces to collapse. This in turn affects the availability and quality of water, the growth of plants, and increases soil stripping (erosion) and coastal flooding. In addition, sea surface temperatures rise in most parts of the Arctic, which can extend the sea ice-free period. Coasts are then exposed to strong waves for much longer, especially during the stormy fall season. Arctic shoreline changes Comparing the rates of change of Arctic coastlines shows that the overwhelming majority of permafrost coasts are receding due to erosion. Northern Canada's Herschel Island, for example, loses up to 22 meters of bluff per year. When permafrost thaws, it allows organic carbon, nutrients and pollutants to be released into the nearshore environment and the atmosphere. Experts estimate that coastal erosion releases about 14 megatons of organic carbon into the Arctic Ocean each year—which is higher than the amount of particulate organic carbon provided by Arctic rivers. The thawing of previously solid soils is also affecting local people. Around 4.3 million of them will be confronted with the consequences: they will lose buildings and roads, traditional hunting grounds and also cultural sites. In Alaska, already entire settlements need to be abandoned and people have to relocate. The erosion of frozen areas increases the risks of permafrost thaws and currently incalculable environmental pollution from industrial infrastructures. Only in the long term, new opportunities could open up as a result of the changes, due to access to resources in previously inaccessible regions, new agricultural areas and shipping routes for trade and tourism. Accurate data for good living conditions at Arctic coasts "Our current understanding of Arctic coastal dynamics is fragmented, with too few data with high spatial and temporal resolution on environmental factors and shoreline changes," says Anna Irrgang. "While such datasets already exist for some regions such as northern Alaska, most of the Arctic coast is poorly mapped." Yet Arctic-wide observations of environmental factors and coastal changes are urgently needed to reduce uncertainties in forecasts. These would help local communities to deal with new socio-ecological developments. "For this, we need to develop adaptation methods that enable good and sustainable living conditions in Arctic coastal settlements. Close cooperation with local people is central to this," says Anna Irrgang. The analysis of Arctic coastal change is part of the special issue "Permafrost" of the journal Nature Reviews Earth & Environment. The AWI Permafrost Section is also involved with two additional contributions: In a review, researchers show how millions of dew lakes and drained lake basins have formed and grown in Arctic and boreal lowland areas as a result of the melting of ice-rich permafrost. These processes influence landscape and ecosystem processes as well as human livelihoods in the vast Arctic lowland regions. A third article presents the "Permafrost Comics" project, which uses cartoons to make knowledge about permafrost more easily accessible to a broad and especially young audience. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Sepsis, a condition caused by severe infections, affects more than 30 million people worldwide every year and remains the leading cause of death in hospitals 1 , 2 . Moreover, antimicrobial resistance has become an additional challenge in the treatment of sepsis 3 , and thus, alternative therapeutic approaches are urgently needed 2 , 3 . Here, we show that adoptive transfer of macrophages containing antimicrobial peptides linked to cathepsin B in the lysosomes (MACs) can be applied for the treatment of multidrug-resistant bacteria-induced sepsis in mice with immunosuppression. The MACs are constructed by transfection of vitamin C lipid nanoparticles that deliver antimicrobial peptide and cathepsin B (AMP-CatB) mRNA. The vitamin C lipid nanoparticles allow the specific accumulation of AMP-CatB in macrophage lysosomes, which is the key location for bactericidal activities. Our results demonstrate that adoptive MAC transfer leads to the elimination of multidrug-resistant bacteria, including Staphylococcus aureus and Escherichia coli , leading to the complete recovery of immunocompromised septic mice. Our work provides an alternative strategy for overcoming multidrug-resistant bacteria-induced sepsis and opens up possibilities for the development of nanoparticle-enabled cell therapy for infectious diseases. Main Traditionally, sepsis has been viewed as an uncontrollable inflammatory response to pathogens 2 , 4 . However, recent clinical data reveal that more than 60% of septic patients survive through the initial inflammatory storm but rapidly progress to a longer immunosuppressive state, which is characterized by the paralysis and death of immune cells, leading to an inability to clear invading pathogens, increased susceptibility to hospital-acquired infections and a high mortality rate 2 , 4 , 5 , 6 . As a result, potential therapeutic targets have been extensively explored in order to treat sepsis, such as removing the anaphylatoxin C5a or blocking the C5a receptor 7 , 8 . Meanwhile, approaches aiming to restore immune function have been developed and tested in patients with sepsis 2 , 4 , 6 . Macrophages are one of the most efficient pathogen scavengers during infections 9 . Indeed, in septic patients, impaired macrophages/monocytes seem to be primarily responsible for insufficient antimicrobial defense 6 , 9 , 10 , 11 , 12 . Several small clinical trials of immunostimulatory agents indicate benefits in reversing the deactivated macrophages/monocytes, thus enhancing infection eradication 10 , 11 . However, meta-analysis of large clinical trials did not show significant changes in reducing patient mortality 13 . Differences in clinical results may be explained as follows 10 , 14 , 15 , 16 . First, immunostimulatory agents are not able to restore the function of impaired macrophages/monocytes to their original levels 10 . Second, invaded bacteria are usually trapped in macrophage phagolysosomes, where reactive oxygen species, reactive nitrogen species and lysozymes work synergistically to clear bacteria 17 . However, many bacteria, such as S . aureus and E . coli , have evolved immune escape mechanisms for thwarting phagolysosomal killing, resulting in intracellular survival and recurrent infections 14 , 15 , 16 . Third, although antibiotic therapy is the standard treatment in the sepsis clinical guideline, 70–80% of sepsis death is related to persistent infections, thus indicating the prevalence of antibiotic resistance and the paucity of effective antimicrobial agents 3 , 6 . Based on the above research findings, we hypothesized that adoptive transfer of MACs may enable the immunocompromised sepsis host to boost innate immunity, prevent bacterial immune evasion and eliminate multidrug-resistant (MDR) bacteria. To test our hypothesis, we first designed and constructed the AMP-CatB mRNA encoding an antimicrobial peptide IB367 (AMP-IB367), a cathepsin B (CatB) and a CatB-sensitive linker. AMP-IB367 is a broad-spectrum AMP with rapid bactericidal activity that has been confirmed in clinical trials 18 . CatB, an endogenous lysosomal protein, is first translated as an inactive precursor in the cytoplasm. After translocation into the lysosome, the precursor is processed into mature CatB (ref. 19 ). In this study, the CatB component is incorporated to transport the AMP-IB367 into lysosomes. In order to equip macrophages with the AMP-CatB mRNA, we designed a series of vitamin-derived lipid nanomaterials. As illustrated in Fig. 1a , the mRNA is translated to functional proteins in the cytoplasm and the proteins are further translocated into lysosomes 19 , where the linker is cleaved by CatB proteins and thus the APM-IB367 is released 20 . When phagosomes encapsulating bacteria fuse with lysosomes, the ingested bacteria are exposed to both pre-stored AMP-IB367 and lysosomal antimicrobial components. Although immune evasion strategies may protect MDR bacteria from phagolysosomal killing mechanisms, the AMP-IB367 is able to kill these bacteria. Consequently, the adoptive transfer of MACs rescues MDR bacteria-induced sepsis mice with immunosuppression by restoring the innate immunity, overcoming bacterial immune evasion and eradicating the infection. Fig. 1: Schematic illustration of adoptive macrophage transfer and chemical structures of the vitamin-derived lipids. a , Construction of MACs for sepsis therapy. The AMP-CatB mRNA is encapsulated in the V C LNP and delivered to the macrophage where the mRNA is translated in the cytoplasm and translocated into the lysosomes. Within the lysosomes, the cleavable linker is cleaved by the lysosomal CatB, releasing the AMP-IB367. After phagosomes carrying MDR bacteria fuse with the lysosomes, the ingested MDR bacteria are eradicated by the pre-stored AMP-IB367. b , Chemical structures of vitamin-derived lipids including V B3 -Lipid, V C -Lipid, V D -Lipid, V E -Lipid and V H -Lipid. Full size image In this study, we first synthesized five vitamin-derived lipids: V B3 -Lipid, V C -Lipid, V D -Lipid, V E -Lipid and V H -Lipid (Fig. 1b ). Tertiary amines in the lipid chain can be ionized at an acidic condition and interact with mRNAs. The structures of these vitamin-derived lipids were confirmed by 1 H NMR and mass spectrometry (Supplementary Figs. 1 – 5 ). Next, we formulated these vitamin-derived lipids into vitamin lipid nanoparticles (VLNPs). The particle size of the VLNPs ranged from 127 ± 1 to 174 ± 1 nm with a polydispersity index (PDI) < 0.3 except in vitamin H lipid nanoparticles (V H LNPs; Supplementary Fig.", "role": "user" }, { "content": "Researchers have developed a way to prop up a struggling immune system to enable its fight against sepsis, a deadly condition resulting from the body's extreme reaction to infection. The scientists used nanotechnology to transform donated healthy immune cells into a drug with enhanced power to kill bacteria. In experiments treating mice with sepsis, the engineered immune cells eliminated bacteria in blood and major organs, dramatically improving survival rates. This work focuses on a treatment for late-stage sepsis, when the immune system is compromised and unable to clear invading bacteria. The scientists are collaborating with clinicians specializing in sepsis treatment to accelerate the drug-development process. \"Sepsis remains the leading cause of death in hospitals. There hasn't been an effective treatment for late-stage sepsis for a long time. We're thinking this cell therapy can help patients who get to the late stage of sepsis,\" said Yizhou Dong, senior author and associate professor of pharmaceutics and pharmacology at The Ohio State University. \"For translation in the clinic, we believe this could be used in combination with current intensive-care treatment for sepsis patients.\" The study is published today in Nature Nanotechnology. Sepsis itself is not an infection—it's a life-threatening systemic response to infection that can lead to tissue damage, organ failure and death, according to The Centers for Disease Control and Prevention. The CDC estimates that 1.7 million adults in the United States develop sepsis each year, and one in three patients who die in a hospital have sepsis. This work combined two primary types of technology: using vitamins as the main component in making lipid nanoparticles, and using those nanoparticles to capitalize on natural cell processes in the creation of a new antibacterial drug. Cells called macrophages are one of the first responders in the immune system, with the job of \"eating\" invading pathogens. However, in patients with sepsis, the number of macrophages and other immune cells are lower than normal and they don't function as they should. In this study, Dong and colleagues collected monocytes from the bone marrow of healthy mice and cultured them in conditions that transformed them into macrophages. (Monocytes are white blood cells that are able to differentiate into other types of immune cells.) The lab also developed vitamin-based nanoparticles that were especially good at delivering messenger RNA, molecules that translate genetic information into functional proteins. The scientists, who specialize in messenger RNA for therapeutic purposes, constructed a messenger RNA encoding an antimicrobial peptide and a signal protein. The signal protein enabled the specific accumulation of the antimicrobial peptide in internal macrophage structures called lysosomes, the key location for bacteria-killing activities. From here, researchers delivered the nanoparticles loaded with that messenger RNA into the macrophages they had produced with donor monocytes, and let the cells take it from there to \"manufacture\" a new therapy. \"Macrophages have antibacterial activity naturally. So if we add the additional antibacterial peptide into the cell, those antibacterial peptides can further enhance the antibacterial activity and help the whole macrophage clear bacteria,\" Dong said. After seeing promising results in cell tests, the researchers administered the cell therapy to mice. The mouse models of sepsis in this study were infected with multidrug-resistant Staphylococcus aureus and E. coli and their immune systems were suppressed. Each treatment consisted of about 4 million engineered macrophages. Controls for comparison included ordinary macrophages and a placebo. Compared to controls, the treatment resulted in a significant reduction in bacteria in the blood after 24 hours—and for those with lingering bacteria in the blood, a second treatment cleared them away. Dong considers the lipid nanoparticle delivery of messenger RNA into certain kinds of immune cells applicable to other diseases, and his lab is currently working on development of cancer immunotherapy using this technology. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Sepsis, a condition caused by severe infections, affects more than 30 million people worldwide every year and remains the leading cause of death in hospitals 1 , 2 . Moreover, antimicrobial resistance has become an additional challenge in the treatment of sepsis 3 , and thus, alternative therapeutic approaches are urgently needed 2 , 3 . Here, we show that adoptive transfer of macrophages containing antimicrobial peptides linked to cathepsin B in the lysosomes (MACs) can be applied for the treatment of multidrug-resistant bacteria-induced sepsis in mice with immunosuppression. The MACs are constructed by transfection of vitamin C lipid nanoparticles that deliver antimicrobial peptide and cathepsin B (AMP-CatB) mRNA. The vitamin C lipid nanoparticles allow the specific accumulation of AMP-CatB in macrophage lysosomes, which is the key location for bactericidal activities. Our results demonstrate that adoptive MAC transfer leads to the elimination of multidrug-resistant bacteria, including Staphylococcus aureus and Escherichia coli , leading to the complete recovery of immunocompromised septic mice. Our work provides an alternative strategy for overcoming multidrug-resistant bacteria-induced sepsis and opens up possibilities for the development of nanoparticle-enabled cell therapy for infectious diseases. Main Traditionally, sepsis has been viewed as an uncontrollable inflammatory response to pathogens 2 , 4 . However, recent clinical data reveal that more than 60% of septic patients survive through the initial inflammatory storm but rapidly progress to a longer immunosuppressive state, which is characterized by the paralysis and death of immune cells, leading to an inability to clear invading pathogens, increased susceptibility to hospital-acquired infections and a high mortality rate 2 , 4 , 5 , 6 . As a result, potential therapeutic targets have been extensively explored in order to treat sepsis, such as removing the anaphylatoxin C5a or blocking the C5a receptor 7 , 8 . Meanwhile, approaches aiming to restore immune function have been developed and tested in patients with sepsis 2 , 4 , 6 . Macrophages are one of the most efficient pathogen scavengers during infections 9 . Indeed, in septic patients, impaired macrophages/monocytes seem to be primarily responsible for insufficient antimicrobial defense 6 , 9 , 10 , 11 , 12 . Several small clinical trials of immunostimulatory agents indicate benefits in reversing the deactivated macrophages/monocytes, thus enhancing infection eradication 10 , 11 . However, meta-analysis of large clinical trials did not show significant changes in reducing patient mortality 13 . Differences in clinical results may be explained as follows 10 , 14 , 15 , 16 . First, immunostimulatory agents are not able to restore the function of impaired macrophages/monocytes to their original levels 10 . Second, invaded bacteria are usually trapped in macrophage phagolysosomes, where reactive oxygen species, reactive nitrogen species and lysozymes work synergistically to clear bacteria 17 . However, many bacteria, such as S . aureus and E . coli , have evolved immune escape mechanisms for thwarting phagolysosomal killing, resulting in intracellular survival and recurrent infections 14 , 15 , 16 . Third, although antibiotic therapy is the standard treatment in the sepsis clinical guideline, 70–80% of sepsis death is related to persistent infections, thus indicating the prevalence of antibiotic resistance and the paucity of effective antimicrobial agents 3 , 6 . Based on the above research findings, we hypothesized that adoptive transfer of MACs may enable the immunocompromised sepsis host to boost innate immunity, prevent bacterial immune evasion and eliminate multidrug-resistant (MDR) bacteria. To test our hypothesis, we first designed and constructed the AMP-CatB mRNA encoding an antimicrobial peptide IB367 (AMP-IB367), a cathepsin B (CatB) and a CatB-sensitive linker. AMP-IB367 is a broad-spectrum AMP with rapid bactericidal activity that has been confirmed in clinical trials 18 . CatB, an endogenous lysosomal protein, is first translated as an inactive precursor in the cytoplasm. After translocation into the lysosome, the precursor is processed into mature CatB (ref. 19 ). In this study, the CatB component is incorporated to transport the AMP-IB367 into lysosomes. In order to equip macrophages with the AMP-CatB mRNA, we designed a series of vitamin-derived lipid nanomaterials. As illustrated in Fig. 1a , the mRNA is translated to functional proteins in the cytoplasm and the proteins are further translocated into lysosomes 19 , where the linker is cleaved by CatB proteins and thus the APM-IB367 is released 20 . When phagosomes encapsulating bacteria fuse with lysosomes, the ingested bacteria are exposed to both pre-stored AMP-IB367 and lysosomal antimicrobial components. Although immune evasion strategies may protect MDR bacteria from phagolysosomal killing mechanisms, the AMP-IB367 is able to kill these bacteria. Consequently, the adoptive transfer of MACs rescues MDR bacteria-induced sepsis mice with immunosuppression by restoring the innate immunity, overcoming bacterial immune evasion and eradicating the infection. Fig. 1: Schematic illustration of adoptive macrophage transfer and chemical structures of the vitamin-derived lipids. a , Construction of MACs for sepsis therapy. The AMP-CatB mRNA is encapsulated in the V C LNP and delivered to the macrophage where the mRNA is translated in the cytoplasm and translocated into the lysosomes. Within the lysosomes, the cleavable linker is cleaved by the lysosomal CatB, releasing the AMP-IB367. After phagosomes carrying MDR bacteria fuse with the lysosomes, the ingested MDR bacteria are eradicated by the pre-stored AMP-IB367. b , Chemical structures of vitamin-derived lipids including V B3 -Lipid, V C -Lipid, V D -Lipid, V E -Lipid and V H -Lipid. Full size image In this study, we first synthesized five vitamin-derived lipids: V B3 -Lipid, V C -Lipid, V D -Lipid, V E -Lipid and V H -Lipid (Fig. 1b ). Tertiary amines in the lipid chain can be ionized at an acidic condition and interact with mRNAs. The structures of these vitamin-derived lipids were confirmed by 1 H NMR and mass spectrometry (Supplementary Figs. 1 – 5 ). Next, we formulated these vitamin-derived lipids into vitamin lipid nanoparticles (VLNPs). The particle size of the VLNPs ranged from 127 ± 1 to 174 ± 1 nm with a polydispersity index (PDI) < 0.3 except in vitamin H lipid nanoparticles (V H LNPs; Supplementary Fig.<|im_end|> <|im_start|>assistant Researchers have developed a way to prop up a struggling immune system to enable its fight against sepsis, a deadly condition resulting from the body's extreme reaction to infection. The scientists used nanotechnology to transform donated healthy immune cells into a drug with enhanced power to kill bacteria. In experiments treating mice with sepsis, the engineered immune cells eliminated bacteria in blood and major organs, dramatically improving survival rates. This work focuses on a treatment for late-stage sepsis, when the immune system is compromised and unable to clear invading bacteria. The scientists are collaborating with clinicians specializing in sepsis treatment to accelerate the drug-development process. "Sepsis remains the leading cause of death in hospitals. There hasn't been an effective treatment for late-stage sepsis for a long time. We're thinking this cell therapy can help patients who get to the late stage of sepsis," said Yizhou Dong, senior author and associate professor of pharmaceutics and pharmacology at The Ohio State University. "For translation in the clinic, we believe this could be used in combination with current intensive-care treatment for sepsis patients." The study is published today in Nature Nanotechnology. Sepsis itself is not an infection—it's a life-threatening systemic response to infection that can lead to tissue damage, organ failure and death, according to The Centers for Disease Control and Prevention. The CDC estimates that 1.7 million adults in the United States develop sepsis each year, and one in three patients who die in a hospital have sepsis. This work combined two primary types of technology: using vitamins as the main component in making lipid nanoparticles, and using those nanoparticles to capitalize on natural cell processes in the creation of a new antibacterial drug. Cells called macrophages are one of the first responders in the immune system, with the job of "eating" invading pathogens. However, in patients with sepsis, the number of macrophages and other immune cells are lower than normal and they don't function as they should. In this study, Dong and colleagues collected monocytes from the bone marrow of healthy mice and cultured them in conditions that transformed them into macrophages. (Monocytes are white blood cells that are able to differentiate into other types of immune cells.) The lab also developed vitamin-based nanoparticles that were especially good at delivering messenger RNA, molecules that translate genetic information into functional proteins. The scientists, who specialize in messenger RNA for therapeutic purposes, constructed a messenger RNA encoding an antimicrobial peptide and a signal protein. The signal protein enabled the specific accumulation of the antimicrobial peptide in internal macrophage structures called lysosomes, the key location for bacteria-killing activities. From here, researchers delivered the nanoparticles loaded with that messenger RNA into the macrophages they had produced with donor monocytes, and let the cells take it from there to "manufacture" a new therapy. "Macrophages have antibacterial activity naturally. So if we add the additional antibacterial peptide into the cell, those antibacterial peptides can further enhance the antibacterial activity and help the whole macrophage clear bacteria," Dong said. After seeing promising results in cell tests, the researchers administered the cell therapy to mice. The mouse models of sepsis in this study were infected with multidrug-resistant Staphylococcus aureus and E. coli and their immune systems were suppressed. Each treatment consisted of about 4 million engineered macrophages. Controls for comparison included ordinary macrophages and a placebo. Compared to controls, the treatment resulted in a significant reduction in bacteria in the blood after 24 hours—and for those with lingering bacteria in the blood, a second treatment cleared them away. Dong considers the lipid nanoparticle delivery of messenger RNA into certain kinds of immune cells applicable to other diseases, and his lab is currently working on development of cancer immunotherapy using this technology. <|im_end|>

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6514, 23803, 1124, 3201, 13, 53483, 32238, 279, 68700, 76307, 7203, 9889, 315, 50596, 41214, 1139, 3738, 13124, 315, 22852, 7917, 8581, 311, 1023, 19338, 11, 323, 813, 10278, 374, 5131, 3318, 389, 4500, 315, 9572, 33119, 42811, 1701, 420, 5557, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Lung ageing, a significant risk factor for chronic human lung diseases such as COPD and emphysema, is characterised by airspace enlargement and decreasing lung function. Likewise, in prematurely ageing telomerase null (terc−/−) mice, p53 stabilisation within diminishing numbers of alveolar epithelial type 2 cells (AEC2) accompanies reduced lung function. Resveratrol (RSL) is a plant phytoalexin that has previously showed efficacy in enhancing invertebrate longevity and supporting mammalian muscle metabolism when delivered orally. Here, we tested whether inhaled RSL could protect young, terc−/− mice from accelerated ageing of the lung. Methods terc−/− mice aged 2 months inhaled 1 mg/kg RSL that was instilled intratracheally once per month for 3 months. One month after the last inhalation, whole lung function, structure and cellular DNA damage were evaluated and AEC2 survival was assessed by western blotting for survival pathway gene expression. Results RSL treatments delayed the loss of lung compliance (p<0.05), maintained lung structure (p<0.001) and blocked parenchymal cell DNA damage as measured by TdT Nick-End Labeling (TUNEL). RSL, a known agonist of deacetylase SIRT1, supported AEC2 survival by stimulating SIRT1 expression, promoting p53 destabilisation and decreasing Bax expression and by maintaining expression levels of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), activated p-Akt and p-Mdm2 and inactivated Phospho-Phosphatase and tensin homolog (p-PTEN). Conclusions RSL prophylaxis by inhalation is a potential approach for slowing ageing-related deterioration of lung function and structure by maintaining AEC2 integrity. Airway Epithelium COPD Pathology Histology/Cytology Lung Physiology Respiratory Measurement googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 9 news outlets Blogged by 1 Tweeted by 38 On 4 Facebook pages 48 readers on Mendeley Linked Articles Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version=\"1.0\" encoding=\"UTF-8\" ? Request permissions Airway Epithelium COPD Pathology Histology/Cytology Lung Physiology Respiratory Measurement Key messages What is the key question? Can the accumulation of ageing-related degenerative changes in the lung be slowed by inhaled, prophylactic treatments? What is the bottom line? Inhaled, prophylactic resveratrol treatments can slow the rate of the lung function decline, alveolar enlargement and alveolar epithelial type 2 cell DNA damage that occurs in the early stages of lung ageing. Why read on? Administration of resveratrol directly to the lungs may be an effective intervention for lung ageing, which is a major risk factor for development of chronic lung disease. Introduction In healthy young adults, breathing is an essential, efficient process, but natural ageing of the lung then occurs at a steady and irreversible rate, as measured by an inexorable decline in lung function. 1–3 Altered properties of lung structure and compromise of cell populations due to wear, telomere shortening, increased senescence and regenerative stem cell failure drive this process. 4–7 Thus, natural deterioration leads to a significantly reduced quality of life, over a time frame dependent on genetic and environmental factors. Although some available therapies can ameliorate symptoms, ageing-related lung failure is generally irreversible and is accompanied by high rates of morbidity and mortality due to increased disease risk, including development of COPD, with accompanying emphysema and chronic bronchitis. 8 Mouse models are becoming increasingly informative for determining specific mechanisms that contribute to irreversible lung ageing. 9 The terc−/− mouse is a serviceable model of accelerated ageing. 10 In humans, telomere shortening has been linked to development of lung fibrosis and emphysema. 11 Our laboratory has previously shown that terc−/− mice also exhibit several hallmarks of ageing in both whole lung and in alveolar epithelial type 2 cells (AEC2), which have been identified as stem cells of the adult lung alveoli. 12 We showed that whole lung structure, collagen deposition, AEC2 integrity and the ability to survive and regenerate lung tissue following partial pneumonectomy are compromised in the terc−/− model, in a way tightly correlated to telomere length. 13 , 14 Armanios and Hogan recently showed that telomere dysfunction, specifically in AEC2, causes whole organ vulnerability to lung injury. 15 Taken together, these studies show that the AEC2 population is both a marker of, and a critical target for, lung ageing. Despite evidence that shows AEC2 integrity plays a significant role in maintaining lung health and homeostasis, there is currently little understanding of how to inhibit loss of AEC2 or replenish the population, or what impact AEC2 preservation might have on whole lung ageing. Resveratrol (RSL) is an agonist of sirtuin deacetylase SIRT1. 16 , 17 Sirtuins are master regulators of metabolism with multiple targets. 18 , 19 SIRT1 deacetylates Trp53, which destabilises it and leads to cell cycle entry and inhibition of apoptosis. 20 , 21 The role of Trp53 stabilisation in increased lung disease risk and decreased ability to respond to injury has recently been recognised by our lab and others. 11 , 13 , 14 , 22 SIRT1 also activates PGC-1α, a master regulator of mitochondrial biogenesis. 23 , 24 SIRT1 expression and activity decrease with age and the onset of ageing-related diseases, including COPD. 8 , 16 , 25 While RSL treatment effectively extends lifespan in lower organisms, 26 this result has not been directly duplicated in mice or humans. 27 , 28 Controversies regarding effective RSL dose, administration strategies and efficacy still exist. However, there current data indicate that RSL may extend the mammalian healthspan by supporting the efficient function of critical organs and their progenitor populations over the lifetime of the organism, potentially including the lung. 29–32 To determine whether prophylactic RSL inhalational treatments of terc−/− mice aged 2–4 months from the second filial (F2) generation (terc−/−F2) could preserve youthful whole lung function and AEC2 survival, cohorts aged 2 months received either RSL or vehicle by intratracheal (IT) instillation once per month for 3 months. One month following the final treatment, whole lung function was assessed by plethysmography and whole lung tissue and AEC2", "role": "user" }, { "content": "In a study led by Barbara Driscoll, PhD, of The Saban Research Institute of Children's Hospital Los Angeles, researchers demonstrate, for the first time that inhaled resveratrol treatments slow aging-related degenerative changes in mouse lung. Lung aging, characterized by airspace enlargement and decreasing lung function, is a significant risk factor for chronic human lung diseases. The study is published online in the journal Thorax. \"We believe that ours is the first study to demonstrate a beneficial effect of lung-directed resveratrol treatments on aging lung function,\" said Driscoll. Resveratrol (RSL), a chemical found in red wine, is an antimicrobial chemical substance produced by plants to protect against infection and stress-related changes. It has previously been shown to support muscle metabolism when delivered orally. RSL prophylaxis by inhalation was a novel measure taken by the research team as a potential approach for slowing age-related deterioration of lung function and structure by preserving alveolar epithelial type 2 cells (AEC2) which line alveoli (the tiny air sacs in the lungs through which the exchange of oxygen and carbon dioxide takes place) and produce surfactant which is vital for efficient breathing. In healthy young adults, breathing is an essential, efficient process, but natural aging of the lung occurs at a steady and irreversible rate, as measured by a decline in lung function. This natural deterioration leads to a significantly reduced quality of life, over a time frame dependent on genetic and environmental factors. Although some available therapies can ameliorate symptoms, aging-related lung failure is generally irreversible and is accompanied by high rates of morbidity and mortality due to increased disease risk, including development of COPD, with accompanying emphysema and chronic bronchitis. Using a rapidly aging mouse model, the research team investigated whether the accumulation of age-related degenerative changes in the lung could be slowed by inhaled RSL. Treatment cohorts received either RSL or vehicle by intratracheal (IT) instillation monthly for three months. One month following the final treatment, whole lung function and injury-related gene expression in AEC2 were assessed. The research team found that inhaled, prophylactic resveratrol treatments can slow the rate of lung function decline, alveolar enlargement and alveolar epithelial type 2 cell DNA damage that occurs in the early stages of lung aging. They concluded that administration of resveratrol directly to the lungs may be an effective intervention for lung aging, which is a significant risk factor for development of chronic lung disease. \"While the natural deterioration of the human lung generally occurs over decades, the injury to lung cells is analogous to the lung cell damage that occurs in premature infants who experience respiratory distress before their lungs have fully developed,\" added Driscoll. \"Identifying a way to protect and strengthen young lungs before significant damage occurs is the goal of our research.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Lung ageing, a significant risk factor for chronic human lung diseases such as COPD and emphysema, is characterised by airspace enlargement and decreasing lung function. Likewise, in prematurely ageing telomerase null (terc−/−) mice, p53 stabilisation within diminishing numbers of alveolar epithelial type 2 cells (AEC2) accompanies reduced lung function. Resveratrol (RSL) is a plant phytoalexin that has previously showed efficacy in enhancing invertebrate longevity and supporting mammalian muscle metabolism when delivered orally. Here, we tested whether inhaled RSL could protect young, terc−/− mice from accelerated ageing of the lung. Methods terc−/− mice aged 2 months inhaled 1 mg/kg RSL that was instilled intratracheally once per month for 3 months. One month after the last inhalation, whole lung function, structure and cellular DNA damage were evaluated and AEC2 survival was assessed by western blotting for survival pathway gene expression. Results RSL treatments delayed the loss of lung compliance (p<0.05), maintained lung structure (p<0.001) and blocked parenchymal cell DNA damage as measured by TdT Nick-End Labeling (TUNEL). RSL, a known agonist of deacetylase SIRT1, supported AEC2 survival by stimulating SIRT1 expression, promoting p53 destabilisation and decreasing Bax expression and by maintaining expression levels of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), activated p-Akt and p-Mdm2 and inactivated Phospho-Phosphatase and tensin homolog (p-PTEN). Conclusions RSL prophylaxis by inhalation is a potential approach for slowing ageing-related deterioration of lung function and structure by maintaining AEC2 integrity. Airway Epithelium COPD Pathology Histology/Cytology Lung Physiology Respiratory Measurement googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 9 news outlets Blogged by 1 Tweeted by 38 On 4 Facebook pages 48 readers on Mendeley Linked Articles Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version="1.0" encoding="UTF-8" ? Request permissions Airway Epithelium COPD Pathology Histology/Cytology Lung Physiology Respiratory Measurement Key messages What is the key question? Can the accumulation of ageing-related degenerative changes in the lung be slowed by inhaled, prophylactic treatments? What is the bottom line? Inhaled, prophylactic resveratrol treatments can slow the rate of the lung function decline, alveolar enlargement and alveolar epithelial type 2 cell DNA damage that occurs in the early stages of lung ageing. Why read on? Administration of resveratrol directly to the lungs may be an effective intervention for lung ageing, which is a major risk factor for development of chronic lung disease. Introduction In healthy young adults, breathing is an essential, efficient process, but natural ageing of the lung then occurs at a steady and irreversible rate, as measured by an inexorable decline in lung function. 1–3 Altered properties of lung structure and compromise of cell populations due to wear, telomere shortening, increased senescence and regenerative stem cell failure drive this process. 4–7 Thus, natural deterioration leads to a significantly reduced quality of life, over a time frame dependent on genetic and environmental factors. Although some available therapies can ameliorate symptoms, ageing-related lung failure is generally irreversible and is accompanied by high rates of morbidity and mortality due to increased disease risk, including development of COPD, with accompanying emphysema and chronic bronchitis. 8 Mouse models are becoming increasingly informative for determining specific mechanisms that contribute to irreversible lung ageing. 9 The terc−/− mouse is a serviceable model of accelerated ageing. 10 In humans, telomere shortening has been linked to development of lung fibrosis and emphysema. 11 Our laboratory has previously shown that terc−/− mice also exhibit several hallmarks of ageing in both whole lung and in alveolar epithelial type 2 cells (AEC2), which have been identified as stem cells of the adult lung alveoli. 12 We showed that whole lung structure, collagen deposition, AEC2 integrity and the ability to survive and regenerate lung tissue following partial pneumonectomy are compromised in the terc−/− model, in a way tightly correlated to telomere length. 13 , 14 Armanios and Hogan recently showed that telomere dysfunction, specifically in AEC2, causes whole organ vulnerability to lung injury. 15 Taken together, these studies show that the AEC2 population is both a marker of, and a critical target for, lung ageing. Despite evidence that shows AEC2 integrity plays a significant role in maintaining lung health and homeostasis, there is currently little understanding of how to inhibit loss of AEC2 or replenish the population, or what impact AEC2 preservation might have on whole lung ageing. Resveratrol (RSL) is an agonist of sirtuin deacetylase SIRT1. 16 , 17 Sirtuins are master regulators of metabolism with multiple targets. 18 , 19 SIRT1 deacetylates Trp53, which destabilises it and leads to cell cycle entry and inhibition of apoptosis. 20 , 21 The role of Trp53 stabilisation in increased lung disease risk and decreased ability to respond to injury has recently been recognised by our lab and others. 11 , 13 , 14 , 22 SIRT1 also activates PGC-1α, a master regulator of mitochondrial biogenesis. 23 , 24 SIRT1 expression and activity decrease with age and the onset of ageing-related diseases, including COPD. 8 , 16 , 25 While RSL treatment effectively extends lifespan in lower organisms, 26 this result has not been directly duplicated in mice or humans. 27 , 28 Controversies regarding effective RSL dose, administration strategies and efficacy still exist. However, there current data indicate that RSL may extend the mammalian healthspan by supporting the efficient function of critical organs and their progenitor populations over the lifetime of the organism, potentially including the lung. 29–32 To determine whether prophylactic RSL inhalational treatments of terc−/− mice aged 2–4 months from the second filial (F2) generation (terc−/−F2) could preserve youthful whole lung function and AEC2 survival, cohorts aged 2 months received either RSL or vehicle by intratracheal (IT) instillation once per month for 3 months. One month following the final treatment, whole lung function was assessed by plethysmography and whole lung tissue and AEC2<|im_end|> <|im_start|>assistant In a study led by Barbara Driscoll, PhD, of The Saban Research Institute of Children's Hospital Los Angeles, researchers demonstrate, for the first time that inhaled resveratrol treatments slow aging-related degenerative changes in mouse lung. Lung aging, characterized by airspace enlargement and decreasing lung function, is a significant risk factor for chronic human lung diseases. The study is published online in the journal Thorax. "We believe that ours is the first study to demonstrate a beneficial effect of lung-directed resveratrol treatments on aging lung function," said Driscoll. Resveratrol (RSL), a chemical found in red wine, is an antimicrobial chemical substance produced by plants to protect against infection and stress-related changes. It has previously been shown to support muscle metabolism when delivered orally. RSL prophylaxis by inhalation was a novel measure taken by the research team as a potential approach for slowing age-related deterioration of lung function and structure by preserving alveolar epithelial type 2 cells (AEC2) which line alveoli (the tiny air sacs in the lungs through which the exchange of oxygen and carbon dioxide takes place) and produce surfactant which is vital for efficient breathing. In healthy young adults, breathing is an essential, efficient process, but natural aging of the lung occurs at a steady and irreversible rate, as measured by a decline in lung function. This natural deterioration leads to a significantly reduced quality of life, over a time frame dependent on genetic and environmental factors. Although some available therapies can ameliorate symptoms, aging-related lung failure is generally irreversible and is accompanied by high rates of morbidity and mortality due to increased disease risk, including development of COPD, with accompanying emphysema and chronic bronchitis. Using a rapidly aging mouse model, the research team investigated whether the accumulation of age-related degenerative changes in the lung could be slowed by inhaled RSL. Treatment cohorts received either RSL or vehicle by intratracheal (IT) instillation monthly for three months. One month following the final treatment, whole lung function and injury-related gene expression in AEC2 were assessed. The research team found that inhaled, prophylactic resveratrol treatments can slow the rate of lung function decline, alveolar enlargement and alveolar epithelial type 2 cell DNA damage that occurs in the early stages of lung aging. They concluded that administration of resveratrol directly to the lungs may be an effective intervention for lung aging, which is a significant risk factor for development of chronic lung disease. "While the natural deterioration of the human lung generally occurs over decades, the injury to lung cells is analogous to the lung cell damage that occurs in premature infants who experience respiratory distress before their lungs have fully developed," added Driscoll. "Identifying a way to protect and strengthen young lungs before significant damage occurs is the goal of our research." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract SLITRK2 is a single-pass transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse maintenance. In the present study, we report on rare variants (one nonsense and six missense variants) in SLITRK2 on the X chromosome identified by exome sequencing in individuals with neurodevelopmental disorders. Functional studies showed that some variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Strikingly, these variations abolished the ability of SLITRK2 wild-type to reduce the levels of the receptor tyrosine kinase TrkB in neurons. Moreover, Slitrk2 conditional knockout mice exhibited impaired long-term memory and abnormal gait, recapitulating a subset of clinical features of patients with SLITRK2 variants. Furthermore, impaired excitatory synapse maintenance induced by hippocampal CA1-specific cKO of Slitrk2 caused abnormalities in spatial reference memory. Collectively, these data suggest that SLITRK2 is involved in X-linked neurodevelopmental disorders that are caused by perturbation of diverse facets of SLITRK2 function. Introduction Intellectual disability (ID) affects about 3% of the general population and is the most common reason for referral to genetic centers. It is estimated that at least half of cases have a monogenic cause, with more than 1000 genes corresponding to an equivalent number of rare diseases currently identified. The most frequently identified genes are responsible for at most 0.5% of cases. All modes of transmission—autosomal dominant, recessive, and X-linked (dominant or recessive)—are observed. Because of the disproportionate number of males among individuals with ID and the possibility of performing genetic studies of X-linked patterns of inheritance in large families, special attention has been paid to identifying the genetic basis of X-linked ID (XLID). Prior to the advent of next-generation sequencing (NGS), major efforts by the EuroMRX consortium, the Sanger Center, and other international groups encompassing thousands of families 1 , 2 , 3 , 4 , led to the identification of a large number of XLID genes. The generalization of NGS approaches, including exome sequencing and whole-genome sequencing has greatly accelerated the discovery of autosomal and XLID genes and increased the diagnostic yield of ID, resulting in a shortened diagnostic odyssey for families and expanded access to genetic counseling, including prenatal and pre-implantation genetic diagnosis. Thus, there are now about ~130 identified XLID genes, with an additional ~50 potential candidate XLID genes 5 , 6 , 7 . These include SLITRK2 , a gene encoding a transmembrane protein that is highly expressed in the brain. Slit- and Trk-like family proteins, composed of six members (Slitrk1-6), are type I transmembrane proteins that are strongly expressed in the central nervous system 8 , 9 . Intriguingly, Slitrks positively regulate excitatory and inhibitory synapse development in cultured hippocampal neurons in a paralog-dependent manner 10 , 11 . Extensive analyses have shown that Slitrks interact with distinct members of the LAR-RPTP (leukocyte common antigen-related receptor protein tyrosine phosphatase) family to promote presynaptic assembly 10 , 12 . In addition, Slitrk5 interacts with receptor tyrosine kinase TrkB in cis to regulate their interactions with LAR-RPTPs 13 . Structural analyses have further demonstrated that the N-terminal leucine-rich repeat 1 (LRR1) of Slitrks interacts with splicing variants of LAR-RPTPs that contain an insert at the MeB site 14 , 15 . Divergent intracellular mechanisms of Slitrk2 and Slitrk3 also appear to be involved in their synaptic functions 16 , 17 . Furthermore, systematic analyses to investigate the effects of previously reported SLITRK missense variants revealed that a subset of SLITRK variants associated with neuropsychiatric disorders 18 disrupt the trafficking of Slitrks to the cell surface and impair their synapse-promoting function 19 . Collectively, these prior studies have established Slitrks as important synapse organizers. The precise role of the Slitrk2 protein has not yet been clearly defined. The human SLITRK2 gene is located on the X chromosome, and two missense variants, p. S549F and p.V89M, were reported to be associated with schizophrenia in two female patients who inherited the missense variants from their asymptomatic heterozygous mothers 18 . Furthermore, SLITRK2 interacts with the PDZ domain-containing excitatory scaffold Shank3 17 , a gene associated with autism spectrum disorders (ASDs) 20 , suggesting its potential involvement in the pathogenesis of neurodevelopmental disorders (NDD). Here, we report that eight individuals from seven unrelated families with moderate to severe ID and/or NDDs, including neuropsychiatric and behavioral problems, harbor rare potential disease-causing variants of the X-linked gene, SLITRK2 . We systemically investigated the effects of SLITRK2 variants on biochemical properties, surface transport, ligand-binding activity, and synaptogenic activities in cultured neurons. In addition, we analyzed the synaptic and behavioral effects of a Slitrk2 deficiency using Slitrk2 conditional knockout (cKO) mice. Results Identification of individuals with rare variants i n SLITRK2 Exome sequencing, used as a diagnostic approach in individual P1, identified a nonsense c.1381G>T p.E461* variant in the SLITRK2 gene (Table 1 and Fig. S 1a ). Sanger sequencing confirmed that this variant was present in his affected brother (P2), but absent from mother’s blood, suggesting a de novo occurrence in the maternal germ line (Fig. 1 and Fig. S 1a ). Because the SLITRK2 gene contains only one coding exon, we suspected that the mutant transcript does not undergo nonsense mRNA-mediated decay. Through an international data-sharing arrangement initiated through Genematcher 21 , we identified six additional individuals with NDDs carrying rare nonsynonymous SLITRK2 variants predicted to be damaging. Among those were six missense variants—c.221T>C p.L74S (P7), c.628G>A p.E210K (P10), c.934A>G p.T312A (P3), c.1121C>G p.P374R (P8), c.1276C>T p.R426C (P4) and c.1531G>A p.V511M (P5), all found in male individuals (except p.R426C)—that were not previously reported in hemizygous state in gnomAD (Table S1 ). In all but one of these individuals, no other diagnostic candidate variants were identified during exome sequencing analyses. In P7, a likely pathogenic variant in the homeobox transcription factor ARX (c.1109C>T p.A370V) was identified but this did not seem likely to fully explain the patient’s phenotype, suggesting that the p.L74S variant identified in SLITRK2 contributes to the observed symptoms. One variant (p.R426C) occurred de novo, and extended segregation analyses showed that one maternally inherited variant (p.P374R) occurred de novo in the", "role": "user" }, { "content": "A joint research team of Daegu Gyeongbuk Institute of Science and Technology professors Um Ji-won and Ko Jae-won of the Department of Brain Sciences reported a new genetic mutation related to intellectual disability and discovered an excitatory synaptic activation signaling mechanism related to the mutation. The discovery is expected to present a new research direction to the treatment of brain developmental disorders by coordinating the excitatory synaptic signaling activity. A synapse is a special channel that transmits neural information quickly and accurately, and it controls all brain functions. Synapses are divided into excitatory synapses and inhibitory synapses. These synapses cooperate with each other so that brain functions work normally and maintain the balance of the neural circuit network. It is known that various brain developmental diseases, mental diseases, degenerative brain diseases, etc. occur when this balance is disturbed. Meanwhile, synaptic adhesion proteins bind with each other physically and chemically and then transmit cellular signals in both directions. However, how signals are transmitted within cells by this binding has not been clearly shown. Since 2013, a joint research team led by Professor Um Ji-won and Ko Jae-won discovered many synaptic adhesion proteins and studied their functions. In particular, the research team identified the Slitrk synaptic adhesive protein group as a key factor involved in the development of excitatory and inhibitory synapses. Among these, Slitrk2 protein is specifically involved in the formation of excitatory synapses, and is closely related to brain diseases such as X-linked intellectual disability, autism, intellectual disability, etc. Various SlitTrack2 gene mutations related to schizophrenia and bipolar disorder have actually been reported previously, but how these mutations affect the function of the SlitTrack2 protein and cause brain disease has not been clearly known. This study detected various SlitTrack2 gene mutations that were not previously reported through exome sequencing in patients with brain, mental and developmental disorders and systematically analyzed how these mutations affect the structure and function of the SlitTrack2 protein. In particular, the research team found that some of the mutations inhibited the excitatory synaptic neuro-transmission process by disrupting the SlitTrack2 protein functions from being properly expressed in the cell membrane. Interestingly, all of the novel SlitTrack2 mutations associated with brain developmental diseases abnormally altered the expression and activity of track B receptors. Track B receptors are important proteins that work with BDNF factor to mediate synaptic development. Its association with brain developmental diseases such as autism is also well known. The results of this study are expected to provide important clues for the development of new therapeutics for psychiatric disorders targeting the SlitTrack2-TrackB complex. Professor Um Ji-won of the Department of Brain Sciences at DGIST says that \"this study is the first thesis that presents key evidences that a problem in the SlitTrack2 gene can cause X chromosome-related intellectual disability in collaboration with overseas clinical geneticists.\" Professor Ko Jae-won says that \"this suggests that the SlitTrk2-TrkB complex can be an important biomarker for related brain developmental diseases, and we are currently carrying out follow-up studies.\" The research was published in Nature Communications. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract SLITRK2 is a single-pass transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse maintenance. In the present study, we report on rare variants (one nonsense and six missense variants) in SLITRK2 on the X chromosome identified by exome sequencing in individuals with neurodevelopmental disorders. Functional studies showed that some variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Strikingly, these variations abolished the ability of SLITRK2 wild-type to reduce the levels of the receptor tyrosine kinase TrkB in neurons. Moreover, Slitrk2 conditional knockout mice exhibited impaired long-term memory and abnormal gait, recapitulating a subset of clinical features of patients with SLITRK2 variants. Furthermore, impaired excitatory synapse maintenance induced by hippocampal CA1-specific cKO of Slitrk2 caused abnormalities in spatial reference memory. Collectively, these data suggest that SLITRK2 is involved in X-linked neurodevelopmental disorders that are caused by perturbation of diverse facets of SLITRK2 function. Introduction Intellectual disability (ID) affects about 3% of the general population and is the most common reason for referral to genetic centers. It is estimated that at least half of cases have a monogenic cause, with more than 1000 genes corresponding to an equivalent number of rare diseases currently identified. The most frequently identified genes are responsible for at most 0.5% of cases. All modes of transmission—autosomal dominant, recessive, and X-linked (dominant or recessive)—are observed. Because of the disproportionate number of males among individuals with ID and the possibility of performing genetic studies of X-linked patterns of inheritance in large families, special attention has been paid to identifying the genetic basis of X-linked ID (XLID). Prior to the advent of next-generation sequencing (NGS), major efforts by the EuroMRX consortium, the Sanger Center, and other international groups encompassing thousands of families 1 , 2 , 3 , 4 , led to the identification of a large number of XLID genes. The generalization of NGS approaches, including exome sequencing and whole-genome sequencing has greatly accelerated the discovery of autosomal and XLID genes and increased the diagnostic yield of ID, resulting in a shortened diagnostic odyssey for families and expanded access to genetic counseling, including prenatal and pre-implantation genetic diagnosis. Thus, there are now about ~130 identified XLID genes, with an additional ~50 potential candidate XLID genes 5 , 6 , 7 . These include SLITRK2 , a gene encoding a transmembrane protein that is highly expressed in the brain. Slit- and Trk-like family proteins, composed of six members (Slitrk1-6), are type I transmembrane proteins that are strongly expressed in the central nervous system 8 , 9 . Intriguingly, Slitrks positively regulate excitatory and inhibitory synapse development in cultured hippocampal neurons in a paralog-dependent manner 10 , 11 . Extensive analyses have shown that Slitrks interact with distinct members of the LAR-RPTP (leukocyte common antigen-related receptor protein tyrosine phosphatase) family to promote presynaptic assembly 10 , 12 . In addition, Slitrk5 interacts with receptor tyrosine kinase TrkB in cis to regulate their interactions with LAR-RPTPs 13 . Structural analyses have further demonstrated that the N-terminal leucine-rich repeat 1 (LRR1) of Slitrks interacts with splicing variants of LAR-RPTPs that contain an insert at the MeB site 14 , 15 . Divergent intracellular mechanisms of Slitrk2 and Slitrk3 also appear to be involved in their synaptic functions 16 , 17 . Furthermore, systematic analyses to investigate the effects of previously reported SLITRK missense variants revealed that a subset of SLITRK variants associated with neuropsychiatric disorders 18 disrupt the trafficking of Slitrks to the cell surface and impair their synapse-promoting function 19 . Collectively, these prior studies have established Slitrks as important synapse organizers. The precise role of the Slitrk2 protein has not yet been clearly defined. The human SLITRK2 gene is located on the X chromosome, and two missense variants, p. S549F and p.V89M, were reported to be associated with schizophrenia in two female patients who inherited the missense variants from their asymptomatic heterozygous mothers 18 . Furthermore, SLITRK2 interacts with the PDZ domain-containing excitatory scaffold Shank3 17 , a gene associated with autism spectrum disorders (ASDs) 20 , suggesting its potential involvement in the pathogenesis of neurodevelopmental disorders (NDD). Here, we report that eight individuals from seven unrelated families with moderate to severe ID and/or NDDs, including neuropsychiatric and behavioral problems, harbor rare potential disease-causing variants of the X-linked gene, SLITRK2 . We systemically investigated the effects of SLITRK2 variants on biochemical properties, surface transport, ligand-binding activity, and synaptogenic activities in cultured neurons. In addition, we analyzed the synaptic and behavioral effects of a Slitrk2 deficiency using Slitrk2 conditional knockout (cKO) mice. Results Identification of individuals with rare variants i n SLITRK2 Exome sequencing, used as a diagnostic approach in individual P1, identified a nonsense c.1381G>T p.E461* variant in the SLITRK2 gene (Table 1 and Fig. S 1a ). Sanger sequencing confirmed that this variant was present in his affected brother (P2), but absent from mother’s blood, suggesting a de novo occurrence in the maternal germ line (Fig. 1 and Fig. S 1a ). Because the SLITRK2 gene contains only one coding exon, we suspected that the mutant transcript does not undergo nonsense mRNA-mediated decay. Through an international data-sharing arrangement initiated through Genematcher 21 , we identified six additional individuals with NDDs carrying rare nonsynonymous SLITRK2 variants predicted to be damaging. Among those were six missense variants—c.221T>C p.L74S (P7), c.628G>A p.E210K (P10), c.934A>G p.T312A (P3), c.1121C>G p.P374R (P8), c.1276C>T p.R426C (P4) and c.1531G>A p.V511M (P5), all found in male individuals (except p.R426C)—that were not previously reported in hemizygous state in gnomAD (Table S1 ). In all but one of these individuals, no other diagnostic candidate variants were identified during exome sequencing analyses. In P7, a likely pathogenic variant in the homeobox transcription factor ARX (c.1109C>T p.A370V) was identified but this did not seem likely to fully explain the patient’s phenotype, suggesting that the p.L74S variant identified in SLITRK2 contributes to the observed symptoms. One variant (p.R426C) occurred de novo, and extended segregation analyses showed that one maternally inherited variant (p.P374R) occurred de novo in the<|im_end|> <|im_start|>assistant A joint research team of Daegu Gyeongbuk Institute of Science and Technology professors Um Ji-won and Ko Jae-won of the Department of Brain Sciences reported a new genetic mutation related to intellectual disability and discovered an excitatory synaptic activation signaling mechanism related to the mutation. The discovery is expected to present a new research direction to the treatment of brain developmental disorders by coordinating the excitatory synaptic signaling activity. A synapse is a special channel that transmits neural information quickly and accurately, and it controls all brain functions. Synapses are divided into excitatory synapses and inhibitory synapses. These synapses cooperate with each other so that brain functions work normally and maintain the balance of the neural circuit network. It is known that various brain developmental diseases, mental diseases, degenerative brain diseases, etc. occur when this balance is disturbed. Meanwhile, synaptic adhesion proteins bind with each other physically and chemically and then transmit cellular signals in both directions. However, how signals are transmitted within cells by this binding has not been clearly shown. Since 2013, a joint research team led by Professor Um Ji-won and Ko Jae-won discovered many synaptic adhesion proteins and studied their functions. In particular, the research team identified the Slitrk synaptic adhesive protein group as a key factor involved in the development of excitatory and inhibitory synapses. Among these, Slitrk2 protein is specifically involved in the formation of excitatory synapses, and is closely related to brain diseases such as X-linked intellectual disability, autism, intellectual disability, etc. Various SlitTrack2 gene mutations related to schizophrenia and bipolar disorder have actually been reported previously, but how these mutations affect the function of the SlitTrack2 protein and cause brain disease has not been clearly known. This study detected various SlitTrack2 gene mutations that were not previously reported through exome sequencing in patients with brain, mental and developmental disorders and systematically analyzed how these mutations affect the structure and function of the SlitTrack2 protein. In particular, the research team found that some of the mutations inhibited the excitatory synaptic neuro-transmission process by disrupting the SlitTrack2 protein functions from being properly expressed in the cell membrane. Interestingly, all of the novel SlitTrack2 mutations associated with brain developmental diseases abnormally altered the expression and activity of track B receptors. Track B receptors are important proteins that work with BDNF factor to mediate synaptic development. Its association with brain developmental diseases such as autism is also well known. The results of this study are expected to provide important clues for the development of new therapeutics for psychiatric disorders targeting the SlitTrack2-TrackB complex. Professor Um Ji-won of the Department of Brain Sciences at DGIST says that "this study is the first thesis that presents key evidences that a problem in the SlitTrack2 gene can cause X chromosome-related intellectual disability in collaboration with overseas clinical geneticists." Professor Ko Jae-won says that "this suggests that the SlitTrk2-TrkB complex can be an important biomarker for related brain developmental diseases, and we are currently carrying out follow-up studies." The research was published in Nature Communications. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Cells release extracellular vesicles (EVs) to communicate over long distances, which requires EVs to traverse the extracellular matrix (ECM). However, given that the size of EVs is usually larger than the mesh size of the ECM, it is not clear how they can travel through the dense ECM. Here we show that, in contrast to synthetic nanoparticles, EVs readily transport through nanoporous ECM. Using engineered hydrogels, we demonstrate that the mechanical properties of the matrix regulate anomalous EV transport under confinement. Matrix stress relaxation allows EVs to overcome the confinement, and a higher crosslinking density facilitates a fluctuating transport motion through the polymer mesh, which leads to free diffusion and fast transport. Furthermore, water permeation through aquaporin-1 mediates the EV deformability, which further supports EV transport in hydrogels and a decellularized matrix. Our results provide evidence for the nature of EV transport within confined environments and demonstrate an unexpected dependence on matrix mechanics and water permeation. Main EVs are cell-derived particles found in the ECM 1 and described as ranging from 50 to 500 nm in diameter 2 . However, the ECM has a range of mechanical properties and often features average mesh sizes smaller than those of the EVs 3 (Fig. 1a ). Fig. 1: EVs transport within decellularized lung tissue. a , EVs exist within ECMs, where often the mesh size is smaller than the size of EVs. Mechanisms and dependencies directing their potential transport under confinement are unclear. b , Representative images of collagen (top left), K2S-EVs (bottom left) and combined (top middle) of decellularized lung tissue with EVs passively loaded, imaged using second harmonic multiphoton microscopy. Scale bars, 15 µm. A pixel intensity chart (bottom right) drawn along the dotted line in the combined image demonstrates that EVs existed along fibres as the K2S pixel intensity correlates strongly with the collagen pixel intensity. The mean Pearson’s correlation coefficient (top right) is reported for N = 9 regions of interest analysed across 3 pairs of background-subtracted images. * P < 10 −15 via an unpaired two-tailed t -test. Error bars denote the s.e.m. c , Mean % of EV released from the decellularized lung tissue over time with t 1/2 = 24.7 h. N = 5 tissue slices across 3 independent experiments. d , Representative images of EV load (after 72 h) and release (after 24 h) in decellularized lung tissue. a.u., arbitrary units. Scale bars, 2 mm. Error bars denote the s.d. Full size image To evaluate the extent to which EVs transport through the interstitial ECM, we engineered EVs from mouse mesenchymal stromal cells (MSCs) to contain the EV marker CD63 fused with Katushka2S (K2S, a far-red fluorescent protein 4 ) to visualize them after passive loading by incubation in a decellularized matrix from lung tissue. MSCs were chosen as the source of EVs because in vivo they are often present in interstitial regions surrounded by matrix 5 . The expression of CD63–K2S in EVs (K2S–EVs) did not alter their expected size distribution (diameter ( d ) ≈ 50–150 nm) (Supplementary Fig. 1a ). Multiphoton second harmonic imaging analysis showed that the EVs were distributed throughout the collagen fibres within the matrix (Fig. 1b ). Despite a nanoscale mean porosity (Supplementary Fig. 1b,c ) of the matrix, ~50% of the loaded CD63–K2S–EVs were released from the matrix within ~24.7 h (Fig. 1c,d ), which suggests that EVs readily transport through naturally derived nanoporous matrices. A decellularized matrix exhibited a complex shear modulus magnitude G * of ~750 Pa with a loss tangent (viscous modulus/elastic modulus, G ″/ G ′) of ~0.15 (Fig. 2a and Supplementary Fig. 2a ), and a stress relaxation behaviour ( t 1/2 ≈ 15 s) (Fig. 2b ). To determine whether the matrix mechanics mediates the EV transport, we engineered alginate-based hydrogels with a range of mechanical properties known to be present in tissues 6 . Importantly, alginate-based hydrogels are bio-inert, non-degradable and exhibit homogeneous nanoporous structures 7 , which makes them ideal to model ECM without the influence of biochemical or degrading interactions. Hydrogels can be crosslinked physically through divalent cations or covalently through click chemistry, and G * is tunable for both (Fig. 2c (left) and Supplementary Fig. 2b ). Physical crosslinking leads to stress relaxing hydrogels and covalent crosslinking leads to elastic hydrogels, as indicated by the loss tangent (Fig. 2c (right)) and stress relaxation times (Fig. 2d ) 8 . We consider G* ≈ 500 Pa as ‘soft’ and G* ≈ 3,000 Pa as ‘stiff’. Alginate-based hydrogels are nanoporous, like the decellularized matrix (Supplementary Fig. 2c ), regardless of the crosslinking density or type. This is consistent with the egg-box model of crosslinking between alginate chains 9 , in which increased crosslinking is not expected to dramatically alter the mesh size. As expected, after dextran–FITC (hydrodynamic radius ~15 nm (ref. 10 )) molecules were encapsulated in the hydrogels, most released completely within 24 hours (Fig. 2e ). In contrast, a minimal release was observed for polystyrene nanoparticles (NPs; d ≈ 80–100 nm) (Supplementary Fig. 2d ). As for decellularized tissue, some EVs released from the hydrogels; however, surprisingly, EV release was greater from stress relaxing hydrogels with a higher G *. This effect occurred for EVs from other cells (Supplementary Fig. 2e ), which suggests its generalizability across cell type. Liposomes with a similar size (Supplementary Fig. 2f ) and lipid content as those of EVs 11 did not exhibit a higher release from stress relaxing hydrogels with a higher G * (Supplementary Fig. 2g ). Hydrogels did not undergo degradation or loss of mass over the tested time period (Supplementary Fig. 3a ), which confirms the independence of degradation. Importantly, this observation is independent of Ca 2+ , as treatment with ionomycin or EGTA did not affect the release (Supplementary Fig. 3b,c ). To test whether the EV release is mechanosensitive in a more natural ECM composition, an interpenetrating network hydrogel of alginate and collagen-I polymers was fabricated 12 in which the hydrogel G *", "role": "user" }, { "content": "An extracellular vesicle—a nanoparticle released by cells—can use jerky movements similar to a car weaving in and out of traffic to navigate the obstacle-filled environment outside of cells, according to new discoveries made by researchers at the University of Illinois at Chicago. Their findings, published in Nature Nanotechnology, are a key first step to efficiently use extracellular vesicles, or EVs, as a therapeutic that targets diseases, such as lung injury and cancer. \"Although EVs were discovered over 30 years ago, many believed that EVs were cellular junk that was trapped in the extracellular matrix,\" said senior author Jae-Won Shin, UIC assistant professor of pharmacology and bioengineering at the College of Medicine. \"Within the last 10 years, the field has learned that EVs aren't junk. They play a critical role in sending signals for long-distance communication between cells.\" The extracellular matrix is a gel-like net of compacted protein chains and sugars that surrounds cells. To understand how billions of EVs navigate through the matrix, Shin's lab used improved imaging, vesicle labeling and motion capturing technologies that weren't available decades ago. \"We saw that the gaps in the matrix were smaller than the size of EVs and thought travel would be difficult,\" Shin said. \"It was a surprise when we observed that the EVs traveled much more readily than we thought in certain conditions.\" The researchers utilized an artificial matrix, called a hydrogel, to study whether its structure played a role in EV navigation. They customize the hydrogel's stiffness and how well the hydrogel could relax after being stressed by an object in order to make the hydrogel more or less like the matrix in the body. \"The EVs became stuck when the hydrogel couldn't relax over time, like rubber,\" said Stephen Lenzini, first author and UIC graduate student in the College of Engineering. \"The hydrogel needed to have a stiff backbone to provide some sort of structure, but after a stress it also had to relax enough to rearrange itself over time, which allowed the EVs to move around. The interesting finding was that this ability to move that occurred for EVs in some materials did not occur for synthetic particles of similar size.\" The same membrane that EVs use to protect their cargo also was essential for its own flexibility in tight spaces. When aquaporin-1—a membrane protein that allows water in and out of EVs—stopped functioning, the EVs became stuck. The permeation of water through aquaporin-1 in the membrane was essential for EVs to slip through the hydrogel gaps. \"This study has opened new avenues into studying the distribution of EVs and their contents through tissues,\" Lenzini said. The findings advance the UIC research group closer to engineering effective delivery systems, according to Shin. \"There are a range of diseases that undergo substantial changes in their environment. In fibrosis and some cancers, the tissues and matrix become more rigid as time progresses. In some cancers, the distribution of EVs have led to disease spreading,\" he said. \"So, understanding how EVs are dispersed is critical for developing these cell-free therapeutics and stopping disease progression.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Cells release extracellular vesicles (EVs) to communicate over long distances, which requires EVs to traverse the extracellular matrix (ECM). However, given that the size of EVs is usually larger than the mesh size of the ECM, it is not clear how they can travel through the dense ECM. Here we show that, in contrast to synthetic nanoparticles, EVs readily transport through nanoporous ECM. Using engineered hydrogels, we demonstrate that the mechanical properties of the matrix regulate anomalous EV transport under confinement. Matrix stress relaxation allows EVs to overcome the confinement, and a higher crosslinking density facilitates a fluctuating transport motion through the polymer mesh, which leads to free diffusion and fast transport. Furthermore, water permeation through aquaporin-1 mediates the EV deformability, which further supports EV transport in hydrogels and a decellularized matrix. Our results provide evidence for the nature of EV transport within confined environments and demonstrate an unexpected dependence on matrix mechanics and water permeation. Main EVs are cell-derived particles found in the ECM 1 and described as ranging from 50 to 500 nm in diameter 2 . However, the ECM has a range of mechanical properties and often features average mesh sizes smaller than those of the EVs 3 (Fig. 1a ). Fig. 1: EVs transport within decellularized lung tissue. a , EVs exist within ECMs, where often the mesh size is smaller than the size of EVs. Mechanisms and dependencies directing their potential transport under confinement are unclear. b , Representative images of collagen (top left), K2S-EVs (bottom left) and combined (top middle) of decellularized lung tissue with EVs passively loaded, imaged using second harmonic multiphoton microscopy. Scale bars, 15 µm. A pixel intensity chart (bottom right) drawn along the dotted line in the combined image demonstrates that EVs existed along fibres as the K2S pixel intensity correlates strongly with the collagen pixel intensity. The mean Pearson’s correlation coefficient (top right) is reported for N = 9 regions of interest analysed across 3 pairs of background-subtracted images. * P < 10 −15 via an unpaired two-tailed t -test. Error bars denote the s.e.m. c , Mean % of EV released from the decellularized lung tissue over time with t 1/2 = 24.7 h. N = 5 tissue slices across 3 independent experiments. d , Representative images of EV load (after 72 h) and release (after 24 h) in decellularized lung tissue. a.u., arbitrary units. Scale bars, 2 mm. Error bars denote the s.d. Full size image To evaluate the extent to which EVs transport through the interstitial ECM, we engineered EVs from mouse mesenchymal stromal cells (MSCs) to contain the EV marker CD63 fused with Katushka2S (K2S, a far-red fluorescent protein 4 ) to visualize them after passive loading by incubation in a decellularized matrix from lung tissue. MSCs were chosen as the source of EVs because in vivo they are often present in interstitial regions surrounded by matrix 5 . The expression of CD63–K2S in EVs (K2S–EVs) did not alter their expected size distribution (diameter ( d ) ≈ 50–150 nm) (Supplementary Fig. 1a ). Multiphoton second harmonic imaging analysis showed that the EVs were distributed throughout the collagen fibres within the matrix (Fig. 1b ). Despite a nanoscale mean porosity (Supplementary Fig. 1b,c ) of the matrix, ~50% of the loaded CD63–K2S–EVs were released from the matrix within ~24.7 h (Fig. 1c,d ), which suggests that EVs readily transport through naturally derived nanoporous matrices. A decellularized matrix exhibited a complex shear modulus magnitude G * of ~750 Pa with a loss tangent (viscous modulus/elastic modulus, G ″/ G ′) of ~0.15 (Fig. 2a and Supplementary Fig. 2a ), and a stress relaxation behaviour ( t 1/2 ≈ 15 s) (Fig. 2b ). To determine whether the matrix mechanics mediates the EV transport, we engineered alginate-based hydrogels with a range of mechanical properties known to be present in tissues 6 . Importantly, alginate-based hydrogels are bio-inert, non-degradable and exhibit homogeneous nanoporous structures 7 , which makes them ideal to model ECM without the influence of biochemical or degrading interactions. Hydrogels can be crosslinked physically through divalent cations or covalently through click chemistry, and G * is tunable for both (Fig. 2c (left) and Supplementary Fig. 2b ). Physical crosslinking leads to stress relaxing hydrogels and covalent crosslinking leads to elastic hydrogels, as indicated by the loss tangent (Fig. 2c (right)) and stress relaxation times (Fig. 2d ) 8 . We consider G* ≈ 500 Pa as ‘soft’ and G* ≈ 3,000 Pa as ‘stiff’. Alginate-based hydrogels are nanoporous, like the decellularized matrix (Supplementary Fig. 2c ), regardless of the crosslinking density or type. This is consistent with the egg-box model of crosslinking between alginate chains 9 , in which increased crosslinking is not expected to dramatically alter the mesh size. As expected, after dextran–FITC (hydrodynamic radius ~15 nm (ref. 10 )) molecules were encapsulated in the hydrogels, most released completely within 24 hours (Fig. 2e ). In contrast, a minimal release was observed for polystyrene nanoparticles (NPs; d ≈ 80–100 nm) (Supplementary Fig. 2d ). As for decellularized tissue, some EVs released from the hydrogels; however, surprisingly, EV release was greater from stress relaxing hydrogels with a higher G *. This effect occurred for EVs from other cells (Supplementary Fig. 2e ), which suggests its generalizability across cell type. Liposomes with a similar size (Supplementary Fig. 2f ) and lipid content as those of EVs 11 did not exhibit a higher release from stress relaxing hydrogels with a higher G * (Supplementary Fig. 2g ). Hydrogels did not undergo degradation or loss of mass over the tested time period (Supplementary Fig. 3a ), which confirms the independence of degradation. Importantly, this observation is independent of Ca 2+ , as treatment with ionomycin or EGTA did not affect the release (Supplementary Fig. 3b,c ). To test whether the EV release is mechanosensitive in a more natural ECM composition, an interpenetrating network hydrogel of alginate and collagen-I polymers was fabricated 12 in which the hydrogel G *<|im_end|> <|im_start|>assistant An extracellular vesicle—a nanoparticle released by cells—can use jerky movements similar to a car weaving in and out of traffic to navigate the obstacle-filled environment outside of cells, according to new discoveries made by researchers at the University of Illinois at Chicago. Their findings, published in Nature Nanotechnology, are a key first step to efficiently use extracellular vesicles, or EVs, as a therapeutic that targets diseases, such as lung injury and cancer. "Although EVs were discovered over 30 years ago, many believed that EVs were cellular junk that was trapped in the extracellular matrix," said senior author Jae-Won Shin, UIC assistant professor of pharmacology and bioengineering at the College of Medicine. "Within the last 10 years, the field has learned that EVs aren't junk. They play a critical role in sending signals for long-distance communication between cells." The extracellular matrix is a gel-like net of compacted protein chains and sugars that surrounds cells. To understand how billions of EVs navigate through the matrix, Shin's lab used improved imaging, vesicle labeling and motion capturing technologies that weren't available decades ago. "We saw that the gaps in the matrix were smaller than the size of EVs and thought travel would be difficult," Shin said. "It was a surprise when we observed that the EVs traveled much more readily than we thought in certain conditions." The researchers utilized an artificial matrix, called a hydrogel, to study whether its structure played a role in EV navigation. They customize the hydrogel's stiffness and how well the hydrogel could relax after being stressed by an object in order to make the hydrogel more or less like the matrix in the body. "The EVs became stuck when the hydrogel couldn't relax over time, like rubber," said Stephen Lenzini, first author and UIC graduate student in the College of Engineering. "The hydrogel needed to have a stiff backbone to provide some sort of structure, but after a stress it also had to relax enough to rearrange itself over time, which allowed the EVs to move around. The interesting finding was that this ability to move that occurred for EVs in some materials did not occur for synthetic particles of similar size." The same membrane that EVs use to protect their cargo also was essential for its own flexibility in tight spaces. When aquaporin-1—a membrane protein that allows water in and out of EVs—stopped functioning, the EVs became stuck. The permeation of water through aquaporin-1 in the membrane was essential for EVs to slip through the hydrogel gaps. "This study has opened new avenues into studying the distribution of EVs and their contents through tissues," Lenzini said. The findings advance the UIC research group closer to engineering effective delivery systems, according to Shin. "There are a range of diseases that undergo substantial changes in their environment. In fibrosis and some cancers, the tissues and matrix become more rigid as time progresses. In some cancers, the distribution of EVs have led to disease spreading," he said. "So, understanding how EVs are dispersed is critical for developing these cell-free therapeutics and stopping disease progression." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Extremely rare circulating tumor cell (CTC) clusters are both increasingly appreciated as highly metastatic precursors and virtually unexplored. Technologies are primarily designed to detect single CTCs and often fail to account for the fragility of clusters or to leverage cluster-specific markers for higher sensitivity. Meanwhile, the few technologies targeting CTC clusters lack scalability. Here, we introduce the Cluster-Wells, which combines the speed and practicality of membrane filtration with the sensitive and deterministic screening afforded by microfluidic chips. The >100,000 microwells in the Cluster-Wells physically arrest CTC clusters in unprocessed whole blood, gently isolating virtually all clusters at a throughput of >25 mL/h, and allow viable clusters to be retrieved from the device. Using the Cluster-Wells, we isolated CTC clusters ranging from 2 to 100+ cells from prostate and ovarian cancer patients and analyzed a subset using RNA sequencing. Routine isolation of CTC clusters will democratize research on their utility in managing cancer. Introduction Single circulating tumor cells (CTCs) harvested from the bloodstream of cancer patients provide valuable information on the stage of the disease 1 , enable minimally invasive prognosis and diagnosis 2 , 3 , 4 , enhance our understanding of metastasis at the cellular level 5 , 6 , and offer the potential to improve the clinical management of cancer 7 , 8 . In addition to these single CTCs, CTC aggregates that remain attached in circulation have been of great scientific and clinical interest since the 1950s. Although these CTC clusters, or circulating tumor microemboli, are extremely rare (estimated at only 2–5% of all CTCs), they are disproportionately efficient at seeding metastases. Their metastatic propensity is estimated to be 100 times higher than that of single CTCs 9 , 10 , 11 , based on their lower apoptosis rate and reduced prolonged survival attributes 9 , 12 . Moreover, a subset of patient-derived CTC clusters was found to include host immune cells 13 , 14 , highlighting the utility of these metastatic precursors to shed light on tumor–immune system interactions and their role in metastasis. For example, CTC clusters carrying neutrophils have been shown to have increased metastatic potential in advanced breast cancer patients 14 , where the neutrophil-associated CTCs demonstrate higher expression levels of proliferation marker protein (Ki67) and of genes associated with cell-cycle progression. Clinical studies have supported the results of these biological investigations, finding that the presence of CTC clusters is associated with shorter progression-free survival and overall patient survival 15 . The increased study of CTC clusters, then, offers great promise in improving the understanding and management of metastasis. To date, reliable and efficient isolation of viable CTC clusters has been limited because the sensitivity and specificity of CTC isolation technologies are primarily calibrated for single cell detection 16 , 17 , 18 , 19 . Microfiltration techniques, for example, are widely employed as CTC assays due to their fast and straightforward operation 16 , 19 , 20 . However, CTC clusters under physiological pressure can reorganize themselves as single-file chain-like structures and traverse constrictions as small as 5 μm 11 , which suggests that aggregates can likely pass through filter pores, given the much higher pressures employed in filtration. Moreover, higher shear forces experienced during microfiltration could damage CTC clusters or dissociate them into single cells 21 , undermining efficient enrichment. On the other hand, antibody-based enrichment systems, which have long been used for isolation of single CTCs 17 , 22 , 23 , can only detect a select sub-population of CTC clusters within the heterogenous CTC population due to their dependency on specific membrane antigens 13 , 24 . Additionally, the smaller surface-area-to-volume ratio of CTC clusters negatively impacts the immunocapture efficiencies of antibody-based technologies 25 , rendering them particularly inefficient for CTC cluster enrichment. More promising in this regard are recent microfluidic chips specifically targeting CTC clusters, which can achieve relatively higher sensitivities. Unfortunately, they do so either at clinically unworkable processing rates 21 , 26 or under threat of cluster damage due to the high flow rates in narrow channels 27 ,—a concern especially relevant for large clusters, which were reported to be occasionally comprised of as many as tens of tumor cells 28 . To address these limitations for the isolation and study of CTC clusters, we have developed the Cluster-Wells. This high-sensitivity, high-throughput polymer device gently isolates CTC clusters, small and large, from unprocessed whole blood specimens without the need for targeting tumor-specific antigens. Instead, the Cluster-Wells retains CTC clusters in microwells engineered to physically recognize cellular aggregates and preserve their integrity under sub-physiological flow rates. Moreover, unrestricted access to purified CTC clusters in microwells permits further investigation via imaging, and functional and molecular assays. Results Design and microfabrication of the Cluster-Wells The Cluster-Wells captures CTC clusters in microwells designed to retain cell aggregates while being permeable to single cells in blood (Fig. 1a ). At the bottom of each well is a micromesh with openings of 15 μm × 15 μm, a size that lets leukocytes, erythrocytes, and platelets pass unimpeded. Thus, unprocessed whole blood flows easily through the device, but CTC clusters, too big to commit to any single opening, are captured when individual cells within the cluster lodge in neighboring mesh openings. Once inside a well, CTC clusters are constrained on the mesh by slanted sidewalls, which restrict potential reorientation under flow and protect the cells from the damaging transverse stresses found in traditional membrane filters. Fig. 1: Design and microfabrication of the Cluster-Wells. a Schematic illustration of the Cluster-Wells’ working principle. While single cells pass unimpeded, the Cluster-Wells captures CTC clusters owing to their multicellular morphology from blood samples of cancer patients, independent of cancer type and their molecular character. b A photo of the Cluster-Wells manufactured in the form of a 47 mm-diameter membrane to be used in commercial filter holder. Close-up image (inset) shows individual wells designed to capture CTC clusters. (Right) Scanning electron micrograph of a blood-spiked LNCaP cluster as captured by one of the wells on the device", "role": "user" }, { "content": "Researchers at the Georgia Institute of Technology have found a detection method that could revolutionize cancer treatment by showing how cancers metastasize and what stage they are. Cancer spreads via circulating tumor cells (CTCs) that travel through the blood to other organs, and they are nearly impossible to track. Now, researchers at the Georgia Institute of Technology have found a detection method that could revolutionize cancer treatment by showing how cancers metastasize and what stage they are. This could lead to earlier and more targeted treatment, beginning with a simple blood test. When a tumor starts metastasizing, it sheds its cell into the blood. An individual cell often doesn't survive the bloodstream on its own, but clusters of cells are much more robust and can travel to other organs, effectively pushing the cancer to a metastatic state. CTCs have proven difficult to study, let alone treat. Blood contains billions of cells per milliliter, and only a handful of those cells would be CTCs in a patient with metastatic cancer. Such intense filtration has been inaccessible using conventional lab methods. Most traditional filtration is too aggressive and would break the cluster back into single cells and ruin the ability to study the effect of a cluster. \"That's what got engineers like me interested in this because we are really good at creating sensors, or small devices that actually do sensitive analysis,\" said School of Electrical and Computer Engineering Associate Professor Fatih Sarioglu. \"We started developing technologies to catch these precious cells to help manage cancer better.\" Sarioglu presented the research in \"High Throughput, Label-free Isolation of Circulating Tumor Cell Clusters in Meshed Microwells,\" recently published in Nature Communications. Creating the Cluster-Well chip Sarioglu's lab invented a new type of chip called the Cluster-Well, combining the precision of microfluidic chips with the efficiency of membrane filtration to find CTC clusters. Using micron-sized features, microfluidic chips can precisely locate each cell in a blood sample and determine if it's cancerous. \"Microfluidic chips give you more control as a designer to actually ask whatever question that you want to ask those cells,\" Sarioglu said. \"It increases the precision and sensitivity, which is what you need for an application like this because you want to find that single cell out of many blood cells.\" To rapidly process a clinically relevant volume of blood, the researchers relied on membrane filtration to make the chip operation more scalable. In effect, the chip looks like a standard membrane filter, but under an electron microscope the microfluidic chip reveals its delicate structure used to capture clusters while letting other blood cells pass through. Practicality was just as important as functionality to the researchers. Although the chip is initially fabricated with silicon just like a central processing unit in a computer, it is later transferred to polymers to make it accessible, affordable, and single-use, while still retaining its delicacy and precision. \"We really created only the traps that we need to have for recognizing the clusters with the microfluidic chip, and the rest is just a standard filter holder,\" Sarioglu said. \"Compared to a conventional microfluidic chip, you will get a much more practical assay with orders of magnitude improvement in throughput and a higher sensitivity.\" Analyzing patient tumor cell clusters The researchers used the chip to screen blood samples from patients with ovarian or prostate cancers through a partnership with the Emory and Northside Hospitals. They isolated CTC clusters ranging from two to 100 or more cells from prostate and ovarian cancer patients and used RNA sequencing to analyze a subset. The chip's unique design means CTC clusters are filtered in microwells and can later be accessed for further analysis. Even a single CTC can contain a significant amount of data on the patient and their specific cancer, which can be critical for managing the disease. For example, the researchers noted hundreds of CTCs in clusters in the blood of ovarian cancer patients, some still alive, a finding that could be consequential to the spread of the disease. Also, by sequencing the RNA in prostate CTC clusters isolated by the chip, the researchers identified specific genes expressed by these metastasizing cells. Importantly, CTC clusters from different patients were shown to express different genes, which can be potentially utilized to develop personalized, targeted therapies. Sarioglu envisions Cluster-Wells as being a routine part of the treatment process to determine what stage the cancer is at from a simple blood draw. \"Finding these clusters was very elusive,\" Sarioglu said. \"But this is a technology that allows these precious circulating tumor cell clusters virtually in any cancer to be accessed with precision and practicality that has not been possible before.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Extremely rare circulating tumor cell (CTC) clusters are both increasingly appreciated as highly metastatic precursors and virtually unexplored. Technologies are primarily designed to detect single CTCs and often fail to account for the fragility of clusters or to leverage cluster-specific markers for higher sensitivity. Meanwhile, the few technologies targeting CTC clusters lack scalability. Here, we introduce the Cluster-Wells, which combines the speed and practicality of membrane filtration with the sensitive and deterministic screening afforded by microfluidic chips. The >100,000 microwells in the Cluster-Wells physically arrest CTC clusters in unprocessed whole blood, gently isolating virtually all clusters at a throughput of >25 mL/h, and allow viable clusters to be retrieved from the device. Using the Cluster-Wells, we isolated CTC clusters ranging from 2 to 100+ cells from prostate and ovarian cancer patients and analyzed a subset using RNA sequencing. Routine isolation of CTC clusters will democratize research on their utility in managing cancer. Introduction Single circulating tumor cells (CTCs) harvested from the bloodstream of cancer patients provide valuable information on the stage of the disease 1 , enable minimally invasive prognosis and diagnosis 2 , 3 , 4 , enhance our understanding of metastasis at the cellular level 5 , 6 , and offer the potential to improve the clinical management of cancer 7 , 8 . In addition to these single CTCs, CTC aggregates that remain attached in circulation have been of great scientific and clinical interest since the 1950s. Although these CTC clusters, or circulating tumor microemboli, are extremely rare (estimated at only 2–5% of all CTCs), they are disproportionately efficient at seeding metastases. Their metastatic propensity is estimated to be 100 times higher than that of single CTCs 9 , 10 , 11 , based on their lower apoptosis rate and reduced prolonged survival attributes 9 , 12 . Moreover, a subset of patient-derived CTC clusters was found to include host immune cells 13 , 14 , highlighting the utility of these metastatic precursors to shed light on tumor–immune system interactions and their role in metastasis. For example, CTC clusters carrying neutrophils have been shown to have increased metastatic potential in advanced breast cancer patients 14 , where the neutrophil-associated CTCs demonstrate higher expression levels of proliferation marker protein (Ki67) and of genes associated with cell-cycle progression. Clinical studies have supported the results of these biological investigations, finding that the presence of CTC clusters is associated with shorter progression-free survival and overall patient survival 15 . The increased study of CTC clusters, then, offers great promise in improving the understanding and management of metastasis. To date, reliable and efficient isolation of viable CTC clusters has been limited because the sensitivity and specificity of CTC isolation technologies are primarily calibrated for single cell detection 16 , 17 , 18 , 19 . Microfiltration techniques, for example, are widely employed as CTC assays due to their fast and straightforward operation 16 , 19 , 20 . However, CTC clusters under physiological pressure can reorganize themselves as single-file chain-like structures and traverse constrictions as small as 5 μm 11 , which suggests that aggregates can likely pass through filter pores, given the much higher pressures employed in filtration. Moreover, higher shear forces experienced during microfiltration could damage CTC clusters or dissociate them into single cells 21 , undermining efficient enrichment. On the other hand, antibody-based enrichment systems, which have long been used for isolation of single CTCs 17 , 22 , 23 , can only detect a select sub-population of CTC clusters within the heterogenous CTC population due to their dependency on specific membrane antigens 13 , 24 . Additionally, the smaller surface-area-to-volume ratio of CTC clusters negatively impacts the immunocapture efficiencies of antibody-based technologies 25 , rendering them particularly inefficient for CTC cluster enrichment. More promising in this regard are recent microfluidic chips specifically targeting CTC clusters, which can achieve relatively higher sensitivities. Unfortunately, they do so either at clinically unworkable processing rates 21 , 26 or under threat of cluster damage due to the high flow rates in narrow channels 27 ,—a concern especially relevant for large clusters, which were reported to be occasionally comprised of as many as tens of tumor cells 28 . To address these limitations for the isolation and study of CTC clusters, we have developed the Cluster-Wells. This high-sensitivity, high-throughput polymer device gently isolates CTC clusters, small and large, from unprocessed whole blood specimens without the need for targeting tumor-specific antigens. Instead, the Cluster-Wells retains CTC clusters in microwells engineered to physically recognize cellular aggregates and preserve their integrity under sub-physiological flow rates. Moreover, unrestricted access to purified CTC clusters in microwells permits further investigation via imaging, and functional and molecular assays. Results Design and microfabrication of the Cluster-Wells The Cluster-Wells captures CTC clusters in microwells designed to retain cell aggregates while being permeable to single cells in blood (Fig. 1a ). At the bottom of each well is a micromesh with openings of 15 μm × 15 μm, a size that lets leukocytes, erythrocytes, and platelets pass unimpeded. Thus, unprocessed whole blood flows easily through the device, but CTC clusters, too big to commit to any single opening, are captured when individual cells within the cluster lodge in neighboring mesh openings. Once inside a well, CTC clusters are constrained on the mesh by slanted sidewalls, which restrict potential reorientation under flow and protect the cells from the damaging transverse stresses found in traditional membrane filters. Fig. 1: Design and microfabrication of the Cluster-Wells. a Schematic illustration of the Cluster-Wells’ working principle. While single cells pass unimpeded, the Cluster-Wells captures CTC clusters owing to their multicellular morphology from blood samples of cancer patients, independent of cancer type and their molecular character. b A photo of the Cluster-Wells manufactured in the form of a 47 mm-diameter membrane to be used in commercial filter holder. Close-up image (inset) shows individual wells designed to capture CTC clusters. (Right) Scanning electron micrograph of a blood-spiked LNCaP cluster as captured by one of the wells on the device<|im_end|> <|im_start|>assistant Researchers at the Georgia Institute of Technology have found a detection method that could revolutionize cancer treatment by showing how cancers metastasize and what stage they are. Cancer spreads via circulating tumor cells (CTCs) that travel through the blood to other organs, and they are nearly impossible to track. Now, researchers at the Georgia Institute of Technology have found a detection method that could revolutionize cancer treatment by showing how cancers metastasize and what stage they are. This could lead to earlier and more targeted treatment, beginning with a simple blood test. When a tumor starts metastasizing, it sheds its cell into the blood. An individual cell often doesn't survive the bloodstream on its own, but clusters of cells are much more robust and can travel to other organs, effectively pushing the cancer to a metastatic state. CTCs have proven difficult to study, let alone treat. Blood contains billions of cells per milliliter, and only a handful of those cells would be CTCs in a patient with metastatic cancer. Such intense filtration has been inaccessible using conventional lab methods. Most traditional filtration is too aggressive and would break the cluster back into single cells and ruin the ability to study the effect of a cluster. "That's what got engineers like me interested in this because we are really good at creating sensors, or small devices that actually do sensitive analysis," said School of Electrical and Computer Engineering Associate Professor Fatih Sarioglu. "We started developing technologies to catch these precious cells to help manage cancer better." Sarioglu presented the research in "High Throughput, Label-free Isolation of Circulating Tumor Cell Clusters in Meshed Microwells," recently published in Nature Communications. Creating the Cluster-Well chip Sarioglu's lab invented a new type of chip called the Cluster-Well, combining the precision of microfluidic chips with the efficiency of membrane filtration to find CTC clusters. Using micron-sized features, microfluidic chips can precisely locate each cell in a blood sample and determine if it's cancerous. "Microfluidic chips give you more control as a designer to actually ask whatever question that you want to ask those cells," Sarioglu said. "It increases the precision and sensitivity, which is what you need for an application like this because you want to find that single cell out of many blood cells." To rapidly process a clinically relevant volume of blood, the researchers relied on membrane filtration to make the chip operation more scalable. In effect, the chip looks like a standard membrane filter, but under an electron microscope the microfluidic chip reveals its delicate structure used to capture clusters while letting other blood cells pass through. Practicality was just as important as functionality to the researchers. Although the chip is initially fabricated with silicon just like a central processing unit in a computer, it is later transferred to polymers to make it accessible, affordable, and single-use, while still retaining its delicacy and precision. "We really created only the traps that we need to have for recognizing the clusters with the microfluidic chip, and the rest is just a standard filter holder," Sarioglu said. "Compared to a conventional microfluidic chip, you will get a much more practical assay with orders of magnitude improvement in throughput and a higher sensitivity." Analyzing patient tumor cell clusters The researchers used the chip to screen blood samples from patients with ovarian or prostate cancers through a partnership with the Emory and Northside Hospitals. They isolated CTC clusters ranging from two to 100 or more cells from prostate and ovarian cancer patients and used RNA sequencing to analyze a subset. The chip's unique design means CTC clusters are filtered in microwells and can later be accessed for further analysis. Even a single CTC can contain a significant amount of data on the patient and their specific cancer, which can be critical for managing the disease. For example, the researchers noted hundreds of CTCs in clusters in the blood of ovarian cancer patients, some still alive, a finding that could be consequential to the spread of the disease. Also, by sequencing the RNA in prostate CTC clusters isolated by the chip, the researchers identified specific genes expressed by these metastasizing cells. Importantly, CTC clusters from different patients were shown to express different genes, which can be potentially utilized to develop personalized, targeted therapies. Sarioglu envisions Cluster-Wells as being a routine part of the treatment process to determine what stage the cancer is at from a simple blood draw. "Finding these clusters was very elusive," Sarioglu said. "But this is a technology that allows these precious circulating tumor cell clusters virtually in any cancer to be accessed with precision and practicality that has not been possible before." <|im_end|>

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2,327

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract While amino acid restriction remains an attractive strategy for cancer therapy, metabolic adaptations limit its effectiveness. Here we demonstrate a role of translational reprogramming in the survival of asparagine-restricted cancer cells. Asparagine limitation in melanoma and pancreatic cancer cells activates receptor tyrosine kinase–MAPK signalling as part of a feedforward mechanism involving mammalian target of rapamycin complex 1 (mTORC1)-dependent increase in MAPK-interacting kinase 1 (MNK1) and eukaryotic translation initiation factor 4E (eIF4E), resulting in enhanced translation of activating transcription factor 4 ( ATF4 ) mRNA. MAPK inhibition attenuates translational induction of ATF4 and the expression of its target asparagine synthetase (ASNS), sensitizing melanoma and pancreatic tumours to asparagine restriction, reflected in inhibition of their growth. Correspondingly, low ASNS expression is among the top predictors of response to inhibitors of MAPK signalling in patients with melanoma and is associated with favourable prognosis when combined with low MAPK signalling activity. These studies reveal an axis of adaptation to asparagine deprivation and present a rationale for clinical evaluation of MAPK inhibitors in combination with asparagine restriction approaches. Main Rapidly proliferating tumours exhibit an increased requirement for macromolecules to meet expanding energetic and biosynthetic needs. Therefore, nutrient limitation is widely recognized as a potential therapeutic strategy. However, cancer cells successfully endure harsh, nutrient-restricted environments, often by rewiring metabolic pathways. Accordingly, de novo synthesis of non-essential amino acids has been demonstrated to impede durable therapeutic responses 1 , 2 . While supporting enhanced protein synthesis in tumour cells and antioxidant defence through glutathione biosynthesis, glutamine anaplerotically fuels the tricarboxylic acid cycle, thus generating ATP and precursors for nucleotide, amino acid and lipid biosynthesis 3 , 4 . Cancer cells can sustain glutamine-dependent processes in the absence of exogenous glutamine through de novo glutamine biosynthesis, with the notable exception of asparagine biosynthesis 5 , 6 . Since the inability to maintain cellular asparagine levels underlies the tumour growth suppression seen on glutamine restriction, curtailing cellular asparagine levels is an appealing alternative to limit tumour growth 7 , 8 . ASNS catalyses the conversion of aspartate to asparagine, which is accompanied by glutamine deamidation. A deficiency of ASNS in acute lymphoblastic leukaemia renders cells sensitive to asparagine restriction 9 . However, asparagine restriction approaches were ineffective in solid tumours that express low levels of ASNS 10 , 11 , 12 , 13 . Here we show that MAPK signalling supports translational reprogramming, promoting survival of asparagine-restricted tumours, thus providing the molecular basis for rational combination therapies that rely on asparagine restriction strategies. Results ATF4 activity impedes growth suppression in response to asparagine limitation We first determined the effect of ASNS depletion on a panel of pancreatic, breast, prostate and melanoma cell lines. ASNS suppression using short interfering RNA (siRNA) (si ASNS ) compromised proliferation in all cell lines tested relative to those treated with non-targeting (NT)-siRNA (Fig. 1a ). Gas chromatography–mass spectrometry (GC–MS) analysis confirmed a decrease in asparagine levels following ASNS depletion (Extended Data Fig. 1a ). si ASNS -mediated suppression of pancreatic cancer and melanoma cell proliferation was largely abolished when cultured in growth medium containing l -asparagine ( l -Asn) (Fig. 1b and Extended Data Fig. 1b ). Conversely, addition of l -asparaginase ( l -Aase) to the l -Asn-containing medium impaired proliferation of si ASNS -treated cells (Fig. 1b ). Thus, suppressing de novo biosynthesis and compromising exogenous asparagine availability enables effective inhibition of cancer cell proliferation. Fig. 1: ATF4 activity impedes growth suppression in response to asparagine limitation. a , Proliferation of indicated cancer cell lines 48 h after transfection with si ASNS #1 or si ASNS #2 relative to cells transfected with NT-siRNA (value set to 1.0). b , Proliferation of cancer cell lines as in a , but 72 h after indicated treatment. [l -Asn] = 0.3 mM; [ l -Aase] = 1 U ml −1 . Data are shown relative to mock (NT-siRNA + dH 2 0)-treated cells. c , Immunoblotting of AAR pathway proteins in indicated cells 72 h after treatment with si ASNS #1, si ASNS #2 or si ASNS #3. d , Reverse transcription with quantitative PCR (RT–qPCR) of transcripts encoding ATF4 targets in indicated cells 48 h after treatment with si ASNS #1 or si ASNS #2. e , Immunoblotting of AAR pathway proteins in indicated cancer cell lines 72 h after treatment with si ASNS and l -Asn, with or without l -Aase. f , Immunoblotting of ASNS, GCN2 and ATF4 in melanoma cells 72 h after treatment with si ASNS , si GCN2 or both. g , Proliferation of melanoma cells over indicated times following treatment with si ASNS , si GCN2 or both. h , Immunoblotting of ATF4 in melanoma cells 72 h after treatment with si ASNS , si ATF4 or both. i , RT–qPCR of transcripts encoding ATF4 targets in indicated cells treated as in h for 48 h. j , Proliferation of cancer cell lines treated as in h for 48 h. k , Model depicting the pathway of ATF4 induction following asparagine suppression (Asn lo ). Data are representative of three independent experiments and presented as the mean ± s.e.m. of n = 3 biological replicates in a , b , g , j , and mean ± s.e.m. of n = 4 and n = 3 technical replicates in d and i , respectively. Statistical significance was calculated using two-tailed unpaired Student’s t -test except in g , where two-way ANOVA was used. In g , P values in black correspond to the comparison between si ASNS #1 and si ASNS #1 + si GCN2 and P values in orange correspond to the comparison between si ASNS #2 and si ASNS #2 + si GCN2 , respectively. Source Data Full size image ASNS depletion in A375 and UACC-903 melanoma cells resulted in the activation of general control nonderepressible 2 (GCN2), which was accompanied by increased eIF2α phosphorylation, increased ATF4 protein levels and increased expression of ATF4 target genes compared with control cells (Fig. 1c,d ), reflecting activation", "role": "user" }, { "content": "Scientists at Sanford Burnham Prebys Medical Discovery Institute have identified a combination of two anti-cancer compounds that shrank pancreatic tumors in mice—supporting the immediate evaluation of the drugs in a clinical trial. U.S. Food and Drug Administration (FDA)-approved versions of the compounds are used today to treat certain leukemias and solid tumors, including melanoma. The study was published in Nature Cell Biology. \"The sad reality is that at present, pancreatic cancer therapy is lagging since there is no effective treatment for these tumors,\" says Ze'ev Ronai, Ph.D., professor in Sanford Burnham Prebys' Tumor Initiation and Maintenance Program and senior author of the study. \"Our study identifies a potential treatment combination that can immediately be tested against these aggressive tumors. We are already meeting with oncologists at Oregon Health & Science University to discuss how to advance this discovery into clinical evaluation.\" Pancreatic cancer is one of the deadliest cancers. It is often difficult to diagnose because symptoms—such as pain in the abdomen, yellow skin and eyes, and weight loss—don't typically occur until the disease is advanced. Less than 10 percent of people with pancreatic cancer remain alive five years later. More than 56,000 Americans are expected to receive a pancreatic cancer diagnosis in 2019, according to the American Cancer Society. In the study, the scientists used a drug called L-asparaginase to starve pancreatic tumors of a key nutrient, asparagine—an amino acid required for protein synthesis. Instead of dying, they found that the tumor turned on a stress response pathway that allowed the cancer cells to produce asparagine themselves. The scientists then treated mice with a second drug that blocked the stress response pathway and shrank the pancreatic tumor. L-asparaginase is FDA approved to treat certain leukemias; and the second drug, a MEK inhibitor, is approved for the treatment of solid tumors, including melanoma, a type of skin cancer. \"This research lays the basis for the inhibition of pancreatic tumor growth by a combined synergistic attack based on asparagine restriction and MAPK signaling inhibition,\" says Eytan Ruppin, M.D., Ph.D., a study author and chief of the Cancer Data Science Library at the National Cancer Institute, part of the National Institutes of Health (NIH). \"Our lab was able to further support these findings through a computational analysis of patient data.\" Adds Rosalie C. Sears, Ph.D., a professor at Oregon Health & Science University, \"It's clear we're not going to find a single magic bullet that cures cancer but will instead need several drugs that target multiple vulnerabilities. This study identifies a promising dual treatment for pancreatic cancer—one of the deadliest cancers—and I look forward to seeing these drugs tested in patients.\" In the same study, the scientists showed that the two treatments also shrank melanoma tumors in mice. Due to the large unmet clinical need in pancreatic cancer, the scientists have decided to focus on this cancer first. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract While amino acid restriction remains an attractive strategy for cancer therapy, metabolic adaptations limit its effectiveness. Here we demonstrate a role of translational reprogramming in the survival of asparagine-restricted cancer cells. Asparagine limitation in melanoma and pancreatic cancer cells activates receptor tyrosine kinase–MAPK signalling as part of a feedforward mechanism involving mammalian target of rapamycin complex 1 (mTORC1)-dependent increase in MAPK-interacting kinase 1 (MNK1) and eukaryotic translation initiation factor 4E (eIF4E), resulting in enhanced translation of activating transcription factor 4 ( ATF4 ) mRNA. MAPK inhibition attenuates translational induction of ATF4 and the expression of its target asparagine synthetase (ASNS), sensitizing melanoma and pancreatic tumours to asparagine restriction, reflected in inhibition of their growth. Correspondingly, low ASNS expression is among the top predictors of response to inhibitors of MAPK signalling in patients with melanoma and is associated with favourable prognosis when combined with low MAPK signalling activity. These studies reveal an axis of adaptation to asparagine deprivation and present a rationale for clinical evaluation of MAPK inhibitors in combination with asparagine restriction approaches. Main Rapidly proliferating tumours exhibit an increased requirement for macromolecules to meet expanding energetic and biosynthetic needs. Therefore, nutrient limitation is widely recognized as a potential therapeutic strategy. However, cancer cells successfully endure harsh, nutrient-restricted environments, often by rewiring metabolic pathways. Accordingly, de novo synthesis of non-essential amino acids has been demonstrated to impede durable therapeutic responses 1 , 2 . While supporting enhanced protein synthesis in tumour cells and antioxidant defence through glutathione biosynthesis, glutamine anaplerotically fuels the tricarboxylic acid cycle, thus generating ATP and precursors for nucleotide, amino acid and lipid biosynthesis 3 , 4 . Cancer cells can sustain glutamine-dependent processes in the absence of exogenous glutamine through de novo glutamine biosynthesis, with the notable exception of asparagine biosynthesis 5 , 6 . Since the inability to maintain cellular asparagine levels underlies the tumour growth suppression seen on glutamine restriction, curtailing cellular asparagine levels is an appealing alternative to limit tumour growth 7 , 8 . ASNS catalyses the conversion of aspartate to asparagine, which is accompanied by glutamine deamidation. A deficiency of ASNS in acute lymphoblastic leukaemia renders cells sensitive to asparagine restriction 9 . However, asparagine restriction approaches were ineffective in solid tumours that express low levels of ASNS 10 , 11 , 12 , 13 . Here we show that MAPK signalling supports translational reprogramming, promoting survival of asparagine-restricted tumours, thus providing the molecular basis for rational combination therapies that rely on asparagine restriction strategies. Results ATF4 activity impedes growth suppression in response to asparagine limitation We first determined the effect of ASNS depletion on a panel of pancreatic, breast, prostate and melanoma cell lines. ASNS suppression using short interfering RNA (siRNA) (si ASNS ) compromised proliferation in all cell lines tested relative to those treated with non-targeting (NT)-siRNA (Fig. 1a ). Gas chromatography–mass spectrometry (GC–MS) analysis confirmed a decrease in asparagine levels following ASNS depletion (Extended Data Fig. 1a ). si ASNS -mediated suppression of pancreatic cancer and melanoma cell proliferation was largely abolished when cultured in growth medium containing l -asparagine ( l -Asn) (Fig. 1b and Extended Data Fig. 1b ). Conversely, addition of l -asparaginase ( l -Aase) to the l -Asn-containing medium impaired proliferation of si ASNS -treated cells (Fig. 1b ). Thus, suppressing de novo biosynthesis and compromising exogenous asparagine availability enables effective inhibition of cancer cell proliferation. Fig. 1: ATF4 activity impedes growth suppression in response to asparagine limitation. a , Proliferation of indicated cancer cell lines 48 h after transfection with si ASNS #1 or si ASNS #2 relative to cells transfected with NT-siRNA (value set to 1.0). b , Proliferation of cancer cell lines as in a , but 72 h after indicated treatment. [l -Asn] = 0.3 mM; [ l -Aase] = 1 U ml −1 . Data are shown relative to mock (NT-siRNA + dH 2 0)-treated cells. c , Immunoblotting of AAR pathway proteins in indicated cells 72 h after treatment with si ASNS #1, si ASNS #2 or si ASNS #3. d , Reverse transcription with quantitative PCR (RT–qPCR) of transcripts encoding ATF4 targets in indicated cells 48 h after treatment with si ASNS #1 or si ASNS #2. e , Immunoblotting of AAR pathway proteins in indicated cancer cell lines 72 h after treatment with si ASNS and l -Asn, with or without l -Aase. f , Immunoblotting of ASNS, GCN2 and ATF4 in melanoma cells 72 h after treatment with si ASNS , si GCN2 or both. g , Proliferation of melanoma cells over indicated times following treatment with si ASNS , si GCN2 or both. h , Immunoblotting of ATF4 in melanoma cells 72 h after treatment with si ASNS , si ATF4 or both. i , RT–qPCR of transcripts encoding ATF4 targets in indicated cells treated as in h for 48 h. j , Proliferation of cancer cell lines treated as in h for 48 h. k , Model depicting the pathway of ATF4 induction following asparagine suppression (Asn lo ). Data are representative of three independent experiments and presented as the mean ± s.e.m. of n = 3 biological replicates in a , b , g , j , and mean ± s.e.m. of n = 4 and n = 3 technical replicates in d and i , respectively. Statistical significance was calculated using two-tailed unpaired Student’s t -test except in g , where two-way ANOVA was used. In g , P values in black correspond to the comparison between si ASNS #1 and si ASNS #1 + si GCN2 and P values in orange correspond to the comparison between si ASNS #2 and si ASNS #2 + si GCN2 , respectively. Source Data Full size image ASNS depletion in A375 and UACC-903 melanoma cells resulted in the activation of general control nonderepressible 2 (GCN2), which was accompanied by increased eIF2α phosphorylation, increased ATF4 protein levels and increased expression of ATF4 target genes compared with control cells (Fig. 1c,d ), reflecting activation<|im_end|> <|im_start|>assistant Scientists at Sanford Burnham Prebys Medical Discovery Institute have identified a combination of two anti-cancer compounds that shrank pancreatic tumors in mice—supporting the immediate evaluation of the drugs in a clinical trial. U.S. Food and Drug Administration (FDA)-approved versions of the compounds are used today to treat certain leukemias and solid tumors, including melanoma. The study was published in Nature Cell Biology. "The sad reality is that at present, pancreatic cancer therapy is lagging since there is no effective treatment for these tumors," says Ze'ev Ronai, Ph.D., professor in Sanford Burnham Prebys' Tumor Initiation and Maintenance Program and senior author of the study. "Our study identifies a potential treatment combination that can immediately be tested against these aggressive tumors. We are already meeting with oncologists at Oregon Health & Science University to discuss how to advance this discovery into clinical evaluation." Pancreatic cancer is one of the deadliest cancers. It is often difficult to diagnose because symptoms—such as pain in the abdomen, yellow skin and eyes, and weight loss—don't typically occur until the disease is advanced. Less than 10 percent of people with pancreatic cancer remain alive five years later. More than 56,000 Americans are expected to receive a pancreatic cancer diagnosis in 2019, according to the American Cancer Society. In the study, the scientists used a drug called L-asparaginase to starve pancreatic tumors of a key nutrient, asparagine—an amino acid required for protein synthesis. Instead of dying, they found that the tumor turned on a stress response pathway that allowed the cancer cells to produce asparagine themselves. The scientists then treated mice with a second drug that blocked the stress response pathway and shrank the pancreatic tumor. L-asparaginase is FDA approved to treat certain leukemias; and the second drug, a MEK inhibitor, is approved for the treatment of solid tumors, including melanoma, a type of skin cancer. "This research lays the basis for the inhibition of pancreatic tumor growth by a combined synergistic attack based on asparagine restriction and MAPK signaling inhibition," says Eytan Ruppin, M.D., Ph.D., a study author and chief of the Cancer Data Science Library at the National Cancer Institute, part of the National Institutes of Health (NIH). "Our lab was able to further support these findings through a computational analysis of patient data." Adds Rosalie C. Sears, Ph.D., a professor at Oregon Health & Science University, "It's clear we're not going to find a single magic bullet that cures cancer but will instead need several drugs that target multiple vulnerabilities. This study identifies a promising dual treatment for pancreatic cancer—one of the deadliest cancers—and I look forward to seeing these drugs tested in patients." In the same study, the scientists showed that the two treatments also shrank melanoma tumors in mice. Due to the large unmet clinical need in pancreatic cancer, the scientists have decided to focus on this cancer first. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract It is essential to identify the neuronal mechanisms of Alzheimer’s Disease (AD)-associated neuropsychiatric symptoms, e.g., apathy, before improving the life quality of AD patients. Here, we focused on the nucleus accumbens (NAc), a critical brain region processing motivation, also known to display AD-associated pathological changes in human cases. We found that the synaptic calcium permeable (CP)-AMPA receptors (AMPARs), which are normally absent in the NAc, can be revealed by acute exposure to Aβ oligomers (AβOs), and play a critical role in the emergence of synaptic loss and motivation deficits. Blockade of NAc CP-AMPARs can effectively prevent AβO-induced downsizing and pruning of spines and silencing of excitatory synaptic transmission. We conclude that AβO-triggered synaptic insertion of CP-AMPARs is a key mechanism mediating synaptic degeneration in AD, and preserving synaptic integrity may prevent or delay the onset of AD-associated psychiatric symptoms. Introduction Among a broad spectrum of Alzheimer’s Disease (AD)-associated symptoms, progressive decline of cognition has been extensively investigated [ 1 ]. However, limited symptomatic relief in AD patients by available medications demonstrates lack of understanding of the neuronal and circuit substrates of AD, especially the AD-associated neuropsychiatric symptoms (NPSs) [ 2 ]. A meta-analysis of 12 NPSs reported in the NeuroPsychiatric Inventory identified apathy as the most common NPS in AD patients and the primary cause of caregiver distress [ 3 ]. Specifically, apathy, characterized by lack of motivation, is commonly diagnosed in pre-dementia stages, deteriorates as the disease progresses, and predicts phenoconversion from normal cognition to mild cognitive impairment (MCI), and from MCI to dementia [ 4 , 5 , 6 , 7 ]. Thus, apathy has been widely accepted as a predictor of human AD progression [ 8 ]. Unfortunately, little is known about the neuronal mechanisms of AD-associated apathy. A substantial body of evidence, from both clinical and laboratory studies, demonstrates that the cortical and hippocampal regions are primarily affected in AD [ 9 , 10 ]. Subcortical structures, including striatum, have been gradually uncovered with significant atrophy in AD by human imaging studies [ 11 ]. Among multiple sub-regions of striatum, the nucleus accumbens (NAc), as the major component of the ventral striatum and enriched with excitatory innervation from, among others, the cortex and hippocampus, displayed significantly higher densities of neurofibrillary degeneration [ 12 , 13 ]. In fact, atrophy of the NAc was found in both MCI and AD human cases [ 11 ]. Smaller volume of the NAc, considered as a predictor of AD onset within 2 years, was proportionally associated with increased risk of transition from MCI to AD [ 14 ]. Extracellular amyloid Beta (Aβ) plaques, well-investigated molecular events in AD subjects [ 15 , 16 ], have been detected in the NAc but absent from age-matched non-AD controls [ 17 , 18 ]. Furthermore, cortical activation, specifically the glutamatergic input from the medial prefrontal cortex (mPFC), is required for the functional activation of corticostriatal synapses onto medium-sized spiny neurons (MSNs), the major neuronal population of the NAc. This cortical excitatory innervation, although essential for normal MSN function, also confers vulnerability of MSNs in the NAc of AD subjects due to AD-associated cortical damage [ 19 , 20 , 21 ]. Aβ peptides, particularly the non-aggregated, soluble assemblies of Aβ oligomers (AβOs), are known to be the main source of toxicity [ 22 , 23 ]. Although extensive investigations have been made on Aβ peptides in relation to cognition impairments in corresponding brain regions such as hippocampus and cerebral cortex [ 24 , 25 , 26 ], little is known about the involvement of Aβ peptides in AD-associated NPSs. Synaptic loss in AD, hypothesized to be a consequence of the amyloid cascade [ 27 ], could be caused by glutamate excitotoxicity, which happens much earlier than complete neuronal loss [ 28 , 29 , 30 , 31 ]. While there is a consensus in the AD field that deranged Ca 2+ homeostasis is the main cause of synapse and cell loss [ 32 , 33 , 34 ], the exact source of excessive intracellular Ca 2+ flux remains obscure. As one of the major types of ionotropic glutamate receptors, AMPA receptors (AMPARs) are typically GluA2 subunit-containing and Ca 2+ impermeable (CI). In addition, an atypical form of the AMPA receptor, the GluA2-lacking Ca 2+ permeable (CP) AMPAR, is widely recognized as an indicator of brain dysfunction when present in adult brains [ 29 ]. Here we focused on the role of CP-AMPA receptors, particularly in the mPFC projection to D2-receptor expressing MSNs, in AβO-induced low motivation and excitatory synapse loss in the NAc. Methods (More details are available in Supplementary Information ). Animals All procedures were performed in accordance with the United States Public Health Service Guide for Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use committee at Indiana University School of Medicine. In vivo procedures Surgical procedures, including guide cannula and catheter implantation, and non-surgical in vivo procedures, including self-administration, were done as described in publications from our group [ 35 , 36 , 37 ] and others [ 38 , 39 , 40 ]. In vitro procedures Brain slices for whole-cell patch clamp recordings were prepared by standard procedures as detailed in our previous publications [ 35 , 36 , 37 , 41 , 42 ]. These slices were also used for Western blot analysis, immunofluorescent staining, and DiI spine staining. Data analysis Detailed statistics information for Figs. 1 – 5 is available in Tables S1 – S5 . Fig. 1: Behavioral effects of intra-NAc delivery of AβOs. A Experimental timeline for data collection in Figs. 1, S1 and S2 . Experimental procedure ( B ) and summarized data ( C ) showing that intra-NAc delivery of AβOs increased the % time of immobility in the forced swimming test. Experimental procedure ( D ) and summarized data ( E ) showing similar acquisition of sucrose SA between NAc-Veh and NAc-AβO mice under FR1 and FR5 schedules. Representative time course of lever presses", "role": "user" }, { "content": "Researchers from Indiana University School of Medicine are studying why neuropsychiatric symptoms, such as apathy and irritability, appear in most Alzheimer's disease patients before the onset of memory loss. The study, led by Yao-Ying Ma, MD, Ph.D., assistant professor of pharmacology and toxicology, was recently featured in the publication Molecular Psychiatry. The team of researchers identified a receptor in the brain that leads to a loss of neurons and synaptic structure when used in an Alzheimer's disease model. The investigation focused on the nucleus accumbens, a critical brain region processing motivation. Located in the ventral striatum, this region is not studied much among Alzheimer's disease researchers, Ma said; it's mainly researched to understand motivational and emotional processes. Previous studies, Ma said, have shown that the volume of nucleus accumbens, like the cortical and hippocampal regions in the brain, is reduced in adults with Alzheimer's disease. Ma, who is relatively new to the field of Alzheimer's disease research, has a background in drug addiction studies and synaptic communication—the process by which neurons talk to each other in the brain. Some of the neuropsychiatric symptoms among people who suffer from substance abuse—apathy, mood swings, anxiety—are also found in Alzheimer's disease patients. \"Even before the onset of cognitive deficits, a significant number of Alzheimer's patients start showing mood swings, and they have a greater chance to have symptoms of depression,\" Ma said. These neuropsychiatric symptoms, however, tend to occur earlier than memory loss, but no effective treatments are available, Ma said. She emphasized that there is an urgent need to understand why those symptoms exist and how they correlate with cognitive deficits. Ma said this study identified synaptic calcium permeable receptors (CP-AMPARs) in the nucleus accumbens in an Alzheimer's disease model. The receptor, which is normally absent in that part of the brain, gives permission for calcium to enter the neurons. This leads to an overload of calcium, which leads to a breakdown of its synaptic structure. In turn, calcium accumulation triggers a cascade of intracellular changes that can be lethal to the neuron by amplifying calcium overload via a positive feedback mechanism. This synaptic loss in the brain causes motivation deficits. Knowing this, Ma said that targeting these receptors in the brain and blocking them could prevent or delay the onset of Alzheimer's disease associated neuropsychiatric symptoms, and ultimately cognitive deficits. \"If we can postpone the pathological progression in one of the affected areas, like the nucleus accumbens,\" Ma said, \"that may delay pathological changes in other regions.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract It is essential to identify the neuronal mechanisms of Alzheimer’s Disease (AD)-associated neuropsychiatric symptoms, e.g., apathy, before improving the life quality of AD patients. Here, we focused on the nucleus accumbens (NAc), a critical brain region processing motivation, also known to display AD-associated pathological changes in human cases. We found that the synaptic calcium permeable (CP)-AMPA receptors (AMPARs), which are normally absent in the NAc, can be revealed by acute exposure to Aβ oligomers (AβOs), and play a critical role in the emergence of synaptic loss and motivation deficits. Blockade of NAc CP-AMPARs can effectively prevent AβO-induced downsizing and pruning of spines and silencing of excitatory synaptic transmission. We conclude that AβO-triggered synaptic insertion of CP-AMPARs is a key mechanism mediating synaptic degeneration in AD, and preserving synaptic integrity may prevent or delay the onset of AD-associated psychiatric symptoms. Introduction Among a broad spectrum of Alzheimer’s Disease (AD)-associated symptoms, progressive decline of cognition has been extensively investigated [ 1 ]. However, limited symptomatic relief in AD patients by available medications demonstrates lack of understanding of the neuronal and circuit substrates of AD, especially the AD-associated neuropsychiatric symptoms (NPSs) [ 2 ]. A meta-analysis of 12 NPSs reported in the NeuroPsychiatric Inventory identified apathy as the most common NPS in AD patients and the primary cause of caregiver distress [ 3 ]. Specifically, apathy, characterized by lack of motivation, is commonly diagnosed in pre-dementia stages, deteriorates as the disease progresses, and predicts phenoconversion from normal cognition to mild cognitive impairment (MCI), and from MCI to dementia [ 4 , 5 , 6 , 7 ]. Thus, apathy has been widely accepted as a predictor of human AD progression [ 8 ]. Unfortunately, little is known about the neuronal mechanisms of AD-associated apathy. A substantial body of evidence, from both clinical and laboratory studies, demonstrates that the cortical and hippocampal regions are primarily affected in AD [ 9 , 10 ]. Subcortical structures, including striatum, have been gradually uncovered with significant atrophy in AD by human imaging studies [ 11 ]. Among multiple sub-regions of striatum, the nucleus accumbens (NAc), as the major component of the ventral striatum and enriched with excitatory innervation from, among others, the cortex and hippocampus, displayed significantly higher densities of neurofibrillary degeneration [ 12 , 13 ]. In fact, atrophy of the NAc was found in both MCI and AD human cases [ 11 ]. Smaller volume of the NAc, considered as a predictor of AD onset within 2 years, was proportionally associated with increased risk of transition from MCI to AD [ 14 ]. Extracellular amyloid Beta (Aβ) plaques, well-investigated molecular events in AD subjects [ 15 , 16 ], have been detected in the NAc but absent from age-matched non-AD controls [ 17 , 18 ]. Furthermore, cortical activation, specifically the glutamatergic input from the medial prefrontal cortex (mPFC), is required for the functional activation of corticostriatal synapses onto medium-sized spiny neurons (MSNs), the major neuronal population of the NAc. This cortical excitatory innervation, although essential for normal MSN function, also confers vulnerability of MSNs in the NAc of AD subjects due to AD-associated cortical damage [ 19 , 20 , 21 ]. Aβ peptides, particularly the non-aggregated, soluble assemblies of Aβ oligomers (AβOs), are known to be the main source of toxicity [ 22 , 23 ]. Although extensive investigations have been made on Aβ peptides in relation to cognition impairments in corresponding brain regions such as hippocampus and cerebral cortex [ 24 , 25 , 26 ], little is known about the involvement of Aβ peptides in AD-associated NPSs. Synaptic loss in AD, hypothesized to be a consequence of the amyloid cascade [ 27 ], could be caused by glutamate excitotoxicity, which happens much earlier than complete neuronal loss [ 28 , 29 , 30 , 31 ]. While there is a consensus in the AD field that deranged Ca 2+ homeostasis is the main cause of synapse and cell loss [ 32 , 33 , 34 ], the exact source of excessive intracellular Ca 2+ flux remains obscure. As one of the major types of ionotropic glutamate receptors, AMPA receptors (AMPARs) are typically GluA2 subunit-containing and Ca 2+ impermeable (CI). In addition, an atypical form of the AMPA receptor, the GluA2-lacking Ca 2+ permeable (CP) AMPAR, is widely recognized as an indicator of brain dysfunction when present in adult brains [ 29 ]. Here we focused on the role of CP-AMPA receptors, particularly in the mPFC projection to D2-receptor expressing MSNs, in AβO-induced low motivation and excitatory synapse loss in the NAc. Methods (More details are available in Supplementary Information ). Animals All procedures were performed in accordance with the United States Public Health Service Guide for Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use committee at Indiana University School of Medicine. In vivo procedures Surgical procedures, including guide cannula and catheter implantation, and non-surgical in vivo procedures, including self-administration, were done as described in publications from our group [ 35 , 36 , 37 ] and others [ 38 , 39 , 40 ]. In vitro procedures Brain slices for whole-cell patch clamp recordings were prepared by standard procedures as detailed in our previous publications [ 35 , 36 , 37 , 41 , 42 ]. These slices were also used for Western blot analysis, immunofluorescent staining, and DiI spine staining. Data analysis Detailed statistics information for Figs. 1 – 5 is available in Tables S1 – S5 . Fig. 1: Behavioral effects of intra-NAc delivery of AβOs. A Experimental timeline for data collection in Figs. 1, S1 and S2 . Experimental procedure ( B ) and summarized data ( C ) showing that intra-NAc delivery of AβOs increased the % time of immobility in the forced swimming test. Experimental procedure ( D ) and summarized data ( E ) showing similar acquisition of sucrose SA between NAc-Veh and NAc-AβO mice under FR1 and FR5 schedules. Representative time course of lever presses<|im_end|> <|im_start|>assistant Researchers from Indiana University School of Medicine are studying why neuropsychiatric symptoms, such as apathy and irritability, appear in most Alzheimer's disease patients before the onset of memory loss. The study, led by Yao-Ying Ma, MD, Ph.D., assistant professor of pharmacology and toxicology, was recently featured in the publication Molecular Psychiatry. The team of researchers identified a receptor in the brain that leads to a loss of neurons and synaptic structure when used in an Alzheimer's disease model. The investigation focused on the nucleus accumbens, a critical brain region processing motivation. Located in the ventral striatum, this region is not studied much among Alzheimer's disease researchers, Ma said; it's mainly researched to understand motivational and emotional processes. Previous studies, Ma said, have shown that the volume of nucleus accumbens, like the cortical and hippocampal regions in the brain, is reduced in adults with Alzheimer's disease. Ma, who is relatively new to the field of Alzheimer's disease research, has a background in drug addiction studies and synaptic communication—the process by which neurons talk to each other in the brain. Some of the neuropsychiatric symptoms among people who suffer from substance abuse—apathy, mood swings, anxiety—are also found in Alzheimer's disease patients. "Even before the onset of cognitive deficits, a significant number of Alzheimer's patients start showing mood swings, and they have a greater chance to have symptoms of depression," Ma said. These neuropsychiatric symptoms, however, tend to occur earlier than memory loss, but no effective treatments are available, Ma said. She emphasized that there is an urgent need to understand why those symptoms exist and how they correlate with cognitive deficits. Ma said this study identified synaptic calcium permeable receptors (CP-AMPARs) in the nucleus accumbens in an Alzheimer's disease model. The receptor, which is normally absent in that part of the brain, gives permission for calcium to enter the neurons. This leads to an overload of calcium, which leads to a breakdown of its synaptic structure. In turn, calcium accumulation triggers a cascade of intracellular changes that can be lethal to the neuron by amplifying calcium overload via a positive feedback mechanism. This synaptic loss in the brain causes motivation deficits. Knowing this, Ma said that targeting these receptors in the brain and blocking them could prevent or delay the onset of Alzheimer's disease associated neuropsychiatric symptoms, and ultimately cognitive deficits. "If we can postpone the pathological progression in one of the affected areas, like the nucleus accumbens," Ma said, "that may delay pathological changes in other regions." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women’s risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80–0.88) and 0.81 (95% CI: 0.76–0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk. Introduction Breast cancer is by far the most common cancer in females in general, and a leading cause of death in young women 1 . To date, the identification of individuals with primary cancer is achieved by assessing evidence directly from the tumour (e.g. imaging 2 or detection of cancer cell products released into the system 3 , 4 ). Currently, available early detection strategies, such as mammography screening, suffer from low performance in young women, over-diagnosis, and decreasing attendance rates, and its benefit on mortality reduction has recently been questioned 5 . High-risk prevention strategies and risk-stratified screening require high discriminatory accuracy, that can only be achieved with predictors much stronger than those yet discovered 6 . Yet the best predictive models combining non-genetic factors and a polygenic risk score have only led to a Receiver Operator Characteristic (ROC) Area Under the Curve (AUC) of 0.68 7 . In contrast, cervical cancer screening (i.e. assessing cervical samples) that offers simple non-invasive access to precancerous cells has reduced the incidence and mortality from cervical cancer by more than 50% 8 . Epigenetic (i.e. DNAme) changes have been identified in normal breast tissue adjacent to breast cancers 9 and could potentially serve as a surrogate for both genetic and non-genetic factors including lifestyle, reproductive and environmental exposures contributing to breast cancer development 10 . A number of proof of principle studies, so far exclusively performed in blood, have demonstrated that certain DNAme changes are associated with breast cancer predisposition 11 , 12 , 13 , 14 , 15 , 16 . Steroid hormones are essential drivers of breast cancer formation and hence it is a requirement that surrogate tissue is sufficiently hormone sensitive. For instance, prolonged 17 or higher 18 exposure to progesterone is strongly associated with the formation of poor prognostic breast cancer 17 , 18 , 19 , 20 , 21 , 22 and the progesterone receptor antagonist mifepristone effectively prevents breast cancer formation in mice 23 . Sample heterogeneity and the choice of surrogate tissue are deemed to be among the most important factors for impending clinical implementation 24 . Thus, we aimed to assess whether DNAme profiles derived from cervical liquid-based cytology samples (i.e. containing hormone-sensitive epithelial cells, which are capable of recording breast cancer-predisposing factors at the level of the epigenome 24 and can be self-collected), are able to identify women with primary breast cancer. Here, we perform an epigenome-wide DNAme analysis in cervical liquid-based cytology samples from women who had recently been diagnosed with breast cancer and in matched controls. We establish the WID-BC test (Women’s risk IDentification for Breast Cancer index) and validate it in independent sets of cervical samples. We also carry out further validation in samples from women with ovarian cancer and a set of matched cervical, buccal, and blood samples from BRCA mutation carriers and in archived samples from a population cohort. In addition, we specifically assess DNAme at progesterone receptor binding sites (PR-BS) in breast and cervical samples to evaluate whether systemic factors driving carcinogenesis in the breast can be captured by assessment of the cervical epigenome. Results Sample heterogeneity and differential methylation For the discovery set, we collected samples from 329 women with primary breast cancer with poor prognosis features (defined by >2 cm cancers and/or lymph-node positive and/or hormone-receptor negative and/or grade 3) from 14 European centres at the time of diagnosis and before treatment commenced, and 869 women without breast cancer (593 from the general population and 276 from women attending hospital for benign women-specific conditions) (Fig. 1 ). Epidemiological and clinical characteristics in the discovery set are presented in Supplementary Tables 1 and 3 . Epigenome-wide DNAme was analysed using an Illumina Infinium EPIC bead chip array which encompasses over 850,000 CpG sites 25 . Fig. 1: Overview of experimental design and datasets. We included women with breast cancer who had at least one poor prognostic feature and recruited both hospital-based controls and controls from the general population. The discovery set was further subdivided into a training set and internal validation set and was used to derive the WID-BC-index. For a subset of individuals in the internal validation set, matched buccal samples and SNP data were available. The WID-BC-index was evaluated in the external validation set. Additional datasets for evaluation of the WID-BC-index consisted of cervical samples from individuals with endometrial or ovarian cancer, or BRCA mutation carriers, as well as breast tissue samples from healthy controls, BRCA mutation carriers, or normal tissue adjacent to triple-negative breast cancer. Predictive assessment of the WID-BC-index was carried out using samples from a Swedish Biobank which included cervical smears from healthy controls and women who were diagnosed with breast cancer 1 to 5 years after sample collection. Source data are provided as a Source Data file. Full size image We assessed the level of cell-type heterogeneity in each cervical sample using EpiDISH 26 , an algorithm that infers the relative proportion of epithelial cells, fibroblasts, and seven subtypes", "role": "user" }, { "content": "Pap tests have long been used to detect cervical cancer early, but preliminary research suggests that cervical cells collected during those tests could also be used to catch other cancers, including deadly ovarian tumors. Researchers found that by analyzing a particular molecular \"signature\" in cervical cells, they could accurately identify women with ovarian cancer up to 71% of the time. Using a similar approach, they were also able detect a majority of women who had breast cancer with a poor prognosis. The findings suggest that the molecular signatures in cervical cells may be picking up a predisposition to other women-specific cancers, said senior researcher Dr. Martin Widschwendter, a professor of cancer prevention and screening at the University of Innsbruck in Austria. The hope, he explained, is to one day have a simple \"first-line\" screening test for four cancers: cervical, endometrial, breast and ovarian. Women deemed to be at high risk for any of the diseases could then undergo more intensive screening for them, said Widschwendter. He noted that of all cancers women develop before the age of 65, more than half are breast, ovarian, endometrial or cervical. Ovarian cancer, in particular, lacks any good test to use for routine screening. The disease is often deadly, largely because it is typically diagnosed after it has spread. \"Our aim is to identify the vast majority of women who are at risk of developing a woman-specific cancer—irrespective of genetic or non-genetic factors,\" Widschwendter said. However, an ovarian cancer specialist urged caution in interpreting the findings. They show a \"moderate association\" between the molecular signature and ovarian cancer, said Dr. Rebecca Stone, director of the Kelly Gynecologic Oncology Service at Johns Hopkins Hospital in Baltimore. \"They are not showing that it's predictive or diagnostic,\" Stone stressed. To see whether the cervical cell signature actually predicts cancer, she said, a study would need to follow a large group of women over a long period. Widschwendter said such a study is planned. The latest findings were published Feb. 1 in the journal Nature Communications. The research focuses on a process known as DNA methylation—chemical modifications to DNA that do not cause mutations in genes, but do determine whether a gene is active or dormant at certain times. Those modifications accumulate over a person's lifetime, and are influenced by genes and a wide range of other factors, including diet, exercise, smoking and hormones—exposures that also sway cancer risk. So the DNA methylation signature in body cells could be seen as a record of a person's cancer-linked exposures, according to Widschwendter. He and his colleagues are developing a test called WID (Women's Risk Identification) that analyzes the DNA methylation signature in cervical cells, partly because they are easily accessed via a Pap smear test. They hope that by calculating women's WID risk score, they can identify those at high risk of developing any of the four cancers. One of the studies involved 242 women with ovarian cancer and 869 without the disease. They found that the WID index identified 71% of women younger than 50 who had the cancer, and about 55% of those patients older than 50. The researchers further validated the test in another group of women, where 47 had ovarian cancer and 225 did not. They found that ovarian cancer risk was greatly increased among women whose WID index was in the top 25%. Like Stone, Widschwendter said the findings do not prove the WID index actually predicts ovarian cancer. But he argued the evidence suggests the test is, indeed, picking up cancer predisposition. For one, he said, the results were similar in yet another validation group, of women with a different disease—endometrial cancer. Widschwendter also pointed to the second study, which involved 329 women with aggressive breast cancer and 869 without the disease. The WID index was able to identify women with the disease, and those who scored the top 25% had a greatly increased risk of breast cancer. Widschwendter said the researchers will study whether the WID test can identify women at high risk and, most importantly, whether further measures can catch cancer early. For women at risk of aggressive breast cancer, that could mean screening more frequently, with MRI scans. For women at risk of ovarian cancer, that could mean using approaches that are under study—like a combination of the CA 125 blood test and a test that looks for \"altered cancer DNA\" in the plasma, Widschwendter said. Stone had a more guarded take on the findings. \"These data are hypothesis-generating,\" she said. At this point, characterizing the test as revealing cancer predisposition, she added, \"is a stretch.\" As for preventing ovarian cancer deaths, Stone pointed to an alternative to awaiting advanced tests. It's become clear, she said, that most deadly ovarian tumors actually begin in the fallopian tubes, which connect the ovaries and uterus. Ovarian cancers could be prevented, Stone suggested, by offering women the option of having their tubes removed once they are done having children. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women’s risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80–0.88) and 0.81 (95% CI: 0.76–0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk. Introduction Breast cancer is by far the most common cancer in females in general, and a leading cause of death in young women 1 . To date, the identification of individuals with primary cancer is achieved by assessing evidence directly from the tumour (e.g. imaging 2 or detection of cancer cell products released into the system 3 , 4 ). Currently, available early detection strategies, such as mammography screening, suffer from low performance in young women, over-diagnosis, and decreasing attendance rates, and its benefit on mortality reduction has recently been questioned 5 . High-risk prevention strategies and risk-stratified screening require high discriminatory accuracy, that can only be achieved with predictors much stronger than those yet discovered 6 . Yet the best predictive models combining non-genetic factors and a polygenic risk score have only led to a Receiver Operator Characteristic (ROC) Area Under the Curve (AUC) of 0.68 7 . In contrast, cervical cancer screening (i.e. assessing cervical samples) that offers simple non-invasive access to precancerous cells has reduced the incidence and mortality from cervical cancer by more than 50% 8 . Epigenetic (i.e. DNAme) changes have been identified in normal breast tissue adjacent to breast cancers 9 and could potentially serve as a surrogate for both genetic and non-genetic factors including lifestyle, reproductive and environmental exposures contributing to breast cancer development 10 . A number of proof of principle studies, so far exclusively performed in blood, have demonstrated that certain DNAme changes are associated with breast cancer predisposition 11 , 12 , 13 , 14 , 15 , 16 . Steroid hormones are essential drivers of breast cancer formation and hence it is a requirement that surrogate tissue is sufficiently hormone sensitive. For instance, prolonged 17 or higher 18 exposure to progesterone is strongly associated with the formation of poor prognostic breast cancer 17 , 18 , 19 , 20 , 21 , 22 and the progesterone receptor antagonist mifepristone effectively prevents breast cancer formation in mice 23 . Sample heterogeneity and the choice of surrogate tissue are deemed to be among the most important factors for impending clinical implementation 24 . Thus, we aimed to assess whether DNAme profiles derived from cervical liquid-based cytology samples (i.e. containing hormone-sensitive epithelial cells, which are capable of recording breast cancer-predisposing factors at the level of the epigenome 24 and can be self-collected), are able to identify women with primary breast cancer. Here, we perform an epigenome-wide DNAme analysis in cervical liquid-based cytology samples from women who had recently been diagnosed with breast cancer and in matched controls. We establish the WID-BC test (Women’s risk IDentification for Breast Cancer index) and validate it in independent sets of cervical samples. We also carry out further validation in samples from women with ovarian cancer and a set of matched cervical, buccal, and blood samples from BRCA mutation carriers and in archived samples from a population cohort. In addition, we specifically assess DNAme at progesterone receptor binding sites (PR-BS) in breast and cervical samples to evaluate whether systemic factors driving carcinogenesis in the breast can be captured by assessment of the cervical epigenome. Results Sample heterogeneity and differential methylation For the discovery set, we collected samples from 329 women with primary breast cancer with poor prognosis features (defined by >2 cm cancers and/or lymph-node positive and/or hormone-receptor negative and/or grade 3) from 14 European centres at the time of diagnosis and before treatment commenced, and 869 women without breast cancer (593 from the general population and 276 from women attending hospital for benign women-specific conditions) (Fig. 1 ). Epidemiological and clinical characteristics in the discovery set are presented in Supplementary Tables 1 and 3 . Epigenome-wide DNAme was analysed using an Illumina Infinium EPIC bead chip array which encompasses over 850,000 CpG sites 25 . Fig. 1: Overview of experimental design and datasets. We included women with breast cancer who had at least one poor prognostic feature and recruited both hospital-based controls and controls from the general population. The discovery set was further subdivided into a training set and internal validation set and was used to derive the WID-BC-index. For a subset of individuals in the internal validation set, matched buccal samples and SNP data were available. The WID-BC-index was evaluated in the external validation set. Additional datasets for evaluation of the WID-BC-index consisted of cervical samples from individuals with endometrial or ovarian cancer, or BRCA mutation carriers, as well as breast tissue samples from healthy controls, BRCA mutation carriers, or normal tissue adjacent to triple-negative breast cancer. Predictive assessment of the WID-BC-index was carried out using samples from a Swedish Biobank which included cervical smears from healthy controls and women who were diagnosed with breast cancer 1 to 5 years after sample collection. Source data are provided as a Source Data file. Full size image We assessed the level of cell-type heterogeneity in each cervical sample using EpiDISH 26 , an algorithm that infers the relative proportion of epithelial cells, fibroblasts, and seven subtypes<|im_end|> <|im_start|>assistant Pap tests have long been used to detect cervical cancer early, but preliminary research suggests that cervical cells collected during those tests could also be used to catch other cancers, including deadly ovarian tumors. Researchers found that by analyzing a particular molecular "signature" in cervical cells, they could accurately identify women with ovarian cancer up to 71% of the time. Using a similar approach, they were also able detect a majority of women who had breast cancer with a poor prognosis. The findings suggest that the molecular signatures in cervical cells may be picking up a predisposition to other women-specific cancers, said senior researcher Dr. Martin Widschwendter, a professor of cancer prevention and screening at the University of Innsbruck in Austria. The hope, he explained, is to one day have a simple "first-line" screening test for four cancers: cervical, endometrial, breast and ovarian. Women deemed to be at high risk for any of the diseases could then undergo more intensive screening for them, said Widschwendter. He noted that of all cancers women develop before the age of 65, more than half are breast, ovarian, endometrial or cervical. Ovarian cancer, in particular, lacks any good test to use for routine screening. The disease is often deadly, largely because it is typically diagnosed after it has spread. "Our aim is to identify the vast majority of women who are at risk of developing a woman-specific cancer—irrespective of genetic or non-genetic factors," Widschwendter said. However, an ovarian cancer specialist urged caution in interpreting the findings. They show a "moderate association" between the molecular signature and ovarian cancer, said Dr. Rebecca Stone, director of the Kelly Gynecologic Oncology Service at Johns Hopkins Hospital in Baltimore. "They are not showing that it's predictive or diagnostic," Stone stressed. To see whether the cervical cell signature actually predicts cancer, she said, a study would need to follow a large group of women over a long period. Widschwendter said such a study is planned. The latest findings were published Feb. 1 in the journal Nature Communications. The research focuses on a process known as DNA methylation—chemical modifications to DNA that do not cause mutations in genes, but do determine whether a gene is active or dormant at certain times. Those modifications accumulate over a person's lifetime, and are influenced by genes and a wide range of other factors, including diet, exercise, smoking and hormones—exposures that also sway cancer risk. So the DNA methylation signature in body cells could be seen as a record of a person's cancer-linked exposures, according to Widschwendter. He and his colleagues are developing a test called WID (Women's Risk Identification) that analyzes the DNA methylation signature in cervical cells, partly because they are easily accessed via a Pap smear test. They hope that by calculating women's WID risk score, they can identify those at high risk of developing any of the four cancers. One of the studies involved 242 women with ovarian cancer and 869 without the disease. They found that the WID index identified 71% of women younger than 50 who had the cancer, and about 55% of those patients older than 50. The researchers further validated the test in another group of women, where 47 had ovarian cancer and 225 did not. They found that ovarian cancer risk was greatly increased among women whose WID index was in the top 25%. Like Stone, Widschwendter said the findings do not prove the WID index actually predicts ovarian cancer. But he argued the evidence suggests the test is, indeed, picking up cancer predisposition. For one, he said, the results were similar in yet another validation group, of women with a different disease—endometrial cancer. Widschwendter also pointed to the second study, which involved 329 women with aggressive breast cancer and 869 without the disease. The WID index was able to identify women with the disease, and those who scored the top 25% had a greatly increased risk of breast cancer. Widschwendter said the researchers will study whether the WID test can identify women at high risk and, most importantly, whether further measures can catch cancer early. For women at risk of aggressive breast cancer, that could mean screening more frequently, with MRI scans. For women at risk of ovarian cancer, that could mean using approaches that are under study—like a combination of the CA 125 blood test and a test that looks for "altered cancer DNA" in the plasma, Widschwendter said. Stone had a more guarded take on the findings. "These data are hypothesis-generating," she said. At this point, characterizing the test as revealing cancer predisposition, she added, "is a stretch." As for preventing ovarian cancer deaths, Stone pointed to an alternative to awaiting advanced tests. It's become clear, she said, that most deadly ovarian tumors actually begin in the fallopian tubes, which connect the ovaries and uterus. Ovarian cancers could be prevented, Stone suggested, by offering women the option of having their tubes removed once they are done having children. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Researchers and educators have long wrestled with the question of how best to teach their clients be they humans, non-human animals or machines. Here, we examine the role of a single variable, the difficulty of training, on the rate of learning. In many situations we find that there is a sweet spot in which training is neither too easy nor too hard, and where learning progresses most quickly. We derive conditions for this sweet spot for a broad class of learning algorithms in the context of binary classification tasks. For all of these stochastic gradient-descent based learning algorithms, we find that the optimal error rate for training is around 15.87% or, conversely, that the optimal training accuracy is about 85%. We demonstrate the efficacy of this ‘Eighty Five Percent Rule’ for artificial neural networks used in AI and biologically plausible neural networks thought to describe animal learning. Introduction When we learn something new, like a language or musical instrument, we often seek challenges at the edge of our competence—not so hard that we are discouraged, but not so easy that we get bored. This simple intuition, that there is a sweet spot of difficulty, a ‘Goldilocks zone’ 1 , for motivation and learning is at the heart of modern teaching methods 2 and is thought to account for differences in infant attention between more and less learnable stimuli 1 . In the animal learning literature it is the intuition behind shaping 3 and fading 4 , whereby complex tasks are taught by steadily increasing the difficulty of a training task. It is also observable in the nearly universal ‘levels’ feature in video games, in which the player is encouraged, or even forced, to a higher level of difficulty once a performance criterion has been achieved. Similarly in machine learning, steadily increasing the difficulty of training has proven useful for teaching large scale neural networks in a variety of tasks 5 , 6 , where it is known as ‘Curriculum Learning’ 7 and ‘Self-Paced Learning’ 8 . Despite this long history of empirical results, it is unclear why a particular difficulty level may be beneficial for learning nor what that optimal level might be. In this paper we address this issue of optimal training difficulty for a broad class of learning algorithms in the context of binary classification tasks, in which ambiguous stimuli must be classified into one of two classes (e.g., cat or dog). In particular, we focus on the class of stochastic gradient-descent based learning algorithms. In these algorithms, parameters of the model (e.g., the weights in a neural network) are adjusted based on feedback in such a way as to reduce the average error rate over time 9 . That is, these algorithms descend the gradient of error rate as a function of model parameters. Such gradient-descent learning forms the basis of many algorithms in AI, from single-layer perceptrons to deep neural networks 10 , and provides a quantitative description of human and animal learning in a variety of situations, from perception 11 , to motor control 12 to reinforcement learning 13 . For these algorithms, we provide a general result for the optimal difficulty in terms of a target error rate for training. Under the assumption of a Gaussian noise process underlying the errors, this optimal error rate is around 15.87%, a number that varies slightly depending on the noise in the learning process. That is the optimal accuracy for training is around 85%. We show theoretically that training at this optimal difficulty can lead to exponential improvements in the rate of learning. Finally, we demonstrate the applicability of the Eighty Five Percent Rule to artificial one- and two-layer neural networks 9 , 14 , and a model from computational neuroscience that is thought to describe human and animal perceptual learning 11 . Results Optimal training difficulty for binary classification tasks In a standard binary classification task, an animal or machine ‘agent’ makes binary decisions about simple stimuli. For example, in the classic Random Dot Motion paradigm from Psychology and Neuroscience 15 , 16 , stimuli consist of a patch of moving dots—most moving randomly but a small fraction moving coherently either to the left or the right—and participants must decide in which direction the coherent dots are moving. A major factor in determining the difficulty of this perceptual decision is the fraction of coherently moving dots, which can be manipulated by the experimenter to achieve a fixed error rate during training using a procedure known as ‘staircasing’ 17 . We assume that agents make their decision on the basis of a scalar, subjective decision variable, h , which is computed from a stimulus that can be represented as a vector x (e.g., the direction of motion of all dots) $$h = \\Phi ({\\mathbf{x}},{\\boldsymbol{\\phi }})$$ (1) where Φ( ⋅ ) is a function of the stimulus and (tunable) parameters ϕ . We assume that this transformation of stimulus x into the subjective decision variable h yields a noisy representation of the true decision variable, Δ (e.g., the fraction of dots moving left). That is, we write $$h = \\Delta + n$$ (2) where the noise, n , arises due to the imperfect representation of the decision variable. We further assume that this noise, n , is random and sampled from a zero-mean Gaussian distribution with standard deviation σ (Fig. 1a ). Fig. 1 Illustration of the model. a Distributions over decision variable h given a particular difficulty, Δ = 16, with lower precision before learning and higher precision after learning. The shaded regions corresponds to the error rate—the probability of making an incorrect response at each difficulty. b The error rate as a function of difficulty before and after learning. c The derivative that determines the rate of learning as a function of difficulty before and after learning showing that the optimal difficulty for learning is lower after learning than before. d The same derivative as in c re-plotted as a function of error rate showing", "role": "user" }, { "content": "To learn new things, we must sometimes fail. But what's the right amount of failure? New research led by the University of Arizona proposes a mathematical answer to that question. Educators and educational scholars have long recognized that there is something of a \"sweet spot\" when it comes to learning. That is, we learn best when we are challenged to grasp something just outside the bounds of our existing knowledge. When a challenge is too simple, we don't learn anything new; likewise, we don't enhance our knowledge when a challenge is so difficult that we fail entirely or give up. So where does the sweet spot lie? According to the new study, to be published in the journal Nature Communications, it's when failure occurs 15% of the time. Put another way, it's when the right answer is given 85% of the time. \"These ideas that were out there in the education field—that there is this 'zone of proximal difficulty,' in which you ought to be maximizing your learning—we've put that on a mathematical footing,\" said UArizona assistant professor of psychology and cognitive science Robert Wilson, lead author of the study, titled \"The Eighty Five Percent Rule for Optimal Learning.\" Wilson and his collaborators at Brown University, the University of California, Los Angeles and Princeton came up with the so-called \"85% Rule\" after conducting a series of machine-learning experiments in which they taught computers simple tasks, such as classifying different patterns into one of two categories or classifying photographs of handwritten digits as odd versus even numbers, or low versus high numbers. The computers learned fastest in situations in which the difficulty was such that they responded with 85% accuracy. \"If you have an error rate of 15% or accuracy of 85%, you are always maximizing your rate of learning in these two-choice tasks,\" Wilson said. When researchers looked at previous studies of animal learning, they found that the 85% Rule held true in those instances as well, Wilson said. When we think about how humans learn, the 85% Rule would mostly likely apply to perceptual learning, in which we gradually learn through experience and examples, Wilson said. Imagine, for instance, a radiologist learning to tell the difference between images of tumors and non-tumors. \"You get better at figuring out there's a tumor in an image over time, and you need experience and you need examples to get better,\" Wilson said. \"I can imagine giving easy examples and giving difficult examples and giving intermediate examples. If I give really easy examples, you get 100% right all the time and there's nothing left to learn. If I give really hard examples, you'll be 50% correct and still not learning anything new, whereas if I give you something in between, you can be at this sweet spot where you are getting the most information from each particular example.\" Since Wilson and his collaborators were looking only at simple tasks in which there was a clear correct and incorrect answer, Wilson won't go so far as to say that students should aim for a B average in school. However, he does think there might be some lessons for education that are worth further exploration. \"If you are taking classes that are too easy and acing them all the time, then you probably aren't getting as much out of a class as someone who's struggling but managing to keep up,\" he said. \"The hope is we can expand this work and start to talk about more complicated forms of learning.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Researchers and educators have long wrestled with the question of how best to teach their clients be they humans, non-human animals or machines. Here, we examine the role of a single variable, the difficulty of training, on the rate of learning. In many situations we find that there is a sweet spot in which training is neither too easy nor too hard, and where learning progresses most quickly. We derive conditions for this sweet spot for a broad class of learning algorithms in the context of binary classification tasks. For all of these stochastic gradient-descent based learning algorithms, we find that the optimal error rate for training is around 15.87% or, conversely, that the optimal training accuracy is about 85%. We demonstrate the efficacy of this ‘Eighty Five Percent Rule’ for artificial neural networks used in AI and biologically plausible neural networks thought to describe animal learning. Introduction When we learn something new, like a language or musical instrument, we often seek challenges at the edge of our competence—not so hard that we are discouraged, but not so easy that we get bored. This simple intuition, that there is a sweet spot of difficulty, a ‘Goldilocks zone’ 1 , for motivation and learning is at the heart of modern teaching methods 2 and is thought to account for differences in infant attention between more and less learnable stimuli 1 . In the animal learning literature it is the intuition behind shaping 3 and fading 4 , whereby complex tasks are taught by steadily increasing the difficulty of a training task. It is also observable in the nearly universal ‘levels’ feature in video games, in which the player is encouraged, or even forced, to a higher level of difficulty once a performance criterion has been achieved. Similarly in machine learning, steadily increasing the difficulty of training has proven useful for teaching large scale neural networks in a variety of tasks 5 , 6 , where it is known as ‘Curriculum Learning’ 7 and ‘Self-Paced Learning’ 8 . Despite this long history of empirical results, it is unclear why a particular difficulty level may be beneficial for learning nor what that optimal level might be. In this paper we address this issue of optimal training difficulty for a broad class of learning algorithms in the context of binary classification tasks, in which ambiguous stimuli must be classified into one of two classes (e.g., cat or dog). In particular, we focus on the class of stochastic gradient-descent based learning algorithms. In these algorithms, parameters of the model (e.g., the weights in a neural network) are adjusted based on feedback in such a way as to reduce the average error rate over time 9 . That is, these algorithms descend the gradient of error rate as a function of model parameters. Such gradient-descent learning forms the basis of many algorithms in AI, from single-layer perceptrons to deep neural networks 10 , and provides a quantitative description of human and animal learning in a variety of situations, from perception 11 , to motor control 12 to reinforcement learning 13 . For these algorithms, we provide a general result for the optimal difficulty in terms of a target error rate for training. Under the assumption of a Gaussian noise process underlying the errors, this optimal error rate is around 15.87%, a number that varies slightly depending on the noise in the learning process. That is the optimal accuracy for training is around 85%. We show theoretically that training at this optimal difficulty can lead to exponential improvements in the rate of learning. Finally, we demonstrate the applicability of the Eighty Five Percent Rule to artificial one- and two-layer neural networks 9 , 14 , and a model from computational neuroscience that is thought to describe human and animal perceptual learning 11 . Results Optimal training difficulty for binary classification tasks In a standard binary classification task, an animal or machine ‘agent’ makes binary decisions about simple stimuli. For example, in the classic Random Dot Motion paradigm from Psychology and Neuroscience 15 , 16 , stimuli consist of a patch of moving dots—most moving randomly but a small fraction moving coherently either to the left or the right—and participants must decide in which direction the coherent dots are moving. A major factor in determining the difficulty of this perceptual decision is the fraction of coherently moving dots, which can be manipulated by the experimenter to achieve a fixed error rate during training using a procedure known as ‘staircasing’ 17 . We assume that agents make their decision on the basis of a scalar, subjective decision variable, h , which is computed from a stimulus that can be represented as a vector x (e.g., the direction of motion of all dots) $$h = \Phi ({\mathbf{x}},{\boldsymbol{\phi }})$$ (1) where Φ( ⋅ ) is a function of the stimulus and (tunable) parameters ϕ . We assume that this transformation of stimulus x into the subjective decision variable h yields a noisy representation of the true decision variable, Δ (e.g., the fraction of dots moving left). That is, we write $$h = \Delta + n$$ (2) where the noise, n , arises due to the imperfect representation of the decision variable. We further assume that this noise, n , is random and sampled from a zero-mean Gaussian distribution with standard deviation σ (Fig. 1a ). Fig. 1 Illustration of the model. a Distributions over decision variable h given a particular difficulty, Δ = 16, with lower precision before learning and higher precision after learning. The shaded regions corresponds to the error rate—the probability of making an incorrect response at each difficulty. b The error rate as a function of difficulty before and after learning. c The derivative that determines the rate of learning as a function of difficulty before and after learning showing that the optimal difficulty for learning is lower after learning than before. d The same derivative as in c re-plotted as a function of error rate showing<|im_end|> <|im_start|>assistant To learn new things, we must sometimes fail. But what's the right amount of failure? New research led by the University of Arizona proposes a mathematical answer to that question. Educators and educational scholars have long recognized that there is something of a "sweet spot" when it comes to learning. That is, we learn best when we are challenged to grasp something just outside the bounds of our existing knowledge. When a challenge is too simple, we don't learn anything new; likewise, we don't enhance our knowledge when a challenge is so difficult that we fail entirely or give up. So where does the sweet spot lie? According to the new study, to be published in the journal Nature Communications, it's when failure occurs 15% of the time. Put another way, it's when the right answer is given 85% of the time. "These ideas that were out there in the education field—that there is this 'zone of proximal difficulty,' in which you ought to be maximizing your learning—we've put that on a mathematical footing," said UArizona assistant professor of psychology and cognitive science Robert Wilson, lead author of the study, titled "The Eighty Five Percent Rule for Optimal Learning." Wilson and his collaborators at Brown University, the University of California, Los Angeles and Princeton came up with the so-called "85% Rule" after conducting a series of machine-learning experiments in which they taught computers simple tasks, such as classifying different patterns into one of two categories or classifying photographs of handwritten digits as odd versus even numbers, or low versus high numbers. The computers learned fastest in situations in which the difficulty was such that they responded with 85% accuracy. "If you have an error rate of 15% or accuracy of 85%, you are always maximizing your rate of learning in these two-choice tasks," Wilson said. When researchers looked at previous studies of animal learning, they found that the 85% Rule held true in those instances as well, Wilson said. When we think about how humans learn, the 85% Rule would mostly likely apply to perceptual learning, in which we gradually learn through experience and examples, Wilson said. Imagine, for instance, a radiologist learning to tell the difference between images of tumors and non-tumors. "You get better at figuring out there's a tumor in an image over time, and you need experience and you need examples to get better," Wilson said. "I can imagine giving easy examples and giving difficult examples and giving intermediate examples. If I give really easy examples, you get 100% right all the time and there's nothing left to learn. If I give really hard examples, you'll be 50% correct and still not learning anything new, whereas if I give you something in between, you can be at this sweet spot where you are getting the most information from each particular example." Since Wilson and his collaborators were looking only at simple tasks in which there was a clear correct and incorrect answer, Wilson won't go so far as to say that students should aim for a B average in school. However, he does think there might be some lessons for education that are worth further exploration. "If you are taking classes that are too easy and acing them all the time, then you probably aren't getting as much out of a class as someone who's struggling but managing to keep up," he said. "The hope is we can expand this work and start to talk about more complicated forms of learning." <|im_end|>

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26679, 279, 17250, 315, 420, 78632, 940, 5597, 374, 279, 19983, 315, 1080, 1964, 4501, 7366, 32094, 11, 902, 649, 387, 55315, 555, 279, 2183, 318, 1992, 311, 11322, 264, 8521, 1493, 4478, 2391, 4967, 1701, 264, 10537, 3967, 439, 3451, 267, 1334, 66, 4522, 529, 220, 1114, 662, 1226, 9855, 430, 13307, 1304, 872, 5597, 389, 279, 8197, 315, 264, 17722, 11, 44122, 5597, 3977, 11, 305, 1174, 902, 374, 25157, 505, 264, 39535, 430, 649, 387, 15609, 439, 264, 4724, 865, 320, 68, 1326, 2637, 279, 5216, 315, 11633, 315, 682, 32094, 8, 27199, 71, 284, 1144, 46267, 9657, 59, 10590, 13536, 46440, 92, 16970, 59, 15168, 19314, 36802, 17247, 3954, 8, 14415, 320, 16, 8, 1405, 101989, 7, 2928, 233, 227, 883, 374, 264, 734, 315, 279, 39535, 323, 320, 83, 47028, 8, 5137, 17839, 243, 662, 1226, 9855, 430, 420, 18475, 315, 39535, 865, 1139, 279, 44122, 5597, 3977, 305, 36508, 264, 50380, 13340, 315, 279, 837, 5597, 3977, 11, 82263, 320, 68, 1326, 2637, 279, 19983, 315, 32094, 7366, 2163, 570, 3011, 374, 11, 584, 3350, 27199, 71, 284, 1144, 20892, 489, 308, 14415, 320, 17, 8, 1405, 279, 12248, 11, 308, 1174, 48282, 4245, 311, 279, 69063, 13340, 315, 279, 5597, 3977, 13, 1226, 4726, 9855, 430, 420, 12248, 11, 308, 1174, 374, 4288, 323, 49976, 505, 264, 7315, 84096, 49668, 8141, 449, 5410, 38664, 48823, 320, 30035, 13, 220, 16, 64, 7609, 23966, 13, 220, 16, 39154, 367, 315, 279, 1646, 13, 264, 423, 18478, 927, 5597, 3977, 305, 2728, 264, 4040, 17250, 11, 82263, 284, 220, 845, 11, 449, 4827, 16437, 1603, 6975, 323, 5190, 16437, 1306, 6975, 13, 578, 92866, 13918, 34310, 311, 279, 1493, 4478, 22416, 19463, 315, 3339, 459, 15465, 2077, 520, 1855, 17250, 13, 293, 578, 1493, 4478, 439, 264, 734, 315, 17250, 1603, 323, 1306, 6975, 13, 272, 578, 32905, 430, 27667, 279, 4478, 315, 6975, 439, 264, 734, 315, 17250, 1603, 323, 1306, 6975, 9204, 430, 279, 23669, 17250, 369, 6975, 374, 4827, 1306, 6975, 1109, 1603, 13, 294, 578, 1890, 32905, 439, 304, 272, 312, 33207, 15889, 439, 264, 734, 315, 1493, 4478, 9204, 128257, 198, 128256, 78191, 198, 1271, 4048, 502, 2574, 11, 584, 2011, 7170, 3775, 13, 2030, 1148, 596, 279, 1314, 3392, 315, 8060, 30, 1561, 3495, 6197, 555, 279, 3907, 315, 17368, 55725, 264, 37072, 4320, 311, 430, 3488, 13, 10355, 3046, 323, 16627, 31839, 617, 1317, 15324, 430, 1070, 374, 2555, 315, 264, 330, 95928, 7858, 1, 994, 433, 4131, 311, 6975, 13, 3011, 374, 11, 584, 4048, 1888, 994, 584, 527, 29991, 311, 34477, 2555, 1120, 4994, 279, 14597, 315, 1057, 6484, 6677, 13, 3277, 264, 8815, 374, 2288, 4382, 11, 584, 1541, 956, 4048, 4205, 502, 26, 39022, 11, 584, 1541, 956, 18885, 1057, 6677, 994, 264, 8815, 374, 779, 5107, 430, 584, 3775, 11622, 477, 3041, 709, 13, 2100, 1405, 1587, 279, 10437, 7858, 10457, 30, 10771, 311, 279, 502, 4007, 11, 311, 387, 4756, 304, 279, 8486, 22037, 26545, 11, 433, 596, 994, 8060, 13980, 220, 868, 4, 315, 279, 892, 13, 10435, 2500, 1648, 11, 433, 596, 994, 279, 1314, 4320, 374, 2728, 220, 5313, 4, 315, 279, 892, 13, 330, 9673, 6848, 430, 1051, 704, 1070, 304, 279, 6873, 2115, 41128, 1070, 374, 420, 364, 8855, 315, 22267, 2931, 17250, 2965, 304, 902, 499, 22525, 311, 387, 88278, 701, 6975, 86319, 3077, 2231, 430, 389, 264, 37072, 74503, 1359, 1071, 549, 82591, 18328, 14561, 315, 31018, 323, 25702, 8198, 8563, 17882, 11, 3063, 3229, 315, 279, 4007, 11, 25891, 330, 791, 36944, 88, 21594, 56448, 18592, 369, 16963, 2931, 21579, 1210, 17882, 323, 813, 79119, 520, 10690, 3907, 11, 279, 3907, 315, 7188, 11, 9853, 12167, 323, 50421, 3782, 709, 449, 279, 779, 19434, 330, 5313, 4, 18592, 1, 1306, 31474, 264, 4101, 315, 5780, 71856, 21896, 304, 902, 814, 15972, 19002, 4382, 9256, 11, 1778, 439, 538, 7922, 2204, 12912, 1139, 832, 315, 1403, 11306, 477, 538, 7922, 25232, 315, 99489, 19016, 439, 10535, 19579, 1524, 5219, 11, 477, 3428, 19579, 1579, 5219, 13, 578, 19002, 9687, 26731, 304, 15082, 304, 902, 279, 17250, 574, 1778, 430, 814, 16846, 449, 220, 5313, 4, 13708, 13, 330, 2746, 499, 617, 459, 1493, 4478, 315, 220, 868, 4, 477, 13708, 315, 220, 5313, 13689, 499, 527, 2744, 88278, 701, 4478, 315, 6975, 304, 1521, 1403, 63726, 9256, 1359, 17882, 1071, 13, 3277, 12074, 7111, 520, 3766, 7978, 315, 10065, 6975, 11, 814, 1766, 430, 279, 220, 5313, 4, 18592, 5762, 837, 304, 1884, 13422, 439, 1664, 11, 17882, 1071, 13, 3277, 584, 1781, 922, 1268, 12966, 4048, 11, 279, 220, 5313, 4, 18592, 1053, 10213, 4461, 3881, 311, 78632, 940, 6975, 11, 304, 902, 584, 27115, 4048, 1555, 3217, 323, 10507, 11, 17882, 1071, 13, 38891, 11, 369, 2937, 11, 264, 12164, 16549, 6975, 311, 3371, 279, 6811, 1990, 5448, 315, 56071, 323, 2536, 2442, 372, 1105, 13, 330, 2675, 636, 2731, 520, 48309, 704, 1070, 596, 264, 36254, 304, 459, 2217, 927, 892, 11, 323, 499, 1205, 3217, 323, 499, 1205, 10507, 311, 636, 2731, 1359, 17882, 1071, 13, 330, 40, 649, 13085, 7231, 4228, 10507, 323, 7231, 5107, 10507, 323, 7231, 29539, 10507, 13, 1442, 358, 3041, 2216, 4228, 10507, 11, 499, 636, 220, 1041, 4, 1314, 682, 279, 892, 323, 1070, 596, 4400, 2163, 311, 4048, 13, 1442, 358, 3041, 2216, 2653, 10507, 11, 499, 3358, 387, 220, 1135, 4, 4495, 323, 2103, 539, 6975, 4205, 502, 11, 20444, 422, 358, 3041, 499, 2555, 304, 1990, 11, 499, 649, 387, 520, 420, 10437, 7858, 1405, 499, 527, 3794, 279, 1455, 2038, 505, 1855, 4040, 3187, 1210, 8876, 17882, 323, 813, 79119, 1051, 3411, 1193, 520, 4382, 9256, 304, 902, 1070, 574, 264, 2867, 4495, 323, 15465, 4320, 11, 17882, 2834, 956, 733, 779, 3117, 439, 311, 2019, 430, 4236, 1288, 9395, 369, 264, 426, 5578, 304, 2978, 13, 4452, 11, 568, 1587, 1781, 1070, 2643, 387, 1063, 18872, 369, 6873, 430, 527, 5922, 4726, 27501, 13, 330, 2746, 499, 527, 4737, 6989, 430, 527, 2288, 4228, 323, 1645, 287, 1124, 682, 279, 892, 11, 1243, 499, 4762, 7784, 956, 3794, 439, 1790, 704, 315, 264, 538, 439, 4423, 889, 596, 20558, 719, 18646, 311, 2567, 709, 1359, 568, 1071, 13, 330, 791, 3987, 374, 584, 649, 9407, 420, 990, 323, 1212, 311, 3137, 922, 810, 17395, 7739, 315, 6975, 1210, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [ 11 C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = −6.5 to 24.1%) and 3.8% (95% confidence interval = −11.9 to 9.4) lay within the pre-specified −17% margin for non-inferiority ( P = 0.00055 and P = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA. Main Hypertension is a major cause of deaths from stroke, coronary heart disease, heart failure and renal failure. The most common single cause of hypertension is primary aldosteronism (PA), accounting for 5–14% of all cases and 20–25% of treatment-resistant hypertension 1 , 2 , 3 , 4 . The cardiometabolic consequences of hypertension are approximately twice as likely in individuals with PA compared with age- and sex-matched individuals with essential hypertension 5 , 6 , 7 , 8 . Traditionally, patients with PA are divided equally into those in whom aldosterone excess is due to a unilateral aldosterone-producing adrenal adenoma (APA), in whom surgical cure is possible, and those with bilateral production (often termed idiopathic hyperaldosteronism (IHA)), who require long-term medical therapy. Although recent studies point to a continuum of disease between unilateral and bilateral subtypes, their distinction underpins the binary clinical decision of whether to remove one adrenal gland, and drives the investigations required to make this decision 9 , 10 . Current consensus is that patients with unilateral APAs should be offered laparoscopic surgical removal of that adrenal gland and those with IHA should be treated with aldosterone antagonist drugs 11 . Despite the prevalence and penalty of PA, currently, fewer than 1% of patients are identified and fully investigated 12 . Many reasons exist for this shortfall in clinical care, including: low levels of clinical suspicion; time-consuming and imperfect confirmatory biochemical tests that require discontinuation of many commonly prescribed antihypertensive drugs; difficulties with patient selection for surgical intervention; and uncertainty about outcomes in patients hoping for surgical cure. The paradoxical consequence is patient and physician reluctance to embark on a diagnostic and therapeutic process with a high likelihood of major clinical benefit, and that often sub-optimal medical treatment remains the default for the overwhelming majority of patients 7 , 11 . Molecular imaging has the potential to increase the number of patients with PA who can be fully investigated. The current criterion standard used to distinguish patients with APA from those with IHA is adrenal vein sampling (AVS)—an invasive, technically demanding procedure with restricted availability. Metomidate—a methyl analog of the anesthetic agent etomidate—is a potent inhibitor of CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase), the final two enzymes involved in cortisol and aldosterone synthesis, respectively. Metomidate can be 11 CH 3 labeled and used as a positron emission tomography (PET) radiotracer in combination with high-resolution computed tomography (CT) to detect adrenocortical tumors expressing these enzymes. A previous proof-of-concept study indicated that pre-treatment with dexamethasone for 3 d before [ 11 C]metomidate PET-CT (MTO) scanning suppresses adrenal CYP11B1 (but not CYP11B2) protein expression, thus achieving in vivo selectivity 13 . This selectivity facilitates the detection of focal adrenal lesions with high [ 11 C]metomidate uptake due to CYP11B2 expression and separates them from normal adrenal tissue. International guidelines for the management of PA acknowledge the potential for molecular imaging in the subtyping of PA 11 , but prospective outcomes-based data are needed to influence clinical practice. The primary aim of this study, which we have termed MATCH (Is Metomidate superior to AVS in predicting ouTComes from adrenalectomy in primary Hyperaldosteronism), was to compare the accuracy of AVS and MTO in predicting the outcome from adrenalectomy in patients with PA (Fig. 1a ). The diagnosis of PA, the protocol for and interpretation of AVS, and the biochemical and clinical outcomes after surgery were all assessed and conducted according to international consensus guidelines and/or statements (Fig. 1b and Supplementary Table 1 ) 11 , 14 , 15 . MTO scanning was performed as previously described 13 , and interpreted and graded before, and in ignorance of, the information provided by AVS. The design of the study also permitted the inclusion of a number of mechanistic secondary endpoints that have the potential to refine patient selection for surgery. These mechanistic endpoints included: a trial of aldosterone antagonist therapy (spironolactone or eplerenone) in predicting surgical cure; the influence of ethnicity and tumor genotype on surgical outcome; and the consequences of surgical and medical intervention on indices of cardiac injury and function, as determined by changes in amino (N)-terminal prohormone of brain natriuretic peptide (NT-pro BNP) levels and cardiac chamber dimensions on MRI. Fig. 1: Study outline, hierarchical co-primary endpoints and CONSORT diagram. a , Study outline. Patients with confirmed PA according to the Endocrine Society consensus guidelines underwent both AVS and MTO in random order. All patients were subsequently reviewed at a baseline visit and started on 50 mg spironolactone, which was up-titrated to 100 mg after 2 weeks. The blood pressure response to spironolactone was recorded at 2 and", "role": "user" }, { "content": "Doctors at Queen Mary University of London and Barts Hospital, and Cambridge University Hospital, have led research using a new type of CT scan to light up tiny nodules in a hormone gland and cure high blood pressure by their removal. The nodules are discovered in 1 in 20 people with high blood pressure. Published today in Nature Medicine, the research solves a 60-year problem of how to detect the hormone-producing nodules without a difficult catheter study that is available in only a handful of hospitals, and often fails. The research also found that, when combined with a urine test, the scan detects a group of patients who come off all their blood pressure medicines after treatment. For the study, 128 people were scanned after doctors found that their hypertension (high blood pressure) was caused by the steroid hormone aldosterone. The scan found that in two thirds of patients with elevated aldosterone secretion, the hormone originated from a benign nodule in just one of the adrenal glands, which could be safely removed. The scan uses a short-acting dose of metomidate, a radioactive dye that sticks only to the aldosterone-producing nodule. The scan was as accurate as the old catheter test, but quick, painless and technically successful in every patient. Until now, the catheter test was unable to predict which patients would be completely cured of hypertension by surgical removal of the gland. By contrast, the combination of a \"hot nodule\" on the scan and urine steroid test detected 18 of the 24 patients who achieved a normal blood pressure off all their drugs. Professor Morris Brown, co-senior author of the study and Professor of Endocrine hypertension at Queen Mary University of London, said, \"These aldosterone-producing nodules are very small and easily overlooked on a regular CT scan. When they glow for a few minutes after our injection, they are revealed as the obvious cause of hypertension, which can often then be cured. Until now, 99% are never diagnosed because of the difficulty and unavailability of tests. Hopefully this is about to change.\" Professor William Drake, co-senior author of the study and Professor of Clinical Endocrinology at Queen Mary University of London, said, \"This study was the result of years of hard work and collaboration between centers. across the UK. Much of the 'on the ground' energy and drive came from the talented research fellows who, in addition to doing this innovative work, gave selflessly of their time and energy during the national pandemic emergency. The future of research in this area is in very safe hands.\" In most people with hypertension (high blood pressure), the cause is unknown, and the condition requires life-long treatment by drugs. Previous research by the group at Queen Mary University discovered that in 5% to 10% of people with hypertension, the cause is a gene mutation in the adrenal glands, which results in excessive production of the steroid hormone aldosterone. Aldosterone causes salt to be retained in the body, driving up the blood pressure. Patients with excessive aldosterone levels in the blood are resistant to treatment with the commonly used drugs for hypertension, and at increased risk of heart attacks and strokes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [ 11 C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = −6.5 to 24.1%) and 3.8% (95% confidence interval = −11.9 to 9.4) lay within the pre-specified −17% margin for non-inferiority ( P = 0.00055 and P = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA. Main Hypertension is a major cause of deaths from stroke, coronary heart disease, heart failure and renal failure. The most common single cause of hypertension is primary aldosteronism (PA), accounting for 5–14% of all cases and 20–25% of treatment-resistant hypertension 1 , 2 , 3 , 4 . The cardiometabolic consequences of hypertension are approximately twice as likely in individuals with PA compared with age- and sex-matched individuals with essential hypertension 5 , 6 , 7 , 8 . Traditionally, patients with PA are divided equally into those in whom aldosterone excess is due to a unilateral aldosterone-producing adrenal adenoma (APA), in whom surgical cure is possible, and those with bilateral production (often termed idiopathic hyperaldosteronism (IHA)), who require long-term medical therapy. Although recent studies point to a continuum of disease between unilateral and bilateral subtypes, their distinction underpins the binary clinical decision of whether to remove one adrenal gland, and drives the investigations required to make this decision 9 , 10 . Current consensus is that patients with unilateral APAs should be offered laparoscopic surgical removal of that adrenal gland and those with IHA should be treated with aldosterone antagonist drugs 11 . Despite the prevalence and penalty of PA, currently, fewer than 1% of patients are identified and fully investigated 12 . Many reasons exist for this shortfall in clinical care, including: low levels of clinical suspicion; time-consuming and imperfect confirmatory biochemical tests that require discontinuation of many commonly prescribed antihypertensive drugs; difficulties with patient selection for surgical intervention; and uncertainty about outcomes in patients hoping for surgical cure. The paradoxical consequence is patient and physician reluctance to embark on a diagnostic and therapeutic process with a high likelihood of major clinical benefit, and that often sub-optimal medical treatment remains the default for the overwhelming majority of patients 7 , 11 . Molecular imaging has the potential to increase the number of patients with PA who can be fully investigated. The current criterion standard used to distinguish patients with APA from those with IHA is adrenal vein sampling (AVS)—an invasive, technically demanding procedure with restricted availability. Metomidate—a methyl analog of the anesthetic agent etomidate—is a potent inhibitor of CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase), the final two enzymes involved in cortisol and aldosterone synthesis, respectively. Metomidate can be 11 CH 3 labeled and used as a positron emission tomography (PET) radiotracer in combination with high-resolution computed tomography (CT) to detect adrenocortical tumors expressing these enzymes. A previous proof-of-concept study indicated that pre-treatment with dexamethasone for 3 d before [ 11 C]metomidate PET-CT (MTO) scanning suppresses adrenal CYP11B1 (but not CYP11B2) protein expression, thus achieving in vivo selectivity 13 . This selectivity facilitates the detection of focal adrenal lesions with high [ 11 C]metomidate uptake due to CYP11B2 expression and separates them from normal adrenal tissue. International guidelines for the management of PA acknowledge the potential for molecular imaging in the subtyping of PA 11 , but prospective outcomes-based data are needed to influence clinical practice. The primary aim of this study, which we have termed MATCH (Is Metomidate superior to AVS in predicting ouTComes from adrenalectomy in primary Hyperaldosteronism), was to compare the accuracy of AVS and MTO in predicting the outcome from adrenalectomy in patients with PA (Fig. 1a ). The diagnosis of PA, the protocol for and interpretation of AVS, and the biochemical and clinical outcomes after surgery were all assessed and conducted according to international consensus guidelines and/or statements (Fig. 1b and Supplementary Table 1 ) 11 , 14 , 15 . MTO scanning was performed as previously described 13 , and interpreted and graded before, and in ignorance of, the information provided by AVS. The design of the study also permitted the inclusion of a number of mechanistic secondary endpoints that have the potential to refine patient selection for surgery. These mechanistic endpoints included: a trial of aldosterone antagonist therapy (spironolactone or eplerenone) in predicting surgical cure; the influence of ethnicity and tumor genotype on surgical outcome; and the consequences of surgical and medical intervention on indices of cardiac injury and function, as determined by changes in amino (N)-terminal prohormone of brain natriuretic peptide (NT-pro BNP) levels and cardiac chamber dimensions on MRI. Fig. 1: Study outline, hierarchical co-primary endpoints and CONSORT diagram. a , Study outline. Patients with confirmed PA according to the Endocrine Society consensus guidelines underwent both AVS and MTO in random order. All patients were subsequently reviewed at a baseline visit and started on 50 mg spironolactone, which was up-titrated to 100 mg after 2 weeks. The blood pressure response to spironolactone was recorded at 2 and<|im_end|> <|im_start|>assistant Doctors at Queen Mary University of London and Barts Hospital, and Cambridge University Hospital, have led research using a new type of CT scan to light up tiny nodules in a hormone gland and cure high blood pressure by their removal. The nodules are discovered in 1 in 20 people with high blood pressure. Published today in Nature Medicine, the research solves a 60-year problem of how to detect the hormone-producing nodules without a difficult catheter study that is available in only a handful of hospitals, and often fails. The research also found that, when combined with a urine test, the scan detects a group of patients who come off all their blood pressure medicines after treatment. For the study, 128 people were scanned after doctors found that their hypertension (high blood pressure) was caused by the steroid hormone aldosterone. The scan found that in two thirds of patients with elevated aldosterone secretion, the hormone originated from a benign nodule in just one of the adrenal glands, which could be safely removed. The scan uses a short-acting dose of metomidate, a radioactive dye that sticks only to the aldosterone-producing nodule. The scan was as accurate as the old catheter test, but quick, painless and technically successful in every patient. Until now, the catheter test was unable to predict which patients would be completely cured of hypertension by surgical removal of the gland. By contrast, the combination of a "hot nodule" on the scan and urine steroid test detected 18 of the 24 patients who achieved a normal blood pressure off all their drugs. Professor Morris Brown, co-senior author of the study and Professor of Endocrine hypertension at Queen Mary University of London, said, "These aldosterone-producing nodules are very small and easily overlooked on a regular CT scan. When they glow for a few minutes after our injection, they are revealed as the obvious cause of hypertension, which can often then be cured. Until now, 99% are never diagnosed because of the difficulty and unavailability of tests. Hopefully this is about to change." Professor William Drake, co-senior author of the study and Professor of Clinical Endocrinology at Queen Mary University of London, said, "This study was the result of years of hard work and collaboration between centers. across the UK. Much of the 'on the ground' energy and drive came from the talented research fellows who, in addition to doing this innovative work, gave selflessly of their time and energy during the national pandemic emergency. The future of research in this area is in very safe hands." In most people with hypertension (high blood pressure), the cause is unknown, and the condition requires life-long treatment by drugs. Previous research by the group at Queen Mary University discovered that in 5% to 10% of people with hypertension, the cause is a gene mutation in the adrenal glands, which results in excessive production of the steroid hormone aldosterone. Aldosterone causes salt to be retained in the body, driving up the blood pressure. Patients with excessive aldosterone levels in the blood are resistant to treatment with the commonly used drugs for hypertension, and at increased risk of heart attacks and strokes. <|im_end|>

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2,117

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Strained oxide thin films are of interest for accelerating oxide ion conduction in electrochemical devices. Although the effect of elastic strain has been uncovered theoretically, the effect of dislocations on the diffusion kinetics in such strained oxides is yet unclear. Here we investigate a 1/2<110>{100} edge dislocation by performing atomistic simulations in 4–12% doped CeO 2 as a model fast ion conductor. At equilibrium, depending on the size of the dopant, trivalent cations and oxygen vacancies are found to simultaneously enrich or deplete either in the compressive or in the tensile strain fields around the dislocation. The associative interactions among the point defects in the enrichment zone and the lack of oxygen vacancies in the depletion zone slow down oxide ion transport. This finding is contrary to the fast diffusion of atoms along the dislocations in metals and should be considered when assessing the effects of strain on oxide ion conductivity. Introduction Strain engineering offers a new route to tune the reaction and transport kinetics in oxide materials 1 by altering the inherent energy landscape of reactions, as demonstrated also for metals 2 , 3 and for polymers 4 , 5 . Strain can be induced in a material by lattice mismatch at the interface of a thin film with a substrate or with neighbouring layers (such as in multilayer composites). The lattice mismatch can be accommodated as elastic strain or as a combination of elastic and plastic strain. A high density of dislocations (two orders higher than those in bulk) can be found at the interface of thin films 6 , 7 , 8 upon relaxation of elastic strain. This high density of dislocations makes the study of their effect on the properties of the material of paramount importance. The elastic strain effects in oxides have been extensively studied for transport 9 , 10 , 11 , (electro)catalytic activity 12 , 13 , 14 and multiferroic properties 15 , 16 . On the other hand, only a few recent studies directly assessed the potential role of dislocations on the electrical 17 , 18 , magnetic 19 and chemical 20 , 21 properties of oxides, probably because of the intrinsic difficulty in studying these extended defects one at a time with high spatial resolution. Elastic strain is considered as a new knob to enhance the performance of oxide electrochemical devices, including solid oxide fuel cells (SOFCs) 9 , 10 , 11 , photocatalysts 22 , batteries 23 , electrolysers 24 and redox-based resistive memories 25 , by accelerating ion conduction. However, in most of these studies, the influence of strain was interpreted in terms of elastic strain alone, while plastic strain, that is, strain accommodated by dislocations, has been overlooked. In metals, dislocations are known to be fast diffusion paths due to their open space and low coordination environment 26 , 27 . This phenomenon has been called fast pipe diffusion (orders of magnitude faster than that in bulk). Because of what is known in metals, dislocations have been therefore suggested to enhance ionic conductivity in oxides as well 28 , 29 , 30 . For example, Sillassen et al. 28 have observed 3.5 orders of magnitude acceleration in the ionic conductivity for a 8.7 mol.% yttria-stabilized zirconia (YSZ) epitaxial film on MgO substrate. They attributed this enhancement qualitatively to a combination of misfit dislocations and elastic strain at the interface. Contrary to that example, Li et al. 31 have studied a YSZ/Gd 2 Zr 2 O 7 (YSZ/GZO) multilayer structure, which was said to be dislocation free. They found that YSZ presents a higher conductivity on GZO compared with thin YSZ films on CeO 2 , where dislocations are present. Li et al. 31 suggested that the relaxation of elastic strain brought by dislocations does not enhance ionic conductivity. Atomistic simulations 32 of a hetero-interface with a density of dislocations between CeO 2 and YSZ also showed that the oxygen diffusion coefficient is not enhanced within the interfacial region. However, because of the irregular network of dislocations in that model, the influence of individual dislocations was not accessible one at a time to see the diffusion along and across the dislocation lines. In such complex simulations, it is also not clear whether dislocations or other factors, such as interface chemistry, affect ionic conductivity primarily. Because of the limited number of studies (with contradictory results), it appears unclear whether the concept of pipe diffusion can be applied to oxide ion conductors at all. Indeed, previous experimental studies 33 and numerical calculations 34 of grain boundaries in ceria (which also present an open structure and low coordination environment) shows that ionic conductivity at the grain boundary is lower than that in the bulk of this material. In summary, despite the importance of dislocations in oxide thin films and chemo-mechanics of materials, the fundamental mechanisms by which a dislocation has an impact on the ionic diffusivity in these doped and/or reducible oxides are unknown. The aim of this study is to provide an atomistic view of how dislocations alter the formation, distribution and mobility of oxide ion defects. For this purpose, an ½<110>{100} edge dislocation is studied as a model system in reduced or doped ceria. Ceria is a known fast oxide ion conductor, with an oxygen-vacancy-mediated transport mechanism 35 . The highest ionic conductivities are observed when it is doped with trivalent cations, such as Gd, Sm and Y 36 . For this reason, it has been used as an electrolyte in SOFCs and, recently, its use as an anode or cathode material has also been suggested 36 , 37 . Finally, ceria is also widely used in catalysis 38 and is a state-of-the-art material for thermochemical water splitting 22 . The hypothesis of this study is that the interaction between dislocations and charged point defects, specifically dopant cations, reduced cerium cation (Ce 3+ ) and oxygen vacancies, can have an impact on the distribution and mobility of oxygen vacancies. Here, dislocations in reduced ceria (CDC), Gd-doped ceria (GDC), Y-doped", "role": "user" }, { "content": "Dislocations in oxides such as cerium dioxide, a solid electrolyte for fuel cells, turn out to have a property that is the opposite of what researchers had expected, according to a new analysis at MIT. Researchers had thought that a certain kind of strain—specifically, strain caused by dislocations in the material's atomic lattice—would speed the transport of oxygen ions through the material, potentially leading to the much faster diffusion that is necessary in high-performance solid oxide fuel cells, water-splitting, or oxygen-separation membranes. But the new atomic-level simulation of oxide ion transport has revealed that while these dislocations do greatly accelerate atom transport in metals, they can have the opposite effect in this metal-oxide material, and possibly in many others. Instead of easing ion mobility, it turns out that dislocations in cerium dioxide cause a kind of \"traffic jam\" for the flowing ions, slowing them to a crawl, says MIT graduate student Lixin Sun, lead author of a paper describing the analysis in the journal Nature Communications. In cerium dioxide, which is already used as an electrolyte material in solid oxide fuel cells, the simulation shows that \"edge dislocations slow down oxide ion diffusion, contrary to the well-known fast diffusion of atoms along dislocations in metals,\" says Bilge Yildiz, an associate professor of nuclear science and engineering and of materials science and engineering, who was the paper's senior author. The surprising result suggests that researchers will need to pursue different approaches in trying to speed up the movement of these ions. The work is part of ongoing studies by Yildiz and her team, which also includes co-author and research scientist Dario Marrocchelli, into how various kinds of strain in thin-film materials can be used to alter and improve the transport and surface reaction kinetics of those materials, often in dramatic ways. \"People have argued about the role of strain [in cerium dioxide],\" Sun says. \"Some say strain can enhance the oxide ion transport for devices like solid oxide fuel cells. But others say no, and the experimental results show orders-of-magnitude scatter.\" While there is extensive existing research on ion transport under elastic strain—such as when a rubber band stretches, but then returns to its original length when released—the same is not true of transport along dislocations resulting from plastic strain in oxides. Plastic strain —such as when a stretched piece of taffy remains stretched—introduces extended defects called dislocations into crystalline structures; the accelerating effect that dislocations have on atom transport in metals has been widely studied, Yildiz says. \"But in oxides, which are important in energy-conversion devices such as fuel cells, electrolyzers, and batteries, the dislocation effects remains largely understudied,\" she adds. \"It's never been studied at the atomic level to reveal what an individual dislocation does to oxide ion transport, and that's why we turned our attention to it.\" Because that kind of strain has been more difficult to simulate and measure, Sun says, \"People speculated that it could enhance ionic transport,\" since that's what happens with metals. While the new findings were based on a detailed analysis of the molecular structure of cerium dioxide, Sun says the results \"should be general to those materials that have a high concentration of defects\"—which include many, but not all, metal oxides. Specifically, the results showed that dislocations accumulate too many oxygen vacancies and dopant metal cations, and as a result these ionic defects interact and trap each other, \"like too many cars clogging a highway\", Sun says. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Strained oxide thin films are of interest for accelerating oxide ion conduction in electrochemical devices. Although the effect of elastic strain has been uncovered theoretically, the effect of dislocations on the diffusion kinetics in such strained oxides is yet unclear. Here we investigate a 1/2<110>{100} edge dislocation by performing atomistic simulations in 4–12% doped CeO 2 as a model fast ion conductor. At equilibrium, depending on the size of the dopant, trivalent cations and oxygen vacancies are found to simultaneously enrich or deplete either in the compressive or in the tensile strain fields around the dislocation. The associative interactions among the point defects in the enrichment zone and the lack of oxygen vacancies in the depletion zone slow down oxide ion transport. This finding is contrary to the fast diffusion of atoms along the dislocations in metals and should be considered when assessing the effects of strain on oxide ion conductivity. Introduction Strain engineering offers a new route to tune the reaction and transport kinetics in oxide materials 1 by altering the inherent energy landscape of reactions, as demonstrated also for metals 2 , 3 and for polymers 4 , 5 . Strain can be induced in a material by lattice mismatch at the interface of a thin film with a substrate or with neighbouring layers (such as in multilayer composites). The lattice mismatch can be accommodated as elastic strain or as a combination of elastic and plastic strain. A high density of dislocations (two orders higher than those in bulk) can be found at the interface of thin films 6 , 7 , 8 upon relaxation of elastic strain. This high density of dislocations makes the study of their effect on the properties of the material of paramount importance. The elastic strain effects in oxides have been extensively studied for transport 9 , 10 , 11 , (electro)catalytic activity 12 , 13 , 14 and multiferroic properties 15 , 16 . On the other hand, only a few recent studies directly assessed the potential role of dislocations on the electrical 17 , 18 , magnetic 19 and chemical 20 , 21 properties of oxides, probably because of the intrinsic difficulty in studying these extended defects one at a time with high spatial resolution. Elastic strain is considered as a new knob to enhance the performance of oxide electrochemical devices, including solid oxide fuel cells (SOFCs) 9 , 10 , 11 , photocatalysts 22 , batteries 23 , electrolysers 24 and redox-based resistive memories 25 , by accelerating ion conduction. However, in most of these studies, the influence of strain was interpreted in terms of elastic strain alone, while plastic strain, that is, strain accommodated by dislocations, has been overlooked. In metals, dislocations are known to be fast diffusion paths due to their open space and low coordination environment 26 , 27 . This phenomenon has been called fast pipe diffusion (orders of magnitude faster than that in bulk). Because of what is known in metals, dislocations have been therefore suggested to enhance ionic conductivity in oxides as well 28 , 29 , 30 . For example, Sillassen et al. 28 have observed 3.5 orders of magnitude acceleration in the ionic conductivity for a 8.7 mol.% yttria-stabilized zirconia (YSZ) epitaxial film on MgO substrate. They attributed this enhancement qualitatively to a combination of misfit dislocations and elastic strain at the interface. Contrary to that example, Li et al. 31 have studied a YSZ/Gd 2 Zr 2 O 7 (YSZ/GZO) multilayer structure, which was said to be dislocation free. They found that YSZ presents a higher conductivity on GZO compared with thin YSZ films on CeO 2 , where dislocations are present. Li et al. 31 suggested that the relaxation of elastic strain brought by dislocations does not enhance ionic conductivity. Atomistic simulations 32 of a hetero-interface with a density of dislocations between CeO 2 and YSZ also showed that the oxygen diffusion coefficient is not enhanced within the interfacial region. However, because of the irregular network of dislocations in that model, the influence of individual dislocations was not accessible one at a time to see the diffusion along and across the dislocation lines. In such complex simulations, it is also not clear whether dislocations or other factors, such as interface chemistry, affect ionic conductivity primarily. Because of the limited number of studies (with contradictory results), it appears unclear whether the concept of pipe diffusion can be applied to oxide ion conductors at all. Indeed, previous experimental studies 33 and numerical calculations 34 of grain boundaries in ceria (which also present an open structure and low coordination environment) shows that ionic conductivity at the grain boundary is lower than that in the bulk of this material. In summary, despite the importance of dislocations in oxide thin films and chemo-mechanics of materials, the fundamental mechanisms by which a dislocation has an impact on the ionic diffusivity in these doped and/or reducible oxides are unknown. The aim of this study is to provide an atomistic view of how dislocations alter the formation, distribution and mobility of oxide ion defects. For this purpose, an ½<110>{100} edge dislocation is studied as a model system in reduced or doped ceria. Ceria is a known fast oxide ion conductor, with an oxygen-vacancy-mediated transport mechanism 35 . The highest ionic conductivities are observed when it is doped with trivalent cations, such as Gd, Sm and Y 36 . For this reason, it has been used as an electrolyte in SOFCs and, recently, its use as an anode or cathode material has also been suggested 36 , 37 . Finally, ceria is also widely used in catalysis 38 and is a state-of-the-art material for thermochemical water splitting 22 . The hypothesis of this study is that the interaction between dislocations and charged point defects, specifically dopant cations, reduced cerium cation (Ce 3+ ) and oxygen vacancies, can have an impact on the distribution and mobility of oxygen vacancies. Here, dislocations in reduced ceria (CDC), Gd-doped ceria (GDC), Y-doped<|im_end|> <|im_start|>assistant Dislocations in oxides such as cerium dioxide, a solid electrolyte for fuel cells, turn out to have a property that is the opposite of what researchers had expected, according to a new analysis at MIT. Researchers had thought that a certain kind of strain—specifically, strain caused by dislocations in the material's atomic lattice—would speed the transport of oxygen ions through the material, potentially leading to the much faster diffusion that is necessary in high-performance solid oxide fuel cells, water-splitting, or oxygen-separation membranes. But the new atomic-level simulation of oxide ion transport has revealed that while these dislocations do greatly accelerate atom transport in metals, they can have the opposite effect in this metal-oxide material, and possibly in many others. Instead of easing ion mobility, it turns out that dislocations in cerium dioxide cause a kind of "traffic jam" for the flowing ions, slowing them to a crawl, says MIT graduate student Lixin Sun, lead author of a paper describing the analysis in the journal Nature Communications. In cerium dioxide, which is already used as an electrolyte material in solid oxide fuel cells, the simulation shows that "edge dislocations slow down oxide ion diffusion, contrary to the well-known fast diffusion of atoms along dislocations in metals," says Bilge Yildiz, an associate professor of nuclear science and engineering and of materials science and engineering, who was the paper's senior author. The surprising result suggests that researchers will need to pursue different approaches in trying to speed up the movement of these ions. The work is part of ongoing studies by Yildiz and her team, which also includes co-author and research scientist Dario Marrocchelli, into how various kinds of strain in thin-film materials can be used to alter and improve the transport and surface reaction kinetics of those materials, often in dramatic ways. "People have argued about the role of strain [in cerium dioxide]," Sun says. "Some say strain can enhance the oxide ion transport for devices like solid oxide fuel cells. But others say no, and the experimental results show orders-of-magnitude scatter." While there is extensive existing research on ion transport under elastic strain—such as when a rubber band stretches, but then returns to its original length when released—the same is not true of transport along dislocations resulting from plastic strain in oxides. Plastic strain —such as when a stretched piece of taffy remains stretched—introduces extended defects called dislocations into crystalline structures; the accelerating effect that dislocations have on atom transport in metals has been widely studied, Yildiz says. "But in oxides, which are important in energy-conversion devices such as fuel cells, electrolyzers, and batteries, the dislocation effects remains largely understudied," she adds. "It's never been studied at the atomic level to reveal what an individual dislocation does to oxide ion transport, and that's why we turned our attention to it." Because that kind of strain has been more difficult to simulate and measure, Sun says, "People speculated that it could enhance ionic transport," since that's what happens with metals. While the new findings were based on a detailed analysis of the molecular structure of cerium dioxide, Sun says the results "should be general to those materials that have a high concentration of defects"—which include many, but not all, metal oxides. Specifically, the results showed that dislocations accumulate too many oxygen vacancies and dopant metal cations, and as a result these ionic defects interact and trap each other, "like too many cars clogging a highway", Sun says. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Comparative analysis of the expanding genomic resources for scleractinian corals may provide insights into the evolution of these organisms, with implications for their continued persistence under global climate change. Here, we sequenced and annotated the genome of Pocillopora damicornis , one of the most abundant and widespread corals in the world. We compared this genome, based on protein-coding gene orthology, with other publicly available coral genomes (Cnidaria, Anthozoa, Scleractinia), as well as genomes from other anthozoan groups (Actiniaria, Corallimorpharia), and two basal metazoan outgroup phlya (Porifera, Ctenophora). We found that 46.6% of P. damicornis genes had orthologs in all other scleractinians, defining a coral ‘core’ genome enriched in basic housekeeping functions. Of these core genes, 3.7% were unique to scleractinians and were enriched in immune functionality, suggesting an important role of the immune system in coral evolution. Genes occurring only in P. damicornis were enriched in cellular signaling and stress response pathways, and we found similar immune-related gene family expansions in each coral species, indicating that immune system diversification may be a prominent feature of scleractinian coral evolution at multiple taxonomic levels. Diversification of the immune gene repertoire may underlie scleractinian adaptations to symbiosis, pathogen interactions, and environmental stress. Introduction Scleractinian corals serve the critical ecological role of building reefs that provide billions of dollars annually in goods and services 1 and sustain high levels of biodiversity 2 . However, corals are declining rapidly as ocean acidification impairs coral calcification and interferes with metabolism 3 , ocean warming disrupts their symbiosis with photosynthetic dinoflagellates (family Symbiodiniaceae) 4 , and outbreaks of coral disease lead to mortality 5 . As basal metazoans, corals provide a model for studying the evolution of biomineralization 6 , symbiosis 7 , and immunity 8 , 9 - key traits which mediate ecological responses to these stressors. Understanding the genomic architecture of these traits is therefore critical to understanding corals’ success over evolutionary time 10 and under future environmental scenarios. In particular, there is great interest in whether corals possess the genes and genetic variation required to acclimatize and/or adapt to rapid climate change 11 , 12 , 13 . Addressing these questions relies on the growing genomic resources available for corals, and establishes a fundamental role for comparative genomic analysis in these organisms. Genomic resources for corals have expanded rapidly in recent years, with genomic or transcriptomic information now available for at least 20 coral species 10 . Comparative genomics in corals has identified genes important in biomineralization, symbiosis, and environmental stress response 10 , and highlighted the evolution of specific immune gene repertoires in corals 14 , 15 However, complete genome sequences have only been analyzed and compared for two coral species, Acropora digitifera 16 and Stylophora pistillata 17 , revealing extensive differences in genomic architecture and content. Therefore, additional complete coral genomes and more comprehensive comparative analysis may be transformative in our understanding of the genomic content and evolutionary history of reef-building corals, as well as the importance of specific gene repertoires and diversification within coral lineages. Here, we present the genome of Pocillopora damicornis , one of the most abundant and widespread reef-building corals in the world 18 . This ecologically important coral is a model species and is commonly used in experimental biology and physiology. It is also the subject of a large body of research on speciation 19 , 20 , 21 , population genetics 22 , 23 , 24 , 25 , symbiosis ecology 26 , 27 , 28 , and reproduction 29 , 30 , 31 . Consequently, the P. damicornis genome sequence advances a number of fields in biology, ecology, and evolution, and provides a direct foundation for future studies in transcriptomics, population genomics, and functional genomics of corals. Using the P. damicornis genome and other publicly available genomes of cnidarians and basal metazoans, we performed a comparative genomic analysis within the Scleractinia. Using this analysis, we address the following critical questions: (1) which genes are specific to or diversified within the scleractinian lineage, (2) which genes are specific to or diversified within individual scleractinian coral species, and (3) which features distinguish the P. damicornis genome from those of other corals. We address these questions based on orthology of protein-coding genes, which generalizes the approaches taken by Bhattacharya et al . 10 and Voolstra et al . 17 to a larger set of complete genomes to describe both shared and unique adaptations in the Scleractinia. In comparing these genomes, we reveal prominent diversification and expansion of immune-related genes, demonstrating that immune pathways are the subject of diverse evolutionary adaptations in corals. Results and Discussion P. damicornis genome assembly and annotation The estimated genome size of P. damicornis is 349 Mb, smaller than other scleractinian genomes analyzed to date (Table 1 ). The size of the final assembly produced here was 234 Mb, and likely lacks high-identity repetitive content (estimated ~25% of the genome based on 31-mers) that could not be assembled. Total non-repetitive 31mer content was estimated at 262 Mb and the sum of contigs was 226 Mb, indicating that up to 14% of non-repetitive content may also be missing from the assembly, likely due to high heterozygosity (Dovetail Genomics, personal communication). However, the assembly comprises 96.3% contiguous sequence, and has the highest contig N50 (28.5 kb) of any cnidarian genome assembly (Table 1 ). We identified 26,077 gene models, which is consistent with the gene content of other scleractinian and cnidarian genomes (Table 1 ). Among these genes, 59.7% had identifiable homologs (E-value \$\\le \$ 10 −5 ) in the SwissProt database, 73% contained identifiable homologs in at least one of the other 10 genomes, and 83.7% contained protein domains annotated by InterProScan. Genome completeness was evaluated using BUSCO, which found that 88.4% of metazoan single-copy orthologs were present and complete (0.5% were duplicated), 2.9% were present but fragmented, and 8.7% were missing. Together, these statistics indicate the P. damicornis genome assembly is of high quality and mostly complete (Table 1 ). Table 1 Assembly", "role": "user" }, { "content": "A new study led by researchers at the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science found that a common coral species might have evolved unique immune strategies to cope with environmental change. Roughly 30 percent of the cauliflower coral's (Pocillopora damicornis) genome was unique compared to several other reef-building corals. In this 30%, many of these genes were related to immune function. This diversity of genes related to immune function, the researchers say, may be important for the long-term survival of coral reefs as climate change and ocean acidification continue to alter the environment to which corals are adapted. \"This coral is traditionally thought of as a weed, and yet it may be one of the last corals to survive environmental changes such as climate change,\" said senior author of the study Nikki Traylor-Knowles, an assistant professor of marine biology and ecology at the UM Rosenstiel School. To conduct the research, the scientists extracted and sequenced the genomic DNA from two healthy fragments and two bleached fragments of P. damicornis, which is one of the most abundant and widespread reef-building corals in the world. Their genome was then compared to publicly available genomes for several other coral species and several other cnidarian species. \"The study shows that this is an important coral with a very complex and unique immune system, which may explain why it is able to survive in so many different locations,\" said the paper's lead author Ross Cunning, who conducted the research as a postdoctoral scientist at the UM Rosenstiel School and is now a researcher at Shedd Aquarium. These results suggest that the evolution of an innate immune system has been a defining feature of the success of hard corals like P. damicornis, and may help facilitate their continued success under climate change scenarios. The immune system of corals, like humans, is vital to protect its overall health and deal with changes in its surroundings. If an animal has a stronger immune system then it will be better equipped to deal with environmental changes. These new findings suggest that some corals have many more and diverse immunity genes than would be expected, which is the hallmark of a very robust immune system. \"This study helps us better understand how corals deal with stress,\" said Traylor-Knowles. \"Its complex immune system indicates that it may have the tools to deal with environmental change much more easily than other corals.\" The study, titled \"Comparative analysis of the Pocillopora damicornis genome highlights role of immune system in coral evolution,\" was published in the October 31, 2018 issue of the journal Scientific Reports. The paper's coauthors include: Nikki Traylor-Knowles, Andrew Baker, and Phil Gillette of the UM Rosenstiel School; UM alumnus Ross Cunning of Shedd Aquarium; and UM alumna Rachael Bay of the University of California Davis. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Comparative analysis of the expanding genomic resources for scleractinian corals may provide insights into the evolution of these organisms, with implications for their continued persistence under global climate change. Here, we sequenced and annotated the genome of Pocillopora damicornis , one of the most abundant and widespread corals in the world. We compared this genome, based on protein-coding gene orthology, with other publicly available coral genomes (Cnidaria, Anthozoa, Scleractinia), as well as genomes from other anthozoan groups (Actiniaria, Corallimorpharia), and two basal metazoan outgroup phlya (Porifera, Ctenophora). We found that 46.6% of P. damicornis genes had orthologs in all other scleractinians, defining a coral ‘core’ genome enriched in basic housekeeping functions. Of these core genes, 3.7% were unique to scleractinians and were enriched in immune functionality, suggesting an important role of the immune system in coral evolution. Genes occurring only in P. damicornis were enriched in cellular signaling and stress response pathways, and we found similar immune-related gene family expansions in each coral species, indicating that immune system diversification may be a prominent feature of scleractinian coral evolution at multiple taxonomic levels. Diversification of the immune gene repertoire may underlie scleractinian adaptations to symbiosis, pathogen interactions, and environmental stress. Introduction Scleractinian corals serve the critical ecological role of building reefs that provide billions of dollars annually in goods and services 1 and sustain high levels of biodiversity 2 . However, corals are declining rapidly as ocean acidification impairs coral calcification and interferes with metabolism 3 , ocean warming disrupts their symbiosis with photosynthetic dinoflagellates (family Symbiodiniaceae) 4 , and outbreaks of coral disease lead to mortality 5 . As basal metazoans, corals provide a model for studying the evolution of biomineralization 6 , symbiosis 7 , and immunity 8 , 9 - key traits which mediate ecological responses to these stressors. Understanding the genomic architecture of these traits is therefore critical to understanding corals’ success over evolutionary time 10 and under future environmental scenarios. In particular, there is great interest in whether corals possess the genes and genetic variation required to acclimatize and/or adapt to rapid climate change 11 , 12 , 13 . Addressing these questions relies on the growing genomic resources available for corals, and establishes a fundamental role for comparative genomic analysis in these organisms. Genomic resources for corals have expanded rapidly in recent years, with genomic or transcriptomic information now available for at least 20 coral species 10 . Comparative genomics in corals has identified genes important in biomineralization, symbiosis, and environmental stress response 10 , and highlighted the evolution of specific immune gene repertoires in corals 14 , 15 However, complete genome sequences have only been analyzed and compared for two coral species, Acropora digitifera 16 and Stylophora pistillata 17 , revealing extensive differences in genomic architecture and content. Therefore, additional complete coral genomes and more comprehensive comparative analysis may be transformative in our understanding of the genomic content and evolutionary history of reef-building corals, as well as the importance of specific gene repertoires and diversification within coral lineages. Here, we present the genome of Pocillopora damicornis , one of the most abundant and widespread reef-building corals in the world 18 . This ecologically important coral is a model species and is commonly used in experimental biology and physiology. It is also the subject of a large body of research on speciation 19 , 20 , 21 , population genetics 22 , 23 , 24 , 25 , symbiosis ecology 26 , 27 , 28 , and reproduction 29 , 30 , 31 . Consequently, the P. damicornis genome sequence advances a number of fields in biology, ecology, and evolution, and provides a direct foundation for future studies in transcriptomics, population genomics, and functional genomics of corals. Using the P. damicornis genome and other publicly available genomes of cnidarians and basal metazoans, we performed a comparative genomic analysis within the Scleractinia. Using this analysis, we address the following critical questions: (1) which genes are specific to or diversified within the scleractinian lineage, (2) which genes are specific to or diversified within individual scleractinian coral species, and (3) which features distinguish the P. damicornis genome from those of other corals. We address these questions based on orthology of protein-coding genes, which generalizes the approaches taken by Bhattacharya et al . 10 and Voolstra et al . 17 to a larger set of complete genomes to describe both shared and unique adaptations in the Scleractinia. In comparing these genomes, we reveal prominent diversification and expansion of immune-related genes, demonstrating that immune pathways are the subject of diverse evolutionary adaptations in corals. Results and Discussion P. damicornis genome assembly and annotation The estimated genome size of P. damicornis is 349 Mb, smaller than other scleractinian genomes analyzed to date (Table 1 ). The size of the final assembly produced here was 234 Mb, and likely lacks high-identity repetitive content (estimated ~25% of the genome based on 31-mers) that could not be assembled. Total non-repetitive 31mer content was estimated at 262 Mb and the sum of contigs was 226 Mb, indicating that up to 14% of non-repetitive content may also be missing from the assembly, likely due to high heterozygosity (Dovetail Genomics, personal communication). However, the assembly comprises 96.3% contiguous sequence, and has the highest contig N50 (28.5 kb) of any cnidarian genome assembly (Table 1 ). We identified 26,077 gene models, which is consistent with the gene content of other scleractinian and cnidarian genomes (Table 1 ). Among these genes, 59.7% had identifiable homologs (E-value $\le $ 10 −5 ) in the SwissProt database, 73% contained identifiable homologs in at least one of the other 10 genomes, and 83.7% contained protein domains annotated by InterProScan. Genome completeness was evaluated using BUSCO, which found that 88.4% of metazoan single-copy orthologs were present and complete (0.5% were duplicated), 2.9% were present but fragmented, and 8.7% were missing. Together, these statistics indicate the P. damicornis genome assembly is of high quality and mostly complete (Table 1 ). Table 1 Assembly<|im_end|> <|im_start|>assistant A new study led by researchers at the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science found that a common coral species might have evolved unique immune strategies to cope with environmental change. Roughly 30 percent of the cauliflower coral's (Pocillopora damicornis) genome was unique compared to several other reef-building corals. In this 30%, many of these genes were related to immune function. This diversity of genes related to immune function, the researchers say, may be important for the long-term survival of coral reefs as climate change and ocean acidification continue to alter the environment to which corals are adapted. "This coral is traditionally thought of as a weed, and yet it may be one of the last corals to survive environmental changes such as climate change," said senior author of the study Nikki Traylor-Knowles, an assistant professor of marine biology and ecology at the UM Rosenstiel School. To conduct the research, the scientists extracted and sequenced the genomic DNA from two healthy fragments and two bleached fragments of P. damicornis, which is one of the most abundant and widespread reef-building corals in the world. Their genome was then compared to publicly available genomes for several other coral species and several other cnidarian species. "The study shows that this is an important coral with a very complex and unique immune system, which may explain why it is able to survive in so many different locations," said the paper's lead author Ross Cunning, who conducted the research as a postdoctoral scientist at the UM Rosenstiel School and is now a researcher at Shedd Aquarium. These results suggest that the evolution of an innate immune system has been a defining feature of the success of hard corals like P. damicornis, and may help facilitate their continued success under climate change scenarios. The immune system of corals, like humans, is vital to protect its overall health and deal with changes in its surroundings. If an animal has a stronger immune system then it will be better equipped to deal with environmental changes. These new findings suggest that some corals have many more and diverse immunity genes than would be expected, which is the hallmark of a very robust immune system. "This study helps us better understand how corals deal with stress," said Traylor-Knowles. "Its complex immune system indicates that it may have the tools to deal with environmental change much more easily than other corals." The study, titled "Comparative analysis of the Pocillopora damicornis genome highlights role of immune system in coral evolution," was published in the October 31, 2018 issue of the journal Scientific Reports. The paper's coauthors include: Nikki Traylor-Knowles, Andrew Baker, and Phil Gillette of the UM Rosenstiel School; UM alumnus Ross Cunning of Shedd Aquarium; and UM alumna Rachael Bay of the University of California Davis. <|im_end|>

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2,088

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Brain function relies on fast and precisely timed synaptic vesicle (SV) release at active zones (AZs). Efficacy of SV release depends on distance from SV to Ca 2+ channel, but molecular mechanisms controlling this are unknown. Here we found that distances can be defined by targeting two unc-13 (Unc13) isoforms to presynaptic AZ subdomains. Super-resolution and intravital imaging of developing Drosophila melanogaster glutamatergic synapses revealed that the Unc13B isoform was recruited to nascent AZs by the scaffolding proteins Syd-1 and Liprin-α, and Unc13A was positioned by Bruchpilot and Rim-binding protein complexes at maturing AZs. Unc13B localized 120 nm away from Ca 2+ channels, whereas Unc13A localized only 70 nm away and was responsible for docking SVs at this distance. Unc13A null mutants suffered from inefficient, delayed and EGTA-supersensitive release. Mathematical modeling suggested that synapses normally operate via two independent release pathways differentially positioned by either isoform. We identified isoform-specific Unc13-AZ scaffold interactions regulating SV-Ca 2+ -channel topology whose developmental tightening optimizes synaptic transmission. Main Synaptic communication relies on the timed fusion of SVs to release neurotransmitter from the presynapse in response to action potentials (APs). To gain release competence, prior reactions need to take place. Docking, the targeted SV localization to the AZ plasma membrane, and priming, the maturation of SVs into a readily releasable pool (RRP), have been shown to require the neuronal SNAREs Syntaxin, SNAP25 and VAMP2 (refs. 1 , 2 , 3 ). A conformational change from closed to open Syntaxin required to engage all three neuronal SNAREs, is thought to be catalyzed by the essential priming factor Unc13 (Munc13 in mammals), thus establishing an RRP and enhancing SV replenishment after exocytosis 2 , 4 , 5 , 6 , 7 . To couple SV release to electrical stimulation by APs, Ca 2+ ions entering the cell through voltage-gated Ca 2+ channels activate the Ca 2+ sensor Synaptotagmin on the SV to trigger fusion 1 . The efficacy of synaptic transmission largely depends on the distance between SVs and voltage-gated Ca 2+ channels. Close proximity is required for immediate responses, which may require active localization of RRP SVs, a process referred to as positional priming 8 , 9 , 10 . At AZs, an evolutionarily conserved set of large proteins is implicated in the spatial organization of synapse topology, including RIM, (M)Unc13, Rim-binding protein (RBP), Liprin-α and ELKS (the mammalian homologue of invertebrate Bruchpilot, BRP) proteins 11 . Among these, ELKS/BRP family proteins, RIMs and RBPs are required to ensure proper Ca 2+ -channel-SV topology and Ca 2+ -channel density, and their levels predict release at single AZs 12 , 13 , 14 , 15 , 16 , 17 . Furthermore, Liprin-α organizes AZ composition 18 , 19 , 20 . Intravital imaging of the trajectory of AZ assembly in the Drosophila neuromuscular junction (NMJ) showed that an early Syd-1 and Liprin-α scaffold protein complex initiates AZ assembly. This protein complex precedes a second one containing BRP and RBP by hours 18 , 21 . Here we found that two scaffold protein complexes define the spatiotemporal organization of two Unc13 isoforms during AZ maturation. Unc13B appeared together with the 'early' Liprin-α/Syd-1 scaffold, and its AZ accumulation was specifically dependent on this scaffold. At matured AZs, Unc13B remained clustered at larger distances from Ca 2+ channels (>100 nm). Later, during the assembly process, Unc13A was positioned and stabilized in discrete clusters via the BRP-RBP scaffold close to presynaptic Ca 2+ channels (<100 nm). In line with a function in both molecular priming and vesicle positioning, we found that Unc13A dominated release not only by enhancing the number of docked and primed vesicles, but also by regulating the probability of release, its latency and sensitivity to Ca 2+ buffers. Our results are in line with two coexisting functional exocytosis pathways with identical Ca 2+ sensing and fusion mechanisms at mature AZs, differentially positioned by the two Unc13 isoforms whose precise spatiotemporal placement determines AZ maturation and function. Results Unc13A and Unc13B are important for efficient AZ formation We have previously analyzed the developmental assembly and maturation of glutamatergic synapses in Drosophila and discovered that the central AZ protein scaffold, consisting of BRP and RBP, is incorporated at an advanced stage of a maturation process lasting many hours 18 . Elimination of either BRP or RBP leads to severe SV release deficits, at least partly caused by reduced coupling of Ca 2+ channels to the SV fusion machinery 14 , 15 . As neither RBP nor BRP are proteins with established direct function in SV exocytosis, we wondered whether additional effectors among release machinery proteins might be organized via the scaffolding function of the RBP-BRP complexes.To identify new RBP interaction partners that might be relevant in this context, we performed a pair-wise yeast two-hybrid (Y2H) matrix screen using a construct consisting of the second and third SH3 domains of Drosophila RBP as bait. The screen recovered a direct binary interaction with an N-terminal proline-rich (PxxP)-motif-containing region of Drosophila Unc13A ( Fig. 1a ), one of the two Unc13 isoforms transcribed from a single Drosophila Unc13 locus ( ). An arrangement in which two promoters of the same locus produce different isoforms has been noted before for the AZ protein BRP 22 . Similar to the BRP isoforms, the two Unc13 isoforms differ in their N-terminal region, but are identical at their C-terminal region, which includes the so-called C1, C 2 B, MUN and C 2 C domains 23 ( Fig. 1a,b ). Binding of diacylglycerol (DAG) to the C1 domain has been shown to induce the translocation of (M)Unc13 proteins to the plasma membrane and to influence vesicular release probability, linking C1 domain activation to a lowering of the energy barrier for SV fusion 24 , 25 . The central C 2 B domain is involved in Ca 2+ -dependent phospholipid binding and modulates presynaptic plasticity 26 . Furthermore, both isoforms harbor the MUN domain, the minimal domain required for molecular priming 27 , 28 . Unlike Unc13B, Unc13A", "role": "user" }, { "content": "Synapses are the power junctions that allow living creatures to function. Popularly associated with learning and memory, they play a more fundamental role in our existence by regulating everything from breathing, sleeping and waking and other bodily functions. Loss of synapses and synapse function sit at the heart of a number of diseases, not just neurodegenerative examples such as dementia and Parkinson's disease but also conditions such as diabetes. We do not fully understand how synapses work, but new research published on Nature Neuroscience's website has shed new light on the role of proteins in the way in which synapses maintain their signalling. The research has been carried out by an international team of scientists from: the Institute for Biology/Genetics and the Institute of Chemistry and Biochemisty/Structural Biochemistry, Freie Universität Berlin; NeuroCure, Cluster of Excellence, Charité Universitätsmedizin, Berlin; Molecular and Theoretical Neuroscience, Leibniz-Institut für Molekulare Pharmakologie, Berlin; Department of Nanobiophotonics, Max Planck Institute for Biophysical Chemistry, Göttingen; Plymouth University Peninsula Schools of Medicine and Dentistry; the Department of Genetics, University of Cambridge, and; the Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Austria. The team used genetics like a scalpel blade to remove individual proteins from the synapse to identify their different roles within the synapse, and how they maintain synaptic transmission. They used synapses from the fruit fly drosophila, which compares remarkably closely to synapses in humans. The team used genetics like a scalpel blade to remove individual proteins from the synapse to identify their different roles within the synapse, and how they maintain synaptic transmission. They used synapses from the fruit fly drosophila, which compares remarkably closely to synapses in humans. The results showed that two variations of a protein called Unc13 work separately to regulate synaptic transmission. The study is the first to show how the different forms of this protein work. The findings of the study will prove invaluable to other research studies examining the role of synapse function in the diagnosis and treatment of neurodegenerative and other diseases. A greater understanding of how synapses work may also find a role in identifying unexpected drug targets for specific diseases. Dr. Iain Robinson, Associate Professor in Neurosciences at Plymouth University Peninsula Schools of Medicine and Dentistry is part of the international research team on this study. He said: \"Using a combination of genetics and state of the art imaging allows us to dissect the function of synapses which are used to convey messages in the brain. We have moved another step nearer to understanding the mechanisms employed by synapses and created knowledge which could play a vital role in research projects with the potential to discover breakthroughs in the diagnosis and treatment of a wide range of debilitating and life-changing diseases.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Brain function relies on fast and precisely timed synaptic vesicle (SV) release at active zones (AZs). Efficacy of SV release depends on distance from SV to Ca 2+ channel, but molecular mechanisms controlling this are unknown. Here we found that distances can be defined by targeting two unc-13 (Unc13) isoforms to presynaptic AZ subdomains. Super-resolution and intravital imaging of developing Drosophila melanogaster glutamatergic synapses revealed that the Unc13B isoform was recruited to nascent AZs by the scaffolding proteins Syd-1 and Liprin-α, and Unc13A was positioned by Bruchpilot and Rim-binding protein complexes at maturing AZs. Unc13B localized 120 nm away from Ca 2+ channels, whereas Unc13A localized only 70 nm away and was responsible for docking SVs at this distance. Unc13A null mutants suffered from inefficient, delayed and EGTA-supersensitive release. Mathematical modeling suggested that synapses normally operate via two independent release pathways differentially positioned by either isoform. We identified isoform-specific Unc13-AZ scaffold interactions regulating SV-Ca 2+ -channel topology whose developmental tightening optimizes synaptic transmission. Main Synaptic communication relies on the timed fusion of SVs to release neurotransmitter from the presynapse in response to action potentials (APs). To gain release competence, prior reactions need to take place. Docking, the targeted SV localization to the AZ plasma membrane, and priming, the maturation of SVs into a readily releasable pool (RRP), have been shown to require the neuronal SNAREs Syntaxin, SNAP25 and VAMP2 (refs. 1 , 2 , 3 ). A conformational change from closed to open Syntaxin required to engage all three neuronal SNAREs, is thought to be catalyzed by the essential priming factor Unc13 (Munc13 in mammals), thus establishing an RRP and enhancing SV replenishment after exocytosis 2 , 4 , 5 , 6 , 7 . To couple SV release to electrical stimulation by APs, Ca 2+ ions entering the cell through voltage-gated Ca 2+ channels activate the Ca 2+ sensor Synaptotagmin on the SV to trigger fusion 1 . The efficacy of synaptic transmission largely depends on the distance between SVs and voltage-gated Ca 2+ channels. Close proximity is required for immediate responses, which may require active localization of RRP SVs, a process referred to as positional priming 8 , 9 , 10 . At AZs, an evolutionarily conserved set of large proteins is implicated in the spatial organization of synapse topology, including RIM, (M)Unc13, Rim-binding protein (RBP), Liprin-α and ELKS (the mammalian homologue of invertebrate Bruchpilot, BRP) proteins 11 . Among these, ELKS/BRP family proteins, RIMs and RBPs are required to ensure proper Ca 2+ -channel-SV topology and Ca 2+ -channel density, and their levels predict release at single AZs 12 , 13 , 14 , 15 , 16 , 17 . Furthermore, Liprin-α organizes AZ composition 18 , 19 , 20 . Intravital imaging of the trajectory of AZ assembly in the Drosophila neuromuscular junction (NMJ) showed that an early Syd-1 and Liprin-α scaffold protein complex initiates AZ assembly. This protein complex precedes a second one containing BRP and RBP by hours 18 , 21 . Here we found that two scaffold protein complexes define the spatiotemporal organization of two Unc13 isoforms during AZ maturation. Unc13B appeared together with the 'early' Liprin-α/Syd-1 scaffold, and its AZ accumulation was specifically dependent on this scaffold. At matured AZs, Unc13B remained clustered at larger distances from Ca 2+ channels (>100 nm). Later, during the assembly process, Unc13A was positioned and stabilized in discrete clusters via the BRP-RBP scaffold close to presynaptic Ca 2+ channels (<100 nm). In line with a function in both molecular priming and vesicle positioning, we found that Unc13A dominated release not only by enhancing the number of docked and primed vesicles, but also by regulating the probability of release, its latency and sensitivity to Ca 2+ buffers. Our results are in line with two coexisting functional exocytosis pathways with identical Ca 2+ sensing and fusion mechanisms at mature AZs, differentially positioned by the two Unc13 isoforms whose precise spatiotemporal placement determines AZ maturation and function. Results Unc13A and Unc13B are important for efficient AZ formation We have previously analyzed the developmental assembly and maturation of glutamatergic synapses in Drosophila and discovered that the central AZ protein scaffold, consisting of BRP and RBP, is incorporated at an advanced stage of a maturation process lasting many hours 18 . Elimination of either BRP or RBP leads to severe SV release deficits, at least partly caused by reduced coupling of Ca 2+ channels to the SV fusion machinery 14 , 15 . As neither RBP nor BRP are proteins with established direct function in SV exocytosis, we wondered whether additional effectors among release machinery proteins might be organized via the scaffolding function of the RBP-BRP complexes.To identify new RBP interaction partners that might be relevant in this context, we performed a pair-wise yeast two-hybrid (Y2H) matrix screen using a construct consisting of the second and third SH3 domains of Drosophila RBP as bait. The screen recovered a direct binary interaction with an N-terminal proline-rich (PxxP)-motif-containing region of Drosophila Unc13A ( Fig. 1a ), one of the two Unc13 isoforms transcribed from a single Drosophila Unc13 locus ( ). An arrangement in which two promoters of the same locus produce different isoforms has been noted before for the AZ protein BRP 22 . Similar to the BRP isoforms, the two Unc13 isoforms differ in their N-terminal region, but are identical at their C-terminal region, which includes the so-called C1, C 2 B, MUN and C 2 C domains 23 ( Fig. 1a,b ). Binding of diacylglycerol (DAG) to the C1 domain has been shown to induce the translocation of (M)Unc13 proteins to the plasma membrane and to influence vesicular release probability, linking C1 domain activation to a lowering of the energy barrier for SV fusion 24 , 25 . The central C 2 B domain is involved in Ca 2+ -dependent phospholipid binding and modulates presynaptic plasticity 26 . Furthermore, both isoforms harbor the MUN domain, the minimal domain required for molecular priming 27 , 28 . Unlike Unc13B, Unc13A<|im_end|> <|im_start|>assistant Synapses are the power junctions that allow living creatures to function. Popularly associated with learning and memory, they play a more fundamental role in our existence by regulating everything from breathing, sleeping and waking and other bodily functions. Loss of synapses and synapse function sit at the heart of a number of diseases, not just neurodegenerative examples such as dementia and Parkinson's disease but also conditions such as diabetes. We do not fully understand how synapses work, but new research published on Nature Neuroscience's website has shed new light on the role of proteins in the way in which synapses maintain their signalling. The research has been carried out by an international team of scientists from: the Institute for Biology/Genetics and the Institute of Chemistry and Biochemisty/Structural Biochemistry, Freie Universität Berlin; NeuroCure, Cluster of Excellence, Charité Universitätsmedizin, Berlin; Molecular and Theoretical Neuroscience, Leibniz-Institut für Molekulare Pharmakologie, Berlin; Department of Nanobiophotonics, Max Planck Institute for Biophysical Chemistry, Göttingen; Plymouth University Peninsula Schools of Medicine and Dentistry; the Department of Genetics, University of Cambridge, and; the Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Austria. The team used genetics like a scalpel blade to remove individual proteins from the synapse to identify their different roles within the synapse, and how they maintain synaptic transmission. They used synapses from the fruit fly drosophila, which compares remarkably closely to synapses in humans. The team used genetics like a scalpel blade to remove individual proteins from the synapse to identify their different roles within the synapse, and how they maintain synaptic transmission. They used synapses from the fruit fly drosophila, which compares remarkably closely to synapses in humans. The results showed that two variations of a protein called Unc13 work separately to regulate synaptic transmission. The study is the first to show how the different forms of this protein work. The findings of the study will prove invaluable to other research studies examining the role of synapse function in the diagnosis and treatment of neurodegenerative and other diseases. A greater understanding of how synapses work may also find a role in identifying unexpected drug targets for specific diseases. Dr. Iain Robinson, Associate Professor in Neurosciences at Plymouth University Peninsula Schools of Medicine and Dentistry is part of the international research team on this study. He said: "Using a combination of genetics and state of the art imaging allows us to dissect the function of synapses which are used to convey messages in the brain. We have moved another step nearer to understanding the mechanisms employed by synapses and created knowledge which could play a vital role in research projects with the potential to discover breakthroughs in the diagnosis and treatment of a wide range of debilitating and life-changing diseases." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Complex biological processes are often performed by self-organizing nanostructures comprising multiple classes of macromolecules, such as ribosomes (proteins and RNA) or enveloped viruses (proteins, nucleic acids and lipids). Approaches have been developed for designing self-assembling structures consisting of either nucleic acids 1 , 2 or proteins 3 , 4 , 5 , but strategies for engineering hybrid biological materials are only beginning to emerge 6 , 7 . Here we describe the design of self-assembling protein nanocages that direct their own release from human cells inside small vesicles in a manner that resembles some viruses. We refer to these hybrid biomaterials as ‘enveloped protein nanocages’ (EPNs). Robust EPN biogenesis requires protein sequence elements that encode three distinct functions: membrane binding, self-assembly, and recruitment of the endosomal sorting complexes required for transport (ESCRT) machinery 8 . A variety of synthetic proteins with these functional elements induce EPN biogenesis, highlighting the modularity and generality of the design strategy. Biochemical analyses and cryo-electron microscopy reveal that one design, EPN-01, comprises small (~100 nm) vesicles containing multiple protein nanocages that closely match the structure of the designed 60-subunit self-assembling scaffold 9 . EPNs that incorporate the vesicular stomatitis viral glycoprotein can fuse with target cells and deliver their contents, thereby transferring cargoes from one cell to another. These results show how proteins can be programmed to direct the formation of hybrid biological materials that perform complex tasks, and establish EPNs as a class of designed, modular, genetically-encoded nanomaterials that can transfer molecules between cells. Main Based on an advancing understanding of enveloped virus assembly, we proposed that synthetic proteins could be engineered to direct their own release from eukaryotic cells within membrane envelopes if they encoded three essential activities: membrane binding (termed ‘M’ domain activity), self-assembly (interaction or ‘I’ domain activity), and the ability to recruit ESCRT machinery to catalyse the final membrane fission step required for release from the cell (late budding or ‘L’ domain activity) 8 , 10 , 11 . To test this hypothesis, we genetically fused peptide sequences capable of membrane binding and ESCRT recruitment to the computationally designed, 60-subunit nanocage I3-01 (ref. 9 ) to create the EPN-01 constructs (see Fig. 1a and Extended Data Fig. 1a for definitions of EPN-01 and EPN-01*). To promote membrane binding, we added to I3-01 an N -myristoylation signal corresponding to the first six amino acids of the HIV-1 structural Gag protein 12 . To promote ESCRT recruitment, we added the 52-residue HIV-1 Gag p6 peptide (p6 Gag ) to the C terminus 8 , 11 . Size-exclusion chromatography and negative-stain electron microscopy of EPN-01* expressed in Escherichia coli cells (which lack N -myristoyltransferase and ESCRT factors and therefore produced non-enveloped nanocages) verified that purified EPN-01*, like the core I3-01 scaffold 9 , self-assembled into regular nanocages approximately 25 nm in diameter ( Extended Data Fig. 2 ). Figure 1: EPN release requires three functional elements. a , Schematic of the EPN-01 construct, with the membrane-binding N -myristoylation element from HIV-1 Gag in orange (underlined G denotes the myristoylated glycine residue), the I3-01 self-assembly domain in green (the L33R mutation has previously been shown to prevent assembly 9 ), the Myc epitope in blue, and the ESCRT-recruiting HIV-1 p6 Gag element in grey. The TSG101/ESCRT-I-, ALIX- and Vpr-binding sites are shown and key interaction residues mutated in this study are underlined. Residue numbers above the construct correspond to individual functional elements, numbers below correspond to the overall construct. b , Left, western blots showing EPN-01 proteins harvested from 293T cell culture supernatants (top blot), cellular EPN-01 proteins in the Triton-insoluble and Triton-soluble fractions (middle blots), and a soluble cellular GAPDH loading control (bottom). To the right, the percentage of EPN-01 and mutants released into the supernatant is plotted (error bars show standard deviations from three technical repetitions). PowerPoint slide Full size image When expressed in human embryonic kidney 293T cells, 13 ± 3% of the EPN-01 protein was released into the culture supernatant in complexes that could be pelleted by centrifugation through a 20% sucrose cushion ( Fig. 1b ). By contrast, a core I3-01–Myc scaffold lacking membrane-binding and ESCRT-recruiting elements was not released. Mutational analyses confirmed that each of the three design elements was required for EPN-01 release. Specifically, EPN-01 constructs with point mutations designed to disrupt myristoylation (ΔM) 12 or the designed assembly interface (ΔI) 9 were not detectably released. Mutations designed to block ESCRT factor recruitment also inhibited EPN-01 release; mutation of the p6 Gag TSG101/ESCRT-I binding site (∆L1) reduced EPN-01 release 18-fold, and mutation of the ALIX binding site (∆L2) abrogated release entirely, either alone or in combination with the TSG101/ESCRT-I binding site mutation (∆L1 + ∆L2). Similar results were obtained with EPN-01* analogues ( Extended Data Fig. 1 ). These experiments demonstrate that all three design elements—membrane binding, self-assembly and ESCRT recruitment—are functionally required for release of EPN-01 proteins from human cells. Three different biochemical assays confirmed that released EPN-01 proteins were encapsulated within intact membrane envelopes. Figure 2a shows that released EPN-01 protein was protected against trypsin digestion in the absence of detergent, but became susceptible in the presence of 1% Triton X-100. In control experiments, non-enveloped EPN-01* nanocages produced in E. coli were degraded by trypsin in both the presence and absence of detergent. Detergent treatment was also required to render released EPN-01 proteins accessible to antibodies or to the small, polar aldolase substrate 2-keto-3-deoxy-6-phosphogluconate (KDPG), as assayed by I3-01 aldolase activity ( Extended Data Fig. 3a, b ). Thus, EPN-01 proteins were released within intact membrane envelopes that were impermeable to proteins or small polar molecules. Figure 2: EPNs comprise cell-derived membrane envelopes containing multiple protein nanocages. a , Top, western blot showing EPN-01 in 293F cells (lane 1) or released from 293F cells and treated as indicated (lanes 2–4). Bottom, western blot showing equivalent samples of non-enveloped EPN-01* nanocages purified from E. coli . b , Representative cryo-EM images showing extracellular vesicles/EPNs in culture supernatants from 293T cells that expressed I3-01–Myc (left) or", "role": "user" }, { "content": "Scientists from the University of Utah and University of Washington have developed blueprints that instruct human cells to assemble a virus-like delivery system that can transport custom cargo from one cell to another. As reported online in Nature on Nov. 30, the research is a step toward a nature-inspired means for delivering therapeutics directly to specific cell types within the body. \"We're shifting our perception from viruses as pathogens, to viruses as inspiration for new tools,\" says Wesley Sundquist, Ph.D., co-chair of the Department of Biochemistry at the University of Utah School of Medicine. He is also co-senior author on the study with Neil King, Ph.D., an assistant professor at the Institute for Protein Design at the University of Washington. The carefully designed instructions set forth a series of self-propelled events that mimic how some viruses transfer their infectious contents from one cell to the next. From the blueprints tumbled out self-assembling, soccer ball-shaped \"nanocages\", the structure of which was reported previously. Adding on specific pieces of genetic code from viruses caused the nanocages to be packaged within cell membranes, and then exported from cells. Like a shuttle leaving Earth to bring goods to a space station, the tiny capsules undocked from one cell, traveled to another and docked there, emptying its contents upon arrival. In this case, the protective nanocages carried cargo that the scientists used like homing beacons to track the vessels' journeys. Next steps are to design nanocages that hold drugs or other small molecules that would be assembled factory-style in one set of cells, and sent out from there. Such biologically-based delivery systems are expected to be better tolerated by the body than other nanoparticles made from synthetic materials. \"We are now able to accurately and consistently design new proteins with tailor-made structures,\" says King. \"Given the remarkably sophisticated and varied functions that natural proteins perform, it's exciting to consider the possibilities that are open to us.\" Nanocages are part of a virus-inspired system for delivering small molecules to cells. The self-assembling cages are built from proteins, also represented as a ribbon structure (green). Credit: David Belnap, Joerg Votteler The researchers' decision to model the microscopic shipping system after viruses was no accident. Viruses have honed their skills to effectively spread their infectious wares to large numbers of cells. Decades of research, including in-depth investigations of the human immunodeficiency virus (HIV) by Sundquist's team, have led to an understanding of how the pathogens accomplish this goal with such efficiency. A test of whether you truly understand something is to build it yourself. And that's what Sundquist and King's teams have done here. \"The success of our system is the first formal proof that this is how virus budding works,\" remarks Sundquist. Viruses taught them that such a delivery system must include three essential properties: an ability to grasp membranes, self-assemble, and to be released from cells. Introducing coding errors into any one of those steps brought shipments to a halt. \"I was sure that this would need fine-tuning but it was clean from the very beginning,\" says lead author Jörg Votteler, Ph.D., a postdoctoral fellow in biochemistry at the University of Utah. When electron microscopist David Belnap, Ph.D. saw that images of the cages aligned closely with computer models, he knew they had made what they set out to design. \"When it's right, you know it,\" he says. The system could be modified as long as the three basic tenets were left intact. For example, the scientists could swap in differently shaped cages, or cause another type of membranes to surround them. Modularity means the vessels can be customized for various applications. This study is proof of principle that the systems works, but more needs to be done before it can be applied therapeutically. Researchers will need to determine whether the capsules can navigate long journeys within living animals, for instance, and whether they can deliver medicines in sufficient quantities. \"As long as we keep pushing knowledge forward we can guarantee there will be good outcomes, though we can't guarantee what or when,\" says Sundquist. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Complex biological processes are often performed by self-organizing nanostructures comprising multiple classes of macromolecules, such as ribosomes (proteins and RNA) or enveloped viruses (proteins, nucleic acids and lipids). Approaches have been developed for designing self-assembling structures consisting of either nucleic acids 1 , 2 or proteins 3 , 4 , 5 , but strategies for engineering hybrid biological materials are only beginning to emerge 6 , 7 . Here we describe the design of self-assembling protein nanocages that direct their own release from human cells inside small vesicles in a manner that resembles some viruses. We refer to these hybrid biomaterials as ‘enveloped protein nanocages’ (EPNs). Robust EPN biogenesis requires protein sequence elements that encode three distinct functions: membrane binding, self-assembly, and recruitment of the endosomal sorting complexes required for transport (ESCRT) machinery 8 . A variety of synthetic proteins with these functional elements induce EPN biogenesis, highlighting the modularity and generality of the design strategy. Biochemical analyses and cryo-electron microscopy reveal that one design, EPN-01, comprises small (~100 nm) vesicles containing multiple protein nanocages that closely match the structure of the designed 60-subunit self-assembling scaffold 9 . EPNs that incorporate the vesicular stomatitis viral glycoprotein can fuse with target cells and deliver their contents, thereby transferring cargoes from one cell to another. These results show how proteins can be programmed to direct the formation of hybrid biological materials that perform complex tasks, and establish EPNs as a class of designed, modular, genetically-encoded nanomaterials that can transfer molecules between cells. Main Based on an advancing understanding of enveloped virus assembly, we proposed that synthetic proteins could be engineered to direct their own release from eukaryotic cells within membrane envelopes if they encoded three essential activities: membrane binding (termed ‘M’ domain activity), self-assembly (interaction or ‘I’ domain activity), and the ability to recruit ESCRT machinery to catalyse the final membrane fission step required for release from the cell (late budding or ‘L’ domain activity) 8 , 10 , 11 . To test this hypothesis, we genetically fused peptide sequences capable of membrane binding and ESCRT recruitment to the computationally designed, 60-subunit nanocage I3-01 (ref. 9 ) to create the EPN-01 constructs (see Fig. 1a and Extended Data Fig. 1a for definitions of EPN-01 and EPN-01*). To promote membrane binding, we added to I3-01 an N -myristoylation signal corresponding to the first six amino acids of the HIV-1 structural Gag protein 12 . To promote ESCRT recruitment, we added the 52-residue HIV-1 Gag p6 peptide (p6 Gag ) to the C terminus 8 , 11 . Size-exclusion chromatography and negative-stain electron microscopy of EPN-01* expressed in Escherichia coli cells (which lack N -myristoyltransferase and ESCRT factors and therefore produced non-enveloped nanocages) verified that purified EPN-01*, like the core I3-01 scaffold 9 , self-assembled into regular nanocages approximately 25 nm in diameter ( Extended Data Fig. 2 ). Figure 1: EPN release requires three functional elements. a , Schematic of the EPN-01 construct, with the membrane-binding N -myristoylation element from HIV-1 Gag in orange (underlined G denotes the myristoylated glycine residue), the I3-01 self-assembly domain in green (the L33R mutation has previously been shown to prevent assembly 9 ), the Myc epitope in blue, and the ESCRT-recruiting HIV-1 p6 Gag element in grey. The TSG101/ESCRT-I-, ALIX- and Vpr-binding sites are shown and key interaction residues mutated in this study are underlined. Residue numbers above the construct correspond to individual functional elements, numbers below correspond to the overall construct. b , Left, western blots showing EPN-01 proteins harvested from 293T cell culture supernatants (top blot), cellular EPN-01 proteins in the Triton-insoluble and Triton-soluble fractions (middle blots), and a soluble cellular GAPDH loading control (bottom). To the right, the percentage of EPN-01 and mutants released into the supernatant is plotted (error bars show standard deviations from three technical repetitions). PowerPoint slide Full size image When expressed in human embryonic kidney 293T cells, 13 ± 3% of the EPN-01 protein was released into the culture supernatant in complexes that could be pelleted by centrifugation through a 20% sucrose cushion ( Fig. 1b ). By contrast, a core I3-01–Myc scaffold lacking membrane-binding and ESCRT-recruiting elements was not released. Mutational analyses confirmed that each of the three design elements was required for EPN-01 release. Specifically, EPN-01 constructs with point mutations designed to disrupt myristoylation (ΔM) 12 or the designed assembly interface (ΔI) 9 were not detectably released. Mutations designed to block ESCRT factor recruitment also inhibited EPN-01 release; mutation of the p6 Gag TSG101/ESCRT-I binding site (∆L1) reduced EPN-01 release 18-fold, and mutation of the ALIX binding site (∆L2) abrogated release entirely, either alone or in combination with the TSG101/ESCRT-I binding site mutation (∆L1 + ∆L2). Similar results were obtained with EPN-01* analogues ( Extended Data Fig. 1 ). These experiments demonstrate that all three design elements—membrane binding, self-assembly and ESCRT recruitment—are functionally required for release of EPN-01 proteins from human cells. Three different biochemical assays confirmed that released EPN-01 proteins were encapsulated within intact membrane envelopes. Figure 2a shows that released EPN-01 protein was protected against trypsin digestion in the absence of detergent, but became susceptible in the presence of 1% Triton X-100. In control experiments, non-enveloped EPN-01* nanocages produced in E. coli were degraded by trypsin in both the presence and absence of detergent. Detergent treatment was also required to render released EPN-01 proteins accessible to antibodies or to the small, polar aldolase substrate 2-keto-3-deoxy-6-phosphogluconate (KDPG), as assayed by I3-01 aldolase activity ( Extended Data Fig. 3a, b ). Thus, EPN-01 proteins were released within intact membrane envelopes that were impermeable to proteins or small polar molecules. Figure 2: EPNs comprise cell-derived membrane envelopes containing multiple protein nanocages. a , Top, western blot showing EPN-01 in 293F cells (lane 1) or released from 293F cells and treated as indicated (lanes 2–4). Bottom, western blot showing equivalent samples of non-enveloped EPN-01* nanocages purified from E. coli . b , Representative cryo-EM images showing extracellular vesicles/EPNs in culture supernatants from 293T cells that expressed I3-01–Myc (left) or<|im_end|> <|im_start|>assistant Scientists from the University of Utah and University of Washington have developed blueprints that instruct human cells to assemble a virus-like delivery system that can transport custom cargo from one cell to another. As reported online in Nature on Nov. 30, the research is a step toward a nature-inspired means for delivering therapeutics directly to specific cell types within the body. "We're shifting our perception from viruses as pathogens, to viruses as inspiration for new tools," says Wesley Sundquist, Ph.D., co-chair of the Department of Biochemistry at the University of Utah School of Medicine. He is also co-senior author on the study with Neil King, Ph.D., an assistant professor at the Institute for Protein Design at the University of Washington. The carefully designed instructions set forth a series of self-propelled events that mimic how some viruses transfer their infectious contents from one cell to the next. From the blueprints tumbled out self-assembling, soccer ball-shaped "nanocages", the structure of which was reported previously. Adding on specific pieces of genetic code from viruses caused the nanocages to be packaged within cell membranes, and then exported from cells. Like a shuttle leaving Earth to bring goods to a space station, the tiny capsules undocked from one cell, traveled to another and docked there, emptying its contents upon arrival. In this case, the protective nanocages carried cargo that the scientists used like homing beacons to track the vessels' journeys. Next steps are to design nanocages that hold drugs or other small molecules that would be assembled factory-style in one set of cells, and sent out from there. Such biologically-based delivery systems are expected to be better tolerated by the body than other nanoparticles made from synthetic materials. "We are now able to accurately and consistently design new proteins with tailor-made structures," says King. "Given the remarkably sophisticated and varied functions that natural proteins perform, it's exciting to consider the possibilities that are open to us." Nanocages are part of a virus-inspired system for delivering small molecules to cells. The self-assembling cages are built from proteins, also represented as a ribbon structure (green). Credit: David Belnap, Joerg Votteler The researchers' decision to model the microscopic shipping system after viruses was no accident. Viruses have honed their skills to effectively spread their infectious wares to large numbers of cells. Decades of research, including in-depth investigations of the human immunodeficiency virus (HIV) by Sundquist's team, have led to an understanding of how the pathogens accomplish this goal with such efficiency. A test of whether you truly understand something is to build it yourself. And that's what Sundquist and King's teams have done here. "The success of our system is the first formal proof that this is how virus budding works," remarks Sundquist. Viruses taught them that such a delivery system must include three essential properties: an ability to grasp membranes, self-assemble, and to be released from cells. Introducing coding errors into any one of those steps brought shipments to a halt. "I was sure that this would need fine-tuning but it was clean from the very beginning," says lead author Jörg Votteler, Ph.D., a postdoctoral fellow in biochemistry at the University of Utah. When electron microscopist David Belnap, Ph.D. saw that images of the cages aligned closely with computer models, he knew they had made what they set out to design. "When it's right, you know it," he says. The system could be modified as long as the three basic tenets were left intact. For example, the scientists could swap in differently shaped cages, or cause another type of membranes to surround them. Modularity means the vessels can be customized for various applications. This study is proof of principle that the systems works, but more needs to be done before it can be applied therapeutically. Researchers will need to determine whether the capsules can navigate long journeys within living animals, for instance, and whether they can deliver medicines in sufficient quantities. "As long as we keep pushing knowledge forward we can guarantee there will be good outcomes, though we can't guarantee what or when," says Sundquist. <|im_end|>

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2,481

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Thousands of genomic structural variants (SVs) segregate in the human population and can impact phenotypic traits and diseases. Their identification in whole-genome sequence data of large cohorts is a major computational challenge. Most current approaches identify SVs in single genomes and afterwards merge the identified variants into a joint call set across many genomes. We describe the approach PopDel, which directly identifies deletions of about 500 to at least 10,000 bp in length in data of many genomes jointly, eliminating the need for subsequent variant merging. PopDel scales to tens of thousands of genomes as we demonstrate in evaluations on up to 49,962 genomes. We show that PopDel reliably reports common, rare and de novo deletions. On genomes with available high-confidence reference call sets PopDel shows excellent recall and precision. Genotype inheritance patterns in up to 6794 trios indicate that genotypes predicted by PopDel are more reliable than those of previous SV callers. Furthermore, PopDel’s running time is competitive with the fastest tested previous tools. The demonstrated scalability and accuracy of PopDel enables routine scans for deletions in large-scale sequencing studies. Introduction Comprehensive and reliable collections of genetic variation are a foundation for research on human diversity and disease 1 . They facilitate a wide range of studies investigating mutation rates 2 , 3 , 4 , mutational mechanisms 5 , 6 , 7 , functional consequences of variants 8 , 9 , 10 , ancestry relationships 11 , disease risks 12 , or treatment options 13 . Due to increased throughput and decreased cost, whole-genome sequencing is now performed on cohorts of thousands of individuals, for example, sequencing at the population level in Iceland 14 , the United Kingdom 15 , or Crete 16 , as well as sequencing of large cohorts for specific diseases, such as autism 17 or asthma 18 , and in the general health research context in projects like GnomAD 19 or TopMed 20 . To create meaningful collections of genetic variation, the data from these large numbers of individuals need to be integrated. The most direct way of achieving this is done in joint variant calling approaches: detecting variant positions and inferring variant genotypes from data of many individuals together. For single-nucleotide variants (SNVs) and small insertions/deletions (indels), joint calling has become the state of the art with tools that scale to tens of thousands of individuals 21 , 22 . For structural variants (SVs), the analysis of increasingly large numbers of individuals remains a major bioinformatic challenge 23 . Jointly detecting SVs in up to hundreds of individuals is a great achievement of previous projects and tools 24 , 25 . However, for larger cohorts, catalogs of SVs are generally created in a multistep approach by first analyzing the data of each individual separately or in small subsets of individuals, subsequently merging the resulting call sets and, finally, determining genotypes for all individuals on the merged call set 26 , 27 . Merging of SV call sets across individuals is often problematic and arbitrary when the same SV is detected with shifted positions in several individuals 28 , 29 . In addition, variants that are only weakly supported by the data may not be discovered using this multistep approach. Furthermore, the aligned read data is accessed at least twice in the process, for detecting and for genotyping SVs, requiring substantial computational resources. A joint SV detection approach simplifies the calling process, is computationally more efficient if accessing the large amounts of input data only once, eliminates the need for an error-prone variant merging step, and may reveal weakly supported variants if carried by several individuals as the support can be accumulated across individuals. In this work, we overcome these limitations of current SV callers by introducing a joint calling approach, PopDel, for deletions of a few hundred up to tens of thousands of base pairs (bp) in length. We specifically designed the approach to scale to large cohorts and demonstrate that it jointly discovers SVs across tens of thousands of individuals, thereby directly creating joint call sets. Nevertheless, it can also be applied to a single genome or small numbers of genomes, where it achieves comparable or even better accuracy than widely used deletion callers. We demonstrate the high accuracy on simulated data, public benchmark data from the Genome-in-a-Bottle (GIAB) consortium, and on data of parent-child trios, which allows us to validate predicted genotypes using the genetic laws of inheritance. Our results demonstrate that the joint deletion detection approach can yield reliable call sets across very many genomes. Results Our main result is a computational approach that can detect and genotype deletions in tens of thousands of genomes jointly. We have implemented the approach in the tool PopDel and evaluate PopDel’s performance in comparison to previous popular tools for SV calling. Computational approach for joint deletion calling Deletions can manifest themselves in the reference alignment of short-read sequences as local drops in read depth, aberrations in the distance between the alignment of two reads in a pair, and split-aligned reads 30 . To detect deletions, PopDel focuses on local changes in the read pair alignment distance compared to the genome-wide distribution of read pair alignment distances. Split-aligned reads are used to infer a precise start position of detected deletions and read depth is used implicitly during genotyping. To achieve scalability to very large numbers of individuals, PopDel has two steps: a profiling step, which reduces the aligned input sequencing read data per individual into a small read pair profile, followed by a joint calling step, which takes as input the read pair profiles and outputs deletion calls with genotypes across all individuals (Fig. 1 ; see “Methods”). While the two individual steps are novel, the enclosing two-step design is reminiscent of joint calling of small variants in the GATK HaplotypeCaller 21 and copy-number variant calling approaches that are based on read depth profiles 31 , 32 . Read pair profiles contain the sequencing experiment’s distribution of read pair distances as well as", "role": "user" }, { "content": "The human genome contains roughly three million letters and is distributed over 46 chromosomes. Yet the genetic variation from person to person is very small: the genome sequences of any two people differ from each other by about one in every 1,000 letters. Sometimes single letters are exchanged in the genome, while other times whole sections are moved around. \"Many of these differences go unnoticed, because they do not affect the structure of the proteins encoded in the genome and do not cause any diseases,\" says Birte Kehr, a junior group leader at the Berlin Institute of Health (BIH) who was recently appointed professor at the Regensburg Center for Interventional Immunology (RCI). The bioinformatician is working on so-called structural variants, in which larger segments of the genome are deleted, duplicated or even swapped between chromosomes. The researchers have now published their findings in the journal Nature Communications. Large structural changes have a big impact \"Large structural changes are much rarer than changes in single letters,\" Kehr explains, \"but they often have a bigger impact and are also harder to detect.\" To learn more about these bigger changes, it is helpful to use large databases to search for them. That's where the collaboration with the Icelandic company deCODE Genetics came in, whose database contains some 50,000 human genome sequences and where Kehr formerly worked as a postdoc. \"We always planned to search for deletions in the data, but we didn't have a program capable of reliably and quickly processing such huge amounts of data.\" When Kehr joined the BIH in Berlin, she gave this task to her first Ph.D. student, Sebastian Niehus. Data is valuable only if it is used The programs previously available for identifying structural variants such as deletions could only process data from a few individuals at a time. For large data sets, such as those in the deCODE genome database, the results then had to be combined, which was a cumbersome and error-prone process. \"We first wanted to develop a statistical model that would enable us to evaluate information from all genomes simultaneously,\" Niehus reports. \"To do this, the program had to be designed so that a computer could quickly sift through huge quantities of data. We also had to compress the files to 1 to 2 percent of their original size to be able to work with them at all.\" Faster and more accurate than other software Once a prototype was developed, the PopDel program had to prove itself against other programs in various scenarios. These included simulated sequence data from up to 1,000 \"individuals\"; sequence data from 49 parent-child trios, which allowed a thorough analysis of whether inheritance patterns were reconstructed correctly; sequence data from 150 individuals of different ethnicities, which made it possible to evaluate population structures; and finally the approximately 50,000 genomes from the Icelandic cooperation partner deCODE Genetics. \"We were able to show that PopDel produced good results in a quick, reliable and resource-efficient way, both with data from a single person and with data from the largest cohorts,\" Niehus reports with pride. Kehr adds: \"PopDel only needed two days to analyze the genomes of 150 individuals where other programs had taken four weeks. And PopDel's results were better.\" Rare gene variant discovered The highlight for the researchers was the discovery of a rare, previously unknown gene variant in only one family out of the 50,000 Icelanders analyzed. \"The gene for the LDL receptor showed a larger deletion, or gap, in these family members. This was coupled with very low levels of cholesterol in these individuals,\" explains Kehr. Her collaborators at deCODE Genetics have since been able to show that the change in the LDL receptor gene is indeed responsible for the low cholesterol levels in affected individuals. \"One affected individual died at the age of 85, while six other affected individuals aged 35 to 65 are all very healthy with their low cholesterol levels,\" says Kehr. \"The results are therefore also very interesting from a medical point of view, because we seem to have discovered a genetic variant that contributes to healthy lipid metabolism.\" In the next step, the researchers want to develop the program further. They are continuing to work on it themselves, but have also deposited PopDel's source code on an open server so that anyone can view, use and improve it. \"PopDel can so far only detect deleted DNA segments, but there are also genetic variants where segments have been duplicated, inverted or translocated. We would now like to find all of them with PopDel as well,\" says Niehus, looking to the future. And Kehr hopes that, in the long run, the findings will lead to the development of new therapies and treatment approaches—in keeping with BIH's motto of \"Turning Research into Health.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Thousands of genomic structural variants (SVs) segregate in the human population and can impact phenotypic traits and diseases. Their identification in whole-genome sequence data of large cohorts is a major computational challenge. Most current approaches identify SVs in single genomes and afterwards merge the identified variants into a joint call set across many genomes. We describe the approach PopDel, which directly identifies deletions of about 500 to at least 10,000 bp in length in data of many genomes jointly, eliminating the need for subsequent variant merging. PopDel scales to tens of thousands of genomes as we demonstrate in evaluations on up to 49,962 genomes. We show that PopDel reliably reports common, rare and de novo deletions. On genomes with available high-confidence reference call sets PopDel shows excellent recall and precision. Genotype inheritance patterns in up to 6794 trios indicate that genotypes predicted by PopDel are more reliable than those of previous SV callers. Furthermore, PopDel’s running time is competitive with the fastest tested previous tools. The demonstrated scalability and accuracy of PopDel enables routine scans for deletions in large-scale sequencing studies. Introduction Comprehensive and reliable collections of genetic variation are a foundation for research on human diversity and disease 1 . They facilitate a wide range of studies investigating mutation rates 2 , 3 , 4 , mutational mechanisms 5 , 6 , 7 , functional consequences of variants 8 , 9 , 10 , ancestry relationships 11 , disease risks 12 , or treatment options 13 . Due to increased throughput and decreased cost, whole-genome sequencing is now performed on cohorts of thousands of individuals, for example, sequencing at the population level in Iceland 14 , the United Kingdom 15 , or Crete 16 , as well as sequencing of large cohorts for specific diseases, such as autism 17 or asthma 18 , and in the general health research context in projects like GnomAD 19 or TopMed 20 . To create meaningful collections of genetic variation, the data from these large numbers of individuals need to be integrated. The most direct way of achieving this is done in joint variant calling approaches: detecting variant positions and inferring variant genotypes from data of many individuals together. For single-nucleotide variants (SNVs) and small insertions/deletions (indels), joint calling has become the state of the art with tools that scale to tens of thousands of individuals 21 , 22 . For structural variants (SVs), the analysis of increasingly large numbers of individuals remains a major bioinformatic challenge 23 . Jointly detecting SVs in up to hundreds of individuals is a great achievement of previous projects and tools 24 , 25 . However, for larger cohorts, catalogs of SVs are generally created in a multistep approach by first analyzing the data of each individual separately or in small subsets of individuals, subsequently merging the resulting call sets and, finally, determining genotypes for all individuals on the merged call set 26 , 27 . Merging of SV call sets across individuals is often problematic and arbitrary when the same SV is detected with shifted positions in several individuals 28 , 29 . In addition, variants that are only weakly supported by the data may not be discovered using this multistep approach. Furthermore, the aligned read data is accessed at least twice in the process, for detecting and for genotyping SVs, requiring substantial computational resources. A joint SV detection approach simplifies the calling process, is computationally more efficient if accessing the large amounts of input data only once, eliminates the need for an error-prone variant merging step, and may reveal weakly supported variants if carried by several individuals as the support can be accumulated across individuals. In this work, we overcome these limitations of current SV callers by introducing a joint calling approach, PopDel, for deletions of a few hundred up to tens of thousands of base pairs (bp) in length. We specifically designed the approach to scale to large cohorts and demonstrate that it jointly discovers SVs across tens of thousands of individuals, thereby directly creating joint call sets. Nevertheless, it can also be applied to a single genome or small numbers of genomes, where it achieves comparable or even better accuracy than widely used deletion callers. We demonstrate the high accuracy on simulated data, public benchmark data from the Genome-in-a-Bottle (GIAB) consortium, and on data of parent-child trios, which allows us to validate predicted genotypes using the genetic laws of inheritance. Our results demonstrate that the joint deletion detection approach can yield reliable call sets across very many genomes. Results Our main result is a computational approach that can detect and genotype deletions in tens of thousands of genomes jointly. We have implemented the approach in the tool PopDel and evaluate PopDel’s performance in comparison to previous popular tools for SV calling. Computational approach for joint deletion calling Deletions can manifest themselves in the reference alignment of short-read sequences as local drops in read depth, aberrations in the distance between the alignment of two reads in a pair, and split-aligned reads 30 . To detect deletions, PopDel focuses on local changes in the read pair alignment distance compared to the genome-wide distribution of read pair alignment distances. Split-aligned reads are used to infer a precise start position of detected deletions and read depth is used implicitly during genotyping. To achieve scalability to very large numbers of individuals, PopDel has two steps: a profiling step, which reduces the aligned input sequencing read data per individual into a small read pair profile, followed by a joint calling step, which takes as input the read pair profiles and outputs deletion calls with genotypes across all individuals (Fig. 1 ; see “Methods”). While the two individual steps are novel, the enclosing two-step design is reminiscent of joint calling of small variants in the GATK HaplotypeCaller 21 and copy-number variant calling approaches that are based on read depth profiles 31 , 32 . Read pair profiles contain the sequencing experiment’s distribution of read pair distances as well as<|im_end|> <|im_start|>assistant The human genome contains roughly three million letters and is distributed over 46 chromosomes. Yet the genetic variation from person to person is very small: the genome sequences of any two people differ from each other by about one in every 1,000 letters. Sometimes single letters are exchanged in the genome, while other times whole sections are moved around. "Many of these differences go unnoticed, because they do not affect the structure of the proteins encoded in the genome and do not cause any diseases," says Birte Kehr, a junior group leader at the Berlin Institute of Health (BIH) who was recently appointed professor at the Regensburg Center for Interventional Immunology (RCI). The bioinformatician is working on so-called structural variants, in which larger segments of the genome are deleted, duplicated or even swapped between chromosomes. The researchers have now published their findings in the journal Nature Communications. Large structural changes have a big impact "Large structural changes are much rarer than changes in single letters," Kehr explains, "but they often have a bigger impact and are also harder to detect." To learn more about these bigger changes, it is helpful to use large databases to search for them. That's where the collaboration with the Icelandic company deCODE Genetics came in, whose database contains some 50,000 human genome sequences and where Kehr formerly worked as a postdoc. "We always planned to search for deletions in the data, but we didn't have a program capable of reliably and quickly processing such huge amounts of data." When Kehr joined the BIH in Berlin, she gave this task to her first Ph.D. student, Sebastian Niehus. Data is valuable only if it is used The programs previously available for identifying structural variants such as deletions could only process data from a few individuals at a time. For large data sets, such as those in the deCODE genome database, the results then had to be combined, which was a cumbersome and error-prone process. "We first wanted to develop a statistical model that would enable us to evaluate information from all genomes simultaneously," Niehus reports. "To do this, the program had to be designed so that a computer could quickly sift through huge quantities of data. We also had to compress the files to 1 to 2 percent of their original size to be able to work with them at all." Faster and more accurate than other software Once a prototype was developed, the PopDel program had to prove itself against other programs in various scenarios. These included simulated sequence data from up to 1,000 "individuals"; sequence data from 49 parent-child trios, which allowed a thorough analysis of whether inheritance patterns were reconstructed correctly; sequence data from 150 individuals of different ethnicities, which made it possible to evaluate population structures; and finally the approximately 50,000 genomes from the Icelandic cooperation partner deCODE Genetics. "We were able to show that PopDel produced good results in a quick, reliable and resource-efficient way, both with data from a single person and with data from the largest cohorts," Niehus reports with pride. Kehr adds: "PopDel only needed two days to analyze the genomes of 150 individuals where other programs had taken four weeks. And PopDel's results were better." Rare gene variant discovered The highlight for the researchers was the discovery of a rare, previously unknown gene variant in only one family out of the 50,000 Icelanders analyzed. "The gene for the LDL receptor showed a larger deletion, or gap, in these family members. This was coupled with very low levels of cholesterol in these individuals," explains Kehr. Her collaborators at deCODE Genetics have since been able to show that the change in the LDL receptor gene is indeed responsible for the low cholesterol levels in affected individuals. "One affected individual died at the age of 85, while six other affected individuals aged 35 to 65 are all very healthy with their low cholesterol levels," says Kehr. "The results are therefore also very interesting from a medical point of view, because we seem to have discovered a genetic variant that contributes to healthy lipid metabolism." In the next step, the researchers want to develop the program further. They are continuing to work on it themselves, but have also deposited PopDel's source code on an open server so that anyone can view, use and improve it. "PopDel can so far only detect deleted DNA segments, but there are also genetic variants where segments have been duplicated, inverted or translocated. We would now like to find all of them with PopDel as well," says Niehus, looking to the future. And Kehr hopes that, in the long run, the findings will lead to the development of new therapies and treatment approaches—in keeping with BIH's motto of "Turning Research into Health." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Autism spectrum disorder (ASD) is thought to emerge during early cortical development. However, the exact developmental stages and associated molecular networks that prime disease propensity are elusive. To profile early neurodevelopmental alterations in ASD with macrocephaly, we monitored subject-derived induced pluripotent stem cells (iPSCs) throughout the recapitulation of cortical development. Our analysis revealed ASD-associated changes in the maturational sequence of early neuron development, involving temporal dysregulation of specific gene networks and morphological growth acceleration. The observed changes tracked back to a pathologically primed stage in neural stem cells (NSCs), reflected by altered chromatin accessibility. Concerted over-representation of network factors in control NSCs was sufficient to trigger ASD-like features, and circumventing the NSC stage by direct conversion of ASD iPSCs into induced neurons abolished ASD-associated phenotypes. Our findings identify heterochronic dynamics of a gene network that, while established earlier in development, contributes to subsequent neurodevelopmental aberrations in ASD. Main Autism spectrum disorder is a highly heritable neurodevelopmental condition defined by deficits in social interaction and communication accompanied by restrictive, repetitive behaviors. Considerable genetic and phenotypic heterogeneity has complicated the efforts to find common biological substrates of the syndrome. Meanwhile, recent advances in systems biology approaches have caused a paradigm shift in the field of biomedical sciences from a single-gene causation model to pathway perturbation models 1 , 2 . Implementing high-confidence risk variants discovered in ASD cohorts into a data-driven framework of gene network analysis revealed a convergence on molecular processes that implicate specific perturbations during human fetal cortical development 3 , 4 . One complication is that many of the genes identified are involved at multiple time points and in different neural cell types, such as neural stem cells (NSCs), as well as in maturing neurons during human cortical development. Thus, a major challenge in the field is to determine the critical developmental periods, their associated cellular states and the molecular networks that might provide a basis for the emergence of common pathological phenotypes during ASD development. Here we have performed a time series analysis to follow human idiopathic ASD subject-specific iPSCs during their early neuronal development to examine when and how the earliest ASD-specific molecular abnormalities and phenotypes arise. Time series transcriptome and cellular phenotype analyses in ASD NSCs and their progeny identified dysregulation of specific transcriptional networks that caused aberrant neuronal maturation of ASD cortical neurons. Temporal reconstruction and network-based screening revealed that coherent neurodevelopmental gene modules were accelerated in ASD and appeared to be enriched with several ASD risk genes. Surprisingly, we found that dysregulation of these modules arose even before the neuronal stage, as module-specific signatures were already present during the NSC stage. Genome-wide comparisons of chromatin accessibility revealed a prevalent pathologically primed state in ASD NSCs that precedes the occurrence of aberrant gene network dynamics at the consecutive neuronal stage. Concerted transgenic expression of subsets of module genes was used to mimic ASD-associated gene network-related changes in healthy controls, and was sufficient to recapitulate the occurrence of aberrant neurodevelopmental growth trajectories at the subsequent neuronal stage. We further demonstrated that skipping the NSC stage by direct iPSC-to-neuron conversion (iPSC-iN) also circumvented the critical period for the ASD signature to establish itself, thereby preventing neuronal ASD phenotypes from manifesting. Our study provides a thorough temporal analysis of the neurodevelopmental regulatory gene networks that become impaired in ASD, and shows that some of these changes are triggered during early developmental periods. Results Time series-based transcriptome analysis All iPSC lines used in this study were obtained from a cohort of eight idiopathic ASD subjects with early developmental brain overgrowth, and five unaffected individuals as controls. Children with such signs of early brain enlargement have been shown to be part of a group of subjects with a high probability of receiving diagnosis 5 , 6 , 7 , 8 . Primary skin fibroblasts were harvested and reprogrammed to iPSCs using retroviral vectors expressing the four Yamanaka factors 9 (Supplementary Fig. 1a and Supplementary Table 1 ). Our previous study showed that neuronal cultures derived from these subjects bear an impaired neuronal network connectivity at later, more mature, neuronal stages. Other iPSC studies have also reported aberrant features of neuronal connectivity as a phenotypic hallmark for various forms of autism 9 , 10 , 11 . However, whether dynamic neurodevelopmental aberrations exist that precede the appearance of such advanced phenotypic disease states remains unresolved. Integrative bioinformatics approaches suggest that ASD pathologies may arise from combined deficiencies during distinct phases of human cortical development 3 , 4 . To model these early periods, we differentiated the iPSCs into NSCs and then further into functional excitatory MAP2 + neurons (Supplementary Fig. 1b–d ) using a reported protocol 9 , 12 . All subject-derived cells adopted a cortical fate (Supplementary Figs. 1e–h and 2a,b ), and global transcriptional comparison to the BrainSpan dataset 13 revealed high correspondence to the dorsal telencephalon (cerebral cortex with dorsolateral, medial and orbitofrontal cortical areas) during early human fetal cortical development (Supplementary Fig. 2c–e ). Furthermore, continuous electrophysiological recordings showed a consecutive transition through stages of functional maturation, including the firing of multiple evoked action potentials after 22 days of differentiation (Supplementary Fig. 2f ). One major aim of this study was to model the temporal dimension of shifting biological processes by treating the disorder as an evolving, dynamic system. We reasoned that a tight recapitulation of the consecutive developmental stages of early neuronal development in ASD and control cases would allow us to reconstruct time-related maturational processes. We first used fluorescence-activated cell sorting (FACS) to purify a homogeneous population of NSCs based on the expression of the cell-surface markers CD184 + /CD271 − /CD44 − /CD24 − /CD15 + (ref. 14 ). To trace ASD and control neurons over time, we performed a series of retroviral lineage-tracing experiments to isolate the progenies of dividing NSCs using a retroviral vector expressing a membrane-tagged enhanced green fluorescent protein (eGFP) (CAG::LckN-eGFP). Because differentiating neurons express PSA-NCAM on the cell surface (Supplementary Fig. 3a,b ), we established a FACS-based protocol", "role": "user" }, { "content": "Autism spectrum disorder (ASD) is a relatively common developmental disorder of communication and behavior that affects about 1 in 59 children in the US, according to the Centers for Disease Control and Prevention. Despite its prevalence, it is still unclear what causes the disease and what are the best ways to treat it. Researchers at the Salk Institute compared stem cells created from individuals with ASD against stem cells created from those without ASD to uncover, for the first time, measurable differences in the patterns and speed of development in the ASD-derived cells. The findings, published January 7, 2019, in the journal Nature Neuroscience, could lead to diagnostic methods to detect ASD at an early stage, when preventive interventions could potentially take place. \"Although our work only examined cells in cultures, it may help us understand how early changes in gene expression could lead to altered brain development in individuals with ASD,\" says Salk Professor Rusty Gage, the study's senior author and president of the Institute. \"We hope that this work will open up new ways to study neuropsychiatric and neurodevelopmental disorders.\" For the study, the researchers took skin cells from eight people with ASD and five people without ASD and turned them into pluripotent stem cells—cells that have the ability to develop into any cell type. They then coaxed the stem cells to develop along the path of becoming neurons by exposing them to certain chemical factors. By using molecular \"snapshots\" from different developmental stages in the stem cells, the team was able to track genetic programs that switched on in a certain order as the stem cells developed into neurons. This revealed key differences in the cells derived from people with ASD. For instance, the Salk team observed that the genetic program associated with the neural stem-cell stage turned on earlier in the ASD cells than it did in the cells from those without ASD. This genetic program includes many genes that have been associated with higher chances of ASD. In addition, the neurons that eventually developed from the people with ASD grew faster and had more complex branches than those from the control group. \"It's currently hypothesized that abnormalities in early brain development lead to autism, but the transition from a normally developing brain to an ASD diagnosis is blurred,\" says first author Simon Schafer, a postdoctoral fellow in the Gage lab. \"A major challenge in the field has been to determine the critical developmental periods and their associated cellular states. This research could provide a basis for discovering the common pathological traits that emerge during ASD development.\" \"This is a very exciting finding, and it encourages us to further refine our methodological framework to help advance our understanding of the early cell biological events that precede the onset of symptoms,\" adds Gage, who holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease. \"Studying system dynamics could maximize our chance of capturing relevant mechanistic disease states.\" The researchers say the experiments in this study will lead to more dynamic approaches for studying the mechanisms that are involved in ASD predisposition and progression. They next plan to focus on the creation of brain organoids, three-dimensional models of brain development in a dish that enable scientists to study the interactions between different types of brain cells. \"The current diagnostic methods are mostly subjective and occur after the emergence of behavioral abnormalities in young children,\" Schafer says. \"We hope these studies will serve as a framework for developing novel approaches for diagnosis during an early period of child development—long before behavioral symptoms manifest—to have the maximum impact on treatment and intervention.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Autism spectrum disorder (ASD) is thought to emerge during early cortical development. However, the exact developmental stages and associated molecular networks that prime disease propensity are elusive. To profile early neurodevelopmental alterations in ASD with macrocephaly, we monitored subject-derived induced pluripotent stem cells (iPSCs) throughout the recapitulation of cortical development. Our analysis revealed ASD-associated changes in the maturational sequence of early neuron development, involving temporal dysregulation of specific gene networks and morphological growth acceleration. The observed changes tracked back to a pathologically primed stage in neural stem cells (NSCs), reflected by altered chromatin accessibility. Concerted over-representation of network factors in control NSCs was sufficient to trigger ASD-like features, and circumventing the NSC stage by direct conversion of ASD iPSCs into induced neurons abolished ASD-associated phenotypes. Our findings identify heterochronic dynamics of a gene network that, while established earlier in development, contributes to subsequent neurodevelopmental aberrations in ASD. Main Autism spectrum disorder is a highly heritable neurodevelopmental condition defined by deficits in social interaction and communication accompanied by restrictive, repetitive behaviors. Considerable genetic and phenotypic heterogeneity has complicated the efforts to find common biological substrates of the syndrome. Meanwhile, recent advances in systems biology approaches have caused a paradigm shift in the field of biomedical sciences from a single-gene causation model to pathway perturbation models 1 , 2 . Implementing high-confidence risk variants discovered in ASD cohorts into a data-driven framework of gene network analysis revealed a convergence on molecular processes that implicate specific perturbations during human fetal cortical development 3 , 4 . One complication is that many of the genes identified are involved at multiple time points and in different neural cell types, such as neural stem cells (NSCs), as well as in maturing neurons during human cortical development. Thus, a major challenge in the field is to determine the critical developmental periods, their associated cellular states and the molecular networks that might provide a basis for the emergence of common pathological phenotypes during ASD development. Here we have performed a time series analysis to follow human idiopathic ASD subject-specific iPSCs during their early neuronal development to examine when and how the earliest ASD-specific molecular abnormalities and phenotypes arise. Time series transcriptome and cellular phenotype analyses in ASD NSCs and their progeny identified dysregulation of specific transcriptional networks that caused aberrant neuronal maturation of ASD cortical neurons. Temporal reconstruction and network-based screening revealed that coherent neurodevelopmental gene modules were accelerated in ASD and appeared to be enriched with several ASD risk genes. Surprisingly, we found that dysregulation of these modules arose even before the neuronal stage, as module-specific signatures were already present during the NSC stage. Genome-wide comparisons of chromatin accessibility revealed a prevalent pathologically primed state in ASD NSCs that precedes the occurrence of aberrant gene network dynamics at the consecutive neuronal stage. Concerted transgenic expression of subsets of module genes was used to mimic ASD-associated gene network-related changes in healthy controls, and was sufficient to recapitulate the occurrence of aberrant neurodevelopmental growth trajectories at the subsequent neuronal stage. We further demonstrated that skipping the NSC stage by direct iPSC-to-neuron conversion (iPSC-iN) also circumvented the critical period for the ASD signature to establish itself, thereby preventing neuronal ASD phenotypes from manifesting. Our study provides a thorough temporal analysis of the neurodevelopmental regulatory gene networks that become impaired in ASD, and shows that some of these changes are triggered during early developmental periods. Results Time series-based transcriptome analysis All iPSC lines used in this study were obtained from a cohort of eight idiopathic ASD subjects with early developmental brain overgrowth, and five unaffected individuals as controls. Children with such signs of early brain enlargement have been shown to be part of a group of subjects with a high probability of receiving diagnosis 5 , 6 , 7 , 8 . Primary skin fibroblasts were harvested and reprogrammed to iPSCs using retroviral vectors expressing the four Yamanaka factors 9 (Supplementary Fig. 1a and Supplementary Table 1 ). Our previous study showed that neuronal cultures derived from these subjects bear an impaired neuronal network connectivity at later, more mature, neuronal stages. Other iPSC studies have also reported aberrant features of neuronal connectivity as a phenotypic hallmark for various forms of autism 9 , 10 , 11 . However, whether dynamic neurodevelopmental aberrations exist that precede the appearance of such advanced phenotypic disease states remains unresolved. Integrative bioinformatics approaches suggest that ASD pathologies may arise from combined deficiencies during distinct phases of human cortical development 3 , 4 . To model these early periods, we differentiated the iPSCs into NSCs and then further into functional excitatory MAP2 + neurons (Supplementary Fig. 1b–d ) using a reported protocol 9 , 12 . All subject-derived cells adopted a cortical fate (Supplementary Figs. 1e–h and 2a,b ), and global transcriptional comparison to the BrainSpan dataset 13 revealed high correspondence to the dorsal telencephalon (cerebral cortex with dorsolateral, medial and orbitofrontal cortical areas) during early human fetal cortical development (Supplementary Fig. 2c–e ). Furthermore, continuous electrophysiological recordings showed a consecutive transition through stages of functional maturation, including the firing of multiple evoked action potentials after 22 days of differentiation (Supplementary Fig. 2f ). One major aim of this study was to model the temporal dimension of shifting biological processes by treating the disorder as an evolving, dynamic system. We reasoned that a tight recapitulation of the consecutive developmental stages of early neuronal development in ASD and control cases would allow us to reconstruct time-related maturational processes. We first used fluorescence-activated cell sorting (FACS) to purify a homogeneous population of NSCs based on the expression of the cell-surface markers CD184 + /CD271 − /CD44 − /CD24 − /CD15 + (ref. 14 ). To trace ASD and control neurons over time, we performed a series of retroviral lineage-tracing experiments to isolate the progenies of dividing NSCs using a retroviral vector expressing a membrane-tagged enhanced green fluorescent protein (eGFP) (CAG::LckN-eGFP). Because differentiating neurons express PSA-NCAM on the cell surface (Supplementary Fig. 3a,b ), we established a FACS-based protocol<|im_end|> <|im_start|>assistant Autism spectrum disorder (ASD) is a relatively common developmental disorder of communication and behavior that affects about 1 in 59 children in the US, according to the Centers for Disease Control and Prevention. Despite its prevalence, it is still unclear what causes the disease and what are the best ways to treat it. Researchers at the Salk Institute compared stem cells created from individuals with ASD against stem cells created from those without ASD to uncover, for the first time, measurable differences in the patterns and speed of development in the ASD-derived cells. The findings, published January 7, 2019, in the journal Nature Neuroscience, could lead to diagnostic methods to detect ASD at an early stage, when preventive interventions could potentially take place. "Although our work only examined cells in cultures, it may help us understand how early changes in gene expression could lead to altered brain development in individuals with ASD," says Salk Professor Rusty Gage, the study's senior author and president of the Institute. "We hope that this work will open up new ways to study neuropsychiatric and neurodevelopmental disorders." For the study, the researchers took skin cells from eight people with ASD and five people without ASD and turned them into pluripotent stem cells—cells that have the ability to develop into any cell type. They then coaxed the stem cells to develop along the path of becoming neurons by exposing them to certain chemical factors. By using molecular "snapshots" from different developmental stages in the stem cells, the team was able to track genetic programs that switched on in a certain order as the stem cells developed into neurons. This revealed key differences in the cells derived from people with ASD. For instance, the Salk team observed that the genetic program associated with the neural stem-cell stage turned on earlier in the ASD cells than it did in the cells from those without ASD. This genetic program includes many genes that have been associated with higher chances of ASD. In addition, the neurons that eventually developed from the people with ASD grew faster and had more complex branches than those from the control group. "It's currently hypothesized that abnormalities in early brain development lead to autism, but the transition from a normally developing brain to an ASD diagnosis is blurred," says first author Simon Schafer, a postdoctoral fellow in the Gage lab. "A major challenge in the field has been to determine the critical developmental periods and their associated cellular states. This research could provide a basis for discovering the common pathological traits that emerge during ASD development." "This is a very exciting finding, and it encourages us to further refine our methodological framework to help advance our understanding of the early cell biological events that precede the onset of symptoms," adds Gage, who holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease. "Studying system dynamics could maximize our chance of capturing relevant mechanistic disease states." The researchers say the experiments in this study will lead to more dynamic approaches for studying the mechanisms that are involved in ASD predisposition and progression. They next plan to focus on the creation of brain organoids, three-dimensional models of brain development in a dish that enable scientists to study the interactions between different types of brain cells. "The current diagnostic methods are mostly subjective and occur after the emergence of behavioral abnormalities in young children," Schafer says. "We hope these studies will serve as a framework for developing novel approaches for diagnosis during an early period of child development—long before behavioral symptoms manifest—to have the maximum impact on treatment and intervention." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Human-human social touch improves mood and alleviates pain. No studies have so far tested the effect of human-robot emotional touch on experimentally induced pain ratings, on mood and on oxytocin levels in healthy young adults. Here, we assessed the effect of touching the robot PARO on pain perception, on mood and on salivary oxytocin levels, in 83 young adults. We measured their perceived pain, happiness state, and salivary oxytocin. For the 63 participants in the PARO group, pain was assessed in three conditions: Baseline, Touch (touching PARO) and No-Touch (PARO present). The control group (20 participants) underwent the same measurements without ever encountering PARO. There was a decrease in pain ratings and in oxytocin levels and an increase in happiness ratings compared to baseline only in the PARO group. The Touch condition yielded a larger decrease in pain ratings compared to No-Touch. These effects correlated with the participants’ positive perceptions of the interaction with PARO. Participants with higher perceived ability to communicate with PARO experienced a greater hypoalgesic effect when touching PARO. We show that human-robot social touch is effective in reducing pain ratings, improving mood and - surprisingly - reducing salivary oxytocin levels in adults. Introduction Social interaction is one of the most basic survival needs of humans 1 . Both in childhood 2 , 3 , 4 , 5 and in older ages 6 , 7 , 8 , the impact of social connections on health seems to be crucial. For example, poor social relationships and social isolation were associated with high incidence of general morbidity 9 , 10 , stress disorders 11 , 12 and chronic pain 11 , 13 , 14 . Close relationships, however, were found to be a protective factor against stress and pain disorders 15 , 16 , 17 , 18 . Close interpersonal relationships often involve emotional touch, which may act as a mediating factor in the effect of social relationships on pain relief. Emotional touch is defined as a pleasant touch between two humans 19 . Emotional touch may include active touching (i.e. stroking another person), passive touching (being touched by another person) or dyadic touching (i.e. hand holding) 20 , 21 . Indeed, several studies have found that handholding 22 and hugging 23 reduce the physiological and psychological response to stress among men and women. It was suggested that empathic abilities of both the person touching and the person touched play a fundamental role in this effect 24 . Emotional touch also stimulates the hypothalamic-pituitary system to secrete oxytocin 20 , 25 , a hormone that has been characterized as having a central role in mediating feelings of love, social attachment and communication in both animals and humans 26 , 27 , 28 , 29 . In an animal study, there was an increase in pain thresholds following petting, as well as following injection of oxytocin. In both situations (petting or injection of oxytocin), the effect on the pain threshold disappeared with the administration of an oxytocin antagonist 30 . Similarly, in humans, Kreuder et al . 31 , recently demonstrated that administration of nasal oxytocin enhances the pain-relieving effects of social support in romantic couples. In addition, it was found that being touched by another person 32 and handholding with a spouse 33 , 34 induce a reduction in pain ratings among women. The level of the analgesic effect when holding a partner’s hand was associated with the toucher’s empathic tendencies 33 . These studies suggest that emotional touch may lead to decreased sensitivity to pain that may be associated with the release of oxytocin. How, then, can the beneficial effect of emotional touch on the perception of pain be provided to individuals who do not have access to it? One way to fill this need may be through a social robot. A social robot may take on a human-like 35 , 36 or a pet-like appearance, or move like one e.g 37 , 38 .. It is designed to create social relationships with people 39 for either entertainment 40 , education 41 , or for therapeutic purposes 42 , 43 . Shibata 44 developed a seal-like robot named PARO designed to elicit a feeling of social connection. Interaction with PARO was found to improve mood 45 , 46 , and to reduce stress and anxiety of older people, and of individuals with dementia 45 , 46 , 47 , as well as to improve the mood of pediatric patients 48 . In one study, participants interacted with PARO for the duration of one year, during which the effects on mood were maintained 46 . In addition, interaction with PARO 49 and with a humanoid robot 50 was found to reduce stress, anxiety and pain levels during medical procedures (chemotherapy among women and vaccination among children, respectively). However, a recent review concluded that better methodology and measures are needed to draw conclusions about the effect of human-robot social interactions on pain 51 . Indeed, no controlled studies specifically examined the effect of the robot’s touch as opposed to the robot’s presence , without any physical contact, on the perception of pain. In addition, no controlled studies have examined the effect of human-robot social interaction on either oxytocin secretion or on experimentally induced pain ratings. The aim of the current experiment was, therefore, to examine the effect of interaction with the social robot PARO on pain perception, emotional state, and salivary oxytocin levels. Specifically, we examined, in a group of men and women: (1) What is the effect of human-robot interaction on the (a) happiness state, (b) salivary oxytocin levels and (c) pain perception? (2) What is the effect of social robot’s touch vs. the social robot’s presence on pain perception? (3) Are there correlations between pain perception and (a) the level of salivary oxytocin; and (b) the participant’s perception of the interaction with the robot? Methods Participants Eighty-three healthy adults (42 female, 41 male; age: 25.1 ± 2.7 years old (mean ± STD)) were allocated using a computer-generated", "role": "user" }, { "content": "Could furry social robots help bolster moods and reduce pain when human to human contact isn't an option, for example, during a pandemic? According to a new study by Ben-Gurion University of the Negev (BGU) researchers published in Scientific Reports, a one-time, hour-long session with a plush, seal-like social robot reduced pain and oxytocin levels, and increased happiness. The Japanese social robot, PARO, emits seal-like sounds and moves its head and flippers in response to being spoken to and touched. Human-to-human contact has been found to bolster mood and reduce pain in previous studies. Dr. Shelly Levy-Tzedek of the BGU Department of Physical Therapy and her team investigated whether a furry social robot could induce similar effects when normal human-to-human contact is not available. Levy-Tzedek and her team discovered that a single, 60-minute interaction with PARO actually improved mood as well as reduced mild or severe pain. When participants touched PARO, they experienced greater pain reduction than when it was simply present in their room. Surprisingly, the BGU researchers discovered lower oxytocin levels in those who interacted with PARO than in the control group participants, who did not meet PARO. Typically, oxytocin, sometimes called \"the love homone,\" is elevated among romantic partners or mothers playing with their children, so a lower level of oxytocin wasn't expected. However, more recent studies have shown that outside of close relationships, oxytocin production is a stress indicator and therefore, a reduction could indicate relaxation. \"These findings offer new strategies for pain management and for improving well-being, which are particularly needed at this time, when social distancing is a crucial factor in public health,\" says Dr. Levy-Tzedek. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Human-human social touch improves mood and alleviates pain. No studies have so far tested the effect of human-robot emotional touch on experimentally induced pain ratings, on mood and on oxytocin levels in healthy young adults. Here, we assessed the effect of touching the robot PARO on pain perception, on mood and on salivary oxytocin levels, in 83 young adults. We measured their perceived pain, happiness state, and salivary oxytocin. For the 63 participants in the PARO group, pain was assessed in three conditions: Baseline, Touch (touching PARO) and No-Touch (PARO present). The control group (20 participants) underwent the same measurements without ever encountering PARO. There was a decrease in pain ratings and in oxytocin levels and an increase in happiness ratings compared to baseline only in the PARO group. The Touch condition yielded a larger decrease in pain ratings compared to No-Touch. These effects correlated with the participants’ positive perceptions of the interaction with PARO. Participants with higher perceived ability to communicate with PARO experienced a greater hypoalgesic effect when touching PARO. We show that human-robot social touch is effective in reducing pain ratings, improving mood and - surprisingly - reducing salivary oxytocin levels in adults. Introduction Social interaction is one of the most basic survival needs of humans 1 . Both in childhood 2 , 3 , 4 , 5 and in older ages 6 , 7 , 8 , the impact of social connections on health seems to be crucial. For example, poor social relationships and social isolation were associated with high incidence of general morbidity 9 , 10 , stress disorders 11 , 12 and chronic pain 11 , 13 , 14 . Close relationships, however, were found to be a protective factor against stress and pain disorders 15 , 16 , 17 , 18 . Close interpersonal relationships often involve emotional touch, which may act as a mediating factor in the effect of social relationships on pain relief. Emotional touch is defined as a pleasant touch between two humans 19 . Emotional touch may include active touching (i.e. stroking another person), passive touching (being touched by another person) or dyadic touching (i.e. hand holding) 20 , 21 . Indeed, several studies have found that handholding 22 and hugging 23 reduce the physiological and psychological response to stress among men and women. It was suggested that empathic abilities of both the person touching and the person touched play a fundamental role in this effect 24 . Emotional touch also stimulates the hypothalamic-pituitary system to secrete oxytocin 20 , 25 , a hormone that has been characterized as having a central role in mediating feelings of love, social attachment and communication in both animals and humans 26 , 27 , 28 , 29 . In an animal study, there was an increase in pain thresholds following petting, as well as following injection of oxytocin. In both situations (petting or injection of oxytocin), the effect on the pain threshold disappeared with the administration of an oxytocin antagonist 30 . Similarly, in humans, Kreuder et al . 31 , recently demonstrated that administration of nasal oxytocin enhances the pain-relieving effects of social support in romantic couples. In addition, it was found that being touched by another person 32 and handholding with a spouse 33 , 34 induce a reduction in pain ratings among women. The level of the analgesic effect when holding a partner’s hand was associated with the toucher’s empathic tendencies 33 . These studies suggest that emotional touch may lead to decreased sensitivity to pain that may be associated with the release of oxytocin. How, then, can the beneficial effect of emotional touch on the perception of pain be provided to individuals who do not have access to it? One way to fill this need may be through a social robot. A social robot may take on a human-like 35 , 36 or a pet-like appearance, or move like one e.g 37 , 38 .. It is designed to create social relationships with people 39 for either entertainment 40 , education 41 , or for therapeutic purposes 42 , 43 . Shibata 44 developed a seal-like robot named PARO designed to elicit a feeling of social connection. Interaction with PARO was found to improve mood 45 , 46 , and to reduce stress and anxiety of older people, and of individuals with dementia 45 , 46 , 47 , as well as to improve the mood of pediatric patients 48 . In one study, participants interacted with PARO for the duration of one year, during which the effects on mood were maintained 46 . In addition, interaction with PARO 49 and with a humanoid robot 50 was found to reduce stress, anxiety and pain levels during medical procedures (chemotherapy among women and vaccination among children, respectively). However, a recent review concluded that better methodology and measures are needed to draw conclusions about the effect of human-robot social interactions on pain 51 . Indeed, no controlled studies specifically examined the effect of the robot’s touch as opposed to the robot’s presence , without any physical contact, on the perception of pain. In addition, no controlled studies have examined the effect of human-robot social interaction on either oxytocin secretion or on experimentally induced pain ratings. The aim of the current experiment was, therefore, to examine the effect of interaction with the social robot PARO on pain perception, emotional state, and salivary oxytocin levels. Specifically, we examined, in a group of men and women: (1) What is the effect of human-robot interaction on the (a) happiness state, (b) salivary oxytocin levels and (c) pain perception? (2) What is the effect of social robot’s touch vs. the social robot’s presence on pain perception? (3) Are there correlations between pain perception and (a) the level of salivary oxytocin; and (b) the participant’s perception of the interaction with the robot? Methods Participants Eighty-three healthy adults (42 female, 41 male; age: 25.1 ± 2.7 years old (mean ± STD)) were allocated using a computer-generated<|im_end|> <|im_start|>assistant Could furry social robots help bolster moods and reduce pain when human to human contact isn't an option, for example, during a pandemic? According to a new study by Ben-Gurion University of the Negev (BGU) researchers published in Scientific Reports, a one-time, hour-long session with a plush, seal-like social robot reduced pain and oxytocin levels, and increased happiness. The Japanese social robot, PARO, emits seal-like sounds and moves its head and flippers in response to being spoken to and touched. Human-to-human contact has been found to bolster mood and reduce pain in previous studies. Dr. Shelly Levy-Tzedek of the BGU Department of Physical Therapy and her team investigated whether a furry social robot could induce similar effects when normal human-to-human contact is not available. Levy-Tzedek and her team discovered that a single, 60-minute interaction with PARO actually improved mood as well as reduced mild or severe pain. When participants touched PARO, they experienced greater pain reduction than when it was simply present in their room. Surprisingly, the BGU researchers discovered lower oxytocin levels in those who interacted with PARO than in the control group participants, who did not meet PARO. Typically, oxytocin, sometimes called "the love homone," is elevated among romantic partners or mothers playing with their children, so a lower level of oxytocin wasn't expected. However, more recent studies have shown that outside of close relationships, oxytocin production is a stress indicator and therefore, a reduction could indicate relaxation. "These findings offer new strategies for pain management and for improving well-being, which are particularly needed at this time, when social distancing is a crucial factor in public health," says Dr. Levy-Tzedek. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that purinergic receptor P2X3 ( P2rx3 , also known as P2x3 ) mRNA expression is upregulated substantially in chemoreceptive petrosal sensory neurons in rats with hypertension. These neurons generate both tonic drive and hyperreflexia in hypertensive (but not normotensive) rats, and both phenomena are normalized by the blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduces arterial pressure and basal sympathetic activity and normalizes carotid body hyperreflexia in conscious rats with hypertension; no effect was observed in rats without hypertension. We verified P2X3 receptor expression in human carotid bodies and observed hyperactivity of carotid bodies in individuals with hypertension. These data support the identification of the P2X3 receptor as a potential new target for the control of human hypertension. Main One-third of the human population has hypertension. In the USA, despite the fact that 75% of individuals use antihypertensive medication, in only 53% ( ∼ 41 million) of those taking such medication is blood pressure controlled 1 . This low rate of control might, in part, reflect a serious problem with drug adherence, owing to the asymptomatic nature of hypertension and the poorly tolerated side effects of current medications. Substantial savings in healthcare costs would result if an individual's blood pressure could be reduced to <140/90 mmHg 2 . In adults over 40 years of age, there is clear evidence that a 10-mmHg rise in diastolic blood pressure (DBP) above normal levels (80 mmHg) doubles the risk of death from cardiovascular disease 3 . Furthermore, at least 8% of an estimated 900 million people with hypertension worldwide 4 have developed and currently experience drug resistance 5 , 6 . Categorically, there remains an unmet clinical need for ways to control blood pressure. The most recently introduced antihypertensive drug is aliskiren, a renin inhibitor released in 2007. This was the first new drug to emerge for hypertension in 13 years, yet its efficacy beyond the existing renin-angiotensin–aldosterone enzyme inhibitors and receptor blockers is questionable, and associated adverse effects call into question its long-term benefit–harm relationship 7 . The paucity of new pharmacological antihypertensive agents has led to a series of device-based interventional studies, including renal denervation 8 , stimulation of carotid baroreceptors 9 , deep brain stimulation 10 and arterial venous anastomosis 11 , 12 . Here we introduce a new mechanistic approach that uses a highly selective small-molecule antagonist, and we provide preclinical and clinical data to justify its use in a future clinical trial for hypertension. Currently, the carotid body is under consideration as a therapeutic target for cardiovascular disease. The carotid body chemoreflex-evoked sympathoexcitatory response is potentiated in both a preclinical model of hypertension—the spontaneously hypertensive (SH) rat—and in humans with hypertension 13 , 14 , 15 , 16 , 17 , 18 , and denervation of the carotid body is evidently an effective way to control both the development and maintenance of high blood pressure in the SH rat 19 , 20 . On the basis of these findings, we concluded that in conditions of hypertension, the carotid body chemoreceptors generate aberrant excitatory tone that drives up sympathetic activity and causes high blood pressure 14 , 21 . Indeed, we found that when this carotid body tone is switched off through hyperoxia or nerve section to disconnect the carotid body from the brain, arterial pressure and sympathetic activity are reduced in SH rats, but are unaffected in a normotensive rat strain 14 . In humans with hypertension, hyperoxia lowers sympathetic activity 18 , and carotid body resection can reduce arterial pressure substantially 22 . Thus, these animal and human data support the presence of aberrant carotid body discharge as contributing to hypertension. Although the mechanistic basis for the carotid body aberrant tone is unknown, it could be pivotal for refining new pharmacological antihypertensive approaches, as we propose here. A plethora of mechanisms governs carotid body signaling 23 , 24 , 25 , 26 , 27 . In our current investigation, we have studied the role of adenosine triphosphate (ATP)-gated ion channels (called purinergic P2X receptors), specifically the C-fiber-localized, P2X3-receptor subtypes, which are commonly associated with afferent sensitization and might contribute to hyperreflexic disease states in a variety of organs 28 , 29 . ATP is one of a number of transmitters involved in hypoxic signaling in the carotid body 30 , 31 , 32 , 33 , 34 , 35 . P2X3-receptor expression is present in both carotid bodies and petrosal ganglia neurons of normotensive rats 36 . Moreover, combined P2X2- and P2X3-subunit deletion in mice reduces the ventilatory response to hypoxia, as compared to wild types 37 . We hypothesized that the P2X3 receptor contributes to both peripheral chemo-hyperreflexia and aberrant discharge of the carotid body in hypertension, and that blockade of this receptor would cause an antihypertensive effect. To address this, we have tested the effects of highly selective P2X3-receptor antagonists on hypertension in rats and have demonstrated the applicability of these preclinical findings to humans with hypertension. Results Hyperactivity of carotid bodies in hypertensive rats We first tested whether the carotid body was more active in conditions of high blood pressure. We recorded carotid body afferent discharge from the carotid sinus nerve of the in situ preparation (an unanesthetized decerebrated rat on cardiopulmonary bypass). Sodium cyanide (NaCN), simulating hypoxia, was used to stimulate the peripheral chemoreflex response because this treatment provides a specific, quantifiable and temporally controlled stimulus that is repeatable over a course of hours. Both basal discharge and chemoreflex-evoked volleys (15–30 μg NaCN, intra-arterially (i.a.)) were elevated in rats with hypertension, as compared to those without hypertension (SH versus Wistar rats: basal, 24.9 ± 2 versus 1.4 ± 0.3 spikes/s, respectively, P < 0.001; chemoreflex, 62.3 ± 3 versus 28.3 ± 2", "role": "user" }, { "content": "Researchers at the University of Bristol and Afferent Pharmaceuticals have identified a potential new way of treating high blood pressure, or hypertension, by targeting aberrant nerve signals in the carotid bodies, which sit on the common carotid arteries on each side of the neck. The study, \"Purinergic receptors in the carotid body as a new drug target for controlling hypertension,\" was led by Julian Paton, professor of physiology at the University of Bristol, and published in the 5 September online edition of Nature Medicine. Instead of treating high blood pressure by targeting directly the functions within end organs, such as the heart, kidneys and vasculature, this novel approach aims to reduce nervous system activity from a sensory organ - the carotid body - which, when activated can cause blood pressure to rise uncontrollably. Such a treatment may offer superiority over existing medications, principally by lowering blood pressure directly at a common source. Beneficial outcomes may also extend to other cardiometabolic disorders, such as heart failure and sleep apnoea, in which the carotid bodies are known to be sensitised. In preclinical models, researchers were able to block this carotid body aberrant signaling activity with an investigational drug candidate, MK-7624 (also known as AF-219), demonstrating a significant reduction in blood pressure. \"With this research, we've validated P2X3 receptors as a novel drug target for the treatment of cardiovascular disease, by demonstrating that blockade of these receptors with a selective antagonist controls carotid body activity,\" said Dr Angus Nightingale, a cardiology consultant, who runs the specialist hypertensive clinic at the Bristol Heart Institute, and co-author of the study. \"The question now is whether blocking these P2X3 receptors in humans will lower elevated blood pressure, and how we can best identify those patients with carotid body hyperactivity who are most likely to respond to treatment.\" \"The carotid bodies lie at the bifurcation (fork) of the common carotid artery on each side of the neck and are the body's smallest organs, each about the size of a rice grain,\" said Professor Paton, who co-led the research with Dr Anthony Ford, founder and chief scientific officer of Afferent Pharmaceuticals. \"These organs sense chemicals such as oxygen in the blood. When oxygen levels fall, the carotid bodies become active and send signals to the brain that trigger increases in breathing and blood pressure.\" The researchers collaborated to test whether MK-7624/AF-219, a highly selective and potent orally available P2X3 receptor antagonist, can stop this nervous activity from occurring, thereby lowering blood pressure. \"In healthy individuals, the carotid bodies have very low levels of activity,\" said Professor Paton. \"We discovered that these tiny organs become hyperactive in conditions of hypertension, generating what we have called aberrant or tonic discharge, which is sent into the brain regions controlling cardiovascular activity. In this way, changes within the carotid body may be a cause of high blood pressure and therefore represent a novel target for controlling blood pressure.\" Previous research by Professor Paton and collaborators, published in The Journal of the American College of Cardiology, showed that removing one carotid body was effective in lowering blood pressure in human patients with drug-resistant hypertension. The next step was to find out why the carotid body can become hyperactive in hypertension, and to develop a pharmacological approach to normalise its activity. To carry out the research, the team utilised an established animal model of human hypertension. They discovered the energy molecule ATP (adenosine triphosphate), a recognized common signaling nucleotide, was able to persistently activate the P2X3 receptor, and that this protein was upregulated by almost 5 fold in the carotid body in hypertension. By blocking this receptor in the carotid body with MK-7264/AF-219, blood pressure fell significantly in hypertensive rats. \"Crucially, unlike carotid body removal, the drug did not render the carotid body inoperable,\" said Professor Paton. \"Instead, it normalized its activity levels to those found in a normotensive state. Think of it in terms of a domestic fire alarm – it switches off after the smoke disappears, but the battery remains in place, meaning it can still respond in an emergency.\" \"We have developed some unique tests to assess the activity state of the carotid body in human hypertensive patients,\" said Dr. Nightingale. \"We are hoping to initiate a clinical trial to test P2X3 receptor antagonism in hypertensive patients who exhibit hyperactive carotid bodies in the near future.\" High blood pressure is the world's leading contributor to mortality. In the UK, its cost to the National Health Service is around £2 billion per year, and it remains poorly controlled, triggering heart and renal failure, and strokes. The World Health Organization has identified high blood pressure as the single most important risk factor for the global burden of disease and death. \"This approach may be the first novel anti-hypertensive treatment strategy in more than 15 years, and perhaps the first directed at a root cause of excessive sympathetic discharge to cardiovascular end-organs,\" said Professor Paton. \"This research was translational from molecule to medicine, and reflects the critical importance of integrative physiology as a subject. Our study was an inter-disciplinary team effort, and would not have been possible without close working with colleagues from the University of Bristol, University Hospital Trust Bristol, the University of Sao Paulo, Brazil, the University of Auckland, New Zealand, and Afferent Pharmaceuticals. Nor would it have been possible without funding from The British Heart Foundation and Afferent Pharmaceuticals.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that purinergic receptor P2X3 ( P2rx3 , also known as P2x3 ) mRNA expression is upregulated substantially in chemoreceptive petrosal sensory neurons in rats with hypertension. These neurons generate both tonic drive and hyperreflexia in hypertensive (but not normotensive) rats, and both phenomena are normalized by the blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduces arterial pressure and basal sympathetic activity and normalizes carotid body hyperreflexia in conscious rats with hypertension; no effect was observed in rats without hypertension. We verified P2X3 receptor expression in human carotid bodies and observed hyperactivity of carotid bodies in individuals with hypertension. These data support the identification of the P2X3 receptor as a potential new target for the control of human hypertension. Main One-third of the human population has hypertension. In the USA, despite the fact that 75% of individuals use antihypertensive medication, in only 53% ( ∼ 41 million) of those taking such medication is blood pressure controlled 1 . This low rate of control might, in part, reflect a serious problem with drug adherence, owing to the asymptomatic nature of hypertension and the poorly tolerated side effects of current medications. Substantial savings in healthcare costs would result if an individual's blood pressure could be reduced to <140/90 mmHg 2 . In adults over 40 years of age, there is clear evidence that a 10-mmHg rise in diastolic blood pressure (DBP) above normal levels (80 mmHg) doubles the risk of death from cardiovascular disease 3 . Furthermore, at least 8% of an estimated 900 million people with hypertension worldwide 4 have developed and currently experience drug resistance 5 , 6 . Categorically, there remains an unmet clinical need for ways to control blood pressure. The most recently introduced antihypertensive drug is aliskiren, a renin inhibitor released in 2007. This was the first new drug to emerge for hypertension in 13 years, yet its efficacy beyond the existing renin-angiotensin–aldosterone enzyme inhibitors and receptor blockers is questionable, and associated adverse effects call into question its long-term benefit–harm relationship 7 . The paucity of new pharmacological antihypertensive agents has led to a series of device-based interventional studies, including renal denervation 8 , stimulation of carotid baroreceptors 9 , deep brain stimulation 10 and arterial venous anastomosis 11 , 12 . Here we introduce a new mechanistic approach that uses a highly selective small-molecule antagonist, and we provide preclinical and clinical data to justify its use in a future clinical trial for hypertension. Currently, the carotid body is under consideration as a therapeutic target for cardiovascular disease. The carotid body chemoreflex-evoked sympathoexcitatory response is potentiated in both a preclinical model of hypertension—the spontaneously hypertensive (SH) rat—and in humans with hypertension 13 , 14 , 15 , 16 , 17 , 18 , and denervation of the carotid body is evidently an effective way to control both the development and maintenance of high blood pressure in the SH rat 19 , 20 . On the basis of these findings, we concluded that in conditions of hypertension, the carotid body chemoreceptors generate aberrant excitatory tone that drives up sympathetic activity and causes high blood pressure 14 , 21 . Indeed, we found that when this carotid body tone is switched off through hyperoxia or nerve section to disconnect the carotid body from the brain, arterial pressure and sympathetic activity are reduced in SH rats, but are unaffected in a normotensive rat strain 14 . In humans with hypertension, hyperoxia lowers sympathetic activity 18 , and carotid body resection can reduce arterial pressure substantially 22 . Thus, these animal and human data support the presence of aberrant carotid body discharge as contributing to hypertension. Although the mechanistic basis for the carotid body aberrant tone is unknown, it could be pivotal for refining new pharmacological antihypertensive approaches, as we propose here. A plethora of mechanisms governs carotid body signaling 23 , 24 , 25 , 26 , 27 . In our current investigation, we have studied the role of adenosine triphosphate (ATP)-gated ion channels (called purinergic P2X receptors), specifically the C-fiber-localized, P2X3-receptor subtypes, which are commonly associated with afferent sensitization and might contribute to hyperreflexic disease states in a variety of organs 28 , 29 . ATP is one of a number of transmitters involved in hypoxic signaling in the carotid body 30 , 31 , 32 , 33 , 34 , 35 . P2X3-receptor expression is present in both carotid bodies and petrosal ganglia neurons of normotensive rats 36 . Moreover, combined P2X2- and P2X3-subunit deletion in mice reduces the ventilatory response to hypoxia, as compared to wild types 37 . We hypothesized that the P2X3 receptor contributes to both peripheral chemo-hyperreflexia and aberrant discharge of the carotid body in hypertension, and that blockade of this receptor would cause an antihypertensive effect. To address this, we have tested the effects of highly selective P2X3-receptor antagonists on hypertension in rats and have demonstrated the applicability of these preclinical findings to humans with hypertension. Results Hyperactivity of carotid bodies in hypertensive rats We first tested whether the carotid body was more active in conditions of high blood pressure. We recorded carotid body afferent discharge from the carotid sinus nerve of the in situ preparation (an unanesthetized decerebrated rat on cardiopulmonary bypass). Sodium cyanide (NaCN), simulating hypoxia, was used to stimulate the peripheral chemoreflex response because this treatment provides a specific, quantifiable and temporally controlled stimulus that is repeatable over a course of hours. Both basal discharge and chemoreflex-evoked volleys (15–30 μg NaCN, intra-arterially (i.a.)) were elevated in rats with hypertension, as compared to those without hypertension (SH versus Wistar rats: basal, 24.9 ± 2 versus 1.4 ± 0.3 spikes/s, respectively, P < 0.001; chemoreflex, 62.3 ± 3 versus 28.3 ± 2<|im_end|> <|im_start|>assistant Researchers at the University of Bristol and Afferent Pharmaceuticals have identified a potential new way of treating high blood pressure, or hypertension, by targeting aberrant nerve signals in the carotid bodies, which sit on the common carotid arteries on each side of the neck. The study, "Purinergic receptors in the carotid body as a new drug target for controlling hypertension," was led by Julian Paton, professor of physiology at the University of Bristol, and published in the 5 September online edition of Nature Medicine. Instead of treating high blood pressure by targeting directly the functions within end organs, such as the heart, kidneys and vasculature, this novel approach aims to reduce nervous system activity from a sensory organ - the carotid body - which, when activated can cause blood pressure to rise uncontrollably. Such a treatment may offer superiority over existing medications, principally by lowering blood pressure directly at a common source. Beneficial outcomes may also extend to other cardiometabolic disorders, such as heart failure and sleep apnoea, in which the carotid bodies are known to be sensitised. In preclinical models, researchers were able to block this carotid body aberrant signaling activity with an investigational drug candidate, MK-7624 (also known as AF-219), demonstrating a significant reduction in blood pressure. "With this research, we've validated P2X3 receptors as a novel drug target for the treatment of cardiovascular disease, by demonstrating that blockade of these receptors with a selective antagonist controls carotid body activity," said Dr Angus Nightingale, a cardiology consultant, who runs the specialist hypertensive clinic at the Bristol Heart Institute, and co-author of the study. "The question now is whether blocking these P2X3 receptors in humans will lower elevated blood pressure, and how we can best identify those patients with carotid body hyperactivity who are most likely to respond to treatment." "The carotid bodies lie at the bifurcation (fork) of the common carotid artery on each side of the neck and are the body's smallest organs, each about the size of a rice grain," said Professor Paton, who co-led the research with Dr Anthony Ford, founder and chief scientific officer of Afferent Pharmaceuticals. "These organs sense chemicals such as oxygen in the blood. When oxygen levels fall, the carotid bodies become active and send signals to the brain that trigger increases in breathing and blood pressure." The researchers collaborated to test whether MK-7624/AF-219, a highly selective and potent orally available P2X3 receptor antagonist, can stop this nervous activity from occurring, thereby lowering blood pressure. "In healthy individuals, the carotid bodies have very low levels of activity," said Professor Paton. "We discovered that these tiny organs become hyperactive in conditions of hypertension, generating what we have called aberrant or tonic discharge, which is sent into the brain regions controlling cardiovascular activity. In this way, changes within the carotid body may be a cause of high blood pressure and therefore represent a novel target for controlling blood pressure." Previous research by Professor Paton and collaborators, published in The Journal of the American College of Cardiology, showed that removing one carotid body was effective in lowering blood pressure in human patients with drug-resistant hypertension. The next step was to find out why the carotid body can become hyperactive in hypertension, and to develop a pharmacological approach to normalise its activity. To carry out the research, the team utilised an established animal model of human hypertension. They discovered the energy molecule ATP (adenosine triphosphate), a recognized common signaling nucleotide, was able to persistently activate the P2X3 receptor, and that this protein was upregulated by almost 5 fold in the carotid body in hypertension. By blocking this receptor in the carotid body with MK-7264/AF-219, blood pressure fell significantly in hypertensive rats. "Crucially, unlike carotid body removal, the drug did not render the carotid body inoperable," said Professor Paton. "Instead, it normalized its activity levels to those found in a normotensive state. Think of it in terms of a domestic fire alarm – it switches off after the smoke disappears, but the battery remains in place, meaning it can still respond in an emergency." "We have developed some unique tests to assess the activity state of the carotid body in human hypertensive patients," said Dr. Nightingale. "We are hoping to initiate a clinical trial to test P2X3 receptor antagonism in hypertensive patients who exhibit hyperactive carotid bodies in the near future." High blood pressure is the world's leading contributor to mortality. In the UK, its cost to the National Health Service is around £2 billion per year, and it remains poorly controlled, triggering heart and renal failure, and strokes. The World Health Organization has identified high blood pressure as the single most important risk factor for the global burden of disease and death. "This approach may be the first novel anti-hypertensive treatment strategy in more than 15 years, and perhaps the first directed at a root cause of excessive sympathetic discharge to cardiovascular end-organs," said Professor Paton. "This research was translational from molecule to medicine, and reflects the critical importance of integrative physiology as a subject. Our study was an inter-disciplinary team effort, and would not have been possible without close working with colleagues from the University of Bristol, University Hospital Trust Bristol, the University of Sao Paulo, Brazil, the University of Auckland, New Zealand, and Afferent Pharmaceuticals. Nor would it have been possible without funding from The British Heart Foundation and Afferent Pharmaceuticals." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Species’ vulnerability to extinction is strongly impacted by their geographical range size. Formulating effective conservation strategies therefore requires a better understanding of how the ranges of the world’s species have changed in the past, and how they will change under alternative future scenarios. Here, we use reconstructions of global land use and biomes since 1700, and 16 possible climatic and socio-economic scenarios until the year 2100, to map the habitat ranges of 16,919 mammal, bird, and amphibian species through time. We estimate that species have lost an average of 18% of their natural habitat range sizes thus far, and may lose up to 23% by 2100. Our data reveal that range losses have been increasing disproportionately in relation to the area of destroyed habitat, driven by a long-term increase of land use in tropical biodiversity hotspots. The outcomes of different future climate and land use trajectories for global habitat ranges vary drastically, providing important quantitative evidence for conservation planners and policy makers of the costs and benefits of alternative pathways for the future of global biodiversity. Introduction Habitat range size is a strong predictor of species’ vulnerability to extinction 1 , 2 . As a result, two major drivers of the decline of geographic range sizes—the conversion of natural vegetation to agricultural and urban land, and the transformation of suitable habitat caused by climate change—are considered two of the most important threats to global terrestrial biodiversity 3 . Land-use change has caused staggering levels of habitat contractions for a range of mammal 4 , 5 , 6 , bird 7 , and amphibian species 8 . Simultaneously, anthropogenic climate change has been driving shifts in species’ ranges 9 , 10 , 11 , 12 , which, whilst resulting in larger range sizes for some species, has led to severe range retractions for others 11 , 13 , 14 . Declines in global range sizes due to land-use and climate change heavily contribute to the loss of local species richness 15 , 16 , 17 and abundance 17 , 18 , 19 in many parts of the world, thereby threatening essential ecosystem functions 17 , 20 . With global agricultural area potentially increasing drastically in the coming decades 21 , and climate change continuing to drive ecosystem change at an accelerating pace 22 , future projections suggest that past trends in range contractions may continue 23 , 24 , and likely contribute to projected large-scale faunal extinctions 12 , 13 , 25 , 26 . Considering the crucial role that species’ range sizes play for extinction risks, a better understanding of the long-term range dynamics of individual species, and projections of future changes under alternative scenarios, is crucial for conservation planning from the local to the global scale. Such estimates would allow quantification of historical pressures on species, and inform prioritisation of future efforts. Here, we estimate the habitat range sizes of 16,919 mammal, bird and amphibian species from the year 1700 until 2100 based on global land use and climatic conditions. We use empirical datasets of the global distribution of species, and combine these with species-specific biome preferences to estimate local habitat suitability under natural vegetation, cropland, pasture and urban land cover. By overlaying these data with reconstructions of global biomes corresponding to past climatic conditions, and agricultural and urban areas since 1700, we estimate the historical habitat ranges of each species (‘Methods’). We then extend the analysis into the future based on 16 alternative land use and climate trajectories until the year 2100, representing four emission scenarios (representative concentration pathways (RCPs) 2.6, 4.5, 6.0, 8.5), and five socio-economic pathways (shared socio-economic pathways (SSPs) 1–5) (‘Methods’). SSP1 and SSP3 represent futures where socio-economic challenges for adaptation and mitigation to climate change are both low and both high, respectively; SSP4 combines high challenges to adaptation with low challenges to mitigation, while SSP5 represents the opposite case; SSP2 is a middle-of-the-road scenario of intermediate challenges to adaptation and mitigation 27 , 28 RCPs 2.6–8.5 represent increasing levels of global warming by the end of the century 29 . Considering all possible SSPs for any given RCP is crucial, as using only one realisation per RCP can conflate effects and lead to contestable patterns (e.g., ref. 16 ). By design of the method used here, modelled species’ habitat ranges do not exceed the outermost geographic limits of species’ observed and projected occurrences. Whilst this approach still allows for ample range shifts and expansions (‘Methods’), climate change may push some species beyond these bounds, which our estimates would not account for. Furthermore, our method does not account for habitat range shifts from climatic changes that are too small to manifest as biome changes (‘Methods’); thus, range shifts in highly climatically sensitive species may be underdetected. Our estimates of the distribution of species’ habitat ranges based on land use and climate represent upper estimates for the actual distribution of populations. They neither incorporate other types of human influence, such as hunting 30 , suppression by introduced species 31 and pathogens 32 , nor do they account for species’ mobility 33 , or the impacts of habitat fragmentation 34 and trophic cascade effects 35 on the viability of local populations. Our analysis reveals that species have lost an average of 18% of their natural range sizes thus far, a figure that may drop to 13% or increase to 23% by the end of the century, depending on future global climatic and socioeconomic developments. Results and discussion Historical changes in habitat range sizes With moderate impacts on the habitat ranges of most species’ up until the industrial revolution, the expansion of agricultural production and settlements alongside the rise in population growth since the early 1800 s has drastically reduced range sizes of most mammals, birds, and amphibians (Fig. 1a ). Using potential natural ranges in 1850 as a reference (‘Methods’), we estimate that species had lost an average of 18% of their natural habitat area by 2016. For most species, alterations in the global distribution of", "role": "user" }, { "content": "Mammals, birds and amphibians worldwide have lost on average 18% of their natural habitat range as a result of changes in land use and climate change, a new study has found. In a worst-case scenario this loss could increase to 23% over the next 80 years. The study, published today in the journal Nature Communications, analyzed changes in the geographical range of 16,919 species from 1700 to the present day. The data were also used to predict future changes up to the year 2100 under 16 different climate and socio-economic scenarios. A diverse abundance of species underpins essential ecosystem functions from pest regulation to carbon storage. Species' vulnerability to extinction is strongly impacted by their geographical range size, and devising effective conservation strategies requires a better understanding of how ranges have changed in the past, and how they will change under alternative future scenarios. \"The habitat size of almost all known birds, mammals and amphibians is shrinking, primarily because of land conversion by humans as we continue to expand our agricultural and urban areas,\" said Dr. Robert Beyer in the University of Cambridge's Department of Zoology, first author of the report. Some species are more heavily impacted than others. A worrying 16% of species have lost over half their estimated natural historical range, a figure that could rise to 26% by the end of the century. Species' geographical ranges were found to have recently shrunk most significantly in tropical areas. Until around 50 years ago, most agricultural development was in Europe and North America. Since then, large areas of land have been converted for agriculture in the tropics: clearance of rainforest for oil palm plantations in South East Asia, and for pasture land in South America, for example. As humans move their activities deeper into the tropics, the effect on species ranges is becoming disproportionately larger because of a greater species richness in these areas, and because the natural ranges of these species are smaller to begin with. \"The tropics are biodiversity hotspots with lots of small-range species. If one hectare of tropical forest is converted to agricultural land, a lot more species lose larger proportions of their home than in places like Europe,\" said Beyer. The results predict that climate change will have an increasing impact on species' geographical ranges. Rising temperatures and changing rainfall patterns will alter habitats significantly, for example: other studies have predicted that without climate action, large parts of the Amazon may change from canopy rainforest to a savannah-like mix of woodland and open grassland in the next 100 years. \"Species in the Amazon have adapted to living in a tropical rainforest. If climate change causes this ecosystem to change, many of those species won't be able to survive—or they will at least be pushed into smaller areas of remaining rainforest,\" said Beyer. He added: \"We found that the higher the carbon emissions, the worse it gets for most species in terms of habitat loss.\" The results provide quantitative support for policy measures aiming at limiting the global area of agricultural land—for example by sustainably intensifying food production, encouraging dietary shifts towards eating less meat, and stabilizing population growth. The conversion of natural vegetation to agricultural and urban land, and the transformation of suitable habitat caused by climate change are major causes of the decline in range sizes, and two of the most important threats to global terrestrial biodiversity. \"Whether these past trends in habitat range losses will reverse, continue, or accelerate will depend on future global carbon emissions and societal choices in the coming years and decades,\" Professor Andrea Manica in the University of Cambridge's Department of Zoology, who led the study. He added: \"While our study quantifies the drastic consequences for species' ranges if global land use and climate change are left unchecked, they also demonstrate the tremendous potential of timely and concerted policy action for halting—and indeed partially reversing—previous trends in global range contractions. It all depends on what we do next.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Species’ vulnerability to extinction is strongly impacted by their geographical range size. Formulating effective conservation strategies therefore requires a better understanding of how the ranges of the world’s species have changed in the past, and how they will change under alternative future scenarios. Here, we use reconstructions of global land use and biomes since 1700, and 16 possible climatic and socio-economic scenarios until the year 2100, to map the habitat ranges of 16,919 mammal, bird, and amphibian species through time. We estimate that species have lost an average of 18% of their natural habitat range sizes thus far, and may lose up to 23% by 2100. Our data reveal that range losses have been increasing disproportionately in relation to the area of destroyed habitat, driven by a long-term increase of land use in tropical biodiversity hotspots. The outcomes of different future climate and land use trajectories for global habitat ranges vary drastically, providing important quantitative evidence for conservation planners and policy makers of the costs and benefits of alternative pathways for the future of global biodiversity. Introduction Habitat range size is a strong predictor of species’ vulnerability to extinction 1 , 2 . As a result, two major drivers of the decline of geographic range sizes—the conversion of natural vegetation to agricultural and urban land, and the transformation of suitable habitat caused by climate change—are considered two of the most important threats to global terrestrial biodiversity 3 . Land-use change has caused staggering levels of habitat contractions for a range of mammal 4 , 5 , 6 , bird 7 , and amphibian species 8 . Simultaneously, anthropogenic climate change has been driving shifts in species’ ranges 9 , 10 , 11 , 12 , which, whilst resulting in larger range sizes for some species, has led to severe range retractions for others 11 , 13 , 14 . Declines in global range sizes due to land-use and climate change heavily contribute to the loss of local species richness 15 , 16 , 17 and abundance 17 , 18 , 19 in many parts of the world, thereby threatening essential ecosystem functions 17 , 20 . With global agricultural area potentially increasing drastically in the coming decades 21 , and climate change continuing to drive ecosystem change at an accelerating pace 22 , future projections suggest that past trends in range contractions may continue 23 , 24 , and likely contribute to projected large-scale faunal extinctions 12 , 13 , 25 , 26 . Considering the crucial role that species’ range sizes play for extinction risks, a better understanding of the long-term range dynamics of individual species, and projections of future changes under alternative scenarios, is crucial for conservation planning from the local to the global scale. Such estimates would allow quantification of historical pressures on species, and inform prioritisation of future efforts. Here, we estimate the habitat range sizes of 16,919 mammal, bird and amphibian species from the year 1700 until 2100 based on global land use and climatic conditions. We use empirical datasets of the global distribution of species, and combine these with species-specific biome preferences to estimate local habitat suitability under natural vegetation, cropland, pasture and urban land cover. By overlaying these data with reconstructions of global biomes corresponding to past climatic conditions, and agricultural and urban areas since 1700, we estimate the historical habitat ranges of each species (‘Methods’). We then extend the analysis into the future based on 16 alternative land use and climate trajectories until the year 2100, representing four emission scenarios (representative concentration pathways (RCPs) 2.6, 4.5, 6.0, 8.5), and five socio-economic pathways (shared socio-economic pathways (SSPs) 1–5) (‘Methods’). SSP1 and SSP3 represent futures where socio-economic challenges for adaptation and mitigation to climate change are both low and both high, respectively; SSP4 combines high challenges to adaptation with low challenges to mitigation, while SSP5 represents the opposite case; SSP2 is a middle-of-the-road scenario of intermediate challenges to adaptation and mitigation 27 , 28 RCPs 2.6–8.5 represent increasing levels of global warming by the end of the century 29 . Considering all possible SSPs for any given RCP is crucial, as using only one realisation per RCP can conflate effects and lead to contestable patterns (e.g., ref. 16 ). By design of the method used here, modelled species’ habitat ranges do not exceed the outermost geographic limits of species’ observed and projected occurrences. Whilst this approach still allows for ample range shifts and expansions (‘Methods’), climate change may push some species beyond these bounds, which our estimates would not account for. Furthermore, our method does not account for habitat range shifts from climatic changes that are too small to manifest as biome changes (‘Methods’); thus, range shifts in highly climatically sensitive species may be underdetected. Our estimates of the distribution of species’ habitat ranges based on land use and climate represent upper estimates for the actual distribution of populations. They neither incorporate other types of human influence, such as hunting 30 , suppression by introduced species 31 and pathogens 32 , nor do they account for species’ mobility 33 , or the impacts of habitat fragmentation 34 and trophic cascade effects 35 on the viability of local populations. Our analysis reveals that species have lost an average of 18% of their natural range sizes thus far, a figure that may drop to 13% or increase to 23% by the end of the century, depending on future global climatic and socioeconomic developments. Results and discussion Historical changes in habitat range sizes With moderate impacts on the habitat ranges of most species’ up until the industrial revolution, the expansion of agricultural production and settlements alongside the rise in population growth since the early 1800 s has drastically reduced range sizes of most mammals, birds, and amphibians (Fig. 1a ). Using potential natural ranges in 1850 as a reference (‘Methods’), we estimate that species had lost an average of 18% of their natural habitat area by 2016. For most species, alterations in the global distribution of<|im_end|> <|im_start|>assistant Mammals, birds and amphibians worldwide have lost on average 18% of their natural habitat range as a result of changes in land use and climate change, a new study has found. In a worst-case scenario this loss could increase to 23% over the next 80 years. The study, published today in the journal Nature Communications, analyzed changes in the geographical range of 16,919 species from 1700 to the present day. The data were also used to predict future changes up to the year 2100 under 16 different climate and socio-economic scenarios. A diverse abundance of species underpins essential ecosystem functions from pest regulation to carbon storage. Species' vulnerability to extinction is strongly impacted by their geographical range size, and devising effective conservation strategies requires a better understanding of how ranges have changed in the past, and how they will change under alternative future scenarios. "The habitat size of almost all known birds, mammals and amphibians is shrinking, primarily because of land conversion by humans as we continue to expand our agricultural and urban areas," said Dr. Robert Beyer in the University of Cambridge's Department of Zoology, first author of the report. Some species are more heavily impacted than others. A worrying 16% of species have lost over half their estimated natural historical range, a figure that could rise to 26% by the end of the century. Species' geographical ranges were found to have recently shrunk most significantly in tropical areas. Until around 50 years ago, most agricultural development was in Europe and North America. Since then, large areas of land have been converted for agriculture in the tropics: clearance of rainforest for oil palm plantations in South East Asia, and for pasture land in South America, for example. As humans move their activities deeper into the tropics, the effect on species ranges is becoming disproportionately larger because of a greater species richness in these areas, and because the natural ranges of these species are smaller to begin with. "The tropics are biodiversity hotspots with lots of small-range species. If one hectare of tropical forest is converted to agricultural land, a lot more species lose larger proportions of their home than in places like Europe," said Beyer. The results predict that climate change will have an increasing impact on species' geographical ranges. Rising temperatures and changing rainfall patterns will alter habitats significantly, for example: other studies have predicted that without climate action, large parts of the Amazon may change from canopy rainforest to a savannah-like mix of woodland and open grassland in the next 100 years. "Species in the Amazon have adapted to living in a tropical rainforest. If climate change causes this ecosystem to change, many of those species won't be able to survive—or they will at least be pushed into smaller areas of remaining rainforest," said Beyer. He added: "We found that the higher the carbon emissions, the worse it gets for most species in terms of habitat loss." The results provide quantitative support for policy measures aiming at limiting the global area of agricultural land—for example by sustainably intensifying food production, encouraging dietary shifts towards eating less meat, and stabilizing population growth. The conversion of natural vegetation to agricultural and urban land, and the transformation of suitable habitat caused by climate change are major causes of the decline in range sizes, and two of the most important threats to global terrestrial biodiversity. "Whether these past trends in habitat range losses will reverse, continue, or accelerate will depend on future global carbon emissions and societal choices in the coming years and decades," Professor Andrea Manica in the University of Cambridge's Department of Zoology, who led the study. He added: "While our study quantifies the drastic consequences for species' ranges if global land use and climate change are left unchecked, they also demonstrate the tremendous potential of timely and concerted policy action for halting—and indeed partially reversing—previous trends in global range contractions. It all depends on what we do next." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The Polycomb group of epigenetic enzymes represses expression of developmentally regulated genes in many eukaryotes. This group includes the Polycomb repressive complex 1 (PRC1), which ubiquitylates nucleosomal histone H2A Lys 119 using its E3 ubiquitin ligase subunits, Ring1B and Bmi1, together with an E2 ubiquitin-conjugating enzyme, UbcH5c. However, the molecular mechanism of nucleosome substrate recognition by PRC1 or other chromatin enzymes is unclear. Here we present the crystal structure of the human Ring1B–Bmi1–UbcH5c E3–E2 complex (the PRC1 ubiquitylation module) bound to its nucleosome core particle substrate. The structure shows how a chromatin enzyme achieves substrate specificity by interacting with several nucleosome surfaces spatially distinct from the site of catalysis. Our structure further reveals an unexpected role for the ubiquitin E2 enzyme in substrate recognition, and provides insight into how the related histone H2A E3 ligase, BRCA1, interacts with and ubiquitylates the nucleosome. Main The Polycomb group (PcG) proteins are transcriptional repressors that correlate with diverse human cancers and constitute key epigenetic regulators of stem-cell self-renewal and lineage development 1 , 2 , 3 , 4 , 5 . The PcG proteins assemble into multi-component complexes that remodel chromatin structure both directly and through the establishment and removal of histone post-translational modifications 6 , 7 . One of these complexes, PRC1, monoubiquitylates histone H2A Lys 119 (refs 8 , 9 ). Once thought of as a unique complex, it is now clear that human PRC1 exists as a modular subset of complexes with distinct functions and gene targets 10 , 11 . All PRC1 complexes share a common core — the RING-type E3 ubiquitin ligase composed of Ring1B (also known as RNF2) or Ring1A, and Bmi1 (also known as PCGF4) or one of five other Polycomb group RING finger (PCGF) paralogues with potential for H2A ubiquitylation. This E3 core combines with accessory subunits to form canonical and variant PRC1s. Variant complexes, especially those containing histone demethylase KDM2B and/or RYBP, seem to be primarily responsible for H2A ubiquitylation 10 , 12 , 13 , 14 . Protein ubiquitylation is accomplished through a cascade of E1, E2 and E3 enzymes 15 . First, an E1 activates and transfers ubiquitin to an E2-conjugating enzyme, forming a thioester between ubiquitin and a cysteine in the E2 active site. Then, in an E3-dependent manner, the carboxy terminus of ubiquitin is attached to the ε-NH 2 of a target protein lysine side chain through an isopeptide bond. RING family E3 ligases, such as those found in PRC1, bridge an E2 and a target protein, presenting the target lysine to the E2 active site and constraining the geometry of the ubiquityl-E2 thioester, priming it for catalysis 16 , 17 , 18 . The E3 is considered the primary specificity determinant of ubiquitylation, reflecting the scarcity of E2s ( ∼ 40 proteins in human) relative to E3s (more than 600 proteins) 19 . Although the cognate E2 for PRC1 in vivo is not established, the Ring1B–Bmi1 E3 ligase can pair with one of several E2s, including UbcH5c (also known as UBE2D3), to ubiquitylate nucleosomes in vitro 20 . The nucleosome core particle (NCP) is the fundamental unit of the eukaryotic genome formed by 145–147 base pairs (bp) of DNA wrapped around an octameric scaffold of histone proteins (two copies each of H2A, H2B, H3 and H4) 21 . H2A–H2B dimers and H2A alone are not substrates for Ring1B–Bmi1, suggesting that surfaces formed only in the context of the nucleosome are required for the E3 ligase activity of PRC1 (refs 22 , 23 ). A minimal RING heterodimer of Ring1B and Bmi1 exhibits comparable activity to the full-length complex, implicating the RING domains in both E2 and substrate binding 20 . However, we lack a fundamental mechanistic understanding of how the Ring1B–Bmi1 E3 ligase interacts with the nucleosome to direct H2A Lys 119 ubiquitylation, or more generally, for how chromatin enzymes recognize their nucleosome substrate. We have crystallized the PRC1 ubiquitylation module, an E2–E3 enzyme complex composed of UbcH5c and the minimal Ring1B–Bmi1 RING heterodimer, bound to its NCP substrate, and solved the structure at 3.3 Å resolution ( Supplementary Table 1 ). To our knowledge, this is the first crystal structure of a histone-modifying-enzyme–nucleosome complex or of a ubiquitin E2–E3–substrate complex. The structure shows that in contrast to most chromatin modification enzymes studied so far, the vast majority of interactions between the PRC1 ubiquitylation module and the nucleosome occur away from the catalytic site. Ring1B and Bmi1 bind to the histone surface of the NCP to orient UbcH5c for H2A ubiquitylation. Surprisingly, UbcH5c also makes direct contacts with the NCP that are crucial for nucleosome binding and ubiquitylation. This presents a novel role of ubiquitin E2 enzymes in substrate recognition. Overview of complex The structure shows one PRC1 ubiquitylation module bound to each disk face of the nucleosome ( Fig. 1a, b ). The two PRC1 modules more than double the height of the NCP and with the exception of the C-terminal region of UbcH5c, are entirely contained within a cylinder projecting up from the NCP disk surface. Each PRC1 ubiquitylation module forms a crescent with two halves of the crescent contributed by the E2 and E3, respectively. The Ring1B–Bmi1 E3 heterodimer binds to the central histone surface of the NCP. The E2 UbcH5c completes the crescent, following the inner curvature of the DNA from its interface with Ring1B past the DNA end, ultimately terminating above the nucleosomal dyad. In this manner, the Ring1B–Bmi1 E3 ligase positions the active site of UbcH5c over the C-terminal tail of H2A near the target residue Lys 119 ( Fig. 1c ). All three components of the PRC1 ubiquitylation module contact histone and/or DNA components of the nucleosome burying 1,470 Å 2 of solvent accessible surface. Figure 1: Crystal structure of PRC1 ubiquitylation module–NCP complex. a , View of the complex looking down on the DNA superhelical axis. b , Orthogonal view of the complex with proximal and distal halves of the structure indicated. c , Zoomed view demonstrating Ring1B–Bmi1 heterodimer positioning", "role": "user" }, { "content": "A landmark study to be published in the October 30, 2014 print edition of the journal Nature provides new insight into the function of an enzyme related to the BRCA1 breast-cancer protein. The study by a team at Penn State University is the first to produce a detailed working image of an enzyme in the Polycomb Repressive Complex 1 (PRC1)—a group that regulates cell development and is associated with many types of cancer. Enzymes like PRC1 turn on or turn off the activity of genes in a cell by manipulating individual chromosome units called nucleosomes. \"The nucleosome is a key target of the enzymes that conduct genetic processes critical for life,\" said Song Tan, professor of biochemistry and molecular biology at Penn State University and the leader of the study's research team. The Penn State scientists obtained the first crystal structure of a gene-regulation enzyme while it is working on a nucleosome. The image reveals previously unknown information about how the enzyme attaches to its nucleosome target. Before this study, scientists had been unable to picture exactly how cancer-related enzymes in the PRC1 group interacted with a nucleosome to control gene activity. The study is also the first to determine the crystal structure of a multisubunit protein complex bound to a nucleosome, which itself is a complex assembly of DNA and 4 histone proteins. The research is the culmination of over 12 years of research by the Tan laboratory to capture an image of this important class of enzymes bound to the nucleosome. His lab earlier had determined the first structure of another nucleosome-bound protein, RCC1. \"This is the second important structure from the Tan lab to date of a nucleosome in complex with a protein known to interact with and modify chromatin behavior, which in turn can influence human gene expression,\" said Peter Preusch, Ph.D., of the National Institutes of Health's National Institute of General Medical Sciences, which partially funded the research. \"Along with Dr. Tan's previous work detailing a nucleosome bound to the key regulatory protein, RCC1, this new structure adds to our knowledge of how proteins can regulate the structure and function of our genetic material.\" This image is the first detailed picture of the crystal structure of a gene-regulation enzyme while it is working on a nucleosome -- a fundamental component of the chromosomes that provide structure and organization for an organism's genes. Nucleosomes are key targets of the enzymes that conduct genetic processes critical for life. This image reveals the crystal structure of the PRC1 enzyme (yellow, blue and red) bound to the nucleosome (DNA in light blue, histone proteins in purple, light green, light yellow and pink) This image was obtained in the lab of Song Tan at Penn State University and is published in the print edition of the journal Nature on Oct. 30, 2014. Credit: Song Tan lab, Penn State University The research project was proposed and executed by team member Robert K. McGinty, a Damon Runyon postdoctoral fellow at Penn State. McGinty and Ryan C. Henrici, an undergraduate student in the Penn State Schreyer Honors College, grew crystals of the PRC1 enzyme bound to the nucleosome. The team then solved the three-dimensional structure of this large molecular assembly by X-ray crystallography. \"We are excited about this crystal structure because it provides new paradigms for understanding how chromatin enzymes function,\" McGinty said. The study performed in the Penn State Center for Eukaryotic Gene Regulation provides unexpected insight into the workings of the BRCA1 breast-cancer-associated tumor-suppressor protein. Like PRC1, BRCA1 is a chromatin enzyme that shares a similar activity on the nucleosome. Tan said, \"Our study suggests that BRCA1 and PRC1 employ a similar mechanism to anchor to the nucleosome.\" Tan and his team now are working to visualize how BRCA1 and other disease-related chromatin enzymes interact with the nucleosome. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The Polycomb group of epigenetic enzymes represses expression of developmentally regulated genes in many eukaryotes. This group includes the Polycomb repressive complex 1 (PRC1), which ubiquitylates nucleosomal histone H2A Lys 119 using its E3 ubiquitin ligase subunits, Ring1B and Bmi1, together with an E2 ubiquitin-conjugating enzyme, UbcH5c. However, the molecular mechanism of nucleosome substrate recognition by PRC1 or other chromatin enzymes is unclear. Here we present the crystal structure of the human Ring1B–Bmi1–UbcH5c E3–E2 complex (the PRC1 ubiquitylation module) bound to its nucleosome core particle substrate. The structure shows how a chromatin enzyme achieves substrate specificity by interacting with several nucleosome surfaces spatially distinct from the site of catalysis. Our structure further reveals an unexpected role for the ubiquitin E2 enzyme in substrate recognition, and provides insight into how the related histone H2A E3 ligase, BRCA1, interacts with and ubiquitylates the nucleosome. Main The Polycomb group (PcG) proteins are transcriptional repressors that correlate with diverse human cancers and constitute key epigenetic regulators of stem-cell self-renewal and lineage development 1 , 2 , 3 , 4 , 5 . The PcG proteins assemble into multi-component complexes that remodel chromatin structure both directly and through the establishment and removal of histone post-translational modifications 6 , 7 . One of these complexes, PRC1, monoubiquitylates histone H2A Lys 119 (refs 8 , 9 ). Once thought of as a unique complex, it is now clear that human PRC1 exists as a modular subset of complexes with distinct functions and gene targets 10 , 11 . All PRC1 complexes share a common core — the RING-type E3 ubiquitin ligase composed of Ring1B (also known as RNF2) or Ring1A, and Bmi1 (also known as PCGF4) or one of five other Polycomb group RING finger (PCGF) paralogues with potential for H2A ubiquitylation. This E3 core combines with accessory subunits to form canonical and variant PRC1s. Variant complexes, especially those containing histone demethylase KDM2B and/or RYBP, seem to be primarily responsible for H2A ubiquitylation 10 , 12 , 13 , 14 . Protein ubiquitylation is accomplished through a cascade of E1, E2 and E3 enzymes 15 . First, an E1 activates and transfers ubiquitin to an E2-conjugating enzyme, forming a thioester between ubiquitin and a cysteine in the E2 active site. Then, in an E3-dependent manner, the carboxy terminus of ubiquitin is attached to the ε-NH 2 of a target protein lysine side chain through an isopeptide bond. RING family E3 ligases, such as those found in PRC1, bridge an E2 and a target protein, presenting the target lysine to the E2 active site and constraining the geometry of the ubiquityl-E2 thioester, priming it for catalysis 16 , 17 , 18 . The E3 is considered the primary specificity determinant of ubiquitylation, reflecting the scarcity of E2s ( ∼ 40 proteins in human) relative to E3s (more than 600 proteins) 19 . Although the cognate E2 for PRC1 in vivo is not established, the Ring1B–Bmi1 E3 ligase can pair with one of several E2s, including UbcH5c (also known as UBE2D3), to ubiquitylate nucleosomes in vitro 20 . The nucleosome core particle (NCP) is the fundamental unit of the eukaryotic genome formed by 145–147 base pairs (bp) of DNA wrapped around an octameric scaffold of histone proteins (two copies each of H2A, H2B, H3 and H4) 21 . H2A–H2B dimers and H2A alone are not substrates for Ring1B–Bmi1, suggesting that surfaces formed only in the context of the nucleosome are required for the E3 ligase activity of PRC1 (refs 22 , 23 ). A minimal RING heterodimer of Ring1B and Bmi1 exhibits comparable activity to the full-length complex, implicating the RING domains in both E2 and substrate binding 20 . However, we lack a fundamental mechanistic understanding of how the Ring1B–Bmi1 E3 ligase interacts with the nucleosome to direct H2A Lys 119 ubiquitylation, or more generally, for how chromatin enzymes recognize their nucleosome substrate. We have crystallized the PRC1 ubiquitylation module, an E2–E3 enzyme complex composed of UbcH5c and the minimal Ring1B–Bmi1 RING heterodimer, bound to its NCP substrate, and solved the structure at 3.3 Å resolution ( Supplementary Table 1 ). To our knowledge, this is the first crystal structure of a histone-modifying-enzyme–nucleosome complex or of a ubiquitin E2–E3–substrate complex. The structure shows that in contrast to most chromatin modification enzymes studied so far, the vast majority of interactions between the PRC1 ubiquitylation module and the nucleosome occur away from the catalytic site. Ring1B and Bmi1 bind to the histone surface of the NCP to orient UbcH5c for H2A ubiquitylation. Surprisingly, UbcH5c also makes direct contacts with the NCP that are crucial for nucleosome binding and ubiquitylation. This presents a novel role of ubiquitin E2 enzymes in substrate recognition. Overview of complex The structure shows one PRC1 ubiquitylation module bound to each disk face of the nucleosome ( Fig. 1a, b ). The two PRC1 modules more than double the height of the NCP and with the exception of the C-terminal region of UbcH5c, are entirely contained within a cylinder projecting up from the NCP disk surface. Each PRC1 ubiquitylation module forms a crescent with two halves of the crescent contributed by the E2 and E3, respectively. The Ring1B–Bmi1 E3 heterodimer binds to the central histone surface of the NCP. The E2 UbcH5c completes the crescent, following the inner curvature of the DNA from its interface with Ring1B past the DNA end, ultimately terminating above the nucleosomal dyad. In this manner, the Ring1B–Bmi1 E3 ligase positions the active site of UbcH5c over the C-terminal tail of H2A near the target residue Lys 119 ( Fig. 1c ). All three components of the PRC1 ubiquitylation module contact histone and/or DNA components of the nucleosome burying 1,470 Å 2 of solvent accessible surface. Figure 1: Crystal structure of PRC1 ubiquitylation module–NCP complex. a , View of the complex looking down on the DNA superhelical axis. b , Orthogonal view of the complex with proximal and distal halves of the structure indicated. c , Zoomed view demonstrating Ring1B–Bmi1 heterodimer positioning<|im_end|> <|im_start|>assistant A landmark study to be published in the October 30, 2014 print edition of the journal Nature provides new insight into the function of an enzyme related to the BRCA1 breast-cancer protein. The study by a team at Penn State University is the first to produce a detailed working image of an enzyme in the Polycomb Repressive Complex 1 (PRC1)—a group that regulates cell development and is associated with many types of cancer. Enzymes like PRC1 turn on or turn off the activity of genes in a cell by manipulating individual chromosome units called nucleosomes. "The nucleosome is a key target of the enzymes that conduct genetic processes critical for life," said Song Tan, professor of biochemistry and molecular biology at Penn State University and the leader of the study's research team. The Penn State scientists obtained the first crystal structure of a gene-regulation enzyme while it is working on a nucleosome. The image reveals previously unknown information about how the enzyme attaches to its nucleosome target. Before this study, scientists had been unable to picture exactly how cancer-related enzymes in the PRC1 group interacted with a nucleosome to control gene activity. The study is also the first to determine the crystal structure of a multisubunit protein complex bound to a nucleosome, which itself is a complex assembly of DNA and 4 histone proteins. The research is the culmination of over 12 years of research by the Tan laboratory to capture an image of this important class of enzymes bound to the nucleosome. His lab earlier had determined the first structure of another nucleosome-bound protein, RCC1. "This is the second important structure from the Tan lab to date of a nucleosome in complex with a protein known to interact with and modify chromatin behavior, which in turn can influence human gene expression," said Peter Preusch, Ph.D., of the National Institutes of Health's National Institute of General Medical Sciences, which partially funded the research. "Along with Dr. Tan's previous work detailing a nucleosome bound to the key regulatory protein, RCC1, this new structure adds to our knowledge of how proteins can regulate the structure and function of our genetic material." This image is the first detailed picture of the crystal structure of a gene-regulation enzyme while it is working on a nucleosome -- a fundamental component of the chromosomes that provide structure and organization for an organism's genes. Nucleosomes are key targets of the enzymes that conduct genetic processes critical for life. This image reveals the crystal structure of the PRC1 enzyme (yellow, blue and red) bound to the nucleosome (DNA in light blue, histone proteins in purple, light green, light yellow and pink) This image was obtained in the lab of Song Tan at Penn State University and is published in the print edition of the journal Nature on Oct. 30, 2014. Credit: Song Tan lab, Penn State University The research project was proposed and executed by team member Robert K. McGinty, a Damon Runyon postdoctoral fellow at Penn State. McGinty and Ryan C. Henrici, an undergraduate student in the Penn State Schreyer Honors College, grew crystals of the PRC1 enzyme bound to the nucleosome. The team then solved the three-dimensional structure of this large molecular assembly by X-ray crystallography. "We are excited about this crystal structure because it provides new paradigms for understanding how chromatin enzymes function," McGinty said. The study performed in the Penn State Center for Eukaryotic Gene Regulation provides unexpected insight into the workings of the BRCA1 breast-cancer-associated tumor-suppressor protein. Like PRC1, BRCA1 is a chromatin enzyme that shares a similar activity on the nucleosome. Tan said, "Our study suggests that BRCA1 and PRC1 employ a similar mechanism to anchor to the nucleosome." Tan and his team now are working to visualize how BRCA1 and other disease-related chromatin enzymes interact with the nucleosome. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Impulsivity, defined as impaired decision making, is associated with many psychiatric and behavioral disorders, such as attention-deficit/hyperactivity disorder as well as eating disorders. Recent data indicate that there is a strong positive correlation between food reward behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Here we hypothesize that ghrelin, an orexigenic hormone produced by the stomach and known to increase food reward behavior, also increases impulsivity. In order to assess the impact of ghrelin on impulsivity, rats were trained in three complementary tests of impulsive behavior and choice: differential reinforcement of low rate (DRL), go/no-go, and delay discounting. Ghrelin injection into the lateral ventricle increased impulsive behavior, as indicated by reduced efficiency of performance in the DRL test, and increased lever pressing during the no-go periods of the go/no-go test. Central ghrelin stimulation also increased impulsive choice, as evidenced by the reduced choice for large rewards when delivered with a delay in the delay discounting test. In order to determine whether signaling at the central ghrelin receptors is necessary for maintenance of normal levels of impulsive behavior, DRL performance was assessed following ghrelin receptor blockade with central infusion of a ghrelin receptor antagonist. Central ghrelin receptor blockade reduced impulsive behavior, as reflected by increased efficiency of performance in the DRL task. To further investigate the neurobiological substrate underlying the impulsivity effect of ghrelin, we microinjected ghrelin into the ventral tegmental area, an area harboring dopaminergic cell bodies. Ghrelin receptor stimulation within the VTA was sufficient to increase impulsive behavior. We further evaluated the impact of ghrelin on dopamine-related gene expression and dopamine turnover in brain areas key in impulsive behavior control. This study provides the first demonstration that the stomach-produced hormone ghrelin increases impulsivity and also indicates that ghrelin can change two major components of impulsivity—motor and choice impulsivity. INTRODUCTION Impulsivity, defined as impaired decision making or action without foresight, is associated with many psychiatric and behavioral disorders such as attention-deficit/hyperactivity disorder, substance abuse, and eating disorders ( Dawe and Loxton, 2004 ; Schag et al, 2013 ). Much remains to be discovered about the neurobiological mechanisms that govern impulsivity. Understanding factors that induce impulsive behavior can provide new therapeutic avenues for many impulsivity-associated psychiatric disorders. Major neurotransmitters, such as dopamine and serotonin, have been implicated in regulating impulsive behavior ( Bizot et al, 1999 ; Eagle et al, 2009 ). Reduced dorsal striatal dopamine signaling at the dopamine 1 receptor (D1R) reduces impulsivity and at the dopamine 2 receptor (D2R) increases impulsivity ( Eagle et al, 2011 ). Reduced central serotonin signaling increases impulsive action and choice in rats and pharmacological and optogenetic activation of dorsal raphe serotonin neurons reduces choice impulsivity ( Harrison et al, 1997 ; Miyazaki et al, 2012 , 2014 ). Interestingly both dopamine and serotonin are modulated by a stomach-produced hormone—ghrelin ( Abizaid et al, 2006 ; Skibicka et al, 2013 ; Hansson et al, 2014 )—however, the impact of ghrelin on impulsivity remains unexplored. Ghrelin, a hormone produced in the stomach, is primarily recognized for its orexigenic role. Ghrelin levels increase before each meal that subsequently leads to the food intake ( Cummings et al, 2004 ). The orexigenic action of ghrelin is primarily mediated by the growth hormone secretagogue receptors (GHSR) in the central nervous system. But ghrelin’s actions in the brain are not limited to control of basic food intake; ghrelin also increases reward behavior for food, alcohol, and other substances of abuse ( Jerlhag et al, 2009 ; Skibicka et al, 2011a ; Menzies et al, 2013 ). The impact of ghrelin on reward is thought to be mediated by dopamine and opioid signaling ( Skibicka and Dickson, 2011 , Skibicka et al, 2012 , 2013 ). Food reward behavior has recently been shown to positively correlate with impulsivity ( Velazquez-Sanchez et al, 2014 ). The impact of ghrelin on neurotransmitters critical for regulation of impulsive behavior, taken together with the regulatory role for ghrelin on food reward behavior (a behavior that correlates with impulsivity), led us to hypothesize that ghrelin’s neurobiological role could extend to the regulation of impulsivity. Impulsivity is a heterogeneous construct and in its simplest form can be deconstructed into two components: impulsive action (motor disinhibition) and impulsive choice (impulsive decision making). In order to assess the role of ghrelin in impulsivity, three complementary rodent tests were used: differential reinforcement of low rate (DRL), go/no-go, and delay discounting. All three tests measure the ability to inhibit a behavioral response. While DRL and go/no-go measure impulsive action (the ability to restrain a response), delay discounting measures impulsive choice (the ability to defer gratification) ( Bari and Robbins, 2013 ). The application of different tests in the current study allowed us to assess different aspects of impulsivity after ghrelin or a GHSR antagonist was infused into the lateral ventricle (LV). In order to further understand the neuroanatomical substrate underlying ghrelin’s impact on impulsivity, measured in the DRL task, ghrelin was also directly microinjected into the ventral tegmental area (VTA), an area harboring dopaminergic cell bodies of neurons projecting to, for example, the nucleus accumbens (NAc) and the orbitofrontal cortex (OFC). Finally, we measured dopamine turnover and the expression of genes previously associated with impulsivity in four brain nuclei strongly implicated in impulsivity control—the OFC, the dorsal striatum, the medial prefrontal cortex (mPFC), and the NAc ( Bari and Robbins, 2013 ; Jupp et al, 2013 ). MATERIALS AND METHODS Animals Adult male Sprague-Dawley rats, weighing 200–250 g (Charles River, Germany) were housed in individual plastic cages under 12/12-h dark/light cycle, at 20 °C and 50% humidity. Standard chow (Harlan Tekland; Norfolk, England) and water were available ad libitum unless otherwise indicated. The University of Göteborg Institutional Animal Care and Use Committee guidelines approved all experiments (ethical permission 195-13). Drugs Ghrelin and angiotensin II were purchased from Tocris (Bristol, UK). JMV2959, a ghrelin receptor antagonist, was obtained from Aeterna Zentaris GmbH (Frankfurt, Germany) ( Moulin et al, 2007 ). All drugs were dissolved in artificial", "role": "user" }, { "content": "Never make a decision when you are hungry. The hormone ghrelin - that is released before meals and known to increase appetite - has a negative effect on both decision making and impulse control. Such were the results of a recently conducted study at Sahlgrenska University. When hungry, the hormone ghrelin is produced in the stomach. In a new study conducted on rats at Sahlgrenska Academy, University of Gothenburg, the hormone has been shown to have a negative effect on decision making capabilities and impulse control. \"For the first time, we have been able to show that increasing ghrelin to levels that are seen prior to meals or during fasting, causes the brain to act impulsively and also affects the ability to make rational decisions,\" says Karolina Skibicka, docent at Sahlgrenska Academy, University of Gothenburg. Impulsivity Impulsivity is complex, but can be broken down into impulsive action (inability to resist a motoric response) and impulsive choice (inability to delay gratification). Many have experienced the difficulty of resisting getting a sandwich or something else, even if we know that dinner will be served soon, and the same is true for the rats used in the study. The rats can be trained to be rewarded (with sugar) when they execute an action such as pressing a lever (\"go\") - or instead they can be rewarded only when they resist pressing the lever (\"no-go\") when an appropriate learned signal is given. They learn this by repeatedly being given a signal, for example, a flash of light or a buzzing sound that tells them which action should be executed for them to receive their reward. Were given ghrelin An inability to resist pressing the lever, when the \"no-go\" signal is given, is a sign of impulsivity. Researchers found that rats given ghrelin directly into the brain, which mimics how the stomach would notify us of a need to eat, were more likely to press the lever instead of waiting, despite it causing them loose their reward. The ability to delay gratification in order to get a greater reward later is a comparable measure of impulsive choice (decision). It can be illustrated by options such as those between getting a single cookie now or several cookies if you wait a few minutes, or overeating high-calorie foods for immediate feeling of pleasure while disregarding the long term benefits of eating less or eating healthy. The person who chooses immediate gratification even though waiting provides a greater reward, is characterized as being more impulsive and that implies a poorer ability to make rational decisions. Reduced the impulsive behavior Researchers at Sahlgrenska Academy found that higher levels of ghrelin prevented the rats from being able to wait for the greater reward. They further evaluated where in the brain ghrelin acts to affect impulsivity. \"Our results showed that restricting ghrelin effects to the ventral tegmental area, the part of the brain that is a crucial component of the reward system, was sufficient to make the rats more impulsive. Importantly, when we blocked ghrelin, the impulsive behavior was greatly reduced,\" says Karolina Skibicka. Even a short period of fasting, a more natural way of increasing the release of ghrelin, increased impulsive behavior. Long-term changes Impulsivity is a distinctive feature of many neuropsychiatric disorders and behavior disorders such as ADHD, obsessive compulsive disorder (OCD), autism spectrum disorder (ASD), drug abuse and eating disorders. The study also showed that increased levels of ghrelin even caused long-term genetic changes in the brain circuits that are linked to impulsivity and decision making. A ghrelin injection into the brain that resulted in impulsive behavior in rats, caused the same type of changes in dopamine related genes and enzymes as can be seen in ADHD and OCD. \"Our results indicate that the ghrelin receptors in the brain can be a possible target for future treatment of psychiatric disorders that are characterized by problems with impulsivity and even eating disorders,\" says Karolina Skibicka. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Impulsivity, defined as impaired decision making, is associated with many psychiatric and behavioral disorders, such as attention-deficit/hyperactivity disorder as well as eating disorders. Recent data indicate that there is a strong positive correlation between food reward behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Here we hypothesize that ghrelin, an orexigenic hormone produced by the stomach and known to increase food reward behavior, also increases impulsivity. In order to assess the impact of ghrelin on impulsivity, rats were trained in three complementary tests of impulsive behavior and choice: differential reinforcement of low rate (DRL), go/no-go, and delay discounting. Ghrelin injection into the lateral ventricle increased impulsive behavior, as indicated by reduced efficiency of performance in the DRL test, and increased lever pressing during the no-go periods of the go/no-go test. Central ghrelin stimulation also increased impulsive choice, as evidenced by the reduced choice for large rewards when delivered with a delay in the delay discounting test. In order to determine whether signaling at the central ghrelin receptors is necessary for maintenance of normal levels of impulsive behavior, DRL performance was assessed following ghrelin receptor blockade with central infusion of a ghrelin receptor antagonist. Central ghrelin receptor blockade reduced impulsive behavior, as reflected by increased efficiency of performance in the DRL task. To further investigate the neurobiological substrate underlying the impulsivity effect of ghrelin, we microinjected ghrelin into the ventral tegmental area, an area harboring dopaminergic cell bodies. Ghrelin receptor stimulation within the VTA was sufficient to increase impulsive behavior. We further evaluated the impact of ghrelin on dopamine-related gene expression and dopamine turnover in brain areas key in impulsive behavior control. This study provides the first demonstration that the stomach-produced hormone ghrelin increases impulsivity and also indicates that ghrelin can change two major components of impulsivity—motor and choice impulsivity. INTRODUCTION Impulsivity, defined as impaired decision making or action without foresight, is associated with many psychiatric and behavioral disorders such as attention-deficit/hyperactivity disorder, substance abuse, and eating disorders ( Dawe and Loxton, 2004 ; Schag et al, 2013 ). Much remains to be discovered about the neurobiological mechanisms that govern impulsivity. Understanding factors that induce impulsive behavior can provide new therapeutic avenues for many impulsivity-associated psychiatric disorders. Major neurotransmitters, such as dopamine and serotonin, have been implicated in regulating impulsive behavior ( Bizot et al, 1999 ; Eagle et al, 2009 ). Reduced dorsal striatal dopamine signaling at the dopamine 1 receptor (D1R) reduces impulsivity and at the dopamine 2 receptor (D2R) increases impulsivity ( Eagle et al, 2011 ). Reduced central serotonin signaling increases impulsive action and choice in rats and pharmacological and optogenetic activation of dorsal raphe serotonin neurons reduces choice impulsivity ( Harrison et al, 1997 ; Miyazaki et al, 2012 , 2014 ). Interestingly both dopamine and serotonin are modulated by a stomach-produced hormone—ghrelin ( Abizaid et al, 2006 ; Skibicka et al, 2013 ; Hansson et al, 2014 )—however, the impact of ghrelin on impulsivity remains unexplored. Ghrelin, a hormone produced in the stomach, is primarily recognized for its orexigenic role. Ghrelin levels increase before each meal that subsequently leads to the food intake ( Cummings et al, 2004 ). The orexigenic action of ghrelin is primarily mediated by the growth hormone secretagogue receptors (GHSR) in the central nervous system. But ghrelin’s actions in the brain are not limited to control of basic food intake; ghrelin also increases reward behavior for food, alcohol, and other substances of abuse ( Jerlhag et al, 2009 ; Skibicka et al, 2011a ; Menzies et al, 2013 ). The impact of ghrelin on reward is thought to be mediated by dopamine and opioid signaling ( Skibicka and Dickson, 2011 , Skibicka et al, 2012 , 2013 ). Food reward behavior has recently been shown to positively correlate with impulsivity ( Velazquez-Sanchez et al, 2014 ). The impact of ghrelin on neurotransmitters critical for regulation of impulsive behavior, taken together with the regulatory role for ghrelin on food reward behavior (a behavior that correlates with impulsivity), led us to hypothesize that ghrelin’s neurobiological role could extend to the regulation of impulsivity. Impulsivity is a heterogeneous construct and in its simplest form can be deconstructed into two components: impulsive action (motor disinhibition) and impulsive choice (impulsive decision making). In order to assess the role of ghrelin in impulsivity, three complementary rodent tests were used: differential reinforcement of low rate (DRL), go/no-go, and delay discounting. All three tests measure the ability to inhibit a behavioral response. While DRL and go/no-go measure impulsive action (the ability to restrain a response), delay discounting measures impulsive choice (the ability to defer gratification) ( Bari and Robbins, 2013 ). The application of different tests in the current study allowed us to assess different aspects of impulsivity after ghrelin or a GHSR antagonist was infused into the lateral ventricle (LV). In order to further understand the neuroanatomical substrate underlying ghrelin’s impact on impulsivity, measured in the DRL task, ghrelin was also directly microinjected into the ventral tegmental area (VTA), an area harboring dopaminergic cell bodies of neurons projecting to, for example, the nucleus accumbens (NAc) and the orbitofrontal cortex (OFC). Finally, we measured dopamine turnover and the expression of genes previously associated with impulsivity in four brain nuclei strongly implicated in impulsivity control—the OFC, the dorsal striatum, the medial prefrontal cortex (mPFC), and the NAc ( Bari and Robbins, 2013 ; Jupp et al, 2013 ). MATERIALS AND METHODS Animals Adult male Sprague-Dawley rats, weighing 200–250 g (Charles River, Germany) were housed in individual plastic cages under 12/12-h dark/light cycle, at 20 °C and 50% humidity. Standard chow (Harlan Tekland; Norfolk, England) and water were available ad libitum unless otherwise indicated. The University of Göteborg Institutional Animal Care and Use Committee guidelines approved all experiments (ethical permission 195-13). Drugs Ghrelin and angiotensin II were purchased from Tocris (Bristol, UK). JMV2959, a ghrelin receptor antagonist, was obtained from Aeterna Zentaris GmbH (Frankfurt, Germany) ( Moulin et al, 2007 ). All drugs were dissolved in artificial<|im_end|> <|im_start|>assistant Never make a decision when you are hungry. The hormone ghrelin - that is released before meals and known to increase appetite - has a negative effect on both decision making and impulse control. Such were the results of a recently conducted study at Sahlgrenska University. When hungry, the hormone ghrelin is produced in the stomach. In a new study conducted on rats at Sahlgrenska Academy, University of Gothenburg, the hormone has been shown to have a negative effect on decision making capabilities and impulse control. "For the first time, we have been able to show that increasing ghrelin to levels that are seen prior to meals or during fasting, causes the brain to act impulsively and also affects the ability to make rational decisions," says Karolina Skibicka, docent at Sahlgrenska Academy, University of Gothenburg. Impulsivity Impulsivity is complex, but can be broken down into impulsive action (inability to resist a motoric response) and impulsive choice (inability to delay gratification). Many have experienced the difficulty of resisting getting a sandwich or something else, even if we know that dinner will be served soon, and the same is true for the rats used in the study. The rats can be trained to be rewarded (with sugar) when they execute an action such as pressing a lever ("go") - or instead they can be rewarded only when they resist pressing the lever ("no-go") when an appropriate learned signal is given. They learn this by repeatedly being given a signal, for example, a flash of light or a buzzing sound that tells them which action should be executed for them to receive their reward. Were given ghrelin An inability to resist pressing the lever, when the "no-go" signal is given, is a sign of impulsivity. Researchers found that rats given ghrelin directly into the brain, which mimics how the stomach would notify us of a need to eat, were more likely to press the lever instead of waiting, despite it causing them loose their reward. The ability to delay gratification in order to get a greater reward later is a comparable measure of impulsive choice (decision). It can be illustrated by options such as those between getting a single cookie now or several cookies if you wait a few minutes, or overeating high-calorie foods for immediate feeling of pleasure while disregarding the long term benefits of eating less or eating healthy. The person who chooses immediate gratification even though waiting provides a greater reward, is characterized as being more impulsive and that implies a poorer ability to make rational decisions. Reduced the impulsive behavior Researchers at Sahlgrenska Academy found that higher levels of ghrelin prevented the rats from being able to wait for the greater reward. They further evaluated where in the brain ghrelin acts to affect impulsivity. "Our results showed that restricting ghrelin effects to the ventral tegmental area, the part of the brain that is a crucial component of the reward system, was sufficient to make the rats more impulsive. Importantly, when we blocked ghrelin, the impulsive behavior was greatly reduced," says Karolina Skibicka. Even a short period of fasting, a more natural way of increasing the release of ghrelin, increased impulsive behavior. Long-term changes Impulsivity is a distinctive feature of many neuropsychiatric disorders and behavior disorders such as ADHD, obsessive compulsive disorder (OCD), autism spectrum disorder (ASD), drug abuse and eating disorders. The study also showed that increased levels of ghrelin even caused long-term genetic changes in the brain circuits that are linked to impulsivity and decision making. A ghrelin injection into the brain that resulted in impulsive behavior in rats, caused the same type of changes in dopamine related genes and enzymes as can be seen in ADHD and OCD. "Our results indicate that the ghrelin receptors in the brain can be a possible target for future treatment of psychiatric disorders that are characterized by problems with impulsivity and even eating disorders," says Karolina Skibicka. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The interplay between symmetry and topology leads to a rich variety of electronic topological phases, protecting states such as the topological insulators and Dirac semimetals. Previous results, like the Fu-Kane parity criterion for inversion-symmetric topological insulators, demonstrate that symmetry labels can sometimes unambiguously indicate underlying band topology. Here we develop a systematic approach to expose all such symmetry-based indicators of band topology in all the 230 space groups. This is achieved by first developing an efficient way to represent band structures in terms of elementary basis states, and then isolating the topological ones by removing the subset of atomic insulators, defined by the existence of localized symmetric Wannier functions. Aside from encompassing all earlier results on such indicators, including in particular the notion of filling-enforced quantum band insulators, our theory identifies symmetry settings with previously hidden forms of band topology, and can be applied to the search for topological materials. Introduction The discovery of topological insulators (TIs) has reinvigorated the well-established theory of electronic band structures (BSs) 1 , 2 . Exploration along this dimension has led to an ever-growing arsenal of topological materials, which include, for instance, topological (crystalline) insulators 3 , 4 , 5 , quantum anomalous Hall insulators 6 and Weyl and Dirac semimetals 7 . Such materials possess unprecedented physical properties, like quantized response and gapless surface states, that are robust against all symmetry-preserving perturbations as long as a band picture remains valid 1 , 2 , 7 . Soon after these developments, it was realized that symmetries of energy bands, a thoroughly studied aspect of band theory, is also profoundly intertwined with topology. This is exemplified by the celebrated Fu-Kane criterion for inversion-symmetric materials, which demarcates TIs from trivial insulators using only their parity eigenvalues 8 . This criterion, when applicable, greatly simplifies the topological analysis of real materials, and underpins the theoretical prediction and subsequent experimental verification of many TIs 8 , 9 , 10 , 11 , 12 . It is of fundamental interest to obtain results akin to the Fu-Kane criterion in other symmetry settings. Early generalizations in systems without time-reversal (TR) symmetry in two-dimensional (2D) constrained the Chern number ( C ). The eigenvalues of an n -fold rotation were found to determine C modulo n 13 , 14 , 15 . This is characteristic of a symmetry-based indicator of topology—when the indicator is nonvanishing, band topology is guaranteed, but certain topological phases (i.e., C a multiple of n in this context) may be invisible to the indicator. In three-dimensional (3D) systems, it was also recognized that spatial inversion alone can protect nontrivial phases. A feature here is that these phases do not host protected surface states, since inversion symmetry is broken at the surface, but they do represent distinct phases of matter. For example, they possess nontrivial Berry phase structure in the Brillouin zone, which leads to robust entanglement signatures 13 , 14 , 16 , 17 and, in some cases, quantized responses 13 , 14 , 18 . Interestingly, in the absence of TR invariance the inversion eigenvalues can also protect Weyl semimetals 13 , 14 , which informed early work on materials candidates 19 . Hence, these symmetry-based indicators are relevant both to the search for nontrivial insulating phases, and also to the study of topological semimetals. It is also important to note that the goal here is to identify signatures of band topology in the symmetry transformations of the state, which is distinct from the full classification of topological phases. An important open problem is to extend these powerful symmetry indicators for band topology to all space groups (SGs). Earlier studies have emphasized the topological perspective, which typically rely on constructions that are specifically tailored to particular band topology of interest 8 , 15 , 20 , 21 . While some general mathematical frameworks have been developed 22 , 23 , 24 , obtaining a full list of concrete results from such an approach faces an inherent challenge stemming from the sheer multitude of physically relevant symmetry settings—there are 230 SGs in 3D, and each of them is further enriched by the presence or absence of both spin–orbit coupling and TR symmetry. A complementary, symmetry-focused perspective leverages the existing exhaustive results on band symmetries 25 , 26 to simplify the analysis. Previous work along these lines has covered restricted cases 13 , 14 , 27 , 28 . For instance, in ref. 28 , which focuses on systems in the wallpaper groups without any additional symmetry, such an approach was adopted to help develop a more physical understanding of the mathematical treatment of ref. 22 . However, the notion of nontriviality is a relative concept in these approaches. While such formulation is well-suited for the study of phase transitions between different systems in the same symmetry setting, it does not always indicate the presence of underlying band topology. As an extreme example, such classifications generally regard atomic insulators (AIs) with different electron fillings as distinct phases, although all the underlying BSs are topologically trivial. Here, we adopt a symmetry-based approach that focuses on probing the underlying band topology. At the crux of our analysis is the observation that topological BSs arise whenever there is a mismatch between momentum-space and real-space solutions to symmetry constraints 29 , 30 . To quantitatively expose such mismatches, we first develop a mathematical framework to efficiently analyze all possible BSs consistent with any symmetry setting, and then discuss how to identify the subset of BSs arising from AIs, which are formed by localizing electrons to definite orbitals in real space. The mentioned mismatch then follows naturally as the quotient between the allowed BSs and those arising from real-space specification. We compute this quotient for all 230 SGs with or without spin–orbit coupling and/or TR symmetry. Using these results, we highlight symmetry settings suitable for finding topological materials, including both insulators and semimetals. In particular, we will point out that, in the presence of inversion symmetry, stacking two strong 3D TIs will", "role": "user" }, { "content": "In the decades since they were first theorized, scientists have suggested that the exotic properties of topological materials—that is, materials that maintain their electrical properties even in the face of radical temperature shifts or structural deformation—could result in everything from more energy-efficient electronics to the development of novel superconductors and quantum computers. The problem, however, is that identifying the materials with those properties is frustratingly difficult. To speed up the process, Professor of Physics Ashvin Vishwanath and his colleagues conducted a series of studies to develop methods for efficiently identifying new materials that display topological properties. The first two, published in Nature Communications and Science Advances, and co-authored with MIT Fellow Hoi Chun \"Adrian\" Po, Ph.D. '18, and Professor Haruki Watanabe of Tokyo University, lay the groundwork for bridging the relevant abstract mathematical concepts with the pragmatic problem of materials discovery. The second, published in Nature this February and co-authored with Po and Feng Tang and Xingang Wan, from Nanjing University, demonstrates the power of the approach and predicts thousands of topological materials candidates. \"In the early days, a lot of effort was focused on being able to predict whether a material would be an insulator or metallic,\" Vishwanath said. \"About 10 or 20 years ago, though, people realized we could produce these topological materials.\" Topological materials defy this simple dichotomy. For example, they may have an electrically insulating interior, which is wrapped in a thin skin of metal. The presence of this metallic coating is protected by topology, a mathematical concept concerned with properties that are robust against small physical changes of the system. In other words, if you try to peel off the metallic skin of a topological insulator, the layer underneath will suddenly become metallic. \"Insight into the mathematics of these exotic materials would help us find real materials with these topological properties,\" Po said. \"Right now, the way people do this is really more of a guess … what we wanted to do is to come up with efficient ways of diagnosing whether the materials you're interested in have a good chance of having topological properties.\" The insight required provides a good understanding of how the behavior of the electrons is intertwined with the symmetries of a material's crystal structure, which can be viewed as an almost infinite array of atoms assembled into delicate patterns. These patterns often remain unchanged if you tilt your head by 90 degrees, or reflect them in a mirror. In physics this property is known as symmetry. In the first two papers, Vishwanath and his collaborators performed a systematic study on this intriguing intertwinement between electrons and symmetries. \"The first problem is the huge number of ways in which atoms can form crystals,\" he said. \"Even if you forget about the chemical complexity, forget about which elements are in there, just in the structure … just from symmetry considerations, there are 230 ways in which you can put atoms together into crystals.\" And the complexity doesn't end there. When magnetism is incorporated the number increases dramatically, from 230 to 1,651. One solution to the problem, Watanabe said, would be to simply test every possible combination to arrive at an eventual solution, but that doesn't offer any insight into what creates the topological states researchers are after. \"We took a different approach,\" he said. \"The key idea was … we found an efficient way to reformulate the problem such that the symmetry properties of electrons are mapped to coordinates in some high-dimensional space.\" These coordinates are like addresses, and the team was able to tell if a material was insulating, metallic, or topological based on its symmetry indicator— the analog of a postal code. Importantly, this \"postal code\" can be readily characterized. \"While the analysis of each magnetic space group would previously have taken a graduate student a day to figure out,\" Po said, \"our new formulation allows for a simple automation of the task, which is completed on a laptop for all 1,651 instances in half a day.\" The new Nature study builds on the ideas outlined in the earlier works, applying them to analyze existing material databases for the discovery of topological materials candidates. Working with collaborators in China, Vishwanath said, the team was able to quickly diagnose the topological properties of tens of thousands of materials using symmetry indicators. \"In a way, it's stage two,\" he said of the Nature study. \"It proves the utility of the symmetry indicators.\" \"It's not a complete free lunch,\" he said. \"It's not that you look at the crystal and analyze in detail what the electrons are doing. Rather, we're only looking at a very small aspect of a complicated system, so it's a bit like Sherlock Holmes—from a very few clues we can actually infer a lot about the characteristics of a system.\" The hope, Vishwanath said, is that these studies will pave the way for developing a \"library\" of topological materials that can then be further characterized and potentially used for a wide variety of applications. \"There are some materials which are predicted to have topological properties, but for which we don't have an example,\" he said. \"In other cases, we may only have one kind of topological state … but we may want to have others, not just the one example people have found before.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The interplay between symmetry and topology leads to a rich variety of electronic topological phases, protecting states such as the topological insulators and Dirac semimetals. Previous results, like the Fu-Kane parity criterion for inversion-symmetric topological insulators, demonstrate that symmetry labels can sometimes unambiguously indicate underlying band topology. Here we develop a systematic approach to expose all such symmetry-based indicators of band topology in all the 230 space groups. This is achieved by first developing an efficient way to represent band structures in terms of elementary basis states, and then isolating the topological ones by removing the subset of atomic insulators, defined by the existence of localized symmetric Wannier functions. Aside from encompassing all earlier results on such indicators, including in particular the notion of filling-enforced quantum band insulators, our theory identifies symmetry settings with previously hidden forms of band topology, and can be applied to the search for topological materials. Introduction The discovery of topological insulators (TIs) has reinvigorated the well-established theory of electronic band structures (BSs) 1 , 2 . Exploration along this dimension has led to an ever-growing arsenal of topological materials, which include, for instance, topological (crystalline) insulators 3 , 4 , 5 , quantum anomalous Hall insulators 6 and Weyl and Dirac semimetals 7 . Such materials possess unprecedented physical properties, like quantized response and gapless surface states, that are robust against all symmetry-preserving perturbations as long as a band picture remains valid 1 , 2 , 7 . Soon after these developments, it was realized that symmetries of energy bands, a thoroughly studied aspect of band theory, is also profoundly intertwined with topology. This is exemplified by the celebrated Fu-Kane criterion for inversion-symmetric materials, which demarcates TIs from trivial insulators using only their parity eigenvalues 8 . This criterion, when applicable, greatly simplifies the topological analysis of real materials, and underpins the theoretical prediction and subsequent experimental verification of many TIs 8 , 9 , 10 , 11 , 12 . It is of fundamental interest to obtain results akin to the Fu-Kane criterion in other symmetry settings. Early generalizations in systems without time-reversal (TR) symmetry in two-dimensional (2D) constrained the Chern number ( C ). The eigenvalues of an n -fold rotation were found to determine C modulo n 13 , 14 , 15 . This is characteristic of a symmetry-based indicator of topology—when the indicator is nonvanishing, band topology is guaranteed, but certain topological phases (i.e., C a multiple of n in this context) may be invisible to the indicator. In three-dimensional (3D) systems, it was also recognized that spatial inversion alone can protect nontrivial phases. A feature here is that these phases do not host protected surface states, since inversion symmetry is broken at the surface, but they do represent distinct phases of matter. For example, they possess nontrivial Berry phase structure in the Brillouin zone, which leads to robust entanglement signatures 13 , 14 , 16 , 17 and, in some cases, quantized responses 13 , 14 , 18 . Interestingly, in the absence of TR invariance the inversion eigenvalues can also protect Weyl semimetals 13 , 14 , which informed early work on materials candidates 19 . Hence, these symmetry-based indicators are relevant both to the search for nontrivial insulating phases, and also to the study of topological semimetals. It is also important to note that the goal here is to identify signatures of band topology in the symmetry transformations of the state, which is distinct from the full classification of topological phases. An important open problem is to extend these powerful symmetry indicators for band topology to all space groups (SGs). Earlier studies have emphasized the topological perspective, which typically rely on constructions that are specifically tailored to particular band topology of interest 8 , 15 , 20 , 21 . While some general mathematical frameworks have been developed 22 , 23 , 24 , obtaining a full list of concrete results from such an approach faces an inherent challenge stemming from the sheer multitude of physically relevant symmetry settings—there are 230 SGs in 3D, and each of them is further enriched by the presence or absence of both spin–orbit coupling and TR symmetry. A complementary, symmetry-focused perspective leverages the existing exhaustive results on band symmetries 25 , 26 to simplify the analysis. Previous work along these lines has covered restricted cases 13 , 14 , 27 , 28 . For instance, in ref. 28 , which focuses on systems in the wallpaper groups without any additional symmetry, such an approach was adopted to help develop a more physical understanding of the mathematical treatment of ref. 22 . However, the notion of nontriviality is a relative concept in these approaches. While such formulation is well-suited for the study of phase transitions between different systems in the same symmetry setting, it does not always indicate the presence of underlying band topology. As an extreme example, such classifications generally regard atomic insulators (AIs) with different electron fillings as distinct phases, although all the underlying BSs are topologically trivial. Here, we adopt a symmetry-based approach that focuses on probing the underlying band topology. At the crux of our analysis is the observation that topological BSs arise whenever there is a mismatch between momentum-space and real-space solutions to symmetry constraints 29 , 30 . To quantitatively expose such mismatches, we first develop a mathematical framework to efficiently analyze all possible BSs consistent with any symmetry setting, and then discuss how to identify the subset of BSs arising from AIs, which are formed by localizing electrons to definite orbitals in real space. The mentioned mismatch then follows naturally as the quotient between the allowed BSs and those arising from real-space specification. We compute this quotient for all 230 SGs with or without spin–orbit coupling and/or TR symmetry. Using these results, we highlight symmetry settings suitable for finding topological materials, including both insulators and semimetals. In particular, we will point out that, in the presence of inversion symmetry, stacking two strong 3D TIs will<|im_end|> <|im_start|>assistant In the decades since they were first theorized, scientists have suggested that the exotic properties of topological materials—that is, materials that maintain their electrical properties even in the face of radical temperature shifts or structural deformation—could result in everything from more energy-efficient electronics to the development of novel superconductors and quantum computers. The problem, however, is that identifying the materials with those properties is frustratingly difficult. To speed up the process, Professor of Physics Ashvin Vishwanath and his colleagues conducted a series of studies to develop methods for efficiently identifying new materials that display topological properties. The first two, published in Nature Communications and Science Advances, and co-authored with MIT Fellow Hoi Chun "Adrian" Po, Ph.D. '18, and Professor Haruki Watanabe of Tokyo University, lay the groundwork for bridging the relevant abstract mathematical concepts with the pragmatic problem of materials discovery. The second, published in Nature this February and co-authored with Po and Feng Tang and Xingang Wan, from Nanjing University, demonstrates the power of the approach and predicts thousands of topological materials candidates. "In the early days, a lot of effort was focused on being able to predict whether a material would be an insulator or metallic," Vishwanath said. "About 10 or 20 years ago, though, people realized we could produce these topological materials." Topological materials defy this simple dichotomy. For example, they may have an electrically insulating interior, which is wrapped in a thin skin of metal. The presence of this metallic coating is protected by topology, a mathematical concept concerned with properties that are robust against small physical changes of the system. In other words, if you try to peel off the metallic skin of a topological insulator, the layer underneath will suddenly become metallic. "Insight into the mathematics of these exotic materials would help us find real materials with these topological properties," Po said. "Right now, the way people do this is really more of a guess … what we wanted to do is to come up with efficient ways of diagnosing whether the materials you're interested in have a good chance of having topological properties." The insight required provides a good understanding of how the behavior of the electrons is intertwined with the symmetries of a material's crystal structure, which can be viewed as an almost infinite array of atoms assembled into delicate patterns. These patterns often remain unchanged if you tilt your head by 90 degrees, or reflect them in a mirror. In physics this property is known as symmetry. In the first two papers, Vishwanath and his collaborators performed a systematic study on this intriguing intertwinement between electrons and symmetries. "The first problem is the huge number of ways in which atoms can form crystals," he said. "Even if you forget about the chemical complexity, forget about which elements are in there, just in the structure … just from symmetry considerations, there are 230 ways in which you can put atoms together into crystals." And the complexity doesn't end there. When magnetism is incorporated the number increases dramatically, from 230 to 1,651. One solution to the problem, Watanabe said, would be to simply test every possible combination to arrive at an eventual solution, but that doesn't offer any insight into what creates the topological states researchers are after. "We took a different approach," he said. "The key idea was … we found an efficient way to reformulate the problem such that the symmetry properties of electrons are mapped to coordinates in some high-dimensional space." These coordinates are like addresses, and the team was able to tell if a material was insulating, metallic, or topological based on its symmetry indicator— the analog of a postal code. Importantly, this "postal code" can be readily characterized. "While the analysis of each magnetic space group would previously have taken a graduate student a day to figure out," Po said, "our new formulation allows for a simple automation of the task, which is completed on a laptop for all 1,651 instances in half a day." The new Nature study builds on the ideas outlined in the earlier works, applying them to analyze existing material databases for the discovery of topological materials candidates. Working with collaborators in China, Vishwanath said, the team was able to quickly diagnose the topological properties of tens of thousands of materials using symmetry indicators. "In a way, it's stage two," he said of the Nature study. "It proves the utility of the symmetry indicators." "It's not a complete free lunch," he said. "It's not that you look at the crystal and analyze in detail what the electrons are doing. Rather, we're only looking at a very small aspect of a complicated system, so it's a bit like Sherlock Holmes—from a very few clues we can actually infer a lot about the characteristics of a system." The hope, Vishwanath said, is that these studies will pave the way for developing a "library" of topological materials that can then be further characterized and potentially used for a wide variety of applications. "There are some materials which are predicted to have topological properties, but for which we don't have an example," he said. "In other cases, we may only have one kind of topological state … but we may want to have others, not just the one example people have found before." <|im_end|>

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2,441

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Bacteria can form biofilms that consist of multicellular communities embedded in an extracellular matrix (ECM). In Bacillus subtilis , the main protein component of the ECM is the functional amyloid TasA. Here, we study further the roles played by TasA in B. subtilis physiology and biofilm formation on plant leaves and in vitro. We show that Δ tasA cells exhibit a range of cytological symptoms indicative of excessive cellular stress leading to increased cell death. TasA associates to the detergent-resistant fraction of the cell membrane, and the distribution of the flotillin-like protein FloT is altered in Δ tasA cells. We propose that, in addition to a structural function during ECM assembly and interactions with plants, TasA contributes to the stabilization of membrane dynamics as cells enter stationary phase. Introduction In response to a wide range of environmental factors 1 , 2 , some bacterial species establish complex communities called biofilms 3 . To do so, planktonic cells initiate a transition into a sedentary lifestyle and trigger a cell differentiation program that leads to: (1) a division of labor, in which different subpopulations of cells are dedicated to covering different processes needed to maintain the viability of the community 4 , 5 , and (2) the secretion of a battery of molecules that assemble the extracellular matrix (ECM) 3 , 6 . Studies of Bacillus subtilis biofilms have contributed to our understanding of the intricate developmental program that underlies biofilm formation 7 , 8 , 9 , 10 that ends with the secretion of ECM components. It is known that the genetic pathways involved in biofilm formation are active during the interaction of several microbial species with plants 11 , 12 . In B. subtilis , the lipopeptide surfactin acts as a self-trigger of biofilm formation on the melon phylloplane, which is connected with the suppressive activity of this bacterial species against phytopathogenic fungi 13 . Currently, the B. subtilis ECM is known to consist mainly of exopolysaccharide (EPS) and the TasA and BslA proteins 7 . The EPS acts as the adhesive element of the biofilm cells at the cell-to-surface interface, which is important for biofilm attachment 14 , and BslA is a hydrophobin that forms a thin external hydrophobic layer and is the main factor that confers hydrophobic properties to biofilms 15 . Both structural factors contribute to maintain the defense function performed by the ECM 11 , 15 . TasA is a functional amyloid protein that forms fibers resistant to adverse physicochemical conditions that confer biofilms with structural stability 16 , 17 . Additional proteins are needed for the polymerization of these fibers: TapA appears to favor the transition of TasA into the fiber state, and the signal peptidase SipW processes both proteins into their mature forms 18 , 19 . The ability of amyloids to transition from monomers into fibers represents a structural, biochemical, and functional versatility that microbes exploit in different contexts and for different purposes 20 . Like in eukaryotic tissues, the bacterial ECM is a dynamic structure that supports cellular adhesion, regulates the flux of signals to ensure cell differentiation 21 , 22 , provides stability and serves as an interface with the external environment, working as a formidable physicochemical barrier against external assaults 23 , 24 , 25 . In eukaryotic cells, the ECM plays an important role in signaling 26 , 27 and has been described as a reservoir for the localization and concentration of growth factors, which in turn form gradients that are critical for the establishment of developmental patterning during morphogenesis 28 , 29 , 30 . Interestingly, in senescent cells, partial loss of the ECM can influence cell fate, e.g., by activating the apoptotic program 31 , 32 . In both eukaryotes and prokaryotes, senescence involves global changes in cellular physiology, and in some microbes, this process begins with the entry of the cells into stationary phase 33 , 34 , 35 . This process triggers a response typified by molecular mechanisms evolved to overcome environmental adversities and to ensure survival, including the activation of general stress response genes 36 , 37 , a shift to anaerobic respiration 38 , enhanced DNA repair 39 , and induction of pathways for the metabolism of alternative nutrient sources or sub-products of primary metabolism 40 . Based on previous works 13 , we hypothesize that the ECM makes a major contribution to the ecology of B. subtilis in the poorly explored phyllosphere. Our study of the ecology of B. subtilis NCIB3610-derived strains carrying single mutations in different ECM components in the phyllosphere highlights the role of TasA in bacteria-plant interactions. Moreover, we demonstrate a complementary role for TasA in the stabilization of the bacteria’s physiology. In Δ tasA cells, gene expression changes and dynamic cytological alterations eventually lead to a premature increase in cell death within the colony. Complementary evidences prove that these alterations are independent of the structural role of TasA in ECM assembly. All these results indicate that these two complementary roles of TasA, both as part of the ECM and in contributing to the regulation of cell membrane dynamics, are important to preserve cell viability within the colony and for the ecological fitness of B. subtilis in the phylloplane. Results TasA contributes to the fitness of Bacillus on the phylloplane Surfactin, a member of a subfamily of lipopeptides produced by B. subtilis and related species, contributes to multicellularity in B. subtilis biofilms 41 . We previously reported how a mutant strain defective for lipopeptide production showed impaired biofilm assembly on the phylloplane 13 . These observations led us to evaluate the specific contributions made by the ECM structural components TasA and the EPS to B. subtilis fitness on melon leaves. Although not directly linked to the surfactin-activated regulatory pathway, we also studied the gene encoding the hydrophobin protein BslA (another important ECM component). A tasA mutant strain (Δ tasA ) is defective in the initial cell attachment to plant surfaces (4 h and 2 days post-inoculation) (Fig. 1A", "role": "user" }, { "content": "The laboratory of the UMA \"BacBio\" has proved that Bacillus subtilis cells, when deprived of an amyloid protein (TasA), exhibit a range of cytological anomalies and dysfunctions leading to their premature death. This discovery enables progress to be made in understanding the role of these proteins, widely distributed in the microbial world, and helps improve biological control methods in sustainable agriculture. This research has been recently published in the scientific journal Nature Communications. The UMA research team has particularly evidenced how this amyloid protein TasA, required for the assembly of the bacterial communities known as \"biofilms,\" also prevents bacterial cell death, but preserves cell membrane integrity. \"That is, we observed a complementary role in these proteins in addition to their merely structural role,\" explains the main author of this study, the researcher Diego Romero, who is also a member of the Institute for Mediterranean and Subtropical Horticulture \"La Mayora\" (IHSM), a joint research institute of the Spanish National Research Council (CSIC) and the UMA. According to the expert, this dual functionality is reflected in bacterial attachment to plant surfaces, where the protein contributes to combat pathogen attack and improve bacterial fitness. \"We aim to boost its use in sustainable models of crop production and protection,\" says the Professor of the UMA Department of Microbiology. Thus, this study has worked on the bacterium Bacillus subtilis placing emphasis on two aspects: the study of its molecular bases, that lead to the formation of bacterial communities known as \"biofilms,\" and how these biofilms contribute to the beneficial activity of Bacillus as a biocontrol agent in sustainable agriculture models. The amyloids: Dual functionality Amyloids are proteins primarily known for their relation to degenerative diseases in human beings. In fact, \"amyloidosis,\" an ailment caused by amyloid accumulation in organs or tissues, is named after them. However, as noted by this research, amyloid proteins (TasA among them) have the ability to adopt a great variety of purposes in nature, the reason why they are called functional amyloids. \"The fact that these proteins are widely distributed in the microbial world entails the possibility that they might play a role in other bacterial species stabilizing cell integrity, or at least a different and complementary role to that initially observed in each of these systems,\" clarifies Romero. The expert states that the importance of these results is twofold. From the agrobiotechnological point of view, it allows researchers to better understand the behaviour of beneficial bacteria,and hence to improve and reinforce its use in sustainable production and protection programmes. On the other hand, from the microbial point of view, where amyloid proteins are highly distributed, a new target has been identified for attack should they wish to target pathogenic microorganisms. The study has been supported by funding granted by the European Research Council (ERC-StG programme), which promotes top-quality research projects, and the Spanish Ministry of Economy and Competitiveness. BacBio Laboratory, located in the Bioinnovation building of the UMA, has been studying bacteria physiology and their interaction with the environment since 2013. Plants are another priority line of research, particularly the Cucurbitaceae, a plant family which comprises melon and cucumber. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Bacteria can form biofilms that consist of multicellular communities embedded in an extracellular matrix (ECM). In Bacillus subtilis , the main protein component of the ECM is the functional amyloid TasA. Here, we study further the roles played by TasA in B. subtilis physiology and biofilm formation on plant leaves and in vitro. We show that Δ tasA cells exhibit a range of cytological symptoms indicative of excessive cellular stress leading to increased cell death. TasA associates to the detergent-resistant fraction of the cell membrane, and the distribution of the flotillin-like protein FloT is altered in Δ tasA cells. We propose that, in addition to a structural function during ECM assembly and interactions with plants, TasA contributes to the stabilization of membrane dynamics as cells enter stationary phase. Introduction In response to a wide range of environmental factors 1 , 2 , some bacterial species establish complex communities called biofilms 3 . To do so, planktonic cells initiate a transition into a sedentary lifestyle and trigger a cell differentiation program that leads to: (1) a division of labor, in which different subpopulations of cells are dedicated to covering different processes needed to maintain the viability of the community 4 , 5 , and (2) the secretion of a battery of molecules that assemble the extracellular matrix (ECM) 3 , 6 . Studies of Bacillus subtilis biofilms have contributed to our understanding of the intricate developmental program that underlies biofilm formation 7 , 8 , 9 , 10 that ends with the secretion of ECM components. It is known that the genetic pathways involved in biofilm formation are active during the interaction of several microbial species with plants 11 , 12 . In B. subtilis , the lipopeptide surfactin acts as a self-trigger of biofilm formation on the melon phylloplane, which is connected with the suppressive activity of this bacterial species against phytopathogenic fungi 13 . Currently, the B. subtilis ECM is known to consist mainly of exopolysaccharide (EPS) and the TasA and BslA proteins 7 . The EPS acts as the adhesive element of the biofilm cells at the cell-to-surface interface, which is important for biofilm attachment 14 , and BslA is a hydrophobin that forms a thin external hydrophobic layer and is the main factor that confers hydrophobic properties to biofilms 15 . Both structural factors contribute to maintain the defense function performed by the ECM 11 , 15 . TasA is a functional amyloid protein that forms fibers resistant to adverse physicochemical conditions that confer biofilms with structural stability 16 , 17 . Additional proteins are needed for the polymerization of these fibers: TapA appears to favor the transition of TasA into the fiber state, and the signal peptidase SipW processes both proteins into their mature forms 18 , 19 . The ability of amyloids to transition from monomers into fibers represents a structural, biochemical, and functional versatility that microbes exploit in different contexts and for different purposes 20 . Like in eukaryotic tissues, the bacterial ECM is a dynamic structure that supports cellular adhesion, regulates the flux of signals to ensure cell differentiation 21 , 22 , provides stability and serves as an interface with the external environment, working as a formidable physicochemical barrier against external assaults 23 , 24 , 25 . In eukaryotic cells, the ECM plays an important role in signaling 26 , 27 and has been described as a reservoir for the localization and concentration of growth factors, which in turn form gradients that are critical for the establishment of developmental patterning during morphogenesis 28 , 29 , 30 . Interestingly, in senescent cells, partial loss of the ECM can influence cell fate, e.g., by activating the apoptotic program 31 , 32 . In both eukaryotes and prokaryotes, senescence involves global changes in cellular physiology, and in some microbes, this process begins with the entry of the cells into stationary phase 33 , 34 , 35 . This process triggers a response typified by molecular mechanisms evolved to overcome environmental adversities and to ensure survival, including the activation of general stress response genes 36 , 37 , a shift to anaerobic respiration 38 , enhanced DNA repair 39 , and induction of pathways for the metabolism of alternative nutrient sources or sub-products of primary metabolism 40 . Based on previous works 13 , we hypothesize that the ECM makes a major contribution to the ecology of B. subtilis in the poorly explored phyllosphere. Our study of the ecology of B. subtilis NCIB3610-derived strains carrying single mutations in different ECM components in the phyllosphere highlights the role of TasA in bacteria-plant interactions. Moreover, we demonstrate a complementary role for TasA in the stabilization of the bacteria’s physiology. In Δ tasA cells, gene expression changes and dynamic cytological alterations eventually lead to a premature increase in cell death within the colony. Complementary evidences prove that these alterations are independent of the structural role of TasA in ECM assembly. All these results indicate that these two complementary roles of TasA, both as part of the ECM and in contributing to the regulation of cell membrane dynamics, are important to preserve cell viability within the colony and for the ecological fitness of B. subtilis in the phylloplane. Results TasA contributes to the fitness of Bacillus on the phylloplane Surfactin, a member of a subfamily of lipopeptides produced by B. subtilis and related species, contributes to multicellularity in B. subtilis biofilms 41 . We previously reported how a mutant strain defective for lipopeptide production showed impaired biofilm assembly on the phylloplane 13 . These observations led us to evaluate the specific contributions made by the ECM structural components TasA and the EPS to B. subtilis fitness on melon leaves. Although not directly linked to the surfactin-activated regulatory pathway, we also studied the gene encoding the hydrophobin protein BslA (another important ECM component). A tasA mutant strain (Δ tasA ) is defective in the initial cell attachment to plant surfaces (4 h and 2 days post-inoculation) (Fig. 1A<|im_end|> <|im_start|>assistant The laboratory of the UMA "BacBio" has proved that Bacillus subtilis cells, when deprived of an amyloid protein (TasA), exhibit a range of cytological anomalies and dysfunctions leading to their premature death. This discovery enables progress to be made in understanding the role of these proteins, widely distributed in the microbial world, and helps improve biological control methods in sustainable agriculture. This research has been recently published in the scientific journal Nature Communications. The UMA research team has particularly evidenced how this amyloid protein TasA, required for the assembly of the bacterial communities known as "biofilms," also prevents bacterial cell death, but preserves cell membrane integrity. "That is, we observed a complementary role in these proteins in addition to their merely structural role," explains the main author of this study, the researcher Diego Romero, who is also a member of the Institute for Mediterranean and Subtropical Horticulture "La Mayora" (IHSM), a joint research institute of the Spanish National Research Council (CSIC) and the UMA. According to the expert, this dual functionality is reflected in bacterial attachment to plant surfaces, where the protein contributes to combat pathogen attack and improve bacterial fitness. "We aim to boost its use in sustainable models of crop production and protection," says the Professor of the UMA Department of Microbiology. Thus, this study has worked on the bacterium Bacillus subtilis placing emphasis on two aspects: the study of its molecular bases, that lead to the formation of bacterial communities known as "biofilms," and how these biofilms contribute to the beneficial activity of Bacillus as a biocontrol agent in sustainable agriculture models. The amyloids: Dual functionality Amyloids are proteins primarily known for their relation to degenerative diseases in human beings. In fact, "amyloidosis," an ailment caused by amyloid accumulation in organs or tissues, is named after them. However, as noted by this research, amyloid proteins (TasA among them) have the ability to adopt a great variety of purposes in nature, the reason why they are called functional amyloids. "The fact that these proteins are widely distributed in the microbial world entails the possibility that they might play a role in other bacterial species stabilizing cell integrity, or at least a different and complementary role to that initially observed in each of these systems," clarifies Romero. The expert states that the importance of these results is twofold. From the agrobiotechnological point of view, it allows researchers to better understand the behaviour of beneficial bacteria,and hence to improve and reinforce its use in sustainable production and protection programmes. On the other hand, from the microbial point of view, where amyloid proteins are highly distributed, a new target has been identified for attack should they wish to target pathogenic microorganisms. The study has been supported by funding granted by the European Research Council (ERC-StG programme), which promotes top-quality research projects, and the Spanish Ministry of Economy and Competitiveness. BacBio Laboratory, located in the Bioinnovation building of the UMA, has been studying bacteria physiology and their interaction with the environment since 2013. Plants are another priority line of research, particularly the Cucurbitaceae, a plant family which comprises melon and cucumber. <|im_end|>

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2,030

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The removal of ethane (C 2 H 6 ) from its analogous ethylene (C 2 H 4 ) is of paramount importance in the petrochemical industry, but highly challenging due to their similar physicochemical properties. The use of emerging porous organic cage (POC) materials for C 2 H 6 /C 2 H 4 separation is still in its infancy. Here, we report the benchmark example of a truncated octahedral calix[4]resorcinarene-based POC adsorbent (CPOC-301), preferring to adsorb C 2 H 6 than C 2 H 4 , and thus can be used as a robust absorbent to directly separate high-purity C 2 H 4 from the C 2 H 6 /C 2 H 4 mixture. Molecular modelling studies suggest the exceptional C 2 H 6 selectivity is due to the suitable resorcin[4]arene cavities in CPOC-301, which form more multiple C–H···π hydrogen bonds with C 2 H 6 than with C 2 H 4 guests. This work provides a fresh avenue to utilize POC materials for highly selective separation of industrially important hydrocarbons. Introduction Ethylene (C 2 H 4 ), the largest feedstock in petrochemical industries with a global production capacity of more than 170 million tons in 2018, exceeds any other chemical feedstock molecules for its wide application in polyethylene manufacture 1 . The industrial separation of C 2 H 4 from ethane (C 2 H 6 ) is typically through cryogenic distillation at high pressure and very low temperature, using very high towers, because they have similar sizes and volatilities 2 . Such a process is highly energy consuming, and thus exploring of other effective C 2 H 4 separation methods at ambient conditions is highly demanded. Selective adsorption by porous materials for producing high-purity C 2 H 4 has been determined to be one of the most desired methods for its low energy consumption 3 , 4 . Of particular recent interest in this regard is using C 2 H 6 -selective porous materials enriched with nonpolar/inert surfaces (e.g., introducing aromatic or aliphatic entities), because they prefer to capture more polarizable C 2 H 6 , and thus can directly afford high-purity C 2 H 4 in a single adsorption step, avoiding an additional high-energy-consuming desorption step 5 , 6 . So far, most of the developed C 2 H 6 -selective adsorbents are metal-containing materials 6 , 7 , 8 , 9 , 10 . However, the polar metal centers in these materials can interact with unsaturated C 2 H 4 molecules via strong π-complexation interactions, and thus weaken their C 2 H 6 /C 2 H 4 separation abilities 11 . Therefore, developing other C 2 H 6 -selective adsorbents such as metal-free organic porous materials is highly required 12 , 13 , because they cannot only avoid the abovementioned problem, but also are easier to construct inert surfaces. However, the research of such materials is still in its initial stage 14 , 15 . Porous organic cages (POCs), as a type of porous materials, are intrinsically porous given their hollow cavities 16 , 17 , 18 , 19 , 20 , 21 . The discrete inherent nature of POCs makes them possessing distinct benefits in solution processing, regeneration as well as post-synthesis modification 21 , 22 , 23 , 24 . Following the first elegant research reported in 2009 by Cooper et al. 25 , the number of POCs with different shapes, sizes and properties has increased substantially 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , but robust POCs with high surface areas are still few, which highly hinder their practical use in gas storage as well as separation. Over the past decade, although Brunauer–Emmett–Teller (BET) surface areas of POCs have increased from the initial 624 to 3758 m 2 g –1 , most of POCs have BET values <1000 m 2 /g 37 , 38 . As for binary gas mixture separation, Cooper et al. first reported that imine-linked tetrahedral POC (CC3) exhibits selectivity of 20.4 for noble gas Xe/Kr separations at low concentrations in 2014 39 . Two years later, they showed that CC3 could also separate sulfur hexafluoride (SF 6 ), a much more potent greenhouse gas than carbon dioxide, from nitrogen (N 2 ) with the highest SF 6 /N 2 selectivity reported for any material under ambient conditions 40 . The selectivity for the abovementioned two cases arises from the precise size matching between Xe and SF 6 with organic cage cavity than Kr and N 2 , respectively. In 2019, their team utilized post modification synthesis method to alter internal cavities of CC3 to produce hybrid cocrystal material (6ET-RCC3-R/CC3-S), which are excellent quantum sieves for hydrogen isotope separation with excellent deuterium/hydrogen selectivity (8.0) 41 . In the same year, Zhang’s and Zaworotko’s groups presented a soft imide-based POC (NKPOC-1) with gate opening behavior and could efficiently separate binary or ternary C3 hydrocarbon mixtures 42 . Up to now, POC adsorbents have only been limited to separate the above gas components by mixed gas experiments, and thus there is still much room to explore POC materials for real gas separation applications, especially for industrially important gases. Calix[4]resorcinarenes, a subset of calixarenes, were derived from acid-catalyzed condensation between resorcinol and various kinds of aldehydes 43 , 44 , 45 . They possess electron-rich π cavities and eight upper-rim phenolic groups, and are effective hosts for inclusion of various guests ranging from small gases to large organic molecules 45 , 46 , 47 , 48 , 49 . Notably, their upper rims can be easily functionalized, making them good molecular building blocks for constructing self-assembled cages as well as porous polymers 50 , 51 , 52 , 53 , 54 , 55 , 56 . Very recently, our group employed predesigned concave-shaped tetraformylresorcin[4]arene (RC4ACHO) as secondary building blocks and different diamines as linkers to systematically design and synthesize several porous POCs with structural diversity from [2 + 4]", "role": "user" }, { "content": "The removal of ethane (C2H6) from its analogous ethylene (C2H4) is of great importance in the petrochemical industry, and is highly challenging due to their similar physicochemical properties. The use of emerging porous organic cage (POC) materials for C2H6/C2H4 separation is still in its infancy. Calix[4]resorcinarene, a kind of macrocyclic cavitand with an intrinsic cavity and eigh polar upper-rim phenolic groups, has been documented as excellent building block to construct cage compounds with tunable cavities for encapsulating various guest molecules. In a study published in Nature Communications, the research group led by Prof. Yuan Daqiang from Fujian Institute of Research on the Structure of Matter of the Chinese Academy of Sciences reported that a [6+12] octahedral calix[4]resorcinarene-based POC (CPOC-301) is an excellent C2H6 -selective material, and can be used as a robust absorbent to directly afford high-purity C2H4 from C2H6/C2H4 mixture. The researchers prepared CPOC-301 via self-assembly of tetraformylresorcin[4]arene and p-phenylenediamine under mild condition. Single-crystal X-ray diffraction revealed that CPOC-301 has a truncated octahedron structure, with eight trigonal ports having edge length reaching about 12 Å, and a large cavity with inner diameter as well as volume that respectively reach 16.8 Å and 4270 Å3. The solid-state packing of CPOC-301 suggested that it possesses a one-dimensional channel, with a diameter of ~7 Å, viewed from [001] direction. The nitrogen (N2) gas adsorption isotherm of CPOC-301 showed a typical type I curve with a small fraction of a type IV adsorption behavior. The maximum N2 adsorption is 670 cm3 g-1, and the calculated Brunauer–Emmett–Teller (BET) of CPOC-301 is up to 1962 m2 g-1. Moreover, CPOC-301 exhibited preferential adsorption of C2H6 over C2H4 at room temperature. The ideal adsorbed solution theory (IAST) calculation result demonstrated that C2H6/C2H4 selectivity range for CPOC-301 is from 1.3 to 1.4 at 293 K. The breakthrough curves further proved that CPOC-301 can efficiently realize the complete separation of C2H4 from C2H6/C2H4 mixtures, and its separation performance does not obviously change within seven continuous cycles. Molecular modeling studies suggested the exceptional C2H6 selectivity is due to the suitable resorcin[4]arene cavities in CPOC-301, which form more multiple C–H···π hydrogen bonds with C2H6 than with C2H4 guests. This study sheds light on the design and synthesis of POCs based on supramolecular cavitands as \"porous additives\" in column and membrane separation applications for industrially important gases in the future. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The removal of ethane (C 2 H 6 ) from its analogous ethylene (C 2 H 4 ) is of paramount importance in the petrochemical industry, but highly challenging due to their similar physicochemical properties. The use of emerging porous organic cage (POC) materials for C 2 H 6 /C 2 H 4 separation is still in its infancy. Here, we report the benchmark example of a truncated octahedral calix[4]resorcinarene-based POC adsorbent (CPOC-301), preferring to adsorb C 2 H 6 than C 2 H 4 , and thus can be used as a robust absorbent to directly separate high-purity C 2 H 4 from the C 2 H 6 /C 2 H 4 mixture. Molecular modelling studies suggest the exceptional C 2 H 6 selectivity is due to the suitable resorcin[4]arene cavities in CPOC-301, which form more multiple C–H···π hydrogen bonds with C 2 H 6 than with C 2 H 4 guests. This work provides a fresh avenue to utilize POC materials for highly selective separation of industrially important hydrocarbons. Introduction Ethylene (C 2 H 4 ), the largest feedstock in petrochemical industries with a global production capacity of more than 170 million tons in 2018, exceeds any other chemical feedstock molecules for its wide application in polyethylene manufacture 1 . The industrial separation of C 2 H 4 from ethane (C 2 H 6 ) is typically through cryogenic distillation at high pressure and very low temperature, using very high towers, because they have similar sizes and volatilities 2 . Such a process is highly energy consuming, and thus exploring of other effective C 2 H 4 separation methods at ambient conditions is highly demanded. Selective adsorption by porous materials for producing high-purity C 2 H 4 has been determined to be one of the most desired methods for its low energy consumption 3 , 4 . Of particular recent interest in this regard is using C 2 H 6 -selective porous materials enriched with nonpolar/inert surfaces (e.g., introducing aromatic or aliphatic entities), because they prefer to capture more polarizable C 2 H 6 , and thus can directly afford high-purity C 2 H 4 in a single adsorption step, avoiding an additional high-energy-consuming desorption step 5 , 6 . So far, most of the developed C 2 H 6 -selective adsorbents are metal-containing materials 6 , 7 , 8 , 9 , 10 . However, the polar metal centers in these materials can interact with unsaturated C 2 H 4 molecules via strong π-complexation interactions, and thus weaken their C 2 H 6 /C 2 H 4 separation abilities 11 . Therefore, developing other C 2 H 6 -selective adsorbents such as metal-free organic porous materials is highly required 12 , 13 , because they cannot only avoid the abovementioned problem, but also are easier to construct inert surfaces. However, the research of such materials is still in its initial stage 14 , 15 . Porous organic cages (POCs), as a type of porous materials, are intrinsically porous given their hollow cavities 16 , 17 , 18 , 19 , 20 , 21 . The discrete inherent nature of POCs makes them possessing distinct benefits in solution processing, regeneration as well as post-synthesis modification 21 , 22 , 23 , 24 . Following the first elegant research reported in 2009 by Cooper et al. 25 , the number of POCs with different shapes, sizes and properties has increased substantially 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , but robust POCs with high surface areas are still few, which highly hinder their practical use in gas storage as well as separation. Over the past decade, although Brunauer–Emmett–Teller (BET) surface areas of POCs have increased from the initial 624 to 3758 m 2 g –1 , most of POCs have BET values <1000 m 2 /g 37 , 38 . As for binary gas mixture separation, Cooper et al. first reported that imine-linked tetrahedral POC (CC3) exhibits selectivity of 20.4 for noble gas Xe/Kr separations at low concentrations in 2014 39 . Two years later, they showed that CC3 could also separate sulfur hexafluoride (SF 6 ), a much more potent greenhouse gas than carbon dioxide, from nitrogen (N 2 ) with the highest SF 6 /N 2 selectivity reported for any material under ambient conditions 40 . The selectivity for the abovementioned two cases arises from the precise size matching between Xe and SF 6 with organic cage cavity than Kr and N 2 , respectively. In 2019, their team utilized post modification synthesis method to alter internal cavities of CC3 to produce hybrid cocrystal material (6ET-RCC3-R/CC3-S), which are excellent quantum sieves for hydrogen isotope separation with excellent deuterium/hydrogen selectivity (8.0) 41 . In the same year, Zhang’s and Zaworotko’s groups presented a soft imide-based POC (NKPOC-1) with gate opening behavior and could efficiently separate binary or ternary C3 hydrocarbon mixtures 42 . Up to now, POC adsorbents have only been limited to separate the above gas components by mixed gas experiments, and thus there is still much room to explore POC materials for real gas separation applications, especially for industrially important gases. Calix[4]resorcinarenes, a subset of calixarenes, were derived from acid-catalyzed condensation between resorcinol and various kinds of aldehydes 43 , 44 , 45 . They possess electron-rich π cavities and eight upper-rim phenolic groups, and are effective hosts for inclusion of various guests ranging from small gases to large organic molecules 45 , 46 , 47 , 48 , 49 . Notably, their upper rims can be easily functionalized, making them good molecular building blocks for constructing self-assembled cages as well as porous polymers 50 , 51 , 52 , 53 , 54 , 55 , 56 . Very recently, our group employed predesigned concave-shaped tetraformylresorcin[4]arene (RC4ACHO) as secondary building blocks and different diamines as linkers to systematically design and synthesize several porous POCs with structural diversity from [2 + 4]<|im_end|> <|im_start|>assistant The removal of ethane (C2H6) from its analogous ethylene (C2H4) is of great importance in the petrochemical industry, and is highly challenging due to their similar physicochemical properties. The use of emerging porous organic cage (POC) materials for C2H6/C2H4 separation is still in its infancy. Calix[4]resorcinarene, a kind of macrocyclic cavitand with an intrinsic cavity and eigh polar upper-rim phenolic groups, has been documented as excellent building block to construct cage compounds with tunable cavities for encapsulating various guest molecules. In a study published in Nature Communications, the research group led by Prof. Yuan Daqiang from Fujian Institute of Research on the Structure of Matter of the Chinese Academy of Sciences reported that a [6+12] octahedral calix[4]resorcinarene-based POC (CPOC-301) is an excellent C2H6 -selective material, and can be used as a robust absorbent to directly afford high-purity C2H4 from C2H6/C2H4 mixture. The researchers prepared CPOC-301 via self-assembly of tetraformylresorcin[4]arene and p-phenylenediamine under mild condition. Single-crystal X-ray diffraction revealed that CPOC-301 has a truncated octahedron structure, with eight trigonal ports having edge length reaching about 12 Å, and a large cavity with inner diameter as well as volume that respectively reach 16.8 Å and 4270 Å3. The solid-state packing of CPOC-301 suggested that it possesses a one-dimensional channel, with a diameter of ~7 Å, viewed from [001] direction. The nitrogen (N2) gas adsorption isotherm of CPOC-301 showed a typical type I curve with a small fraction of a type IV adsorption behavior. The maximum N2 adsorption is 670 cm3 g-1, and the calculated Brunauer–Emmett–Teller (BET) of CPOC-301 is up to 1962 m2 g-1. Moreover, CPOC-301 exhibited preferential adsorption of C2H6 over C2H4 at room temperature. The ideal adsorbed solution theory (IAST) calculation result demonstrated that C2H6/C2H4 selectivity range for CPOC-301 is from 1.3 to 1.4 at 293 K. The breakthrough curves further proved that CPOC-301 can efficiently realize the complete separation of C2H4 from C2H6/C2H4 mixtures, and its separation performance does not obviously change within seven continuous cycles. Molecular modeling studies suggested the exceptional C2H6 selectivity is due to the suitable resorcin[4]arene cavities in CPOC-301, which form more multiple C–H···π hydrogen bonds with C2H6 than with C2H4 guests. This study sheds light on the design and synthesis of POCs based on supramolecular cavitands as "porous additives" in column and membrane separation applications for industrially important gases in the future. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Hybrid materials composed of metal nanoparticles and metal-organic frameworks have attracted attention for various applications because of the synergistic functionality between their constituent materials. Interfacial interaction is expected however the mechanism remains ambiguous. Here we report the valence bands of palladium nanocubes covered by copper(II) 1, 3, 5-benzenetricarboxylate (HKUST-1), denoted as Pd@HKUST-1, and the charge transfer from the palladium nanocubes to HKUST-1 at the Pd/HKUST-1 interface is investigated quantitatively. Interfacial density of states are different from those of internal constituents and imply that the Cu–O group in HKUST-1 acts as a charge accepter. The role of Cu–O group in charge transfer behaviour is also observed experimentally. Finally, we reveal the charge transfer mechanism from the Pd 4 d bands to the Cu 3 d (4 sp ) – O 2 p hybridization bands of HKUST-1 at the Pd/HKUST-1 interface, which explains the enhanced hydrogen storage capacity in Pd@HKUST-1. Introduction Hybrid materials composed of transition-metal nanoparticles and metal-organic frameworks (MOFs) have attracted interests increasingly because of their potential applications in gas storage, catalysis and chemical sensing 1 . However, the design of new hybrid materials remains a great challenge in chemistry, physics and materials science on such a small scale. The mechanism of interaction between the constituent materials remains unclear. Recently, charge-transfer behaviour has been shown to play an important role in the catalytic activity and hydrogen storage properties of these materials 2 , 3 , 4 . For example, the charge transfer behaviour of palladium (Pd) nanocubes covered by copper(II) 1, 3, 5- benzenetricarboxylate (HKUST-1), denoted by Pd@HKUST-1, has been shown to improve its hydrogen storage properties 5 , 6 . Hydrogen is an essential component in many industrial processes and also a potential clean energy source that does not emit air pollution or greenhouse gases on burning 7 . As a representative metal/MOF hybrid material, Pd@HKUST-1 is an important example for studying the interaction between the constituent materials linked with improved hydrogen storage, thus aiding the design of other functional hybrid materials through rational modification of their electronic structures. Palladium nanoparticles can absorb large amounts of hydrogen at ambient pressure and room temperature, which is related to their electronic structures with unfilled bands 8 , 9 . The density of states (DOS) of palladium is composed of Pd 4 d bands and 5 s bands 10 , 11 . Theoretically, the hydrogen concentration in palladium is only related to the number of holes in the 4 d band, because the transfer of H 1 s electrons into Pd 4 d holes creates Pd–H bonds 12 , 13 . As a representative MOF, HKUST-1 has a richly porous structure consisting of copper atoms interlinked organic 1, 3, 5- benzenetricarboxylate (BTC) frame ligands 14 , 15 . The electronic structure of HKUST-1 is mainly composed of two partial DOS: one from Cu and the other from O 16 . In previous studies, the core-level spectra of Pd@HKUST-1 were investigated with laboratory X-ray photoelectron spectroscopy (XPS) 5 , 13 . The core-level Pd 3 d peak of Pd@HKUST-1 was shifted to a higher binding energy compared with that of palladium nanocubes. The core-level Cu 2 p peak was shifted to a lower energy compared with that of HKUST-1 13 . Recently, a density functional theory calculation has suggested that atomic charge displacement occurs between palladium atom and copper atom at the interface of palladium (100) surface and Cu-edged HKUST-1 17 . These results clearly imply the possibility of the charge transfer between Pd and Cu at the Pd/HKUST-1 interface in Pd@HKUST-1. To reveal the charge transfer behaviour, the valence bands and the conduction bands near the Fermi level are more informative than the core-level spectra. However, the electronic structure of Pd@HKUST-1 near the Fermi level has not yet been experimentally investigated. In studying the electronic structure of Pd@HKUST-1 near the Fermi level based on charge transfer, it is important to investigate the valence bands of the transition metals, palladium and copper, in bulk materials and at Pd/HKUST-1 interface. However, photoelectron spectroscopy using UV light or soft X-rays provides only a surface-sensitive electronic structure because of the short probing depth. By contrast, with the use of hard X-rays photoelectron spectroscopy (HAXPES), the kinetic energy of photoelectrons can be enhanced, and the probing depth is much greater 18 . Additionally, near-edge X-ray absorption fine structure (NEXAFS) are equally applicable for determining the conduction bands 19 . Both the total electron yield from surface electrons from a nanometre-thick layer and the fluorescence yield from bulk electrons from a layer hundreds of nanometres thick can be used to distinguish the intrinsic signal from the surface contamination. To reveal intrinsic electronic structure, we use HAXPES and NEXAFS to analyse the electronic structures of Pd, HKUST-1 and Pd@HKUST-1. Furthermore, we compare the observed valence band of Pd@HKUST-1 with the simple physical mixing of the spectra of Pd and HKUST-1 using the Kerkhof–Moulijn model to analyse these spectra quantitatively 20 . To the best of our knowledge, this work is the first study using HAXPES and NEXAFS to investigate the electronic structure of Pd@HKUST-1, as opposed to previous studies of the core-level spectra. The findings show that the hydrogen storage properties of Pd@HKUST-1 can be explained through the electronic structure near the Fermi level, which arises from an interfacial charge transfer. Results Interfacial charge transfer from Pd 4 d to Cu 3 d in Pd@HKUST-1 investigated by HAXPES We used the same samples as reported in the previous work 5 . Pd@HKUST-1 was prepared by a facile reactive seeding method. As observed by transmission electron microscopy (TEM), shown in Fig. 1a , Pd nanocubes had an average edge length of 10 nm (±2 nm, error bar from size analysis of TEM image). The flat {100} facets of Pd nanocubes acted as the seeds for the HKUST-1 growth, such that all the Pd nanocubes were completely covered by HKUST-1 MOF. The Pd nanocubes were dispersed homogeneously in HKUST-1 of 3 nm (±2 nm) thickness, which was measured from the", "role": "user" }, { "content": "NIMS, Kyushu University and Kyoto University jointly identified a mechanism by which a hybrid material composed of palladium (Pd) and metal-organic frameworks (MOFs) is capable of storing approximately twice as much hydrogen as a material composed solely of Pd. The greater hydrogen storage capacity of the hybrid material is associated with a slight change in its electronic state caused by the transfer of an electric charge—amounting to approximately 0.4 electrons—from the Pd to the MOFs. The joint research team therefore successfully determined the quantitative relationships between the materials' electronic states and their hydrogen storage properties. These findings may facilitate the development of new hybrid materials with superior hydrogen storage properties or with the capability to efficiently catalyze hydrogenation reactions. Hydrogen is a viable next-generation energy source. Widespread use of hydrogen will require efficient hydrogen storage methods. Transition metals, such as Pd, are known to possess excellent hydrogen storage properties. Recent reports indicated that the hydrogen storage capabilities of materials composed of transition metal nanoparticles and MOFs are significantly higher than those of materials composed solely of a transition metal. It had been predicted that these increased hydrogen storage capabilities are associated with the transfer of electric charge at the interface between the transition metals and the MOFs. However, the mechanisms responsible for the increased hydrogen storage capabilities were not quantitatively understood (e.g., the amount of charge transferred). The researchers investigated the electronic state of a hybrid material, Pd@HKUST-1, which is composed of Pd nanocubes and MOFs (specifically, copper(II) 1, 3, 5-benzenetricarboxylate, or HKUST-1) and capable of storing approximately twice the amount of hydrogen of materials composed solely of Pd nanocubes. For this investigation, the researchers used NIMS's synchrotron X-ray beamline at SPring-8, the world's largest synchrotron radiation facility. In addition, they calculated the electronic states of Pd and HKUST-1 separately and compared them with the electronic state of Pd@HKUST-1. As a result, they found that an electric charge amounting to approximately 0.4 electrons had been transferred from the Pd nanocubes to the MOFs. This small charge transfer presumably enabled the electron bands in the Pd nanocubes to store more hydrogen, resulting in approximately doubled hydrogen storage capacity for the hybrid material compared to a material composed solely of Pd nanocubes. Hybrid materials composed of transition metal nanoparticles and MOFs are potentially capable not only of storing large amounts of hydrogen but also of efficiently catalyzing hydrogenation reactions. The methods developed and used in this study to measure and analyze electronic states may accelerate the development of new hybrid materials with greatly increased hydrogen storage and catalytic capabilities. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Hybrid materials composed of metal nanoparticles and metal-organic frameworks have attracted attention for various applications because of the synergistic functionality between their constituent materials. Interfacial interaction is expected however the mechanism remains ambiguous. Here we report the valence bands of palladium nanocubes covered by copper(II) 1, 3, 5-benzenetricarboxylate (HKUST-1), denoted as Pd@HKUST-1, and the charge transfer from the palladium nanocubes to HKUST-1 at the Pd/HKUST-1 interface is investigated quantitatively. Interfacial density of states are different from those of internal constituents and imply that the Cu–O group in HKUST-1 acts as a charge accepter. The role of Cu–O group in charge transfer behaviour is also observed experimentally. Finally, we reveal the charge transfer mechanism from the Pd 4 d bands to the Cu 3 d (4 sp ) – O 2 p hybridization bands of HKUST-1 at the Pd/HKUST-1 interface, which explains the enhanced hydrogen storage capacity in Pd@HKUST-1. Introduction Hybrid materials composed of transition-metal nanoparticles and metal-organic frameworks (MOFs) have attracted interests increasingly because of their potential applications in gas storage, catalysis and chemical sensing 1 . However, the design of new hybrid materials remains a great challenge in chemistry, physics and materials science on such a small scale. The mechanism of interaction between the constituent materials remains unclear. Recently, charge-transfer behaviour has been shown to play an important role in the catalytic activity and hydrogen storage properties of these materials 2 , 3 , 4 . For example, the charge transfer behaviour of palladium (Pd) nanocubes covered by copper(II) 1, 3, 5- benzenetricarboxylate (HKUST-1), denoted by Pd@HKUST-1, has been shown to improve its hydrogen storage properties 5 , 6 . Hydrogen is an essential component in many industrial processes and also a potential clean energy source that does not emit air pollution or greenhouse gases on burning 7 . As a representative metal/MOF hybrid material, Pd@HKUST-1 is an important example for studying the interaction between the constituent materials linked with improved hydrogen storage, thus aiding the design of other functional hybrid materials through rational modification of their electronic structures. Palladium nanoparticles can absorb large amounts of hydrogen at ambient pressure and room temperature, which is related to their electronic structures with unfilled bands 8 , 9 . The density of states (DOS) of palladium is composed of Pd 4 d bands and 5 s bands 10 , 11 . Theoretically, the hydrogen concentration in palladium is only related to the number of holes in the 4 d band, because the transfer of H 1 s electrons into Pd 4 d holes creates Pd–H bonds 12 , 13 . As a representative MOF, HKUST-1 has a richly porous structure consisting of copper atoms interlinked organic 1, 3, 5- benzenetricarboxylate (BTC) frame ligands 14 , 15 . The electronic structure of HKUST-1 is mainly composed of two partial DOS: one from Cu and the other from O 16 . In previous studies, the core-level spectra of Pd@HKUST-1 were investigated with laboratory X-ray photoelectron spectroscopy (XPS) 5 , 13 . The core-level Pd 3 d peak of Pd@HKUST-1 was shifted to a higher binding energy compared with that of palladium nanocubes. The core-level Cu 2 p peak was shifted to a lower energy compared with that of HKUST-1 13 . Recently, a density functional theory calculation has suggested that atomic charge displacement occurs between palladium atom and copper atom at the interface of palladium (100) surface and Cu-edged HKUST-1 17 . These results clearly imply the possibility of the charge transfer between Pd and Cu at the Pd/HKUST-1 interface in Pd@HKUST-1. To reveal the charge transfer behaviour, the valence bands and the conduction bands near the Fermi level are more informative than the core-level spectra. However, the electronic structure of Pd@HKUST-1 near the Fermi level has not yet been experimentally investigated. In studying the electronic structure of Pd@HKUST-1 near the Fermi level based on charge transfer, it is important to investigate the valence bands of the transition metals, palladium and copper, in bulk materials and at Pd/HKUST-1 interface. However, photoelectron spectroscopy using UV light or soft X-rays provides only a surface-sensitive electronic structure because of the short probing depth. By contrast, with the use of hard X-rays photoelectron spectroscopy (HAXPES), the kinetic energy of photoelectrons can be enhanced, and the probing depth is much greater 18 . Additionally, near-edge X-ray absorption fine structure (NEXAFS) are equally applicable for determining the conduction bands 19 . Both the total electron yield from surface electrons from a nanometre-thick layer and the fluorescence yield from bulk electrons from a layer hundreds of nanometres thick can be used to distinguish the intrinsic signal from the surface contamination. To reveal intrinsic electronic structure, we use HAXPES and NEXAFS to analyse the electronic structures of Pd, HKUST-1 and Pd@HKUST-1. Furthermore, we compare the observed valence band of Pd@HKUST-1 with the simple physical mixing of the spectra of Pd and HKUST-1 using the Kerkhof–Moulijn model to analyse these spectra quantitatively 20 . To the best of our knowledge, this work is the first study using HAXPES and NEXAFS to investigate the electronic structure of Pd@HKUST-1, as opposed to previous studies of the core-level spectra. The findings show that the hydrogen storage properties of Pd@HKUST-1 can be explained through the electronic structure near the Fermi level, which arises from an interfacial charge transfer. Results Interfacial charge transfer from Pd 4 d to Cu 3 d in Pd@HKUST-1 investigated by HAXPES We used the same samples as reported in the previous work 5 . Pd@HKUST-1 was prepared by a facile reactive seeding method. As observed by transmission electron microscopy (TEM), shown in Fig. 1a , Pd nanocubes had an average edge length of 10 nm (±2 nm, error bar from size analysis of TEM image). The flat {100} facets of Pd nanocubes acted as the seeds for the HKUST-1 growth, such that all the Pd nanocubes were completely covered by HKUST-1 MOF. The Pd nanocubes were dispersed homogeneously in HKUST-1 of 3 nm (±2 nm) thickness, which was measured from the<|im_end|> <|im_start|>assistant NIMS, Kyushu University and Kyoto University jointly identified a mechanism by which a hybrid material composed of palladium (Pd) and metal-organic frameworks (MOFs) is capable of storing approximately twice as much hydrogen as a material composed solely of Pd. The greater hydrogen storage capacity of the hybrid material is associated with a slight change in its electronic state caused by the transfer of an electric charge—amounting to approximately 0.4 electrons—from the Pd to the MOFs. The joint research team therefore successfully determined the quantitative relationships between the materials' electronic states and their hydrogen storage properties. These findings may facilitate the development of new hybrid materials with superior hydrogen storage properties or with the capability to efficiently catalyze hydrogenation reactions. Hydrogen is a viable next-generation energy source. Widespread use of hydrogen will require efficient hydrogen storage methods. Transition metals, such as Pd, are known to possess excellent hydrogen storage properties. Recent reports indicated that the hydrogen storage capabilities of materials composed of transition metal nanoparticles and MOFs are significantly higher than those of materials composed solely of a transition metal. It had been predicted that these increased hydrogen storage capabilities are associated with the transfer of electric charge at the interface between the transition metals and the MOFs. However, the mechanisms responsible for the increased hydrogen storage capabilities were not quantitatively understood (e.g., the amount of charge transferred). The researchers investigated the electronic state of a hybrid material, Pd@HKUST-1, which is composed of Pd nanocubes and MOFs (specifically, copper(II) 1, 3, 5-benzenetricarboxylate, or HKUST-1) and capable of storing approximately twice the amount of hydrogen of materials composed solely of Pd nanocubes. For this investigation, the researchers used NIMS's synchrotron X-ray beamline at SPring-8, the world's largest synchrotron radiation facility. In addition, they calculated the electronic states of Pd and HKUST-1 separately and compared them with the electronic state of Pd@HKUST-1. As a result, they found that an electric charge amounting to approximately 0.4 electrons had been transferred from the Pd nanocubes to the MOFs. This small charge transfer presumably enabled the electron bands in the Pd nanocubes to store more hydrogen, resulting in approximately doubled hydrogen storage capacity for the hybrid material compared to a material composed solely of Pd nanocubes. Hybrid materials composed of transition metal nanoparticles and MOFs are potentially capable not only of storing large amounts of hydrogen but also of efficiently catalyzing hydrogenation reactions. The methods developed and used in this study to measure and analyze electronic states may accelerate the development of new hybrid materials with greatly increased hydrogen storage and catalytic capabilities. <|im_end|>

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2,097

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The efficiency of the repair process following ischemic cardiac injury is a crucial determinant for the progression into heart failure and is controlled by both intra- and intercellular signaling within the heart. An enhanced understanding of this complex interplay will enable better exploitation of these mechanisms for therapeutic use. We used single-cell transcriptomics to collect gene expression data of all main cardiac cell types at different time-points after ischemic injury. These data unveiled cellular and transcriptional heterogeneity and changes in cellular function during cardiac remodeling. Furthermore, we established potential intercellular communication networks after ischemic injury. Follow up experiments confirmed that cardiomyocytes express and secrete elevated levels of beta-2 microglobulin in response to ischemic damage, which can activate fibroblasts in a paracrine manner. Collectively, our data indicate phase-specific changes in cellular heterogeneity during different stages of cardiac remodeling and allow for the identification of therapeutic targets relevant for cardiac repair. Introduction Heart failure due to ischemic heart disease is a worldwide health problem 1 , 2 . Although reperfusion therapy to relieve the arterial occlusion has significantly reduced the mortality rate in patients, long-term survival and quality of life remain poor due to progression into heart failure 3 . To effectively combat the lethality caused by heart failure, a more complete understanding of the wound healing process after ischemic injury is required. Ischemia-reperfusion (IR) injury activates a plethora of cellular and molecular processes for wound healing in the heart, which are crucial determinants for clinical outcome 4 , 5 , 6 , 7 . In a coordinated process involving fibroblasts, neutrophils, macrophages, lymphocytes and endothelial cells, lost cardiomyocytes in the oxygen-deprived area are replaced by scar tissue, which can lead to impaired function and, subsequently, heart failure 4 , 5 , 8 , 9 . Changing the function or recruitment of these cells in the infarcted heart affects cardiac function and mortality in pre-clinical studies 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . Although there is an increasing understanding of processes within and between cell types that are relevant for cardiac repair, many mechanisms and factors are poorly understood or are yet to be identified 4 , 5 , 6 , 7 . Historically, high-throughput, unbiased gene expression studies of the infarcted heart were limited in resolution as they had to be performed on cardiac tissue or on populations of cells isolated by fluorescence-activated cell sorting (FACS) based on expression of a gene marker. These types of studies failed to determine cell-specific gene expression, thereby preventing examination of transcription heterogeneity within cell populations or intercellular communication between cell types within the same tissue. Whole-transcriptome analysis at single-cell resolution overcomes the previous technical limitation, providing a more detailed view on gene expression changes occurring during various cardiac pathologies. Recently, we performed single-cell RNA sequencing (scRNA-seq) on the injured mammalian adult heart, allowing us to study gene expression profiles in all main cardiac cell types 17 , 18 . Here, we used scRNA-seq to get an in-depth view of the cellular and molecular changes within and between cells during multiple phases of the wound healing response following IR. Our data corroborated previously determined functions of multiple cell types during the different repair processes, but additionally revealed the regulation of currently unstudied factors. Based on known ligand-receptor pairing, we also used these data to establish potential intercellular communication networks between all main cardiac cell types during each phase of the wound healing response. As such, we found elevated expression of multiple unstudied secreted factors by stressed cardiomyocytes following IR injury, for which we could also detect an increase in circulating levels. Subsequent in vitro experiments suggested that one of these factors, beta-2 microglobulin (B2M), is able to stimulate the wound healing response via the activation of fibroblasts. Together, our dataset provides detailed information on gene expression differences occurring within and between different cell populations during several stages of cardiac remodeling after ischemic damage. Using these data, we can now link gene expression alterations to changes in cellular function and use them to define new cellular interactions relevant for repair. Ultimately, a full understanding of all these cellular communications and molecular processes could provide a basis for novel therapeutic interventions to improve the wound healing response following ischemic injury of the heart and prevent progression into heart failure. Results Single-cell sequencing reveals dynamic cell type composition during repair of ischemic injury Healing of the heart after ischemic injury is a dynamic process involving multiple cell types. Upon ischemic damage, the distribution and function of different cell types in the damaged myocardium changes over time (Fig. 1a ) 4 , 5 . This organized process suggests strict regulation and coordination of cell recruitment and function during all phases of the wound-healing response. To impartially study how this regulation is achieved, we performed scRNA-seq of cardiac cells at different phases of the healing response after IR in mice. Fig. 1: Single-cell sequencing reveals changes in the cellular composition of the myocardium at different time points after ischemic injury. a Schematic of the study outline indicating time points of tissue harvest after ischemia/reperfusion (IR) injury and representation of the known cellular composition and function at these time points. b Determination of cell viability by DAPI negativity following dissociation and FACS procedure. c Schematic of the experimental setup to determine the percentage cells that are DAPI− but are nucleated as determined by DRAQ5 positivity. d Heatmap of the cell-to-cell transcriptome similarities (1 − Pearson’s correlation coefficient) of 2201 cells obtained from all conditions combined. Cells are clustered based on transcriptome similarity using k-medoids clustering. e t-Distributed Stochastic Neighbor Embedding (tSNE) plot indicating transcriptome similarities across individual cells. Different colors and numbers highlight the clusters identified by k-medoids clustering in ( d ). f Table highlighting cell types that were characterized by the clustering analysis. g Bar graph showing the proportion of cells originating from the different condition per cluster. CM cardiomyocytes, FB fibroblasts, MP macrophages, NP neutrophils, EC endothelial cells.", "role": "user" }, { "content": "Researchers from the Hubrecht Institute have mapped the recovery of the heart after a heart attack with great detail. They found that heart muscle cells called cardiomyocytes play an important role in intracellular communication after a heart attack. The researchers documented their findings in a database that is accessible for scientists around the world. This brings the research field a step closer to the development of therapies for improved recovery after heart injury. The results were published in Communications Biology on the 29th of January. In the Netherlands, an average of 95 people end up in the hospital each day because of a heart attack. During a heart attack, the blood supply to a part of the heart is blocked, for example, due to a blood clot in a coronary artery. Attempts to restore the blood supply known as reperfusion, are made as soon as possible. However, a part of the heart has already been without oxygen for some time. Depending on the size and duration of the infarction, this causes cardiomyocytes to die. This can result in the formation of scar tissue, which is stiffer than normal heart tissue and therefore makes it more difficult for the heart to properly contract. This can cause the pumping function of the heart to deteriorate, which can eventually lead to heart failure. In other words, insight into the recovery of the heart after a heart attack and how this leads to the formation of scar tissue is extremely important. However, much is still unknown. Researchers from the lab of Eva van Rooij have therefore examined this further. They studied how the hearts of mice recover at three different time points following a heart attack. To this end, they used single-cell sequencing, a technique that enables the examination of the RNA of individual cells. The researchers generated an enormous dataset with information about the role of different types of cells during the recovery process after a heart attack. Shown is a control heart in which green represents cardiomyocytes (heart muscle cells), red shows B2M expression and blue represents cell nuclei. Credit: Louk Timmer © Hubrecht Institute Communication network Consequently, they used the data to map a communication network. Louk Timmer, researcher on the project, says, \"Cells communicate with each other by secreting molecules. These molecules then trigger the recipient cell to take a specific action, which may be important for the recovery process. We have now mapped with great detail how different cells communicate with each other at different time points after a heart attack. That had never been done so thoroughly before.\" This communication network is now documented in a database and accessible to scientists around the world. Formation of scar tissue The role of cardiomyocytes in the recovery following a heart attack has been largely unknown, partly because of technical difficulties. However, another recent paper from Van Rooij's lab overcame these obstacles, allowing the researchers to specifically study the function of cardiomyocytes in the recovery process. \"We noticed that at the earliest time point measured after the heart attack, cardiomyocytes were secreting increased amounts of a molecule called B2M. Subsequent experiments showed that the secretion of B2M can result in the activation of so-called fibroblasts—cells responsible for the formation of scar tissue,\" says Timmer. Cardiomyocytes thus seem to indirectly stimulate the production of scar tissue early in the recovery process. \"Intuitively, we already thought that cardiomyocytes play an important role in intracellular communication during heart recovery, and it is great that we have now been able to confirm that.\" When asked about the next research steps, Timmer emphasized the importance of additional studies. \"Various scientists and experts can use this data, which enables us to gain a better understanding of the cells and molecules that are involved in the recovery of the heart and the way they communicate with each other. Hopefully, we can eventually improve the recovery process so that people end up with less damage after a heart attack.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The efficiency of the repair process following ischemic cardiac injury is a crucial determinant for the progression into heart failure and is controlled by both intra- and intercellular signaling within the heart. An enhanced understanding of this complex interplay will enable better exploitation of these mechanisms for therapeutic use. We used single-cell transcriptomics to collect gene expression data of all main cardiac cell types at different time-points after ischemic injury. These data unveiled cellular and transcriptional heterogeneity and changes in cellular function during cardiac remodeling. Furthermore, we established potential intercellular communication networks after ischemic injury. Follow up experiments confirmed that cardiomyocytes express and secrete elevated levels of beta-2 microglobulin in response to ischemic damage, which can activate fibroblasts in a paracrine manner. Collectively, our data indicate phase-specific changes in cellular heterogeneity during different stages of cardiac remodeling and allow for the identification of therapeutic targets relevant for cardiac repair. Introduction Heart failure due to ischemic heart disease is a worldwide health problem 1 , 2 . Although reperfusion therapy to relieve the arterial occlusion has significantly reduced the mortality rate in patients, long-term survival and quality of life remain poor due to progression into heart failure 3 . To effectively combat the lethality caused by heart failure, a more complete understanding of the wound healing process after ischemic injury is required. Ischemia-reperfusion (IR) injury activates a plethora of cellular and molecular processes for wound healing in the heart, which are crucial determinants for clinical outcome 4 , 5 , 6 , 7 . In a coordinated process involving fibroblasts, neutrophils, macrophages, lymphocytes and endothelial cells, lost cardiomyocytes in the oxygen-deprived area are replaced by scar tissue, which can lead to impaired function and, subsequently, heart failure 4 , 5 , 8 , 9 . Changing the function or recruitment of these cells in the infarcted heart affects cardiac function and mortality in pre-clinical studies 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . Although there is an increasing understanding of processes within and between cell types that are relevant for cardiac repair, many mechanisms and factors are poorly understood or are yet to be identified 4 , 5 , 6 , 7 . Historically, high-throughput, unbiased gene expression studies of the infarcted heart were limited in resolution as they had to be performed on cardiac tissue or on populations of cells isolated by fluorescence-activated cell sorting (FACS) based on expression of a gene marker. These types of studies failed to determine cell-specific gene expression, thereby preventing examination of transcription heterogeneity within cell populations or intercellular communication between cell types within the same tissue. Whole-transcriptome analysis at single-cell resolution overcomes the previous technical limitation, providing a more detailed view on gene expression changes occurring during various cardiac pathologies. Recently, we performed single-cell RNA sequencing (scRNA-seq) on the injured mammalian adult heart, allowing us to study gene expression profiles in all main cardiac cell types 17 , 18 . Here, we used scRNA-seq to get an in-depth view of the cellular and molecular changes within and between cells during multiple phases of the wound healing response following IR. Our data corroborated previously determined functions of multiple cell types during the different repair processes, but additionally revealed the regulation of currently unstudied factors. Based on known ligand-receptor pairing, we also used these data to establish potential intercellular communication networks between all main cardiac cell types during each phase of the wound healing response. As such, we found elevated expression of multiple unstudied secreted factors by stressed cardiomyocytes following IR injury, for which we could also detect an increase in circulating levels. Subsequent in vitro experiments suggested that one of these factors, beta-2 microglobulin (B2M), is able to stimulate the wound healing response via the activation of fibroblasts. Together, our dataset provides detailed information on gene expression differences occurring within and between different cell populations during several stages of cardiac remodeling after ischemic damage. Using these data, we can now link gene expression alterations to changes in cellular function and use them to define new cellular interactions relevant for repair. Ultimately, a full understanding of all these cellular communications and molecular processes could provide a basis for novel therapeutic interventions to improve the wound healing response following ischemic injury of the heart and prevent progression into heart failure. Results Single-cell sequencing reveals dynamic cell type composition during repair of ischemic injury Healing of the heart after ischemic injury is a dynamic process involving multiple cell types. Upon ischemic damage, the distribution and function of different cell types in the damaged myocardium changes over time (Fig. 1a ) 4 , 5 . This organized process suggests strict regulation and coordination of cell recruitment and function during all phases of the wound-healing response. To impartially study how this regulation is achieved, we performed scRNA-seq of cardiac cells at different phases of the healing response after IR in mice. Fig. 1: Single-cell sequencing reveals changes in the cellular composition of the myocardium at different time points after ischemic injury. a Schematic of the study outline indicating time points of tissue harvest after ischemia/reperfusion (IR) injury and representation of the known cellular composition and function at these time points. b Determination of cell viability by DAPI negativity following dissociation and FACS procedure. c Schematic of the experimental setup to determine the percentage cells that are DAPI− but are nucleated as determined by DRAQ5 positivity. d Heatmap of the cell-to-cell transcriptome similarities (1 − Pearson’s correlation coefficient) of 2201 cells obtained from all conditions combined. Cells are clustered based on transcriptome similarity using k-medoids clustering. e t-Distributed Stochastic Neighbor Embedding (tSNE) plot indicating transcriptome similarities across individual cells. Different colors and numbers highlight the clusters identified by k-medoids clustering in ( d ). f Table highlighting cell types that were characterized by the clustering analysis. g Bar graph showing the proportion of cells originating from the different condition per cluster. CM cardiomyocytes, FB fibroblasts, MP macrophages, NP neutrophils, EC endothelial cells.<|im_end|> <|im_start|>assistant Researchers from the Hubrecht Institute have mapped the recovery of the heart after a heart attack with great detail. They found that heart muscle cells called cardiomyocytes play an important role in intracellular communication after a heart attack. The researchers documented their findings in a database that is accessible for scientists around the world. This brings the research field a step closer to the development of therapies for improved recovery after heart injury. The results were published in Communications Biology on the 29th of January. In the Netherlands, an average of 95 people end up in the hospital each day because of a heart attack. During a heart attack, the blood supply to a part of the heart is blocked, for example, due to a blood clot in a coronary artery. Attempts to restore the blood supply known as reperfusion, are made as soon as possible. However, a part of the heart has already been without oxygen for some time. Depending on the size and duration of the infarction, this causes cardiomyocytes to die. This can result in the formation of scar tissue, which is stiffer than normal heart tissue and therefore makes it more difficult for the heart to properly contract. This can cause the pumping function of the heart to deteriorate, which can eventually lead to heart failure. In other words, insight into the recovery of the heart after a heart attack and how this leads to the formation of scar tissue is extremely important. However, much is still unknown. Researchers from the lab of Eva van Rooij have therefore examined this further. They studied how the hearts of mice recover at three different time points following a heart attack. To this end, they used single-cell sequencing, a technique that enables the examination of the RNA of individual cells. The researchers generated an enormous dataset with information about the role of different types of cells during the recovery process after a heart attack. Shown is a control heart in which green represents cardiomyocytes (heart muscle cells), red shows B2M expression and blue represents cell nuclei. Credit: Louk Timmer © Hubrecht Institute Communication network Consequently, they used the data to map a communication network. Louk Timmer, researcher on the project, says, "Cells communicate with each other by secreting molecules. These molecules then trigger the recipient cell to take a specific action, which may be important for the recovery process. We have now mapped with great detail how different cells communicate with each other at different time points after a heart attack. That had never been done so thoroughly before." This communication network is now documented in a database and accessible to scientists around the world. Formation of scar tissue The role of cardiomyocytes in the recovery following a heart attack has been largely unknown, partly because of technical difficulties. However, another recent paper from Van Rooij's lab overcame these obstacles, allowing the researchers to specifically study the function of cardiomyocytes in the recovery process. "We noticed that at the earliest time point measured after the heart attack, cardiomyocytes were secreting increased amounts of a molecule called B2M. Subsequent experiments showed that the secretion of B2M can result in the activation of so-called fibroblasts—cells responsible for the formation of scar tissue," says Timmer. Cardiomyocytes thus seem to indirectly stimulate the production of scar tissue early in the recovery process. "Intuitively, we already thought that cardiomyocytes play an important role in intracellular communication during heart recovery, and it is great that we have now been able to confirm that." When asked about the next research steps, Timmer emphasized the importance of additional studies. "Various scientists and experts can use this data, which enables us to gain a better understanding of the cells and molecules that are involved in the recovery of the heart and the way they communicate with each other. Hopefully, we can eventually improve the recovery process so that people end up with less damage after a heart attack." <|im_end|>

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7645, 12062, 31965, 2949, 323, 1990, 2204, 2849, 22673, 2391, 3892, 18094, 315, 47345, 70430, 1306, 98108, 292, 5674, 13, 12362, 1521, 828, 11, 584, 649, 1457, 2723, 15207, 7645, 61086, 311, 4442, 304, 35693, 734, 323, 1005, 1124, 311, 7124, 502, 35693, 22639, 9959, 369, 13023, 13, 55106, 11, 264, 2539, 8830, 315, 682, 1521, 35693, 17320, 323, 31206, 11618, 1436, 3493, 264, 8197, 369, 11775, 37471, 39455, 311, 7417, 279, 27653, 21730, 2077, 2768, 98108, 292, 11134, 315, 279, 4851, 323, 5471, 33824, 1139, 4851, 8060, 13, 18591, 11579, 33001, 62119, 21667, 8915, 2849, 955, 18528, 2391, 13023, 315, 98108, 292, 11134, 49741, 315, 279, 4851, 1306, 98108, 292, 11134, 374, 264, 8915, 1920, 16239, 5361, 2849, 4595, 13, 30538, 98108, 292, 5674, 11, 279, 8141, 323, 734, 315, 2204, 2849, 4595, 304, 279, 20727, 95736, 2411, 4442, 927, 892, 320, 30035, 13, 220, 16, 64, 883, 220, 19, 1174, 220, 20, 662, 1115, 17057, 1920, 13533, 7452, 19812, 323, 38793, 315, 2849, 34102, 323, 734, 2391, 682, 35530, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy. Results We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model. Conclusion PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models. Background Lung cancer is the most common cancer worldwide, claiming 1.76 million lives in 2018 alone (WHO cancer statistics 2018). This is exceeding total numbers of colon, breast and prostate cancer combined [ 1 , 2 , 3 , 4 ]. In the past decade, with the advent of targeted and immune-checkpoint blockade therapy, major improvements in treatment response of advanced NSCLC (non-small cell lung cancer) were achieved [ 5 ]. Targeted therapies are predominantly validated in the treatment of late stage patients (UICC stage IV) [ 6 ]. Other patients (UICC stage I, II and III) [ 7 ], rarely benefit from these combinatorial treatments and survival rates have only marginally improved, with many patients still succumbing to lung cancer within five years [ 8 ]. Furthermore, not all patients benefit equally from these novel therapeutic approaches [ 9 , 10 , 11 ]. Genetic analysis of tumor samples by Next Generation Sequencing (NGS) from treatment resistant patients highlighted that several genetic alterations can contribute to therapy resistance and reduced patient survival e.g. KRAS, STK11, KEAP1 and the phosphatase and tensin homologue ( PTEN ) [ 12 , 13 , 14 ]. PTEN was initially described as a phosphatase involved in the homeostatic maintenance of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) cascade leading to suppression of phospho-AKT [ 15 ]. It functions as a tumor suppressor via affecting cell cycle progression, inhibition of cell death, transcription, translation, stimulation of angiogenesis, and maintenance of stem cell self-properties via mTOR signalling [ 16 ]. NGS of tumor samples revealed that PTEN is frequently deleted or mutated in a variety of tumors [ 2 ], including NSCLC (Adenocarcinoma and Squamous cell carcinoma) [ 3 , 4 ]. PTEN itself, as a tumor suppressor, is not a direct target for cancer therapy, but can serve as a prognostic marker [ 17 ]. Mutations in PTEN result in resistance towards ‘standard of care’ therapies, such as radiotherapy and chemotherapy, by hyperactivation of the AKT pathway [ 18 ]. Additionally, loss of PTEN limits the employment of personalized therapy, as it is blunting therapeutic responses relying on immune checkpoint blockade and drives resistance to established targeted therapies like EGFR antagonists [ 19 , 20 ]. Nuclear PTEN is involved in the control of essential biological processes, such as maintenance of genome integrity [ 21 ], APC/C-CDH1-dependent PLK and AURK degradation [ 22 ], chromatin remodelling [ 23 ] and double strand break repair [ 24 ]. DNA damage inducing therapies, such as ionizing radiation (IR), rely on the inability of tumor cells to efficiently clear all damage, while wild type cells undergo cell cycle arrest to gain sufficient time to repair [ 25 , 26 ]. Here, DNA damage sensing enzymes, such as DNA-PK, ATR and ATM are key players and dictate the route taken for repair of the damaged DNA [ 27 , 28 ]. Ataxia telangiectasia mutated kinase (ATM) is the prime sensor of double strand breaks induced by ionizing radiation [ 28 ]. It is required for downstream activation of SMC1, CHEK2, RAD50-MRE11 and BRCA1 signalling cascades, thereby contributing to radiation resistance and cell cycle checkpoint progression and arrest [ 29 ]. An alternative source of ATM activation is the induction of reactive oxygen species, a by-product of IR therapy [ 30 ]. Previous reports also highlighted a deregulation of ATM in PTEN mutant tumors, suggesting that the ATM-PTEN axis is of therapeutic value for certain cancers [ 31 , 32 ]. Together, these data argue that inhibition of DNA damage sensors may restore therapy responses in PTEN mutant NSCLC and suggest that this strategy may have therapeutic efficacy in lung cancer. Results Alterations in PTEN affect patient survival and radiation therapy outcome in NSCLC To assess the mutational as well the expression status of PTEN in human malignancy, we analysed public available patient data. Alterations in PTEN were frequently observed in lung cancer, both in adenocarcinoma (ADC) and squamous cell carcinoma (SCC), ranging between 15 and 38%, respectively (Fig. 1 A). PTEN is frequently altered in invasive tumors and reduced expression or mutation correlate with overall shortened patient survival (Fig. 1 B and Additional file 1 : Fig. S1A). Irrespective of NSCLC subtype, patient data suggest that PTEN loss is a direct prognostic marker for shorter survival, including tumor mutational burden (TMB) low patients, which are otherwise not amenable to immunotherapy and treated with chemotherapy (Additional file 1 : Fig. S1A). Not only do PTEN mutant/low patients have an overall shortened life expectancy; when treated with radiotherapy alone, they have a poorer overall survival (p = 0.00017) compared to a PTEN high patient cohort (Fig. 1 B). These data demonstrate that reduced expression or mutation of PTEN is a frequent event and significantly correlates with poor patient survival and treatment failure. Fig. 1 PTEN alterations; impact on pathways and radiation resistance. A PTEN alteration frequency of NSCLC", "role": "user" }, { "content": "Lung cancer is the most common cancer in the world, with 2.2 million new cases and around 1.8 million deaths in 2020 alone. Although knowledge about the disease has improved considerably, and new therapeutic strategies can prolong the lives of previously incurable patients, the numbers clearly show that lung cancer is still a serious disease and the mortality rate is still far too high. To further reduce the number of deaths from this type of tumor, novel and improved treatments are needed. Würzburg researchers are concentrating on radiotherapy. In combination with chemotherapy, this is still one of the most important treatment approaches. This is especially true for late-stage non-small cell lung tumors, where treatment options are rather limited. PTEN mutation is suitable as a biomarker In this type of lung tumor, radiotherapy can be ineffective. This is due to the interaction of a common, specific mutation in the PTEN gene with the DNA repair enzyme ATM, as the Würzburg team found out. However, lung tumors, in which this mutation occurs, can be therapeutically influenced. With two experimental inhibitors, the researchers succeeded in blocking the DNA repair enzyme in the tumor cells. As a result, the tumors became sensitive to radiation again and could be killed in tumor models. Inhibitors in preclinical testing \"Such inhibitors have not yet been approved for use in humans, but partake in clinical trials,\" explains cancer researcher Dr. Markus Diefenbacher from the Biocentre at the University of Würzburg. His team has published the new findings in the journal Cell & Bioscience together with a group led by radiotherapist Dr. Thomas Fischer from Professor Michael Flentje's research group at the University Hospital Würzburg. If the inhibitors pass the clinical tests, they offer a new opportunity: the PTEN mutation is suitable as a biomarker that indicates a tumor's resistance to radiation. With corresponding analyses, one could specifically identify patients who might benefit from a combination of inhibitor and radiotherapy. This could be realized quickly: patients with non-small cell lung cancer are already routinely examined for PTEN and other disease-relevant mutations. Focus on radiation dose reduction Currently, several clinical trials are looking at the impact of PTEN and ATM on treatment outcomes. \"We are confident that our new findings will generate a lot of interest in pursuing this innovative strategy for the treatment of non-small cell lung tumors,\" says Professor Michael Flentje. Radiotherapy is a mainstay in the treatment of late-stage tumors of the respiratory tract and other organs. The Würzburg team is therefore continuing to research new strategies and targets. One focus is on reducing the radiation dose in such a way that the desired therapeutic success is still achieved and at the same time the healthy tissue around the tumor is spared as much as possible. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy. Results We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model. Conclusion PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models. Background Lung cancer is the most common cancer worldwide, claiming 1.76 million lives in 2018 alone (WHO cancer statistics 2018). This is exceeding total numbers of colon, breast and prostate cancer combined [ 1 , 2 , 3 , 4 ]. In the past decade, with the advent of targeted and immune-checkpoint blockade therapy, major improvements in treatment response of advanced NSCLC (non-small cell lung cancer) were achieved [ 5 ]. Targeted therapies are predominantly validated in the treatment of late stage patients (UICC stage IV) [ 6 ]. Other patients (UICC stage I, II and III) [ 7 ], rarely benefit from these combinatorial treatments and survival rates have only marginally improved, with many patients still succumbing to lung cancer within five years [ 8 ]. Furthermore, not all patients benefit equally from these novel therapeutic approaches [ 9 , 10 , 11 ]. Genetic analysis of tumor samples by Next Generation Sequencing (NGS) from treatment resistant patients highlighted that several genetic alterations can contribute to therapy resistance and reduced patient survival e.g. KRAS, STK11, KEAP1 and the phosphatase and tensin homologue ( PTEN ) [ 12 , 13 , 14 ]. PTEN was initially described as a phosphatase involved in the homeostatic maintenance of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) cascade leading to suppression of phospho-AKT [ 15 ]. It functions as a tumor suppressor via affecting cell cycle progression, inhibition of cell death, transcription, translation, stimulation of angiogenesis, and maintenance of stem cell self-properties via mTOR signalling [ 16 ]. NGS of tumor samples revealed that PTEN is frequently deleted or mutated in a variety of tumors [ 2 ], including NSCLC (Adenocarcinoma and Squamous cell carcinoma) [ 3 , 4 ]. PTEN itself, as a tumor suppressor, is not a direct target for cancer therapy, but can serve as a prognostic marker [ 17 ]. Mutations in PTEN result in resistance towards ‘standard of care’ therapies, such as radiotherapy and chemotherapy, by hyperactivation of the AKT pathway [ 18 ]. Additionally, loss of PTEN limits the employment of personalized therapy, as it is blunting therapeutic responses relying on immune checkpoint blockade and drives resistance to established targeted therapies like EGFR antagonists [ 19 , 20 ]. Nuclear PTEN is involved in the control of essential biological processes, such as maintenance of genome integrity [ 21 ], APC/C-CDH1-dependent PLK and AURK degradation [ 22 ], chromatin remodelling [ 23 ] and double strand break repair [ 24 ]. DNA damage inducing therapies, such as ionizing radiation (IR), rely on the inability of tumor cells to efficiently clear all damage, while wild type cells undergo cell cycle arrest to gain sufficient time to repair [ 25 , 26 ]. Here, DNA damage sensing enzymes, such as DNA-PK, ATR and ATM are key players and dictate the route taken for repair of the damaged DNA [ 27 , 28 ]. Ataxia telangiectasia mutated kinase (ATM) is the prime sensor of double strand breaks induced by ionizing radiation [ 28 ]. It is required for downstream activation of SMC1, CHEK2, RAD50-MRE11 and BRCA1 signalling cascades, thereby contributing to radiation resistance and cell cycle checkpoint progression and arrest [ 29 ]. An alternative source of ATM activation is the induction of reactive oxygen species, a by-product of IR therapy [ 30 ]. Previous reports also highlighted a deregulation of ATM in PTEN mutant tumors, suggesting that the ATM-PTEN axis is of therapeutic value for certain cancers [ 31 , 32 ]. Together, these data argue that inhibition of DNA damage sensors may restore therapy responses in PTEN mutant NSCLC and suggest that this strategy may have therapeutic efficacy in lung cancer. Results Alterations in PTEN affect patient survival and radiation therapy outcome in NSCLC To assess the mutational as well the expression status of PTEN in human malignancy, we analysed public available patient data. Alterations in PTEN were frequently observed in lung cancer, both in adenocarcinoma (ADC) and squamous cell carcinoma (SCC), ranging between 15 and 38%, respectively (Fig. 1 A). PTEN is frequently altered in invasive tumors and reduced expression or mutation correlate with overall shortened patient survival (Fig. 1 B and Additional file 1 : Fig. S1A). Irrespective of NSCLC subtype, patient data suggest that PTEN loss is a direct prognostic marker for shorter survival, including tumor mutational burden (TMB) low patients, which are otherwise not amenable to immunotherapy and treated with chemotherapy (Additional file 1 : Fig. S1A). Not only do PTEN mutant/low patients have an overall shortened life expectancy; when treated with radiotherapy alone, they have a poorer overall survival (p = 0.00017) compared to a PTEN high patient cohort (Fig. 1 B). These data demonstrate that reduced expression or mutation of PTEN is a frequent event and significantly correlates with poor patient survival and treatment failure. Fig. 1 PTEN alterations; impact on pathways and radiation resistance. A PTEN alteration frequency of NSCLC<|im_end|> <|im_start|>assistant Lung cancer is the most common cancer in the world, with 2.2 million new cases and around 1.8 million deaths in 2020 alone. Although knowledge about the disease has improved considerably, and new therapeutic strategies can prolong the lives of previously incurable patients, the numbers clearly show that lung cancer is still a serious disease and the mortality rate is still far too high. To further reduce the number of deaths from this type of tumor, novel and improved treatments are needed. Würzburg researchers are concentrating on radiotherapy. In combination with chemotherapy, this is still one of the most important treatment approaches. This is especially true for late-stage non-small cell lung tumors, where treatment options are rather limited. PTEN mutation is suitable as a biomarker In this type of lung tumor, radiotherapy can be ineffective. This is due to the interaction of a common, specific mutation in the PTEN gene with the DNA repair enzyme ATM, as the Würzburg team found out. However, lung tumors, in which this mutation occurs, can be therapeutically influenced. With two experimental inhibitors, the researchers succeeded in blocking the DNA repair enzyme in the tumor cells. As a result, the tumors became sensitive to radiation again and could be killed in tumor models. Inhibitors in preclinical testing "Such inhibitors have not yet been approved for use in humans, but partake in clinical trials," explains cancer researcher Dr. Markus Diefenbacher from the Biocentre at the University of Würzburg. His team has published the new findings in the journal Cell & Bioscience together with a group led by radiotherapist Dr. Thomas Fischer from Professor Michael Flentje's research group at the University Hospital Würzburg. If the inhibitors pass the clinical tests, they offer a new opportunity: the PTEN mutation is suitable as a biomarker that indicates a tumor's resistance to radiation. With corresponding analyses, one could specifically identify patients who might benefit from a combination of inhibitor and radiotherapy. This could be realized quickly: patients with non-small cell lung cancer are already routinely examined for PTEN and other disease-relevant mutations. Focus on radiation dose reduction Currently, several clinical trials are looking at the impact of PTEN and ATM on treatment outcomes. "We are confident that our new findings will generate a lot of interest in pursuing this innovative strategy for the treatment of non-small cell lung tumors," says Professor Michael Flentje. Radiotherapy is a mainstay in the treatment of late-stage tumors of the respiratory tract and other organs. The Würzburg team is therefore continuing to research new strategies and targets. One focus is on reducing the radiation dose in such a way that the desired therapeutic success is still achieved and at the same time the healthy tissue around the tumor is spared as much as possible. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract It has been hypothesized that some antibiotic resistance genes (ARGs) found in pathogenic bacteria derive from antibiotic-producing actinobacteria. Here we provide bioinformatic and experimental evidence supporting this hypothesis. We identify genes in proteobacteria, including some pathogens, that appear to be closely related to actinobacterial ARGs known to confer resistance against clinically important antibiotics. Furthermore, we identify two potential examples of recent horizontal transfer of actinobacterial ARGs to proteobacterial pathogens. Based on this bioinformatic evidence, we propose and experimentally test a ‘carry-back’ mechanism for the transfer, involving conjugative transfer of a carrier sequence from proteobacteria to actinobacteria, recombination of the carrier sequence with the actinobacterial ARG, followed by natural transformation of proteobacteria with the carrier-sandwiched ARG. Our results support the existence of ancient and, possibly, recent transfers of ARGs from antibiotic-producing actinobacteria to proteobacteria, and provide evidence for a defined mechanism. Introduction The discovery of antibiotics from microorganisms and their development into clinical drugs constitutes one of the greatest advances in medical history, but the acquisition and dissemination of genes that confer antibiotic resistance among pathogens has severely curtailed the effectiveness of many of these compounds. Elucidating the origins of these antibiotic resistance genes (ARGs) and the mechanisms mediating their spread to pathogens is consequently a public health priority 1 . Actinobacteria, especially of the genus Streptomyces , produce many clinically important antibiotics. In most cases, the gene clusters encoding the biosynthesis of these compounds also contain resistance genes as a self-protecting mechanism towards these compounds 2 or to modulate their signalling activity 3 . As early as 1973, it was hypothesized that the enzymes found in Gram-negative pathogens that inactivate aminoglycoside antibiotics could have originated from the ARGs of actinobacteria that produce this class of antibiotics through ancient horizontal gene transfer (HGT), based on the discovery that they employ the same enzymatic mechanisms 4 . This ‘producer hypothesis’ was subsequently proposed for additional ARGs, for example, some class-A β-lactamases 5 in Gram-negative pathogens, and erythromycin 6 and vancomycin resistance genes 7 in Gram-positive pathogens. However, in these cases the sequence similarities between ARG proteins in actinobacteria and Gram-negative pathogens are low, making it difficult to distinguish if they result from ancient HGT or from other types of evolutionary processes 8 . Compared with ancient transfers, recent ARG dissemination from actinobacteria to pathogens may pose an even more urgent threat to human health 9 , as actinobacterial ARGs make up a large portion of the environmental resistome. In addition to self-protecting ARGs, most actinobacteria also carry ARGs horizontally obtained from other actinobacteria 6 , 10 . In an investigation of actinomycetes from soil, isolates were on average resistant towards seven to eight antibiotics from a collection of 21 representative antibiotics 11 . In a functional metagenomics study using Escherichia coli as an expression host, actinobacteria were found to be the most enriched source of resistance-conferring DNA fragments relative to their abundance 12 . However, since no recent transfer from actinobacteria to Gram-negative pathogens has been discovered and many recent studies showed that phylogenetic and ecological boundaries are two major ARG transfer barriers 12 , 13 , 14 , 15 , the clinical relevance of this large resistome remains unclear 16 , 17 . Here, we examine a large collection of known Streptomyces ARGs, and find more examples supporting the ‘producer hypothesis’. Specifically, we provide evidence that two ARGs conferring resistance against chloramphenicol and lincomycin might have been recently transferred from actinobacteria to human and animal pathogens. Based on their surrounding sequence, we propose and test a potential mechanism mediating gene transfer from Gram-positive actinobacteria to Gram-negative pathogens. Results Actinobacterial ARGs have related proteins in proteobacteria Proteobacteria encompass many important human pathogens such as Escherichia coli , Pseudomonas aeruginosa and others. We therefore sought to examine the similarity between corresponding ARGs in actinobacteria and proteobacteria. First, we extracted all experimentally validated Streptomyces ARG proteins from ARDB 18 and CARD 19 databases. A majority (39 of 57) of them are reported to have self-protecting roles or are located within antibiotic biosynthesis gene clusters as analysed by antiSMASH 20 ( Supplementary Data 1 ). Their most similar homologues in proteobacteria were subsequently identified from the NCBI non-redundant protein database by BLASTP, with sequence identities ranging from 23 to 68%. Seven of these proteobacterial proteins have sequences more similar to actinobacterial proteins than to proteins from any other phyla, including proteobacteria ( Supplementary Data 1 ). Furthermore, phylogenetic trees were constructed and showed that 12 (including the above seven) of the proteobacterial proteins may have originated from actinobacteria by interphylum HGT ( Fig. 1 and Supplementary Fig. 1 ) 21 . Potential HGTs in the opposite direction, from proteobacteria to actinobacteria, were also noticed in some trees. In particular, the Streptomyces ARG sul1 (AFN41071.1) shares 95% sequence identity with a proteobacterial gene ( Supplementary Fig. 1 ). Figure 1: Proteobacterial proteins related to Streptomyces ARG proteins. Relationships between all experimentally validated Streptomyces ARG proteins and their most similar homologues in proteobacteria were analysed by phylogenetic analysis ( Supplementary Fig. 1 ). Selected pairs that might be connected via interphylum HGT are summarized here, with the proposed transfer direction indicated by an arrow. Protein sequence identity was determined by BLASTP. a The proteins were BLASTed against pathogen genome database PATRIC to see if they have close homologues (sequence identity threshold of 90%) in pathogens. Full size image By examining neighbouring genes, we also found evidence for potential cotransfer of additional genes in the case of the ARG pac (conferring resistance to puromycin). The products of six neighbouring genes also show higher similarity to actinobacterial proteins than to proteins from any other phyla, suggesting that they might have been transferred together from actinobacteria to proteobacteria ( Supplementary Fig. 2 ). Of the 12 proteobacterial proteins that might have originated from actinobacteria, nine are encoded in genomes of environmental species, one of which has close homologues encoded in the genomes of pathogens from the database PATRIC 22 . The other three proteins are harboured by pathogens, including", "role": "user" }, { "content": "To win the war against antibiotic-resistant superbugs, scientists seek the origin of resistance genes to identify how they are introduced to disease-causing bacteria. Identifying the origin of resistance genes and how they spread is comparable to finding patient zero in an outbreak, which is not an easy task. For more than 30 years, scientists have proposed that resistance genes actually originate from the microorganisms producing the antibiotic. However, scientists have not been able to find direct proof of this transfer. Now, research conducted at the Technical University of Denmark shows that antibiotic resistance genes originate from the same place as the antibiotic compounds, i.e. from a group of soil bacteria called Actinobacteria. The study is published in Nature Communications. More than three-fourths of all current antibiotics used to treat human infections are produced by Actinobacteria, which also carry antibiotic resistance genes. In these experiments, the researchers surprisingly found that many resistance genes in disease-causing microbes (gram negative pathogens) were very similar to resistance genes found in Actinobacteria. In one case, the genes were 100 percent identical. \"It has been suspected that pathogens can obtain resistance genes from Actinobacteria for half a century. The 100 percent identical genes are the smoking gun,\" says postdoc Xinglin Jiang from DTU Biosustain. Gram negative pathogens constitute a large group of species, among which are pseudomonas, which can cause lung and urinary tract infections. At first, it was difficult to imagine how pathogens could acquire genes from Actinobacteria, because they are so different and unrelated to each other. But by investigating the DNA sequence around the resistance genes, the team figured out how the transfer occurred through a new mechanism called \"carry back\", in which the pathogen basically has a primitive form of \"sex\" with the Actinobacterium and acquires its resistance genes after it dies. This gene transfer by carry back could, in principle, happen when pathogens come into contact with Actinobacteria, like in an animal farm or in soil polluted with untreated hospital waste. In this way, the pathogen can become resistant and endanger human lives in the next round of infection. Understanding the origin is therefore key to counteracting the spread of antibiotic resistance, explains senior researcher Tilmann Weber from DTU Biosustain: \"We can't stop this gene transfer, but when you know which resistance genes pathogens may harbor, you can personalize the antibiotic treatment. Also, with this knowledge, you can try to develop new antibiotics with other properties that the pathogens don't have a defense against.\" Here is how the carry back process works: 1. The Gram negative pathogen injects its DNA into the Actinobacteria. Gram negative bacteria naturally have an ability called conjugation by which bacterial cells can inject their own DNA into other bacterial cells. It is called the bacterial equivalent of sex, because it is usually used to exchange gene information between Gram negative bacteria. But sometimes Gram negative bacteria can also use this mechanism to inject DNA into unrelated Gram positive bacteria like Actinobacteria. 2. Inside the Actinobacteria, the injected DNA recombines with the host's DNA containing resistance genes. After the Actinobacterium dies, the recombinant DNA is released into the environment. 3. Lastly, the injected DNA can act as \"gluing DNA\" and mediate the uptake of the resistance gene back to the pathogens through a phenomenon called natural transformation. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract It has been hypothesized that some antibiotic resistance genes (ARGs) found in pathogenic bacteria derive from antibiotic-producing actinobacteria. Here we provide bioinformatic and experimental evidence supporting this hypothesis. We identify genes in proteobacteria, including some pathogens, that appear to be closely related to actinobacterial ARGs known to confer resistance against clinically important antibiotics. Furthermore, we identify two potential examples of recent horizontal transfer of actinobacterial ARGs to proteobacterial pathogens. Based on this bioinformatic evidence, we propose and experimentally test a ‘carry-back’ mechanism for the transfer, involving conjugative transfer of a carrier sequence from proteobacteria to actinobacteria, recombination of the carrier sequence with the actinobacterial ARG, followed by natural transformation of proteobacteria with the carrier-sandwiched ARG. Our results support the existence of ancient and, possibly, recent transfers of ARGs from antibiotic-producing actinobacteria to proteobacteria, and provide evidence for a defined mechanism. Introduction The discovery of antibiotics from microorganisms and their development into clinical drugs constitutes one of the greatest advances in medical history, but the acquisition and dissemination of genes that confer antibiotic resistance among pathogens has severely curtailed the effectiveness of many of these compounds. Elucidating the origins of these antibiotic resistance genes (ARGs) and the mechanisms mediating their spread to pathogens is consequently a public health priority 1 . Actinobacteria, especially of the genus Streptomyces , produce many clinically important antibiotics. In most cases, the gene clusters encoding the biosynthesis of these compounds also contain resistance genes as a self-protecting mechanism towards these compounds 2 or to modulate their signalling activity 3 . As early as 1973, it was hypothesized that the enzymes found in Gram-negative pathogens that inactivate aminoglycoside antibiotics could have originated from the ARGs of actinobacteria that produce this class of antibiotics through ancient horizontal gene transfer (HGT), based on the discovery that they employ the same enzymatic mechanisms 4 . This ‘producer hypothesis’ was subsequently proposed for additional ARGs, for example, some class-A β-lactamases 5 in Gram-negative pathogens, and erythromycin 6 and vancomycin resistance genes 7 in Gram-positive pathogens. However, in these cases the sequence similarities between ARG proteins in actinobacteria and Gram-negative pathogens are low, making it difficult to distinguish if they result from ancient HGT or from other types of evolutionary processes 8 . Compared with ancient transfers, recent ARG dissemination from actinobacteria to pathogens may pose an even more urgent threat to human health 9 , as actinobacterial ARGs make up a large portion of the environmental resistome. In addition to self-protecting ARGs, most actinobacteria also carry ARGs horizontally obtained from other actinobacteria 6 , 10 . In an investigation of actinomycetes from soil, isolates were on average resistant towards seven to eight antibiotics from a collection of 21 representative antibiotics 11 . In a functional metagenomics study using Escherichia coli as an expression host, actinobacteria were found to be the most enriched source of resistance-conferring DNA fragments relative to their abundance 12 . However, since no recent transfer from actinobacteria to Gram-negative pathogens has been discovered and many recent studies showed that phylogenetic and ecological boundaries are two major ARG transfer barriers 12 , 13 , 14 , 15 , the clinical relevance of this large resistome remains unclear 16 , 17 . Here, we examine a large collection of known Streptomyces ARGs, and find more examples supporting the ‘producer hypothesis’. Specifically, we provide evidence that two ARGs conferring resistance against chloramphenicol and lincomycin might have been recently transferred from actinobacteria to human and animal pathogens. Based on their surrounding sequence, we propose and test a potential mechanism mediating gene transfer from Gram-positive actinobacteria to Gram-negative pathogens. Results Actinobacterial ARGs have related proteins in proteobacteria Proteobacteria encompass many important human pathogens such as Escherichia coli , Pseudomonas aeruginosa and others. We therefore sought to examine the similarity between corresponding ARGs in actinobacteria and proteobacteria. First, we extracted all experimentally validated Streptomyces ARG proteins from ARDB 18 and CARD 19 databases. A majority (39 of 57) of them are reported to have self-protecting roles or are located within antibiotic biosynthesis gene clusters as analysed by antiSMASH 20 ( Supplementary Data 1 ). Their most similar homologues in proteobacteria were subsequently identified from the NCBI non-redundant protein database by BLASTP, with sequence identities ranging from 23 to 68%. Seven of these proteobacterial proteins have sequences more similar to actinobacterial proteins than to proteins from any other phyla, including proteobacteria ( Supplementary Data 1 ). Furthermore, phylogenetic trees were constructed and showed that 12 (including the above seven) of the proteobacterial proteins may have originated from actinobacteria by interphylum HGT ( Fig. 1 and Supplementary Fig. 1 ) 21 . Potential HGTs in the opposite direction, from proteobacteria to actinobacteria, were also noticed in some trees. In particular, the Streptomyces ARG sul1 (AFN41071.1) shares 95% sequence identity with a proteobacterial gene ( Supplementary Fig. 1 ). Figure 1: Proteobacterial proteins related to Streptomyces ARG proteins. Relationships between all experimentally validated Streptomyces ARG proteins and their most similar homologues in proteobacteria were analysed by phylogenetic analysis ( Supplementary Fig. 1 ). Selected pairs that might be connected via interphylum HGT are summarized here, with the proposed transfer direction indicated by an arrow. Protein sequence identity was determined by BLASTP. a The proteins were BLASTed against pathogen genome database PATRIC to see if they have close homologues (sequence identity threshold of 90%) in pathogens. Full size image By examining neighbouring genes, we also found evidence for potential cotransfer of additional genes in the case of the ARG pac (conferring resistance to puromycin). The products of six neighbouring genes also show higher similarity to actinobacterial proteins than to proteins from any other phyla, suggesting that they might have been transferred together from actinobacteria to proteobacteria ( Supplementary Fig. 2 ). Of the 12 proteobacterial proteins that might have originated from actinobacteria, nine are encoded in genomes of environmental species, one of which has close homologues encoded in the genomes of pathogens from the database PATRIC 22 . The other three proteins are harboured by pathogens, including<|im_end|> <|im_start|>assistant To win the war against antibiotic-resistant superbugs, scientists seek the origin of resistance genes to identify how they are introduced to disease-causing bacteria. Identifying the origin of resistance genes and how they spread is comparable to finding patient zero in an outbreak, which is not an easy task. For more than 30 years, scientists have proposed that resistance genes actually originate from the microorganisms producing the antibiotic. However, scientists have not been able to find direct proof of this transfer. Now, research conducted at the Technical University of Denmark shows that antibiotic resistance genes originate from the same place as the antibiotic compounds, i.e. from a group of soil bacteria called Actinobacteria. The study is published in Nature Communications. More than three-fourths of all current antibiotics used to treat human infections are produced by Actinobacteria, which also carry antibiotic resistance genes. In these experiments, the researchers surprisingly found that many resistance genes in disease-causing microbes (gram negative pathogens) were very similar to resistance genes found in Actinobacteria. In one case, the genes were 100 percent identical. "It has been suspected that pathogens can obtain resistance genes from Actinobacteria for half a century. The 100 percent identical genes are the smoking gun," says postdoc Xinglin Jiang from DTU Biosustain. Gram negative pathogens constitute a large group of species, among which are pseudomonas, which can cause lung and urinary tract infections. At first, it was difficult to imagine how pathogens could acquire genes from Actinobacteria, because they are so different and unrelated to each other. But by investigating the DNA sequence around the resistance genes, the team figured out how the transfer occurred through a new mechanism called "carry back", in which the pathogen basically has a primitive form of "sex" with the Actinobacterium and acquires its resistance genes after it dies. This gene transfer by carry back could, in principle, happen when pathogens come into contact with Actinobacteria, like in an animal farm or in soil polluted with untreated hospital waste. In this way, the pathogen can become resistant and endanger human lives in the next round of infection. Understanding the origin is therefore key to counteracting the spread of antibiotic resistance, explains senior researcher Tilmann Weber from DTU Biosustain: "We can't stop this gene transfer, but when you know which resistance genes pathogens may harbor, you can personalize the antibiotic treatment. Also, with this knowledge, you can try to develop new antibiotics with other properties that the pathogens don't have a defense against." Here is how the carry back process works: 1. The Gram negative pathogen injects its DNA into the Actinobacteria. Gram negative bacteria naturally have an ability called conjugation by which bacterial cells can inject their own DNA into other bacterial cells. It is called the bacterial equivalent of sex, because it is usually used to exchange gene information between Gram negative bacteria. But sometimes Gram negative bacteria can also use this mechanism to inject DNA into unrelated Gram positive bacteria like Actinobacteria. 2. Inside the Actinobacteria, the injected DNA recombines with the host's DNA containing resistance genes. After the Actinobacterium dies, the recombinant DNA is released into the environment. 3. Lastly, the injected DNA can act as "gluing DNA" and mediate the uptake of the resistance gene back to the pathogens through a phenomenon called natural transformation. <|im_end|>

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2,158

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Brown adipose tissue (BAT) is able to rapidly generate heat and metabolise macronutrients, such as glucose and lipids, through activation of mitochondrial uncoupling protein 1 (UCP1). Diet can modulate UCP1 function but the capacity of individual nutrients to promote the abundance and activity of UCP1 is not well established. Caffeine consumption has been associated with loss of body weight and increased energy expenditure, but whether it can activate UCP1 is unknown. This study examined the effect of caffeine on BAT thermogenesis in vitro and in vivo . Stem cell-derived adipocytes exposed to caffeine (1 mM) showed increased UCP1 protein abundance and cell metabolism with enhanced oxygen consumption and proton leak. These functional responses were associated with browning-like structural changes in mitochondrial and lipid droplet content. Caffeine also increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression and mitochondrial biogenesis, together with a number of BAT selective and beige gene markers. In vivo , drinking coffee (but not water) stimulated the temperature of the supraclavicular region, which co-locates to the main region of BAT in adult humans, and is indicative of thermogenesis. Taken together, these results demonstrate that caffeine can promote BAT function at thermoneutrality and may have the potential to be used therapeutically in adult humans. Introduction Brown adipose tissue (BAT) is rapidly activated by diet and cold exposure and has the potential to improve metabolic homeostasis in adults 1 , 2 , 3 . This adaptation is characterised by enhanced function of the BAT specific uncoupling protein 1 (UCP1), located on the inner mitochondrial membrane 4 . In adult humans, as the amount of BAT decreases with age and is negatively correlated with body mass index (BMI) 5 , 6 , 7 , 8 , changing the rate of BAT loss could have marked benefits for metabolic health. This could be achieved through dietary ingredients but, although it has been shown that diet can stimulate BAT function 9 , the extent to which individual nutrients can have comparable effects is not well established. Animal studies indicate that brown and beige cells could be activated through nutrients such as capsaicin analogs 10 , 11 , and capsinoids exert similar effects in increasing BAT-dependent energy expenditure as cold exposure 12 . Caffeine (1,3,7-trimethylxantine), a plant alkaloid found in coffee, tea, cola, and chocolate, is widely consumed, has been associated with weight loss and increased energy expenditure in both human and animal models in vivo , and reduces the risk of type 2 diabetes 13 , 14 , 15 , 16 , 17 , 18 . Although caffeine has been reported to upregulate UCP1 in obese mice 19 , the extent to which caffeine (or coffee) may directly stimulate BAT is not known. To elucidate this, we utilised a recently established stem cell model of browning 20 to determine whether a physiological amount of caffeine could change mitochondrial function and lipid handling through promotion of UCP1 function. Based on the recent literature 21 , 22 , 23 , a caffeine concentration of 1 mM was used for in vitro cell culture. A human in vivo study was then undertaken to determine whether the amount of caffeine normally present in a standard coffee beverage can elicit a thermogenic effect on supraclavicular BAT in adult humans. This was assessed by an increase in temperature measured using thermal imaging of the supraclavicular region. Increases in temperature in the region is well correlated with the enhanced radiolabelled glucose uptake into BAT measured during cold exposure using positron emission tomography-computed tomography (PET-CT) 24 . Methods Cell culture Mouse mesenchymal stem cells (mMSCs) were cultured as previously described 20 and adipogenesis induced using a growth medium supplemented with 1 μM dexamethasone (Cayman Chemicals, USA), 100 µM isobutylmethylxanthine (IBMX) (Sigma-Aldrich, UK), 1 μM rosiglitazone (Cayman Chemicals, USA), 10 μg/ml insulin (Sigma-Aldrich, UK) and 1 nM triiodothyronine (T3) (Sigma-Aldrich, UK)). To establish the optimal amount of caffeine, mMSCs were differentiated in increasing concentrations ranging from 0.1–10 mM over 7 days. This demonstrated that the optimum concentration for viability and differentiation was 1 mM (Fig. S1 ) and this was, therefore, used in all subsequent experiments. A similar treatment (with an increased IBMX concentration to 500 μM) was applied to primary human bone marrow-derived stem cells (hMSCs) (Lonza, UK) over 21 days. For both cell types, cell viability assay and Oil Red O (ORO) staining were performed as previously described 20 . The analysis performed in this study was carried out on 3 batches of cells (each one done with 3 technical replicates). Mitochondrial staining and Immunocytochemistry Cells cultured on coverslips were stained with 100 nM MitoTracker Deep Red FM and then examined using a Zeiss Elyra PS.1 microscope to determine the intensity of mitochondrial staining 20 . Cells were fixed and the abundance of UCP1 and proliferator-activated receptor gamma coactivator (PGC-1α) was determined using validated primary antibodies (ab10983; ab54481, Abcam, UK) 20 , 25 , 26 , 27 , 28 , 29 . Twenty fields of view from three experiments for each condition (three biological replicates) were randomly selected, and the overall fluorescence intensity for UCP1 and MitoTracker signals was measured applying identical instrument settings (scanning laser power 633 nm at 4%, detector gain set at 750 and detector offset was set to zero). Image processing and fluorescence measurements were done using original raw files on the manufacturer’s software ZEN blue 2.1 ( ). Transmission electron microscopy analysis Cells were fixed in pre-warm (37 °C) fixative solution (2.5% glutaraldehyde in 0.1 M cacodylate buffer, pH 7.2) and post-fixed in 1% osmium tetroxide in the same buffer following washing. Each sample was then infiltrated with a mixture of epoxy resin and propylene oxide, polymerized with resin and sectioned on a Leica UC6 ultramicrotome (Leica Microsystems, UK). For ultrastructural examination, ultrathin sections were mounted on grids, contrasted with uranyl acetate followed by lead acetate and examined using a FEI Tecnai 12 Biotwin transmission electron microscope (TEM). Gene expression analysis Extraction of total RNA and quantitative PCR were performed as previously described 20", "role": "user" }, { "content": "Scientists from the University of Nottingham have discovered that drinking a cup of coffee can stimulate 'brown fat', the body's own fat-fighting defenses, which could be the key to tackling obesity and diabetes. The pioneering study, published today in the journal Scientific Reports, is one of the first to be carried out in humans to find components which could have a direct effect on 'brown fat' functions, an important part of the human body which plays a key role in how quickly we can burn calories as energy. Brown adipose tissue (BAT), also known as brown fat, is one of two types of fat found in humans and other mammals. Initially only attributed to babies and hibernating mammals, it was discovered in recent years that adults can have brown fat too. Its main function is to generate body heat by burning calories (opposed to white fat, which is a result of storing excess calories). People with a lower body mass index (BMI) therefore have a higher amount of brown fat. Professor Michael Symonds, from the School of Medicine at the University of Nottingham who co-directed the study said: \"Brown fat works in a different way to other fat in your body and produces heat by burning sugar and fat, often in response to cold. Increasing its activity improves blood sugar control as well as improving blood lipid levels and the extra calories burnt help with weight loss. However, until now, no one has found an acceptable way to stimulate its activity in humans. \"This is the first study in humans to show that something like a cup of coffee can have a direct effect on our brown fat functions. The potential implications of our results are pretty big, as obesity is a major health concern for society and we also have a growing diabetes epidemic and brown fat could potentially be part of the solution in tackling them.\" The team started with a series of stem cell studies to see if caffeine would stimulate brown fat. Once they had found the right dose, they then moved on to humans to see if the results were similar. The team used a thermal imaging technique, which they'd previously pioneered, to trace the body's brown fat reserves. The non-invasive technique helps the team to locate brown fat and assess its capacity to produce heat. \"From our previous work, we knew that brown fat is mainly located in the neck region, so we were able to image someone straight after they had a drink to see if the brown fat got hotter,\" said Professor Symonds. \"The results were positive and we now need to ascertain that caffeine as one of the ingredients in the coffee is acting as the stimulus or if there's another component helping with the activation of brown fat. We are currently looking at caffeine supplements to test whether the effect is similar. Once we have confirmed which component is responsible for this, it could potentially be used as part of a weight management regime or as part of glucose regulation programme to help prevent diabetes.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Brown adipose tissue (BAT) is able to rapidly generate heat and metabolise macronutrients, such as glucose and lipids, through activation of mitochondrial uncoupling protein 1 (UCP1). Diet can modulate UCP1 function but the capacity of individual nutrients to promote the abundance and activity of UCP1 is not well established. Caffeine consumption has been associated with loss of body weight and increased energy expenditure, but whether it can activate UCP1 is unknown. This study examined the effect of caffeine on BAT thermogenesis in vitro and in vivo . Stem cell-derived adipocytes exposed to caffeine (1 mM) showed increased UCP1 protein abundance and cell metabolism with enhanced oxygen consumption and proton leak. These functional responses were associated with browning-like structural changes in mitochondrial and lipid droplet content. Caffeine also increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression and mitochondrial biogenesis, together with a number of BAT selective and beige gene markers. In vivo , drinking coffee (but not water) stimulated the temperature of the supraclavicular region, which co-locates to the main region of BAT in adult humans, and is indicative of thermogenesis. Taken together, these results demonstrate that caffeine can promote BAT function at thermoneutrality and may have the potential to be used therapeutically in adult humans. Introduction Brown adipose tissue (BAT) is rapidly activated by diet and cold exposure and has the potential to improve metabolic homeostasis in adults 1 , 2 , 3 . This adaptation is characterised by enhanced function of the BAT specific uncoupling protein 1 (UCP1), located on the inner mitochondrial membrane 4 . In adult humans, as the amount of BAT decreases with age and is negatively correlated with body mass index (BMI) 5 , 6 , 7 , 8 , changing the rate of BAT loss could have marked benefits for metabolic health. This could be achieved through dietary ingredients but, although it has been shown that diet can stimulate BAT function 9 , the extent to which individual nutrients can have comparable effects is not well established. Animal studies indicate that brown and beige cells could be activated through nutrients such as capsaicin analogs 10 , 11 , and capsinoids exert similar effects in increasing BAT-dependent energy expenditure as cold exposure 12 . Caffeine (1,3,7-trimethylxantine), a plant alkaloid found in coffee, tea, cola, and chocolate, is widely consumed, has been associated with weight loss and increased energy expenditure in both human and animal models in vivo , and reduces the risk of type 2 diabetes 13 , 14 , 15 , 16 , 17 , 18 . Although caffeine has been reported to upregulate UCP1 in obese mice 19 , the extent to which caffeine (or coffee) may directly stimulate BAT is not known. To elucidate this, we utilised a recently established stem cell model of browning 20 to determine whether a physiological amount of caffeine could change mitochondrial function and lipid handling through promotion of UCP1 function. Based on the recent literature 21 , 22 , 23 , a caffeine concentration of 1 mM was used for in vitro cell culture. A human in vivo study was then undertaken to determine whether the amount of caffeine normally present in a standard coffee beverage can elicit a thermogenic effect on supraclavicular BAT in adult humans. This was assessed by an increase in temperature measured using thermal imaging of the supraclavicular region. Increases in temperature in the region is well correlated with the enhanced radiolabelled glucose uptake into BAT measured during cold exposure using positron emission tomography-computed tomography (PET-CT) 24 . Methods Cell culture Mouse mesenchymal stem cells (mMSCs) were cultured as previously described 20 and adipogenesis induced using a growth medium supplemented with 1 μM dexamethasone (Cayman Chemicals, USA), 100 µM isobutylmethylxanthine (IBMX) (Sigma-Aldrich, UK), 1 μM rosiglitazone (Cayman Chemicals, USA), 10 μg/ml insulin (Sigma-Aldrich, UK) and 1 nM triiodothyronine (T3) (Sigma-Aldrich, UK)). To establish the optimal amount of caffeine, mMSCs were differentiated in increasing concentrations ranging from 0.1–10 mM over 7 days. This demonstrated that the optimum concentration for viability and differentiation was 1 mM (Fig. S1 ) and this was, therefore, used in all subsequent experiments. A similar treatment (with an increased IBMX concentration to 500 μM) was applied to primary human bone marrow-derived stem cells (hMSCs) (Lonza, UK) over 21 days. For both cell types, cell viability assay and Oil Red O (ORO) staining were performed as previously described 20 . The analysis performed in this study was carried out on 3 batches of cells (each one done with 3 technical replicates). Mitochondrial staining and Immunocytochemistry Cells cultured on coverslips were stained with 100 nM MitoTracker Deep Red FM and then examined using a Zeiss Elyra PS.1 microscope to determine the intensity of mitochondrial staining 20 . Cells were fixed and the abundance of UCP1 and proliferator-activated receptor gamma coactivator (PGC-1α) was determined using validated primary antibodies (ab10983; ab54481, Abcam, UK) 20 , 25 , 26 , 27 , 28 , 29 . Twenty fields of view from three experiments for each condition (three biological replicates) were randomly selected, and the overall fluorescence intensity for UCP1 and MitoTracker signals was measured applying identical instrument settings (scanning laser power 633 nm at 4%, detector gain set at 750 and detector offset was set to zero). Image processing and fluorescence measurements were done using original raw files on the manufacturer’s software ZEN blue 2.1 ( ). Transmission electron microscopy analysis Cells were fixed in pre-warm (37 °C) fixative solution (2.5% glutaraldehyde in 0.1 M cacodylate buffer, pH 7.2) and post-fixed in 1% osmium tetroxide in the same buffer following washing. Each sample was then infiltrated with a mixture of epoxy resin and propylene oxide, polymerized with resin and sectioned on a Leica UC6 ultramicrotome (Leica Microsystems, UK). For ultrastructural examination, ultrathin sections were mounted on grids, contrasted with uranyl acetate followed by lead acetate and examined using a FEI Tecnai 12 Biotwin transmission electron microscope (TEM). Gene expression analysis Extraction of total RNA and quantitative PCR were performed as previously described 20<|im_end|> <|im_start|>assistant Scientists from the University of Nottingham have discovered that drinking a cup of coffee can stimulate 'brown fat', the body's own fat-fighting defenses, which could be the key to tackling obesity and diabetes. The pioneering study, published today in the journal Scientific Reports, is one of the first to be carried out in humans to find components which could have a direct effect on 'brown fat' functions, an important part of the human body which plays a key role in how quickly we can burn calories as energy. Brown adipose tissue (BAT), also known as brown fat, is one of two types of fat found in humans and other mammals. Initially only attributed to babies and hibernating mammals, it was discovered in recent years that adults can have brown fat too. Its main function is to generate body heat by burning calories (opposed to white fat, which is a result of storing excess calories). People with a lower body mass index (BMI) therefore have a higher amount of brown fat. Professor Michael Symonds, from the School of Medicine at the University of Nottingham who co-directed the study said: "Brown fat works in a different way to other fat in your body and produces heat by burning sugar and fat, often in response to cold. Increasing its activity improves blood sugar control as well as improving blood lipid levels and the extra calories burnt help with weight loss. However, until now, no one has found an acceptable way to stimulate its activity in humans. "This is the first study in humans to show that something like a cup of coffee can have a direct effect on our brown fat functions. The potential implications of our results are pretty big, as obesity is a major health concern for society and we also have a growing diabetes epidemic and brown fat could potentially be part of the solution in tackling them." The team started with a series of stem cell studies to see if caffeine would stimulate brown fat. Once they had found the right dose, they then moved on to humans to see if the results were similar. The team used a thermal imaging technique, which they'd previously pioneered, to trace the body's brown fat reserves. The non-invasive technique helps the team to locate brown fat and assess its capacity to produce heat. "From our previous work, we knew that brown fat is mainly located in the neck region, so we were able to image someone straight after they had a drink to see if the brown fat got hotter," said Professor Symonds. "The results were positive and we now need to ascertain that caffeine as one of the ingredients in the coffee is acting as the stimulus or if there's another component helping with the activation of brown fat. We are currently looking at caffeine supplements to test whether the effect is similar. Once we have confirmed which component is responsible for this, it could potentially be used as part of a weight management regime or as part of glucose regulation programme to help prevent diabetes." <|im_end|>

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7633, 220, 508, 662, 578, 6492, 10887, 304, 420, 4007, 574, 11953, 704, 389, 220, 18, 45892, 315, 7917, 320, 9739, 832, 2884, 449, 220, 18, 11156, 29641, 988, 570, 22515, 47517, 6757, 88896, 323, 67335, 34946, 998, 52755, 59190, 89948, 389, 14861, 75, 3153, 1051, 61152, 449, 220, 1041, 308, 44, 386, 6491, 32233, 18682, 3816, 24342, 323, 1243, 25078, 1701, 264, 10120, 1056, 469, 398, 969, 11659, 13, 16, 73757, 311, 8417, 279, 21261, 315, 72061, 88896, 220, 508, 662, 59190, 1051, 8521, 323, 279, 37492, 315, 549, 7269, 16, 323, 43036, 859, 12, 31262, 35268, 22350, 1080, 9035, 859, 320, 11637, 34, 12, 16, 19481, 8, 574, 11075, 1701, 33432, 6156, 59854, 320, 370, 7743, 6069, 26, 671, 21239, 5932, 11, 3765, 11860, 11, 6560, 8, 220, 508, 1174, 220, 914, 1174, 220, 1627, 1174, 220, 1544, 1174, 220, 1591, 1174, 220, 1682, 662, 44956, 5151, 315, 1684, 505, 2380, 21896, 369, 1855, 3044, 320, 28956, 24156, 29641, 988, 8, 1051, 27716, 4183, 11, 323, 279, 8244, 97332, 21261, 369, 549, 7269, 16, 323, 386, 6491, 32233, 17738, 574, 17303, 19486, 20086, 14473, 5110, 320, 2445, 6073, 21120, 2410, 220, 23736, 26807, 520, 220, 19, 13689, 32314, 8895, 743, 520, 220, 11711, 323, 32314, 4445, 574, 743, 311, 7315, 570, 4758, 8863, 323, 97332, 22323, 1051, 2884, 1701, 4113, 7257, 3626, 389, 279, 14290, 753, 3241, 1901, 965, 6437, 220, 17, 13, 16, 320, 7609, 48125, 17130, 92914, 6492, 59190, 1051, 8521, 304, 864, 2695, 2227, 320, 1806, 37386, 34, 8, 5155, 1413, 6425, 320, 17, 13, 20, 4, 35169, 277, 278, 86836, 304, 220, 15, 13, 16, 386, 83981, 1094, 5185, 4240, 11, 37143, 220, 22, 13, 17, 8, 323, 1772, 54864, 304, 220, 16, 4, 2709, 51318, 259, 8980, 87, 579, 304, 279, 1890, 4240, 2768, 28786, 13, 9062, 6205, 574, 1243, 43364, 660, 449, 264, 21655, 315, 97744, 54614, 323, 2047, 64651, 51180, 11, 47393, 1534, 449, 54614, 323, 3857, 291, 389, 264, 2009, 3074, 31613, 21, 37232, 309, 2823, 83, 638, 320, 2356, 3074, 95761, 11, 6560, 570, 1789, 24955, 96797, 24481, 11, 37232, 589, 258, 14491, 1051, 22563, 389, 57449, 11, 13168, 291, 449, 4433, 91014, 65802, 349, 8272, 555, 3063, 65802, 349, 323, 25078, 1701, 264, 29031, 40, 88320, 2192, 220, 717, 426, 11345, 7678, 18874, 17130, 73757, 320, 21695, 570, 24983, 7645, 6492, 95606, 315, 2860, 41214, 323, 47616, 67791, 1051, 10887, 439, 8767, 7633, 220, 508, 128257, 198, 128256, 78191, 198, 72326, 505, 279, 3907, 315, 67659, 617, 11352, 430, 16558, 264, 10747, 315, 11033, 649, 51077, 364, 65561, 8834, 518, 279, 2547, 596, 1866, 8834, 2269, 45850, 46616, 11, 902, 1436, 387, 279, 1401, 311, 57911, 33048, 323, 20335, 13, 578, 71674, 4007, 11, 4756, 3432, 304, 279, 8486, 38130, 29140, 11, 374, 832, 315, 279, 1176, 311, 387, 11953, 704, 304, 12966, 311, 1505, 6956, 902, 1436, 617, 264, 2167, 2515, 389, 364, 65561, 8834, 6, 5865, 11, 459, 3062, 961, 315, 279, 3823, 2547, 902, 11335, 264, 1401, 3560, 304, 1268, 6288, 584, 649, 8395, 25247, 439, 4907, 13, 10690, 30366, 974, 20438, 320, 62403, 705, 1101, 3967, 439, 14198, 8834, 11, 374, 832, 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2,054

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Mitochondrial diseases are commonly caused by mutated mitochondrial DNA (mtDNA), which in most cases coexists with wild-type mtDNA, resulting in mtDNA heteroplasmy. We have engineered transcription activator-like effector nucleases (TALENs) to localize to mitochondria and cleave different classes of pathogenic mtDNA mutations. Mitochondria-targeted TALEN (mitoTALEN) expression led to permanent reductions in deletion or point-mutant mtDNA in patient-derived cells, raising the possibility that these mitochondrial nucleases can be therapeutic for some mitochondrial diseases. Main Most often, pathogenic mtDNA mutations are heteroplasmic, and residual wild-type mtDNA can partially compensate for the mutated mtDNA 1 , 2 , 3 , averting a bioenergetic crisis. However, when the ratio of mutant mtDNA to wild-type mtDNA exceeds approximately 4:1, biochemical and clinical manifestations can result 1 . Therefore, several approaches have been tried to selectively reduce the levels of mutant mtDNA while sparing wild-type mtDNA to skew this ratio back to a healthier range 4 , 5 , 6 . However, previous attempts have been ineffective in living cells and have lacked the flexibility to target clinically relevant mutations, did not produce stable changes in heteroplasmy or were not readily translatable to animals. The use of mitochondria-targeted nucleases showed some promise in their ability to alter mtDNA heteroplasmy in living cells 4 , 7 . To expand their use, we re-engineered TALENs 8 , 9 as a potentially flexible platform to reduce the abundance of mutated mtDNA relative to wild-type mtDNA. We tested this approach by designing a mitoTALEN to cleave the breakpoint region of an mtDNA with a large 5-kilobase deletion, m.8483_13459del4977. This mutation is known as the 'common deletion' because it is present in approximately 30% of all patients with mtDNA deletions 10 , as well as in normal aging tissues 11 , 12 . We exploited the dimerization requirement of TALENs and designed the mitoTALEN for eliminating the common deletion (Δ5-mitoTALEN) so that each monomer binds a specific wild-type sequence flanking the region to be removed. Only when bound to deletion-mutant mtDNA are the Δ5-mitoTALEN monomers close enough to promote FokI dimerization and cleavage ( Fig. 1a ). BLAST analysis did not detect perfect homology of the selected target region in the nuclear genome ( Supplementary Table 1 ). Figure 1: Rationale, verification and efficacy of the Δ5-mitoTALEN for elimination of mtDNAs with the common deletion. ( a ) Diagram illustrating the location of each mitoTALEN monomer recognition site on wild-type mtDNA and mtDNA carrying the 'common deletion'. ( b ) Components of the plasmid used to express the mitoTALEN monomer linked to mCherry. A similar plasmid, not illustrated here, was used for the mitoTALEN monomer linked to eGFP. CMV prmt, cytomegalovirus promoter; SOD2 MLS, superoxide dismutase 2 mitochondrial localization signal; HA, hemagglutinin tag; TAL D5, TAL DNA binding domain; FokI, endonuclease domain; T2A, picornovirus translational stuttering sequence; SOD2 3′ UTR, 3′ untranslated region of the gene encoding SOD2; KanR, kanamycin resistance; pUC ori, plasmid origin of replication. ( c ) Verification of mitochondrial localization of Δ5-mitoTALEN monomers in COS-7 cells 24 h after transfection using antibodies against Flag or HA immuno-tags. Scale bars, 10 μm. ( d ) Gates used for cell sorting of eGFP ('Green') and mCherry ('Red') expression 48 h after transfection with plasmids for the Δ5-mitoTALEN monomers. Cell fractions that were not expressing fluorescent markers ('Black'), only one marker ('Green') and both eGFP and mCherry ('Yellow') were collected for analyses. ( e ) Three-primer PCR analysis to quantify the relative levels of deleted mtDNA, performed with the primers depicted by colored arrows in a . MW, molecular weight standard, 1,500–200 bp; WT, wild-type; Δ, deleted. ( f ) Quantification of three independent transfection experiments using three-primer PCR. Unpaired t -test between 'black' and 'yellow' values; n = 3; *** P < 0.001. Data are expressed as mean ± s.d. Full size image We made a series of modifications to rationally design mitoTALENs ( Fig. 1b ). Each TALEN monomer had a unique epitope tag and a mitochondrial localization sequence at the N terminus. The basic structure of the protein is shown in Supplementary Figure 1a . Western blots showed that proteins of the expected size were synthesized after transient transfection with plasmids coding for the monomers ( Supplementary Fig. 1b ). Likewise, immunocytochemistry showed that they colocalized with the mitochondrial marker Mitotracker ( Fig. 1c ). Within the transcriptional unit of each mitoTALEN monomer, we added a fluorescent marker so that transfected cells could be sorted by FACS, with mCherry for the left monomer and eGFP for the right monomer ( Fig 1b ). We tested the Δ5-mitoTALEN in human osteosarcoma cells heteroplasmic for the mtDNA common deletion (BH10.9 cells) 13 by transfecting them simultaneously with two independent plasmids, each coding for one Δ5-mitoTALEN monomer. Two days after transfection, cells were sorted by FACS gating for mCherry ('red') and eGFP ('green') expression ( Fig. 1d ). Cells expressing both markers, termed 'yellow', were expected to express both Δ5-mitoTALEN monomers. We also isolated cells not expressing any fluorescent markers ('black') and cells expressing only eGFP ('green'). Yields of cells expressing only mCherry were too low to permit analysis. We analyzed mtDNA heteroplasmy with a three-primer PCR technique ( Online Methods ) using the primers depicted in Figure 1a . This analysis showed that the Δ5-mitoTALEN was effective in reducing the mtDNA deletion load and changing mtDNA heteroplasmy to a predominance of wild-type mtDNA ( Fig. 1e,f ). We then measured the levels of the different mtDNA species by quantitative PCR (qPCR) and found that the change in heteroplasmy was primarily caused by a reduction in the absolute levels of deletion-mutant mtDNA ( Supplementary Fig. 2 ). There was a trend toward a reduction in the total mtDNA levels after 2 d, and we also observed a small reduction after 14 d ( Supplementary Fig. 2b,c ). However, we observed a significant compensatory increase in wild-type mtDNA levels at 14 d ( Supplementary Fig. 2 ). Transfection with the Δ5-mitoTALEN in the homoplasmic parental osteosarcoma line (143B) did not", "role": "user" }, { "content": "By borrowing a tool from bacteria that infect plants, scientists have developed a new approach to eliminate mutated DNA inside mitochondria—the energy factories within cells. Doctors might someday use the approach to treat a variety of mitochondrial diseases, including the degenerative eye disease Leber hereditary optic neuropathy (LHON). The research, published online today in Nature Medicine, was funded by the National Eye Institute (NEI), a part of the National Institutes of Health (NIH). Mitochondria convert fuel from food into a form of energy that cells can use. They also make enzymes for a variety of cell functions, and in humans they are the only cell component other than the nucleus that houses genes. Mitochondrial gene mutations can lead to a variety of health problems including muscle weakness, heart disease, and blindness in the case of LHON. Most cells contain thousands of mitochondrial DNA (mtDNA) copies. People with mitochondrial disease often have both mutant and normal mtDNA within their cells. No cures exist for mitochondrial diseases and few effective treatments are available. Searching for strategies to repair mitochondrial gene defects, a group of investigators at the University of Miami Miller School of Medicine explored proteins called transcription activator-like (TAL) effectors. In nature, TAL effectors are found only in certain types of plant-infecting bacteria. They enable the bacteria to use plant DNA to multiply and spread infection. Scientists recently began using TAL effectors to modify DNA in a variety of organisms. In the lab, TAL effectors can be fused with DNA-breaking proteins called nucleases. These TAL effector nucleases (TALENs) can be used to add or remove specific genes or correct gene mutations—techniques that fall under the broad category of genome editing. During the past few years, scientists have begun adapting TALENs and other genome-editing tools for gene therapy. Until now, scientists had only used TALENs to edit genes in the cell nucleus. Today's report marks the first time TALENs have been used to edit mitochondrial genes. \"Mitochondrial-targeted TALENS (mitoTALENs) represent the most promising hope for an effective treatment of diseases caused by mutations in mtDNA,\" said Carlos T. Moraes, Ph.D., a professor of neurology and cell biology at the University of Miami Miller School of Medicine and principal investigator of the study. \"Our research demonstrates that mitoTALENs can substantially decrease or eliminate mutant mtDNA without harming normal mtDNA.\" Using cells in the lab, the investigators designed mitoTALENs to bind and cut mitochondrial DNA that had a specific mutation in the gene Complex I, which causes LHON. The scientists then tested whether the mitoTALENs eliminated the mutant mtDNA. Analysis revealed a temporary drop in cells' total mtDNA, which was due to a reduction in mutant mtDNA. \"Once the mitoTALENs bound and cut the DNA at the specified target, the mutant mtDNA was degraded,\" said Moraes. \"The drop in total mtDNA stimulated the cells to increase their mtDNA by replicating the unaffected molecules. Two weeks later, mtDNA levels had returned to normal. But since the mutant mtDNA was destroyed, the cells had mostly normal mtDNA.\" Reducing but not necessarily eliminating all mutant mtDNA from a person's cells would be sufficient to treat many mitochondrial diseases, Moraes said. Mutant mtDNA typically does not cause signs of disease until it makes up 80 percent or more of the total mtDNA in a cell, which helps explain why age of onset, the constellation of symptoms, and disease severity varies among individuals with the same mutation. \"A modest reduction in mutant mtDNA is likely sufficient to effectively treat disease,\" he said. \"The science in this project advances an imaginative and very clever approach that may one day lead to a therapeutic strategy for mitochondrial diseases,\" said Houmam Araj, Ph.D., director of the lens/cataract and oculomotor/neuro-ophthalmology programs at the NEI. Symptoms of LHON include an abrupt loss of central vision at about age 20 in one eye followed shortly thereafter by the other eye. Although a variety of gene mutations are linked to the disease, most cases involve Complex I mutations, which cause degeneration of the nerves in the back of the eye that transmit visual information to the brain. Neurological problems such as tremors may also occur. Getting mitoTALENs into cells in tissues presents a formidable challenge, however. The scientists plan next to test the approach in animals. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Mitochondrial diseases are commonly caused by mutated mitochondrial DNA (mtDNA), which in most cases coexists with wild-type mtDNA, resulting in mtDNA heteroplasmy. We have engineered transcription activator-like effector nucleases (TALENs) to localize to mitochondria and cleave different classes of pathogenic mtDNA mutations. Mitochondria-targeted TALEN (mitoTALEN) expression led to permanent reductions in deletion or point-mutant mtDNA in patient-derived cells, raising the possibility that these mitochondrial nucleases can be therapeutic for some mitochondrial diseases. Main Most often, pathogenic mtDNA mutations are heteroplasmic, and residual wild-type mtDNA can partially compensate for the mutated mtDNA 1 , 2 , 3 , averting a bioenergetic crisis. However, when the ratio of mutant mtDNA to wild-type mtDNA exceeds approximately 4:1, biochemical and clinical manifestations can result 1 . Therefore, several approaches have been tried to selectively reduce the levels of mutant mtDNA while sparing wild-type mtDNA to skew this ratio back to a healthier range 4 , 5 , 6 . However, previous attempts have been ineffective in living cells and have lacked the flexibility to target clinically relevant mutations, did not produce stable changes in heteroplasmy or were not readily translatable to animals. The use of mitochondria-targeted nucleases showed some promise in their ability to alter mtDNA heteroplasmy in living cells 4 , 7 . To expand their use, we re-engineered TALENs 8 , 9 as a potentially flexible platform to reduce the abundance of mutated mtDNA relative to wild-type mtDNA. We tested this approach by designing a mitoTALEN to cleave the breakpoint region of an mtDNA with a large 5-kilobase deletion, m.8483_13459del4977. This mutation is known as the 'common deletion' because it is present in approximately 30% of all patients with mtDNA deletions 10 , as well as in normal aging tissues 11 , 12 . We exploited the dimerization requirement of TALENs and designed the mitoTALEN for eliminating the common deletion (Δ5-mitoTALEN) so that each monomer binds a specific wild-type sequence flanking the region to be removed. Only when bound to deletion-mutant mtDNA are the Δ5-mitoTALEN monomers close enough to promote FokI dimerization and cleavage ( Fig. 1a ). BLAST analysis did not detect perfect homology of the selected target region in the nuclear genome ( Supplementary Table 1 ). Figure 1: Rationale, verification and efficacy of the Δ5-mitoTALEN for elimination of mtDNAs with the common deletion. ( a ) Diagram illustrating the location of each mitoTALEN monomer recognition site on wild-type mtDNA and mtDNA carrying the 'common deletion'. ( b ) Components of the plasmid used to express the mitoTALEN monomer linked to mCherry. A similar plasmid, not illustrated here, was used for the mitoTALEN monomer linked to eGFP. CMV prmt, cytomegalovirus promoter; SOD2 MLS, superoxide dismutase 2 mitochondrial localization signal; HA, hemagglutinin tag; TAL D5, TAL DNA binding domain; FokI, endonuclease domain; T2A, picornovirus translational stuttering sequence; SOD2 3′ UTR, 3′ untranslated region of the gene encoding SOD2; KanR, kanamycin resistance; pUC ori, plasmid origin of replication. ( c ) Verification of mitochondrial localization of Δ5-mitoTALEN monomers in COS-7 cells 24 h after transfection using antibodies against Flag or HA immuno-tags. Scale bars, 10 μm. ( d ) Gates used for cell sorting of eGFP ('Green') and mCherry ('Red') expression 48 h after transfection with plasmids for the Δ5-mitoTALEN monomers. Cell fractions that were not expressing fluorescent markers ('Black'), only one marker ('Green') and both eGFP and mCherry ('Yellow') were collected for analyses. ( e ) Three-primer PCR analysis to quantify the relative levels of deleted mtDNA, performed with the primers depicted by colored arrows in a . MW, molecular weight standard, 1,500–200 bp; WT, wild-type; Δ, deleted. ( f ) Quantification of three independent transfection experiments using three-primer PCR. Unpaired t -test between 'black' and 'yellow' values; n = 3; *** P < 0.001. Data are expressed as mean ± s.d. Full size image We made a series of modifications to rationally design mitoTALENs ( Fig. 1b ). Each TALEN monomer had a unique epitope tag and a mitochondrial localization sequence at the N terminus. The basic structure of the protein is shown in Supplementary Figure 1a . Western blots showed that proteins of the expected size were synthesized after transient transfection with plasmids coding for the monomers ( Supplementary Fig. 1b ). Likewise, immunocytochemistry showed that they colocalized with the mitochondrial marker Mitotracker ( Fig. 1c ). Within the transcriptional unit of each mitoTALEN monomer, we added a fluorescent marker so that transfected cells could be sorted by FACS, with mCherry for the left monomer and eGFP for the right monomer ( Fig 1b ). We tested the Δ5-mitoTALEN in human osteosarcoma cells heteroplasmic for the mtDNA common deletion (BH10.9 cells) 13 by transfecting them simultaneously with two independent plasmids, each coding for one Δ5-mitoTALEN monomer. Two days after transfection, cells were sorted by FACS gating for mCherry ('red') and eGFP ('green') expression ( Fig. 1d ). Cells expressing both markers, termed 'yellow', were expected to express both Δ5-mitoTALEN monomers. We also isolated cells not expressing any fluorescent markers ('black') and cells expressing only eGFP ('green'). Yields of cells expressing only mCherry were too low to permit analysis. We analyzed mtDNA heteroplasmy with a three-primer PCR technique ( Online Methods ) using the primers depicted in Figure 1a . This analysis showed that the Δ5-mitoTALEN was effective in reducing the mtDNA deletion load and changing mtDNA heteroplasmy to a predominance of wild-type mtDNA ( Fig. 1e,f ). We then measured the levels of the different mtDNA species by quantitative PCR (qPCR) and found that the change in heteroplasmy was primarily caused by a reduction in the absolute levels of deletion-mutant mtDNA ( Supplementary Fig. 2 ). There was a trend toward a reduction in the total mtDNA levels after 2 d, and we also observed a small reduction after 14 d ( Supplementary Fig. 2b,c ). However, we observed a significant compensatory increase in wild-type mtDNA levels at 14 d ( Supplementary Fig. 2 ). Transfection with the Δ5-mitoTALEN in the homoplasmic parental osteosarcoma line (143B) did not<|im_end|> <|im_start|>assistant By borrowing a tool from bacteria that infect plants, scientists have developed a new approach to eliminate mutated DNA inside mitochondria—the energy factories within cells. Doctors might someday use the approach to treat a variety of mitochondrial diseases, including the degenerative eye disease Leber hereditary optic neuropathy (LHON). The research, published online today in Nature Medicine, was funded by the National Eye Institute (NEI), a part of the National Institutes of Health (NIH). Mitochondria convert fuel from food into a form of energy that cells can use. They also make enzymes for a variety of cell functions, and in humans they are the only cell component other than the nucleus that houses genes. Mitochondrial gene mutations can lead to a variety of health problems including muscle weakness, heart disease, and blindness in the case of LHON. Most cells contain thousands of mitochondrial DNA (mtDNA) copies. People with mitochondrial disease often have both mutant and normal mtDNA within their cells. No cures exist for mitochondrial diseases and few effective treatments are available. Searching for strategies to repair mitochondrial gene defects, a group of investigators at the University of Miami Miller School of Medicine explored proteins called transcription activator-like (TAL) effectors. In nature, TAL effectors are found only in certain types of plant-infecting bacteria. They enable the bacteria to use plant DNA to multiply and spread infection. Scientists recently began using TAL effectors to modify DNA in a variety of organisms. In the lab, TAL effectors can be fused with DNA-breaking proteins called nucleases. These TAL effector nucleases (TALENs) can be used to add or remove specific genes or correct gene mutations—techniques that fall under the broad category of genome editing. During the past few years, scientists have begun adapting TALENs and other genome-editing tools for gene therapy. Until now, scientists had only used TALENs to edit genes in the cell nucleus. Today's report marks the first time TALENs have been used to edit mitochondrial genes. "Mitochondrial-targeted TALENS (mitoTALENs) represent the most promising hope for an effective treatment of diseases caused by mutations in mtDNA," said Carlos T. Moraes, Ph.D., a professor of neurology and cell biology at the University of Miami Miller School of Medicine and principal investigator of the study. "Our research demonstrates that mitoTALENs can substantially decrease or eliminate mutant mtDNA without harming normal mtDNA." Using cells in the lab, the investigators designed mitoTALENs to bind and cut mitochondrial DNA that had a specific mutation in the gene Complex I, which causes LHON. The scientists then tested whether the mitoTALENs eliminated the mutant mtDNA. Analysis revealed a temporary drop in cells' total mtDNA, which was due to a reduction in mutant mtDNA. "Once the mitoTALENs bound and cut the DNA at the specified target, the mutant mtDNA was degraded," said Moraes. "The drop in total mtDNA stimulated the cells to increase their mtDNA by replicating the unaffected molecules. Two weeks later, mtDNA levels had returned to normal. But since the mutant mtDNA was destroyed, the cells had mostly normal mtDNA." Reducing but not necessarily eliminating all mutant mtDNA from a person's cells would be sufficient to treat many mitochondrial diseases, Moraes said. Mutant mtDNA typically does not cause signs of disease until it makes up 80 percent or more of the total mtDNA in a cell, which helps explain why age of onset, the constellation of symptoms, and disease severity varies among individuals with the same mutation. "A modest reduction in mutant mtDNA is likely sufficient to effectively treat disease," he said. "The science in this project advances an imaginative and very clever approach that may one day lead to a therapeutic strategy for mitochondrial diseases," said Houmam Araj, Ph.D., director of the lens/cataract and oculomotor/neuro-ophthalmology programs at the NEI. Symptoms of LHON include an abrupt loss of central vision at about age 20 in one eye followed shortly thereafter by the other eye. Although a variety of gene mutations are linked to the disease, most cases involve Complex I mutations, which cause degeneration of the nerves in the back of the eye that transmit visual information to the brain. Neurological problems such as tremors may also occur. Getting mitoTALENs into cells in tissues presents a formidable challenge, however. The scientists plan next to test the approach in animals. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Superconducting spintronics has emerged in the past decade as a promising new field that seeks to open a new dimension for nanoelectronics by utilizing the internal spin structure of the superconducting Cooper pair as a new degree of freedom 1 , 2 . Its basic building blocks are spin-triplet Cooper pairs with equally aligned spins, which are promoted by proximity of a conventional superconductor to a ferromagnetic material with inhomogeneous macroscopic magnetization 3 . Using low-energy muon spin-rotation experiments we find an unanticipated effect, in contradiction with the existing theoretical models of superconductivity and ferromagnetism: the appearance of a magnetization in a thin layer of a non-magnetic metal (gold), separated from a ferromagnetic double layer by a 50-nm-thick superconducting layer of Nb. The effect can be controlled either by temperature or by using a magnetic field to control the state of the remote ferromagnetic elements, and may act as a basic building block for a new generation of quantum interference devices based on the spin of a Cooper pair. Main The ability to manipulate the spin degree of freedom of charge carriers is key to realizing future spin-based electronics. Integrating superconductors into spintronic devices can greatly enhance performance 1 and allows the transport of spin over long distances without the dissipation of heat 2 . To achieve the alignment of electron spins, ferromagnetic materials are used. Superconductivity and ferromagnetism are, however, antagonistic states of matter, and the interplay between these two states results in the conversion of conventional spin-singlet into spin-triplet pair correlations 3 . Whereas spin-singlet pairs have spin angular momentum S = 0, spin-triplet pairs have S = 1, with three possible spin projections s z = −1, 0, +1. The realization of such spin-triplet pairs in mesoscopic systems containing interfaces between superconducting (S) and ferromagnetic (F) layers has attracted much interest from both the theoretical and experimental communities. Interaction of spin-singlet superconductivity with collinear ferromagnetism leads to oscillations and suppression of the pair correlation at a short distance ξ f due to the exchange magnetic field in the ferromagnet, which tends to align the spins of electrons parallel 4 , 5 , 6 , 7 . However, to create longer-range penetration of spin-triplet superconductivity into the ferromagnet, interaction with a non-collinear magnetism is required 8 , 9 , 10 , motivating the discovery of superconducting currents through ferromagnetic metals over distances far longer than the singlet penetration length ξ f (refs 11 , 12 , 13 ). These long-range triplet components (LRTC) have parallel spin projections ( s z = ±1), and are not suppressed by the exchange field. Theory predicts that the conversion into spin-triplet pairs should also give rise to an induced magnetic moment in the superconductor, decaying away from the interface 14 , 15 , 16 , often called the inverse or magnetic proximity effect. For diffusive systems this induced magnetic moment is predicted to be negative (opposite to the magnetization of itinerant electrons in the adjacent F layer) and accompanied by a small decrease of magnetization of this F layer on the scale of the ferromagnetic coherence length ξ f . There are a small number of reports with observations that are attributed to this effect 17 , 18 , 19 , although none use a measurement technique that has the required spatial sensitivity to uniquely determine this. A further report involving low-energy muon spin-rotation (LE-μSR) measurements, a technique possessing the required spatial sensitivity to determine the location of the moment, found contradictory evidence 20 . The moment was found not to penetrate into the S layer over the expected distance of a coherence length, but rather it existed over a very much shorter length scale, indicating a rather different interfacial mechanism at play in that system, and possibly also in related works. Here we report results obtained by high-precision LE-μSR that are in conflict with the current theoretical predictions, and which yield instead a very surprising, hitherto unknown effect. We find a switchable magnetic moment to be induced remotely from the superconductor–ferromagnet interface, at a non-magnetic superconductor–normal metal interface about 150 atomic layers away from the ferromagnet. The moment appears, however, not inside the S layer, but in an adjacent normal metal (N) layer. It first appears at the onset of superconductivity and increases as the temperature is lowered. This remote induced magnetic moment also exhibits a spin-valve effect: a significant change in magnitude ( ∼ 20 times) depending on the mutual orientation of magnetization in the F layers in the NSFF multilayered structure. The effect almost disappears when switching the spin-valve into a collinear state of the F layers’ magnetization, when LRTC are absent. This shows that LRTC in the ferromagnetic regions are a crucial ingredient contributing to the effect. For our experiments we use superconducting spin-valve structures Au( x )/Nb(50)/Co(2.4)/Nb(3)/Co(1.2)/IrMn(4)/Co(3)/Ta(7.5)/Si-substrate with numbers indicating the layer thicknesses in nm and x = 5 or 70. They consist of an S/F interface with an additional N layer atop the S, as well as a second F layer separated from the first by a thin normal metal spacer (n), creating a NSFnF device, shown schematically in Fig. 1 (see Supplementary Information for more details of our spin-valves). In our devices the exchange field of the outer F layer (Co(1.2)) can be pinned magnetically, by using an anti-ferromagnet (IrMn), while retaining easy manipulation of the other F layer (Co(2.4)). This enables us to control the angle between the two F magnetizations and thus explore the inverse proximity effect in both the orthogonal configuration as well as the collinear configuration. In other words, to examine the (possible) induction of magnetic moments when the LRTC are present (non-collinear configuration) and compare it with the case where they are absent (collinear configuration). A dependence of T c on the magnetic configuration in such structures has been proposed 21 and measured 22 , 23 , 24 . For the case of a strongly spin-polarized ferromagnet, owing to the appearance of the new LRTC channel for drainage of", "role": "user" }, { "content": "Under certain conditions, superconductivity, which is basically incompatible with magnetism, can promote magnetization. Russian scientist Natalya Pugach from the Skobeltsyn Institute of Nuclear Physics at the Lomonosov Moscow State University discovered this still unexplained effect with her British colleagues, whose theory group was headed by Professor Matthias Eschrig. They suggest that techniques based on this effect can move us closer to future supercomputers—spintronic devices. Their study was published in Nature Physics. The research team, which included Natalya Pugach from the Skobeltsyn Institute of Nuclear Physics, studied the interactions between superconductivity and magnetization in order to understand how to control electron spins (electron magnetic moments) and to create next-generation electronics. In traditional microelectronics, information is coded via the electric charges. In spin electronics—or spintronics—information is coded via the electron spin, which can be directed along or against a particular axis. \"Superconducting spintronic devices will demand far less energy and emit less heat. It means that this technology will allow us to create much more economical and stable computing machines and supercomputers,\" Natalya Pugach explains. The main obstacle to the development of these devices is that the spins of electrons and of other charged particles are very difficult to control. The results of this new research show that superconductors may be useful in the process of spin transportation, and ferromagnetics may be used to control spins. Superconducting states are very sensitive to magnetic fields—strong magnetic fields destroy superconductivity, but superconductors expel magnetic fields completely. It is almost impossible to make ordinary superconductors and magnetic materials interact with each other due to their opposed magnetic ordering directions: In magnetic storage systems, the magnetic field arranges spins in one direction, but the Cooper pair (BCS pair) in ordinary superconductors have spins in the opposite direction. \"My colleagues experimented with devices called superconducting spin valves. They look like a 'sandwich' made of nanolayers of ferromagnetic material, superconductors and other metals. By changing the direction of magnetization, it is possible to control the current in the superconductor. The thickness of layers is crucial, because in the case of the 'thick' superconductor, it is impossible to see any interesting effects,\" Natalya Pugach explains. During the experiments, scientists bombarded the experimental samples with muons (particles that resemble electrons, but are 200 times heavier) and analyzed their dissipation scattering. This method made it possible to understand how the magnetization proceeds in different layers of the sample. The spin valve consisted of two ferromagnetic cobalt layers, one superconductive niobium layer with a thickness of approximately 150 atoms and a layer of gold. In the experiment, researchers discovered an unexpected effect: When magnetization directions in two ferromagnetic layers were not parallel, the interaction between these layers and the superconductive layer induced magnetization in the gold layer, jumping over the superconductor. When scientists changed the magnetization directions in two layers, making them parallel, this effect almost disappeared—field intensity decreased 20-fold. \"This effect was unexpected. We were very surprised to discover it. Previously, we tried to explain the results with a known magnetization distribution pattern, but in vain. We have some hypotheses, but we still do not have any complete explanation. Nevertheless, this effect allows us to use a new method of manipulations with spins,\" Natalya Pugach says. It is quite possible that the finding will lead to conceptually new spintronic elements. According to Natalya Pugach, superconductive spintronics technologies may help to build supercomputers and powerful servers minimizing the energy consumption and heat emissions of current supercomputers. \"Computer technologies are based on semiconductors, which are good for personal computers. But when you use these semiconductors to build supercomputers, they produce heat and noise, and demand powerful cooling systems. Spintronics could solve all these problems,\" Natalya Pugach concludes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Superconducting spintronics has emerged in the past decade as a promising new field that seeks to open a new dimension for nanoelectronics by utilizing the internal spin structure of the superconducting Cooper pair as a new degree of freedom 1 , 2 . Its basic building blocks are spin-triplet Cooper pairs with equally aligned spins, which are promoted by proximity of a conventional superconductor to a ferromagnetic material with inhomogeneous macroscopic magnetization 3 . Using low-energy muon spin-rotation experiments we find an unanticipated effect, in contradiction with the existing theoretical models of superconductivity and ferromagnetism: the appearance of a magnetization in a thin layer of a non-magnetic metal (gold), separated from a ferromagnetic double layer by a 50-nm-thick superconducting layer of Nb. The effect can be controlled either by temperature or by using a magnetic field to control the state of the remote ferromagnetic elements, and may act as a basic building block for a new generation of quantum interference devices based on the spin of a Cooper pair. Main The ability to manipulate the spin degree of freedom of charge carriers is key to realizing future spin-based electronics. Integrating superconductors into spintronic devices can greatly enhance performance 1 and allows the transport of spin over long distances without the dissipation of heat 2 . To achieve the alignment of electron spins, ferromagnetic materials are used. Superconductivity and ferromagnetism are, however, antagonistic states of matter, and the interplay between these two states results in the conversion of conventional spin-singlet into spin-triplet pair correlations 3 . Whereas spin-singlet pairs have spin angular momentum S = 0, spin-triplet pairs have S = 1, with three possible spin projections s z = −1, 0, +1. The realization of such spin-triplet pairs in mesoscopic systems containing interfaces between superconducting (S) and ferromagnetic (F) layers has attracted much interest from both the theoretical and experimental communities. Interaction of spin-singlet superconductivity with collinear ferromagnetism leads to oscillations and suppression of the pair correlation at a short distance ξ f due to the exchange magnetic field in the ferromagnet, which tends to align the spins of electrons parallel 4 , 5 , 6 , 7 . However, to create longer-range penetration of spin-triplet superconductivity into the ferromagnet, interaction with a non-collinear magnetism is required 8 , 9 , 10 , motivating the discovery of superconducting currents through ferromagnetic metals over distances far longer than the singlet penetration length ξ f (refs 11 , 12 , 13 ). These long-range triplet components (LRTC) have parallel spin projections ( s z = ±1), and are not suppressed by the exchange field. Theory predicts that the conversion into spin-triplet pairs should also give rise to an induced magnetic moment in the superconductor, decaying away from the interface 14 , 15 , 16 , often called the inverse or magnetic proximity effect. For diffusive systems this induced magnetic moment is predicted to be negative (opposite to the magnetization of itinerant electrons in the adjacent F layer) and accompanied by a small decrease of magnetization of this F layer on the scale of the ferromagnetic coherence length ξ f . There are a small number of reports with observations that are attributed to this effect 17 , 18 , 19 , although none use a measurement technique that has the required spatial sensitivity to uniquely determine this. A further report involving low-energy muon spin-rotation (LE-μSR) measurements, a technique possessing the required spatial sensitivity to determine the location of the moment, found contradictory evidence 20 . The moment was found not to penetrate into the S layer over the expected distance of a coherence length, but rather it existed over a very much shorter length scale, indicating a rather different interfacial mechanism at play in that system, and possibly also in related works. Here we report results obtained by high-precision LE-μSR that are in conflict with the current theoretical predictions, and which yield instead a very surprising, hitherto unknown effect. We find a switchable magnetic moment to be induced remotely from the superconductor–ferromagnet interface, at a non-magnetic superconductor–normal metal interface about 150 atomic layers away from the ferromagnet. The moment appears, however, not inside the S layer, but in an adjacent normal metal (N) layer. It first appears at the onset of superconductivity and increases as the temperature is lowered. This remote induced magnetic moment also exhibits a spin-valve effect: a significant change in magnitude ( ∼ 20 times) depending on the mutual orientation of magnetization in the F layers in the NSFF multilayered structure. The effect almost disappears when switching the spin-valve into a collinear state of the F layers’ magnetization, when LRTC are absent. This shows that LRTC in the ferromagnetic regions are a crucial ingredient contributing to the effect. For our experiments we use superconducting spin-valve structures Au( x )/Nb(50)/Co(2.4)/Nb(3)/Co(1.2)/IrMn(4)/Co(3)/Ta(7.5)/Si-substrate with numbers indicating the layer thicknesses in nm and x = 5 or 70. They consist of an S/F interface with an additional N layer atop the S, as well as a second F layer separated from the first by a thin normal metal spacer (n), creating a NSFnF device, shown schematically in Fig. 1 (see Supplementary Information for more details of our spin-valves). In our devices the exchange field of the outer F layer (Co(1.2)) can be pinned magnetically, by using an anti-ferromagnet (IrMn), while retaining easy manipulation of the other F layer (Co(2.4)). This enables us to control the angle between the two F magnetizations and thus explore the inverse proximity effect in both the orthogonal configuration as well as the collinear configuration. In other words, to examine the (possible) induction of magnetic moments when the LRTC are present (non-collinear configuration) and compare it with the case where they are absent (collinear configuration). A dependence of T c on the magnetic configuration in such structures has been proposed 21 and measured 22 , 23 , 24 . For the case of a strongly spin-polarized ferromagnet, owing to the appearance of the new LRTC channel for drainage of<|im_end|> <|im_start|>assistant Under certain conditions, superconductivity, which is basically incompatible with magnetism, can promote magnetization. Russian scientist Natalya Pugach from the Skobeltsyn Institute of Nuclear Physics at the Lomonosov Moscow State University discovered this still unexplained effect with her British colleagues, whose theory group was headed by Professor Matthias Eschrig. They suggest that techniques based on this effect can move us closer to future supercomputers—spintronic devices. Their study was published in Nature Physics. The research team, which included Natalya Pugach from the Skobeltsyn Institute of Nuclear Physics, studied the interactions between superconductivity and magnetization in order to understand how to control electron spins (electron magnetic moments) and to create next-generation electronics. In traditional microelectronics, information is coded via the electric charges. In spin electronics—or spintronics—information is coded via the electron spin, which can be directed along or against a particular axis. "Superconducting spintronic devices will demand far less energy and emit less heat. It means that this technology will allow us to create much more economical and stable computing machines and supercomputers," Natalya Pugach explains. The main obstacle to the development of these devices is that the spins of electrons and of other charged particles are very difficult to control. The results of this new research show that superconductors may be useful in the process of spin transportation, and ferromagnetics may be used to control spins. Superconducting states are very sensitive to magnetic fields—strong magnetic fields destroy superconductivity, but superconductors expel magnetic fields completely. It is almost impossible to make ordinary superconductors and magnetic materials interact with each other due to their opposed magnetic ordering directions: In magnetic storage systems, the magnetic field arranges spins in one direction, but the Cooper pair (BCS pair) in ordinary superconductors have spins in the opposite direction. "My colleagues experimented with devices called superconducting spin valves. They look like a 'sandwich' made of nanolayers of ferromagnetic material, superconductors and other metals. By changing the direction of magnetization, it is possible to control the current in the superconductor. The thickness of layers is crucial, because in the case of the 'thick' superconductor, it is impossible to see any interesting effects," Natalya Pugach explains. During the experiments, scientists bombarded the experimental samples with muons (particles that resemble electrons, but are 200 times heavier) and analyzed their dissipation scattering. This method made it possible to understand how the magnetization proceeds in different layers of the sample. The spin valve consisted of two ferromagnetic cobalt layers, one superconductive niobium layer with a thickness of approximately 150 atoms and a layer of gold. In the experiment, researchers discovered an unexpected effect: When magnetization directions in two ferromagnetic layers were not parallel, the interaction between these layers and the superconductive layer induced magnetization in the gold layer, jumping over the superconductor. When scientists changed the magnetization directions in two layers, making them parallel, this effect almost disappeared—field intensity decreased 20-fold. "This effect was unexpected. We were very surprised to discover it. Previously, we tried to explain the results with a known magnetization distribution pattern, but in vain. We have some hypotheses, but we still do not have any complete explanation. Nevertheless, this effect allows us to use a new method of manipulations with spins," Natalya Pugach says. It is quite possible that the finding will lead to conceptually new spintronic elements. According to Natalya Pugach, superconductive spintronics technologies may help to build supercomputers and powerful servers minimizing the energy consumption and heat emissions of current supercomputers. "Computer technologies are based on semiconductors, which are good for personal computers. But when you use these semiconductors to build supercomputers, they produce heat and noise, and demand powerful cooling systems. Spintronics could solve all these problems," Natalya Pugach concludes. <|im_end|>

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279, 502, 445, 49773, 5613, 369, 58592, 315, 128257, 198, 128256, 78191, 198, 16648, 3738, 4787, 11, 2307, 77752, 1968, 11, 902, 374, 13524, 53924, 449, 33297, 2191, 11, 649, 12192, 33297, 2065, 13, 8690, 28568, 42701, 7911, 393, 773, 613, 505, 279, 4923, 78206, 2641, 1910, 10181, 315, 38544, 28415, 520, 279, 445, 35685, 437, 869, 23223, 3314, 3907, 11352, 420, 2103, 653, 81950, 2515, 449, 1077, 8013, 18105, 11, 6832, 10334, 1912, 574, 19946, 555, 17054, 90587, 9419, 331, 14746, 13, 2435, 4284, 430, 12823, 3196, 389, 420, 2515, 649, 3351, 603, 12401, 311, 3938, 2307, 66047, 388, 2345, 42682, 376, 14338, 7766, 13, 11205, 4007, 574, 4756, 304, 22037, 28415, 13, 578, 3495, 2128, 11, 902, 5343, 42701, 7911, 393, 773, 613, 505, 279, 4923, 78206, 2641, 1910, 10181, 315, 38544, 28415, 11, 20041, 279, 22639, 1990, 2307, 77752, 1968, 323, 33297, 2065, 304, 2015, 311, 3619, 1268, 311, 2585, 17130, 45858, 320, 75603, 24924, 14269, 8, 323, 311, 1893, 1828, 43927, 31591, 13, 763, 8776, 8162, 79666, 11, 2038, 374, 47773, 4669, 279, 9249, 10405, 13, 763, 12903, 31591, 51749, 12903, 35785, 1233, 2345, 26125, 374, 47773, 4669, 279, 17130, 12903, 11, 902, 649, 387, 15910, 3235, 477, 2403, 264, 4040, 8183, 13, 330, 19841, 77752, 287, 12903, 376, 14338, 7766, 690, 7631, 3117, 2753, 4907, 323, 17105, 2753, 8798, 13, 1102, 3445, 430, 420, 5557, 690, 2187, 603, 311, 1893, 1790, 810, 60618, 323, 15528, 25213, 12933, 323, 2307, 66047, 388, 1359, 42701, 7911, 393, 773, 613, 15100, 13, 578, 1925, 33287, 311, 279, 4500, 315, 1521, 7766, 374, 430, 279, 45858, 315, 57678, 323, 315, 1023, 11684, 19252, 527, 1633, 5107, 311, 2585, 13, 578, 3135, 315, 420, 502, 3495, 1501, 430, 2307, 77752, 1105, 1253, 387, 5505, 304, 279, 1920, 315, 12903, 18386, 11, 323, 18728, 442, 3326, 25265, 1253, 387, 1511, 311, 2585, 45858, 13, 7445, 77752, 287, 5415, 527, 1633, 16614, 311, 24924, 5151, 2345, 4620, 24924, 5151, 7066, 2307, 77752, 1968, 11, 719, 2307, 77752, 1105, 1367, 301, 24924, 5151, 6724, 13, 1102, 374, 4661, 12266, 311, 1304, 19664, 2307, 77752, 1105, 323, 24924, 7384, 16681, 449, 1855, 1023, 4245, 311, 872, 16475, 24924, 22106, 18445, 25, 763, 24924, 5942, 6067, 11, 279, 24924, 2115, 2961, 5637, 45858, 304, 832, 5216, 11, 719, 279, 24421, 6857, 320, 5002, 50, 6857, 8, 304, 19664, 2307, 77752, 1105, 617, 45858, 304, 279, 14329, 5216, 13, 330, 5159, 18105, 98504, 449, 7766, 2663, 2307, 77752, 287, 12903, 64100, 13, 2435, 1427, 1093, 264, 364, 92346, 17316, 6, 1903, 315, 20622, 337, 5184, 315, 18728, 442, 39100, 3769, 11, 2307, 77752, 1105, 323, 1023, 37182, 13, 3296, 10223, 279, 5216, 315, 33297, 2065, 11, 433, 374, 3284, 311, 2585, 279, 1510, 304, 279, 2307, 444, 36869, 13, 578, 26839, 315, 13931, 374, 16996, 11, 1606, 304, 279, 1162, 315, 279, 364, 339, 875, 6, 2307, 444, 36869, 11, 433, 374, 12266, 311, 1518, 904, 7185, 6372, 1359, 42701, 7911, 393, 773, 613, 15100, 13, 12220, 279, 21896, 11, 14248, 13054, 21632, 279, 22772, 10688, 449, 12097, 2439, 320, 69598, 430, 52280, 57678, 11, 719, 527, 220, 1049, 3115, 44922, 8, 323, 30239, 872, 14091, 49686, 72916, 13, 1115, 1749, 1903, 433, 3284, 311, 3619, 1268, 279, 33297, 2065, 34555, 304, 2204, 13931, 315, 279, 6205, 13, 578, 12903, 32530, 44660, 315, 1403, 18728, 442, 39100, 34928, 3223, 13931, 11, 832, 2307, 444, 68243, 13080, 677, 2411, 6324, 449, 264, 26839, 315, 13489, 220, 3965, 33299, 323, 264, 6324, 315, 6761, 13, 763, 279, 9526, 11, 12074, 11352, 459, 16907, 2515, 25, 3277, 33297, 2065, 18445, 304, 1403, 18728, 442, 39100, 13931, 1051, 539, 15638, 11, 279, 16628, 1990, 1521, 13931, 323, 279, 2307, 444, 68243, 6324, 36572, 33297, 2065, 304, 279, 6761, 6324, 11, 30102, 927, 279, 2307, 444, 36869, 13, 3277, 14248, 5614, 279, 33297, 2065, 18445, 304, 1403, 13931, 11, 3339, 1124, 15638, 11, 420, 2515, 4661, 29496, 2345, 2630, 21261, 25983, 220, 508, 24325, 13, 330, 2028, 2515, 574, 16907, 13, 1226, 1051, 1633, 14792, 311, 7142, 433, 13, 59787, 11, 584, 6818, 311, 10552, 279, 3135, 449, 264, 3967, 33297, 2065, 8141, 5497, 11, 719, 304, 46604, 13, 1226, 617, 1063, 74513, 11, 719, 584, 2103, 656, 539, 617, 904, 4686, 16540, 13, 35053, 11, 420, 2515, 6276, 603, 311, 1005, 264, 502, 1749, 315, 14951, 7607, 449, 45858, 1359, 42701, 7911, 393, 773, 613, 2795, 13, 1102, 374, 5115, 3284, 430, 279, 9455, 690, 3063, 311, 7434, 1870, 502, 12903, 376, 14338, 5540, 13, 10771, 311, 42701, 7911, 393, 773, 613, 11, 2307, 444, 68243, 12903, 35785, 1233, 14645, 1253, 1520, 311, 1977, 2307, 66047, 388, 323, 8147, 16692, 77391, 279, 4907, 15652, 323, 8798, 20748, 315, 1510, 2307, 66047, 388, 13, 330, 38432, 14645, 527, 3196, 389, 5347, 1965, 1076, 1105, 11, 902, 527, 1695, 369, 4443, 19002, 13, 2030, 994, 499, 1005, 1521, 5347, 1965, 1076, 1105, 311, 1977, 2307, 66047, 388, 11, 814, 8356, 8798, 323, 12248, 11, 323, 7631, 8147, 28015, 6067, 13, 41785, 35785, 1233, 1436, 11886, 682, 1521, 5435, 1359, 42701, 7911, 393, 773, 613, 45537, 13, 220, 128257, 198 ]

2,262

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Purpose Glioblastoma (GBM) is the most common and deadliest brain tumor with unrelenting and rapid disease progression. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Treatment failure and resistance is the rule and despite advances in imaging technology, early detection of treatment failure or impending resistance remains a challenge. There is a dire, unmet, need in clinical practice for minimally-invasive diagnostic tools to enable timely understanding of disease progression and treatment response. Here, we aim to address this clinical need by leveraging a unique characteristic of GBM: the overexpression of the α2 variant of the IL-13 receptor in over 75% of GBM tumors. Methods In this study we examined patients with primary GBM from Penn State and Cleveland Clinic compared to healthy controls. Results IL13Rα2 was detectable in plasma of GBM patients using ELISA but detection could be optimized by PEG precipitation to enrich for extracellular vesicles (EVs). Patients with GBM had elevated levels of plasma IL13Rα2, which correlated to levels of this receptor in the tumor tissue. Elevated plasma levels of IL13Rα2 predicted longer overall survival (OS) (19.8 vs. 13.2 months). Similarly, detection of IL13Rα2 + cells in tumor tissue also predicted longer OS (22.1 vs. 12.2 months). Conclusion These findings strongly suggest that expression of the IL13Rα2 receptor confer survival advantage in GBM patients, which can be determined through a minimally-invasive liquid biopsy. Detection of plasma IL13Rα2 can also be used to select GBM patients for targeted tumor therapy. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Gliomas are tumors with histologic features resembling normal glial cells and are characterized by histopathologic appearance and molecular parameters [ 1 ]. Glioblastoma (GBM) is both the most common and deadly malignant primary brain tumor with a 1-year survival of 37.2% and a 5-year survival of just 5.1% [ 2 ]. Molecular parameters play an ever-increasing role in the classification of gliomas, guiding prognosis and treatment decisions [ 1 , 3 ]. Disease progression is unrelenting, although patients carrying some molecular variants such as IDH mutations display a modestly better prognosis [ 4 ]. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Treatment failure and resistance is the rule and despite advances in imaging technology, early identification of treatment failure or impending resistance remains a challenge [ 5 ]. There is a dire, unmet, gap in clinical practice for minimally-invasive diagnostic tools to enable timely understanding of disease progression and treatment response. A liquid biopsy is a minimally-invasive approach centered on detecting tumor-derived and disease-associated biomarkers in the patient’s biofluids such as blood, cerebrospinal fluid (CSF), urine, and saliva. Clinical experience with other solid tumors points to the enormous potential of liquid biopsies [ 6 ]. First, they can provide the physician with useful diagnostic and prognostic data. Second, the ease of longitudinal sampling can help track progression of the disease and provide timely differentiation between treatment resistance and response. Finally, liquid biopsies can be used guide treatment through differentiating disease variants and identifying targetable proteins and mutations. Discussion of liquid biopsy would not be complete without including extracellular vesicles (EVs). EVs is a broad term for lipid bilayer particles released by virtually all cells, including tumor cells, and their contents directly correlate to the cells of origin [ 7 ]. EV functions include intercellular communication, disposal of undesirable material, transfer of proteins and RNA [ 7 ]. Crucially, EVs stabilize their molecular cargo, delaying degradation of biofluids, and have been shown to pass through an intact blood-brain barrier via transcytosis [ 8 ]. Initial groundbreaking steps in the discovery of GBM biomarkers have unsurprisingly focused on circulating genetic material due to the highly-sensitive and specific nature of PCR amplification. Ebrahimkhani et al. demonstrated that a serum signature of 7 miRNAs could reliably distinguish GBM patients from controls, albeit without distinguishing tumor-derived and tumor-associated miRNAs [ 9 ]. Evidence that circulating plasma EVs are representative of the tumor was provided by Batool et al. who were able to detect a tumor-specific EGFRvIII mutation in circulating EVs of patients with GBM [ 10 ]. In contrast to genetic-focused approaches, peptide-based liquid biopsies have had a slower start. Initial studies focused on hormones and cytokines known to be involved in GBM pathogenesis, and have yielded some success. For example, IL-6 levels have been shown to increase tumor associated macrophage migration into the cerebrospinal fluid (CSF) to further the development of neural tumors through growth, angiogenesis, and tumor invasion [ 11 ]. Peles et al. determined that CSF angiogenic factors including bFGF and VEGF are useful in predicting overall survival (OS) [ 12 ]. Recently, Rategui et al. have shown that the tumor-specific and clinically relevant EGFRvIII receptor could be used as a target to isolate tumor-specific EVs. By combining a hydrogel substrate, anisotropic flow pattern, and PEG-linked affinity purification antibodies on a microfluidic chip, individual tumor-derived EVs could be captured, quantified, and assayed using proteomic and genomic methods [ 13 ]. Another promising tumor-specific biomarker is the α2 variant of the IL-13 receptor (IL13Rα2), which is overexpressed in > 75% of GBM patients while being undetectable in normal tissue [ 14 , 15 , 16 , 17 ]. To date, only two studies have focused on the diagnostic and prognostic utility of IL13Rα2. In terms of bulk mRNA expression data, IL13Rα2 expression appears to have negative prognostic significance in glioma patients [ 18 ]. This negative correlation between IL13Ra2 mRNA expression and poor prognosis was confirmed by Han et al. through extensive analysis of The Cancer Genome Atlas [ 19 ]. However, whereas these studies have focused on bulk mRNA expression data, no studies have explored the diagnostic and prognostic potential of IL13Rα2 protein circulating in patient biofluids. Building on the premise that IL13Rα2 is overexpressed in GBM tumor tissue, we explore its potential as a liquid biopsy", "role": "user" }, { "content": "Glioblastoma (GBM) is the most common and deadliest type of brain cancer with a five-year survival rate of only 5%. Researchers at Penn State College of Medicine have identified a biomarker that can be used in blood tests to diagnose GBM, track its progression and guide treatment. The researchers said that such a non-invasive liquid biopsy for GBM could help patients get the care they need more quickly. \"Patients normally receive imaging, such as MRI or CT scans, to diagnose and track the progression of brain tumors, but it can be difficult for physicians to tell from those scans if the patient is getting better or worse because they don't provide detail at the cellular or molecular level,\" said Vladimir Khristov, graduate and medical student, Penn State. \"That is why we need a supplemental diagnostic test to help physicians determine if the tumors are responding to therapy and regressing, or if they are getting worse and need additional treatment.\" Indeed, added Brad Zacharia, associate professor of neurosurgery and of otolaryngology, Penn State, a liquid biopsy for glioblastoma could be of tremendous value to patients suffering from this devastating tumor. \"A liquid biopsy may facilitate diagnosis and more importantly provide a better understanding of the tumor's response to treatment in a way that is lacking with our current technologies,\" he said. The team studied a certain antigen receptor, called interleukin-13 receptor α2 (IL13Rα2), which is known to be elevated in the tumor tissue of more than 75% of GBM patients. \"Despite being significantly overexpressed in tumor tissue, no studies have explored the diagnostic and prognostic potential of IL13Rα2 circulating in patient biofluids,\" said James Connor, distinguished professor of neuroscience and anatomy, Penn State. To investigate the utility of IL13Rα2 as a biomarker for GBM, the researchers examined the tumor tissue and blood plasma of 79 patients with primary GBM, along with the blood plasma of 23 control patients, from two different health systems. The control patients had primary diagnoses of either spinal stenosis or arteriovenous malformation but did not have any malignancy or chronic inflammation. In the patients' plasma, the researchers looked specifically at extracellular vesicles, which are small particles that are released by cells and carry material from those cells. They found that patients with GBM had significantly elevated levels of IL13Rα2 in their blood plasma compared to control patients and that the IL13Rα2 was likely concentrated on extracellular vesicles derived from tumor cells. They also found that these IL13Rα2 levels in blood plasma were correlated with the IL13Rα2 levels in the patients' tumors. Their findings published in the Journal of Neuro-Oncology. \"The fact that we documented IL13Rα2 on tumor-derived extracellular vesicles and that we observed a correlation between plasma and tumor levels of IL13Rα2 suggests that plasma IL13Rα2 does indeed derive from GBM tumors,\" said Khristov. \"This is important because previously it was difficult to tell if the IL13Rα2 in plasma came from the tumors, or if they came from the body's response to the tumors. Our findings suggest that IL13Rα2 does have utility as a biomarker for glioblastoma.\" Connor noted that the finding is especially significant given that IL13Rα2 has been shown to have a patchy distribution in GBM tumors, raising the question of whether a needle biopsy or small sample of tumor tissue is representative of the tumor as a whole. \"Testing for IL13Rα2 circulating in plasma may provide an even better picture of the presence and extent of GBM than a tumor sample,\" said Connor. Additionally, he said, \"the tumor-specific nature of IL13Rα2 implies that it can be used for tumor-targeted therapies without affecting outside tissues.\" Interestingly, the team found that elevated levels of IL13Rα2 in both plasma and tumors predicted longer overall survival. In fact, patients with high levels of plasma IL13Rα2 had a 6.5 month longer median overall survival compared to patients with low levels. \"It seems counterintuitive that high levels of plasma IL13Rα would confer a survival advantage since their presence indicates a tumor and, ultimately, we do not know why this is the case,\" said Khristov. \"However, there is some evidence that increased IL13Rα2 is correlated increased fibrosis in the tumor, which indicates tissue healing. It's important for patients to know if they may have this survival advantage or not.\" Zacharia noted that this work, and that of many other studies, relies on biological specimens, such as blood, tumor tissue and spinal fluid, from patients. \"Their generous and selfless gifts of these specimens to the Penn State Neuroscience Institute Biorepository make this work possible,\" he said, \"and we are forever grateful to the patients and their families.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Purpose Glioblastoma (GBM) is the most common and deadliest brain tumor with unrelenting and rapid disease progression. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Treatment failure and resistance is the rule and despite advances in imaging technology, early detection of treatment failure or impending resistance remains a challenge. There is a dire, unmet, need in clinical practice for minimally-invasive diagnostic tools to enable timely understanding of disease progression and treatment response. Here, we aim to address this clinical need by leveraging a unique characteristic of GBM: the overexpression of the α2 variant of the IL-13 receptor in over 75% of GBM tumors. Methods In this study we examined patients with primary GBM from Penn State and Cleveland Clinic compared to healthy controls. Results IL13Rα2 was detectable in plasma of GBM patients using ELISA but detection could be optimized by PEG precipitation to enrich for extracellular vesicles (EVs). Patients with GBM had elevated levels of plasma IL13Rα2, which correlated to levels of this receptor in the tumor tissue. Elevated plasma levels of IL13Rα2 predicted longer overall survival (OS) (19.8 vs. 13.2 months). Similarly, detection of IL13Rα2 + cells in tumor tissue also predicted longer OS (22.1 vs. 12.2 months). Conclusion These findings strongly suggest that expression of the IL13Rα2 receptor confer survival advantage in GBM patients, which can be determined through a minimally-invasive liquid biopsy. Detection of plasma IL13Rα2 can also be used to select GBM patients for targeted tumor therapy. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Gliomas are tumors with histologic features resembling normal glial cells and are characterized by histopathologic appearance and molecular parameters [ 1 ]. Glioblastoma (GBM) is both the most common and deadly malignant primary brain tumor with a 1-year survival of 37.2% and a 5-year survival of just 5.1% [ 2 ]. Molecular parameters play an ever-increasing role in the classification of gliomas, guiding prognosis and treatment decisions [ 1 , 3 ]. Disease progression is unrelenting, although patients carrying some molecular variants such as IDH mutations display a modestly better prognosis [ 4 ]. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Treatment failure and resistance is the rule and despite advances in imaging technology, early identification of treatment failure or impending resistance remains a challenge [ 5 ]. There is a dire, unmet, gap in clinical practice for minimally-invasive diagnostic tools to enable timely understanding of disease progression and treatment response. A liquid biopsy is a minimally-invasive approach centered on detecting tumor-derived and disease-associated biomarkers in the patient’s biofluids such as blood, cerebrospinal fluid (CSF), urine, and saliva. Clinical experience with other solid tumors points to the enormous potential of liquid biopsies [ 6 ]. First, they can provide the physician with useful diagnostic and prognostic data. Second, the ease of longitudinal sampling can help track progression of the disease and provide timely differentiation between treatment resistance and response. Finally, liquid biopsies can be used guide treatment through differentiating disease variants and identifying targetable proteins and mutations. Discussion of liquid biopsy would not be complete without including extracellular vesicles (EVs). EVs is a broad term for lipid bilayer particles released by virtually all cells, including tumor cells, and their contents directly correlate to the cells of origin [ 7 ]. EV functions include intercellular communication, disposal of undesirable material, transfer of proteins and RNA [ 7 ]. Crucially, EVs stabilize their molecular cargo, delaying degradation of biofluids, and have been shown to pass through an intact blood-brain barrier via transcytosis [ 8 ]. Initial groundbreaking steps in the discovery of GBM biomarkers have unsurprisingly focused on circulating genetic material due to the highly-sensitive and specific nature of PCR amplification. Ebrahimkhani et al. demonstrated that a serum signature of 7 miRNAs could reliably distinguish GBM patients from controls, albeit without distinguishing tumor-derived and tumor-associated miRNAs [ 9 ]. Evidence that circulating plasma EVs are representative of the tumor was provided by Batool et al. who were able to detect a tumor-specific EGFRvIII mutation in circulating EVs of patients with GBM [ 10 ]. In contrast to genetic-focused approaches, peptide-based liquid biopsies have had a slower start. Initial studies focused on hormones and cytokines known to be involved in GBM pathogenesis, and have yielded some success. For example, IL-6 levels have been shown to increase tumor associated macrophage migration into the cerebrospinal fluid (CSF) to further the development of neural tumors through growth, angiogenesis, and tumor invasion [ 11 ]. Peles et al. determined that CSF angiogenic factors including bFGF and VEGF are useful in predicting overall survival (OS) [ 12 ]. Recently, Rategui et al. have shown that the tumor-specific and clinically relevant EGFRvIII receptor could be used as a target to isolate tumor-specific EVs. By combining a hydrogel substrate, anisotropic flow pattern, and PEG-linked affinity purification antibodies on a microfluidic chip, individual tumor-derived EVs could be captured, quantified, and assayed using proteomic and genomic methods [ 13 ]. Another promising tumor-specific biomarker is the α2 variant of the IL-13 receptor (IL13Rα2), which is overexpressed in > 75% of GBM patients while being undetectable in normal tissue [ 14 , 15 , 16 , 17 ]. To date, only two studies have focused on the diagnostic and prognostic utility of IL13Rα2. In terms of bulk mRNA expression data, IL13Rα2 expression appears to have negative prognostic significance in glioma patients [ 18 ]. This negative correlation between IL13Ra2 mRNA expression and poor prognosis was confirmed by Han et al. through extensive analysis of The Cancer Genome Atlas [ 19 ]. However, whereas these studies have focused on bulk mRNA expression data, no studies have explored the diagnostic and prognostic potential of IL13Rα2 protein circulating in patient biofluids. Building on the premise that IL13Rα2 is overexpressed in GBM tumor tissue, we explore its potential as a liquid biopsy<|im_end|> <|im_start|>assistant Glioblastoma (GBM) is the most common and deadliest type of brain cancer with a five-year survival rate of only 5%. Researchers at Penn State College of Medicine have identified a biomarker that can be used in blood tests to diagnose GBM, track its progression and guide treatment. The researchers said that such a non-invasive liquid biopsy for GBM could help patients get the care they need more quickly. "Patients normally receive imaging, such as MRI or CT scans, to diagnose and track the progression of brain tumors, but it can be difficult for physicians to tell from those scans if the patient is getting better or worse because they don't provide detail at the cellular or molecular level," said Vladimir Khristov, graduate and medical student, Penn State. "That is why we need a supplemental diagnostic test to help physicians determine if the tumors are responding to therapy and regressing, or if they are getting worse and need additional treatment." Indeed, added Brad Zacharia, associate professor of neurosurgery and of otolaryngology, Penn State, a liquid biopsy for glioblastoma could be of tremendous value to patients suffering from this devastating tumor. "A liquid biopsy may facilitate diagnosis and more importantly provide a better understanding of the tumor's response to treatment in a way that is lacking with our current technologies," he said. The team studied a certain antigen receptor, called interleukin-13 receptor α2 (IL13Rα2), which is known to be elevated in the tumor tissue of more than 75% of GBM patients. "Despite being significantly overexpressed in tumor tissue, no studies have explored the diagnostic and prognostic potential of IL13Rα2 circulating in patient biofluids," said James Connor, distinguished professor of neuroscience and anatomy, Penn State. To investigate the utility of IL13Rα2 as a biomarker for GBM, the researchers examined the tumor tissue and blood plasma of 79 patients with primary GBM, along with the blood plasma of 23 control patients, from two different health systems. The control patients had primary diagnoses of either spinal stenosis or arteriovenous malformation but did not have any malignancy or chronic inflammation. In the patients' plasma, the researchers looked specifically at extracellular vesicles, which are small particles that are released by cells and carry material from those cells. They found that patients with GBM had significantly elevated levels of IL13Rα2 in their blood plasma compared to control patients and that the IL13Rα2 was likely concentrated on extracellular vesicles derived from tumor cells. They also found that these IL13Rα2 levels in blood plasma were correlated with the IL13Rα2 levels in the patients' tumors. Their findings published in the Journal of Neuro-Oncology. "The fact that we documented IL13Rα2 on tumor-derived extracellular vesicles and that we observed a correlation between plasma and tumor levels of IL13Rα2 suggests that plasma IL13Rα2 does indeed derive from GBM tumors," said Khristov. "This is important because previously it was difficult to tell if the IL13Rα2 in plasma came from the tumors, or if they came from the body's response to the tumors. Our findings suggest that IL13Rα2 does have utility as a biomarker for glioblastoma." Connor noted that the finding is especially significant given that IL13Rα2 has been shown to have a patchy distribution in GBM tumors, raising the question of whether a needle biopsy or small sample of tumor tissue is representative of the tumor as a whole. "Testing for IL13Rα2 circulating in plasma may provide an even better picture of the presence and extent of GBM than a tumor sample," said Connor. Additionally, he said, "the tumor-specific nature of IL13Rα2 implies that it can be used for tumor-targeted therapies without affecting outside tissues." Interestingly, the team found that elevated levels of IL13Rα2 in both plasma and tumors predicted longer overall survival. In fact, patients with high levels of plasma IL13Rα2 had a 6.5 month longer median overall survival compared to patients with low levels. "It seems counterintuitive that high levels of plasma IL13Rα would confer a survival advantage since their presence indicates a tumor and, ultimately, we do not know why this is the case," said Khristov. "However, there is some evidence that increased IL13Rα2 is correlated increased fibrosis in the tumor, which indicates tissue healing. It's important for patients to know if they may have this survival advantage or not." Zacharia noted that this work, and that of many other studies, relies on biological specimens, such as blood, tumor tissue and spinal fluid, from patients. "Their generous and selfless gifts of these specimens to the Penn State Neuroscience Institute Biorepository make this work possible," he said, "and we are forever grateful to the patients and their families." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The relationship between humans and robots is increasingly becoming focus of interest for many fields of research. The studies investigating the dynamics underpinning the human–robot interaction have, up to date, mainly analysed adults’ behaviour when interacting with artificial agents. In this study, we present results associated with the human–robot interaction involving children aged 5 to 6 years playing the Ultimatum Game (UG) with either another child or a humanoid robot. Assessment of children’s attribution of mental and physical properties to the interactive agents showed that children recognized the robot as a distinct entity compared to the human. Nevertheless, consistently with previous studies on adults, the results on the UG revealed very similar behavioural responses and reasoning when the children played with the other child and with the robot. Finally, by analysing children’s justifications for their behaviour at the UG, we found that children tended to consider “fair” only the divisions that were exactly equal (5–5 divisions), and to justify them either in quantitative terms (outcome) or in terms of equity. These results are discussed in terms of theory of mind, as well as in light of developmental theories underpinning children’s behaviour at the Ultimatum Game. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes 1 Introduction The introduction of social robots—defined as “autonomous or semi-autonomous robots that interact and communicate with humans by following the behavioural norms expected by the people with whom the robot is intended to interact” [ 5 , p. 1]—is deeply affecting our society in different fields of human life. The robots used in industrial processes, for instance, are modifying job roles and rules ([ 1 , 50 , 58 ]; see also [ 26 ]). Prospectively, the introduction of robots in other contexts, such as households, education, care assistance, manufacturing, etc., will also presumably have an increasingly significant effect on human activities and roles. In this perspective, several researchers are working towards the implementation of robots in the attempt to make them behaviourally and physically similar to the human being [ 2 , 25 , 38 , 84 ]. The humanoid robots—the ultimate realization of these attempts—are characterized by human-like physical features, behaviours, and cognitive processes, which call to mind the idea of “they are more like-me” [ 68 ]. The implementation of human-like artificial agents is also aimed at supporting scientific research in different fields, such as anthropology, psychology, ethics, sociology, engineering, informatics, mathematics, physics, etc. Referring to psychology, Scassellati [ 87 , 88 ], for example, suggests that the use of human-like robots is beneficial to the study of typical and atypical human social development, allowing to test cognitive, behavioural and developmental psychological models. In fact, employment of human-like robots may serve both as “stimuli” to study the human cognition by evoking social cognitive processes [ 101 ], as well as “agents” the humans can observe and interact with [ 103 ]. In this respect, Wykowska and colleagues [ 103 ] showed that—by combining experimental control and ecological validity—manipulation of various behavioral and physical parameters in humanoid robots during a robot-human interaction may provide insightful information concerning the social cognitive processes in the human brain. It was shown, for example, that, while low-level perceptual mechanisms are similarly activated when both artificial and natural agents are observed, activation of high order social cognitive mechanisms requires the artificial agents to be endowed of human-like features, which allow the emulation—in the human—of human-like behaviours. By contributing to the understanding and identification of the precursors underlying human sociality and their ontogenesis, knowledge from developmental psychology is also crucial to the implementation of psychological models to be used in the human–robot interaction. Growing recognition of the role of developmental psychology for the understanding of the human–robot interaction is evidenced by the substantial increase—in the last decades—of researches focussing on the child-robot interaction (e.g., [ 7 , 11 , 12 , 47 , 48 , 61 , 71 , 72 , 77 ]). The results of these studies consistently show that children tend to attribute mental states to humanoid robots, treating the robots as human agents (for review, see [ 64 ]). Connecting developmental psychology to the study of the human–robot interaction from a multidisciplinary perspective, Itakura [ 42 ] proposed a new research domain named Developmental Cybernetics (DC; [ 42 ]; see also [ 45 , 46 , 76 , 77 ]). Developmental Cybernetics explores the child-robot interaction through the construction of theoretical frameworks that characterize the design of the robot with the aim to facilitate these interactions [ 42 , 46 ]. It focuses on three abilities, which are critical for making a robot a social agent: theory of communication (ToC; [ 43 , 44 , 76 ]), theory of body (ToB; [ 70 , 72 ]), and theory of mind (ToM; [ 42 , 45 , 46 ]). With particular focus on the theory of mind, several contributions have now demonstrated its significance for the development of social competences: through this human psychological ability it is possible to understand one’s own and other people’s mental states (intentions, emotions, desires, beliefs), allowing to predict and interpret one’s own and others’ behaviours on the basis of such meta-representations ([ 21 , 59 , 80 , 82 , 102 ], for a review, see [ 98 ]). There are different behaviours and cognitive processes that are linked to ToM: imitation [ 4 , 8 , 9 , 83 ]; joint attention, pointing, gaze-following [ 13 , 14 , 23 , 67 , 68 , 78 ]; and intentionality understanding [ 4 , 20 , 30 , 36 ]. Several studies have investigated the effect of these precursors on the interaction between humans and robots [ 22 , 29 , 40 , 41 , 49 , 51 , 69 , 71 , 72 , 73 , 78 , 79 , 90 , 99 ]. For example, by examining the influence of an online eye-contact of a humanoid robot on", "role": "user" }, { "content": "The relationship between humans and robots has become the focus of an increasing number of research studies, in light of the approaching integration of robots within a variety of fields, including professional and educational contexts. An international and interdisciplinary team of researchers including psychologists and roboticists at Università Cattolica del Sacro Cuore in Milan (Prof. Antonella Marchetti, Prof. Davide Massaro, Dr. Cinzia Di Dio and Dr. Federico Manzi), Kyoto University (Prof., Shoji Itakura and Prof. Takayuki Kanda), Osaka University (Prof. Hiroshi Ishiguro) and Advanced Telecommunications Research Institute International (ATR) in Kyoto have carried out a study investigating human-robot interactions, which involved five- and six-year-old children playing with other children and robotic partners. \"Human beings are in continuous development, and the most complex phases of change and maturation of psychological processes and competencies, including the development of social skills, occur during the first years of life,\" the researchers told TechXplore, via email. \"If life is a succession of decisions, very soon, we will also be called upon to make decisions with robotic partners. Given the increasing presence and relevance of robotic artifacts in our society, it is fundamental to begin investigating how relational patterns change when relating to a robot and, with specific reference to our experimental study, how decision-making processes are affected by the partner's agency in a lifespan perspective. Connecting developmental psychology to the study of human–robot interactions from a multidisciplinary perspective, Itakura proposed a new research domain named Developmental Cybernetics, which we used in this study.\" The authors of the paper, which was published on Springer's International Journal of Social Robotics, are interested in uncovering the psychological mechanisms and processes behind human-robot interactions. Their study particularly focuses on children, as they believe that this could help to define the developmental benchmarks that characterize such relational patterns. \"After all, a five-year-old child would possibly engage in a unique relational modality to a robot as compared to an older child or an adult,\" the authors said. In their study, the authors administered a series of tests to 31 Italian kindergarten children, some of which assessed their theory of mind (ToM), which is the human ability to recognize mental states (e.g. thoughts, perceptions, feelings, etc.) in oneself and others. In particular, the experimenters assessed the children' understanding of false belief using the classical Unexpected Transfer Task and a set of videos of the Unexpected Transfer Task in which the characters are either children or robots. This allowed them to assess the children's ability to ascribe a false belief, and so a theory of mind, to another human and to the robot. The Unexpected Transfer Task, often used to test young children on ToM, involves a character who puts an object under a box and then leaves the room. While he is away, a second character enters the room and moves the object somewhere else. The first character then comes back into the room looking for the object that he had originally placed under the box. The experimenters narrated this story using two dolls, a ball, a box and a basket. When they finished telling the story, they asked participants a series of questions that assessed their memory and ToM. The children were then shown four videos of the same story, but with a robotic agent as one of the characters. The two characters in the videos were either two children, two robots, or a child and a robot, while the displaced object was a teddy bear. Pairings within and between agent-types (human and robot) were to assess the effectiveness of all possible relational and role combinations in evaluating the children's ToM. After watching the videos, the children were asked the same questions that they were asked previously, during the classical ToM task. The key aim of this experiment was to determine whether the children attributed 'false belief' (i.e. believing that a displaced object is where one last saw it) to both another child and a robotic agent, or whether these attributions were somewhat different. Subsequently, the researchers tested the children on the ultimatum game, evaluating the fairness with which they distributed a 'special object' (i.e. stickers) between themselves and another player (i.e. either another child or a robot). Screenshot of one of the videos used in the researchers’ experiments. Credit: Di Dio et al. \"To study the dynamics underpinning decision-making processes and, more specifically, one's inclination and sensitivity to fairness, we used an interactive game derived from the Theory of Economic Games, the Ultimatum Game, which is broadly used in psychology,\" the authors explained. \"The advantage of this experimental situation is that it can be used across different ages, enabling the experimenter to compare data from early childhood to adulthood in a controlled manner. Likewise, the same protocol can be used transversally to compare sensitivity to fairness when playing with different agents, in our case with a human or a robot.\" In the Ultimatum Game, one player (the proposer) divides a sum of money (or goods) with another player (the receiver). Once the proposers communicate their decision, the receiver can either accept or reject it. If she/he accepts, the money is divided as proposed; if she/he doesn't, however, both players receive nothing. One of the distinctive features of the Ultimatum Game is that it requires reciprocity. In fact, when acting as the proposer, a player needs to consider the other's 'mind,' anticipating her/his response in order to gain a good, as the proposal's rejection would result in no gain whatsoever. The researchers chose this game as it would help them to better understand what children expected a robot's responses to be and how their viewed his 'mind.' \"To evaluate how children perceive the interactive partner in mental and physical terms, we then administered the Attribution of Mental and Physical States (AMPS) questionnaire developed ad hoc and derived from scientific literature,\" the authors said. \"We are increasingly using the AMPS questionnaire because it allows us to investigate the attribution of a 'mind' that subjects of various ages have of robotic agents and compare it with the human agent.\" The experiments carried out by the researchers yielded interesting results. While children appeared to recognize robots as distinct entities compared to humans, in the Ultimatum Game, their behavioral responses and reasoning were similar when playing with another child and with a robot. Furthermore, the results to the ToM tasks showed that all children attribute a false belief to the child independent of whether the task was administered in the form of storyboard or video. Interestingly, all children attributed a false belief to the robot, independent of its role in the game, suggesting that the robot's, like the human's mind, is subject to informational access limits. These data indicate that mechanisms and beliefs associated with human-robot interactions might develop fairly early in our lifespan. \"Children attribute different physical and mental states to the robotic and the human agent,\" the authors said. \"However, they tend to make similar economic decisions when interacting with another child or when interacting with a robot. If the relationship with the robot shows in children behaviors similar to those observed with human partners, then the use of robots in different contexts, from educational to rehabilitative, can be particularly crucial.\" The study carried out by this interdisciplinary team of researchers provides valuable insight into how humans, particularly children, relate to robots and how they perceive these 'new entities.' To improve the generalizability of their findings, however, the researchers would need to replicate their study with a bigger group of participants. Further research could also compare how humans interact with robots to how they interact with other non-human entities, such as animals, toys, or other objects. \"Currently, we are expanding both the type of psychological functions and the type of socially relevant situations in which the human partner could be sided by a robotic partner,\" the authors said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The relationship between humans and robots is increasingly becoming focus of interest for many fields of research. The studies investigating the dynamics underpinning the human–robot interaction have, up to date, mainly analysed adults’ behaviour when interacting with artificial agents. In this study, we present results associated with the human–robot interaction involving children aged 5 to 6 years playing the Ultimatum Game (UG) with either another child or a humanoid robot. Assessment of children’s attribution of mental and physical properties to the interactive agents showed that children recognized the robot as a distinct entity compared to the human. Nevertheless, consistently with previous studies on adults, the results on the UG revealed very similar behavioural responses and reasoning when the children played with the other child and with the robot. Finally, by analysing children’s justifications for their behaviour at the UG, we found that children tended to consider “fair” only the divisions that were exactly equal (5–5 divisions), and to justify them either in quantitative terms (outcome) or in terms of equity. These results are discussed in terms of theory of mind, as well as in light of developmental theories underpinning children’s behaviour at the Ultimatum Game. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes 1 Introduction The introduction of social robots—defined as “autonomous or semi-autonomous robots that interact and communicate with humans by following the behavioural norms expected by the people with whom the robot is intended to interact” [ 5 , p. 1]—is deeply affecting our society in different fields of human life. The robots used in industrial processes, for instance, are modifying job roles and rules ([ 1 , 50 , 58 ]; see also [ 26 ]). Prospectively, the introduction of robots in other contexts, such as households, education, care assistance, manufacturing, etc., will also presumably have an increasingly significant effect on human activities and roles. In this perspective, several researchers are working towards the implementation of robots in the attempt to make them behaviourally and physically similar to the human being [ 2 , 25 , 38 , 84 ]. The humanoid robots—the ultimate realization of these attempts—are characterized by human-like physical features, behaviours, and cognitive processes, which call to mind the idea of “they are more like-me” [ 68 ]. The implementation of human-like artificial agents is also aimed at supporting scientific research in different fields, such as anthropology, psychology, ethics, sociology, engineering, informatics, mathematics, physics, etc. Referring to psychology, Scassellati [ 87 , 88 ], for example, suggests that the use of human-like robots is beneficial to the study of typical and atypical human social development, allowing to test cognitive, behavioural and developmental psychological models. In fact, employment of human-like robots may serve both as “stimuli” to study the human cognition by evoking social cognitive processes [ 101 ], as well as “agents” the humans can observe and interact with [ 103 ]. In this respect, Wykowska and colleagues [ 103 ] showed that—by combining experimental control and ecological validity—manipulation of various behavioral and physical parameters in humanoid robots during a robot-human interaction may provide insightful information concerning the social cognitive processes in the human brain. It was shown, for example, that, while low-level perceptual mechanisms are similarly activated when both artificial and natural agents are observed, activation of high order social cognitive mechanisms requires the artificial agents to be endowed of human-like features, which allow the emulation—in the human—of human-like behaviours. By contributing to the understanding and identification of the precursors underlying human sociality and their ontogenesis, knowledge from developmental psychology is also crucial to the implementation of psychological models to be used in the human–robot interaction. Growing recognition of the role of developmental psychology for the understanding of the human–robot interaction is evidenced by the substantial increase—in the last decades—of researches focussing on the child-robot interaction (e.g., [ 7 , 11 , 12 , 47 , 48 , 61 , 71 , 72 , 77 ]). The results of these studies consistently show that children tend to attribute mental states to humanoid robots, treating the robots as human agents (for review, see [ 64 ]). Connecting developmental psychology to the study of the human–robot interaction from a multidisciplinary perspective, Itakura [ 42 ] proposed a new research domain named Developmental Cybernetics (DC; [ 42 ]; see also [ 45 , 46 , 76 , 77 ]). Developmental Cybernetics explores the child-robot interaction through the construction of theoretical frameworks that characterize the design of the robot with the aim to facilitate these interactions [ 42 , 46 ]. It focuses on three abilities, which are critical for making a robot a social agent: theory of communication (ToC; [ 43 , 44 , 76 ]), theory of body (ToB; [ 70 , 72 ]), and theory of mind (ToM; [ 42 , 45 , 46 ]). With particular focus on the theory of mind, several contributions have now demonstrated its significance for the development of social competences: through this human psychological ability it is possible to understand one’s own and other people’s mental states (intentions, emotions, desires, beliefs), allowing to predict and interpret one’s own and others’ behaviours on the basis of such meta-representations ([ 21 , 59 , 80 , 82 , 102 ], for a review, see [ 98 ]). There are different behaviours and cognitive processes that are linked to ToM: imitation [ 4 , 8 , 9 , 83 ]; joint attention, pointing, gaze-following [ 13 , 14 , 23 , 67 , 68 , 78 ]; and intentionality understanding [ 4 , 20 , 30 , 36 ]. Several studies have investigated the effect of these precursors on the interaction between humans and robots [ 22 , 29 , 40 , 41 , 49 , 51 , 69 , 71 , 72 , 73 , 78 , 79 , 90 , 99 ]. For example, by examining the influence of an online eye-contact of a humanoid robot on<|im_end|> <|im_start|>assistant The relationship between humans and robots has become the focus of an increasing number of research studies, in light of the approaching integration of robots within a variety of fields, including professional and educational contexts. An international and interdisciplinary team of researchers including psychologists and roboticists at Università Cattolica del Sacro Cuore in Milan (Prof. Antonella Marchetti, Prof. Davide Massaro, Dr. Cinzia Di Dio and Dr. Federico Manzi), Kyoto University (Prof., Shoji Itakura and Prof. Takayuki Kanda), Osaka University (Prof. Hiroshi Ishiguro) and Advanced Telecommunications Research Institute International (ATR) in Kyoto have carried out a study investigating human-robot interactions, which involved five- and six-year-old children playing with other children and robotic partners. "Human beings are in continuous development, and the most complex phases of change and maturation of psychological processes and competencies, including the development of social skills, occur during the first years of life," the researchers told TechXplore, via email. "If life is a succession of decisions, very soon, we will also be called upon to make decisions with robotic partners. Given the increasing presence and relevance of robotic artifacts in our society, it is fundamental to begin investigating how relational patterns change when relating to a robot and, with specific reference to our experimental study, how decision-making processes are affected by the partner's agency in a lifespan perspective. Connecting developmental psychology to the study of human–robot interactions from a multidisciplinary perspective, Itakura proposed a new research domain named Developmental Cybernetics, which we used in this study." The authors of the paper, which was published on Springer's International Journal of Social Robotics, are interested in uncovering the psychological mechanisms and processes behind human-robot interactions. Their study particularly focuses on children, as they believe that this could help to define the developmental benchmarks that characterize such relational patterns. "After all, a five-year-old child would possibly engage in a unique relational modality to a robot as compared to an older child or an adult," the authors said. In their study, the authors administered a series of tests to 31 Italian kindergarten children, some of which assessed their theory of mind (ToM), which is the human ability to recognize mental states (e.g. thoughts, perceptions, feelings, etc.) in oneself and others. In particular, the experimenters assessed the children' understanding of false belief using the classical Unexpected Transfer Task and a set of videos of the Unexpected Transfer Task in which the characters are either children or robots. This allowed them to assess the children's ability to ascribe a false belief, and so a theory of mind, to another human and to the robot. The Unexpected Transfer Task, often used to test young children on ToM, involves a character who puts an object under a box and then leaves the room. While he is away, a second character enters the room and moves the object somewhere else. The first character then comes back into the room looking for the object that he had originally placed under the box. The experimenters narrated this story using two dolls, a ball, a box and a basket. When they finished telling the story, they asked participants a series of questions that assessed their memory and ToM. The children were then shown four videos of the same story, but with a robotic agent as one of the characters. The two characters in the videos were either two children, two robots, or a child and a robot, while the displaced object was a teddy bear. Pairings within and between agent-types (human and robot) were to assess the effectiveness of all possible relational and role combinations in evaluating the children's ToM. After watching the videos, the children were asked the same questions that they were asked previously, during the classical ToM task. The key aim of this experiment was to determine whether the children attributed 'false belief' (i.e. believing that a displaced object is where one last saw it) to both another child and a robotic agent, or whether these attributions were somewhat different. Subsequently, the researchers tested the children on the ultimatum game, evaluating the fairness with which they distributed a 'special object' (i.e. stickers) between themselves and another player (i.e. either another child or a robot). Screenshot of one of the videos used in the researchers’ experiments. Credit: Di Dio et al. "To study the dynamics underpinning decision-making processes and, more specifically, one's inclination and sensitivity to fairness, we used an interactive game derived from the Theory of Economic Games, the Ultimatum Game, which is broadly used in psychology," the authors explained. "The advantage of this experimental situation is that it can be used across different ages, enabling the experimenter to compare data from early childhood to adulthood in a controlled manner. Likewise, the same protocol can be used transversally to compare sensitivity to fairness when playing with different agents, in our case with a human or a robot." In the Ultimatum Game, one player (the proposer) divides a sum of money (or goods) with another player (the receiver). Once the proposers communicate their decision, the receiver can either accept or reject it. If she/he accepts, the money is divided as proposed; if she/he doesn't, however, both players receive nothing. One of the distinctive features of the Ultimatum Game is that it requires reciprocity. In fact, when acting as the proposer, a player needs to consider the other's 'mind,' anticipating her/his response in order to gain a good, as the proposal's rejection would result in no gain whatsoever. The researchers chose this game as it would help them to better understand what children expected a robot's responses to be and how their viewed his 'mind.' "To evaluate how children perceive the interactive partner in mental and physical terms, we then administered the Attribution of Mental and Physical States (AMPS) questionnaire developed ad hoc and derived from scientific literature," the authors said. "We are increasingly using the AMPS questionnaire because it allows us to investigate the attribution of a 'mind' that subjects of various ages have of robotic agents and compare it with the human agent." The experiments carried out by the researchers yielded interesting results. While children appeared to recognize robots as distinct entities compared to humans, in the Ultimatum Game, their behavioral responses and reasoning were similar when playing with another child and with a robot. Furthermore, the results to the ToM tasks showed that all children attribute a false belief to the child independent of whether the task was administered in the form of storyboard or video. Interestingly, all children attributed a false belief to the robot, independent of its role in the game, suggesting that the robot's, like the human's mind, is subject to informational access limits. These data indicate that mechanisms and beliefs associated with human-robot interactions might develop fairly early in our lifespan. "Children attribute different physical and mental states to the robotic and the human agent," the authors said. "However, they tend to make similar economic decisions when interacting with another child or when interacting with a robot. If the relationship with the robot shows in children behaviors similar to those observed with human partners, then the use of robots in different contexts, from educational to rehabilitative, can be particularly crucial." The study carried out by this interdisciplinary team of researchers provides valuable insight into how humans, particularly children, relate to robots and how they perceive these 'new entities.' To improve the generalizability of their findings, however, the researchers would need to replicate their study with a bigger group of participants. Further research could also compare how humans interact with robots to how they interact with other non-human entities, such as animals, toys, or other objects. "Currently, we are expanding both the type of psychological functions and the type of socially relevant situations in which the human partner could be sided by a robotic partner," the authors said. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure of this balance leads to conditions such as inflammatory bowel diseases, food allergies and invasive gastrointestinal infections 1 . Multiple immune mechanisms are therefore in place to maintain tissue integrity, including balanced generation of effector T (T H ) cells and FOXP3 + regulatory T (pT reg ) cells, which mediate resistance to pathogens and regulate excessive immune activation, respectively 1 , 2 , 3 , 4 . The gut-draining lymph nodes (gLNs) are key sites for orchestrating adaptive immunity to luminal perturbations 5 , 6 , 7 . However, it is unclear how they simultaneously support tolerogenic and inflammatory reactions. Here we show that gLNs are immunologically specific to the functional gut segment that they drain. Stromal and dendritic cell gene signatures and polarization of T cells against the same luminal antigen differ between gLNs, with the proximal small intestine-draining gLNs preferentially giving rise to tolerogenic responses and the distal gLNs to pro-inflammatory T cell responses. This segregation permitted the targeting of distal gLNs for vaccination and the maintenance of duodenal pT reg cell induction during colonic infection. Conversely, the compartmentalized dichotomy was perturbed by surgical removal of select distal gLNs and duodenal infection, with effects on both lymphoid organ and tissue immune responses. Our findings reveal that the conflict between tolerogenic and inflammatory intestinal responses is in part resolved by discrete gLN drainage, and encourage antigen targeting to specific gut segments for therapeutic immune modulation. Main Appropriate lymphatic trafficking of immune cells to gLNs is essential for intestinal adaptive immunity 6 , 8 (Fig. 1a ). Previous studies have mapped drainage to various gLNs along the mouse gut 9 , 10 , 11 , 12 , and described immunological differences between gLNs 11 , 13 , but, to our knowledge, the underlying cellular components and functional consequences of gut segment-specific drainage have not been systematically addressed. We sought to understand how compartmentalized lymphatic drainage of the intestinal milieu contributes to distinct immune responses towards luminal antigens. We first imaged the gut lymphatic system using 3D imaging of solvent-cleared tissue stained with an antibody against the lymphatic endothelial cell (LEC) surface marker LYVE-1. En bloc imaging exposed the lymphatic route of the intestine to gLNs via afferent lymphatic vessels in the mesentery (Fig. 1a–c , Extended Data Fig. 1a–c , Supplementary Videos 1 – 4 ). The size and shape of individual gLNs differs considerably regardless of the presence or absence of microbiota (Extended Data Fig. 1d, e ). Dye injected into individual gLNs did not spread to other gLNs, suggesting that the lymph remains compartmentalized until it reaches the thoracic duct (Extended Data Fig. 1f–i ). Injection of dye into the intestinal muscularis confirmed that the gLNs drain different gut segments 9 , 10 , 11 , 12 despite the network-like lymphatic structure in the gut wall (Extended Data Fig. 1j–q , Supplementary Videos 5 – 7 ). The progressive shortening of the lymphatic lacteals in the villi along the small intestine is modulated by the microbiome, as germ-free mice showed lengthened duodenal and shortened ileal lacteals (Extended Data Fig. 2a ). To investigate whether the combination of compartmentalized absorption and drainage results in differential nutrient exposure in the gLNs, we tracked the uptake of radiolabelled retinol after feeding; retinol is a lipid-soluble proxy and an immunomodulatory nutrient, and its uptake depends largely on packing into chylomicrons and lymphatic absorption by the upper small intestine (Extended Data Fig. 2b ). Most retinol was absorbed in the duodenum with a gradient along the intestine, and this was mirrored in the gLNs (Fig. 1d, e , Extended Data Fig. 2b–g ), illustrating that the gLNs are exposed to region-specific lymph composition. Fig. 1: The gLNs are metabolically and immunologically unique according to the gut segment drained. a , Schematic of gLNs. b , c , 3D reconstruction of mouse lymphatics (anti-LYVE-1) and position after iDISCO + procedure (see Methods ) ( b ), co-stained with anti-GFP (in Itgax Venus mice, where GFP is expressed under the Cd11c promoter) and anti-insulin ( c ). d , e , Percentage of [ 3 H]retinol absorption into indicated gut segment ( d ) or gLN ( e ) of mice 3 h after gavage with 1 µCi [ 3 H]retinol in 100 µl olive oil with or without pre-treatment with 5 µl chylomicron formation inhibitor Pluronic L-81 (PL81) 3 h before gavage ( n = 4 per group). f , RNA sequencing (RNA-seq) PCA of FRCs and LECs sorted from D-, I- and C-gLNs (for example, cLEC denotes LECs from C-gLNs) from SPF C57BL/6 mice ( n = 3, pooled from two mice each). PC1 accounts for 65.1% and PC2 for 5.7% of the variance. g , h , Volcano plots depicting genes that are differentially expressed among LECs ( g ) and FRCs ( h ) from D- or C-gLNs (CL and DL, LECs from C- and D-gLNs, respectively; CF and DF, FRCs from C- and D-gLNs, respectively). Blue, metabolism-related genes; red, immunity-related genes. C, colon; C1, caecal colonic; C2, ascending colonic; D, duodenum; D1, portal lymph nodes; D2, distal duodenum gLNs; Pan, pancreas; I, ileum; ing, inguinal lymph node; IL and CA, iliac and caudal (both rectal) gLNs; J, jejunum. * P < 0.05, ** P < 0.01, *** P < 0.005 (ANOVA); mean ± s.e.m. Full size image We investigated how compartmentalized drainage affects gLNs on a cellular level. Stromal cells of pooled gLNs were shown to be tolerance-promoting compared to non-intestinal lymph nodes 14 , 15 , so we analysed the transcriptomes of two major stromal cell populations, lymphatic endothelial cells (LECs) and fibroblastic reticular cells (FRCs), isolated from duodenal, ileal and caecal-colonic gLNs (D-, I- and C-gLNs, respectively; Extended Data Fig. 3a ). Principal component analysis (PCA) indicated that LECs and FRCs showed differential gene expression according to the gut segment the gLNs drained", "role": "user" }, { "content": "As food enters the intestine, it embarks on windy, lengthy journey. For most of the route, its surroundings don't appear to change much. But new research from Rockefeller's Daniel Mucida shows that the food-processing canal consists of compartments that pace the immune system's reactions to the food passing through—with less aggressive defenses in the first segments where nutrients are absorbed, and more forceful responses at the end, where pathogens are eliminated. The findings, published in Nature, provide new insights about how the intestine maximizes nutrient uptake while protecting the body from potentially dangerous invading microbes, two seemingly conflicting functions. The research has potential to improve drugs for gastrointestinal disorders, as well as inform the development of oral vaccines. \"At first glance the intestine appears uniform throughout,\" says Mucida. \"But we've found a sophisticated functional system lurking beneath the surface, organized in segments to allow different immune system functions in different locations.\" Intestinal divide Mucida and colleagues uncovered a functional segmentation in mice by examining intestinal structures called gut draining lymph nodes, which orchestrate immune responses. The researchers found that nodes in different part of the intestine had different cell composition, and when they challenged the mice with a pathogen such as Salmonella, they saw different immune responses between segments. Having immune responses separated by location likely increases the chance that the immune system reacts appropriately to what's passing through, Mucida says. Once most nutrients have been absorbed, the system can focus more aggressively on eliminating pathogens without interfering with food uptake. Segment-focused therapy According to Mucida, the immunological differences between the gut segments could be exploited for a number of therapeutic purposes, including for treating gastrointestinal disorders. For example, by targeting immune-suppressing drugs to the segment where they'll have the most effect, it might be possible to dampen their side-effects. Additionally, outcomes of surgeries that remove part of the intestine could improve if variations between segments were taken into account. The spectrum of immune responses along the intestine could also be used to make new and better oral vaccines. Thus far, scientists' efforts to design oral vaccines—attractive to many because of the absence of needles—have been stymied by the difficulty of generating a robust immune response (and unless the immune system mounts a strong enough reaction to the vaccine, it cannot create the molecular \"memory\" of the pathogen needed to prepare the body against recurring attacks). According to Mucida, the muted immune response at the beginning of the intestine might be part of the reason why oral vaccines tend to be less effective than injections. \"In theory, targeting the distant end of the intestine could be more efficient in inducing the immune response required,\" he says. \"If we harness the right region of the gut, we might see some vaccines work that have previously failed.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure of this balance leads to conditions such as inflammatory bowel diseases, food allergies and invasive gastrointestinal infections 1 . Multiple immune mechanisms are therefore in place to maintain tissue integrity, including balanced generation of effector T (T H ) cells and FOXP3 + regulatory T (pT reg ) cells, which mediate resistance to pathogens and regulate excessive immune activation, respectively 1 , 2 , 3 , 4 . The gut-draining lymph nodes (gLNs) are key sites for orchestrating adaptive immunity to luminal perturbations 5 , 6 , 7 . However, it is unclear how they simultaneously support tolerogenic and inflammatory reactions. Here we show that gLNs are immunologically specific to the functional gut segment that they drain. Stromal and dendritic cell gene signatures and polarization of T cells against the same luminal antigen differ between gLNs, with the proximal small intestine-draining gLNs preferentially giving rise to tolerogenic responses and the distal gLNs to pro-inflammatory T cell responses. This segregation permitted the targeting of distal gLNs for vaccination and the maintenance of duodenal pT reg cell induction during colonic infection. Conversely, the compartmentalized dichotomy was perturbed by surgical removal of select distal gLNs and duodenal infection, with effects on both lymphoid organ and tissue immune responses. Our findings reveal that the conflict between tolerogenic and inflammatory intestinal responses is in part resolved by discrete gLN drainage, and encourage antigen targeting to specific gut segments for therapeutic immune modulation. Main Appropriate lymphatic trafficking of immune cells to gLNs is essential for intestinal adaptive immunity 6 , 8 (Fig. 1a ). Previous studies have mapped drainage to various gLNs along the mouse gut 9 , 10 , 11 , 12 , and described immunological differences between gLNs 11 , 13 , but, to our knowledge, the underlying cellular components and functional consequences of gut segment-specific drainage have not been systematically addressed. We sought to understand how compartmentalized lymphatic drainage of the intestinal milieu contributes to distinct immune responses towards luminal antigens. We first imaged the gut lymphatic system using 3D imaging of solvent-cleared tissue stained with an antibody against the lymphatic endothelial cell (LEC) surface marker LYVE-1. En bloc imaging exposed the lymphatic route of the intestine to gLNs via afferent lymphatic vessels in the mesentery (Fig. 1a–c , Extended Data Fig. 1a–c , Supplementary Videos 1 – 4 ). The size and shape of individual gLNs differs considerably regardless of the presence or absence of microbiota (Extended Data Fig. 1d, e ). Dye injected into individual gLNs did not spread to other gLNs, suggesting that the lymph remains compartmentalized until it reaches the thoracic duct (Extended Data Fig. 1f–i ). Injection of dye into the intestinal muscularis confirmed that the gLNs drain different gut segments 9 , 10 , 11 , 12 despite the network-like lymphatic structure in the gut wall (Extended Data Fig. 1j–q , Supplementary Videos 5 – 7 ). The progressive shortening of the lymphatic lacteals in the villi along the small intestine is modulated by the microbiome, as germ-free mice showed lengthened duodenal and shortened ileal lacteals (Extended Data Fig. 2a ). To investigate whether the combination of compartmentalized absorption and drainage results in differential nutrient exposure in the gLNs, we tracked the uptake of radiolabelled retinol after feeding; retinol is a lipid-soluble proxy and an immunomodulatory nutrient, and its uptake depends largely on packing into chylomicrons and lymphatic absorption by the upper small intestine (Extended Data Fig. 2b ). Most retinol was absorbed in the duodenum with a gradient along the intestine, and this was mirrored in the gLNs (Fig. 1d, e , Extended Data Fig. 2b–g ), illustrating that the gLNs are exposed to region-specific lymph composition. Fig. 1: The gLNs are metabolically and immunologically unique according to the gut segment drained. a , Schematic of gLNs. b , c , 3D reconstruction of mouse lymphatics (anti-LYVE-1) and position after iDISCO + procedure (see Methods ) ( b ), co-stained with anti-GFP (in Itgax Venus mice, where GFP is expressed under the Cd11c promoter) and anti-insulin ( c ). d , e , Percentage of [ 3 H]retinol absorption into indicated gut segment ( d ) or gLN ( e ) of mice 3 h after gavage with 1 µCi [ 3 H]retinol in 100 µl olive oil with or without pre-treatment with 5 µl chylomicron formation inhibitor Pluronic L-81 (PL81) 3 h before gavage ( n = 4 per group). f , RNA sequencing (RNA-seq) PCA of FRCs and LECs sorted from D-, I- and C-gLNs (for example, cLEC denotes LECs from C-gLNs) from SPF C57BL/6 mice ( n = 3, pooled from two mice each). PC1 accounts for 65.1% and PC2 for 5.7% of the variance. g , h , Volcano plots depicting genes that are differentially expressed among LECs ( g ) and FRCs ( h ) from D- or C-gLNs (CL and DL, LECs from C- and D-gLNs, respectively; CF and DF, FRCs from C- and D-gLNs, respectively). Blue, metabolism-related genes; red, immunity-related genes. C, colon; C1, caecal colonic; C2, ascending colonic; D, duodenum; D1, portal lymph nodes; D2, distal duodenum gLNs; Pan, pancreas; I, ileum; ing, inguinal lymph node; IL and CA, iliac and caudal (both rectal) gLNs; J, jejunum. * P < 0.05, ** P < 0.01, *** P < 0.005 (ANOVA); mean ± s.e.m. Full size image We investigated how compartmentalized drainage affects gLNs on a cellular level. Stromal cells of pooled gLNs were shown to be tolerance-promoting compared to non-intestinal lymph nodes 14 , 15 , so we analysed the transcriptomes of two major stromal cell populations, lymphatic endothelial cells (LECs) and fibroblastic reticular cells (FRCs), isolated from duodenal, ileal and caecal-colonic gLNs (D-, I- and C-gLNs, respectively; Extended Data Fig. 3a ). Principal component analysis (PCA) indicated that LECs and FRCs showed differential gene expression according to the gut segment the gLNs drained<|im_end|> <|im_start|>assistant As food enters the intestine, it embarks on windy, lengthy journey. For most of the route, its surroundings don't appear to change much. But new research from Rockefeller's Daniel Mucida shows that the food-processing canal consists of compartments that pace the immune system's reactions to the food passing through—with less aggressive defenses in the first segments where nutrients are absorbed, and more forceful responses at the end, where pathogens are eliminated. The findings, published in Nature, provide new insights about how the intestine maximizes nutrient uptake while protecting the body from potentially dangerous invading microbes, two seemingly conflicting functions. The research has potential to improve drugs for gastrointestinal disorders, as well as inform the development of oral vaccines. "At first glance the intestine appears uniform throughout," says Mucida. "But we've found a sophisticated functional system lurking beneath the surface, organized in segments to allow different immune system functions in different locations." Intestinal divide Mucida and colleagues uncovered a functional segmentation in mice by examining intestinal structures called gut draining lymph nodes, which orchestrate immune responses. The researchers found that nodes in different part of the intestine had different cell composition, and when they challenged the mice with a pathogen such as Salmonella, they saw different immune responses between segments. Having immune responses separated by location likely increases the chance that the immune system reacts appropriately to what's passing through, Mucida says. Once most nutrients have been absorbed, the system can focus more aggressively on eliminating pathogens without interfering with food uptake. Segment-focused therapy According to Mucida, the immunological differences between the gut segments could be exploited for a number of therapeutic purposes, including for treating gastrointestinal disorders. For example, by targeting immune-suppressing drugs to the segment where they'll have the most effect, it might be possible to dampen their side-effects. Additionally, outcomes of surgeries that remove part of the intestine could improve if variations between segments were taken into account. The spectrum of immune responses along the intestine could also be used to make new and better oral vaccines. Thus far, scientists' efforts to design oral vaccines—attractive to many because of the absence of needles—have been stymied by the difficulty of generating a robust immune response (and unless the immune system mounts a strong enough reaction to the vaccine, it cannot create the molecular "memory" of the pathogen needed to prepare the body against recurring attacks). According to Mucida, the muted immune response at the beginning of the intestine might be part of the reason why oral vaccines tend to be less effective than injections. "In theory, targeting the distant end of the intestine could be more efficient in inducing the immune response required," he says. "If we harness the right region of the gut, we might see some vaccines work that have previously failed." <|im_end|>

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2,133

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Most scientific studies on microplastic (MP) pollution report their results as number of particles (e.g., particles/m 2 , particles/m 3 , particles/kg dw). An important limitation of this expression is to consider all MP particles as environmentally equivalent, regardless of their size, volume, mass, or specific surface area. Using a theoretical approach, we advocate that including such morphological attributes reveals significant differences in results of supposedly equivalent samples that consider only the number of particles. Our goal is to present how particle size and shape produce different results for hypothetical samples with the same number of particles. Therefore, from these examples we expect to stimulate the debate and contribute to improve accuracy and comparability of studies on MP pollution. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction In the last decade, the scientific community has made a great effort to standardize the definition of microplastics (MPs) and the procedures for sampling and analyzing them in several types of matrices (Frias and Nash 2019 ; Hartmann et al. 2019 ; Enders et al. 2020 ). The general objectives are to implement quality control protocols to reduce the contamination of the samples and to improve comparability and reproducibility (Koelmans et al. 2019 ; de Ruijter et al. 2020 ). Although counting particles is the simplest way to quantify MPs in several cases, it reflects only a facet of plastic pollution and its potential environmental impact. Other attributes of MP particles refer to different aspects of their pollution effect and should be presented in a complementary way: particle size (maximum length), mass, volume, and specific surface area (Covernton et al. 2019 ; Mallow et al. 2020 ). MPs vary remarkably in their morphological, physical, and chemical properties, which are crucial in their classification besides influencing their impacts on biota, dispersion in the environment, and interaction with other pollutants (Chubarenko et al. 2016 ; Scherer et al. 2018 ). The sole expression of the number of particles in a sample (e.g., particles/m 3 , particles/m 2 , or particles/kg dw) implicitly assumes that all MPs are environmentally equivalent regardless of their size, mass, volume, or specific surface area. Several analytical techniques have been improved or adapted to accelerate and make processing and analysis easier, cheaper, and to provide more accurate results (Hanvey et al. 2017 ; Zarfl 2019 ; Mbachu et al. 2020 ; Cutroneo et al. 2020 ). However, most of the papers maintain the number of particles as the main output. Different approaches in sampling, preparing, and analyzing samples can make results virtually incomparable among papers, especially when the number of particles is the only result expressed because it is strongly dependent on the methodological procedures. Our goal is to present how particle size and shape produce different results for hypothetical samples with the same number of particles. Therefore, from these examples we expect to stimulate the debate and contribute to improve accuracy and comparability of studies on MP pollution. Integrating morphological analysis Ideally, the conjunction among the number of particles and their size, volume, mass, and specific surface area may expand the interpretation of environmental impacts caused by MPs. Consider the hypothetical situations illustrated in Fig. 1 , where all the samples contain 100 particles (except sample D). If only this information is available to compare those samples, the obvious conclusion may be that they are equivalent (i.e., same pollution level) regarding plastic pollution. However, MPs in sample B are bigger in volume, mass, and specific surface area. Consequently, sample B has more plastic than other samples, and it is even more susceptible to originate a higher number of smaller particles caused by physical/chemical degradation. In another hypothetical comparison, samples C and D have 100 and 10 MPs, respectively. Again, if only the number of particles is considered to interpret results, the conclusion is that sample C has 10 × more plastic than sample D. Nevertheless, both samples have the same global mass and volume of plastic, but particle size and specific surface area are greater in sample C. Particle shapes exert a significant influence on those morphological attributes, which denotes that comparing only the number of particles is not enough. Samples with fibers (E and F) resulted in smaller volume, mass, and specific surface area than other shapes. Despite samples C and H have nearly the same volume and specific surface area, their masses differ in ~ 3.3 × . A remarkable aspect of such comparisons is that the specific surface areas for all particles summed are dramatically different among the hypothetical samples. For example, although samples C and D have the same volume and mass of plastic, sample C doubled the specific surface area because it is more fragmented, which increases the potential of MPs to carry other adsorbed pollutants and host biofilms on their surface (Rummel et al. 2017 ; Zhang et al. 2018 ; Tu et al. 2020 ). The maximum difference between two samples are observed for B (pellets) and E (fibers) reaching ~ 3600 × (volume and mass) and ~ 164 × (specific surface area). Fig. 1 Hypothetical samples with microplastics with different sizes and shapes. Samples A, B, C, E, F, G, and H have the same number of particles (n), but different shapes, volume, mass, and specific surface area of all particles summed. Samples C and D have the same volume and mass of plastic, but different number of particles and specific surface area. Masses were estimated for a plastic density of 1.38 mg mL −1 . Particle dimensions: d (diameter), l (length), b1 (base 1), b2 (base 2), h (height), t (thickness) Full size image A practical difficulty emerges in obtaining the volume, mass, and specific surface area of MPs mainly if only a few and small particles are found in the sample. The suite of equipment capable to directly measure these attributes (such as X-ray microtomography/micro-CT—resolution up to 350 nm) usually require investments in an amount rarely available", "role": "user" }, { "content": "In the last decade, growing numbers of researchers have studied plastic pollution, one of the world's most pressing environmental hazards. They have made progress but still face challenges, such as the comparability of results, especially with regard to microplastic particles. There is no standard sample collection and analysis methodology, for example. Most studies present conclusions based on numbers of particles as if they were environmentally equivalent regardless of size, volume, mass or surface area. An article by three Brazilian researchers published in Environmental Science and Pollution Research aims to contribute to progress in this field by proposing a novel perspective on particle morphology. Using a theoretical approach, the authors argue that including morphological attributes in the analysis can reveal significant differences between samples of microplastic particles, demonstrating that samples initially considered equivalent because they contain the same number of particles actually have different environmental impacts because of variations in particle size and shape. Microplastic particles (MPs) are artificial polymers with a length of between 0.001 and 5.0 millimeters, or 1-5,000 micrometers (μm), and are found in all kinds of environment. Few studies of pollution by MPs have been published in Brazil, especially regarding inland aquatic areas. \"Most of the research that's been done on MPs reports the number of particles in terms of the unit adopted for the sample type, ranging from volume in the case of water, to mass when the analysis involves soil and sediment, and individuals for biota. We've been researching MPs in the laboratory for several years, and we've confirmed that size is important and makes a difference. We measure particle size in all samples. In this study we found samples with similar numbers of MPs but significant variations in particle size and very different levels of plastic pollution based on particle mass and volume,\" Décio Semensatto, first author of the article, told Agência FAPESP. He is a professor at the Federal University of São Paulo's Institute of Environmental, Chemical and Pharmaceutical Sciences (ICAQF-UNIFESP). The other authors of the article are Professor Geórgia Labuto and Cristiano Rezende Gerolin, a former researcher at UNIFESP. According to Semensatto, the group is finalizing an article on the Guarapiranga reservoir, a source of drinking water for São Paulo and two nearby towns, Itapecerica da Serra and Embu-Guaçu. \"We collected samples in the wet and dry seasons and found more MPs in one season than another, with an even greater difference in terms of each sample's mass and total volume of plastic. Using only numbers of particles as a parameter focuses on just one dimension and ignores that fact that different particle sizes have different effects on ecosystems,\" he said. Comparisons According to the recent article, the researchers analyzed seven samples with 100 MPs each. These would be considered equivalent based on conventional pollution metrics. However, the comparisons made showed that their impact on the environment would be very different. In one sample, the MPs were larger in terms of volume, mass and specific surface area. It therefore had more plastic than the others and was likely to give rise to a larger number of even smaller particles when broken down by physical and chemical degradation. In another comparison, they analyzed samples with 100 MPs and 10 MPs respectively, noting that if only the number of particles were considered, the conclusion would be that the former had ten times more plastic than the latter, although both had the same total mass and volume of plastic, while particle size and specific surface area were larger in the former. The authors also highlight the question of morphology or particle shape. Samples containing fibers had less volume, mass and surface area, for example. \"We also explore the question of specific surface area, which is highly relevant, especially when studying MPs as carriers of other pollutants, such as metals or pharmaceuticals,\" Semensatto said. \"Particle size influences the surface area available for adsorption of these pollutants. In addition, MPs also form a plastisphere that serves as a substrate for organisms and disperses these organisms to other environments, with consequences for global health.\" The plastisphere is the community of bacteria, fungi, algae, viruses and other microorganisms that have evolved to live on man-made plastic. \"By considering particle volume, mass and specific surface area, we can better understand how MPs pollute water bodies and transport other agents responsible for pollution, including microorganisms,\" Semensatto said. \"Analyzing all attributes of samples brings new possibilities into view and extends the comparability of the results.\" The vast scale of the problem World production of plastic reached 348 million metric tons in 2017, up from only 2 million tons in 1950. The global plastic industry is valued at USD 522.6 billion, and its capacity is expected to double by 2040, according to a report by The Pew Charitable Trusts and SystemIQ, partnering with Oxford and Leeds Universities in the UK. Plastic production and pollution affect human health and fuel greenhouse gas emissions. Plastic can be ingested by more than 800 marine and coastal species or cause accidents involving them. Some 11 million tons of plastic waste enter the oceans every year. In 2022, 175 countries represented at the UN General Assembly adopted a historic resolution to sign up by 2024 to a legally binding commitment to end global plastic pollution. To this end, they established an intergovernmental negotiating committee, which held its first session in December. \"With this study, we set out to contribute to academic efforts to develop routines and methodologies for dealing with plastic pollution,\" Semensatto said. \"Our article proposes a discussion within the academic community. The proposal is open to debate. We're inviting other scientists to measure MPs and report their morphological attributes, as a contribution to the discussion of their environmental significance.\" In this context, a group at UNIFESP linked to Semensatto are working with the São Paulo State Environmental Corporation (CETESB) to develop protocols for collecting water samples and analyzing MPs in the coastal region of the state. The main aim is to find a way to compare results so that MPs can become part of continuous environmental monitoring, which they are not right now in São Paulo. This project is being conducted under the aegis of Rede Hydropoll, a network of researchers at various institutions engaged in studying water source pollution. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Most scientific studies on microplastic (MP) pollution report their results as number of particles (e.g., particles/m 2 , particles/m 3 , particles/kg dw). An important limitation of this expression is to consider all MP particles as environmentally equivalent, regardless of their size, volume, mass, or specific surface area. Using a theoretical approach, we advocate that including such morphological attributes reveals significant differences in results of supposedly equivalent samples that consider only the number of particles. Our goal is to present how particle size and shape produce different results for hypothetical samples with the same number of particles. Therefore, from these examples we expect to stimulate the debate and contribute to improve accuracy and comparability of studies on MP pollution. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction In the last decade, the scientific community has made a great effort to standardize the definition of microplastics (MPs) and the procedures for sampling and analyzing them in several types of matrices (Frias and Nash 2019 ; Hartmann et al. 2019 ; Enders et al. 2020 ). The general objectives are to implement quality control protocols to reduce the contamination of the samples and to improve comparability and reproducibility (Koelmans et al. 2019 ; de Ruijter et al. 2020 ). Although counting particles is the simplest way to quantify MPs in several cases, it reflects only a facet of plastic pollution and its potential environmental impact. Other attributes of MP particles refer to different aspects of their pollution effect and should be presented in a complementary way: particle size (maximum length), mass, volume, and specific surface area (Covernton et al. 2019 ; Mallow et al. 2020 ). MPs vary remarkably in their morphological, physical, and chemical properties, which are crucial in their classification besides influencing their impacts on biota, dispersion in the environment, and interaction with other pollutants (Chubarenko et al. 2016 ; Scherer et al. 2018 ). The sole expression of the number of particles in a sample (e.g., particles/m 3 , particles/m 2 , or particles/kg dw) implicitly assumes that all MPs are environmentally equivalent regardless of their size, mass, volume, or specific surface area. Several analytical techniques have been improved or adapted to accelerate and make processing and analysis easier, cheaper, and to provide more accurate results (Hanvey et al. 2017 ; Zarfl 2019 ; Mbachu et al. 2020 ; Cutroneo et al. 2020 ). However, most of the papers maintain the number of particles as the main output. Different approaches in sampling, preparing, and analyzing samples can make results virtually incomparable among papers, especially when the number of particles is the only result expressed because it is strongly dependent on the methodological procedures. Our goal is to present how particle size and shape produce different results for hypothetical samples with the same number of particles. Therefore, from these examples we expect to stimulate the debate and contribute to improve accuracy and comparability of studies on MP pollution. Integrating morphological analysis Ideally, the conjunction among the number of particles and their size, volume, mass, and specific surface area may expand the interpretation of environmental impacts caused by MPs. Consider the hypothetical situations illustrated in Fig. 1 , where all the samples contain 100 particles (except sample D). If only this information is available to compare those samples, the obvious conclusion may be that they are equivalent (i.e., same pollution level) regarding plastic pollution. However, MPs in sample B are bigger in volume, mass, and specific surface area. Consequently, sample B has more plastic than other samples, and it is even more susceptible to originate a higher number of smaller particles caused by physical/chemical degradation. In another hypothetical comparison, samples C and D have 100 and 10 MPs, respectively. Again, if only the number of particles is considered to interpret results, the conclusion is that sample C has 10 × more plastic than sample D. Nevertheless, both samples have the same global mass and volume of plastic, but particle size and specific surface area are greater in sample C. Particle shapes exert a significant influence on those morphological attributes, which denotes that comparing only the number of particles is not enough. Samples with fibers (E and F) resulted in smaller volume, mass, and specific surface area than other shapes. Despite samples C and H have nearly the same volume and specific surface area, their masses differ in ~ 3.3 × . A remarkable aspect of such comparisons is that the specific surface areas for all particles summed are dramatically different among the hypothetical samples. For example, although samples C and D have the same volume and mass of plastic, sample C doubled the specific surface area because it is more fragmented, which increases the potential of MPs to carry other adsorbed pollutants and host biofilms on their surface (Rummel et al. 2017 ; Zhang et al. 2018 ; Tu et al. 2020 ). The maximum difference between two samples are observed for B (pellets) and E (fibers) reaching ~ 3600 × (volume and mass) and ~ 164 × (specific surface area). Fig. 1 Hypothetical samples with microplastics with different sizes and shapes. Samples A, B, C, E, F, G, and H have the same number of particles (n), but different shapes, volume, mass, and specific surface area of all particles summed. Samples C and D have the same volume and mass of plastic, but different number of particles and specific surface area. Masses were estimated for a plastic density of 1.38 mg mL −1 . Particle dimensions: d (diameter), l (length), b1 (base 1), b2 (base 2), h (height), t (thickness) Full size image A practical difficulty emerges in obtaining the volume, mass, and specific surface area of MPs mainly if only a few and small particles are found in the sample. The suite of equipment capable to directly measure these attributes (such as X-ray microtomography/micro-CT—resolution up to 350 nm) usually require investments in an amount rarely available<|im_end|> <|im_start|>assistant In the last decade, growing numbers of researchers have studied plastic pollution, one of the world's most pressing environmental hazards. They have made progress but still face challenges, such as the comparability of results, especially with regard to microplastic particles. There is no standard sample collection and analysis methodology, for example. Most studies present conclusions based on numbers of particles as if they were environmentally equivalent regardless of size, volume, mass or surface area. An article by three Brazilian researchers published in Environmental Science and Pollution Research aims to contribute to progress in this field by proposing a novel perspective on particle morphology. Using a theoretical approach, the authors argue that including morphological attributes in the analysis can reveal significant differences between samples of microplastic particles, demonstrating that samples initially considered equivalent because they contain the same number of particles actually have different environmental impacts because of variations in particle size and shape. Microplastic particles (MPs) are artificial polymers with a length of between 0.001 and 5.0 millimeters, or 1-5,000 micrometers (μm), and are found in all kinds of environment. Few studies of pollution by MPs have been published in Brazil, especially regarding inland aquatic areas. "Most of the research that's been done on MPs reports the number of particles in terms of the unit adopted for the sample type, ranging from volume in the case of water, to mass when the analysis involves soil and sediment, and individuals for biota. We've been researching MPs in the laboratory for several years, and we've confirmed that size is important and makes a difference. We measure particle size in all samples. In this study we found samples with similar numbers of MPs but significant variations in particle size and very different levels of plastic pollution based on particle mass and volume," Décio Semensatto, first author of the article, told Agência FAPESP. He is a professor at the Federal University of São Paulo's Institute of Environmental, Chemical and Pharmaceutical Sciences (ICAQF-UNIFESP). The other authors of the article are Professor Geórgia Labuto and Cristiano Rezende Gerolin, a former researcher at UNIFESP. According to Semensatto, the group is finalizing an article on the Guarapiranga reservoir, a source of drinking water for São Paulo and two nearby towns, Itapecerica da Serra and Embu-Guaçu. "We collected samples in the wet and dry seasons and found more MPs in one season than another, with an even greater difference in terms of each sample's mass and total volume of plastic. Using only numbers of particles as a parameter focuses on just one dimension and ignores that fact that different particle sizes have different effects on ecosystems," he said. Comparisons According to the recent article, the researchers analyzed seven samples with 100 MPs each. These would be considered equivalent based on conventional pollution metrics. However, the comparisons made showed that their impact on the environment would be very different. In one sample, the MPs were larger in terms of volume, mass and specific surface area. It therefore had more plastic than the others and was likely to give rise to a larger number of even smaller particles when broken down by physical and chemical degradation. In another comparison, they analyzed samples with 100 MPs and 10 MPs respectively, noting that if only the number of particles were considered, the conclusion would be that the former had ten times more plastic than the latter, although both had the same total mass and volume of plastic, while particle size and specific surface area were larger in the former. The authors also highlight the question of morphology or particle shape. Samples containing fibers had less volume, mass and surface area, for example. "We also explore the question of specific surface area, which is highly relevant, especially when studying MPs as carriers of other pollutants, such as metals or pharmaceuticals," Semensatto said. "Particle size influences the surface area available for adsorption of these pollutants. In addition, MPs also form a plastisphere that serves as a substrate for organisms and disperses these organisms to other environments, with consequences for global health." The plastisphere is the community of bacteria, fungi, algae, viruses and other microorganisms that have evolved to live on man-made plastic. "By considering particle volume, mass and specific surface area, we can better understand how MPs pollute water bodies and transport other agents responsible for pollution, including microorganisms," Semensatto said. "Analyzing all attributes of samples brings new possibilities into view and extends the comparability of the results." The vast scale of the problem World production of plastic reached 348 million metric tons in 2017, up from only 2 million tons in 1950. The global plastic industry is valued at USD 522.6 billion, and its capacity is expected to double by 2040, according to a report by The Pew Charitable Trusts and SystemIQ, partnering with Oxford and Leeds Universities in the UK. Plastic production and pollution affect human health and fuel greenhouse gas emissions. Plastic can be ingested by more than 800 marine and coastal species or cause accidents involving them. Some 11 million tons of plastic waste enter the oceans every year. In 2022, 175 countries represented at the UN General Assembly adopted a historic resolution to sign up by 2024 to a legally binding commitment to end global plastic pollution. To this end, they established an intergovernmental negotiating committee, which held its first session in December. "With this study, we set out to contribute to academic efforts to develop routines and methodologies for dealing with plastic pollution," Semensatto said. "Our article proposes a discussion within the academic community. The proposal is open to debate. We're inviting other scientists to measure MPs and report their morphological attributes, as a contribution to the discussion of their environmental significance." In this context, a group at UNIFESP linked to Semensatto are working with the São Paulo State Environmental Corporation (CETESB) to develop protocols for collecting water samples and analyzing MPs in the coastal region of the state. The main aim is to find a way to compare results so that MPs can become part of continuous environmental monitoring, which they are not right now in São Paulo. This project is being conducted under the aegis of Rede Hydropoll, a network of researchers at various institutions engaged in studying water source pollution. <|im_end|>

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220, 679, 23, 2652, 29749, 1880, 453, 13, 220, 2366, 15, 7609, 578, 7340, 6811, 1990, 1403, 10688, 527, 13468, 369, 426, 320, 48624, 10145, 8, 323, 469, 320, 76426, 388, 8, 19261, 4056, 220, 6843, 15, 25800, 320, 26116, 323, 3148, 8, 323, 4056, 220, 10513, 25800, 320, 52340, 7479, 3158, 570, 23966, 13, 220, 16, 39515, 8942, 45608, 10688, 449, 8162, 501, 39171, 449, 2204, 12562, 323, 21483, 13, 59450, 362, 11, 426, 11, 356, 11, 469, 11, 435, 11, 480, 11, 323, 473, 617, 279, 1890, 1396, 315, 19252, 320, 77, 705, 719, 2204, 21483, 11, 8286, 11, 3148, 11, 323, 3230, 7479, 3158, 315, 682, 19252, 66766, 13, 59450, 356, 323, 423, 617, 279, 1890, 8286, 323, 3148, 315, 12466, 11, 719, 2204, 1396, 315, 19252, 323, 3230, 7479, 3158, 13, 9346, 288, 1051, 13240, 369, 264, 12466, 17915, 315, 220, 16, 13, 1987, 14060, 65170, 25173, 16, 662, 36954, 15696, 25, 294, 320, 67, 37144, 705, 326, 320, 4222, 705, 293, 16, 320, 3231, 220, 16, 705, 293, 17, 320, 3231, 220, 17, 705, 305, 320, 2627, 705, 259, 320, 92067, 8, 8797, 1404, 2217, 362, 15325, 17250, 59696, 304, 19546, 279, 8286, 11, 3148, 11, 323, 3230, 7479, 3158, 315, 37761, 14918, 422, 1193, 264, 2478, 323, 2678, 19252, 527, 1766, 304, 279, 6205, 13, 578, 16578, 315, 7241, 13171, 311, 6089, 6767, 1521, 8365, 320, 21470, 439, 1630, 30630, 8162, 38501, 5814, 3262, 2823, 12, 1182, 2345, 56856, 709, 311, 220, 8652, 26807, 8, 6118, 1397, 22538, 304, 459, 3392, 19029, 2561, 128257, 198, 128256, 78191, 198, 644, 279, 1566, 13515, 11, 7982, 5219, 315, 12074, 617, 20041, 12466, 25793, 11, 832, 315, 279, 1917, 596, 1455, 26422, 12434, 52642, 13, 2435, 617, 1903, 5208, 719, 2103, 3663, 11774, 11, 1778, 439, 279, 7809, 2968, 315, 3135, 11, 5423, 449, 5363, 311, 8162, 501, 5174, 19252, 13, 2684, 374, 912, 5410, 6205, 4526, 323, 6492, 38152, 11, 369, 3187, 13, 7648, 7978, 3118, 31342, 3196, 389, 5219, 315, 19252, 439, 422, 814, 1051, 57340, 13890, 15851, 315, 1404, 11, 8286, 11, 3148, 477, 7479, 3158, 13, 1556, 4652, 555, 2380, 36083, 12074, 4756, 304, 25027, 10170, 323, 96201, 8483, 22262, 311, 17210, 311, 5208, 304, 420, 2115, 555, 57515, 264, 11775, 13356, 389, 19320, 79612, 13, 12362, 264, 32887, 5603, 11, 279, 12283, 18046, 430, 2737, 27448, 5848, 8365, 304, 279, 6492, 649, 16805, 5199, 12062, 1990, 10688, 315, 8162, 501, 5174, 19252, 11, 45296, 430, 10688, 15453, 6646, 13890, 1606, 814, 6782, 279, 1890, 1396, 315, 19252, 3604, 617, 2204, 12434, 25949, 1606, 315, 27339, 304, 19320, 1404, 323, 6211, 13, 18654, 501, 5174, 19252, 320, 5901, 82, 8, 527, 21075, 46033, 388, 449, 264, 3160, 315, 1990, 220, 15, 13, 4119, 323, 220, 20, 13, 15, 2606, 55336, 11, 477, 220, 16, 12, 20, 11, 931, 19748, 442, 2481, 320, 44223, 76, 705, 323, 527, 1766, 304, 682, 13124, 315, 4676, 13, 44015, 7978, 315, 25793, 555, 37761, 617, 1027, 4756, 304, 16327, 11, 5423, 9002, 77289, 72491, 5789, 13, 330, 13622, 315, 279, 3495, 430, 596, 1027, 2884, 389, 37761, 6821, 279, 1396, 315, 19252, 304, 3878, 315, 279, 5089, 18306, 369, 279, 6205, 955, 11, 24950, 505, 8286, 304, 279, 1162, 315, 3090, 11, 311, 3148, 994, 279, 6492, 18065, 17614, 323, 59132, 11, 323, 7931, 369, 6160, 6217, 13, 1226, 3077, 1027, 45243, 37761, 304, 279, 27692, 369, 3892, 1667, 11, 323, 584, 3077, 11007, 430, 1404, 374, 3062, 323, 3727, 264, 6811, 13, 1226, 6767, 19320, 1404, 304, 682, 10688, 13, 763, 420, 4007, 584, 1766, 10688, 449, 4528, 5219, 315, 37761, 719, 5199, 27339, 304, 19320, 1404, 323, 1633, 2204, 5990, 315, 12466, 25793, 3196, 389, 19320, 3148, 323, 8286, 1359, 423, 20243, 822, 14582, 729, 17173, 11, 1176, 3229, 315, 279, 4652, 11, 3309, 4701, 24625, 435, 2599, 57329, 13, 1283, 374, 264, 14561, 520, 279, 12411, 3907, 315, 48790, 38026, 596, 10181, 315, 25027, 11, 36424, 323, 59373, 23199, 320, 32101, 48, 37, 12, 1899, 2843, 57329, 570, 578, 1023, 12283, 315, 279, 4652, 527, 17054, 4323, 1832, 2026, 689, 11868, 1564, 323, 100215, 1050, 89, 11178, 20524, 37737, 11, 264, 4846, 32185, 520, 6781, 2843, 57329, 13, 10771, 311, 14582, 729, 17173, 11, 279, 1912, 374, 1620, 4954, 459, 4652, 389, 279, 40100, 391, 404, 19934, 45512, 11, 264, 2592, 315, 16558, 3090, 369, 48790, 38026, 323, 1403, 14373, 25861, 11, 1102, 64, 1007, 261, 3074, 3067, 328, 14210, 323, 30227, 84, 12279, 4381, 79884, 13, 330, 1687, 14890, 10688, 304, 279, 14739, 323, 9235, 15956, 323, 1766, 810, 37761, 304, 832, 3280, 1109, 2500, 11, 449, 459, 1524, 7191, 6811, 304, 3878, 315, 1855, 6205, 596, 3148, 323, 2860, 8286, 315, 12466, 13, 12362, 1193, 5219, 315, 19252, 439, 264, 5852, 24400, 389, 1120, 832, 13167, 323, 49378, 430, 2144, 430, 2204, 19320, 12562, 617, 2204, 6372, 389, 61951, 1359, 568, 1071, 13, 23611, 19941, 10771, 311, 279, 3293, 4652, 11, 279, 12074, 30239, 8254, 10688, 449, 220, 1041, 37761, 1855, 13, 4314, 1053, 387, 6646, 13890, 3196, 389, 21349, 25793, 17150, 13, 4452, 11, 279, 36595, 1903, 8710, 430, 872, 5536, 389, 279, 4676, 1053, 387, 1633, 2204, 13, 763, 832, 6205, 11, 279, 37761, 1051, 8294, 304, 3878, 315, 8286, 11, 3148, 323, 3230, 7479, 3158, 13, 1102, 9093, 1047, 810, 12466, 1109, 279, 3885, 323, 574, 4461, 311, 3041, 10205, 311, 264, 8294, 1396, 315, 1524, 9333, 19252, 994, 11102, 1523, 555, 7106, 323, 11742, 53568, 13, 763, 2500, 12593, 11, 814, 30239, 10688, 449, 220, 1041, 37761, 323, 220, 605, 37761, 15947, 11, 27401, 430, 422, 1193, 279, 1396, 315, 19252, 1051, 6646, 11, 279, 17102, 1053, 387, 430, 279, 4846, 1047, 5899, 3115, 810, 12466, 1109, 279, 15629, 11, 8051, 2225, 1047, 279, 1890, 2860, 3148, 323, 8286, 315, 12466, 11, 1418, 19320, 1404, 323, 3230, 7479, 3158, 1051, 8294, 304, 279, 4846, 13, 578, 12283, 1101, 11415, 279, 3488, 315, 79612, 477, 19320, 6211, 13, 59450, 8649, 49774, 1047, 2753, 8286, 11, 3148, 323, 7479, 3158, 11, 369, 3187, 13, 330, 1687, 1101, 13488, 279, 3488, 315, 3230, 7479, 3158, 11, 902, 374, 7701, 9959, 11, 5423, 994, 21630, 37761, 439, 35991, 315, 1023, 83661, 11, 1778, 439, 37182, 477, 35410, 82, 1359, 14582, 729, 17173, 1071, 13, 330, 30108, 1404, 34453, 279, 7479, 3158, 2561, 369, 14058, 66181, 315, 1521, 83661, 13, 763, 5369, 11, 37761, 1101, 1376, 264, 88247, 47894, 430, 17482, 439, 264, 54057, 369, 44304, 323, 79835, 288, 1521, 44304, 311, 1023, 22484, 11, 449, 16296, 369, 3728, 2890, 1210, 578, 88247, 47894, 374, 279, 4029, 315, 24032, 11, 81540, 11, 68951, 11, 42068, 323, 1023, 8162, 76991, 430, 617, 28995, 311, 3974, 389, 893, 27975, 12466, 13, 330, 1383, 13126, 19320, 8286, 11, 3148, 323, 3230, 7479, 3158, 11, 584, 649, 2731, 3619, 1268, 37761, 7230, 1088, 3090, 13162, 323, 7710, 1023, 13307, 8647, 369, 25793, 11, 2737, 8162, 76991, 1359, 14582, 729, 17173, 1071, 13, 330, 74407, 20994, 682, 8365, 315, 10688, 12716, 502, 24525, 1139, 1684, 323, 2289, 279, 7809, 2968, 315, 279, 3135, 1210, 578, 13057, 5569, 315, 279, 3575, 4435, 5788, 315, 12466, 8813, 220, 19746, 3610, 18767, 20181, 304, 220, 679, 22, 11, 709, 505, 1193, 220, 17, 3610, 20181, 304, 220, 6280, 15, 13, 578, 3728, 12466, 5064, 374, 33647, 520, 20121, 220, 20936, 13, 21, 7239, 11, 323, 1202, 8824, 374, 3685, 311, 2033, 555, 220, 7854, 15, 11, 4184, 311, 264, 1934, 555, 578, 57717, 4969, 15729, 17236, 82, 323, 744, 63050, 11, 70220, 449, 26275, 323, 52629, 75898, 304, 279, 6560, 13, 37108, 5788, 323, 25793, 7958, 3823, 2890, 323, 10633, 37647, 6962, 20748, 13, 37108, 649, 387, 6892, 10185, 555, 810, 1109, 220, 4728, 29691, 323, 35335, 9606, 477, 5353, 33788, 16239, 1124, 13, 4427, 220, 806, 3610, 20181, 315, 12466, 12571, 3810, 279, 54280, 1475, 1060, 13, 763, 220, 2366, 17, 11, 220, 10005, 5961, 15609, 520, 279, 6781, 3331, 12000, 18306, 264, 18526, 11175, 311, 1879, 709, 555, 220, 2366, 19, 311, 264, 26267, 11212, 15507, 311, 842, 3728, 12466, 25793, 13, 2057, 420, 842, 11, 814, 9749, 459, 958, 87863, 278, 44725, 13093, 11, 902, 5762, 1202, 1176, 3882, 304, 6790, 13, 330, 2409, 420, 4007, 11, 584, 743, 704, 311, 17210, 311, 14584, 9045, 311, 2274, 30597, 323, 81898, 369, 14892, 449, 12466, 25793, 1359, 14582, 729, 17173, 1071, 13, 330, 8140, 4652, 55725, 264, 10430, 2949, 279, 14584, 4029, 13, 578, 14050, 374, 1825, 311, 11249, 13, 1226, 2351, 42292, 1023, 14248, 311, 6767, 37761, 323, 1934, 872, 27448, 5848, 8365, 11, 439, 264, 19035, 311, 279, 10430, 315, 872, 12434, 26431, 1210, 763, 420, 2317, 11, 264, 1912, 520, 6781, 2843, 57329, 10815, 311, 14582, 729, 17173, 527, 3318, 449, 279, 48790, 38026, 3314, 25027, 13332, 320, 34, 1372, 1600, 33, 8, 311, 2274, 32885, 369, 26984, 3090, 10688, 323, 42118, 37761, 304, 279, 35335, 5654, 315, 279, 1614, 13, 578, 1925, 9395, 374, 311, 1505, 264, 1648, 311, 9616, 3135, 779, 430, 37761, 649, 3719, 961, 315, 19815, 12434, 16967, 11, 902, 814, 527, 539, 1314, 1457, 304, 48790, 38026, 13, 1115, 2447, 374, 1694, 13375, 1234, 279, 264, 91067, 315, 73231, 10320, 6861, 980, 11, 264, 4009, 315, 12074, 520, 5370, 14673, 17045, 304, 21630, 3090, 2592, 25793, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objective . The aim of the study was to screen eight species of berries for their ability to prevent obesity and metabolic abnormalities associated with type 2 diabetes. Methods . C57BL/6J mice were assigned the following diets for 13 weeks: low-fat diet, high-fat diet or high-fat diet supplemented (20%) with lingonberry, blackcurrant, bilberry, raspberry, açai, crowberry, prune or blackberry. Results . The groups receiving a high-fat diet supplemented with lingonberries, blackcurrants, raspberries or bilberries gained less weight and had lower fasting insulin levels than the control group receiving high-fat diet without berries. Lingonberries, and also blackcurrants and bilberries, significantly decreased body fat content, hepatic lipid accumulation, and plasma levels of the inflammatory marker PAI-1, as well as mediated positive effects on glucose homeostasis. The group receiving açai displayed increased weight gain and developed large, steatotic livers. Quercetin glycosides were detected in the lingonberry and the blackcurrant diets. Conclusion . Lingonberries were shown to fully or partially prevent the detrimental metabolic effects induced by high-fat diet. Blackcurrants and bilberries had similar properties, but to a lower degree. We propose that the beneficial metabolic effects of lingonberries could be useful in preventing obesity and related disorders. 1. Introduction During the last decades, the prevalence of obesity and type 2 diabetes mellitus has increased dramatically. This epidemic of lifestyle-related disorders is affecting all parts of the world, and 439 million people are estimated to suffer from diabetes mellitus in 2030 [ 1 ]. Obesity is a strong risk factor for type 2 diabetes with 90% of affected patients being overweight or obese. Obesity is also associated with increased risk of various metabolic disorders including insulin resistance, chronic low-grade inflammation, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease. Oxidative stress, inflammatory response, and altered gut microbiota can play a significant role in the development of obesity-related disorders [ 2 – 4 ]. Type 2 diabetes is a multifactorial disease; however, it appears clear that prevention is possible by avoiding overeating and a sedentary lifestyle to maintain a healthy body weight [ 5 ]. The difficulty for many individuals to comply with dietary and lifestyle changes makes it of great interest to identify new foods with well-established effects on preventing the development of obesity and thereby type 2 diabetes and its associated metabolic complications. Dietary patterns with high consumption of polyphenol rich foods (fruits, vegetables, and berries) have been associated with reduced risk of type 2 diabetes. In general, berries are rich in polyphenols which are suggested to play a role in health benefits of plant-based diets [ 4 , 6 – 8 ]. Plant phenolics are a large group of secondary metabolites which provide color and taste in fruits and berries and include flavonoids (anthocyanins, flavonols, and flavanols), tannins, stilbenoids, and phenolic acids [ 9 ]. The antioxidant effect of berry anthocyanins has been studied extensively, but still little is known about the biological activities linking berries and polyphenols to the prevention of type 2 diabetes [ 4 , 10 , 11 ]. The aim of the present study was to perform a screening to investigate and compare metabolic effects of different berries in the C57BL/6J mouse. The C57BL/6J is a mouse strain that develops obesity and prediabetes when fed a diet rich in fat, thus mimicking detrimental effects of an energy dense western diet [ 12 ]. By supplementing high-fat diets with potentially health-promoting berries, we sought to identify berries capable of ameliorating risk factors from excessive energy intake. Here we report that different berries, possibly due to their polyphenol composition, have varying ability to prevent weight gain and metabolic disorders ultimately leading to diabetes. 2. Methods 2.1. Animals and Study Design The study was approved by the Animal Ethics Committee in Lund, Sweden, (Permit Number: M185-11) and is in accordance with the Council of Europe Convention (ETS 123). Male C57BL/6JBomTac mice, 6 weeks old, g were obtained from Taconic (Skensved, Denmark). The animals were housed in a controlled environment (12 h light/dark cycle, light on 7 a.m.). After 9 days of acclimatization the mice were divided into 10 groups of 12 mice each housed in groups of 6 mice per cage. The mice were fed high-fat diets (45 kcal% fat) (Research diets, New Brunswick, NJ, USA) supplemented (20% w/w) with eight different freeze dried berries ad libitum for 13 weeks. A control group was fed a macronutrient-matched, isocaloric diet without supplements. One group received a low-fat diet (10 kcal% fat) as an internal control to the high-fat diet induced obesity. Body weight and food intake were monitored weekly throughout the study period. The energy intake was calculated based on registered food consumption. Mice were housed with minimal bedding material and feces was quantitatively collected for two consecutive days at the end of the study and stored at −20°C prior to lyophilization, weighing and powdering with a mortar. At the end of the study, 4 h-fasted animals were anesthetized with an intraperitoneal injection of midazolam (Midazolam Panpharma 5 mg/mL, Panpharma S.A., Luitré, France) and a mixture of fluanisone 10 mg/mL and fentanyl citrate 0.315 mg/mL (Hypnorm, VetaPharma, Leeds, UK). Body composition was determined with dual-energy X-ray absorptiometry (DEXA) technique using a Lunar PIXImus (GE Lunar, Madison, WI, USA). Blood samples were taken by intraorbital puncture. The animals were sacrificed by cervical dislocation and liver, cecum, spleen, and epididymal fat pads were excised, weighed, and snap frozen in liquid nitrogen. 2.2. Preparation and Analysis of Diets The experimental diets were high-fat diets supplemented with one of eight freeze dried berries; Lingonberry ( Vaccinium vitis-idaea ), blackcurrant ( Ribes nigrum ), raspberry ( Rubus idaeus ), bilberry ( Vaccinium myrtillus ), and blackberry ( Rubus fruticosus ) were obtained from MOLDA AG (Dahlenburg, Germany). Crowberries ( Empetrum nigrum ) were from Olle Svenssons Partiaffär AB (Olofström, Sweden) and prunes ( Prunus domestica ) from Semper AB (Sundbyberg, Sweden). Freeze dried açai berry powder ( Euterpe oleracea ) was purchased from Superfruit Scandinavia AB (Sweden). Information about origin and processing of the berries can", "role": "user" }, { "content": "Lingonberries almost completely prevented weight gain in mice fed a high-fat diet, a study at Lund University in Sweden has found - whereas the 'super berry' açai led to increased weight gain. The Scandinavian berries also produced lower blood sugar levels and cholesterol. The Lund University research team used a type of mouse that easily stores fat and therefore can be regarded as a model for humans who are overweight and at risk of diabetes. Some of the mice were fed a low-fat diet, while the majority of the animals were fed a diet high in fat. They were then divided into groups, where all except a control group were fed a type of berry – lingonberry, bilberry, raspberry, crowberry, blackberry, prune, blackcurrant or açai berry. When the mice were compared after three months, it could be observed that the lingonberry group had by far the best results. The mice that had eaten lingonberries had not put on more weight than the mice that had eaten a low-fat diet - and their blood sugar and insulin readings were similar to those of the 'low-fat' mice. Their cholesterol levels and levels of fat in the liver were also lower than those of the animals who received a high-fat diet without any berries. According to the Lund University researchers, this is the first study of this kind using lingonberries. \"That is probably because lingonberries are mainly eaten in Scandinavia. At international conferences, I always have to start by explaining what they are, and showing the audience a jar of them\", says Lovisa Heyman, a PhD student in Experimental Medical Science. Blackcurrants and bilberries also produced good effects, although not as pronounced as the lingonberries. The açai berries, on the other hand, came last, although they had actually been included in the study for the opposite reason – the researchers wanted to see how well the Nordic berries would do in comparison with the Brazilian 'super berry'. \"Instead, the opposite happened. In our study, the açai berries led to weight gain and higher levels of fat in the liver\", said Karin Berger, diabetes researcher at Lund University. She believes that açai berries are primarily used as an energy supplement in their homeland Brazil. It is in the US and Europe that açai has been marketed as a 'super berry' with many health benefits, including weight loss. The good results from lingonberries may be due to their polyphenol content, according to the researchers. They will now continue to work on understanding the molecular mechanisms involved in the effect of the lingonberries. They will also see whether the effect can be observed in humans. \"Up to 20 % of our mice's diet was lingonberries. It isn't realistic for humans to eat such a high proportion. However, the goal is not to produce such dramatic effects as in the 'high-fat' mice, but rather to prevent obesity and diabetes by supplementing a more normal diet with berries\", said Karin Berger. However, the Lund researchers do not recommend people start eating large quantities of lingonberry jam. Boiling the berries can affect their nutrient content and jam contains a lot of sugar. Frozen lingonberries on cereal or in a smoothie are considerably better. \"If anyone wonders – yes, we now eat lingonberries on a regular basis!\" said Lovisa Heyman. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objective . The aim of the study was to screen eight species of berries for their ability to prevent obesity and metabolic abnormalities associated with type 2 diabetes. Methods . C57BL/6J mice were assigned the following diets for 13 weeks: low-fat diet, high-fat diet or high-fat diet supplemented (20%) with lingonberry, blackcurrant, bilberry, raspberry, açai, crowberry, prune or blackberry. Results . The groups receiving a high-fat diet supplemented with lingonberries, blackcurrants, raspberries or bilberries gained less weight and had lower fasting insulin levels than the control group receiving high-fat diet without berries. Lingonberries, and also blackcurrants and bilberries, significantly decreased body fat content, hepatic lipid accumulation, and plasma levels of the inflammatory marker PAI-1, as well as mediated positive effects on glucose homeostasis. The group receiving açai displayed increased weight gain and developed large, steatotic livers. Quercetin glycosides were detected in the lingonberry and the blackcurrant diets. Conclusion . Lingonberries were shown to fully or partially prevent the detrimental metabolic effects induced by high-fat diet. Blackcurrants and bilberries had similar properties, but to a lower degree. We propose that the beneficial metabolic effects of lingonberries could be useful in preventing obesity and related disorders. 1. Introduction During the last decades, the prevalence of obesity and type 2 diabetes mellitus has increased dramatically. This epidemic of lifestyle-related disorders is affecting all parts of the world, and 439 million people are estimated to suffer from diabetes mellitus in 2030 [ 1 ]. Obesity is a strong risk factor for type 2 diabetes with 90% of affected patients being overweight or obese. Obesity is also associated with increased risk of various metabolic disorders including insulin resistance, chronic low-grade inflammation, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease. Oxidative stress, inflammatory response, and altered gut microbiota can play a significant role in the development of obesity-related disorders [ 2 – 4 ]. Type 2 diabetes is a multifactorial disease; however, it appears clear that prevention is possible by avoiding overeating and a sedentary lifestyle to maintain a healthy body weight [ 5 ]. The difficulty for many individuals to comply with dietary and lifestyle changes makes it of great interest to identify new foods with well-established effects on preventing the development of obesity and thereby type 2 diabetes and its associated metabolic complications. Dietary patterns with high consumption of polyphenol rich foods (fruits, vegetables, and berries) have been associated with reduced risk of type 2 diabetes. In general, berries are rich in polyphenols which are suggested to play a role in health benefits of plant-based diets [ 4 , 6 – 8 ]. Plant phenolics are a large group of secondary metabolites which provide color and taste in fruits and berries and include flavonoids (anthocyanins, flavonols, and flavanols), tannins, stilbenoids, and phenolic acids [ 9 ]. The antioxidant effect of berry anthocyanins has been studied extensively, but still little is known about the biological activities linking berries and polyphenols to the prevention of type 2 diabetes [ 4 , 10 , 11 ]. The aim of the present study was to perform a screening to investigate and compare metabolic effects of different berries in the C57BL/6J mouse. The C57BL/6J is a mouse strain that develops obesity and prediabetes when fed a diet rich in fat, thus mimicking detrimental effects of an energy dense western diet [ 12 ]. By supplementing high-fat diets with potentially health-promoting berries, we sought to identify berries capable of ameliorating risk factors from excessive energy intake. Here we report that different berries, possibly due to their polyphenol composition, have varying ability to prevent weight gain and metabolic disorders ultimately leading to diabetes. 2. Methods 2.1. Animals and Study Design The study was approved by the Animal Ethics Committee in Lund, Sweden, (Permit Number: M185-11) and is in accordance with the Council of Europe Convention (ETS 123). Male C57BL/6JBomTac mice, 6 weeks old, g were obtained from Taconic (Skensved, Denmark). The animals were housed in a controlled environment (12 h light/dark cycle, light on 7 a.m.). After 9 days of acclimatization the mice were divided into 10 groups of 12 mice each housed in groups of 6 mice per cage. The mice were fed high-fat diets (45 kcal% fat) (Research diets, New Brunswick, NJ, USA) supplemented (20% w/w) with eight different freeze dried berries ad libitum for 13 weeks. A control group was fed a macronutrient-matched, isocaloric diet without supplements. One group received a low-fat diet (10 kcal% fat) as an internal control to the high-fat diet induced obesity. Body weight and food intake were monitored weekly throughout the study period. The energy intake was calculated based on registered food consumption. Mice were housed with minimal bedding material and feces was quantitatively collected for two consecutive days at the end of the study and stored at −20°C prior to lyophilization, weighing and powdering with a mortar. At the end of the study, 4 h-fasted animals were anesthetized with an intraperitoneal injection of midazolam (Midazolam Panpharma 5 mg/mL, Panpharma S.A., Luitré, France) and a mixture of fluanisone 10 mg/mL and fentanyl citrate 0.315 mg/mL (Hypnorm, VetaPharma, Leeds, UK). Body composition was determined with dual-energy X-ray absorptiometry (DEXA) technique using a Lunar PIXImus (GE Lunar, Madison, WI, USA). Blood samples were taken by intraorbital puncture. The animals were sacrificed by cervical dislocation and liver, cecum, spleen, and epididymal fat pads were excised, weighed, and snap frozen in liquid nitrogen. 2.2. Preparation and Analysis of Diets The experimental diets were high-fat diets supplemented with one of eight freeze dried berries; Lingonberry ( Vaccinium vitis-idaea ), blackcurrant ( Ribes nigrum ), raspberry ( Rubus idaeus ), bilberry ( Vaccinium myrtillus ), and blackberry ( Rubus fruticosus ) were obtained from MOLDA AG (Dahlenburg, Germany). Crowberries ( Empetrum nigrum ) were from Olle Svenssons Partiaffär AB (Olofström, Sweden) and prunes ( Prunus domestica ) from Semper AB (Sundbyberg, Sweden). Freeze dried açai berry powder ( Euterpe oleracea ) was purchased from Superfruit Scandinavia AB (Sweden). Information about origin and processing of the berries can<|im_end|> <|im_start|>assistant Lingonberries almost completely prevented weight gain in mice fed a high-fat diet, a study at Lund University in Sweden has found - whereas the 'super berry' açai led to increased weight gain. The Scandinavian berries also produced lower blood sugar levels and cholesterol. The Lund University research team used a type of mouse that easily stores fat and therefore can be regarded as a model for humans who are overweight and at risk of diabetes. Some of the mice were fed a low-fat diet, while the majority of the animals were fed a diet high in fat. They were then divided into groups, where all except a control group were fed a type of berry – lingonberry, bilberry, raspberry, crowberry, blackberry, prune, blackcurrant or açai berry. When the mice were compared after three months, it could be observed that the lingonberry group had by far the best results. The mice that had eaten lingonberries had not put on more weight than the mice that had eaten a low-fat diet - and their blood sugar and insulin readings were similar to those of the 'low-fat' mice. Their cholesterol levels and levels of fat in the liver were also lower than those of the animals who received a high-fat diet without any berries. According to the Lund University researchers, this is the first study of this kind using lingonberries. "That is probably because lingonberries are mainly eaten in Scandinavia. At international conferences, I always have to start by explaining what they are, and showing the audience a jar of them", says Lovisa Heyman, a PhD student in Experimental Medical Science. Blackcurrants and bilberries also produced good effects, although not as pronounced as the lingonberries. The açai berries, on the other hand, came last, although they had actually been included in the study for the opposite reason – the researchers wanted to see how well the Nordic berries would do in comparison with the Brazilian 'super berry'. "Instead, the opposite happened. In our study, the açai berries led to weight gain and higher levels of fat in the liver", said Karin Berger, diabetes researcher at Lund University. She believes that açai berries are primarily used as an energy supplement in their homeland Brazil. It is in the US and Europe that açai has been marketed as a 'super berry' with many health benefits, including weight loss. The good results from lingonberries may be due to their polyphenol content, according to the researchers. They will now continue to work on understanding the molecular mechanisms involved in the effect of the lingonberries. They will also see whether the effect can be observed in humans. "Up to 20 % of our mice's diet was lingonberries. It isn't realistic for humans to eat such a high proportion. However, the goal is not to produce such dramatic effects as in the 'high-fat' mice, but rather to prevent obesity and diabetes by supplementing a more normal diet with berries", said Karin Berger. However, the Lund researchers do not recommend people start eating large quantities of lingonberry jam. Boiling the berries can affect their nutrient content and jam contains a lot of sugar. Frozen lingonberries on cereal or in a smoothie are considerably better. "If anyone wonders – yes, we now eat lingonberries on a regular basis!" said Lovisa Heyman. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the β-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events. Introduction Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease (CVD). 1 As the pathophysiology of hypertension is both complex and unclear. 2 The most frequently targeted pathway in reducing blood pressure is the renin-angiotensin system (RAS). The contribution of the RAS to hypertension and atherosclerosis is not exclusive, as angiotensin II (AngII) can also accelerate atherogenesis independent of hypertension. 4 3 Another major determinant of hypertension is an overactive sympathetic nervous system (SNS). 6 5 There are indications that autonomic input into the bone marrow (BM) may be altered in the setting of hypertension. 10 7 However, the mechanisms promoting atherogenesis with SNS activation associated hypertension are not completely elucidated. While there is an overlap in some atherosclerosis promoting mechanisms between the RAS and SNS, a distinct subset of events is also likely to be evoked by the SNS, which requires further investigation. Atherosclerosis is a disease driven by the infiltration of immune cells, in particular monocytes, into the plaque. 13 11 It is also well established that the abundance of circulating monocytes predicts cardiovascular (CV) events and is directly linked to atherogenesis. 15 14 Interestingly, the SNS plays a direct role in regulating the hematopoietic system from which immune cells, including monocytes, arise. 19 16 In the context of CVD, the mobilization of hematopoietic stem and progenitor cells (HSPCs) from the BM to extramedullary tissues such as the spleen results in the generation of atherogenic monocytes that abundantly enter into the atherosclerotic plaque. 20 Mobilization of HSPCs can be mediated by sympathetic signaling within the BM, particularly in response to granulocyte-colony stimulating factor (G-CSF). The SNS synergizes with G-CSF to promote the breakdown of the HSPC BM microenvironment, which decreases the abundance of key HSPC retention factors and results in the liberation of HSPCs into the circulation. 16 This pathway has also been shown to be activated following a myocardial infarction (MI). 21 Sympathetic activation, along with raised G-CSF levels that are observed in apolipoprotein E knockout ( Apoe −/− ) mice, caused HSPC mobilization from the BM and homing to the spleen where monocytes were subsequently produced that infiltrated atherosclerotic lesions. Interestingly, this promoted an unstable plaque phenotype, prone to rupturing and thus provides a plausible explanation for primary heart attack survivors being highly prone to a secondary, often fatal, CV event. 22 21 Importantly, the involvement of the SNS in driving aberrant hematopoiesis is not restricted to complications following a MI, as similarities in other models of stress and ischemic stroke are evident, suggesting this to be a more general mechanism. The augmented hematopoietic response in these pathologies caused by overactivation of the SNS were inhibited by administration of β-blockers or genetic deletion of β-adrenergic receptors. 25 23 21 There appears to be an important role of the SNS in regulating hematopoiesis in acute stressors (i.e., MI, stroke, variable stress). However, it remains unknown if chronic sympathetic activation invokes this same atherogenic process. Thus, it is plausible that chronic sympathetic activation present in some cases of hypertension could play an important role in regulating atherogenesis by altering hematopoiesis. To address this question, we employed the Schlager hypertensive mice which were crossed onto an Apoe −/− background to produce hypertensive atherosclerosis-prone mice. The Schlager mouse was chosen as it represents a model of hypertension that is almost entirely driven by the SNS, with minimal contribution by the RAS. 26 We sought to characterize the contribution of SNS activation associated hypertension to the development of atherosclerosis, with the aim of understanding whether this form of hypertension was also associated with alterations to the hematopoietic system. Moreover, we aimed to investigate whether targeting the SNS could inhibit atherogenesis and, in turn, reveal an additional mechanism of hypertension associated atherosclerosis. Methods Detailed methods are available in Online supplementary Methods . Animal Models Apoe −/− mice were purchased from Jackson Laboratories and bred at the AMREP Animal centre. To generate hypertensive Apoe −/− mice, BPH/2J mice were crossed with Apoe−/− mice to produce BPH/2J x Apoe −/− (BPH/ Apoe −/− ) mice. At 6 weeks of age, male Apoe −/− and BPH/Apoe−/− mice were placed on a western type diet (WTD - SF00-219, Specialty Feeds, Australia; 21% fat, 0.15% cholesterol) for 16 weeks. In the first cohort of mice, age-matched mice Apoe −/− and BPH/ Apoe −/− were placed on a WTD for 16 weeks for end-point analysis. In a second cohort of mice, obtained from a new set of breeders, three groups of aged-matched mice were employed: 1) Apoe−/−, 2) BPH/ Apoe −/− and 3)", "role": "user" }, { "content": "About 6 million Australians aged 18 years and over have high blood pressure. Of these, more than two thirds had uncontrolled or unmanaged high blood pressure (not taking medication), representing 4 million adult Australians. High blood pressure, or hypertension, is suggested to be one of the leading risk factors for heart disease. The process in which high blood pressure causes heart disease is not completely understood. But now scientists at the Baker Heart and Diabetes Institute have found that high blood pressure caused by specific signalling from the brain promotes heart disease by altering stem cells with the bone marrow. The results, published in Haematologica demonstrate how an overactive sympathetic nervous system that causes elevated blood pressure can instruct bone marrow stem cells to produce more white blood cells that clog up blood vessels. The Baker Institute's Head of Haematopoiesis and Leukocyte Biology, Associate Professor Andrew Murphy says the findings represent a new era of heart disease research. \"Hypertension is a major, independent risk factor of atherosclerotic cardiovascular disease, but we need more information to determine how it is resulting in heart attacks and strokes,\" said Associate Professor Murphy. Atherosclerotic cardiovascular disease is a build-up of cholesterol plaque in the walls of arteries, causing obstruction of blood flow. \"We now know that significance changes in the immune system contributes significantly to heart disease,\" he said. \"We aimed to determine how the sympathetic nervous system through the brain directly promotes atherosclerosis in the setting of hypertension.\" \"We have discovered that this form of high blood pressure, often associated with stress, causes changes within the bone marrow leading to increased white blood cells circulating though our vessels. This is significant as the general view of hypertension is that it is mainly a disease of the blood vessels, which means other heart damaging events are missed.\" The team is now exploring the specific molecules involved, which may shed light as to why some current therapies are ineffective. They also suggest that managing stress, anxiety and pain are likely to help in controlling this form of hypertension and the effects it has on the body's bone marrow stem cells. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the β-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events. Introduction Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease (CVD). 1 As the pathophysiology of hypertension is both complex and unclear. 2 The most frequently targeted pathway in reducing blood pressure is the renin-angiotensin system (RAS). The contribution of the RAS to hypertension and atherosclerosis is not exclusive, as angiotensin II (AngII) can also accelerate atherogenesis independent of hypertension. 4 3 Another major determinant of hypertension is an overactive sympathetic nervous system (SNS). 6 5 There are indications that autonomic input into the bone marrow (BM) may be altered in the setting of hypertension. 10 7 However, the mechanisms promoting atherogenesis with SNS activation associated hypertension are not completely elucidated. While there is an overlap in some atherosclerosis promoting mechanisms between the RAS and SNS, a distinct subset of events is also likely to be evoked by the SNS, which requires further investigation. Atherosclerosis is a disease driven by the infiltration of immune cells, in particular monocytes, into the plaque. 13 11 It is also well established that the abundance of circulating monocytes predicts cardiovascular (CV) events and is directly linked to atherogenesis. 15 14 Interestingly, the SNS plays a direct role in regulating the hematopoietic system from which immune cells, including monocytes, arise. 19 16 In the context of CVD, the mobilization of hematopoietic stem and progenitor cells (HSPCs) from the BM to extramedullary tissues such as the spleen results in the generation of atherogenic monocytes that abundantly enter into the atherosclerotic plaque. 20 Mobilization of HSPCs can be mediated by sympathetic signaling within the BM, particularly in response to granulocyte-colony stimulating factor (G-CSF). The SNS synergizes with G-CSF to promote the breakdown of the HSPC BM microenvironment, which decreases the abundance of key HSPC retention factors and results in the liberation of HSPCs into the circulation. 16 This pathway has also been shown to be activated following a myocardial infarction (MI). 21 Sympathetic activation, along with raised G-CSF levels that are observed in apolipoprotein E knockout ( Apoe −/− ) mice, caused HSPC mobilization from the BM and homing to the spleen where monocytes were subsequently produced that infiltrated atherosclerotic lesions. Interestingly, this promoted an unstable plaque phenotype, prone to rupturing and thus provides a plausible explanation for primary heart attack survivors being highly prone to a secondary, often fatal, CV event. 22 21 Importantly, the involvement of the SNS in driving aberrant hematopoiesis is not restricted to complications following a MI, as similarities in other models of stress and ischemic stroke are evident, suggesting this to be a more general mechanism. The augmented hematopoietic response in these pathologies caused by overactivation of the SNS were inhibited by administration of β-blockers or genetic deletion of β-adrenergic receptors. 25 23 21 There appears to be an important role of the SNS in regulating hematopoiesis in acute stressors (i.e., MI, stroke, variable stress). However, it remains unknown if chronic sympathetic activation invokes this same atherogenic process. Thus, it is plausible that chronic sympathetic activation present in some cases of hypertension could play an important role in regulating atherogenesis by altering hematopoiesis. To address this question, we employed the Schlager hypertensive mice which were crossed onto an Apoe −/− background to produce hypertensive atherosclerosis-prone mice. The Schlager mouse was chosen as it represents a model of hypertension that is almost entirely driven by the SNS, with minimal contribution by the RAS. 26 We sought to characterize the contribution of SNS activation associated hypertension to the development of atherosclerosis, with the aim of understanding whether this form of hypertension was also associated with alterations to the hematopoietic system. Moreover, we aimed to investigate whether targeting the SNS could inhibit atherogenesis and, in turn, reveal an additional mechanism of hypertension associated atherosclerosis. Methods Detailed methods are available in Online supplementary Methods . Animal Models Apoe −/− mice were purchased from Jackson Laboratories and bred at the AMREP Animal centre. To generate hypertensive Apoe −/− mice, BPH/2J mice were crossed with Apoe−/− mice to produce BPH/2J x Apoe −/− (BPH/ Apoe −/− ) mice. At 6 weeks of age, male Apoe −/− and BPH/Apoe−/− mice were placed on a western type diet (WTD - SF00-219, Specialty Feeds, Australia; 21% fat, 0.15% cholesterol) for 16 weeks. In the first cohort of mice, age-matched mice Apoe −/− and BPH/ Apoe −/− were placed on a WTD for 16 weeks for end-point analysis. In a second cohort of mice, obtained from a new set of breeders, three groups of aged-matched mice were employed: 1) Apoe−/−, 2) BPH/ Apoe −/− and 3)<|im_end|> <|im_start|>assistant About 6 million Australians aged 18 years and over have high blood pressure. Of these, more than two thirds had uncontrolled or unmanaged high blood pressure (not taking medication), representing 4 million adult Australians. High blood pressure, or hypertension, is suggested to be one of the leading risk factors for heart disease. The process in which high blood pressure causes heart disease is not completely understood. But now scientists at the Baker Heart and Diabetes Institute have found that high blood pressure caused by specific signalling from the brain promotes heart disease by altering stem cells with the bone marrow. The results, published in Haematologica demonstrate how an overactive sympathetic nervous system that causes elevated blood pressure can instruct bone marrow stem cells to produce more white blood cells that clog up blood vessels. The Baker Institute's Head of Haematopoiesis and Leukocyte Biology, Associate Professor Andrew Murphy says the findings represent a new era of heart disease research. "Hypertension is a major, independent risk factor of atherosclerotic cardiovascular disease, but we need more information to determine how it is resulting in heart attacks and strokes," said Associate Professor Murphy. Atherosclerotic cardiovascular disease is a build-up of cholesterol plaque in the walls of arteries, causing obstruction of blood flow. "We now know that significance changes in the immune system contributes significantly to heart disease," he said. "We aimed to determine how the sympathetic nervous system through the brain directly promotes atherosclerosis in the setting of hypertension." "We have discovered that this form of high blood pressure, often associated with stress, causes changes within the bone marrow leading to increased white blood cells circulating though our vessels. This is significant as the general view of hypertension is that it is mainly a disease of the blood vessels, which means other heart damaging events are missed." The team is now exploring the specific molecules involved, which may shed light as to why some current therapies are ineffective. They also suggest that managing stress, anxiety and pain are likely to help in controlling this form of hypertension and the effects it has on the body's bone marrow stem cells. <|im_end|>

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706, 389, 279, 2547, 596, 17685, 83748, 19646, 7917, 13, 220, 128257, 198 ]

1,927

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Bacteria use adaptive immune systems encoded by CRISPR and Cas genes to maintain genomic integrity when challenged by pathogens and mobile genetic elements 1 , 2 , 3 . Type I CRISPR–Cas systems typically target foreign DNA for degradation via joint action of the ribonucleoprotein complex Cascade and the helicase–nuclease Cas3 4 , 5 , but nuclease-deficient type I systems lacking Cas3 have been repurposed for RNA-guided transposition by bacterial Tn 7 -like transposons 6 , 7 . How CRISPR- and transposon-associated machineries collaborate during DNA targeting and insertion remains unknown. Here we describe structures of a TniQ–Cascade complex encoded by the Vibrio cholerae Tn 6677 transposon using cryo-electron microscopy, revealing the mechanistic basis of this functional coupling. The cryo-electron microscopy maps enabled de novo modelling and refinement of the transposition protein TniQ, which binds to the Cascade complex as a dimer in a head-to-tail configuration, at the interface formed by Cas6 and Cas7 near the 3′ end of the CRISPR RNA (crRNA). The natural Cas8–Cas5 fusion protein binds the 5′ crRNA handle and contacts the TniQ dimer via a flexible insertion domain. A target DNA-bound structure reveals critical interactions necessary for protospacer-adjacent motif recognition and R-loop formation. This work lays the foundation for a structural understanding of how DNA targeting by TniQ–Cascade leads to downstream recruitment of additional transposase proteins, and will guide protein engineering efforts to leverage this system for programmable DNA insertions in genome-engineering applications. Main We previously demonstrated that a transposon derived from V. cholerae Tn 6677 undergoes programmable transposition in Escherichia coli directed by a crRNA, and that this activity requires four transposon- and three CRISPR-associated genes in addition to a CRISPR array 7 (Fig. 1a ). Whereas TnsA, TnsB and TnsC exhibit functions that are consistent with their homologues from the related and well-studied cut-and-paste DNA transposon E. coli Tn 7 8 , we showed that TniQ, a homologue of E. coli TnsD, forms a co-complex with the Cascade ribonucleoprotein complex encoded by the type I-F variant CRISPR–Cas system. This finding suggested an alternative role for TniQ, compared with the role of E. coli TnsD in identifying target sites during Tn 7 transposition. We proposed that RNA-guided DNA targeting by Cascade could deliver TniQ to DNA in a manner compatible with downstream transpososome formation, and that TniQ might interact with Cascade near the 3′ end of the crRNA, consistent with RNA-guided DNA insertion occurring around 49 bp downstream of the protospacer-adjacent motif (PAM)-distal edge of the target site. To determine this unambiguously, we purified the V. cholerae TniQ–Cascade complex loaded with a native crRNA and determined its structure by cryo-electron microscopy (cryo-EM) (Supplementary Table 1 ). Fig. 1: Overall architecture of the V. cholerae TniQ–Cascade complex. a , Genetic architecture of the Tn 6677 transposon (top), and plasmid constructs used to express and purify the TniQ–Cascade complex. Right, selected cryo-EM reference-free two-dimensional class averages in multiple orientations. b , Orthogonal views of the cryo-EM map of the TniQ–Cascade complex, showing Cas8 (purple), six Cas7 monomers (green), Cas6 (salmon), crRNA (grey) and TniQ monomers (blue, yellow). The complex adopts a helical architecture with protuberances at both ends. c , A flexible domain in Cas8 comprising residues 277–385 (grey) could only be visualized in low-pass-filtered maps. The unsharpened map is shown as semi-transparent, grey map overlaid on the post-processed map segmented and coloured as in a . d , Refined model for the TniQ–Cascade complex derived from the cryo-EM maps shown in b . Full size image Cryo-EM structure of TniQ–Cascade complex The overall complex adopts a helical architecture with protuberances at both ends (Fig. 1 , Extended Data Figs. 1 , 2 ). The global architecture is similar to previously determined structures of Cascade from I-E and I-F systems 9 , 10 , 11 , 12 (Extended Data Fig. 3 ), with the exception of a large mass of additional density attributable to TniQ (see below). Maximum likelihood classification methods implemented in Relion3 13 enabled us to identify marked dynamics in the entire complex, which appears to ‘breathe’, widening and narrowing the distance between the two protuberances (Extended Data Fig. 1d , Supplementary Video 1 ). The large subunit encoded by a natural Cas8–Cas5 fusion protein (hereafter referred to simply as Cas8) forms one protuberance and recognizes the 5′ end of the crRNA via base- and backbone-specific contacts (Extended Data Figs. 4 , 5a–c , 6a ), similar to the canonical roles of Cas8 and Cas5 (Extended Data Fig. 3 ). Cas8 contains two primary subdomains formed mainly by α-helices and a third domain of approximately 100 residues (residues 277 to 385) that is predicted to form three α-helices but could not be built in our maps owing to its intrinsic flexibility (Fig. 1c ). However, low-pass-filtered maps revealed that this flexible domain connects with the TniQ protuberance at the opposite end of the crescent-shaped complex (Extended Data Fig. 2e ). Additionally, there seemed to be a loose coupling between the Cas8 flexible domain and overall breathing of the complex, as stronger density for that domain could be observed in the closed state (Extended Data Fig. 1d , Supplementary Video 1 ). Six Cas7 subunits protect much of the crRNA by forming a helical filament along its length (Fig. 1b, d ), similar to other type I Cascade complexes 9 , 10 , 11 , 12 (Extended Data Fig. 3 ). A ‘finger’ motif in Cas7 clamps the crRNA at regular intervals, causing every sixth nucleotide (nt) of the 32-nt spacer to flip out while leaving the flanking nucleotides available for DNA recognition (Extended Data Figs. 4f , 6 ). These bases are pre-ordered in short helical segments, with a conserved phenylalanine stacking below the first base of every segment. Cas7.1, the monomer furthest away from Cas8, interacts with Cas6 (also known as Csy4), which is the RNase responsible for processing of the precursor RNA transcript derived from the CRISPR locus. The Cas6–Cas7.1 interaction is mediated by a β-sheet formed by the contribution of", "role": "user" }, { "content": "Columbia scientists have captured the first images of a new gene editing tool that could improve upon existing CRISPR-based tools. The team developed the tool, called INTEGRATE, after discovering a unique \"jumping gene\" in Vibrio cholerae bacteria that could insert large genetic payloads in the genome without introducing DNA breaks. In the new study, published today in Nature, the researchers harnessed a Nobel Prize-winning technique called cryo-electron microscopy to freeze the gene editing complex in action, revealing high-resolution details about how it works. \"We showed in our first study how to leverage INTEGRATE for targeted DNA insertions in bacterial cells,\" says Sam Sternberg, Ph.D., assistant professor of biochemistry & molecular biophysics at Columbia University Vagelos College of Physicians and Surgeons, who led the research with Israel Fernandez, Ph.D., assistant professor of biochemistry & molecular biophysics at Columbia. \"These new images, a wonderful collaboration with Israel Fernández's lab, explain the biology with incredible molecular detail and will help us improve the system by guiding protein engineering efforts.\" Starts like CRISPR, but has a different ending The researchers used a technique called cryo-electron microscopy, which involves flash freezing a sample of the gene editing complex in liquid nitrogen and bombarding it with electrons. They then used the images they captured with the electron microscope to generate atomic resolution models of the INTEGRATE system. The structural model reveals that the complex is made up of two main sections that are arranged in a helical filament. The larger portion, called Cascade, winds around and carries a guide RNA that it uses to scan the cell for a matching sequence in DNA. Once it locates and binds the target sequence, it threads the DNA strand through the TniQ \"transposition\" proteins that sit on the end of the complex and recruit other enzymes that help modify the DNA. The scanning mechanism of INTEGRATE appears to work in a similar way to other well-studied CRISPR systems, some of which also contain a Cascade complex with guide RNA. However, unlike other CRISPR systems that use Cascade to target DNA for cutting, the function of Cascade within INTEGRATE is to target DNA for highly accurate insertion of genetic payloads. Cryo-electron microscopy images of the INTEGRATE complex bound to DNA (arrows). Credit: Sternberg and Fernández Labs at Columbia University Irving Medical Center \"Visualizing biology on this scale is truly amazing and can easily excite even those unfamiliar with the topic. The quality of this work, and the speed at which it was accomplished, is emblematic of the collaborative environment afforded by great mentors like Sam and Israel,\" says Tyler Halpin-Healy, a Ph.D. student in the cellular, molecular and biophysical studies graduate program at Columbia University Irving Medical Center and first author of the study. In their previous study, Sternberg and colleagues used genetics and biochemistry to propose how the CRISPR machinery would functionally link to the transposition machinery—the molecules responsible for gene \"jumping\"—and the study proved their hypotheses were correct. Why it matters Many researchers around the world now use CRISPR-Cas9 to quickly and cheaply make precise modifications to the genome of a cell. However, most uses of CRISPR involve cutting both strands of the target DNA, and the DNA break must then be repaired by the host cell's own machinery. Controlling this repair process is still a major challenge in the field, and undesired gene edits are often introduced inadvertently in the genome. Additionally, existing tools often perform poorly at inserting large genetic payloads in a precise fashion. Improving the accuracy of gene editing is a priority for researchers and is critical for ensuring the safety of therapies developed with this technique. The new INTEGRATE system developed by the Sternberg lab can accurately insert large DNA sequences without relying on the cell's machinery to repair the strands. As a result, INTEGRATE could prove to be a more accurate and efficient way of making certain gene modifications than the original CRISPR-Cas system that is widely in use. The new tool could also help scientists perform gene editing in cell types with limited DNA repair activity such as neurons, where attempts to use CRISPR have been comparatively less successful. What's next In addition to informing future engineering efforts, the structures highlight a possible proofreading checkpoint. Existing CRISPR technologies often suffer from so-called \"off-target effects,\" in which unintended sequences are promiscuously modified. The new structures reveal how Cascade and TniQ work together to ensure that only the correct \"on-target\" sequences are marked for DNA insertion. The researchers plan to further explore this checkpoint while developing the tool for new therapeutic approaches to disease. The paper, titled \"Structural basis of DNA targeting by a transposon-encoded CRISPR-Cas system,\" was published online Dec. 18 in the journal Nature. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Bacteria use adaptive immune systems encoded by CRISPR and Cas genes to maintain genomic integrity when challenged by pathogens and mobile genetic elements 1 , 2 , 3 . Type I CRISPR–Cas systems typically target foreign DNA for degradation via joint action of the ribonucleoprotein complex Cascade and the helicase–nuclease Cas3 4 , 5 , but nuclease-deficient type I systems lacking Cas3 have been repurposed for RNA-guided transposition by bacterial Tn 7 -like transposons 6 , 7 . How CRISPR- and transposon-associated machineries collaborate during DNA targeting and insertion remains unknown. Here we describe structures of a TniQ–Cascade complex encoded by the Vibrio cholerae Tn 6677 transposon using cryo-electron microscopy, revealing the mechanistic basis of this functional coupling. The cryo-electron microscopy maps enabled de novo modelling and refinement of the transposition protein TniQ, which binds to the Cascade complex as a dimer in a head-to-tail configuration, at the interface formed by Cas6 and Cas7 near the 3′ end of the CRISPR RNA (crRNA). The natural Cas8–Cas5 fusion protein binds the 5′ crRNA handle and contacts the TniQ dimer via a flexible insertion domain. A target DNA-bound structure reveals critical interactions necessary for protospacer-adjacent motif recognition and R-loop formation. This work lays the foundation for a structural understanding of how DNA targeting by TniQ–Cascade leads to downstream recruitment of additional transposase proteins, and will guide protein engineering efforts to leverage this system for programmable DNA insertions in genome-engineering applications. Main We previously demonstrated that a transposon derived from V. cholerae Tn 6677 undergoes programmable transposition in Escherichia coli directed by a crRNA, and that this activity requires four transposon- and three CRISPR-associated genes in addition to a CRISPR array 7 (Fig. 1a ). Whereas TnsA, TnsB and TnsC exhibit functions that are consistent with their homologues from the related and well-studied cut-and-paste DNA transposon E. coli Tn 7 8 , we showed that TniQ, a homologue of E. coli TnsD, forms a co-complex with the Cascade ribonucleoprotein complex encoded by the type I-F variant CRISPR–Cas system. This finding suggested an alternative role for TniQ, compared with the role of E. coli TnsD in identifying target sites during Tn 7 transposition. We proposed that RNA-guided DNA targeting by Cascade could deliver TniQ to DNA in a manner compatible with downstream transpososome formation, and that TniQ might interact with Cascade near the 3′ end of the crRNA, consistent with RNA-guided DNA insertion occurring around 49 bp downstream of the protospacer-adjacent motif (PAM)-distal edge of the target site. To determine this unambiguously, we purified the V. cholerae TniQ–Cascade complex loaded with a native crRNA and determined its structure by cryo-electron microscopy (cryo-EM) (Supplementary Table 1 ). Fig. 1: Overall architecture of the V. cholerae TniQ–Cascade complex. a , Genetic architecture of the Tn 6677 transposon (top), and plasmid constructs used to express and purify the TniQ–Cascade complex. Right, selected cryo-EM reference-free two-dimensional class averages in multiple orientations. b , Orthogonal views of the cryo-EM map of the TniQ–Cascade complex, showing Cas8 (purple), six Cas7 monomers (green), Cas6 (salmon), crRNA (grey) and TniQ monomers (blue, yellow). The complex adopts a helical architecture with protuberances at both ends. c , A flexible domain in Cas8 comprising residues 277–385 (grey) could only be visualized in low-pass-filtered maps. The unsharpened map is shown as semi-transparent, grey map overlaid on the post-processed map segmented and coloured as in a . d , Refined model for the TniQ–Cascade complex derived from the cryo-EM maps shown in b . Full size image Cryo-EM structure of TniQ–Cascade complex The overall complex adopts a helical architecture with protuberances at both ends (Fig. 1 , Extended Data Figs. 1 , 2 ). The global architecture is similar to previously determined structures of Cascade from I-E and I-F systems 9 , 10 , 11 , 12 (Extended Data Fig. 3 ), with the exception of a large mass of additional density attributable to TniQ (see below). Maximum likelihood classification methods implemented in Relion3 13 enabled us to identify marked dynamics in the entire complex, which appears to ‘breathe’, widening and narrowing the distance between the two protuberances (Extended Data Fig. 1d , Supplementary Video 1 ). The large subunit encoded by a natural Cas8–Cas5 fusion protein (hereafter referred to simply as Cas8) forms one protuberance and recognizes the 5′ end of the crRNA via base- and backbone-specific contacts (Extended Data Figs. 4 , 5a–c , 6a ), similar to the canonical roles of Cas8 and Cas5 (Extended Data Fig. 3 ). Cas8 contains two primary subdomains formed mainly by α-helices and a third domain of approximately 100 residues (residues 277 to 385) that is predicted to form three α-helices but could not be built in our maps owing to its intrinsic flexibility (Fig. 1c ). However, low-pass-filtered maps revealed that this flexible domain connects with the TniQ protuberance at the opposite end of the crescent-shaped complex (Extended Data Fig. 2e ). Additionally, there seemed to be a loose coupling between the Cas8 flexible domain and overall breathing of the complex, as stronger density for that domain could be observed in the closed state (Extended Data Fig. 1d , Supplementary Video 1 ). Six Cas7 subunits protect much of the crRNA by forming a helical filament along its length (Fig. 1b, d ), similar to other type I Cascade complexes 9 , 10 , 11 , 12 (Extended Data Fig. 3 ). A ‘finger’ motif in Cas7 clamps the crRNA at regular intervals, causing every sixth nucleotide (nt) of the 32-nt spacer to flip out while leaving the flanking nucleotides available for DNA recognition (Extended Data Figs. 4f , 6 ). These bases are pre-ordered in short helical segments, with a conserved phenylalanine stacking below the first base of every segment. Cas7.1, the monomer furthest away from Cas8, interacts with Cas6 (also known as Csy4), which is the RNase responsible for processing of the precursor RNA transcript derived from the CRISPR locus. The Cas6–Cas7.1 interaction is mediated by a β-sheet formed by the contribution of<|im_end|> <|im_start|>assistant Columbia scientists have captured the first images of a new gene editing tool that could improve upon existing CRISPR-based tools. The team developed the tool, called INTEGRATE, after discovering a unique "jumping gene" in Vibrio cholerae bacteria that could insert large genetic payloads in the genome without introducing DNA breaks. In the new study, published today in Nature, the researchers harnessed a Nobel Prize-winning technique called cryo-electron microscopy to freeze the gene editing complex in action, revealing high-resolution details about how it works. "We showed in our first study how to leverage INTEGRATE for targeted DNA insertions in bacterial cells," says Sam Sternberg, Ph.D., assistant professor of biochemistry & molecular biophysics at Columbia University Vagelos College of Physicians and Surgeons, who led the research with Israel Fernandez, Ph.D., assistant professor of biochemistry & molecular biophysics at Columbia. "These new images, a wonderful collaboration with Israel Fernández's lab, explain the biology with incredible molecular detail and will help us improve the system by guiding protein engineering efforts." Starts like CRISPR, but has a different ending The researchers used a technique called cryo-electron microscopy, which involves flash freezing a sample of the gene editing complex in liquid nitrogen and bombarding it with electrons. They then used the images they captured with the electron microscope to generate atomic resolution models of the INTEGRATE system. The structural model reveals that the complex is made up of two main sections that are arranged in a helical filament. The larger portion, called Cascade, winds around and carries a guide RNA that it uses to scan the cell for a matching sequence in DNA. Once it locates and binds the target sequence, it threads the DNA strand through the TniQ "transposition" proteins that sit on the end of the complex and recruit other enzymes that help modify the DNA. The scanning mechanism of INTEGRATE appears to work in a similar way to other well-studied CRISPR systems, some of which also contain a Cascade complex with guide RNA. However, unlike other CRISPR systems that use Cascade to target DNA for cutting, the function of Cascade within INTEGRATE is to target DNA for highly accurate insertion of genetic payloads. Cryo-electron microscopy images of the INTEGRATE complex bound to DNA (arrows). Credit: Sternberg and Fernández Labs at Columbia University Irving Medical Center "Visualizing biology on this scale is truly amazing and can easily excite even those unfamiliar with the topic. The quality of this work, and the speed at which it was accomplished, is emblematic of the collaborative environment afforded by great mentors like Sam and Israel," says Tyler Halpin-Healy, a Ph.D. student in the cellular, molecular and biophysical studies graduate program at Columbia University Irving Medical Center and first author of the study. In their previous study, Sternberg and colleagues used genetics and biochemistry to propose how the CRISPR machinery would functionally link to the transposition machinery—the molecules responsible for gene "jumping"—and the study proved their hypotheses were correct. Why it matters Many researchers around the world now use CRISPR-Cas9 to quickly and cheaply make precise modifications to the genome of a cell. However, most uses of CRISPR involve cutting both strands of the target DNA, and the DNA break must then be repaired by the host cell's own machinery. Controlling this repair process is still a major challenge in the field, and undesired gene edits are often introduced inadvertently in the genome. Additionally, existing tools often perform poorly at inserting large genetic payloads in a precise fashion. Improving the accuracy of gene editing is a priority for researchers and is critical for ensuring the safety of therapies developed with this technique. The new INTEGRATE system developed by the Sternberg lab can accurately insert large DNA sequences without relying on the cell's machinery to repair the strands. As a result, INTEGRATE could prove to be a more accurate and efficient way of making certain gene modifications than the original CRISPR-Cas system that is widely in use. The new tool could also help scientists perform gene editing in cell types with limited DNA repair activity such as neurons, where attempts to use CRISPR have been comparatively less successful. What's next In addition to informing future engineering efforts, the structures highlight a possible proofreading checkpoint. Existing CRISPR technologies often suffer from so-called "off-target effects," in which unintended sequences are promiscuously modified. The new structures reveal how Cascade and TniQ work together to ensure that only the correct "on-target" sequences are marked for DNA insertion. The researchers plan to further explore this checkpoint while developing the tool for new therapeutic approaches to disease. The paper, titled "Structural basis of DNA targeting by a transposon-encoded CRISPR-Cas system," was published online Dec. 18 in the journal Nature. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background As habitat degradation and fragmentation continue to impact wildlife populations around the world, it is critical to understand the behavioral flexibility of species in these environments. In Uganda, the mostly unprotected forest fragment landscape between the Budongo and Bugoma Forests is a potential corridor for chimpanzees, yet little is known about the status of chimpanzee populations in these fragments. Results From 2011 through 2013, we noninvasively collected 865 chimpanzee fecal samples across 633 km 2 and successfully genotyped 662 (77%) at up to 14 microsatellite loci. These genotypes corresponded to 182 chimpanzees, with a mean of 3.5 captures per individual. We obtained population size estimates of 256 (95% confidence interval 246–321) and 319 (288–357) chimpanzees using capture-with-replacement and spatially explicit capture–recapture models, respectively. The spatial clustering of associated genotypes suggests the presence of at least nine communities containing a minimum of 8–33 individuals each. Putative community distributions defined by the locations of associated genotypes correspond well with the distribution of 14 Y-chromosome haplotypes. Conclusions These census figures are more than three times greater than a previous estimate based on an extrapolation from small-scale nest count surveys that tend to underestimate population size. The distribution of genotype clusters and Y-chromosome haplotypes together indicate the presence of numerous male philopatric chimpanzee communities throughout the corridor habitat. Our findings demonstrate that, despite extensive habitat loss and fragmentation, chimpanzees remain widely distributed and exhibit distinct community home ranges. Our results further imply that elusive and rare species may adapt to degraded habitats more successfully than previously believed. Their long-term persistence is unlikely, however, if protection is not afforded to them and habitat loss continues unabated. Background Habitat loss and fragmentation are key threats to the survival of many species [ 1 ], with global deforestation resulting in the majority of remaining forest lying within 1 km of a forest edge [ 2 ]. Fragmentation can isolate populations, thereby reducing genetic diversity and population viability, which may result in local extinctions [ 3 – 5 ]. As wildlife populations face increasing anthropogenic threats, there is growing urgency to better understand how species respond to environmental disturbances. Although degraded habitats are often thought to have limited conservation value, many threatened species inhabit such environments [ 6 ]. Riparian forest fragments in particular can offer suitable habitat, providing dense resources to support wildlife [ 7 , 8 ]. In addition, fragmented forests can sustain connectivity by linking larger populations, thereby enhancing gene flow and population viability [ 9 – 11 ]. Therefore, the potential of fragmented habitats to support viable populations must be carefully considered alongside the peril they pose to wildlife. Large-bodied, wide-ranging mammals such as great apes are among the taxa most affected by growing habitat fragmentation. These species often live in unprotected areas, which are particularly vulnerable to forest loss and fragmentation [ 12 , 13 ]. In East Africa, deforestation has led to increasing habitat fragmentation and poses a primary threat to the survival of eastern chimpanzees, Pan troglodytes schweinfurthii [ 14 ]. Eastern chimpanzees inhabit lowland and montane forest, woodland, savanna, and swamp forest habitats throughout various parts of East and Central Africa, with much of their current range occurring outside protected areas [ 14 ]. Three-quarters of chimpanzees in Tanzania are estimated to live outside national parks [ 15 ]. In Uganda, logging has led to a 37% reduction in forest cover between 1990 and 2010 [ 1 , 16 ], and much of this deforestation occurred outside protected areas, leaving chimpanzees in such habitats vulnerable to local extinction [ 2 , 17 ]. Similar patterns have also been reported for chimpanzees in West Africa [ 12 , 18 ]. Because chimpanzees are an endangered species [ 19 ], it is essential to better understand their ability to persist in fragmented and degraded habitats. Moreover, precise estimates of the sizes and distributions of remaining populations are needed in order to establish research priorities and conservation management strategies. Such estimates can be challenging to obtain, however. Chimpanzee habituation allows for direct monitoring and hence precise censuses, but is a lengthy process which is necessarily restricted to small numbers of individuals, and may not be ethically appropriate or logistically feasible for many populations [ 20 , 21 ]. Nest count surveys can be used to estimate the distribution and abundance of unhabituated chimpanzee populations. However, these survey methods may be inaccurate and lack the precision necessary to determine trends in population size [ 22 – 24 ]. Such studies are also arduous to carry out, as commonly used nest count methods rely on data regarding nest decay rates and nest building and re-use rates, which can be highly variable and are often unknown locally [ 22 , 23 , 25 , 26 ]. Recently, camera trapping and passive acoustic monitoring have also been utilized to census apes [ 27 – 29 ]. However, these techniques are still in their infancy, while methods for efficiently automating individual identification are still in development [ 15 , 30 ]. The challenges of accurately and precisely enumerating chimpanzee populations are similar to those posed by surveys of other rare and elusive mammal populations, including bears [ 31 ], gorillas [ 32 – 34 ], African elephants [ 35 ], Eurasian otters [ 36 ], and giant pandas [ 37 ]. These challenges have led to the widespread implementation of genetic censusing (e.g., in chimpanzees [ 38 – 40 ]), which relies on the characterization of individual DNA profiles derived from noninvasively collected samples [ 41 ]. The minimum number of individuals using the surveyed area is determined by the number of unique profiles, and resampling frequency can be used to estimate the number of animals that went undetected [ 42 , 43 ]. Standard approaches for genetic censusing have relied upon accumulation curves and Bayesian estimators, along with more recent “capture with replacement” ( capwire ) models [ 43 – 45 ]. However, the population size estimates these methods provide cannot be converted to density", "role": "user" }, { "content": "A chimpanzee population in Uganda has been found to be three times larger than previously estimated, according to research published in the open access journal BMC Ecology. The study suggests that chimpanzees may adapt to degraded habitats better than expected, but also highlights the importance of new and more focused conservation strategies. The protected Budongo and Bugoma Forest Reserves together compose approximately one quarter of the estimated total chimpanzee population in Uganda. The unprotected area between these two reserves is a human-dominated landscape comprising forest with villages, agricultural lands and natural grasslands. At least 450 km2 of forest is estimated to have been lost between the Budongo and Bugoma Forests from 2000 to 2010. As a potential corridor for chimpanzees migrating between two protected areas, these fragmented landscapes could be vital for conservation, but few studies have examined the chimpanzee population of this corridor area. Counting chimpanzee populations also presents a number of challenges. Direct monitoring is a lengthy process, counting nests can be inaccurate, while the use of camera traps and acoustic monitoring is still in its infancy. The researchers spent 15 months carrying out 'genetic censusing' to provide an accurate method for counting chimpanzees in the corridor region. This involved collecting 865 chimpanzee fecal samples across 633 km2 and genetically analysing them to identify the presence of 182 different chimpanzees. They then estimated the total population size of the area to be either 256 or 319 chimpanzees, depending on the calculation used. This suggests the presence of at least nine communities containing a minimum of eight to 33 individuals each. These figures are more than three times greater than a previous estimate of around 70 chimpanzees based on small-scale nest count surveys. A male chimpanzee looks toward a farm from the forest edge. The tree he sits in was logged some days later. Credit: Jack Lester Lead author Maureen McCarthy from University of Southern California, USA, said: \"Our results demonstrate a much larger population than previously estimated in this region. This is very surprising given the fragmentation of forests in this region and the high human population density. Chimpanzees, therefore, appear surprisingly resilient and can survive even in degraded habitats if they are not hunted. However, their future survival remains uncertain if protection is not afforded to them and habitat loss continues unabated.\" The authors say that it is highly improbable that these higher estimates are evidence of population growth since the time of the previous census. This is due to the long interval between chimpanzee births and the high rate of habitat loss throughout the region over the intervening years. The substantially higher estimates instead likely reflect the improved accuracy of the genetic censusing approach over previous estimates. The surprising levels of chimpanzee survival in a fragmented human-dominated habitat are also likely aided by their behavioral flexibility. This includes incorporating new (often human-cultivated) foods into their diets and adopting more aggressive behaviors to mitigate human threats. A chimpanzee walks along a logged eucalyptus tree in a clearing in Hoima District Uganda. Credit: Jack Lester Maureen McCarthy adds: \"Our study demonstrates that even unprotected and degraded habitats can have high conservation value. Though national parks and other protected areas are typically prioritized in conservation planning, unprotected areas should also be considered vital for conservation if they are highly valuable as wildlife corridors that harbor endangered species and maintain gene flow among larger populations of such species.\" The authors predict that a corridor enhancement project in this region would positively impact 30% of Uganda's total chimpanzee population (including the chimpanzee populations of both Budongo and Bugoma Forests and the region between them). ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background As habitat degradation and fragmentation continue to impact wildlife populations around the world, it is critical to understand the behavioral flexibility of species in these environments. In Uganda, the mostly unprotected forest fragment landscape between the Budongo and Bugoma Forests is a potential corridor for chimpanzees, yet little is known about the status of chimpanzee populations in these fragments. Results From 2011 through 2013, we noninvasively collected 865 chimpanzee fecal samples across 633 km 2 and successfully genotyped 662 (77%) at up to 14 microsatellite loci. These genotypes corresponded to 182 chimpanzees, with a mean of 3.5 captures per individual. We obtained population size estimates of 256 (95% confidence interval 246–321) and 319 (288–357) chimpanzees using capture-with-replacement and spatially explicit capture–recapture models, respectively. The spatial clustering of associated genotypes suggests the presence of at least nine communities containing a minimum of 8–33 individuals each. Putative community distributions defined by the locations of associated genotypes correspond well with the distribution of 14 Y-chromosome haplotypes. Conclusions These census figures are more than three times greater than a previous estimate based on an extrapolation from small-scale nest count surveys that tend to underestimate population size. The distribution of genotype clusters and Y-chromosome haplotypes together indicate the presence of numerous male philopatric chimpanzee communities throughout the corridor habitat. Our findings demonstrate that, despite extensive habitat loss and fragmentation, chimpanzees remain widely distributed and exhibit distinct community home ranges. Our results further imply that elusive and rare species may adapt to degraded habitats more successfully than previously believed. Their long-term persistence is unlikely, however, if protection is not afforded to them and habitat loss continues unabated. Background Habitat loss and fragmentation are key threats to the survival of many species [ 1 ], with global deforestation resulting in the majority of remaining forest lying within 1 km of a forest edge [ 2 ]. Fragmentation can isolate populations, thereby reducing genetic diversity and population viability, which may result in local extinctions [ 3 – 5 ]. As wildlife populations face increasing anthropogenic threats, there is growing urgency to better understand how species respond to environmental disturbances. Although degraded habitats are often thought to have limited conservation value, many threatened species inhabit such environments [ 6 ]. Riparian forest fragments in particular can offer suitable habitat, providing dense resources to support wildlife [ 7 , 8 ]. In addition, fragmented forests can sustain connectivity by linking larger populations, thereby enhancing gene flow and population viability [ 9 – 11 ]. Therefore, the potential of fragmented habitats to support viable populations must be carefully considered alongside the peril they pose to wildlife. Large-bodied, wide-ranging mammals such as great apes are among the taxa most affected by growing habitat fragmentation. These species often live in unprotected areas, which are particularly vulnerable to forest loss and fragmentation [ 12 , 13 ]. In East Africa, deforestation has led to increasing habitat fragmentation and poses a primary threat to the survival of eastern chimpanzees, Pan troglodytes schweinfurthii [ 14 ]. Eastern chimpanzees inhabit lowland and montane forest, woodland, savanna, and swamp forest habitats throughout various parts of East and Central Africa, with much of their current range occurring outside protected areas [ 14 ]. Three-quarters of chimpanzees in Tanzania are estimated to live outside national parks [ 15 ]. In Uganda, logging has led to a 37% reduction in forest cover between 1990 and 2010 [ 1 , 16 ], and much of this deforestation occurred outside protected areas, leaving chimpanzees in such habitats vulnerable to local extinction [ 2 , 17 ]. Similar patterns have also been reported for chimpanzees in West Africa [ 12 , 18 ]. Because chimpanzees are an endangered species [ 19 ], it is essential to better understand their ability to persist in fragmented and degraded habitats. Moreover, precise estimates of the sizes and distributions of remaining populations are needed in order to establish research priorities and conservation management strategies. Such estimates can be challenging to obtain, however. Chimpanzee habituation allows for direct monitoring and hence precise censuses, but is a lengthy process which is necessarily restricted to small numbers of individuals, and may not be ethically appropriate or logistically feasible for many populations [ 20 , 21 ]. Nest count surveys can be used to estimate the distribution and abundance of unhabituated chimpanzee populations. However, these survey methods may be inaccurate and lack the precision necessary to determine trends in population size [ 22 – 24 ]. Such studies are also arduous to carry out, as commonly used nest count methods rely on data regarding nest decay rates and nest building and re-use rates, which can be highly variable and are often unknown locally [ 22 , 23 , 25 , 26 ]. Recently, camera trapping and passive acoustic monitoring have also been utilized to census apes [ 27 – 29 ]. However, these techniques are still in their infancy, while methods for efficiently automating individual identification are still in development [ 15 , 30 ]. The challenges of accurately and precisely enumerating chimpanzee populations are similar to those posed by surveys of other rare and elusive mammal populations, including bears [ 31 ], gorillas [ 32 – 34 ], African elephants [ 35 ], Eurasian otters [ 36 ], and giant pandas [ 37 ]. These challenges have led to the widespread implementation of genetic censusing (e.g., in chimpanzees [ 38 – 40 ]), which relies on the characterization of individual DNA profiles derived from noninvasively collected samples [ 41 ]. The minimum number of individuals using the surveyed area is determined by the number of unique profiles, and resampling frequency can be used to estimate the number of animals that went undetected [ 42 , 43 ]. Standard approaches for genetic censusing have relied upon accumulation curves and Bayesian estimators, along with more recent “capture with replacement” ( capwire ) models [ 43 – 45 ]. However, the population size estimates these methods provide cannot be converted to density<|im_end|> <|im_start|>assistant A chimpanzee population in Uganda has been found to be three times larger than previously estimated, according to research published in the open access journal BMC Ecology. The study suggests that chimpanzees may adapt to degraded habitats better than expected, but also highlights the importance of new and more focused conservation strategies. The protected Budongo and Bugoma Forest Reserves together compose approximately one quarter of the estimated total chimpanzee population in Uganda. The unprotected area between these two reserves is a human-dominated landscape comprising forest with villages, agricultural lands and natural grasslands. At least 450 km2 of forest is estimated to have been lost between the Budongo and Bugoma Forests from 2000 to 2010. As a potential corridor for chimpanzees migrating between two protected areas, these fragmented landscapes could be vital for conservation, but few studies have examined the chimpanzee population of this corridor area. Counting chimpanzee populations also presents a number of challenges. Direct monitoring is a lengthy process, counting nests can be inaccurate, while the use of camera traps and acoustic monitoring is still in its infancy. The researchers spent 15 months carrying out 'genetic censusing' to provide an accurate method for counting chimpanzees in the corridor region. This involved collecting 865 chimpanzee fecal samples across 633 km2 and genetically analysing them to identify the presence of 182 different chimpanzees. They then estimated the total population size of the area to be either 256 or 319 chimpanzees, depending on the calculation used. This suggests the presence of at least nine communities containing a minimum of eight to 33 individuals each. These figures are more than three times greater than a previous estimate of around 70 chimpanzees based on small-scale nest count surveys. A male chimpanzee looks toward a farm from the forest edge. The tree he sits in was logged some days later. Credit: Jack Lester Lead author Maureen McCarthy from University of Southern California, USA, said: "Our results demonstrate a much larger population than previously estimated in this region. This is very surprising given the fragmentation of forests in this region and the high human population density. Chimpanzees, therefore, appear surprisingly resilient and can survive even in degraded habitats if they are not hunted. However, their future survival remains uncertain if protection is not afforded to them and habitat loss continues unabated." The authors say that it is highly improbable that these higher estimates are evidence of population growth since the time of the previous census. This is due to the long interval between chimpanzee births and the high rate of habitat loss throughout the region over the intervening years. The substantially higher estimates instead likely reflect the improved accuracy of the genetic censusing approach over previous estimates. The surprising levels of chimpanzee survival in a fragmented human-dominated habitat are also likely aided by their behavioral flexibility. This includes incorporating new (often human-cultivated) foods into their diets and adopting more aggressive behaviors to mitigate human threats. A chimpanzee walks along a logged eucalyptus tree in a clearing in Hoima District Uganda. Credit: Jack Lester Maureen McCarthy adds: "Our study demonstrates that even unprotected and degraded habitats can have high conservation value. Though national parks and other protected areas are typically prioritized in conservation planning, unprotected areas should also be considered vital for conservation if they are highly valuable as wildlife corridors that harbor endangered species and maintain gene flow among larger populations of such species." The authors predict that a corridor enhancement project in this region would positively impact 30% of Uganda's total chimpanzee population (including the chimpanzee populations of both Budongo and Bugoma Forests and the region between them). <|im_end|>

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2,045

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We present results from large ensembles of projected twenty-first century changes in seasonal precipitation and near-surface air temperature for the nation of South Africa. These ensembles are a result of combining Monte Carlo projections from a human-Earth system model of intermediate complexity with pattern-scaled responses from climate models of the Coupled Model Intercomparison Project Phase 5 (CMIP5). These future ensemble scenarios consider a range of global actions to abate emissions through the twenty-first century. We evaluate distributions of surface-air temperature and precipitation change over three sub-national regions: western, central, and eastern South Africa. In all regions, we find that without any emissions or climate targets in place, there is a greater than 50% likelihood that mid-century temperatures will increase threefold over the current climate’s two-standard deviation range of variability. However, scenarios that consider more aggressive climate targets all but eliminate the risk of these salient temperature increases. A preponderance of risk toward decreased precipitation (3 to 4 times higher than increased) exists for western and central South Africa. Strong climate targets abate evolving regional hydroclimatic risks. Under a target to limit global climate warming to 1.5 °C by 2100, the risk of precipitation changes within South Africa toward the end of this century (2065–2074) is commensurate to the risk during the 2030s without any global climate target. Thus, these regional hydroclimate risks over South Africa could be delayed by 30 years and, in doing so, provide invaluable lead-time for national efforts to prepare, fortify, and/or adapt. Working on a manuscript? Avoid the common mistakes 1 Introduction Evidence is mounting that Africa’s climate is changing and that these trends will continue through the twenty-first century (e.g., Niang et al. 2014 ). Current efforts to provide more spatially refined climate change information over Africa are ongoing (e.g., Lennard et al. 2018 ). Yet, these efforts require computationally expensive regional climate models with high spatial resolution to be exercised, and thus limit a comprehensive and coordinated sampling of simulations across structural uncertainties in both the regional and global climate-model responses. As a result, a range of outcomes in climate-change projections derived from individual assessments exist, and studies performed with a small sample size of model simulations lack a complete distribution of outcomes (e.g., Crétat et al. 2012 ). Therefore, there remains a distinct need for efficient methods that provide comprehensive samples of all the plausible model solutions to future human-forced climate change. Furthermore, these large-ensemble simulations should also have the ability to consider a number of different scenarios that consider a range of global emissions pathways and/or climate targets, and provide spatial details that are commensurate to the needs of regional impact studies. In this study, we analyze the likelihood of changes in precipitation and surface-air temperature in the coming decades and into the latter half of this century for the greater southern Africa region with a regional emphasis over South Africa. We employ a technique (Schlosser et al. 2012 ) that constructs large ensembles of plausible climate change. This method combines plausible patterns of human-forced regional climate change with a comprehensive assessment of the global climate change response as determined by the MIT Integrated Global System Model (Reilly et al. 2018 ). We evaluate the resultant distributions over three selected regions over South Africa that correspond with notable climatic features. We identify the salient shifts in these derived distributions from a reference emission scenario to moderate to aggressive climate-stabilization policies. We close with summary remarks and discussion of ongoing work and applications. 2 Assessment of regional climate shifts 2.1 Region of study and variables of interest The overall area of study (Fig. 1 ) is an extension and complement to prior work (Arndt et al. 2019 ; Schlosser and Strzepek 2015 ; and Fant et al. 2015 ) that provides multi-sector socio-economic-environmental assessments of climate risks for developing nations across Africa, and the effectiveness of low-carbon pathways to reduce risks. This study will present a screening-level assessment of potential climate shifts over southern Africa and focus on two key hydro-climatic variables: precipitation and near-surface air temperature ( T a ). In subsequent work, these results will be used as inputs for assessments of climate change impacts to agriculture yields (Thomas et al. 2020 , forthcoming) within South Africa. In this vein, we focus on three sub-regions across South Africa (denoted in Fig. 1 ) and provide a more quantitative analysis of climate risk and the impact of low-carbon pathways across three decadal epochs (2030s, 2050s, and 2065–2075). A description of the model experimentation and methodology is provided in the next section. Below, we describe some of the distinct seasonal features of T a and precipitation of the current climate that are aligned and distinguish our three regional areas of focus: eastern, central, and western South Africa (ESoAfr, CSoAfr, and WSoAfr, respectively). Our historical assessment is based on the observations taken from the Global Precipitation Climatology Project (GPCP, Huffman et al. 2009 , and updates by Adler et al. 2018 ) as well as T a from the Climate Research Unit (CRU, e.g., Osborn and Jones 2014 ). Fig. 1 Seasonal averaged maps (1979–2009) of precipitation (mm/day) for northern Africa. Results are shown for December–February (DJF); March–May (MAM); June–August (JJA); and September–November (SON). Results are based on the data from the Global Precipitation Climatology Project (GPCP, Huffman et al., 2007) Full size image Among the three regions considered, the western South Africa (WSoAfr) region is primarily distinguished by the persistently lowest rates of precipitation across all seasons (Fig. 1 and Table 1 ). This also results in the weakest amplitude in the seasonal cycle of precipitation. Furthermore, due to the localized precipitation maxima over the Cape Town area during JJA, the seasonal cycle of precipitation averaged over the WSoAfr region is opposite in phase to the CSoAfr and ESoAfr regions. In contrast, the ESoAfr region experiences the highest precipitation rates during the summer (DJF) season, and the transition to the wet season is abrupt as the landscape of spring season (SON) precipitation", "role": "user" }, { "content": "In 2018, Cape Town, South Africa's second most populous city, came very close to running out of water as the multi-year \"Day Zero\" drought depleted its reservoirs. Since then, researchers from Stanford University determined that climate change had made this extreme drought five to six times more likely, and warned that a lot more Day Zero events could occur in regions with similar climates in the future. A better understanding of likely surface air temperature and precipitation trends in South Africa and other dry, populated areas around the world in the coming decades could empower decision-makers to pursue science-based climate mitigation and adaptation measures designed to reduce the risk of future Day Zero events. Toward that end, researchers at the MIT Joint Program on the Science and Policy of Global Change, International Food Policy Research Institute, and CGIAR have produced modeled projections of 21st-century changes in seasonal surface air temperature and precipitation for South Africa that systematically and comprehensively account for uncertainties in how Earth and socioeconomic systems behave and co-evolve. Presented in a study in the journal Climatic Change, these projections show how temperature and precipitation over three sub-national regions—western, central, and eastern South Africa—are likely to change under a wide range of global climate mitigation policy scenarios. In a business-as-usual global climate policy scenario in which no emissions or climate targets are set or met, the projections show that for all three regions, there's a greater-than 50 percent likelihood that mid-century temperatures will increase threefold over the current climate's range of variability. But the risk of these mid-century temperature increases is effectively eliminated through more aggressive climate targets. The business-as-usual projections indicate that the risk of decreased precipitation levels in western and central South Africa is three to four times higher than the risk of increased precipitation levels. Under a global climate mitigation policy designed to cap global warming at 1.5 degrees Celsius by 2100, the risk of precipitation changes within South Africa toward the end of the century (2065-74) is similar to the risk during the 2030s in the business-as-usual scenario. Rising risks of substantially reduced precipitation levels throughout this century under a business-as-usual scenario suggest increased reliance and stress on the widespread water-efficiency measures established in the aftermath of the Day Zero drought. But a 1.5 C global climate mitigation policy would delay these risks by 30 years, giving South Africa ample lead time to prepare for and adapt to them. \"Our analysis provides risk-based evidence on the benefits of climate mitigation policies as well as unavoidable climate impacts that will need to be addressed through adaptive measures,\" says MIT Joint Program Deputy Director C. Adam Schlosser, the lead author of the study. \"Global action to limit human-induced warming could give South Africa enough time to secure sufficient water supplies to sustain its population. Otherwise, anticipated climate shifts by the middle of the next decade may well make Day-Zero situations more common.\" This study is part of an ongoing effort to assess the risks that climate change poses for South Africa's agricultural, economic, energy and infrastructure sectors. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract We present results from large ensembles of projected twenty-first century changes in seasonal precipitation and near-surface air temperature for the nation of South Africa. These ensembles are a result of combining Monte Carlo projections from a human-Earth system model of intermediate complexity with pattern-scaled responses from climate models of the Coupled Model Intercomparison Project Phase 5 (CMIP5). These future ensemble scenarios consider a range of global actions to abate emissions through the twenty-first century. We evaluate distributions of surface-air temperature and precipitation change over three sub-national regions: western, central, and eastern South Africa. In all regions, we find that without any emissions or climate targets in place, there is a greater than 50% likelihood that mid-century temperatures will increase threefold over the current climate’s two-standard deviation range of variability. However, scenarios that consider more aggressive climate targets all but eliminate the risk of these salient temperature increases. A preponderance of risk toward decreased precipitation (3 to 4 times higher than increased) exists for western and central South Africa. Strong climate targets abate evolving regional hydroclimatic risks. Under a target to limit global climate warming to 1.5 °C by 2100, the risk of precipitation changes within South Africa toward the end of this century (2065–2074) is commensurate to the risk during the 2030s without any global climate target. Thus, these regional hydroclimate risks over South Africa could be delayed by 30 years and, in doing so, provide invaluable lead-time for national efforts to prepare, fortify, and/or adapt. Working on a manuscript? Avoid the common mistakes 1 Introduction Evidence is mounting that Africa’s climate is changing and that these trends will continue through the twenty-first century (e.g., Niang et al. 2014 ). Current efforts to provide more spatially refined climate change information over Africa are ongoing (e.g., Lennard et al. 2018 ). Yet, these efforts require computationally expensive regional climate models with high spatial resolution to be exercised, and thus limit a comprehensive and coordinated sampling of simulations across structural uncertainties in both the regional and global climate-model responses. As a result, a range of outcomes in climate-change projections derived from individual assessments exist, and studies performed with a small sample size of model simulations lack a complete distribution of outcomes (e.g., Crétat et al. 2012 ). Therefore, there remains a distinct need for efficient methods that provide comprehensive samples of all the plausible model solutions to future human-forced climate change. Furthermore, these large-ensemble simulations should also have the ability to consider a number of different scenarios that consider a range of global emissions pathways and/or climate targets, and provide spatial details that are commensurate to the needs of regional impact studies. In this study, we analyze the likelihood of changes in precipitation and surface-air temperature in the coming decades and into the latter half of this century for the greater southern Africa region with a regional emphasis over South Africa. We employ a technique (Schlosser et al. 2012 ) that constructs large ensembles of plausible climate change. This method combines plausible patterns of human-forced regional climate change with a comprehensive assessment of the global climate change response as determined by the MIT Integrated Global System Model (Reilly et al. 2018 ). We evaluate the resultant distributions over three selected regions over South Africa that correspond with notable climatic features. We identify the salient shifts in these derived distributions from a reference emission scenario to moderate to aggressive climate-stabilization policies. We close with summary remarks and discussion of ongoing work and applications. 2 Assessment of regional climate shifts 2.1 Region of study and variables of interest The overall area of study (Fig. 1 ) is an extension and complement to prior work (Arndt et al. 2019 ; Schlosser and Strzepek 2015 ; and Fant et al. 2015 ) that provides multi-sector socio-economic-environmental assessments of climate risks for developing nations across Africa, and the effectiveness of low-carbon pathways to reduce risks. This study will present a screening-level assessment of potential climate shifts over southern Africa and focus on two key hydro-climatic variables: precipitation and near-surface air temperature ( T a ). In subsequent work, these results will be used as inputs for assessments of climate change impacts to agriculture yields (Thomas et al. 2020 , forthcoming) within South Africa. In this vein, we focus on three sub-regions across South Africa (denoted in Fig. 1 ) and provide a more quantitative analysis of climate risk and the impact of low-carbon pathways across three decadal epochs (2030s, 2050s, and 2065–2075). A description of the model experimentation and methodology is provided in the next section. Below, we describe some of the distinct seasonal features of T a and precipitation of the current climate that are aligned and distinguish our three regional areas of focus: eastern, central, and western South Africa (ESoAfr, CSoAfr, and WSoAfr, respectively). Our historical assessment is based on the observations taken from the Global Precipitation Climatology Project (GPCP, Huffman et al. 2009 , and updates by Adler et al. 2018 ) as well as T a from the Climate Research Unit (CRU, e.g., Osborn and Jones 2014 ). Fig. 1 Seasonal averaged maps (1979–2009) of precipitation (mm/day) for northern Africa. Results are shown for December–February (DJF); March–May (MAM); June–August (JJA); and September–November (SON). Results are based on the data from the Global Precipitation Climatology Project (GPCP, Huffman et al., 2007) Full size image Among the three regions considered, the western South Africa (WSoAfr) region is primarily distinguished by the persistently lowest rates of precipitation across all seasons (Fig. 1 and Table 1 ). This also results in the weakest amplitude in the seasonal cycle of precipitation. Furthermore, due to the localized precipitation maxima over the Cape Town area during JJA, the seasonal cycle of precipitation averaged over the WSoAfr region is opposite in phase to the CSoAfr and ESoAfr regions. In contrast, the ESoAfr region experiences the highest precipitation rates during the summer (DJF) season, and the transition to the wet season is abrupt as the landscape of spring season (SON) precipitation<|im_end|> <|im_start|>assistant In 2018, Cape Town, South Africa's second most populous city, came very close to running out of water as the multi-year "Day Zero" drought depleted its reservoirs. Since then, researchers from Stanford University determined that climate change had made this extreme drought five to six times more likely, and warned that a lot more Day Zero events could occur in regions with similar climates in the future. A better understanding of likely surface air temperature and precipitation trends in South Africa and other dry, populated areas around the world in the coming decades could empower decision-makers to pursue science-based climate mitigation and adaptation measures designed to reduce the risk of future Day Zero events. Toward that end, researchers at the MIT Joint Program on the Science and Policy of Global Change, International Food Policy Research Institute, and CGIAR have produced modeled projections of 21st-century changes in seasonal surface air temperature and precipitation for South Africa that systematically and comprehensively account for uncertainties in how Earth and socioeconomic systems behave and co-evolve. Presented in a study in the journal Climatic Change, these projections show how temperature and precipitation over three sub-national regions—western, central, and eastern South Africa—are likely to change under a wide range of global climate mitigation policy scenarios. In a business-as-usual global climate policy scenario in which no emissions or climate targets are set or met, the projections show that for all three regions, there's a greater-than 50 percent likelihood that mid-century temperatures will increase threefold over the current climate's range of variability. But the risk of these mid-century temperature increases is effectively eliminated through more aggressive climate targets. The business-as-usual projections indicate that the risk of decreased precipitation levels in western and central South Africa is three to four times higher than the risk of increased precipitation levels. Under a global climate mitigation policy designed to cap global warming at 1.5 degrees Celsius by 2100, the risk of precipitation changes within South Africa toward the end of the century (2065-74) is similar to the risk during the 2030s in the business-as-usual scenario. Rising risks of substantially reduced precipitation levels throughout this century under a business-as-usual scenario suggest increased reliance and stress on the widespread water-efficiency measures established in the aftermath of the Day Zero drought. But a 1.5 C global climate mitigation policy would delay these risks by 30 years, giving South Africa ample lead time to prepare for and adapt to them. "Our analysis provides risk-based evidence on the benefits of climate mitigation policies as well as unavoidable climate impacts that will need to be addressed through adaptive measures," says MIT Joint Program Deputy Director C. Adam Schlosser, the lead author of the study. "Global action to limit human-induced warming could give South Africa enough time to secure sufficient water supplies to sustain its population. Otherwise, anticipated climate shifts by the middle of the next decade may well make Day-Zero situations more common." This study is part of an ongoing effort to assess the risks that climate change poses for South Africa's agricultural, economic, energy and infrastructure sectors. <|im_end|>

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315, 5357, 25, 24024, 11, 8792, 11, 323, 19001, 4987, 10384, 320, 1600, 78, 32, 1658, 11, 356, 4516, 32, 1658, 11, 323, 468, 4516, 32, 1658, 11, 15947, 570, 5751, 13970, 15813, 374, 3196, 389, 279, 24654, 4529, 505, 279, 8121, 42770, 575, 7709, 62930, 75014, 5907, 320, 70341, 47, 11, 89597, 1880, 453, 13, 220, 1049, 24, 1174, 323, 9013, 555, 99718, 1880, 453, 13, 220, 679, 23, 883, 439, 1664, 439, 350, 264, 505, 279, 31636, 8483, 8113, 320, 9150, 52, 11, 384, 1326, 2637, 15796, 16381, 323, 12201, 220, 679, 19, 7609, 23966, 13, 220, 16, 14598, 278, 37956, 14370, 320, 4468, 24, 4235, 1049, 24, 8, 315, 61050, 320, 3906, 45839, 8, 369, 18671, 10384, 13, 18591, 527, 6982, 369, 6790, 4235, 33877, 320, 54372, 37, 1237, 5587, 4235, 11356, 320, 44, 1428, 1237, 5651, 4235, 32559, 320, 41, 45280, 1237, 323, 6250, 4235, 34827, 320, 2770, 570, 18591, 527, 3196, 389, 279, 828, 505, 279, 8121, 42770, 575, 7709, 62930, 75014, 5907, 320, 70341, 47, 11, 89597, 1880, 453, 2637, 220, 1049, 22, 8, 8797, 1404, 2217, 22395, 279, 2380, 13918, 6646, 11, 279, 19001, 4987, 10384, 320, 54, 4516, 32, 1658, 8, 5654, 374, 15871, 39575, 555, 279, 23135, 4501, 15821, 7969, 315, 61050, 4028, 682, 15956, 320, 30035, 13, 220, 16, 323, 6771, 220, 16, 7609, 1115, 1101, 3135, 304, 279, 81863, 45209, 304, 279, 36899, 11008, 315, 61050, 13, 24296, 11, 4245, 311, 279, 44589, 61050, 1973, 7675, 927, 279, 29715, 14298, 3158, 2391, 622, 45280, 11, 279, 36899, 11008, 315, 61050, 37956, 927, 279, 468, 4516, 32, 1658, 5654, 374, 14329, 304, 10474, 311, 279, 356, 4516, 32, 1658, 323, 469, 4516, 32, 1658, 13918, 13, 763, 13168, 11, 279, 469, 4516, 32, 1658, 5654, 11704, 279, 8592, 61050, 7969, 2391, 279, 7474, 320, 54372, 37, 8, 3280, 11, 323, 279, 9320, 311, 279, 14739, 3280, 374, 44077, 439, 279, 18921, 315, 10683, 3280, 320, 2770, 8, 61050, 128257, 198, 128256, 78191, 198, 644, 220, 679, 23, 11, 29715, 14298, 11, 4987, 10384, 596, 2132, 1455, 95551, 3363, 11, 3782, 1633, 3345, 311, 4401, 704, 315, 3090, 439, 279, 7447, 4771, 330, 10369, 18811, 1, 37846, 79266, 1202, 45512, 82, 13, 8876, 1243, 11, 12074, 505, 31788, 3907, 11075, 430, 10182, 2349, 1047, 1903, 420, 14560, 37846, 4330, 311, 4848, 3115, 810, 4461, 11, 323, 19201, 430, 264, 2763, 810, 6187, 18811, 4455, 1436, 12446, 304, 13918, 449, 4528, 92399, 304, 279, 3938, 13, 362, 2731, 8830, 315, 4461, 7479, 3805, 9499, 323, 61050, 18845, 304, 4987, 10384, 323, 1023, 9235, 11, 35459, 5789, 2212, 279, 1917, 304, 279, 5108, 11026, 1436, 26285, 5597, 76170, 311, 23564, 8198, 6108, 10182, 66860, 323, 34185, 11193, 6319, 311, 8108, 279, 5326, 315, 3938, 6187, 18811, 4455, 13, 41493, 569, 430, 842, 11, 12074, 520, 279, 15210, 30833, 6826, 389, 279, 10170, 323, 11216, 315, 8121, 10604, 11, 7327, 12369, 11216, 8483, 10181, 11, 323, 64527, 946, 617, 9124, 62653, 41579, 315, 220, 1691, 267, 34457, 4442, 304, 36899, 7479, 3805, 9499, 323, 61050, 369, 4987, 10384, 430, 60826, 323, 12963, 28014, 2759, 369, 69867, 304, 1268, 9420, 323, 80431, 6067, 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1,997

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Here, we describe a novel approach that allows pathologists to three-dimensionally analyse malignant tissues, including the tumour-host tissue interface. Our visualization technique utilizes a combination of ultrafast chemical tissue clearing and light-sheet microscopy to obtain virtual slices and 3D reconstructions of up to multiple centimetre sized tumour resectates. For the clearing of tumours we propose a preparation technique comprising three steps: (a) Fixation and enhancement of tissue autofluorescence with formalin/5-sulfosalicylic acid. (b) Ultrafast active chemical dehydration with 2,2-dimethoxypropane and (c) refractive index matching with dibenzyl ether at up to 56 °C. After clearing, the tumour resectates are imaged. The images are computationally post-processed for contrast enhancement and artefact removal and then 3D reconstructed. Importantly, the sequence a–c is fully reversible, allowing the morphological correlation of one and the same histological structures, once visualized with our novel technique and once visualized by standard H&E- and IHC-staining. After reverting the clearing procedure followed by standard H&E processing, the hallmarks of ductal carcinoma in situ (DCIS) found in the cleared samples could be successfully correlated with the corresponding structures present in H&E and IHC staining. Since the imaging of several thousands of optical sections is a fast process, it is possible to analyse a larger part of the tumour than by mechanical slicing. As this also adds further information about the 3D structure of malignancies, we expect that our technology will become a valuable addition for histological diagnosis in clinical pathology. Introduction Breast cancer is the most common malignancy in women 1 . The largest histological subgroup of invasive breast cancers is formed by invasive breast cancer of no special type (NST), commonly known as ductal carcinoma. Ductal carcinoma in situ (DCIS) is regarded to be its pre-invasive lesion which is, in contrast to the invasive carcinoma, confined to the mammary ductal-lobular system due to a preserved myoepithelial layer. Despite the comprehensive improvement in the field of breast cancer biology, especially in molecular diagnostics and the expansion of targeted therapies, the primary treatment option of both entities is a locoregional tumour resection with the aim of tumour-free resection margins. The guideline recommendation of minimal margin width is currently set to 2 mm provided that post-operative radiation therapy is performed. This threshold is considered to be sufficient enough to control the risk of local recurrence 2 , 3 , 4 . After the surgical resection, a histopathological examination of the anatomical specimen is performed according to standard procedures. Modern pathology relies on a decades-proven framework of 2D histopathological analysis, where tissue resectates are routinely processed by formalin fixation and paraffin embedding of representative tissue samples (FFPE). The paraffin blocks obtained thereby are cut with a microtome and then placed onto glass slides for haematoxylin and eosin (H&E) and/or immunohistochemistry (IHC) staining. This whole procedure takes up to a few days before the images are obtained. In general, only one to two histological sections of a 3–4 mm thick tissue block are produced, apart from especially selected cases, e.g. biopsies or sentinel lymph nodes which are processed by several serial or step sections. Considering that a single section is approximately 5 µm thick, the undersampling factor is about 600–800 with this technique. Although there is a significant risk that important stage-determining hallmarks of cancer are missed, the FFPE technique is still regarded as the gold standard in histopathological tissue analysis. However, it is crucial for the pathologist to see most of the tumour in its immediate vicinity, especially its marginal areas. In recent years, scientists worldwide tried to improve the situation by inventing novel histopathological preparation and imaging techniques 5 , 6 . To our knowledge, the only one among these approaches that is currently used in clinical practice is the whole slide imaging (WSI) technique, where entire glass-mounted H&E-stained slices are scanned. The resulting images can be analysed with specially designed software and represent a convenient tool for the modern histopathology 7 . The drawbacks of this approach are the same as for standard tissue preparation, i.e. artefacts that occur due to the mechanical slicing and staining. Additionally, the scanning time for a single slide is between 5–15 min with an average of 10 min. Usually, the slides are scanned in batches of 80 to 120 and the scanning-time per batch is 12–24 h 8 . The resulting file-size varies from 48 MB to several GB per slide, depending on resolution. These numbers vary depending on the model of scanner, as this branch of digital histopathology is constantly developing, providing novel, improved systems 9 , 10 . Attempts to transfer this existing technique from 2 to 3D, i.e. to create 3D-reconstructions from the series of cut and stained single sections of FFPE-processed specimen gave some interesting results 11 , 12 , 13 , 14 . However, due to the irreversible nature of this method, tissue is completely used up and therefore no longer available for certain additional analyses like the increasingly applied immunohistochemical testing for PD-L1 in the future. In the context of PD-L1 testing unstained sections should not be stored longer than 2–3 months, otherwise there is the risk of false negative staining results, meaning that the patient could be deprived of a potentially highly effective anti-tumoural immunotherapy. Moreover, being extremely time- and labour-intensive it would hardly be applicable in clinical practice. Another attempt made with multiphoton imaging of optically cleared archive-compatible FFPE tissue 15 was limited by the size of the specimen that can be scanned. Also, immunostaining of lymphatic microvasculature and blood vessels in cleared bladder samples of a few mm size required several weeks 16 and was limited to depict tumour vascularization. Intraoperative pathology using fluorescence excitation would be a useful option, if it could be introduced in routine healthcare practice. However, it is presently limited to the surface scanning of freshly resected tissue 17 . Confocal microscopy 18 , as well as light sheet microscopy of needle-core biopsies 19 , 20 , 21 or the specimen surface provides only information about a tiny part of the relatively large", "role": "user" }, { "content": "After cancer surgery, the crucial question is: Are there possibly cancer cells left behind that can continue to grow, or has the entire tumor actually been removed? To find out, the tumor is examined by pathologists. Until now, thin sections were made which were then analyzed under a microscope. A new technique, developed at TU Wien (Vienna), together with the TU Munich, could now initiate a revolution in pathology: Tumor tissue is made transparent and illuminated with a special ultramicroscope. This makes it possible to analyze all the tissue removed in 3-D without the need for slicing up the tumor. That way, the reliability of the diagnosis can be significantly increased. The new technique has now been published in the journal Scientific Reports. Tissue samples that save lives \"Under the microscope you can see whether the removed tumor is surrounded by a seam of healthy tissue,\" says Prof. Hans Ulrich Dodt from the Institute of Solid State Electronics at TU Wien. \"If this is the case, the patient often only needs to recover. If this is not the case, it may be necessary to perform follow-up surgery or additional radiation therapy. Especially after breast cancer operations this happens frequently.\" The problem is that it is never possible to completely examine the entire tumor in this way. \"Usually, an approximately 4 micrometer thick section is made every 5 millimeters. This means that only about one thousandth of the entire tumor volume is actually examined.\" In critical areas, a finer spacing may be chosen, but it is impossible to study the entire tissue in this way. Transparent tissue: ultramicroscopy However, with the help of a special technique called ultramicroscopy, it is now possible to make the entire tumor visible in three dimensions—Inna Sabdyusheva worked on this in the context of her dissertation (at TU Wien and the Center for Brain Research at MedUni Vienna). She developed a chemical process to \"clear\" breast cancer samples—they become transparent, but the structure remains unchanged and the cancer cells can still be recognized. A glimpse into the tumor in 3D Credit: TU Wien The transparent sample is then examined under an ultramicroscope. A so-called 'light sheet,' a thin layer of laser beams, penetrates the tissue. The sample is then analyzed layer by layer, and the computer can then display any section through the tumor, even though it has never been cut up. In this way, insights are gained that were previously impossible: In some tissue samples, for example, milk ducts clogged with cancer cells could be seen. The chemical process on which Inna Sabdyusheva's work is based was developed at TU Wien by Klaus Becker. A special optical system with which particularly long and thin light sheets can be generated was constructed by Saideh Saghafi in the same research group. This was crucial for the current work—the resolution of this microscopy method depends on how thin the light sheet is. The investigations were carried out in close cooperation with the Pathological Institute of the TU Munich, which also provided most of the tumor pieces from breast cancer operations. The Clinic for Surgery at Vienna General Hospital also provided pieces of other tumor types. Revolution in pathology \"We are convinced that this method will revolutionize pathology,\" says Hans-Ulrich Dodt. \"In less time than before, greater reliability in examinations can be achieved. In addition, the new 3-D method should also provide completely new insights into cancer development in the future. Since it is now possible for the first time to display the spread of cancer cells in human surgical specimens in three dimensions, understanding of tumor biology should also make significant progress. The new 3-D tumor microscopy should make work in pathology much easier. \"Instead of inspecting a large number of histological sections under the microscope, pathologists will in future be able to scroll through the images with the mouse, similarly to how radiologists are working today,\" says Hans-Ulrich Dodt. The enormous amount of image data that is generated in the process also opens up completely new opportunities in the field of artificial intelligence, believes Dodt: \"Perhaps such computer programs could speed up and simplify tumor diagnostics in the future.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Here, we describe a novel approach that allows pathologists to three-dimensionally analyse malignant tissues, including the tumour-host tissue interface. Our visualization technique utilizes a combination of ultrafast chemical tissue clearing and light-sheet microscopy to obtain virtual slices and 3D reconstructions of up to multiple centimetre sized tumour resectates. For the clearing of tumours we propose a preparation technique comprising three steps: (a) Fixation and enhancement of tissue autofluorescence with formalin/5-sulfosalicylic acid. (b) Ultrafast active chemical dehydration with 2,2-dimethoxypropane and (c) refractive index matching with dibenzyl ether at up to 56 °C. After clearing, the tumour resectates are imaged. The images are computationally post-processed for contrast enhancement and artefact removal and then 3D reconstructed. Importantly, the sequence a–c is fully reversible, allowing the morphological correlation of one and the same histological structures, once visualized with our novel technique and once visualized by standard H&E- and IHC-staining. After reverting the clearing procedure followed by standard H&E processing, the hallmarks of ductal carcinoma in situ (DCIS) found in the cleared samples could be successfully correlated with the corresponding structures present in H&E and IHC staining. Since the imaging of several thousands of optical sections is a fast process, it is possible to analyse a larger part of the tumour than by mechanical slicing. As this also adds further information about the 3D structure of malignancies, we expect that our technology will become a valuable addition for histological diagnosis in clinical pathology. Introduction Breast cancer is the most common malignancy in women 1 . The largest histological subgroup of invasive breast cancers is formed by invasive breast cancer of no special type (NST), commonly known as ductal carcinoma. Ductal carcinoma in situ (DCIS) is regarded to be its pre-invasive lesion which is, in contrast to the invasive carcinoma, confined to the mammary ductal-lobular system due to a preserved myoepithelial layer. Despite the comprehensive improvement in the field of breast cancer biology, especially in molecular diagnostics and the expansion of targeted therapies, the primary treatment option of both entities is a locoregional tumour resection with the aim of tumour-free resection margins. The guideline recommendation of minimal margin width is currently set to 2 mm provided that post-operative radiation therapy is performed. This threshold is considered to be sufficient enough to control the risk of local recurrence 2 , 3 , 4 . After the surgical resection, a histopathological examination of the anatomical specimen is performed according to standard procedures. Modern pathology relies on a decades-proven framework of 2D histopathological analysis, where tissue resectates are routinely processed by formalin fixation and paraffin embedding of representative tissue samples (FFPE). The paraffin blocks obtained thereby are cut with a microtome and then placed onto glass slides for haematoxylin and eosin (H&E) and/or immunohistochemistry (IHC) staining. This whole procedure takes up to a few days before the images are obtained. In general, only one to two histological sections of a 3–4 mm thick tissue block are produced, apart from especially selected cases, e.g. biopsies or sentinel lymph nodes which are processed by several serial or step sections. Considering that a single section is approximately 5 µm thick, the undersampling factor is about 600–800 with this technique. Although there is a significant risk that important stage-determining hallmarks of cancer are missed, the FFPE technique is still regarded as the gold standard in histopathological tissue analysis. However, it is crucial for the pathologist to see most of the tumour in its immediate vicinity, especially its marginal areas. In recent years, scientists worldwide tried to improve the situation by inventing novel histopathological preparation and imaging techniques 5 , 6 . To our knowledge, the only one among these approaches that is currently used in clinical practice is the whole slide imaging (WSI) technique, where entire glass-mounted H&E-stained slices are scanned. The resulting images can be analysed with specially designed software and represent a convenient tool for the modern histopathology 7 . The drawbacks of this approach are the same as for standard tissue preparation, i.e. artefacts that occur due to the mechanical slicing and staining. Additionally, the scanning time for a single slide is between 5–15 min with an average of 10 min. Usually, the slides are scanned in batches of 80 to 120 and the scanning-time per batch is 12–24 h 8 . The resulting file-size varies from 48 MB to several GB per slide, depending on resolution. These numbers vary depending on the model of scanner, as this branch of digital histopathology is constantly developing, providing novel, improved systems 9 , 10 . Attempts to transfer this existing technique from 2 to 3D, i.e. to create 3D-reconstructions from the series of cut and stained single sections of FFPE-processed specimen gave some interesting results 11 , 12 , 13 , 14 . However, due to the irreversible nature of this method, tissue is completely used up and therefore no longer available for certain additional analyses like the increasingly applied immunohistochemical testing for PD-L1 in the future. In the context of PD-L1 testing unstained sections should not be stored longer than 2–3 months, otherwise there is the risk of false negative staining results, meaning that the patient could be deprived of a potentially highly effective anti-tumoural immunotherapy. Moreover, being extremely time- and labour-intensive it would hardly be applicable in clinical practice. Another attempt made with multiphoton imaging of optically cleared archive-compatible FFPE tissue 15 was limited by the size of the specimen that can be scanned. Also, immunostaining of lymphatic microvasculature and blood vessels in cleared bladder samples of a few mm size required several weeks 16 and was limited to depict tumour vascularization. Intraoperative pathology using fluorescence excitation would be a useful option, if it could be introduced in routine healthcare practice. However, it is presently limited to the surface scanning of freshly resected tissue 17 . Confocal microscopy 18 , as well as light sheet microscopy of needle-core biopsies 19 , 20 , 21 or the specimen surface provides only information about a tiny part of the relatively large<|im_end|> <|im_start|>assistant After cancer surgery, the crucial question is: Are there possibly cancer cells left behind that can continue to grow, or has the entire tumor actually been removed? To find out, the tumor is examined by pathologists. Until now, thin sections were made which were then analyzed under a microscope. A new technique, developed at TU Wien (Vienna), together with the TU Munich, could now initiate a revolution in pathology: Tumor tissue is made transparent and illuminated with a special ultramicroscope. This makes it possible to analyze all the tissue removed in 3-D without the need for slicing up the tumor. That way, the reliability of the diagnosis can be significantly increased. The new technique has now been published in the journal Scientific Reports. Tissue samples that save lives "Under the microscope you can see whether the removed tumor is surrounded by a seam of healthy tissue," says Prof. Hans Ulrich Dodt from the Institute of Solid State Electronics at TU Wien. "If this is the case, the patient often only needs to recover. If this is not the case, it may be necessary to perform follow-up surgery or additional radiation therapy. Especially after breast cancer operations this happens frequently." The problem is that it is never possible to completely examine the entire tumor in this way. "Usually, an approximately 4 micrometer thick section is made every 5 millimeters. This means that only about one thousandth of the entire tumor volume is actually examined." In critical areas, a finer spacing may be chosen, but it is impossible to study the entire tissue in this way. Transparent tissue: ultramicroscopy However, with the help of a special technique called ultramicroscopy, it is now possible to make the entire tumor visible in three dimensions—Inna Sabdyusheva worked on this in the context of her dissertation (at TU Wien and the Center for Brain Research at MedUni Vienna). She developed a chemical process to "clear" breast cancer samples—they become transparent, but the structure remains unchanged and the cancer cells can still be recognized. A glimpse into the tumor in 3D Credit: TU Wien The transparent sample is then examined under an ultramicroscope. A so-called 'light sheet,' a thin layer of laser beams, penetrates the tissue. The sample is then analyzed layer by layer, and the computer can then display any section through the tumor, even though it has never been cut up. In this way, insights are gained that were previously impossible: In some tissue samples, for example, milk ducts clogged with cancer cells could be seen. The chemical process on which Inna Sabdyusheva's work is based was developed at TU Wien by Klaus Becker. A special optical system with which particularly long and thin light sheets can be generated was constructed by Saideh Saghafi in the same research group. This was crucial for the current work—the resolution of this microscopy method depends on how thin the light sheet is. The investigations were carried out in close cooperation with the Pathological Institute of the TU Munich, which also provided most of the tumor pieces from breast cancer operations. The Clinic for Surgery at Vienna General Hospital also provided pieces of other tumor types. Revolution in pathology "We are convinced that this method will revolutionize pathology," says Hans-Ulrich Dodt. "In less time than before, greater reliability in examinations can be achieved. In addition, the new 3-D method should also provide completely new insights into cancer development in the future. Since it is now possible for the first time to display the spread of cancer cells in human surgical specimens in three dimensions, understanding of tumor biology should also make significant progress. The new 3-D tumor microscopy should make work in pathology much easier. "Instead of inspecting a large number of histological sections under the microscope, pathologists will in future be able to scroll through the images with the mouse, similarly to how radiologists are working today," says Hans-Ulrich Dodt. The enormous amount of image data that is generated in the process also opens up completely new opportunities in the field of artificial intelligence, believes Dodt: "Perhaps such computer programs could speed up and simplify tumor diagnostics in the future." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer 1 , 2 , 3 . Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes 4 , 5 . Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival 6 , 7 . We hypothesized that abiraterone is converted by an enzyme to the more active Δ 4 -abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone’s clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation—conversion to a more active agent—for abiraterone’s survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment. Main The central role and critical requirement for androgen metabolism and androgen receptor (AR) in castration-resistant prostate cancer (CRPC) are demonstrated by the clinical benefit and overall survival benefit conferred by abiraterone (Abi) 6 , 7 , which blocks CYP17A1, an enzyme required for androgen synthesis, and enzalutamide, which potently and competitively blocks the AR 8 , 9 . Abi (administered in its acetate form for bioavailability) is a steroidal compound and is therefore potentially subject to conversion by steroid-metabolizing enzymes. We hypothesized that the Δ 5 , 3β-hydroxyl-structure of Abi, which is also present in the natural steroid substrates dehydroepiandrosterone (DHEA) and Δ 5 -androstenediol (A5diol), makes it susceptible to one enzyme conversion by 3βHSD isoenzymes to its Δ 4 , 3-keto congener (Δ 4 -abiraterone or D4A). This, in turn, would make the steroid A and B rings identical to testosterone, enabling inhibitory interactions with AR and additional steroidogenic enzymes, including SRD5A, which are required for DHT synthesis ( Fig. 1a ). Such a conversion in peripheral tissues would allow D4A to engage with multiple targets to potentiate its effects on the androgen pathway, providing an alternative explanation for the clinical efficacy of Abi therapy and thus the possibility that direct treatment might be more efficacious. Figure 1: Structural consequences of the conversion from Abi to D4A that occurs both in mice and in patients, and requires 3βHSD. a , Schematic of Abi conversion to D4A. *Double bond and C3-position for substrates and products of 3βHSD. b , Abi is converted to D4A in vivo . Abi acetate was injected intraperitoneally in five mice. Blood was collected 2 h and 4 h after injection. Serum concentrations of Abi and D4A were quantified by mass spectrometry and are represented as the percentage of the sum total of Abi + D4A. c , D4A is detectable in all patients ( n = 12) with CRPC treated with Abi acetate. d , Representative mass spectrometry tracing of D4A and Abi from the serum of a patient treated with Abi acetate. e , 3βHSD1 is capable of converting Abi to D4A. LAPC4 cells overexpressing 3βHSD1 were treated with 10 µM Abi (or [ 3 H]DHEA) for 24 h. Abi, D4A (as a percentage of Abi + D4A), [ 3 H]DHEA and [ 3 H]DHEA metabolites (labelled metabolites) were separated by HPLC. Results are shown as mean ( n = 3) ± s.d. with biological replicates. The experiment was repeated independently at least three times. PowerPoint slide Full size image We found that D4A is detectable in the sera of mice administered Abi acetate ( Fig. 1b ), as well as in sera from patients with CRPC who were undergoing treatment with Abi acetate ( Fig. 1c, d and Extended Data Fig. 1 ). In the LAPC4 prostate cancer cell line, which usually has low 3βHSD activity 3 , conversion of Abi to D4A is detectable only if 3βHSD is overexpressed ( Fig. 1e and Extended Data Fig. 2a, b ). Other tissues such as the mouse adrenal (but not mouse prostate) that have robust endogenous 3βHSD enzymatic activity also convert Abi to D4A ( Extended Data Fig. 2c ). These results suggest that D4A is a major metabolite of Abi, requires 3βHSD for conversion and may confer effects on the tumour that are indirectly due to Abi. D4A may impinge on multiple steps in the androgen pathway, including CYP17A1, 3βHSD, SRD5A and direct interaction with AR ( Fig. 2a ). Although augmented Abi drug exposure may block 3βHSD, normal dosing probably does not 10 . On the other hand, D4A is approximately tenfold more potent than Abi at blocking the conversion of [ 3 H]DHEA by 3βHSD to Δ 4 -androstenedione (AD) in LNCaP and VCaP cells, as assessed by thin-layer chromatography (TLC; Extended Data Fig. 3a ) and high-performance liquid chromatography (HPLC; Fig. 2b and Extended Data Fig. 3b ). D4A inhibits both human isoenzymes, 3βHSD1 and 3βHSD2, with mixed inhibition kinetics ( Fig. 2c ). CYP17A1 inhibition is the major direct mechanism of action for Abi 11 . Structural studies of modified steroidal azoles suggest that the A-ring conformation of D4A does not significantly perturb binding to CYP17A1 (ref. 12 ). D4A and Abi similarly block conversion of [ 3 H]pregnenolone by CYP17A1 to DHEA (percentage conversion to DHEA after 3 h incubation for vehicle, 1 nM D4A and 1 nM Abi was 70.1%, 4.2% and 2.6%, respectively) by HPLC in intact 293 cells expressing CYP17A1 ( Fig. 2d ). The Δ 4 , 3-keto-structure of D4A is identical to physiological SRD5A substrates, such as testosterone and AD ( Fig. 1a ) 13 . To determine the effect of D4A on endogenously expressed SRD5A, LAPC4 cells, which exhibit robust SRD5A", "role": "user" }, { "content": "Cleveland: Cleveland Clinic researchers have discovered for the first time that a metabolite of an FDA-approved drug for metastatic prostate cancer, abiraterone (Abi), has more anti-cancer properties than its precursor. The research will be published online June 1st in Nature. Cleveland Clinic researcher Nima Sharifi, M.D., found that abiraterone, a steroid inhibitor, is converted into the more physiologically active D4A (Δ4-abiraterone) in both patients and animal models with prostate cancer who take the drug. Furthermore, they found that D4A is more effective than abiraterone at killing aggressive prostate cancer cells, suggesting that some patients may benefit from direct treatment with D4A. Prostate cancer cells are fueled by androgens (male hormones). When prostate cancer spreads, androgen deprivation therapy (\"medical castration\") is used to cut off the tumor's energy supply. However, aggressive, metastatic tumors can become resistant to this type of therapy. In a landmark 2013 publication in Cell, Dr. Sharifi described a genetic mutation that enables prostate cancer cells to produce their own hormones for fuel, making them resistant to traditional hormone deprivation therapies. Abiraterone works by blocking CYP17A1, an enzyme that is crucial for the production of androgens. Dr. Sharifi's team found that the more active D4A inhibits two additional enzymes responsible for producing androgens, as well as blocks the androgen receptor, which renders existing androgens inactive. They found that 12 patients on active abiraterone therapy had detectable serum levels of D4A. D4A levels varied among patients, however, suggesting that individuals may differ in their metabolism of abiraterone to D4A. \"More studies are needed to uncover the exact mechanisms involved, but we predict that direct treatment with D4A could prolong survival in some patients with metastatic prostate cancer,\" said Dr. Sharifi, \"Further studies will also help us develop a potential biomarker profile to predict which patients will respond to D4 - abiraterone.\" Dr. Sharifi holds positions in Cleveland Clinic's Lerner Research Institute, Glickman Urological & Kidney Institute, and Taussig Cancer Institute, and is the Kendrick Family Endowed Chair for Prostate Cancer Research. Prostate cancer is the most common cancer in men, with nearly 240,000 new cases diagnosed each year in the United State. According to the American Cancer Society, there will be an estimated 30,000 deaths due to prostate cancer in 2013. Almost every man who dies of prostate cancer dies with castration-resistant prostate cancer. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer 1 , 2 , 3 . Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes 4 , 5 . Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival 6 , 7 . We hypothesized that abiraterone is converted by an enzyme to the more active Δ 4 -abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone’s clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation—conversion to a more active agent—for abiraterone’s survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment. Main The central role and critical requirement for androgen metabolism and androgen receptor (AR) in castration-resistant prostate cancer (CRPC) are demonstrated by the clinical benefit and overall survival benefit conferred by abiraterone (Abi) 6 , 7 , which blocks CYP17A1, an enzyme required for androgen synthesis, and enzalutamide, which potently and competitively blocks the AR 8 , 9 . Abi (administered in its acetate form for bioavailability) is a steroidal compound and is therefore potentially subject to conversion by steroid-metabolizing enzymes. We hypothesized that the Δ 5 , 3β-hydroxyl-structure of Abi, which is also present in the natural steroid substrates dehydroepiandrosterone (DHEA) and Δ 5 -androstenediol (A5diol), makes it susceptible to one enzyme conversion by 3βHSD isoenzymes to its Δ 4 , 3-keto congener (Δ 4 -abiraterone or D4A). This, in turn, would make the steroid A and B rings identical to testosterone, enabling inhibitory interactions with AR and additional steroidogenic enzymes, including SRD5A, which are required for DHT synthesis ( Fig. 1a ). Such a conversion in peripheral tissues would allow D4A to engage with multiple targets to potentiate its effects on the androgen pathway, providing an alternative explanation for the clinical efficacy of Abi therapy and thus the possibility that direct treatment might be more efficacious. Figure 1: Structural consequences of the conversion from Abi to D4A that occurs both in mice and in patients, and requires 3βHSD. a , Schematic of Abi conversion to D4A. *Double bond and C3-position for substrates and products of 3βHSD. b , Abi is converted to D4A in vivo . Abi acetate was injected intraperitoneally in five mice. Blood was collected 2 h and 4 h after injection. Serum concentrations of Abi and D4A were quantified by mass spectrometry and are represented as the percentage of the sum total of Abi + D4A. c , D4A is detectable in all patients ( n = 12) with CRPC treated with Abi acetate. d , Representative mass spectrometry tracing of D4A and Abi from the serum of a patient treated with Abi acetate. e , 3βHSD1 is capable of converting Abi to D4A. LAPC4 cells overexpressing 3βHSD1 were treated with 10 µM Abi (or [ 3 H]DHEA) for 24 h. Abi, D4A (as a percentage of Abi + D4A), [ 3 H]DHEA and [ 3 H]DHEA metabolites (labelled metabolites) were separated by HPLC. Results are shown as mean ( n = 3) ± s.d. with biological replicates. The experiment was repeated independently at least three times. PowerPoint slide Full size image We found that D4A is detectable in the sera of mice administered Abi acetate ( Fig. 1b ), as well as in sera from patients with CRPC who were undergoing treatment with Abi acetate ( Fig. 1c, d and Extended Data Fig. 1 ). In the LAPC4 prostate cancer cell line, which usually has low 3βHSD activity 3 , conversion of Abi to D4A is detectable only if 3βHSD is overexpressed ( Fig. 1e and Extended Data Fig. 2a, b ). Other tissues such as the mouse adrenal (but not mouse prostate) that have robust endogenous 3βHSD enzymatic activity also convert Abi to D4A ( Extended Data Fig. 2c ). These results suggest that D4A is a major metabolite of Abi, requires 3βHSD for conversion and may confer effects on the tumour that are indirectly due to Abi. D4A may impinge on multiple steps in the androgen pathway, including CYP17A1, 3βHSD, SRD5A and direct interaction with AR ( Fig. 2a ). Although augmented Abi drug exposure may block 3βHSD, normal dosing probably does not 10 . On the other hand, D4A is approximately tenfold more potent than Abi at blocking the conversion of [ 3 H]DHEA by 3βHSD to Δ 4 -androstenedione (AD) in LNCaP and VCaP cells, as assessed by thin-layer chromatography (TLC; Extended Data Fig. 3a ) and high-performance liquid chromatography (HPLC; Fig. 2b and Extended Data Fig. 3b ). D4A inhibits both human isoenzymes, 3βHSD1 and 3βHSD2, with mixed inhibition kinetics ( Fig. 2c ). CYP17A1 inhibition is the major direct mechanism of action for Abi 11 . Structural studies of modified steroidal azoles suggest that the A-ring conformation of D4A does not significantly perturb binding to CYP17A1 (ref. 12 ). D4A and Abi similarly block conversion of [ 3 H]pregnenolone by CYP17A1 to DHEA (percentage conversion to DHEA after 3 h incubation for vehicle, 1 nM D4A and 1 nM Abi was 70.1%, 4.2% and 2.6%, respectively) by HPLC in intact 293 cells expressing CYP17A1 ( Fig. 2d ). The Δ 4 , 3-keto-structure of D4A is identical to physiological SRD5A substrates, such as testosterone and AD ( Fig. 1a ) 13 . To determine the effect of D4A on endogenously expressed SRD5A, LAPC4 cells, which exhibit robust SRD5A<|im_end|> <|im_start|>assistant Cleveland: Cleveland Clinic researchers have discovered for the first time that a metabolite of an FDA-approved drug for metastatic prostate cancer, abiraterone (Abi), has more anti-cancer properties than its precursor. The research will be published online June 1st in Nature. Cleveland Clinic researcher Nima Sharifi, M.D., found that abiraterone, a steroid inhibitor, is converted into the more physiologically active D4A (Δ4-abiraterone) in both patients and animal models with prostate cancer who take the drug. Furthermore, they found that D4A is more effective than abiraterone at killing aggressive prostate cancer cells, suggesting that some patients may benefit from direct treatment with D4A. Prostate cancer cells are fueled by androgens (male hormones). When prostate cancer spreads, androgen deprivation therapy ("medical castration") is used to cut off the tumor's energy supply. However, aggressive, metastatic tumors can become resistant to this type of therapy. In a landmark 2013 publication in Cell, Dr. Sharifi described a genetic mutation that enables prostate cancer cells to produce their own hormones for fuel, making them resistant to traditional hormone deprivation therapies. Abiraterone works by blocking CYP17A1, an enzyme that is crucial for the production of androgens. Dr. Sharifi's team found that the more active D4A inhibits two additional enzymes responsible for producing androgens, as well as blocks the androgen receptor, which renders existing androgens inactive. They found that 12 patients on active abiraterone therapy had detectable serum levels of D4A. D4A levels varied among patients, however, suggesting that individuals may differ in their metabolism of abiraterone to D4A. "More studies are needed to uncover the exact mechanisms involved, but we predict that direct treatment with D4A could prolong survival in some patients with metastatic prostate cancer," said Dr. Sharifi, "Further studies will also help us develop a potential biomarker profile to predict which patients will respond to D4 - abiraterone." Dr. Sharifi holds positions in Cleveland Clinic's Lerner Research Institute, Glickman Urological & Kidney Institute, and Taussig Cancer Institute, and is the Kendrick Family Endowed Chair for Prostate Cancer Research. Prostate cancer is the most common cancer in men, with nearly 240,000 new cases diagnosed each year in the United State. According to the American Cancer Society, there will be an estimated 30,000 deaths due to prostate cancer in 2013. Almost every man who dies of prostate cancer dies with castration-resistant prostate cancer. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Fear and extinction learning are adaptive processes caused by molecular changes in specific neural circuits. Neurons expressing the corticotropin-releasing hormone gene ( Crh ) in central amygdala (CeA) are implicated in threat regulation, yet little is known of cell type-specific gene pathways mediating adaptive learning. We translationally profiled the transcriptome of CeA Crh -expressing cells (Crh neurons) after fear conditioning or extinction in mice using translating ribosome affinity purification (TRAP) and RNAseq. Differential gene expression and co-expression network analyses identified diverse networks activated or inhibited by fear vs extinction. Upstream regulator analysis demonstrated that extinction associates with reduced CREB expression, and viral vector-induced increased CREB expression in Crh neurons increased fear expression and inhibited extinction. These findings suggest that CREB, within CeA Crh neurons, may function as a molecular switch that regulates expression of fear and its extinction. Cell-type specific translational analyses may suggest targets useful for understanding and treating stress-related psychiatric illness. Introduction Fear and fear extinction learning are evolutionarily conserved, homeostatic processes that are critically perturbed in a variety of neuropsychiatric disorders, such as posttraumatic stress disorder (PTSD), generalized anxiety disorders, bipolar disorder, and Alzheimer’s disease 1 , 2 , 3 , 4 . Fear learning is a complex process involving associative learning of explicit trauma-paired cues and more generalized contextual elements 5 . Understanding the neural circuitries regulating this process, and molecular changes in these circuitries following behavior may reveal translationally relevant molecular pathways relevant to the diagnosis, treatment, and even prevention of human disease 6 , 7 . As an example, PTSD has been repeatedly associated with a failure to recover from traumatic events, conceptualized as a failure to extinguish learned fear 8 , 9 , 10 . Notably, the largest-to-date genome-wide association study (GWAS) for PTSD recently found genome-wide level associations between variants of CRHR1 , the gene encoding corticotropin-releasing hormone (CRH) receptor-type 1, genetically regulated brain-specific CRHR1 expression, and PTSD diagnosis and symptom clusters 11 , 12 , along with its identification in large GWAS of anxiety and habitual alcohol use 13 , 14 . The amygdala is a primary integrator of aversive physical stimuli and associated cues 15 , 16 . Specifically, the central amygdala (CeA) plays a well characterized role in regulating the expression of defensive responses via its connections to downstream regions 17 . The CeA comprises three cytoarchitecturally distinct sub-compartments (central capsular (CeC), lateral (CeL), and medial (CeM)). Recent characterizations of CeA circuitry have identified multiple recursive inhibitory loops which hierarchically gate threat responses (reflexive, active, passive, etc.) through their intra-CeA and output projections 18 , 19 , 20 , 21 , 22 . Within the CeA there are several molecularly distinct neuronal populations which mediate specific elements of fear conditioning (FC) and extinction (EXT) learning processes 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 . Specifically, within the CeL, three populations represent the majority of neurons: those marked by Crh, Sst , or Prkcd , 17 , 22 , 23 , 32 . Until recently, it has not been possible to characterize translational regulation of mRNAs selectively within each of these cell populations, this enables identification highly specific processes that could be targeted for diagnostics or therapeutics. Hypothalamic CRH is a critical initiating signal of the stress response that is converted to a whole-body stress response via the hypothalamus–pituitary–adrenal (HPA) axis 34 , 35 , 36 , 37 , 38 . Within the CeL, Crh neurons are critical mediators of the aversive stimulus response, as well as of associative learning 17 , 39 , 40 , 41 . Recently, functional dissection of Crh neuronal activity during FC and EXT demonstrated a critical role for Crh neurons in the acquisition of associative fear, as well as the acquisition of EXT 40 , 42 , 43 , 44 . Crh neuronal activity is necessary for the acquisition of weak threats, whereas these neurons appear to be silenced during extinction of learned fear memories 40 , 42 . In addition, a mutually inhibitory circuit between Crh and Sst neurons gate the generation of active and passive fear responses 17 . FC and EXT precipitate changes in the expression of genes within distinct cellular populations responsible for long-lasting memory. Given the critical role the CeA Crh neuron population plays in fear learning and memory, characterizing the molecular changes specifically within this population during FC and EXT learning may provide valuable insight into potential therapeutic interventions for humans with fear-related disorders 45 . Here, using translating ribosome affinity purification (TRAP) and RNA sequencing (TRAP-seq) 46 , 47 , we examine changes in polysome-associated RNAs of Crh neurons within the CeL, following tone alone (TA), FC, or EXT in both male and female mice 47 , 48 . We perform gene co-expression network analysis 49 , followed by gene set enrichment analaysis (GSEA) 50 and upstream regulator analysis (URA) 51 of gene and gene network changes to identify pathways regulated by EXT in the CeL Crh population, identifying CREB (cAMP response element binding protein) as an upstream regulator of gene expression during EXT in Crh neurons 52 , 53 , 54 , 55 , 56 . By validating genes and networks, together with the use of cell type-specific viral-mediated gene transfer for causal analyses, we discovered that CREB levels in Crh neurons regulate fear expression and the efficacy of EXT learning. Our findings demonstrate distinct patterns of translational change following EXT that validate previous studies, and provide targets for future translational research into cell type-specific control of fear learning and memory. Results Generation of Crh-TRAP line Crh neurons within the amygdala are found primarily in the CeL (Fig. 1a–c ). To examine actively translating mRNA transcripts following FC or EXT, we generated a CRH-TRAP mouse by crossing a Crh-Cre line with a Cre-dependent eGFP-L10a line, which contains a fusion of eGFP with the L10a ribosomal protein (Fig. 1d ) 47 , 57 . Expression patterns of ribosome-tagged eGFP closely recapitulates that", "role": "user" }, { "content": "Fear and fear extinction learning (the gradual reduction of fear by repeated exposure to the feared object) are adaptive processes caused by molecular changes in specific brain circuits, and they're perturbed in conditions such as anxiety and post-traumatic stress disorder. A new study by investigators at McLean Hospital and Massachusetts General Hospital reveals that the expression of a particular gene may function as a switch to regulate feelings of fear and its extinction. The findings point to a potential new target for diagnosing, treating, and preventing fear-related psychiatric illnesses. The research, which is published in Nature Communications, focuses on neurons in the central amygdala that produce a corticotropin-releasing hormone (Crh) and are involved in the brain's response to threats. The scientists examined how different gene pathways are activated within Crh neurons after the expression or extinction of fear. \"This precise analysis utilized a new cell-type-specific technology called translating ribosome affinity purification, or TRAP, to identify gene expression only within the Crh amygdala cells,\" said co-senior author Nikolaos P. Daskalakis, MD, Ph.D., who is the director of the Neurogenomics and Translational Bioinformatics Laboratory at McLean Hospital. \"The results showed that diverse gene networks are activated or inhibited by fear versus extinction learning.\" Additional analyses demonstrated that fear extinction learning requires that Crh neurons reduce their expression of a regulatory gene named CREB, which codes for a protein called cAMP response-element binding protein. Indeed, overexpression of CREB in Crh neurons in mice increased their fear response. \"CREB is well known to be involved in learning and memory, and these data suggest that it may act as a molecular switch that regulates expression of fear and its extinction,\" said co-senior author Kerry J. Ressler, MD, Ph.D., McLean's chief scientific officer, McLean's chief of the Center of Excellence in Depression and Anxiety Disorders, and co-director of the Silvio O. Conte Center for Stress Peptide Advanced Research, Education & Dissemination (SPARED) at McLean Hospital. Targeting CREB expression in Crh neurons in the brain's amygdala may provide a better understanding of the mechanisms behind fear-based psychiatric illnesses and represent a promising treatment strategy. \"Fear is one of the most basic emotions we all experience in response to trauma—and also one of the most complex to study,\" says Magali Haas, MD, Ph.D., CEO and president of Cohen Veterans Bioscience, the nonprofit biotech research organization fast-tracking diagnostics and therapeutics for trauma-related and other brain disorders. \"We are proud to support this latest research into how animal models' brains process fear, which could provide important parallels in humans and lead to new ways to diagnose or treat disorders such as PTSD.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Fear and extinction learning are adaptive processes caused by molecular changes in specific neural circuits. Neurons expressing the corticotropin-releasing hormone gene ( Crh ) in central amygdala (CeA) are implicated in threat regulation, yet little is known of cell type-specific gene pathways mediating adaptive learning. We translationally profiled the transcriptome of CeA Crh -expressing cells (Crh neurons) after fear conditioning or extinction in mice using translating ribosome affinity purification (TRAP) and RNAseq. Differential gene expression and co-expression network analyses identified diverse networks activated or inhibited by fear vs extinction. Upstream regulator analysis demonstrated that extinction associates with reduced CREB expression, and viral vector-induced increased CREB expression in Crh neurons increased fear expression and inhibited extinction. These findings suggest that CREB, within CeA Crh neurons, may function as a molecular switch that regulates expression of fear and its extinction. Cell-type specific translational analyses may suggest targets useful for understanding and treating stress-related psychiatric illness. Introduction Fear and fear extinction learning are evolutionarily conserved, homeostatic processes that are critically perturbed in a variety of neuropsychiatric disorders, such as posttraumatic stress disorder (PTSD), generalized anxiety disorders, bipolar disorder, and Alzheimer’s disease 1 , 2 , 3 , 4 . Fear learning is a complex process involving associative learning of explicit trauma-paired cues and more generalized contextual elements 5 . Understanding the neural circuitries regulating this process, and molecular changes in these circuitries following behavior may reveal translationally relevant molecular pathways relevant to the diagnosis, treatment, and even prevention of human disease 6 , 7 . As an example, PTSD has been repeatedly associated with a failure to recover from traumatic events, conceptualized as a failure to extinguish learned fear 8 , 9 , 10 . Notably, the largest-to-date genome-wide association study (GWAS) for PTSD recently found genome-wide level associations between variants of CRHR1 , the gene encoding corticotropin-releasing hormone (CRH) receptor-type 1, genetically regulated brain-specific CRHR1 expression, and PTSD diagnosis and symptom clusters 11 , 12 , along with its identification in large GWAS of anxiety and habitual alcohol use 13 , 14 . The amygdala is a primary integrator of aversive physical stimuli and associated cues 15 , 16 . Specifically, the central amygdala (CeA) plays a well characterized role in regulating the expression of defensive responses via its connections to downstream regions 17 . The CeA comprises three cytoarchitecturally distinct sub-compartments (central capsular (CeC), lateral (CeL), and medial (CeM)). Recent characterizations of CeA circuitry have identified multiple recursive inhibitory loops which hierarchically gate threat responses (reflexive, active, passive, etc.) through their intra-CeA and output projections 18 , 19 , 20 , 21 , 22 . Within the CeA there are several molecularly distinct neuronal populations which mediate specific elements of fear conditioning (FC) and extinction (EXT) learning processes 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 . Specifically, within the CeL, three populations represent the majority of neurons: those marked by Crh, Sst , or Prkcd , 17 , 22 , 23 , 32 . Until recently, it has not been possible to characterize translational regulation of mRNAs selectively within each of these cell populations, this enables identification highly specific processes that could be targeted for diagnostics or therapeutics. Hypothalamic CRH is a critical initiating signal of the stress response that is converted to a whole-body stress response via the hypothalamus–pituitary–adrenal (HPA) axis 34 , 35 , 36 , 37 , 38 . Within the CeL, Crh neurons are critical mediators of the aversive stimulus response, as well as of associative learning 17 , 39 , 40 , 41 . Recently, functional dissection of Crh neuronal activity during FC and EXT demonstrated a critical role for Crh neurons in the acquisition of associative fear, as well as the acquisition of EXT 40 , 42 , 43 , 44 . Crh neuronal activity is necessary for the acquisition of weak threats, whereas these neurons appear to be silenced during extinction of learned fear memories 40 , 42 . In addition, a mutually inhibitory circuit between Crh and Sst neurons gate the generation of active and passive fear responses 17 . FC and EXT precipitate changes in the expression of genes within distinct cellular populations responsible for long-lasting memory. Given the critical role the CeA Crh neuron population plays in fear learning and memory, characterizing the molecular changes specifically within this population during FC and EXT learning may provide valuable insight into potential therapeutic interventions for humans with fear-related disorders 45 . Here, using translating ribosome affinity purification (TRAP) and RNA sequencing (TRAP-seq) 46 , 47 , we examine changes in polysome-associated RNAs of Crh neurons within the CeL, following tone alone (TA), FC, or EXT in both male and female mice 47 , 48 . We perform gene co-expression network analysis 49 , followed by gene set enrichment analaysis (GSEA) 50 and upstream regulator analysis (URA) 51 of gene and gene network changes to identify pathways regulated by EXT in the CeL Crh population, identifying CREB (cAMP response element binding protein) as an upstream regulator of gene expression during EXT in Crh neurons 52 , 53 , 54 , 55 , 56 . By validating genes and networks, together with the use of cell type-specific viral-mediated gene transfer for causal analyses, we discovered that CREB levels in Crh neurons regulate fear expression and the efficacy of EXT learning. Our findings demonstrate distinct patterns of translational change following EXT that validate previous studies, and provide targets for future translational research into cell type-specific control of fear learning and memory. Results Generation of Crh-TRAP line Crh neurons within the amygdala are found primarily in the CeL (Fig. 1a–c ). To examine actively translating mRNA transcripts following FC or EXT, we generated a CRH-TRAP mouse by crossing a Crh-Cre line with a Cre-dependent eGFP-L10a line, which contains a fusion of eGFP with the L10a ribosomal protein (Fig. 1d ) 47 , 57 . Expression patterns of ribosome-tagged eGFP closely recapitulates that<|im_end|> <|im_start|>assistant Fear and fear extinction learning (the gradual reduction of fear by repeated exposure to the feared object) are adaptive processes caused by molecular changes in specific brain circuits, and they're perturbed in conditions such as anxiety and post-traumatic stress disorder. A new study by investigators at McLean Hospital and Massachusetts General Hospital reveals that the expression of a particular gene may function as a switch to regulate feelings of fear and its extinction. The findings point to a potential new target for diagnosing, treating, and preventing fear-related psychiatric illnesses. The research, which is published in Nature Communications, focuses on neurons in the central amygdala that produce a corticotropin-releasing hormone (Crh) and are involved in the brain's response to threats. The scientists examined how different gene pathways are activated within Crh neurons after the expression or extinction of fear. "This precise analysis utilized a new cell-type-specific technology called translating ribosome affinity purification, or TRAP, to identify gene expression only within the Crh amygdala cells," said co-senior author Nikolaos P. Daskalakis, MD, Ph.D., who is the director of the Neurogenomics and Translational Bioinformatics Laboratory at McLean Hospital. "The results showed that diverse gene networks are activated or inhibited by fear versus extinction learning." Additional analyses demonstrated that fear extinction learning requires that Crh neurons reduce their expression of a regulatory gene named CREB, which codes for a protein called cAMP response-element binding protein. Indeed, overexpression of CREB in Crh neurons in mice increased their fear response. "CREB is well known to be involved in learning and memory, and these data suggest that it may act as a molecular switch that regulates expression of fear and its extinction," said co-senior author Kerry J. Ressler, MD, Ph.D., McLean's chief scientific officer, McLean's chief of the Center of Excellence in Depression and Anxiety Disorders, and co-director of the Silvio O. Conte Center for Stress Peptide Advanced Research, Education & Dissemination (SPARED) at McLean Hospital. Targeting CREB expression in Crh neurons in the brain's amygdala may provide a better understanding of the mechanisms behind fear-based psychiatric illnesses and represent a promising treatment strategy. "Fear is one of the most basic emotions we all experience in response to trauma—and also one of the most complex to study," says Magali Haas, MD, Ph.D., CEO and president of Cohen Veterans Bioscience, the nonprofit biotech research organization fast-tracking diagnostics and therapeutics for trauma-related and other brain disorders. "We are proud to support this latest research into how animal models' brains process fear, which could provide important parallels in humans and lead to new ways to diagnose or treat disorders such as PTSD." <|im_end|>

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220, 1544, 1174, 220, 1591, 1174, 220, 1682, 1174, 220, 966, 1174, 220, 2148, 1174, 220, 843, 1174, 220, 1644, 662, 45863, 11, 2949, 279, 24703, 43, 11, 2380, 22673, 4097, 279, 8857, 315, 34313, 25, 1884, 13160, 555, 4656, 71, 11, 328, 267, 1174, 477, 2394, 74, 4484, 1174, 220, 1114, 1174, 220, 1313, 1174, 220, 1419, 1174, 220, 843, 662, 30070, 6051, 11, 433, 706, 539, 1027, 3284, 311, 70755, 12215, 1697, 19812, 315, 296, 51295, 2170, 82775, 2949, 1855, 315, 1521, 2849, 22673, 11, 420, 20682, 22654, 7701, 3230, 11618, 430, 1436, 387, 17550, 369, 50518, 477, 9139, 88886, 13, 39515, 8942, 278, 4079, 12904, 39, 374, 264, 9200, 79516, 8450, 315, 279, 8631, 2077, 430, 374, 16489, 311, 264, 4459, 9534, 8631, 2077, 4669, 279, 45455, 17243, 355, 4235, 33686, 3159, 661, 4235, 329, 47738, 320, 6748, 32, 8, 8183, 220, 1958, 1174, 220, 1758, 1174, 220, 1927, 1174, 220, 1806, 1174, 220, 1987, 662, 25218, 279, 24703, 43, 11, 4656, 71, 34313, 527, 9200, 25098, 3046, 315, 279, 1860, 53453, 39535, 2077, 11, 439, 1664, 439, 315, 70003, 6975, 220, 1114, 1174, 220, 2137, 1174, 220, 1272, 1174, 220, 3174, 662, 42096, 11, 16003, 834, 2879, 315, 4656, 71, 79402, 5820, 2391, 16396, 323, 34857, 21091, 264, 9200, 3560, 369, 4656, 71, 34313, 304, 279, 24279, 315, 70003, 8850, 11, 439, 1664, 439, 279, 24279, 315, 34857, 220, 1272, 1174, 220, 2983, 1174, 220, 3391, 1174, 220, 2096, 662, 4656, 71, 79402, 5820, 374, 5995, 369, 279, 24279, 315, 7621, 18208, 11, 20444, 1521, 34313, 5101, 311, 387, 92781, 2391, 52609, 315, 9687, 8850, 19459, 220, 1272, 1174, 220, 2983, 662, 763, 5369, 11, 264, 53579, 20747, 10843, 16622, 1990, 4656, 71, 323, 328, 267, 34313, 18618, 279, 9659, 315, 4642, 323, 28979, 8850, 14847, 220, 1114, 662, 16396, 323, 34857, 36841, 20227, 4442, 304, 279, 7645, 315, 21389, 2949, 12742, 35693, 22673, 8647, 369, 1317, 65265, 5044, 13, 16644, 279, 9200, 3560, 279, 24703, 32, 4656, 71, 49384, 7187, 11335, 304, 8850, 6975, 323, 5044, 11, 3752, 4954, 279, 31206, 4442, 11951, 2949, 420, 7187, 2391, 16396, 323, 34857, 6975, 1253, 3493, 15525, 20616, 1139, 4754, 37471, 39455, 369, 12966, 449, 8850, 14228, 24673, 220, 1774, 662, 5810, 11, 1701, 67371, 20735, 32554, 51552, 94536, 320, 2434, 2599, 8, 323, 41214, 62119, 320, 2434, 2599, 7962, 80, 8, 220, 2790, 1174, 220, 2618, 1174, 584, 21635, 4442, 304, 99919, 638, 75968, 46916, 2170, 315, 4656, 71, 34313, 2949, 279, 24703, 43, 11, 2768, 16630, 7636, 320, 15559, 705, 16396, 11, 477, 34857, 304, 2225, 8762, 323, 8954, 24548, 220, 2618, 1174, 220, 2166, 662, 1226, 2804, 15207, 1080, 82593, 4009, 6492, 220, 2491, 1174, 8272, 555, 15207, 743, 70272, 3260, 954, 285, 320, 38, 93052, 8, 220, 1135, 323, 42830, 40704, 6492, 320, 41410, 8, 220, 3971, 315, 15207, 323, 15207, 4009, 4442, 311, 10765, 44014, 35319, 555, 34857, 304, 279, 24703, 43, 4656, 71, 7187, 11, 25607, 50708, 33, 320, 66, 16407, 2077, 2449, 11212, 13128, 8, 439, 459, 42830, 40704, 315, 15207, 7645, 2391, 34857, 304, 4656, 71, 34313, 220, 4103, 1174, 220, 4331, 1174, 220, 4370, 1174, 220, 2131, 1174, 220, 3487, 662, 3296, 69772, 21389, 323, 14488, 11, 3871, 449, 279, 1005, 315, 2849, 955, 19440, 29962, 82076, 15207, 8481, 369, 59557, 29060, 11, 584, 11352, 430, 50708, 33, 5990, 304, 4656, 71, 34313, 37377, 8850, 7645, 323, 279, 41265, 315, 34857, 6975, 13, 5751, 14955, 20461, 12742, 12912, 315, 12215, 1697, 2349, 2768, 34857, 430, 9788, 3766, 7978, 11, 323, 3493, 11811, 369, 3938, 12215, 1697, 3495, 1139, 2849, 955, 19440, 2585, 315, 8850, 6975, 323, 5044, 13, 18591, 24367, 315, 4656, 71, 12, 2434, 2599, 1584, 4656, 71, 34313, 2949, 279, 64383, 29684, 6181, 527, 1766, 15871, 304, 279, 24703, 43, 320, 30035, 13, 220, 16, 64, 4235, 66, 7609, 2057, 21635, 22815, 67371, 78872, 61412, 2768, 16396, 477, 34857, 11, 584, 8066, 264, 12904, 39, 12, 2434, 2599, 8814, 555, 27736, 264, 4656, 71, 7813, 265, 1584, 449, 264, 7948, 43918, 384, 38, 11960, 8288, 605, 64, 1584, 11, 902, 5727, 264, 37608, 315, 384, 38, 11960, 449, 279, 445, 605, 64, 20735, 96108, 13128, 320, 30035, 13, 220, 16, 67, 883, 220, 2618, 1174, 220, 3226, 662, 16783, 12912, 315, 20735, 32554, 39304, 3640, 384, 38, 11960, 15499, 55099, 275, 24031, 430, 128257, 198, 128256, 78191, 198, 91471, 323, 8850, 52609, 6975, 320, 1820, 53722, 14278, 315, 8850, 555, 11763, 14675, 311, 279, 38569, 1665, 8, 527, 48232, 11618, 9057, 555, 31206, 4442, 304, 3230, 8271, 46121, 11, 323, 814, 2351, 18713, 75325, 304, 4787, 1778, 439, 18547, 323, 1772, 80367, 33030, 8631, 19823, 13, 362, 502, 4007, 555, 26453, 520, 4584, 49862, 15429, 323, 22108, 3331, 15429, 21667, 430, 279, 7645, 315, 264, 4040, 15207, 1253, 734, 439, 264, 3480, 311, 37377, 16024, 315, 8850, 323, 1202, 52609, 13, 578, 14955, 1486, 311, 264, 4754, 502, 2218, 369, 13493, 14759, 11, 27723, 11, 323, 27252, 8850, 14228, 47657, 49909, 13, 578, 3495, 11, 902, 374, 4756, 304, 22037, 26545, 11, 24400, 389, 34313, 304, 279, 8792, 64383, 29684, 6181, 430, 8356, 264, 23100, 87537, 897, 258, 5621, 84652, 36908, 320, 16384, 71, 8, 323, 527, 6532, 304, 279, 8271, 596, 2077, 311, 18208, 13, 578, 14248, 25078, 1268, 2204, 15207, 44014, 527, 22756, 2949, 4656, 71, 34313, 1306, 279, 7645, 477, 52609, 315, 8850, 13, 330, 2028, 24473, 6492, 34716, 264, 502, 2849, 10827, 19440, 5557, 2663, 67371, 20735, 32554, 51552, 94536, 11, 477, 5091, 2599, 11, 311, 10765, 15207, 7645, 1193, 2949, 279, 4656, 71, 64383, 29684, 6181, 7917, 1359, 1071, 1080, 1355, 268, 2521, 3229, 97415, 437, 393, 13, 423, 1091, 278, 76877, 11, 14306, 11, 2405, 920, 2637, 889, 374, 279, 7690, 315, 279, 32359, 4469, 24203, 323, 4149, 75, 1697, 24432, 98588, 32184, 520, 4584, 49862, 15429, 13, 330, 791, 3135, 8710, 430, 17226, 15207, 14488, 527, 22756, 477, 99669, 555, 8850, 19579, 52609, 6975, 1210, 24086, 29060, 21091, 430, 8850, 52609, 6975, 7612, 430, 4656, 71, 34313, 8108, 872, 7645, 315, 264, 23331, 15207, 7086, 50708, 33, 11, 902, 14236, 369, 264, 13128, 2663, 272, 16407, 2077, 29552, 11212, 13128, 13, 23150, 11, 927, 29199, 315, 50708, 33, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Colonially-breeding seabirds have long served as indicator species for the health of the oceans on which they depend. Abundance and breeding data are repeatedly collected at fixed study sites in the hopes that changes in abundance and productivity may be useful for adaptive management of marine resources, but their suitability for this purpose is often unknown. To address this, we fit a Bayesian population dynamics model that includes process and observation error to all known Adélie penguin abundance data (1982–2015) in the Antarctic, covering >95% of their population globally. We find that process error exceeds observation error in this system, and that continent-wide “year effects” strongly influence population growth rates. Our findings have important implications for the use of Adélie penguins in Southern Ocean feedback management, and suggest that aggregating abundance across space provides the fastest reliable signal of true population change for species whose dynamics are driven by stochastic processes. Introduction Seabirds are widely considered reliable environmental indicators, as they are sensitive to multiple terrestrial and marine environmental factors 1 , 2 , 3 . In the Southern Ocean, Adélie penguins have played a critical role in understanding how the Antarctic ecosystem is changing in response to climate change, and this information has been key in shaping Antarctic conservation policy and management decisions 4 , 5 , 6 , 7 . However, despite the community’s reliance on the Adélie penguin as a marine sentinel 8 , there has been a nearly 30-year debate over the key mechanisms underlying Adélie population dynamics. The root of this uncertainty involves the relative influence of, and interactions among, factors known to influence Adélie abundance, such as prey and nest availability, sea ice conditions, predation, and weather 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . There have been many recent efforts to understand what drives observed changes in Adélie abundance and distribution (e.g., refs. 17 , 18 , 19 , 20 ) and several recent studies have identified clear trends in abundance within specific regions 12 , 18 , 19 , 20 , 21 , 22 , 23 . However, despite significant advances in understanding long-term trends, much remains unknown about what drives inter-annual variability and whether such fluctuations are informative of underlying ecosystem dynamics. Given the current limits of data and covariate availability, the magnitude of process error (i.e., unexplained variation in true abundance driven by unmodeled biotic or abiotic processes) and its dominance over observation error (i.e., errors due to measurement imprecision) is gaining recognition as an important driver of population dynamics, both in the Antarctic 24 , 25 and in other systems 26 . Moreover, the relative paucity of complete time series has made it difficult to generate robust metrics of environmental change through spatial or temporal aggregation, an idea initially raised by the Commission for the Conservation of Antarctic Marine Living Resources 24 (CCAMLR), which was established with the objective of conserving and managing Antarctic marine life. While CCAMLR has recognized that both stochastic and deterministic influences must be addressed when designing an adaptive feedback management system, tools for doing so remain an area of active development in statistical ecology and have not been fully utilized in the Antarctic. Addressing both the temporal and spatial components of Adélie population change will not only facilitate the use of the Adélie penguin as a tool for feedback management, but will allow for better model predictions on the abundance and distribution of Adélie penguins under climate change 27 . Using all the publicly available data on Adélie penguin abundance and distribution since 1982, we model population growth for each of Antarctica’s 267 known Adélie penguin colonies using a hierarchical Bayesian model that includes both a deterministic component driven by environmental covariates and year-specific stochastic variation (see Methods section and Supplementary Data 1 – 3 ). This model allows us to partition variation in Adélie population growth rates and determine the magnitude and importance of process error in driving Adélie population fluctuations. We use these parameter estimates to simulate time series that demonstrate the extent to which short-term fluctuations in abundance may be considered unreliable measures of ecosystem health and quantify the spatial and temporal aggregation required to reliably detect Adélie population trends. Results Population growth rates and aggregated dynamics Population growth rate was positively associated with peak winter sea ice over the previous 4 years or, put another way, negatively associated with prolonged periods without extensive sea ice (“ice droughts”) (Fig. 1a, c–f ). Growth rate was also weakly correlated with extensive summer sea ice 4 years prior, with a posterior distribution that was negative but overlapped zero (Fig. 1a, c–f ). Fig. 1 Parameter estimates and growth rate as a function of model covariates. a Adélie population growth rate ( r ) at average winter and summer peak sea ice concentrations ( β 1 ), and the effect of a one standard deviation change in winter ( β 2 ) or summer ( β 3 ) peak sea ice concentration on the population growth rate. b The finite-population standard deviation for each source of variation in the Adélie intrinsic growth rate. For a , b , thick lines represent the 50% equal-tailed credible intervals, thin lines represent the 95% equal-tailed credible intervals, and circles are the posterior medians. c , e Adélie population growth rate as a function of winter (summer) peak sea ice concentration, at mean winter (summer) peak sea ice concentration. The gray shaded areas represent the 95% equal-tailed credible intervals and the lines are the posterior medians. d , f Histograms of actual winter and summer peak sea ice conditions for all 267 sites across 34 years. Bars have been color coded to represent values associated with positive ( red ) or negative ( blue ) growth rates; gray bars reflect values associated with credible intervals that include support for both positive and negative growth rates Full size image The average population growth rate multiplier (i.e., the geometric mean of", "role": "user" }, { "content": "Penguins are noisy, as any visitor to an aquarium knows. Penguins may be noisy in others ways too, according to a new study published in Nature Communications. Scientists have long used Adélie penguin populations to monitor the health of the Southern Ocean and to understand how major factors such as fishing and climate change impact the oceans and the animals that rely on them. Now an extensive analysis of all known data on Adélie penguin populations over the last 35 years has found that only a small fraction of year-to-year changes in Adélie penguin populations can be attributed to measureable factors such as changes in sea ice. Instead, most of the short term fluctuations in the number of penguins breeding has no known cause; such 'noise' in the system is likely due to a host of marine and terrestrial factors that have not, or cannot, be measured at the majority of sites where penguins breed. \"In many ways, our study shows that watching Adélie penguin abundance may be like watching the stock market—short term fluctuations may be exceptionally hard to predict and may not signal any change in the fundamental health of the system,\" explains senior author Heather Lynch, Associate Professor of Ecology & Evolution at Stony Brook University. \"Therefore, adaptive management of marine resources, whereby we stand 'at the ready' to adjust our conservation strategy as new data are collected, may be as difficult, and as risky, as trying to time the stock market. Instead, our results suggest that to the extent Adélie penguins are used as a barometer of ecosystem health, the true dynamics may emerge only very slowly.\" This finding, detailed in the paper \"Pan-Antarctic analysis aggregating spatial elements of Adélie penguin abundance reveals robust dynamics despite stochastic noise,\" is important because it means that tracking abundance at individual colonies, one of the cornerstones of monitoring the health of the Antarctic ecosystem, may not provide a reliable signal on short time scales. \"By analyzing the data, we found that relatively little of the year-to-year variability in Adélie penguin abundance could be linked to something in the environment we can actually measure,\" said lead author Dr. Christian Che-Castaldo, a postdoctoral researcher in the Department of Ecology & Evolution at Stony Brook University. \"Precipitation at the site is one factor we know is likely to drive some of this unexplained variation, but like many other potential factors, it's not one we can easily measure in Antarctica.\" \"This doesn't mean that monitoring isn't important, only that we may have to adopt an even more conservative strategy for conserving marine resources. In the face of so much uncertainty, we may not detect a real decline until it's already too late,\" Dr. Lynch explained. Adélie penguins are one of four species of penguins with significant breeding populations in the Antarctic. Adélie penguins are the most well studied of all penguin species and, being distributed around the entire coastline of the Antarctic continent, are often considered the \"canaries in the coal mine\" for anthropogenic threats like fishing and climate change. In this study, the authors analyzed data from all 267 Adélie penguin populations in Antarctica stretching back to 1979, using data collated from the scientific literature under the auspices of a NASA-funded tool called the Mapping Application for Penguin Populations and Predicted Dynamics (MAPPPD). They used a statistical technique known as hierarchical Bayesian modelling to accommodate the fact that most Adélie penguin breeding locations are surveyed only rarely. Finding a statistically-rigorous way to 'fill in' missing data was key to the effort, since it allowed the research team to look at the population dynamics of penguins at larger spatial scales than has been possible in the past. Dr. Lynch emphasized that not only did the research uncover more details about the increase in Adélie penguin populations over the last three decades, but it suggests that monitoring more breeding colonies sporadically, rather than fewer sites consistently, may provide more timely and more reliable information for policymakers, despite short term fluctuations common in Adélie colonies. The study also illustrates a new method of tracking Adélie penguin populations throughout the entire continent rather than at selected study sites where the majority of the data are actually collected. They hope to study other penguin species in Antarctica using the same method. \"The findings, overall, provide clear guidance on how to extract the most information from our monitoring efforts, and highlight the benefits of working across disciplines for effective conservation,\" added co-author Dr. Jenouvrier at WHOI. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Colonially-breeding seabirds have long served as indicator species for the health of the oceans on which they depend. Abundance and breeding data are repeatedly collected at fixed study sites in the hopes that changes in abundance and productivity may be useful for adaptive management of marine resources, but their suitability for this purpose is often unknown. To address this, we fit a Bayesian population dynamics model that includes process and observation error to all known Adélie penguin abundance data (1982–2015) in the Antarctic, covering >95% of their population globally. We find that process error exceeds observation error in this system, and that continent-wide “year effects” strongly influence population growth rates. Our findings have important implications for the use of Adélie penguins in Southern Ocean feedback management, and suggest that aggregating abundance across space provides the fastest reliable signal of true population change for species whose dynamics are driven by stochastic processes. Introduction Seabirds are widely considered reliable environmental indicators, as they are sensitive to multiple terrestrial and marine environmental factors 1 , 2 , 3 . In the Southern Ocean, Adélie penguins have played a critical role in understanding how the Antarctic ecosystem is changing in response to climate change, and this information has been key in shaping Antarctic conservation policy and management decisions 4 , 5 , 6 , 7 . However, despite the community’s reliance on the Adélie penguin as a marine sentinel 8 , there has been a nearly 30-year debate over the key mechanisms underlying Adélie population dynamics. The root of this uncertainty involves the relative influence of, and interactions among, factors known to influence Adélie abundance, such as prey and nest availability, sea ice conditions, predation, and weather 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . There have been many recent efforts to understand what drives observed changes in Adélie abundance and distribution (e.g., refs. 17 , 18 , 19 , 20 ) and several recent studies have identified clear trends in abundance within specific regions 12 , 18 , 19 , 20 , 21 , 22 , 23 . However, despite significant advances in understanding long-term trends, much remains unknown about what drives inter-annual variability and whether such fluctuations are informative of underlying ecosystem dynamics. Given the current limits of data and covariate availability, the magnitude of process error (i.e., unexplained variation in true abundance driven by unmodeled biotic or abiotic processes) and its dominance over observation error (i.e., errors due to measurement imprecision) is gaining recognition as an important driver of population dynamics, both in the Antarctic 24 , 25 and in other systems 26 . Moreover, the relative paucity of complete time series has made it difficult to generate robust metrics of environmental change through spatial or temporal aggregation, an idea initially raised by the Commission for the Conservation of Antarctic Marine Living Resources 24 (CCAMLR), which was established with the objective of conserving and managing Antarctic marine life. While CCAMLR has recognized that both stochastic and deterministic influences must be addressed when designing an adaptive feedback management system, tools for doing so remain an area of active development in statistical ecology and have not been fully utilized in the Antarctic. Addressing both the temporal and spatial components of Adélie population change will not only facilitate the use of the Adélie penguin as a tool for feedback management, but will allow for better model predictions on the abundance and distribution of Adélie penguins under climate change 27 . Using all the publicly available data on Adélie penguin abundance and distribution since 1982, we model population growth for each of Antarctica’s 267 known Adélie penguin colonies using a hierarchical Bayesian model that includes both a deterministic component driven by environmental covariates and year-specific stochastic variation (see Methods section and Supplementary Data 1 – 3 ). This model allows us to partition variation in Adélie population growth rates and determine the magnitude and importance of process error in driving Adélie population fluctuations. We use these parameter estimates to simulate time series that demonstrate the extent to which short-term fluctuations in abundance may be considered unreliable measures of ecosystem health and quantify the spatial and temporal aggregation required to reliably detect Adélie population trends. Results Population growth rates and aggregated dynamics Population growth rate was positively associated with peak winter sea ice over the previous 4 years or, put another way, negatively associated with prolonged periods without extensive sea ice (“ice droughts”) (Fig. 1a, c–f ). Growth rate was also weakly correlated with extensive summer sea ice 4 years prior, with a posterior distribution that was negative but overlapped zero (Fig. 1a, c–f ). Fig. 1 Parameter estimates and growth rate as a function of model covariates. a Adélie population growth rate ( r ) at average winter and summer peak sea ice concentrations ( β 1 ), and the effect of a one standard deviation change in winter ( β 2 ) or summer ( β 3 ) peak sea ice concentration on the population growth rate. b The finite-population standard deviation for each source of variation in the Adélie intrinsic growth rate. For a , b , thick lines represent the 50% equal-tailed credible intervals, thin lines represent the 95% equal-tailed credible intervals, and circles are the posterior medians. c , e Adélie population growth rate as a function of winter (summer) peak sea ice concentration, at mean winter (summer) peak sea ice concentration. The gray shaded areas represent the 95% equal-tailed credible intervals and the lines are the posterior medians. d , f Histograms of actual winter and summer peak sea ice conditions for all 267 sites across 34 years. Bars have been color coded to represent values associated with positive ( red ) or negative ( blue ) growth rates; gray bars reflect values associated with credible intervals that include support for both positive and negative growth rates Full size image The average population growth rate multiplier (i.e., the geometric mean of<|im_end|> <|im_start|>assistant Penguins are noisy, as any visitor to an aquarium knows. Penguins may be noisy in others ways too, according to a new study published in Nature Communications. Scientists have long used Adélie penguin populations to monitor the health of the Southern Ocean and to understand how major factors such as fishing and climate change impact the oceans and the animals that rely on them. Now an extensive analysis of all known data on Adélie penguin populations over the last 35 years has found that only a small fraction of year-to-year changes in Adélie penguin populations can be attributed to measureable factors such as changes in sea ice. Instead, most of the short term fluctuations in the number of penguins breeding has no known cause; such 'noise' in the system is likely due to a host of marine and terrestrial factors that have not, or cannot, be measured at the majority of sites where penguins breed. "In many ways, our study shows that watching Adélie penguin abundance may be like watching the stock market—short term fluctuations may be exceptionally hard to predict and may not signal any change in the fundamental health of the system," explains senior author Heather Lynch, Associate Professor of Ecology & Evolution at Stony Brook University. "Therefore, adaptive management of marine resources, whereby we stand 'at the ready' to adjust our conservation strategy as new data are collected, may be as difficult, and as risky, as trying to time the stock market. Instead, our results suggest that to the extent Adélie penguins are used as a barometer of ecosystem health, the true dynamics may emerge only very slowly." This finding, detailed in the paper "Pan-Antarctic analysis aggregating spatial elements of Adélie penguin abundance reveals robust dynamics despite stochastic noise," is important because it means that tracking abundance at individual colonies, one of the cornerstones of monitoring the health of the Antarctic ecosystem, may not provide a reliable signal on short time scales. "By analyzing the data, we found that relatively little of the year-to-year variability in Adélie penguin abundance could be linked to something in the environment we can actually measure," said lead author Dr. Christian Che-Castaldo, a postdoctoral researcher in the Department of Ecology & Evolution at Stony Brook University. "Precipitation at the site is one factor we know is likely to drive some of this unexplained variation, but like many other potential factors, it's not one we can easily measure in Antarctica." "This doesn't mean that monitoring isn't important, only that we may have to adopt an even more conservative strategy for conserving marine resources. In the face of so much uncertainty, we may not detect a real decline until it's already too late," Dr. Lynch explained. Adélie penguins are one of four species of penguins with significant breeding populations in the Antarctic. Adélie penguins are the most well studied of all penguin species and, being distributed around the entire coastline of the Antarctic continent, are often considered the "canaries in the coal mine" for anthropogenic threats like fishing and climate change. In this study, the authors analyzed data from all 267 Adélie penguin populations in Antarctica stretching back to 1979, using data collated from the scientific literature under the auspices of a NASA-funded tool called the Mapping Application for Penguin Populations and Predicted Dynamics (MAPPPD). They used a statistical technique known as hierarchical Bayesian modelling to accommodate the fact that most Adélie penguin breeding locations are surveyed only rarely. Finding a statistically-rigorous way to 'fill in' missing data was key to the effort, since it allowed the research team to look at the population dynamics of penguins at larger spatial scales than has been possible in the past. Dr. Lynch emphasized that not only did the research uncover more details about the increase in Adélie penguin populations over the last three decades, but it suggests that monitoring more breeding colonies sporadically, rather than fewer sites consistently, may provide more timely and more reliable information for policymakers, despite short term fluctuations common in Adélie colonies. The study also illustrates a new method of tracking Adélie penguin populations throughout the entire continent rather than at selected study sites where the majority of the data are actually collected. They hope to study other penguin species in Antarctica using the same method. "The findings, overall, provide clear guidance on how to extract the most information from our monitoring efforts, and highlight the benefits of working across disciplines for effective conservation," added co-author Dr. Jenouvrier at WHOI. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Pioneer transcription factors establish new cell-fate competence by triggering chromatin remodeling. However, many features of pioneer action, such as their kinetics and stability, remain poorly defined. Here, we show that Pax7, by opening a unique repertoire of enhancers, is necessary and sufficient for specification of one pituitary lineage. Pax7 binds its targeted enhancers rapidly, but chromatin remodeling and gene activation are slower. Enhancers opened by Pax7 show a loss of DNA methylation and acquire stable epigenetic memory, as evidenced by binding of nonpioneer factors after Pax7 withdrawal. This work shows that transient Pax7 expression is sufficient for stable specification of cell identity. Main Cell specification and differentiation occur throughout development in multicellular organisms and, in complex life forms, lead to a high diversity of cells. The differentiation of cells into different lineages is implemented by a unique combination of transcription factors (TFs) that collectively control the program of cell-specific gene expression. During development, progenitors are specified by the action of selector genes that establish the differentiation competence of downstream lineages. Pioneer factors are a class of TFs that establish new differentiation competence, because they have the unique ability to bind condensed, otherwise inaccessible, chromatin and to open this chromatin for access by other TFs. The three pluripotency factors Oct4, Klf4 and Sox2 have pioneer activity on a global scale by widely affecting the epigenome beyond their initial binding sites 1 . In addition, several TFs have been shown to have more localized pioneer activity. The ability of FoxA to specify liver fate relies on its ability to alter chromatin organization after binding nucleosomal target-DNA sequences 2 . We have shown that the factor Pax7 specifies intermediate pituitary melanotrope cell identity through pioneer activity 3 . The pioneer TF C/EBPα has been implicated in macrophage differentiation 4 , and the TF EBF1 has been implicated in B cell development 5 . Recently, two neurogenic bHLH TFs, NeuroD1 and MASH1 (Ascl1), have also been suggested to have pioneer activity during neural development 6 , 7 . Here, we used the Pax7 pituitary model to define the mechanism and stability of cell specification through pioneer action. The pituitary has two lineages that use the same hormone precursor, pro-opiomelanocortin (POMC), for entirely different biological functions. Indeed, POMC-expressing corticotropes produce ACTH, which controls adrenal glucocorticoid synthesis, whereas melanotropes process POMC into α-melanocyte-stimulating hormone, which regulates pigmentation (Fig. 1a ). Transcriptional regulation of the Pomc gene is unique to each lineage, but the same highly cell-restricted factor, Tpit, drives terminal differentiation of both lineages 8 , 9 . Pax7 acts before Tpit in intermediate lobe progenitors and implements a unique tissue identity, after which Tpit-driven differentiation establishes the melanotrope identity 3 . We characterized the actions of Pax7 within the framework of the critical properties of pioneer TFs. These actions include the ability to: (i) bind DNA target sites in heterochromatin; (ii) initiate remodeling of the surrounding chromatin; (iii) facilitate binding of other TFs; and (iv) trigger stable changes in chromatin accessibility, thus ensuring epigenetic stability, i.e., long-term access by nonpioneer factors. Fig. 1: Unique enhancer, but not promoter, repertoires define lineage-specific chromatin landscapes. a , Schematic representation of pituitary tissue and experimental procedure for purification of POMC-expressing melanotropes of the intermediate lobe (NIL) and corticotropes of the anterior lobe (AL). b , Volcano plot of differential gene expression determined by RNA-seq analysis of two independent primary-cell replicates of pituitary corticotropes (cortico) and melanotropes (melano). Blue and red dots represent genes that are differentially expressed (FDR <0.05) in corticotropes and melanotropes, respectively. Genes not significantly differentially expressed are shown in gray. The number of cell-specific genes is indicated; the P values for their enrichment were derived from analyses with the edgeR tool, which assesses differential expression for each gene by using an exact test analogous to Fisher's exact test but adapted for overdispersed data. c , Genomic distribution of the distance between ATAC–seq peaks and the closest TSS. Accessible regions segregate in two groups: proximal (<1 kb from TSS) and distal (>1 kb from TSS) regions. d , Genomic distribution of the distance between lineage-specific differentially accessible regions (DARs, P < 10 −20 ) and the closest TSS. e , Distance from cell-specific DARs to the nearest cortico- or melanospecific gene, as indicated. f , Dispersion plots of ATAC–seq signals from the average of two independent primary-cell replicates of purified corticotropes and melanotropes at the TSS (±200 bp) of differentially expressed genes (left) and at cell-specific DARs (right). Blue, corticotrope genes; red, melanotrope genes. The DARs strongly cluster according to lineage. Dotted lines indicate the threshold of minimal reads per kilobase per million mapped reads (RPKM) signal at statistically significant ( P < 10 −20 ) DARs. g , RNA-seq and ATAC–seq profiles of the melanotrope-specific Pcsk2 locus. Highlighted regions represent the promoter (gray) and DARs (yellow). Rep, replicate; chr, chromosome. Full size image We now show that the bulk of differentially accessible chromatin regions between the two alternate POMC cell fates are at putative enhancers. Pax7 binding is rapid at uniquely marked heterochromatin pioneer sites, and it initiates a slower process of chromatin opening that ultimately provides access to both developmental and signal-dependent TFs. Finally, Pax7 pioneer action is stable and ensures epigenetic memory even after Pax7 withdrawal. This long-term stability is supported by loss of DNA hypermethylation at pioneer-opened (‘pioneered’) enhancers. In summary, the present work defines the critical features of Pax7 pioneer action on tissue-specific progenitors for establishment and maintenance of cell identity. Results Lineage-specific chromatin accessibility at distal, but not promoter, elements To address the relative importance of cell-specific chromatin accessibility in establishing differentiation-specific programs of gene expression, we subjected fluorescence-activated cell sorting (FACS)-purified pituitary corticotropes and melanotropes from Pomc-EGFP transgenic mice 10 , 11 (Fig. 1a ) to RNA-seq and assay for transposon-accessible chromatin (ATAC–seq) analyses (Supplementary Fig. 1a–d ). Differential expression analysis of the transcriptomes showed 504 differentially expressed genes (false discovery rate (FDR) <0.05) with similar transcript proportions enriched in each lineage: 243 corticotrope-specific and 261 melanotrope-specific genes.", "role": "user" }, { "content": "Our genome contains all the information necessary to form a complete human being. This information, encoded in the genome's DNA, stretches over one to two metres long but still manages to squeeze into a cell about 100 times smaller than a green pea. To do so, the genome has to be compacted. Now a team led by Jacques Drouin, a researcher at the Montreal Clinical Research Institute (IRCM) and professor at Université de Montréal's Faculty of Medicine, has identified a key that can open up some parts of the compacted or closed genome. The discovery of this key, a pioneer factor, provides novel insight into mechanisms of genome access. The discovery was recently published in Nature Genetics. Like an archaeologist who unearths a long-buried civilization and reveals a whole new culture, this pioneer factor provides access to parts of the genome that were inaccessible due to its compacted state. Once upon a time, there were two cells Our lives began when two cells - an egg and a sperm - meet. Together, they produce a variety of 'progeny' whose functions and properties differ from their own. The human body actually has many types of cells - about 200. How can this diversity be explained? The answer lies in the genes. Imagine DNA as a book, with each gene amounting to a page of information. When new cells are formed, an army of translators known as 'transcription factors' is called into action. Each factor reproduces specific pages of the book at various stages in a person's development. Thanks to these stacks of pages, a cell differentiates, acquiring a distinct identity. \"That's why a cell in your liver and a cell in the tip of your toe share the same ancestor,\" explained Drouin, who is Director of the IRCM's Molecular Genetics Research Unit. To do their job, transcription factors must have access to the right gene at the right time. But only the uncompacted part of the genome is accessible to transcription factors. So, various parts of the genome have to be \"opened\" to produce different cells. But how? The key called Pax7 This is where Jacques Drouin and his PhD student, Alexandre Mayran, stepped in, examining two types of pituitary cells. \"The two types of cells seemed to use the same transcription factors to develop, right up until the very last stage,\" Drouin recalled. \"In theory, they should be identical, but they have completely different functions and are located in different parts of the pituitary.\" Trying to understand why, the IRCM researchers focused on one molecule, Pax7, and were able to demonstrated its crucial role. \"Pax7 acts like a key, opening specific parts of the genome,\" said Drouin. \"It's what we call a pioneer factor. Acting as a pioneer, Pax7 gives access to 2,500 new sites that transcription factors can bind to and express genes that were previously out of reach.\" Perfectly timed choreography Despite its important role in embryo development, pioneer action is far from being well-understood. Without pioneer factors, our cells wouldn't be able to diversify to such an extent. As well, pioneer action must occur at the right place and at the right time for a tissue to develop normally. If the mechanism fails, some genes will be expressed by mistake and this inappropriate gene expression causes diseases such as cancer. Pursuing their research, the IRCM team will now investigate Pax7's mechanism of action more thoroughly. \"We'd like to identify the proteins that interact with Pax7 in order to open specific parts of the compacted genome; these could be future therapeutic targets,\" said Drouin. Indeed, pioneers are key factors for reprogramming cells - to produce insulin-secreting cells that people with diabetes need, for example, or neurons to replace those lost in the brains of Parkinson's disease patients. Understanding pioneer factors is therefore a priority to realize the promises of cell and gene therapy. For Drouin and his team, the treasure hunt has just begun. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Pioneer transcription factors establish new cell-fate competence by triggering chromatin remodeling. However, many features of pioneer action, such as their kinetics and stability, remain poorly defined. Here, we show that Pax7, by opening a unique repertoire of enhancers, is necessary and sufficient for specification of one pituitary lineage. Pax7 binds its targeted enhancers rapidly, but chromatin remodeling and gene activation are slower. Enhancers opened by Pax7 show a loss of DNA methylation and acquire stable epigenetic memory, as evidenced by binding of nonpioneer factors after Pax7 withdrawal. This work shows that transient Pax7 expression is sufficient for stable specification of cell identity. Main Cell specification and differentiation occur throughout development in multicellular organisms and, in complex life forms, lead to a high diversity of cells. The differentiation of cells into different lineages is implemented by a unique combination of transcription factors (TFs) that collectively control the program of cell-specific gene expression. During development, progenitors are specified by the action of selector genes that establish the differentiation competence of downstream lineages. Pioneer factors are a class of TFs that establish new differentiation competence, because they have the unique ability to bind condensed, otherwise inaccessible, chromatin and to open this chromatin for access by other TFs. The three pluripotency factors Oct4, Klf4 and Sox2 have pioneer activity on a global scale by widely affecting the epigenome beyond their initial binding sites 1 . In addition, several TFs have been shown to have more localized pioneer activity. The ability of FoxA to specify liver fate relies on its ability to alter chromatin organization after binding nucleosomal target-DNA sequences 2 . We have shown that the factor Pax7 specifies intermediate pituitary melanotrope cell identity through pioneer activity 3 . The pioneer TF C/EBPα has been implicated in macrophage differentiation 4 , and the TF EBF1 has been implicated in B cell development 5 . Recently, two neurogenic bHLH TFs, NeuroD1 and MASH1 (Ascl1), have also been suggested to have pioneer activity during neural development 6 , 7 . Here, we used the Pax7 pituitary model to define the mechanism and stability of cell specification through pioneer action. The pituitary has two lineages that use the same hormone precursor, pro-opiomelanocortin (POMC), for entirely different biological functions. Indeed, POMC-expressing corticotropes produce ACTH, which controls adrenal glucocorticoid synthesis, whereas melanotropes process POMC into α-melanocyte-stimulating hormone, which regulates pigmentation (Fig. 1a ). Transcriptional regulation of the Pomc gene is unique to each lineage, but the same highly cell-restricted factor, Tpit, drives terminal differentiation of both lineages 8 , 9 . Pax7 acts before Tpit in intermediate lobe progenitors and implements a unique tissue identity, after which Tpit-driven differentiation establishes the melanotrope identity 3 . We characterized the actions of Pax7 within the framework of the critical properties of pioneer TFs. These actions include the ability to: (i) bind DNA target sites in heterochromatin; (ii) initiate remodeling of the surrounding chromatin; (iii) facilitate binding of other TFs; and (iv) trigger stable changes in chromatin accessibility, thus ensuring epigenetic stability, i.e., long-term access by nonpioneer factors. Fig. 1: Unique enhancer, but not promoter, repertoires define lineage-specific chromatin landscapes. a , Schematic representation of pituitary tissue and experimental procedure for purification of POMC-expressing melanotropes of the intermediate lobe (NIL) and corticotropes of the anterior lobe (AL). b , Volcano plot of differential gene expression determined by RNA-seq analysis of two independent primary-cell replicates of pituitary corticotropes (cortico) and melanotropes (melano). Blue and red dots represent genes that are differentially expressed (FDR <0.05) in corticotropes and melanotropes, respectively. Genes not significantly differentially expressed are shown in gray. The number of cell-specific genes is indicated; the P values for their enrichment were derived from analyses with the edgeR tool, which assesses differential expression for each gene by using an exact test analogous to Fisher's exact test but adapted for overdispersed data. c , Genomic distribution of the distance between ATAC–seq peaks and the closest TSS. Accessible regions segregate in two groups: proximal (<1 kb from TSS) and distal (>1 kb from TSS) regions. d , Genomic distribution of the distance between lineage-specific differentially accessible regions (DARs, P < 10 −20 ) and the closest TSS. e , Distance from cell-specific DARs to the nearest cortico- or melanospecific gene, as indicated. f , Dispersion plots of ATAC–seq signals from the average of two independent primary-cell replicates of purified corticotropes and melanotropes at the TSS (±200 bp) of differentially expressed genes (left) and at cell-specific DARs (right). Blue, corticotrope genes; red, melanotrope genes. The DARs strongly cluster according to lineage. Dotted lines indicate the threshold of minimal reads per kilobase per million mapped reads (RPKM) signal at statistically significant ( P < 10 −20 ) DARs. g , RNA-seq and ATAC–seq profiles of the melanotrope-specific Pcsk2 locus. Highlighted regions represent the promoter (gray) and DARs (yellow). Rep, replicate; chr, chromosome. Full size image We now show that the bulk of differentially accessible chromatin regions between the two alternate POMC cell fates are at putative enhancers. Pax7 binding is rapid at uniquely marked heterochromatin pioneer sites, and it initiates a slower process of chromatin opening that ultimately provides access to both developmental and signal-dependent TFs. Finally, Pax7 pioneer action is stable and ensures epigenetic memory even after Pax7 withdrawal. This long-term stability is supported by loss of DNA hypermethylation at pioneer-opened (‘pioneered’) enhancers. In summary, the present work defines the critical features of Pax7 pioneer action on tissue-specific progenitors for establishment and maintenance of cell identity. Results Lineage-specific chromatin accessibility at distal, but not promoter, elements To address the relative importance of cell-specific chromatin accessibility in establishing differentiation-specific programs of gene expression, we subjected fluorescence-activated cell sorting (FACS)-purified pituitary corticotropes and melanotropes from Pomc-EGFP transgenic mice 10 , 11 (Fig. 1a ) to RNA-seq and assay for transposon-accessible chromatin (ATAC–seq) analyses (Supplementary Fig. 1a–d ). Differential expression analysis of the transcriptomes showed 504 differentially expressed genes (false discovery rate (FDR) <0.05) with similar transcript proportions enriched in each lineage: 243 corticotrope-specific and 261 melanotrope-specific genes.<|im_end|> <|im_start|>assistant Our genome contains all the information necessary to form a complete human being. This information, encoded in the genome's DNA, stretches over one to two metres long but still manages to squeeze into a cell about 100 times smaller than a green pea. To do so, the genome has to be compacted. Now a team led by Jacques Drouin, a researcher at the Montreal Clinical Research Institute (IRCM) and professor at Université de Montréal's Faculty of Medicine, has identified a key that can open up some parts of the compacted or closed genome. The discovery of this key, a pioneer factor, provides novel insight into mechanisms of genome access. The discovery was recently published in Nature Genetics. Like an archaeologist who unearths a long-buried civilization and reveals a whole new culture, this pioneer factor provides access to parts of the genome that were inaccessible due to its compacted state. Once upon a time, there were two cells Our lives began when two cells - an egg and a sperm - meet. Together, they produce a variety of 'progeny' whose functions and properties differ from their own. The human body actually has many types of cells - about 200. How can this diversity be explained? The answer lies in the genes. Imagine DNA as a book, with each gene amounting to a page of information. When new cells are formed, an army of translators known as 'transcription factors' is called into action. Each factor reproduces specific pages of the book at various stages in a person's development. Thanks to these stacks of pages, a cell differentiates, acquiring a distinct identity. "That's why a cell in your liver and a cell in the tip of your toe share the same ancestor," explained Drouin, who is Director of the IRCM's Molecular Genetics Research Unit. To do their job, transcription factors must have access to the right gene at the right time. But only the uncompacted part of the genome is accessible to transcription factors. So, various parts of the genome have to be "opened" to produce different cells. But how? The key called Pax7 This is where Jacques Drouin and his PhD student, Alexandre Mayran, stepped in, examining two types of pituitary cells. "The two types of cells seemed to use the same transcription factors to develop, right up until the very last stage," Drouin recalled. "In theory, they should be identical, but they have completely different functions and are located in different parts of the pituitary." Trying to understand why, the IRCM researchers focused on one molecule, Pax7, and were able to demonstrated its crucial role. "Pax7 acts like a key, opening specific parts of the genome," said Drouin. "It's what we call a pioneer factor. Acting as a pioneer, Pax7 gives access to 2,500 new sites that transcription factors can bind to and express genes that were previously out of reach." Perfectly timed choreography Despite its important role in embryo development, pioneer action is far from being well-understood. Without pioneer factors, our cells wouldn't be able to diversify to such an extent. As well, pioneer action must occur at the right place and at the right time for a tissue to develop normally. If the mechanism fails, some genes will be expressed by mistake and this inappropriate gene expression causes diseases such as cancer. Pursuing their research, the IRCM team will now investigate Pax7's mechanism of action more thoroughly. "We'd like to identify the proteins that interact with Pax7 in order to open specific parts of the compacted genome; these could be future therapeutic targets," said Drouin. Indeed, pioneers are key factors for reprogramming cells - to produce insulin-secreting cells that people with diabetes need, for example, or neurons to replace those lost in the brains of Parkinson's disease patients. Understanding pioneer factors is therefore a priority to realize the promises of cell and gene therapy. For Drouin and his team, the treasure hunt has just begun. <|im_end|>

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2,380

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Emissions of the critical ozone-depleting and greenhouse gas nitrous oxide (N 2 O) from soils and industrial processes have increased considerably over the last decades 1 , 2 , 3 . As the final step of bacterial denitrification, N 2 O is reduced to chemically inert N 2 (refs. 1 , 4 ) in a reaction that is catalysed by the copper-dependent nitrous oxide reductase (N 2 OR) (ref. 5 ). The assembly of its unique [4Cu:2S] active site cluster Cu Z requires both the ATP-binding-cassette (ABC) complex NosDFY and the membrane-anchored copper chaperone NosL (refs. 4 , 6 ). Here we report cryo-electron microscopy structures of Pseudomonas stutzeri NosDFY and its complexes with NosL and N 2 OR, respectively. We find that the periplasmic NosD protein contains a binding site for a Cu + ion and interacts specifically with NosL in its nucleotide-free state, whereas its binding to N 2 OR requires a conformational change that is triggered by ATP binding. Mutually exclusive structures of NosDFY in complex with NosL and with N 2 OR reveal a sequential metal-trafficking and assembly pathway for a highly complex copper site. Within this pathway, NosDFY acts as a mechanical energy transducer rather than as a transporter. It links ATP hydrolysis in the cytoplasm to a conformational transition of the NosD subunit in the periplasm, which is required for NosDFY to switch its interaction partner so that copper ions are handed over from the chaperone NosL to the enzyme N 2 OR. Main The odourless and non-toxic gas N 2 O is formed through biological and abiological processes 7 , 8 , which has led to a steady yearly increase in atmospheric concentrations by 0.2–0.3 % (refs. 9 , 10 ). N 2 O acts as an ozone-depleting substance; its global-warming potential exceeds that of carbon dioxide 300-fold and it has been designated the most critical anthropogenic emission in the 21st century 2 . Microorganisms detoxify N 2 O to N 2 as the final step of denitrification 11 . This reaction is catalysed exclusively by the enzyme N 2 OR (ref. 5 ), and a major factor in atmospheric N 2 O release is the limited ability of microbial N 2 O reducers to process the high flux of nitrogen applied as fertilizers 12 . Consequently, harnessing the performance of N 2 OR for agricultural or bioremediatory applications is of considerable interest and requires a detailed understanding of the enzyme and its maturation. The copper-dependent metalloenzyme N 2 OR is assembled in the periplasm of Gram-negative bacteria or the extracytoplasmic space of Gram-positive bacteria 5 . Besides the [4Cu:2S] Cu Z cluster, it also contains the mixed-valent dicopper electron transfer centre Cu A (Extended Data Fig. 1a ), making it the most complex copper enzyme that is known at present. Various eukaryotic and prokaryotic enzymes use the transition metal copper in processes involving oxygen transport, electron transfer or redox catalysis 13 , but its substantial cytotoxicity, detrimental effect on iron–sulfur cluster metabolism and proclivity to generate reactive oxygen species necessitates tight intracellular homeostasis and regulation 14 . N 2 O reducers circumvent the risks associated with intracellular copper by assembling Cu A and Cu Z entirely outside of the cytoplasm, although apo-N 2 OR is exported already in a folded state through the Tat pathway 15 . This strategy, however, leads to new complications, including in particular the absence of reducing equivalents and high-energy compounds such as nucleoside triphosphates in the periplasm. Clade I N 2 O reducers such as P. stutzeri encode N 2 OR together with the machinery required for its assembly and operation in a gene cluster with the core composition nosRZDFYL (Extended Data Fig. 1b,c ; see Supplementary Discussion ). Following the structural gene for N 2 OR, nosZ , the four genes nosDFYL almost invariably form a transcriptional unit centred on the ABC transporter NosFY. As the largest class of primary active transporters, ABC transporters fulfil a broad range of functions 16 . Their common architecture comprises two nucleotide-binding domains (NBDs; here NosF) and two transmembrane domains (TMDs; here NosY) 17 . Some bacterial exporters further interact with accessory proteins to build up sophisticated transport machineries 18 , 19 , and the NosD protein was suggested to act as such in conjunction with NosFY 20 . A mutant of NosDFY defective in ATP hydrolysis resulted in dysfunctional N 2 OR that lacked the Cu Z cluster 21 . Thus, the ABC transporter complex was hypothesized to export sulfide or another [S] species that is required for Cu Z assembly from the cytoplasm 22 , as it is not readily available in the oxidizing periplasmic environment. An actual cargo molecule for NosDFY has yet to be identified and a periplasmic sulfur source for Cu Z maturation cannot be ruled out. The clade I nos machinery involves at least two further components, NosR and NosL. The integral membrane protein NosR is a putative quinol oxidase that provides electrons for the reduction of N 2 O by N 2 OR and was suggested to have a role in regulating the transcription of other nos genes 5 , 23 (Extended Data Fig. 1b ). The membrane-anchored lipoprotein NosL is a copper chaperone that is required for Cu Z assembly 24 and was proposed to reside in the outer membrane of Gram-negative bacteria 25 , 26 . However, the postulated locations of NosL in the outer membrane and NosDFY in the inner membrane seem to contradict the interplay of the components of this protein machinery during the assembly of N 2 OR in the periplasm. To understand the molecular basis of N 2 OR maturation, we have produced and characterized the NosDFY complex and studied its interaction with both NosL and N 2 OR by cryo-electron microscopy (cryo-EM), revealing a sequential assembly line for the copper sites of the periplasmic enzyme that is driven by ATP hydrolysis in the cytoplasm. Structure of nucleotide-free NosDFY P. stutzeri NosDFY was produced in Escherichia", "role": "user" }, { "content": "An enzyme that combats the greenhouse gas nitrous oxide (N2O) may one day give scientists a potent new tool for reducing the amount of the gas in the atmosphere thanks in part to new findings published today in Nature. The study details how the enzyme—N2O reductase—is assembled and offers key insights into its ability to render nitrous oxide into harmless nitrogen and water. The research was co-led by VAI Associate Professor Juan Du, Ph.D., VAI Associate Professor Wei Lü, Ph.D., and University of Freiburg Professor Oliver Einsle, Ph.D. \"Addressing greenhouse gases is a massive, multi-faceted endeavor. Today's findings are an early but important step toward development of another tool to potentially combat one contributor to climate change,\" Du said. Greenhouse gases trap heat in the Earth's atmosphere and contribute to increasing global temperatures. Nitrous oxide only accounts for about 7% of greenhouse gases produced by human activities but its impact is 300-fold that of the most common greenhouse gas, carbon dioxide. Nitrous oxide is most frequently generated by agricultural practices, such as the use of nitrogen fertilizers, according to the U.S. Environmental Protection Agency. It can remain in the atmosphere for more than a century. N2O reductase is used by certain microbes to break down nitrogen-based molecules as part of the Earth's natural nitrogen cycle. Use of nitrogen-heavy fertilizers can overwhelm these microbes' ability to fully mitigate nitrous oxide, allowing it to escape into the atmosphere. Understanding exactly how this happens is a crucial step toward strategies to mediate nitrous oxide, thus reducing atmospheric levels. The study centered on N2O reductase's structure and the way it interacts with other molecular complexes. Using a host of mapping and modeling techniques, the team discovered that N2O reductase acts as a conduit that converts chemical energy into mechanical energy, which in turn powers the delivery of copper ions required for the creation of more N2O reductase. The findings reshape a decade-old belief about this crucial copper delivery system and reveal a novel mode of operation for similar molecules. Although additional research is needed, the findings provide a detailed blueprint that may be translated into future environmental remediation strategies. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Emissions of the critical ozone-depleting and greenhouse gas nitrous oxide (N 2 O) from soils and industrial processes have increased considerably over the last decades 1 , 2 , 3 . As the final step of bacterial denitrification, N 2 O is reduced to chemically inert N 2 (refs. 1 , 4 ) in a reaction that is catalysed by the copper-dependent nitrous oxide reductase (N 2 OR) (ref. 5 ). The assembly of its unique [4Cu:2S] active site cluster Cu Z requires both the ATP-binding-cassette (ABC) complex NosDFY and the membrane-anchored copper chaperone NosL (refs. 4 , 6 ). Here we report cryo-electron microscopy structures of Pseudomonas stutzeri NosDFY and its complexes with NosL and N 2 OR, respectively. We find that the periplasmic NosD protein contains a binding site for a Cu + ion and interacts specifically with NosL in its nucleotide-free state, whereas its binding to N 2 OR requires a conformational change that is triggered by ATP binding. Mutually exclusive structures of NosDFY in complex with NosL and with N 2 OR reveal a sequential metal-trafficking and assembly pathway for a highly complex copper site. Within this pathway, NosDFY acts as a mechanical energy transducer rather than as a transporter. It links ATP hydrolysis in the cytoplasm to a conformational transition of the NosD subunit in the periplasm, which is required for NosDFY to switch its interaction partner so that copper ions are handed over from the chaperone NosL to the enzyme N 2 OR. Main The odourless and non-toxic gas N 2 O is formed through biological and abiological processes 7 , 8 , which has led to a steady yearly increase in atmospheric concentrations by 0.2–0.3 % (refs. 9 , 10 ). N 2 O acts as an ozone-depleting substance; its global-warming potential exceeds that of carbon dioxide 300-fold and it has been designated the most critical anthropogenic emission in the 21st century 2 . Microorganisms detoxify N 2 O to N 2 as the final step of denitrification 11 . This reaction is catalysed exclusively by the enzyme N 2 OR (ref. 5 ), and a major factor in atmospheric N 2 O release is the limited ability of microbial N 2 O reducers to process the high flux of nitrogen applied as fertilizers 12 . Consequently, harnessing the performance of N 2 OR for agricultural or bioremediatory applications is of considerable interest and requires a detailed understanding of the enzyme and its maturation. The copper-dependent metalloenzyme N 2 OR is assembled in the periplasm of Gram-negative bacteria or the extracytoplasmic space of Gram-positive bacteria 5 . Besides the [4Cu:2S] Cu Z cluster, it also contains the mixed-valent dicopper electron transfer centre Cu A (Extended Data Fig. 1a ), making it the most complex copper enzyme that is known at present. Various eukaryotic and prokaryotic enzymes use the transition metal copper in processes involving oxygen transport, electron transfer or redox catalysis 13 , but its substantial cytotoxicity, detrimental effect on iron–sulfur cluster metabolism and proclivity to generate reactive oxygen species necessitates tight intracellular homeostasis and regulation 14 . N 2 O reducers circumvent the risks associated with intracellular copper by assembling Cu A and Cu Z entirely outside of the cytoplasm, although apo-N 2 OR is exported already in a folded state through the Tat pathway 15 . This strategy, however, leads to new complications, including in particular the absence of reducing equivalents and high-energy compounds such as nucleoside triphosphates in the periplasm. Clade I N 2 O reducers such as P. stutzeri encode N 2 OR together with the machinery required for its assembly and operation in a gene cluster with the core composition nosRZDFYL (Extended Data Fig. 1b,c ; see Supplementary Discussion ). Following the structural gene for N 2 OR, nosZ , the four genes nosDFYL almost invariably form a transcriptional unit centred on the ABC transporter NosFY. As the largest class of primary active transporters, ABC transporters fulfil a broad range of functions 16 . Their common architecture comprises two nucleotide-binding domains (NBDs; here NosF) and two transmembrane domains (TMDs; here NosY) 17 . Some bacterial exporters further interact with accessory proteins to build up sophisticated transport machineries 18 , 19 , and the NosD protein was suggested to act as such in conjunction with NosFY 20 . A mutant of NosDFY defective in ATP hydrolysis resulted in dysfunctional N 2 OR that lacked the Cu Z cluster 21 . Thus, the ABC transporter complex was hypothesized to export sulfide or another [S] species that is required for Cu Z assembly from the cytoplasm 22 , as it is not readily available in the oxidizing periplasmic environment. An actual cargo molecule for NosDFY has yet to be identified and a periplasmic sulfur source for Cu Z maturation cannot be ruled out. The clade I nos machinery involves at least two further components, NosR and NosL. The integral membrane protein NosR is a putative quinol oxidase that provides electrons for the reduction of N 2 O by N 2 OR and was suggested to have a role in regulating the transcription of other nos genes 5 , 23 (Extended Data Fig. 1b ). The membrane-anchored lipoprotein NosL is a copper chaperone that is required for Cu Z assembly 24 and was proposed to reside in the outer membrane of Gram-negative bacteria 25 , 26 . However, the postulated locations of NosL in the outer membrane and NosDFY in the inner membrane seem to contradict the interplay of the components of this protein machinery during the assembly of N 2 OR in the periplasm. To understand the molecular basis of N 2 OR maturation, we have produced and characterized the NosDFY complex and studied its interaction with both NosL and N 2 OR by cryo-electron microscopy (cryo-EM), revealing a sequential assembly line for the copper sites of the periplasmic enzyme that is driven by ATP hydrolysis in the cytoplasm. Structure of nucleotide-free NosDFY P. stutzeri NosDFY was produced in Escherichia<|im_end|> <|im_start|>assistant An enzyme that combats the greenhouse gas nitrous oxide (N2O) may one day give scientists a potent new tool for reducing the amount of the gas in the atmosphere thanks in part to new findings published today in Nature. The study details how the enzyme—N2O reductase—is assembled and offers key insights into its ability to render nitrous oxide into harmless nitrogen and water. The research was co-led by VAI Associate Professor Juan Du, Ph.D., VAI Associate Professor Wei Lü, Ph.D., and University of Freiburg Professor Oliver Einsle, Ph.D. "Addressing greenhouse gases is a massive, multi-faceted endeavor. Today's findings are an early but important step toward development of another tool to potentially combat one contributor to climate change," Du said. Greenhouse gases trap heat in the Earth's atmosphere and contribute to increasing global temperatures. Nitrous oxide only accounts for about 7% of greenhouse gases produced by human activities but its impact is 300-fold that of the most common greenhouse gas, carbon dioxide. Nitrous oxide is most frequently generated by agricultural practices, such as the use of nitrogen fertilizers, according to the U.S. Environmental Protection Agency. It can remain in the atmosphere for more than a century. N2O reductase is used by certain microbes to break down nitrogen-based molecules as part of the Earth's natural nitrogen cycle. Use of nitrogen-heavy fertilizers can overwhelm these microbes' ability to fully mitigate nitrous oxide, allowing it to escape into the atmosphere. Understanding exactly how this happens is a crucial step toward strategies to mediate nitrous oxide, thus reducing atmospheric levels. The study centered on N2O reductase's structure and the way it interacts with other molecular complexes. Using a host of mapping and modeling techniques, the team discovered that N2O reductase acts as a conduit that converts chemical energy into mechanical energy, which in turn powers the delivery of copper ions required for the creation of more N2O reductase. The findings reshape a decade-old belief about this crucial copper delivery system and reveal a novel mode of operation for similar molecules. Although additional research is needed, the findings provide a detailed blueprint that may be translated into future environmental remediation strategies. <|im_end|>

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1,893

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Organoids can shed light on the dynamic interplay between complex tissues and rare cell types within a controlled microenvironment. Here, we develop gut organoid cocultures with type-1 innate lymphoid cells (ILC1) to dissect the impact of their accumulation in inflamed intestines. We demonstrate that murine and human ILC1 secrete transforming growth factor β1, driving expansion of CD44v6 + epithelial crypts. ILC1 additionally express MMP9 and drive gene signatures indicative of extracellular matrix remodelling. We therefore encapsulated human epithelial–mesenchymal intestinal organoids in MMP-sensitive, synthetic hydrogels designed to form efficient networks at low polymer concentrations. Harnessing this defined system, we demonstrate that ILC1 drive matrix softening and stiffening, which we suggest occurs through balanced matrix degradation and deposition. Our platform enabled us to elucidate previously undescribed interactions between ILC1 and their microenvironment, which suggest that they may exacerbate fibrosis and tumour growth when enriched in inflamed patient tissues. Main Intestinal epithelial cells (IEC) 1 interact with innate lymphoid cells (ILC) 2 to form a dynamic barrier between organisms and their environment. Together, they are capable of rapidly responding to danger and damage in an antigen-non-specific manner. For instance, type-3 ILC secrete interleukin-22 (IL-22, Il22 ) in response to extracellular pathogens, which promotes antimicrobial peptide secretion and proliferation of Lgr5 + CD44 + intestinal stem cells 3 . Conversely, type-1 ILC (ILC1) express interferon-γ (IFN-γ, Ifng ) in response to intracellular pathogens, and are composed of circulating natural killer (NK) cells and tissue-resident helper-like ILC1, which are considered less cytotoxic than their NK-cell counterparts 4 . Notably, ILC1 accumulate in the inflamed intestines of patients with inflammatory bowel disease (IBD) 5 ; however, the nature of their subset-specific interactions with the epithelium has remained elusive. Understanding the impact of ILC1 enrichment could inform alternative strategies for treating this complex disease, which is a pressing issue as only a third of patients respond to gold-standard tumour-necrosis factor (TNF)-α-blocking biologics 6 . Teasing apart the role of rare cell populations in multifactorial diseases is challenging, and redundant cytokine signalling pathways in vivo can obscure ILC-specific phenotypes. Thus, to explore the impact of ILC1 on IEC we developed a reductionist coculture system with murine small intestine organoids (SIO) 7 . We unexpectedly found that ILC1-derived transforming growth factor (TGF) β1 induces p38γ phosphorylation, driving proliferation of CD44v6 + epithelial cells. Moreover, pathway analysis of coculture transcriptomes predicted ILC1-driven matrisome remodelling, so we developed highly defined polyethylene glycol (PEG)-based hydrogels to quantitatively characterize the impact of ILC1 on matrix remodelling in a human induced pluripotent stem cell (iPSC)-derived organoid model (HIO) 8 . We confirmed not only that ILC1 derived from patients with IBD express TGFB1 to upregulate intestinal CD44v6, but also that they prompt physical changes in the hydrogel via both degradation and production of peri-organoid matrix. Our findings suggest an unexpected role for ILC1 in intestinal remodelling, which could exacerbate IBD-associated comorbidities when enriched in inflamed intestines. Results ILC1 drive CD44 + crypt expansion To study the impact of ILC1 accumulation on IEC, we established cocultures of murine SIO and small intestinal lamina propria-derived ILC1 (Fig. 1a–c and Supplementary Fig. 1 ). ILC1 maintained characteristic KLRG1 − , RORγt − , NK1.1 + expression after coculture (Supplementary Figs. 2 and 3a ), and expressed Ifng , but not Il22 , matching freshly isolated ILC1 (Fig. 1d ). We tuned this system to contain low levels of IFN-γ secretion (Supplementary Fig. 3b,c ), and cultured SIO either alone or with ILC1 for 4 days. We then purified IEC using fluorescence-activated cell sorting (FACS) for bulk Smart-seq2 Pico RNA sequencing (RNA-seq). ILC1 coculture significantly increased expression of epithelial Cd44 , a common crypt stem cell marker that can act as a growth factor coreceptor or a transcription factor, or mediate cell-surface adhesion 9 (Fig. 1e , Supplementary Fig. 2 and Supplementary Dataset 1 ). ILC1 also promoted the growth of enlarged CD44 + crypt buds (Fig. 1f–h ). To explore whether IFN-γ drove this effect, we supplemented SIO-only cultures with recombinant IFN-γ, which did not increase epithelial proliferation or Cd44 expression (Fig. 1i,j ). Moreover, Ingenuity Pathway Analysis (IPA) of the Smart-Seq2 dataset did not predict IFN-γ activity as a dominant signature of ILC1 coculture (Fig. 1k ), suggesting that ILC1 upregulate CD44 through an alternative mechanism. Fig. 1: ILC1 impact intestinal organoid gene expression. a – c , Bright-field images ( a ), confocal microscopy images ( b ) and FACS plots ( c ) of SIO cultured alone (top) or with ILC1 (bottom) (representative of experiments with ILC1 from N = 3 mice). d , Relative expression of Ifng and Il22 in ILC1 normalized to housekeeping gene Gapdh before ( N = 5 mice, freshly isolated) and after (ILC1 from N = 4 mice) coculture with SIO, each condition with or without 2-h stimulation with 10-ng-ml −1 phorbol myristate acetate (PMA) and 1-µM ionomycin (stim.). n.s., not significant. e , Volcano plot (log 10 of the adjusted p -value p adj versus fold change) of differentially expressed genes in the RNA-seq dataset, with significantly upregulated genes of interest highlighted with a blue circle ( P values calculated using the Markov chain Monte Carlo simulation with multiple testing correction). f , Confocal microscopy images of SIO showing CD44 + crypts with Lysozyme1 + (Lyz1) Paneth cells (representative of N = 3). g , Flow quantification of CD44 expression in IEC (ILC1 from N = 5 mice). h , Quantification of crypt bud number per SIO (ILC1 derived from N = 3 mice; each symbol represents one organoid). i , Number of EpCAM + CD45 − IEC in SIO after 4-day coculture alone, with ILC1 or with 0.01-ng-ml −1 IFN-γ (ILC1 from N = 3 mice). j , Quantitative PCR with reverse transcription (RT–qPCR) of IEC Cd44 expression with or without 0.01-ng-ml −1 IFN-γ ( N = 3 independent experiments). k . IPA of selected upstream regulators predicted to be driving expression signatures in ILC1 cocultures; z score magenta predicts high activity, blue predicts low activity.", "role": "user" }, { "content": "Scientists from King's College London have discovered an unexpected tissue reparative role for a rare immune cell type in the gut that could tip toward fibrosis or cancer if dysregulated. The breakthrough will have important implications for treating patients who suffer from inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. In a paper published today in Nature Materials, the team of researchers from King's College London found that type-1 innate lymphoid cells (ILC1) can promote tissue repair, but when they accumulate in inflamed tissues, can also contribute to IBD co-morbidities such as cancer and fibrosis. It was previously assumed that these cells drove inflammation, so these findings could inspire completely new therapeutic approaches for those suffering from IBD. To understand the impact of ILC1 on the gut, the academics combined ILC1 with intestinal organoids, miniature versions of the normal intestine that are grown in a dish. Whilst they intended to harness this system to study ILC1-driven inflammation in organoids, they instead found that ILC1 secreted additional proteins that promoted both growth of the intestinal barrier and remodeling of the supporting structure beneath it; a response closely resembling wound healing. However, ILC1's healing response was only half the story; the team also found that accumulation of ILC1 could trigger fibrotic lesions or exacerbate tumor growth, two common complications of IBD that severely impact a patient's quality of life. Lead author King's College London Ph.D. student Geraldine Jowett admits this finding came as somewhat of a surprise. \"Even though the signals we identified were established biomarkers that had previously been associated with IBD, it was exciting, unexpected, and important to discover that these signals were actually coming from ILC1.\" she said. Jowett explains: \"It's a matter of balance: On the one hand ILC1s' ability to secrete this protein could suggest that we have been thinking about them the wrong way, and that encouraging this healing response could provide hope for the two thirds of patients who currently don't respond to anti-inflammatory treatments. \"On the other hand, ILC1 may only be beneficial in small doses, and could actually make things worse for IBD patients if they become dysregulated, leading to tumor growth or fibrotic scar tissue formation, outcomes we would want to avoid at all costs.\" This discovery has the potential to inspire new strategies for therapeutic intervention, such as allowing physicians to identify patients that are at high risk for developing IBD co-morbidities that require invasive surgery. A blender rendition of how human, patient-derived ILC1 (blue) can drive degradation of the synthetic hydrogel surrounding an intestinal organoid -Geraldine Jowett. Credit: Geraldine Jowett The team's findings may also have implications for COVD-19 patients, as ILC1 are more typically known as the key first responders to viral infections in the lung and the gut. Even young, asymptomatic patients infected with SARS-CoV2 have presented with early signs of lung fibrosis. Since ILC1 are enriched during chronic viral infections, it is possible that ILC1 also accumulate and play a role in driving fibrosis in the lungs of COVID-19 patients, providing a potential therapeutic target for the urgent research efforts currently underway. The team's findings required the authors to develop a complex culture system, as ILC1 are so rare in the gut that they can be hard to study. To accomplish this, they cultured ILC1 alongside human stem cell-derived intestinal organoids in a dish. They then encapsulated the tissues in a synthetic soft material called a hydrogel, allowing them to mimic the 3-D environment of normal intestinal tissue. Pinning down how the ILC1 could drive fibrosis was particularly challenging and required the team's expertise in materials science. \"Culturing cells in a dish can be so artificial that the results become irrelevant for disease pathology, so it was critical that we performed our key experiments within an environment that could appropriately respond to the biological cues that drive fibrosis,\" explains Dr. Eileen Gentleman, co-senior author on the study. The new hydrogels the team developed for this study were designed using complex computational models, which were key to creating materials that were soft enough to support the organoids, and uniform enough to allow for reproducible measurements of the changes in stiffness created by ILC1. King's College London Mucosal Immunologist and co-senior author Dr. Joana Neves remarks: \"Many environmental and genetic factors can contribute to IBD, so by combining ILC1 from patients with IBD with this synthetic culture system we were able to provide that extra layer of certainty that it was the ILC1 themselves that were driving the wound healing response, without interference from patients' diets, mutations, or treatment regimens.\" Thus, the reductionist system developed by this team provides a powerful template for studying the impact of rare cell types on complex processes of development and teasing apart components of multifactorial diseases. The study was a collaboration of different departments at King's College London, as well as other UK and international partners. Dr. Chris Lorenz, Interim Head of Physics at King's explains their involvement: \"Our coarse-grain molecular dynamics simulations provided a detailed description of how changes in the chemistry of the underlying polymeric building blocks affected the structural properties of the resulting hydrogels. As a result, we were able to inform the design of the hydrogels made by Eileen's group such that in the end the softness and uniformity of the hydrogels were optimized.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Organoids can shed light on the dynamic interplay between complex tissues and rare cell types within a controlled microenvironment. Here, we develop gut organoid cocultures with type-1 innate lymphoid cells (ILC1) to dissect the impact of their accumulation in inflamed intestines. We demonstrate that murine and human ILC1 secrete transforming growth factor β1, driving expansion of CD44v6 + epithelial crypts. ILC1 additionally express MMP9 and drive gene signatures indicative of extracellular matrix remodelling. We therefore encapsulated human epithelial–mesenchymal intestinal organoids in MMP-sensitive, synthetic hydrogels designed to form efficient networks at low polymer concentrations. Harnessing this defined system, we demonstrate that ILC1 drive matrix softening and stiffening, which we suggest occurs through balanced matrix degradation and deposition. Our platform enabled us to elucidate previously undescribed interactions between ILC1 and their microenvironment, which suggest that they may exacerbate fibrosis and tumour growth when enriched in inflamed patient tissues. Main Intestinal epithelial cells (IEC) 1 interact with innate lymphoid cells (ILC) 2 to form a dynamic barrier between organisms and their environment. Together, they are capable of rapidly responding to danger and damage in an antigen-non-specific manner. For instance, type-3 ILC secrete interleukin-22 (IL-22, Il22 ) in response to extracellular pathogens, which promotes antimicrobial peptide secretion and proliferation of Lgr5 + CD44 + intestinal stem cells 3 . Conversely, type-1 ILC (ILC1) express interferon-γ (IFN-γ, Ifng ) in response to intracellular pathogens, and are composed of circulating natural killer (NK) cells and tissue-resident helper-like ILC1, which are considered less cytotoxic than their NK-cell counterparts 4 . Notably, ILC1 accumulate in the inflamed intestines of patients with inflammatory bowel disease (IBD) 5 ; however, the nature of their subset-specific interactions with the epithelium has remained elusive. Understanding the impact of ILC1 enrichment could inform alternative strategies for treating this complex disease, which is a pressing issue as only a third of patients respond to gold-standard tumour-necrosis factor (TNF)-α-blocking biologics 6 . Teasing apart the role of rare cell populations in multifactorial diseases is challenging, and redundant cytokine signalling pathways in vivo can obscure ILC-specific phenotypes. Thus, to explore the impact of ILC1 on IEC we developed a reductionist coculture system with murine small intestine organoids (SIO) 7 . We unexpectedly found that ILC1-derived transforming growth factor (TGF) β1 induces p38γ phosphorylation, driving proliferation of CD44v6 + epithelial cells. Moreover, pathway analysis of coculture transcriptomes predicted ILC1-driven matrisome remodelling, so we developed highly defined polyethylene glycol (PEG)-based hydrogels to quantitatively characterize the impact of ILC1 on matrix remodelling in a human induced pluripotent stem cell (iPSC)-derived organoid model (HIO) 8 . We confirmed not only that ILC1 derived from patients with IBD express TGFB1 to upregulate intestinal CD44v6, but also that they prompt physical changes in the hydrogel via both degradation and production of peri-organoid matrix. Our findings suggest an unexpected role for ILC1 in intestinal remodelling, which could exacerbate IBD-associated comorbidities when enriched in inflamed intestines. Results ILC1 drive CD44 + crypt expansion To study the impact of ILC1 accumulation on IEC, we established cocultures of murine SIO and small intestinal lamina propria-derived ILC1 (Fig. 1a–c and Supplementary Fig. 1 ). ILC1 maintained characteristic KLRG1 − , RORγt − , NK1.1 + expression after coculture (Supplementary Figs. 2 and 3a ), and expressed Ifng , but not Il22 , matching freshly isolated ILC1 (Fig. 1d ). We tuned this system to contain low levels of IFN-γ secretion (Supplementary Fig. 3b,c ), and cultured SIO either alone or with ILC1 for 4 days. We then purified IEC using fluorescence-activated cell sorting (FACS) for bulk Smart-seq2 Pico RNA sequencing (RNA-seq). ILC1 coculture significantly increased expression of epithelial Cd44 , a common crypt stem cell marker that can act as a growth factor coreceptor or a transcription factor, or mediate cell-surface adhesion 9 (Fig. 1e , Supplementary Fig. 2 and Supplementary Dataset 1 ). ILC1 also promoted the growth of enlarged CD44 + crypt buds (Fig. 1f–h ). To explore whether IFN-γ drove this effect, we supplemented SIO-only cultures with recombinant IFN-γ, which did not increase epithelial proliferation or Cd44 expression (Fig. 1i,j ). Moreover, Ingenuity Pathway Analysis (IPA) of the Smart-Seq2 dataset did not predict IFN-γ activity as a dominant signature of ILC1 coculture (Fig. 1k ), suggesting that ILC1 upregulate CD44 through an alternative mechanism. Fig. 1: ILC1 impact intestinal organoid gene expression. a – c , Bright-field images ( a ), confocal microscopy images ( b ) and FACS plots ( c ) of SIO cultured alone (top) or with ILC1 (bottom) (representative of experiments with ILC1 from N = 3 mice). d , Relative expression of Ifng and Il22 in ILC1 normalized to housekeeping gene Gapdh before ( N = 5 mice, freshly isolated) and after (ILC1 from N = 4 mice) coculture with SIO, each condition with or without 2-h stimulation with 10-ng-ml −1 phorbol myristate acetate (PMA) and 1-µM ionomycin (stim.). n.s., not significant. e , Volcano plot (log 10 of the adjusted p -value p adj versus fold change) of differentially expressed genes in the RNA-seq dataset, with significantly upregulated genes of interest highlighted with a blue circle ( P values calculated using the Markov chain Monte Carlo simulation with multiple testing correction). f , Confocal microscopy images of SIO showing CD44 + crypts with Lysozyme1 + (Lyz1) Paneth cells (representative of N = 3). g , Flow quantification of CD44 expression in IEC (ILC1 from N = 5 mice). h , Quantification of crypt bud number per SIO (ILC1 derived from N = 3 mice; each symbol represents one organoid). i , Number of EpCAM + CD45 − IEC in SIO after 4-day coculture alone, with ILC1 or with 0.01-ng-ml −1 IFN-γ (ILC1 from N = 3 mice). j , Quantitative PCR with reverse transcription (RT–qPCR) of IEC Cd44 expression with or without 0.01-ng-ml −1 IFN-γ ( N = 3 independent experiments). k . IPA of selected upstream regulators predicted to be driving expression signatures in ILC1 cocultures; z score magenta predicts high activity, blue predicts low activity.<|im_end|> <|im_start|>assistant Scientists from King's College London have discovered an unexpected tissue reparative role for a rare immune cell type in the gut that could tip toward fibrosis or cancer if dysregulated. The breakthrough will have important implications for treating patients who suffer from inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. In a paper published today in Nature Materials, the team of researchers from King's College London found that type-1 innate lymphoid cells (ILC1) can promote tissue repair, but when they accumulate in inflamed tissues, can also contribute to IBD co-morbidities such as cancer and fibrosis. It was previously assumed that these cells drove inflammation, so these findings could inspire completely new therapeutic approaches for those suffering from IBD. To understand the impact of ILC1 on the gut, the academics combined ILC1 with intestinal organoids, miniature versions of the normal intestine that are grown in a dish. Whilst they intended to harness this system to study ILC1-driven inflammation in organoids, they instead found that ILC1 secreted additional proteins that promoted both growth of the intestinal barrier and remodeling of the supporting structure beneath it; a response closely resembling wound healing. However, ILC1's healing response was only half the story; the team also found that accumulation of ILC1 could trigger fibrotic lesions or exacerbate tumor growth, two common complications of IBD that severely impact a patient's quality of life. Lead author King's College London Ph.D. student Geraldine Jowett admits this finding came as somewhat of a surprise. "Even though the signals we identified were established biomarkers that had previously been associated with IBD, it was exciting, unexpected, and important to discover that these signals were actually coming from ILC1." she said. Jowett explains: "It's a matter of balance: On the one hand ILC1s' ability to secrete this protein could suggest that we have been thinking about them the wrong way, and that encouraging this healing response could provide hope for the two thirds of patients who currently don't respond to anti-inflammatory treatments. "On the other hand, ILC1 may only be beneficial in small doses, and could actually make things worse for IBD patients if they become dysregulated, leading to tumor growth or fibrotic scar tissue formation, outcomes we would want to avoid at all costs." This discovery has the potential to inspire new strategies for therapeutic intervention, such as allowing physicians to identify patients that are at high risk for developing IBD co-morbidities that require invasive surgery. A blender rendition of how human, patient-derived ILC1 (blue) can drive degradation of the synthetic hydrogel surrounding an intestinal organoid -Geraldine Jowett. Credit: Geraldine Jowett The team's findings may also have implications for COVD-19 patients, as ILC1 are more typically known as the key first responders to viral infections in the lung and the gut. Even young, asymptomatic patients infected with SARS-CoV2 have presented with early signs of lung fibrosis. Since ILC1 are enriched during chronic viral infections, it is possible that ILC1 also accumulate and play a role in driving fibrosis in the lungs of COVID-19 patients, providing a potential therapeutic target for the urgent research efforts currently underway. The team's findings required the authors to develop a complex culture system, as ILC1 are so rare in the gut that they can be hard to study. To accomplish this, they cultured ILC1 alongside human stem cell-derived intestinal organoids in a dish. They then encapsulated the tissues in a synthetic soft material called a hydrogel, allowing them to mimic the 3-D environment of normal intestinal tissue. Pinning down how the ILC1 could drive fibrosis was particularly challenging and required the team's expertise in materials science. "Culturing cells in a dish can be so artificial that the results become irrelevant for disease pathology, so it was critical that we performed our key experiments within an environment that could appropriately respond to the biological cues that drive fibrosis," explains Dr. Eileen Gentleman, co-senior author on the study. The new hydrogels the team developed for this study were designed using complex computational models, which were key to creating materials that were soft enough to support the organoids, and uniform enough to allow for reproducible measurements of the changes in stiffness created by ILC1. King's College London Mucosal Immunologist and co-senior author Dr. Joana Neves remarks: "Many environmental and genetic factors can contribute to IBD, so by combining ILC1 from patients with IBD with this synthetic culture system we were able to provide that extra layer of certainty that it was the ILC1 themselves that were driving the wound healing response, without interference from patients' diets, mutations, or treatment regimens." Thus, the reductionist system developed by this team provides a powerful template for studying the impact of rare cell types on complex processes of development and teasing apart components of multifactorial diseases. The study was a collaboration of different departments at King's College London, as well as other UK and international partners. Dr. Chris Lorenz, Interim Head of Physics at King's explains their involvement: "Our coarse-grain molecular dynamics simulations provided a detailed description of how changes in the chemistry of the underlying polymeric building blocks affected the structural properties of the resulting hydrogels. As a result, we were able to inform the design of the hydrogels made by Eileen's group such that in the end the softness and uniformity of the hydrogels were optimized." <|im_end|>

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2,778

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2–20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600–5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics. Main Comprehensive knowledge of the genes underlying human cancers is a critical foundation for cancer diagnostics, therapeutics, clinical-trial design and selection of rational combination therapies. It is now possible to use genomic analysis to identify cancer genes in an unbiased fashion, based on the presence of somatic mutations at a rate significantly higher than the expected background level. Systematic studies have revealed many new cancer genes, as well as new classes of cancer genes 1 , 2 . They have also made clear that, although some cancer genes are mutated at high frequencies, most cancer genes in most patients occur at intermediate frequencies (2–20%) or lower. Accordingly, a complete catalogue of mutations in this frequency class will be essential for recognizing dysregulated pathways and optimal targets for therapeutic intervention. However, recent work suggests major gaps in our knowledge of cancer genes of intermediate frequency. For example, a study of 183 lung adenocarcinomas 3 found that 15% of patients lacked even a single mutation affecting any of the 10 known hallmarks of cancer, and 38% had 3 or fewer such mutations. In this paper, we analysed somatic point mutations (substitutions and small insertion and deletions) in nearly 5,000 human cancers and their matched normal-tissue samples (‘tumour–normal pairs’) across 21 tumour types. The questions that we examine here are: first, whether large-scale genomic analysis across tumour types can reliably identify all known cancer genes; second, whether it will reveal many new candidate cancer genes; and third, how far we are from having a complete catalogue of cancer genes (at least those of intermediate frequency). We used rigorous statistical methods to enumerate candidate cancer genes and then carefully inspected each gene to identify those with strong biological connections to cancer and mutational patterns consistent with the expected function. The analysis reveals nearly all known cancer genes and revealed 33 novel candidates, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Importantly, the data show that the catalogue of cancer genes is still far from complete, with the number of candidate cancer genes still increasing sharply with sample size. These analyses enable us to estimate the sample sizes that will be needed to approach saturation. Cancer-genome data We collected and analysed data from 4,742 samples, consisting primarily of whole-exome sequence from tumour–normal pairs. The samples span 21 tumour types, which include 12 from The Cancer Genome Atlas (TCGA) and 14 from non-TCGA projects at the Broad Institute, with some overlapping tumour types ( Table 1 and Supplementary Table 1 ). The number of samples per tumour type varied between 35 and 892. Table 1 List of the 21 tumour types analysed Full size table Data were all analysed through the Broad’s stringent filtering and annotation pipeline to obtain a uniform set of mutation calls (Methods). The data set consists of 3,078,483 somatic single nucleotide variations (SSNVs), 77,270 small insertions and deletions (SINDELs) and 29,837 somatic di-, tri- or oligonucleotide variations (DNVs, TNVs and ONVs, respectively), with an average of 672 per tumour–normal pair. The mutations include 540,831 missense, 207,144 synonymous, 46,264 nonsense, 33,637 splice-site, and 2,294,935 non-coding mutations (used to improve our background model). The analysis has sensitivity of >90% based on the sequencing depth and tumour purity and ploidy 4 , 5 . Mutation frequencies vary over more than five orders of magnitude (from 0.03 per megabase (Mb) to 7,000 per Mb) within and across tumour types, consistent with our recent study of mutational heterogeneity 6 of approximately 3,000 samples (of which 2,502 are included in this data set) ( Supplementary Fig. 1 ). Mutation spectra also vary sharply within and across tumour types 6 ( Supplementary Fig. 2 ). Cancer-genome analysis We analysed these data to identify candidate cancer genes, by which we mean genes harbouring somatic point mutations (that is, substitutions and small insertion or deletions) at a statistically significant rate or pattern in cancer. (Such genes will ultimately need to be verified by biological experiments to be considered validated cancer genes.) In this paper, we do not seek to implicate genes based on other criteria (such as amplification or deletion, translocations or epigenomic modification; however, see ref. 7 for an analysis of copy-number alterations across many tumour types). In principle, candidate cancer genes can be discovered by sequencing enough tumour–normal pairs; based on the presence of an excess of somatic mutations compared to expectation. However, careful analysis is required to assess statistical significance. The mere presence of somatic mutations is insufficient to implicate a gene in cancer, inasmuch as 93% of genes carried mutations in at least five samples. We showed recently 6 that heterogeneity of mutation rates and patterns in cancer can give rise to false positives and described methods to overcome this problem. We applied these methods to identify candidate cancer genes. We used the most recent version of the MutSig suite of tools ( Supplementary Fig. 3a and Methods), which looks for three independent signals: high mutational burden relative to background expectation, accounting for heterogeneity; clustering of mutations within the gene 8", "role": "user" }, { "content": "(Medical Xpress)—A landmark study across many cancer types reveals that the universe of cancer mutations is much bigger than previously thought. By analyzing the genomes of thousands of patients' tumors, a Broad Institute-led research team has discovered many new cancer genes—expanding the list of known genes tied to these cancers by 25 percent. Moreover, the study shows that many key cancer genes still remain to be discovered. The team's work, which lays a critical foundation for future cancer drug development, also shows that creating a comprehensive catalog of cancer genes for scores of cancer types is feasible with as few as 100,000 patient samples. \"For the first time, we know what it will take to draw the complete genomic picture of human cancer,\" said Broad Institute founding director Eric Lander, a senior co-author of the paper. \"That's tremendously exciting, because the knowledge of genes and their pathways will highlight new, potential drug targets and help lead the way to effective combination therapy.\" Over the past 30 years, scientists had found evidence for about 135 genes that play causal roles in one or more of the 21 tumor types analyzed in the study. The new report not only confirms these genes, but, in one fell swoop, increases the catalog of cancer genes by one-quarter. It uncovers 33 genes with biological roles in cell death, cell growth, genome stability, immune evasion, as well as other processes. The researchers' results appear in print in this week's issue of Nature. \"One of the fundamental questions we need to ask ourselves is: Do we have a complete picture yet? Looking at cancer genomes tells us that the answer is no: there are more cancer genes out there to be discovered,\" said the paper's first author Mike Lawrence, a computational biologist at the Broad. \"We could tell that our current knowledge was incomplete because we discovered many new cancer genes,\" said co-senior author Gad Getz director of the Broad Institute's Cancer Genome Computational Analysis group and a Broad associate member. Getz is also the director of the Bioinformatics Program at Massachusetts General Hospital Cancer Center and the department of pathology. \"Moreover, we could tell that there are many genes still to be discovered by measuring how the number of gene discoveries grows as we increase the number of samples in our analysis. The curve is still going up!\" The researchers estimate that they will need to analyze, on average, about 2,000 samples of each cancer type in order to catalog the vast majority of these mutations – our about 100,000 samples across roughly 50 tumor types. \"Given that there are around 32 million people living with cancer worldwide, this is a very reasonable number to study,\" said Getz. The tumor types analyzed included those in which lots of mutations occur – such as melanoma and forms of lung cancer – and those that have a much lower frequency of mutations – such as rhabdoid and medulloblastoma, both childhood cancers. In total, the researchers analyzed the genomes of nearly 5,000 cancer samples, comparing them with matched samples from normal tissue. Using methods that the group has pioneered over the last few years, they rediscovered nearly all previously known cancer driver genes for these types of cancer, validating their approach. The altered genes that the team has pinpointed will need to be followed up to determine which, if any, could be important targets for drug development. Initiatives at the Broad Institute like the Cancer Program's Target Accelerator intend to do just that. In the meantime, the new work offers a wider view of the cancer genomics universe, and tantalizing clues about what remains to be discovered if more samples are analyzed. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2–20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600–5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics. Main Comprehensive knowledge of the genes underlying human cancers is a critical foundation for cancer diagnostics, therapeutics, clinical-trial design and selection of rational combination therapies. It is now possible to use genomic analysis to identify cancer genes in an unbiased fashion, based on the presence of somatic mutations at a rate significantly higher than the expected background level. Systematic studies have revealed many new cancer genes, as well as new classes of cancer genes 1 , 2 . They have also made clear that, although some cancer genes are mutated at high frequencies, most cancer genes in most patients occur at intermediate frequencies (2–20%) or lower. Accordingly, a complete catalogue of mutations in this frequency class will be essential for recognizing dysregulated pathways and optimal targets for therapeutic intervention. However, recent work suggests major gaps in our knowledge of cancer genes of intermediate frequency. For example, a study of 183 lung adenocarcinomas 3 found that 15% of patients lacked even a single mutation affecting any of the 10 known hallmarks of cancer, and 38% had 3 or fewer such mutations. In this paper, we analysed somatic point mutations (substitutions and small insertion and deletions) in nearly 5,000 human cancers and their matched normal-tissue samples (‘tumour–normal pairs’) across 21 tumour types. The questions that we examine here are: first, whether large-scale genomic analysis across tumour types can reliably identify all known cancer genes; second, whether it will reveal many new candidate cancer genes; and third, how far we are from having a complete catalogue of cancer genes (at least those of intermediate frequency). We used rigorous statistical methods to enumerate candidate cancer genes and then carefully inspected each gene to identify those with strong biological connections to cancer and mutational patterns consistent with the expected function. The analysis reveals nearly all known cancer genes and revealed 33 novel candidates, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Importantly, the data show that the catalogue of cancer genes is still far from complete, with the number of candidate cancer genes still increasing sharply with sample size. These analyses enable us to estimate the sample sizes that will be needed to approach saturation. Cancer-genome data We collected and analysed data from 4,742 samples, consisting primarily of whole-exome sequence from tumour–normal pairs. The samples span 21 tumour types, which include 12 from The Cancer Genome Atlas (TCGA) and 14 from non-TCGA projects at the Broad Institute, with some overlapping tumour types ( Table 1 and Supplementary Table 1 ). The number of samples per tumour type varied between 35 and 892. Table 1 List of the 21 tumour types analysed Full size table Data were all analysed through the Broad’s stringent filtering and annotation pipeline to obtain a uniform set of mutation calls (Methods). The data set consists of 3,078,483 somatic single nucleotide variations (SSNVs), 77,270 small insertions and deletions (SINDELs) and 29,837 somatic di-, tri- or oligonucleotide variations (DNVs, TNVs and ONVs, respectively), with an average of 672 per tumour–normal pair. The mutations include 540,831 missense, 207,144 synonymous, 46,264 nonsense, 33,637 splice-site, and 2,294,935 non-coding mutations (used to improve our background model). The analysis has sensitivity of >90% based on the sequencing depth and tumour purity and ploidy 4 , 5 . Mutation frequencies vary over more than five orders of magnitude (from 0.03 per megabase (Mb) to 7,000 per Mb) within and across tumour types, consistent with our recent study of mutational heterogeneity 6 of approximately 3,000 samples (of which 2,502 are included in this data set) ( Supplementary Fig. 1 ). Mutation spectra also vary sharply within and across tumour types 6 ( Supplementary Fig. 2 ). Cancer-genome analysis We analysed these data to identify candidate cancer genes, by which we mean genes harbouring somatic point mutations (that is, substitutions and small insertion or deletions) at a statistically significant rate or pattern in cancer. (Such genes will ultimately need to be verified by biological experiments to be considered validated cancer genes.) In this paper, we do not seek to implicate genes based on other criteria (such as amplification or deletion, translocations or epigenomic modification; however, see ref. 7 for an analysis of copy-number alterations across many tumour types). In principle, candidate cancer genes can be discovered by sequencing enough tumour–normal pairs; based on the presence of an excess of somatic mutations compared to expectation. However, careful analysis is required to assess statistical significance. The mere presence of somatic mutations is insufficient to implicate a gene in cancer, inasmuch as 93% of genes carried mutations in at least five samples. We showed recently 6 that heterogeneity of mutation rates and patterns in cancer can give rise to false positives and described methods to overcome this problem. We applied these methods to identify candidate cancer genes. We used the most recent version of the MutSig suite of tools ( Supplementary Fig. 3a and Methods), which looks for three independent signals: high mutational burden relative to background expectation, accounting for heterogeneity; clustering of mutations within the gene 8<|im_end|> <|im_start|>assistant (Medical Xpress)—A landmark study across many cancer types reveals that the universe of cancer mutations is much bigger than previously thought. By analyzing the genomes of thousands of patients' tumors, a Broad Institute-led research team has discovered many new cancer genes—expanding the list of known genes tied to these cancers by 25 percent. Moreover, the study shows that many key cancer genes still remain to be discovered. The team's work, which lays a critical foundation for future cancer drug development, also shows that creating a comprehensive catalog of cancer genes for scores of cancer types is feasible with as few as 100,000 patient samples. "For the first time, we know what it will take to draw the complete genomic picture of human cancer," said Broad Institute founding director Eric Lander, a senior co-author of the paper. "That's tremendously exciting, because the knowledge of genes and their pathways will highlight new, potential drug targets and help lead the way to effective combination therapy." Over the past 30 years, scientists had found evidence for about 135 genes that play causal roles in one or more of the 21 tumor types analyzed in the study. The new report not only confirms these genes, but, in one fell swoop, increases the catalog of cancer genes by one-quarter. It uncovers 33 genes with biological roles in cell death, cell growth, genome stability, immune evasion, as well as other processes. The researchers' results appear in print in this week's issue of Nature. "One of the fundamental questions we need to ask ourselves is: Do we have a complete picture yet? Looking at cancer genomes tells us that the answer is no: there are more cancer genes out there to be discovered," said the paper's first author Mike Lawrence, a computational biologist at the Broad. "We could tell that our current knowledge was incomplete because we discovered many new cancer genes," said co-senior author Gad Getz director of the Broad Institute's Cancer Genome Computational Analysis group and a Broad associate member. Getz is also the director of the Bioinformatics Program at Massachusetts General Hospital Cancer Center and the department of pathology. "Moreover, we could tell that there are many genes still to be discovered by measuring how the number of gene discoveries grows as we increase the number of samples in our analysis. The curve is still going up!" The researchers estimate that they will need to analyze, on average, about 2,000 samples of each cancer type in order to catalog the vast majority of these mutations – our about 100,000 samples across roughly 50 tumor types. "Given that there are around 32 million people living with cancer worldwide, this is a very reasonable number to study," said Getz. The tumor types analyzed included those in which lots of mutations occur – such as melanoma and forms of lung cancer – and those that have a much lower frequency of mutations – such as rhabdoid and medulloblastoma, both childhood cancers. In total, the researchers analyzed the genomes of nearly 5,000 cancer samples, comparing them with matched samples from normal tissue. Using methods that the group has pioneered over the last few years, they rediscovered nearly all previously known cancer driver genes for these types of cancer, validating their approach. The altered genes that the team has pinpointed will need to be followed up to determine which, if any, could be important targets for drug development. Initiatives at the Broad Institute like the Cancer Program's Target Accelerator intend to do just that. In the meantime, the new work offers a wider view of the cancer genomics universe, and tantalizing clues about what remains to be discovered if more samples are analyzed. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms. Here we show that, in addition to mechanical stimuli, PIEZO channels are also powerfully modulated by voltage and can even switch to a purely voltage-gated mode. Mutations that cause human diseases, such as xerocytosis, profoundly shift voltage sensitivity of PIEZO1 channels toward the resting membrane potential and strongly promote voltage gating. Voltage modulation may be explained by the presence of an inactivation gate in the pore, the opening of which is promoted by outward permeation. Older invertebrate (fly) and vertebrate (fish) PIEZO proteins are also voltage sensitive, but voltage gating is a much more prominent feature of these older channels. We propose that the voltage sensitivity of PIEZO channels is a deep property co-opted to add a regulatory mechanism for PIEZO activation in widely different cellular contexts. Introduction The mechanically gated ion channels PIEZO1 and PIEZO2 are involved in a variety of physiological functions essential to life. PIEZO1 plays a fundamental role in the development of the mouse vasculature as well as lymphatic systems 1 , 2 , 3 . The PIEZO2 protein is found in sensory neurons of the dorsal root ganglia and Merkel cells where its presence is essential for mechanotransduction 4 , 5 , 6 . Mice without Piezo2 in sensory neurons lack normal touch sensation and proprioception, and severe loss of function alleles in humans are also associated with loss of proprioception and touch sensation 4 , 7 , 8 , 9 . Genetic ablation of either the Piezo1 or Piezo2 genes in mice leads to either embryonic or early post-natal lethality 1 , 2 , 10 . Recently, both mouse and human genetics have revealed roles for PIEZO-mechanosensing ion channels in a variety of non-sensory cellular physiology ranging from cartilage formation by chondrocytes 11 , 12 , epithelial sheet homeostasis 13 , 14 , growth cone guidance 15 , arterial smooth muscle remodeling 16 to blood cell shape regulation 17 . The mouse PIEZO1 protein forms a pore-forming ion channel directly gated by membrane stretch 18 , 19 , 20 . High resolution structures of the mouse PIEZO1 protein were recently obtained revealing a trimeric three-bladed, propeller-shaped structure with a central pore-forming module comprising of an outer helix (OH), C-terminal extracellular domain (CED), inner helix (IH), and intracellular C-terminal domain (CTD) 21 , 22 , 23 . The peripheral regions of PIEZO1 are composed of the extracellular “blade” domains, 36 peripheral helices (PHs) in each subunit and intracellular “beam” and “anchor” domains 23 . The PIEZO1 structure has facilitated biophysical exploration of the ion-channel pore 24 , 25 , 26 , 27 , 28 , and chimeric structures suggest that the N-terminal non-pore containing region confers mechanosensitivity on the channel 28 . However, recent data suggested that these models need further validation 29 . Proteins like STOML3 have been identified that can dramatically increase the sensitivity of PIEZO channels to mechanical force 30 , 31 . However, the role of membrane voltage in modulating PIEZO channel activity has barely been addressed despite the fact that both mammalian stretch-activated potassium channels 32 , 33 , 34 , 35 , 36 , as well as bacterial stretch-activated channels are voltage sensitive 37 . Here, we asked whether voltage can modulate or even gate vertebrate and invertebrate PIEZO channels. We show that both PIEZO1 and PIEZO2 show significant voltage sensitivity that is dependent on critical residues in the pore-lining region of the channel. We provide evidence for an inactivation gate that closes following inward permeation which under physiological conditions renders >90% of the channels unavailable mechanical gating. Outward permeation of the channel is sufficient to initiate a slow conformational change that opens the inactivation gate. Pathological human mutations in Piezo1 primarily weaken the inactivation gate and render the channels less sensitive to voltage modulation. The same mutations also allow PIEZO1 to behave as a voltage-gated ion channel in the absence of mechanical stimuli. Finally, we show that the biophysical properties of both invertebrate ( Drosophila melanogaster ) and other vertebrate ( Danio rerio ) PIEZOs are much more reminiscent of classical voltage-gated channels than mammalian PIEZOs. Results PIEZO1 open probability is increased at positive voltages PIEZO1 channels show a linear I/V relationship between −50 and +50 mV, but the current inactivation is much slower at positive holding potentials compared to negative voltages 5 , 28 . We subjected excised outside-out patches from the N2a cells of the overexpressing mouse PIEZO1 to an I / V protocol from −100 to +100 mV in symmetrical Na + , without divalent cations, while stimulating the patch with a saturating pressure pulse. However, at more positive voltages the I/V relationship showed strong outward rectification (rectification index I −60 mV / I 60 mV 5.3 ± 0.6, 12 cells) (Fig. 1a ). Single PIEZO1 channels may conduct more ions outward than inward, a phenomenon seen in glycine and GABA A channels 38 , however, single channel measurements under identical conditions showed that channel outward conductance was smaller than the inward conductance (Fig. 1b ). Fig. 1 Rectification and voltage modulation of pressure-mediated PIEZO1 currents. a Left: example traces of currents elicited at a constant saturating pressure (70 mmHg) and at increasing voltages (in 20 mV steps from −100 to 100 mV) in symmetrical Na + from excised outside-out patches overexpressing mPIEZO1 in N2a cells. Right: peak currents are plotted against voltage to show an I / V relationship. Note the outward rectifying behavior. b Left: single channel openings were recorded at negative and positive voltages to obtain the slope-conductance values. Right: linear regressions from individual patches were averaged and pooled. Inward slope conductance was significantly higher than outward slope conductance (41.3 ± 0.9 pS and 27.1 ± 1.2 pS, respectively, three cells. Student’s t -test P = 0.0006, d F = 4). c Example trace of instantaneous currents recorded upon switching voltage from +60 to −60 mV during the application of a 70 mmHg", "role": "user" }, { "content": "The Piezo1 and Piezo2 ion channels are known to open up response to the slightest mechanical stimulus. MDC researchers have now discovered that the channels are also sensitive to changes in membrane voltage. The voltage sensitivity appears to be an ancient property of these channels that protects cells from mechanical stress. A light breeze, a gentle stroke - the human skin can sense the slightest touch. A key player in this process is an ion channel in the skin's inner cell membranes that was only discovered seven years ago: Piezo2 responds to mechanical stimuli by opening when the cell membrane surrounding it expands. Opening the channel excites the sensory cell to send signals to the brain. Piezo1 opens in the same way as PIEZO2, but is involved in the formation of blood vessels rather than the sense of touch. New vessels are only created when a blood flow is registered in the body, and Piezo1 is the sensor that registers the flow of blood. This channel is therefore vital for humans and other mammals. Mice that are missing Piezo1 after deletion of the gene die either before or shortly after birth. Most Piezo channels are closed Until now, the assumption was that Piezo1 and Piezo2 reacted solely to mechanical stimuli - perhaps because of the unique structure of the two ion channels, which is fundamentally different to that of classical voltage-gated channels. However, a research team led by Gary Lewin of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin has now discovered that Piezo channels are in fact highly sensitive to changes in membrane voltage. Cells probably use this ability to protect themselves from mechanical overstimulation, as reported in an article published in the journal Nature Communications initiated and carried out by Dr. Mirko Moroni, the lead author, and other members of Lewin's research group. The research was funded by the Alexander von Humboldt Foundation and the German Research Foundation (DFG). Even flies and fish have the protective mechanism \"When the membrane voltage is normal, which in most cells is ?60 mV, around 95 percent of all the Piezo channels are closed and remain closed even when exposed to mechanical stimuli,\" explains Lewin. \"More channels are activated only when the voltage changes and the membrane becomes depolarized.\" The researcher explains that this appears to be a very old evolutionary property, and one that plays an extremely important role. Given that voltage-dependent Piezo channels have also been discovered in fruit flies and zebrafish, the scientists have concluded that this newly discovered protection mechanism has probably existed for many millions of years. In fact, the mechanism is even more pronounced in both these species than it is in evolutionarily younger species like mice and humans. A mutation in Piezo1 damages red blood cells This importance of voltage regulation is not only demonstrated by the fact that it has clearly existed for well over 100 million years, but Moroni also discovered a mutation in the Piezo1 channels of human blood cells that alters the voltage dependence of these ion channels, making them far more sensitive to changes in the membrane potential and thus more sensitive to mechanical stimuli. \"People with this genetic mutation suffer from a disease called hereditary xerocytosis,\" says Lewin. This is a congenital red blood cell abnormality that leads to anemia in affected patients. German speed skater Claudia Pechstein actually suffers from a mild form of this disease, which is why she was found to have too many immature red blood cells in her body in 2014 and was suspected of doping. The mechanism was actually discovered by chance \"The fact that people get sick as a result of a change in the voltage dependence of Piezo channels demonstrates the importance of this mechanism - which remained unnoticed for so long and was first discovered almost by chance by Dr Mirko Moroni,\" says Lewin. The mechanism seems to protect blood cells from the mechanical stress they would otherwise be permanently exposed to as they travel through narrow blood vessels. As a next step, Lewin and his colleagues want to find out whether altering the voltage dependency of Piezo2 has any impact on the skin's sense of touch. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms. Here we show that, in addition to mechanical stimuli, PIEZO channels are also powerfully modulated by voltage and can even switch to a purely voltage-gated mode. Mutations that cause human diseases, such as xerocytosis, profoundly shift voltage sensitivity of PIEZO1 channels toward the resting membrane potential and strongly promote voltage gating. Voltage modulation may be explained by the presence of an inactivation gate in the pore, the opening of which is promoted by outward permeation. Older invertebrate (fly) and vertebrate (fish) PIEZO proteins are also voltage sensitive, but voltage gating is a much more prominent feature of these older channels. We propose that the voltage sensitivity of PIEZO channels is a deep property co-opted to add a regulatory mechanism for PIEZO activation in widely different cellular contexts. Introduction The mechanically gated ion channels PIEZO1 and PIEZO2 are involved in a variety of physiological functions essential to life. PIEZO1 plays a fundamental role in the development of the mouse vasculature as well as lymphatic systems 1 , 2 , 3 . The PIEZO2 protein is found in sensory neurons of the dorsal root ganglia and Merkel cells where its presence is essential for mechanotransduction 4 , 5 , 6 . Mice without Piezo2 in sensory neurons lack normal touch sensation and proprioception, and severe loss of function alleles in humans are also associated with loss of proprioception and touch sensation 4 , 7 , 8 , 9 . Genetic ablation of either the Piezo1 or Piezo2 genes in mice leads to either embryonic or early post-natal lethality 1 , 2 , 10 . Recently, both mouse and human genetics have revealed roles for PIEZO-mechanosensing ion channels in a variety of non-sensory cellular physiology ranging from cartilage formation by chondrocytes 11 , 12 , epithelial sheet homeostasis 13 , 14 , growth cone guidance 15 , arterial smooth muscle remodeling 16 to blood cell shape regulation 17 . The mouse PIEZO1 protein forms a pore-forming ion channel directly gated by membrane stretch 18 , 19 , 20 . High resolution structures of the mouse PIEZO1 protein were recently obtained revealing a trimeric three-bladed, propeller-shaped structure with a central pore-forming module comprising of an outer helix (OH), C-terminal extracellular domain (CED), inner helix (IH), and intracellular C-terminal domain (CTD) 21 , 22 , 23 . The peripheral regions of PIEZO1 are composed of the extracellular “blade” domains, 36 peripheral helices (PHs) in each subunit and intracellular “beam” and “anchor” domains 23 . The PIEZO1 structure has facilitated biophysical exploration of the ion-channel pore 24 , 25 , 26 , 27 , 28 , and chimeric structures suggest that the N-terminal non-pore containing region confers mechanosensitivity on the channel 28 . However, recent data suggested that these models need further validation 29 . Proteins like STOML3 have been identified that can dramatically increase the sensitivity of PIEZO channels to mechanical force 30 , 31 . However, the role of membrane voltage in modulating PIEZO channel activity has barely been addressed despite the fact that both mammalian stretch-activated potassium channels 32 , 33 , 34 , 35 , 36 , as well as bacterial stretch-activated channels are voltage sensitive 37 . Here, we asked whether voltage can modulate or even gate vertebrate and invertebrate PIEZO channels. We show that both PIEZO1 and PIEZO2 show significant voltage sensitivity that is dependent on critical residues in the pore-lining region of the channel. We provide evidence for an inactivation gate that closes following inward permeation which under physiological conditions renders >90% of the channels unavailable mechanical gating. Outward permeation of the channel is sufficient to initiate a slow conformational change that opens the inactivation gate. Pathological human mutations in Piezo1 primarily weaken the inactivation gate and render the channels less sensitive to voltage modulation. The same mutations also allow PIEZO1 to behave as a voltage-gated ion channel in the absence of mechanical stimuli. Finally, we show that the biophysical properties of both invertebrate ( Drosophila melanogaster ) and other vertebrate ( Danio rerio ) PIEZOs are much more reminiscent of classical voltage-gated channels than mammalian PIEZOs. Results PIEZO1 open probability is increased at positive voltages PIEZO1 channels show a linear I/V relationship between −50 and +50 mV, but the current inactivation is much slower at positive holding potentials compared to negative voltages 5 , 28 . We subjected excised outside-out patches from the N2a cells of the overexpressing mouse PIEZO1 to an I / V protocol from −100 to +100 mV in symmetrical Na + , without divalent cations, while stimulating the patch with a saturating pressure pulse. However, at more positive voltages the I/V relationship showed strong outward rectification (rectification index I −60 mV / I 60 mV 5.3 ± 0.6, 12 cells) (Fig. 1a ). Single PIEZO1 channels may conduct more ions outward than inward, a phenomenon seen in glycine and GABA A channels 38 , however, single channel measurements under identical conditions showed that channel outward conductance was smaller than the inward conductance (Fig. 1b ). Fig. 1 Rectification and voltage modulation of pressure-mediated PIEZO1 currents. a Left: example traces of currents elicited at a constant saturating pressure (70 mmHg) and at increasing voltages (in 20 mV steps from −100 to 100 mV) in symmetrical Na + from excised outside-out patches overexpressing mPIEZO1 in N2a cells. Right: peak currents are plotted against voltage to show an I / V relationship. Note the outward rectifying behavior. b Left: single channel openings were recorded at negative and positive voltages to obtain the slope-conductance values. Right: linear regressions from individual patches were averaged and pooled. Inward slope conductance was significantly higher than outward slope conductance (41.3 ± 0.9 pS and 27.1 ± 1.2 pS, respectively, three cells. Student’s t -test P = 0.0006, d F = 4). c Example trace of instantaneous currents recorded upon switching voltage from +60 to −60 mV during the application of a 70 mmHg<|im_end|> <|im_start|>assistant The Piezo1 and Piezo2 ion channels are known to open up response to the slightest mechanical stimulus. MDC researchers have now discovered that the channels are also sensitive to changes in membrane voltage. The voltage sensitivity appears to be an ancient property of these channels that protects cells from mechanical stress. A light breeze, a gentle stroke - the human skin can sense the slightest touch. A key player in this process is an ion channel in the skin's inner cell membranes that was only discovered seven years ago: Piezo2 responds to mechanical stimuli by opening when the cell membrane surrounding it expands. Opening the channel excites the sensory cell to send signals to the brain. Piezo1 opens in the same way as PIEZO2, but is involved in the formation of blood vessels rather than the sense of touch. New vessels are only created when a blood flow is registered in the body, and Piezo1 is the sensor that registers the flow of blood. This channel is therefore vital for humans and other mammals. Mice that are missing Piezo1 after deletion of the gene die either before or shortly after birth. Most Piezo channels are closed Until now, the assumption was that Piezo1 and Piezo2 reacted solely to mechanical stimuli - perhaps because of the unique structure of the two ion channels, which is fundamentally different to that of classical voltage-gated channels. However, a research team led by Gary Lewin of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin has now discovered that Piezo channels are in fact highly sensitive to changes in membrane voltage. Cells probably use this ability to protect themselves from mechanical overstimulation, as reported in an article published in the journal Nature Communications initiated and carried out by Dr. Mirko Moroni, the lead author, and other members of Lewin's research group. The research was funded by the Alexander von Humboldt Foundation and the German Research Foundation (DFG). Even flies and fish have the protective mechanism "When the membrane voltage is normal, which in most cells is ?60 mV, around 95 percent of all the Piezo channels are closed and remain closed even when exposed to mechanical stimuli," explains Lewin. "More channels are activated only when the voltage changes and the membrane becomes depolarized." The researcher explains that this appears to be a very old evolutionary property, and one that plays an extremely important role. Given that voltage-dependent Piezo channels have also been discovered in fruit flies and zebrafish, the scientists have concluded that this newly discovered protection mechanism has probably existed for many millions of years. In fact, the mechanism is even more pronounced in both these species than it is in evolutionarily younger species like mice and humans. A mutation in Piezo1 damages red blood cells This importance of voltage regulation is not only demonstrated by the fact that it has clearly existed for well over 100 million years, but Moroni also discovered a mutation in the Piezo1 channels of human blood cells that alters the voltage dependence of these ion channels, making them far more sensitive to changes in the membrane potential and thus more sensitive to mechanical stimuli. "People with this genetic mutation suffer from a disease called hereditary xerocytosis," says Lewin. This is a congenital red blood cell abnormality that leads to anemia in affected patients. German speed skater Claudia Pechstein actually suffers from a mild form of this disease, which is why she was found to have too many immature red blood cells in her body in 2014 and was suspected of doping. The mechanism was actually discovered by chance "The fact that people get sick as a result of a change in the voltage dependence of Piezo channels demonstrates the importance of this mechanism - which remained unnoticed for so long and was first discovered almost by chance by Dr Mirko Moroni," says Lewin. The mechanism seems to protect blood cells from the mechanical stress they would otherwise be permanently exposed to as they travel through narrow blood vessels. As a next step, Lewin and his colleagues want to find out whether altering the voltage dependency of Piezo2 has any impact on the skin's sense of touch. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Genetic and epigenetic changes in cancer cells are typically divided into ‘drivers’ and ‘passengers’. Drug development strategies target driver mutations, but inter- and intratumoral heterogeneity usually results in emergence of resistance. Here we model intratumoral evolution in the context of a fecundity/survivorship trade-off. Simulations demonstrate that the fitness value of any genetic change is not fixed but dependent on evolutionary triage governed by initial cell properties, current selection forces and prior genotypic/phenotypic trajectories. We demonstrate that spatial variations in molecular properties of tumour cells are the result of changes in environmental selection forces such as blood flow. Simulated therapies targeting fitness-increasing (driver) mutations usually decrease the tumour burden but almost inevitably fail due to population heterogeneity. An alternative strategy targets gene mutations that are never observed. Because up or downregulation of these genes unconditionally reduces cellular fitness, they are eliminated by evolutionary triage but can be exploited for targeted therapy. Introduction The transition from normal to malignant phenotype during carcinogenesis, often described as ‘somatic evolution,’ is associated with the accumulation of genetic (and epigenetic) mutations 1 , 2 , 3 , 4 but typically demonstrates convergence to common phenotypic properties (the cancer ‘hallmarks’ 5 ). Mutations are commonly characterized as a ‘driver’ or ‘passenger’ depending on the contributions to proliferation and invasion 6 , 7 . Targeted therapies can produce significant tumour response by disrupting driver mutations. However, not all tumours have identifiable and/or drugable driver mutations and response to targeted therapy, even when the driver mutation is present, is usually transient as resistant phenotypes repopulate the tumour 8 . Here we investigate genetic heterogeneity, phenotypic convergence, the conventional binary classification of driver/passenger mutations and corresponding targeted therapy in the context of Darwinian dynamics. This extends ongoing efforts to understand cancer from first principles on the basis of evolution by natural selection 9 , 10 , 11 , including the classical trade-offs observed in Darwinian systems. Here, we consider a multi-loci diallelic model of mutation and selection within a finite population of tumour cells evolving along a well-defined adaptive landscape. In examining the evolutionary dynamics during carcinogenesis, we assume that normal epithelial cells exist in an evolutionary and ecological state well below their maximal carrying capacity and individual evolutionary potential for survival and proliferation. That is, normal cells carry out their differentiated tasks for maintaining whole organism function and their population density, survival and proliferation is entirely controlled by tissue signals. Ecologically, a new cancer cell lineage begins with abundant available space (the lumen of a duct, for example) and is initially free from the life history trade-off of proliferation versus survivorship. Evolutionarily, the tumour lineage develops a self-defined fitness function, and then uses the human genome to evolve strategies to enhance survival and/or proliferation. Consistent with the fundamental laws of evolution, each population may initially undergo exponential proliferation but is ultimately ecologically constrained by the limitations of substrate and space. Here, the evolutionary trajectory reaches the classical Darwinian life history trade-off 12 , 13 , in which cancer cells must invest limited available resources in some combination of survival and fecundity that maximizes fitness within the context of their environment. These phenotypic strategies are apparent in the consistent convergence to the ‘hallmarks’ of cancer. We use in silico simulations based on Darwinian first principles and classical evolutionary trade-offs to investigate the genomic dynamics that are both a cause and consequence of tumour development and progression. Our specific interests focus on the conventional designation of driver and passenger mutations, the source of observed spatial intratumoral heterogeneity, and the dynamics of tumour response and resistance to targeted therapies. Our results demonstrate that the fitness value of most genetic and epigenetic events are contextual and depend on extant environmental selection forces, other local populations and the prior evolutionary arc of the cell—dynamics that we collectively describe as ‘evolutionary triage.’ We find that, as a result of evolutionary triage, the same mutation can act as passenger or driver depending on context. In a stable microenvironment, evolutionary triage will reduce tumour cell diversity so that the observed intratumoral molecular heterogeneity is largely due to the variations in local selection pressures caused by, for example, blood flow. Our results demonstrate a previously unrecognized therapeutic target—‘never’ mutations. That is, when a gene is never or rarely observed to be mutated, we must conclude that up or downregulation of that gene unconditionally reduces cell fitness. We demonstrate that targeting never genes can be a highly effective therapeutic strategy. Results Evolutionary triage Pooling genetic data from the 225 carcinogenesis simulations, we observed 3,334 unique genotypes (5.09% of all possible genotypes) within the evolving cancers. Although the model randomly imposed mutations on each gene, the frequency with which each mutation was observable in the tumour was strongly influenced by its associated fitness change—a phenomenon we term ‘evolutionary triage.’ The observed frequency of neutral mutations is 0.6% per generation and at least one neutral mutation is found in ~25% of the cells in the final tumour populations. Thus, the observed frequency of passenger mutations per generation permits, as expected, a reasonable estimate of the actual mutation rate (which was 1% in our simulations). In some simulations, a neutral allele ‘hitchhiked’ with a successful mutation and formed temporary linkage disequilibrium ( Figs 1 and 2 ) so that it was present in a frequency greater than expected. Figure 1: Evolutionary trajectories and gene prevalence. ( a ) During evolution to ESS1 (Evolutionary Stable State 1), the genes highlighted in green conferred increased fitness depending on the starting initial phenotype. The genes circled in red, such as gene 1, reduce both fecundity and survivorship and were never observed in the final simulated cancer populations. ( b ) Multiple evolutionary trajectories exist to ESS1 depending on the initial phenotype. This functional equivalence results in genetic heterogeneity within and between patients as seen in c . ( c ) The mutation prevalence varies greatly depending on the initial phenotype. The orange line represents the neutral mutation prevalence. Full size image Figure 2: Effect", "role": "user" }, { "content": "Moffitt Cancer Center researchers are taking a unique approach to understanding and investigating cancer by utilizing evolutionary principles and computational modeling to examine the role of specific genetic mutations in the Darwinian struggle among tumor and normal cells during cancer growth. Cells become malignant by acquiring genetic mutations that lead to increased survival and reproduction. Many researchers in the past have viewed cancer progression as the result of unlimited accumulation of these genetic mutations. However, Moffitt researchers model cancer progression on the premise that cancer cells live in an environment that has limited resources, such as space and nutrients and, like all living organisms, must obey the laws of evolution. These laws include trade-offs between proliferation and survival. For example, elephants use their available resources primarily to maximize survival so that they have relatively long lives and few offspring. Rabbits, on the other hand, produce many offspring but survive in the wild for less than two years. Similarly, cells that evolve to form cancers can do so by either increasing longevity or increasing the number of offspring. But like elephants and rabbits, they can only move down one evolutionary path at a time, so the mutations observed in cancer cells are limited to this evolutionary trade-off. With this in mind, cancer cells can invest available resources in maximizing their defenses against attacks by the normal tissue or accept a high rate of mortality and overcome it through very rapid proliferation. The cells cannot do both. Moffitt researchers performed computer simulations based on these concepts. They found that the frequency with which any genetic mutation is observed depends on its ability to increase the cell's fitness, its ability to survive and reproduce. The researched called this process \"evolutionary triage.\" \"Genes that increase fitness are observed more frequently than those that do not,\" explained Robert A. Gatenby, M.D., chair of the Department of Diagnostic Imaging and co-director of the Cancer Biology and Evolution Program at Moffitt. \"However, the effect of any mutation on cell fitness can change drastically depending on environmental factors such as blood flow, past genetic mutations, and the properties of competing cells. Currently, cancer biologists divide mutations into 'drivers,' which promote tumor growth and 'passengers,' which have no effect on growth. In the computer simulations, it was clear that many mutations could be drivers in one environment, but passengers in another.\" Since driver mutations are common targets for cancer therapy, the scientists also simulated therapies that seek to disable driver genes. Similar to what is found in clinical settings, they observed that targeted therapies can kill the mutated cells and decrease the tumor size. However, the diversity of tumor environments produces many mutational pathways to formation of a malignant cell. As result, cancer cells that lack the driver mutation and are resistant to therapy were almost invariably present and caused the tumor to recur. The investigators were startled to find that some genes were actually never observed to be mutated in cancers. It turned out that mutations in these genes always reduced the tumor cell's ability to survive or reproduce. As a result, even when they occurred, evolutionary triage eliminated them because they were less fit than their competitors. According to Gatenby, \"our computer simulations demonstrate an unexpected result - genes that are never observed to be mutated might actually be the best targets for therapy. This is because up or down regulation of these genes unconditionally reduces cell fitness.\" The researchers showed that targeting genes that are never mutated, particularly when followed by treatment that targeted cancer driver mutations, was a highly effective treatment strategy. The final question was: \"Do 'never mutations' exist in human cancer?\" Fortunately, large databases that list all of the mutations in clinical cancers have been developed by the National Cancer Institute. With the help of Mohammad Fallahi-Sichani, Ph.D., a bioinformatics expert from the Scripps Research Institute, 1,100 genes that are never mutated in human cancers were identified. The research group, which included Moffitt Physicist Jessica Cunningham and Joel S. Brown, an evolutionary biologist at University of Illinois, is now working with John Cleveland, Ph.D., associate center director of Basic Science at Moffitt, to investigate the possibility of targeting \"never\" genes for therapy. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Genetic and epigenetic changes in cancer cells are typically divided into ‘drivers’ and ‘passengers’. Drug development strategies target driver mutations, but inter- and intratumoral heterogeneity usually results in emergence of resistance. Here we model intratumoral evolution in the context of a fecundity/survivorship trade-off. Simulations demonstrate that the fitness value of any genetic change is not fixed but dependent on evolutionary triage governed by initial cell properties, current selection forces and prior genotypic/phenotypic trajectories. We demonstrate that spatial variations in molecular properties of tumour cells are the result of changes in environmental selection forces such as blood flow. Simulated therapies targeting fitness-increasing (driver) mutations usually decrease the tumour burden but almost inevitably fail due to population heterogeneity. An alternative strategy targets gene mutations that are never observed. Because up or downregulation of these genes unconditionally reduces cellular fitness, they are eliminated by evolutionary triage but can be exploited for targeted therapy. Introduction The transition from normal to malignant phenotype during carcinogenesis, often described as ‘somatic evolution,’ is associated with the accumulation of genetic (and epigenetic) mutations 1 , 2 , 3 , 4 but typically demonstrates convergence to common phenotypic properties (the cancer ‘hallmarks’ 5 ). Mutations are commonly characterized as a ‘driver’ or ‘passenger’ depending on the contributions to proliferation and invasion 6 , 7 . Targeted therapies can produce significant tumour response by disrupting driver mutations. However, not all tumours have identifiable and/or drugable driver mutations and response to targeted therapy, even when the driver mutation is present, is usually transient as resistant phenotypes repopulate the tumour 8 . Here we investigate genetic heterogeneity, phenotypic convergence, the conventional binary classification of driver/passenger mutations and corresponding targeted therapy in the context of Darwinian dynamics. This extends ongoing efforts to understand cancer from first principles on the basis of evolution by natural selection 9 , 10 , 11 , including the classical trade-offs observed in Darwinian systems. Here, we consider a multi-loci diallelic model of mutation and selection within a finite population of tumour cells evolving along a well-defined adaptive landscape. In examining the evolutionary dynamics during carcinogenesis, we assume that normal epithelial cells exist in an evolutionary and ecological state well below their maximal carrying capacity and individual evolutionary potential for survival and proliferation. That is, normal cells carry out their differentiated tasks for maintaining whole organism function and their population density, survival and proliferation is entirely controlled by tissue signals. Ecologically, a new cancer cell lineage begins with abundant available space (the lumen of a duct, for example) and is initially free from the life history trade-off of proliferation versus survivorship. Evolutionarily, the tumour lineage develops a self-defined fitness function, and then uses the human genome to evolve strategies to enhance survival and/or proliferation. Consistent with the fundamental laws of evolution, each population may initially undergo exponential proliferation but is ultimately ecologically constrained by the limitations of substrate and space. Here, the evolutionary trajectory reaches the classical Darwinian life history trade-off 12 , 13 , in which cancer cells must invest limited available resources in some combination of survival and fecundity that maximizes fitness within the context of their environment. These phenotypic strategies are apparent in the consistent convergence to the ‘hallmarks’ of cancer. We use in silico simulations based on Darwinian first principles and classical evolutionary trade-offs to investigate the genomic dynamics that are both a cause and consequence of tumour development and progression. Our specific interests focus on the conventional designation of driver and passenger mutations, the source of observed spatial intratumoral heterogeneity, and the dynamics of tumour response and resistance to targeted therapies. Our results demonstrate that the fitness value of most genetic and epigenetic events are contextual and depend on extant environmental selection forces, other local populations and the prior evolutionary arc of the cell—dynamics that we collectively describe as ‘evolutionary triage.’ We find that, as a result of evolutionary triage, the same mutation can act as passenger or driver depending on context. In a stable microenvironment, evolutionary triage will reduce tumour cell diversity so that the observed intratumoral molecular heterogeneity is largely due to the variations in local selection pressures caused by, for example, blood flow. Our results demonstrate a previously unrecognized therapeutic target—‘never’ mutations. That is, when a gene is never or rarely observed to be mutated, we must conclude that up or downregulation of that gene unconditionally reduces cell fitness. We demonstrate that targeting never genes can be a highly effective therapeutic strategy. Results Evolutionary triage Pooling genetic data from the 225 carcinogenesis simulations, we observed 3,334 unique genotypes (5.09% of all possible genotypes) within the evolving cancers. Although the model randomly imposed mutations on each gene, the frequency with which each mutation was observable in the tumour was strongly influenced by its associated fitness change—a phenomenon we term ‘evolutionary triage.’ The observed frequency of neutral mutations is 0.6% per generation and at least one neutral mutation is found in ~25% of the cells in the final tumour populations. Thus, the observed frequency of passenger mutations per generation permits, as expected, a reasonable estimate of the actual mutation rate (which was 1% in our simulations). In some simulations, a neutral allele ‘hitchhiked’ with a successful mutation and formed temporary linkage disequilibrium ( Figs 1 and 2 ) so that it was present in a frequency greater than expected. Figure 1: Evolutionary trajectories and gene prevalence. ( a ) During evolution to ESS1 (Evolutionary Stable State 1), the genes highlighted in green conferred increased fitness depending on the starting initial phenotype. The genes circled in red, such as gene 1, reduce both fecundity and survivorship and were never observed in the final simulated cancer populations. ( b ) Multiple evolutionary trajectories exist to ESS1 depending on the initial phenotype. This functional equivalence results in genetic heterogeneity within and between patients as seen in c . ( c ) The mutation prevalence varies greatly depending on the initial phenotype. The orange line represents the neutral mutation prevalence. Full size image Figure 2: Effect<|im_end|> <|im_start|>assistant Moffitt Cancer Center researchers are taking a unique approach to understanding and investigating cancer by utilizing evolutionary principles and computational modeling to examine the role of specific genetic mutations in the Darwinian struggle among tumor and normal cells during cancer growth. Cells become malignant by acquiring genetic mutations that lead to increased survival and reproduction. Many researchers in the past have viewed cancer progression as the result of unlimited accumulation of these genetic mutations. However, Moffitt researchers model cancer progression on the premise that cancer cells live in an environment that has limited resources, such as space and nutrients and, like all living organisms, must obey the laws of evolution. These laws include trade-offs between proliferation and survival. For example, elephants use their available resources primarily to maximize survival so that they have relatively long lives and few offspring. Rabbits, on the other hand, produce many offspring but survive in the wild for less than two years. Similarly, cells that evolve to form cancers can do so by either increasing longevity or increasing the number of offspring. But like elephants and rabbits, they can only move down one evolutionary path at a time, so the mutations observed in cancer cells are limited to this evolutionary trade-off. With this in mind, cancer cells can invest available resources in maximizing their defenses against attacks by the normal tissue or accept a high rate of mortality and overcome it through very rapid proliferation. The cells cannot do both. Moffitt researchers performed computer simulations based on these concepts. They found that the frequency with which any genetic mutation is observed depends on its ability to increase the cell's fitness, its ability to survive and reproduce. The researched called this process "evolutionary triage." "Genes that increase fitness are observed more frequently than those that do not," explained Robert A. Gatenby, M.D., chair of the Department of Diagnostic Imaging and co-director of the Cancer Biology and Evolution Program at Moffitt. "However, the effect of any mutation on cell fitness can change drastically depending on environmental factors such as blood flow, past genetic mutations, and the properties of competing cells. Currently, cancer biologists divide mutations into 'drivers,' which promote tumor growth and 'passengers,' which have no effect on growth. In the computer simulations, it was clear that many mutations could be drivers in one environment, but passengers in another." Since driver mutations are common targets for cancer therapy, the scientists also simulated therapies that seek to disable driver genes. Similar to what is found in clinical settings, they observed that targeted therapies can kill the mutated cells and decrease the tumor size. However, the diversity of tumor environments produces many mutational pathways to formation of a malignant cell. As result, cancer cells that lack the driver mutation and are resistant to therapy were almost invariably present and caused the tumor to recur. The investigators were startled to find that some genes were actually never observed to be mutated in cancers. It turned out that mutations in these genes always reduced the tumor cell's ability to survive or reproduce. As a result, even when they occurred, evolutionary triage eliminated them because they were less fit than their competitors. According to Gatenby, "our computer simulations demonstrate an unexpected result - genes that are never observed to be mutated might actually be the best targets for therapy. This is because up or down regulation of these genes unconditionally reduces cell fitness." The researchers showed that targeting genes that are never mutated, particularly when followed by treatment that targeted cancer driver mutations, was a highly effective treatment strategy. The final question was: "Do 'never mutations' exist in human cancer?" Fortunately, large databases that list all of the mutations in clinical cancers have been developed by the National Cancer Institute. With the help of Mohammad Fallahi-Sichani, Ph.D., a bioinformatics expert from the Scripps Research Institute, 1,100 genes that are never mutated in human cancers were identified. The research group, which included Moffitt Physicist Jessica Cunningham and Joel S. Brown, an evolutionary biologist at University of Illinois, is now working with John Cleveland, Ph.D., associate center director of Basic Science at Moffitt, to investigate the possibility of targeting "never" genes for therapy. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The Rubik’s cube is a prototypical combinatorial puzzle that has a large state space with a single goal state. The goal state is unlikely to be accessed using sequences of randomly generated moves, posing unique challenges for machine learning. We solve the Rubik’s cube with DeepCubeA, a deep reinforcement learning approach that learns how to solve increasingly difficult states in reverse from the goal state without any specific domain knowledge. DeepCubeA solves 100% of all test configurations, finding a shortest path to the goal state 60.3% of the time. DeepCubeA generalizes to other combinatorial puzzles and is able to solve the 15 puzzle, 24 puzzle, 35 puzzle, 48 puzzle, Lights Out and Sokoban, finding a shortest path in the majority of verifiable cases. Main The Rubik’s cube is a classic combinatorial puzzle that poses unique and interesting challenges for artificial intelligence and machine learning. Although the state space is exceptionally large (4.3 × 10 19 different states), there is only one goal state. Furthermore, the Rubik’s cube is a single-player game and a sequence of random moves, no matter how long, is unlikely to end in the goal state. Developing machine learning algorithms to deal with this property of the Rubik’s cube might provide insights into learning to solve planning problems with large state spaces. Although machine learning methods have previously been applied to the Rubik’s cube, these methods have either failed to reliably solve the cube 1 , 2 , 3 , 4 or have had to rely on specific domain knowledge 5 , 6 . Outside of machine learning methods, methods based on pattern databases (PDBs) have been effective at solving puzzles such as the Rubik’s cube, the 15 puzzle and the 24 puzzle 7 , 8 , but these methods can be memory-intensive and puzzle-specific. More broadly, a major goal in artificial intelligence is to create algorithms that are able to learn how to master various environments without relying on domain-specific human knowledge. The classical 3 × 3 × 3 Rubik’s cube is only one representative of a larger family of possible environments that broadly share the characteristics described above, including (1) cubes with longer edges or higher dimension (for example, 4 × 4 × 4 or 2 × 2 × 2 × 2), (2) sliding tile puzzles (for example the 15 puzzle, 24 puzzle, 35 puzzle and 48 puzzle), (3) Lights Out and (4) Sokoban. As the size and dimensions are increased, the complexity of the underlying combinatorial problems rapidly increases. For example, while finding an optimal solution to the 15 puzzle takes less than a second on a modern-day desktop, finding an optimal solution to the 24 puzzle can take days, and finding an optimal solution to the 35 puzzle is generally intractable 9 . Not only are the aforementioned puzzles relevant as mathematical games, but they can also be used to test planning algorithms 10 and to assess how well a machine learning approach may generalize to different environments. Furthermore, because the operation of the Rubik’s cube and other combinatorial puzzles are deeply rooted in group theory, these puzzles also raise broader questions about the application of machine learning methods to complex symbolic systems, including mathematics. In short, for all these reasons, the Rubik’s cube poses interesting challenges for machine learning. To address these challenges, we have developed DeepCubeA, which combines deep learning 11 , 12 with classical reinforcement learning 13 (approximate value iteration 14 , 15 , 16 ) and path finding methods (weighted A* search 17 , 18 ). DeepCubeA is able to solve combinatorial puzzles such as the Rubik’s cube, 15 puzzle, 24 puzzle, 35 puzzle, 48 puzzle, Lights Out and Sokoban (Fig. 1 ). DeepCubeA works by using approximate value iteration to train a deep neural network (DNN) to approximate a function that outputs the cost to reach the goal (also known as the cost-to-go function). Given that random play is unlikely to end in the goal state, DeepCubeA trains on states obtained by starting from the goal state and randomly taking moves in reverse. After training, the learned cost-to-go function is used as a heuristic to solve the puzzles using a weighted A* search 17 , 18 , 19 . Fig. 1: Visualization of scrambled states and goal states. Visualization of a scrambled state (top) and the goal state (bottom) for four puzzles investigated here. Full size image DeepCubeA builds on DeepCube 20 , a deep reinforcement learning algorithm that solves the Rubik’s cube using a policy and value function combined with Monte Carlo tree search (MCTS). MCTS, combined with a policy and value function, is also used by AlphaZero, which learns to beat the best existing programs in chess, Go and shogi 21 . In practice, we find that, for combinatorial puzzles, MCTS has relatively long runtimes and often produces solutions many moves longer than the length of a shortest path. In contrast, DeepCubeA finds a shortest path to the goal for puzzles for which a shortest path is computationally verifiable: 60.3% of the time for the Rubik’s cube and over 90% of the time for the 15 puzzle, 24 puzzle and Lights Out. Deep approximate value iteration Value iteration 15 is a dynamic programming algorithm 14 , 16 that iteratively improves a cost-to-go function J . In traditional value iteration, J takes the form of a lookup table where the cost-to-go J ( s ) is stored in a table for all possible states s . However, this lookup table representation becomes infeasible for combinatorial puzzles with large state spaces like the Rubik’s cube. Therefore, we turn to approximate value iteration 16 , where J is represented by a parameterized function implemented by a DNN. The DNN is trained to minimize the mean squared error between its estimation of the cost-to-go of state s , J ( s ), and the updated cost-to-go estimation J ′( s ): $$J\\prime (s) = {\\mathrm{min}}_a(g^a(s,A(s,a)) + J(A(s,a)))$$ (1) where A ( s , a ) is the state obtained", "role": "user" }, { "content": "Since its invention by a Hungarian architect in 1974, the Rubik's Cube has furrowed the brows of many who have tried to solve it, but the 3-D logic puzzle is no match for an artificial intelligence system created by researchers at the University of California, Irvine. DeepCubeA, a deep reinforcement learning algorithm programmed by UCI computer scientists and mathematicians, can find the solution in a fraction of a second, without any specific domain knowledge or in-game coaching from humans. This is no simple task considering that the cube has completion paths numbering in the billions but only one goal state—each of six sides displaying a solid color—which apparently can't be found through random moves. For a study published today in Nature Machine Intelligence, the researchers demonstrated that DeepCubeA solved 100 percent of all test configurations, finding the shortest path to the goal state about 60 percent of the time. The algorithm also works on other combinatorial games such as the sliding tile puzzle, Lights Out and Sokoban. \"Artificial intelligence can defeat the world's best human chess and Go players, but some of the more difficult puzzles, such as the Rubik's Cube, had not been solved by computers, so we thought they were open for AI approaches,\" said senior author Pierre Baldi, UCI Distinguished Professor of computer science. \"The solution to the Rubik's Cube involves more symbolic, mathematical and abstract thinking, so a deep learning machine that can crack such a puzzle is getting closer to becoming a system that can think, reason, plan and make decisions.\" The researchers were interested in understanding how and why the AI made its moves and how long it took to perfect its method. They started with a computer simulation of a completed puzzle and then scrambled the cube. Once the code was in place and running, DeepCubeA trained in isolation for two days, solving an increasingly difficult series of combinations. \"It learned on its own,\" Baldi noted. There are some people, particularly teenagers, who can solve the Rubik's Cube in a hurry, but even they take about 50 moves. \"Our AI takes about 20 moves, most of the time solving it in the minimum number of steps,\" Baldi said. \"Right there, you can see the strategy is different, so my best guess is that the AI's form of reasoning is completely different from a human's.\" The veteran computer scientist said the ultimate goal of projects such as this one is to build the next generation of AI systems. Whether they know it or not, people are touched by artificial intelligence every day through apps such as Siri and Alexa and recommendation engines working behind the scenes of their favorite online services. \"But these systems are not really intelligent; they're brittle, and you can easily break or fool them,\" Baldi said. \"How do we create advanced AI that is smarter, more robust and capable of reasoning, understanding and planning? This work is a step toward this hefty goal.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The Rubik’s cube is a prototypical combinatorial puzzle that has a large state space with a single goal state. The goal state is unlikely to be accessed using sequences of randomly generated moves, posing unique challenges for machine learning. We solve the Rubik’s cube with DeepCubeA, a deep reinforcement learning approach that learns how to solve increasingly difficult states in reverse from the goal state without any specific domain knowledge. DeepCubeA solves 100% of all test configurations, finding a shortest path to the goal state 60.3% of the time. DeepCubeA generalizes to other combinatorial puzzles and is able to solve the 15 puzzle, 24 puzzle, 35 puzzle, 48 puzzle, Lights Out and Sokoban, finding a shortest path in the majority of verifiable cases. Main The Rubik’s cube is a classic combinatorial puzzle that poses unique and interesting challenges for artificial intelligence and machine learning. Although the state space is exceptionally large (4.3 × 10 19 different states), there is only one goal state. Furthermore, the Rubik’s cube is a single-player game and a sequence of random moves, no matter how long, is unlikely to end in the goal state. Developing machine learning algorithms to deal with this property of the Rubik’s cube might provide insights into learning to solve planning problems with large state spaces. Although machine learning methods have previously been applied to the Rubik’s cube, these methods have either failed to reliably solve the cube 1 , 2 , 3 , 4 or have had to rely on specific domain knowledge 5 , 6 . Outside of machine learning methods, methods based on pattern databases (PDBs) have been effective at solving puzzles such as the Rubik’s cube, the 15 puzzle and the 24 puzzle 7 , 8 , but these methods can be memory-intensive and puzzle-specific. More broadly, a major goal in artificial intelligence is to create algorithms that are able to learn how to master various environments without relying on domain-specific human knowledge. The classical 3 × 3 × 3 Rubik’s cube is only one representative of a larger family of possible environments that broadly share the characteristics described above, including (1) cubes with longer edges or higher dimension (for example, 4 × 4 × 4 or 2 × 2 × 2 × 2), (2) sliding tile puzzles (for example the 15 puzzle, 24 puzzle, 35 puzzle and 48 puzzle), (3) Lights Out and (4) Sokoban. As the size and dimensions are increased, the complexity of the underlying combinatorial problems rapidly increases. For example, while finding an optimal solution to the 15 puzzle takes less than a second on a modern-day desktop, finding an optimal solution to the 24 puzzle can take days, and finding an optimal solution to the 35 puzzle is generally intractable 9 . Not only are the aforementioned puzzles relevant as mathematical games, but they can also be used to test planning algorithms 10 and to assess how well a machine learning approach may generalize to different environments. Furthermore, because the operation of the Rubik’s cube and other combinatorial puzzles are deeply rooted in group theory, these puzzles also raise broader questions about the application of machine learning methods to complex symbolic systems, including mathematics. In short, for all these reasons, the Rubik’s cube poses interesting challenges for machine learning. To address these challenges, we have developed DeepCubeA, which combines deep learning 11 , 12 with classical reinforcement learning 13 (approximate value iteration 14 , 15 , 16 ) and path finding methods (weighted A* search 17 , 18 ). DeepCubeA is able to solve combinatorial puzzles such as the Rubik’s cube, 15 puzzle, 24 puzzle, 35 puzzle, 48 puzzle, Lights Out and Sokoban (Fig. 1 ). DeepCubeA works by using approximate value iteration to train a deep neural network (DNN) to approximate a function that outputs the cost to reach the goal (also known as the cost-to-go function). Given that random play is unlikely to end in the goal state, DeepCubeA trains on states obtained by starting from the goal state and randomly taking moves in reverse. After training, the learned cost-to-go function is used as a heuristic to solve the puzzles using a weighted A* search 17 , 18 , 19 . Fig. 1: Visualization of scrambled states and goal states. Visualization of a scrambled state (top) and the goal state (bottom) for four puzzles investigated here. Full size image DeepCubeA builds on DeepCube 20 , a deep reinforcement learning algorithm that solves the Rubik’s cube using a policy and value function combined with Monte Carlo tree search (MCTS). MCTS, combined with a policy and value function, is also used by AlphaZero, which learns to beat the best existing programs in chess, Go and shogi 21 . In practice, we find that, for combinatorial puzzles, MCTS has relatively long runtimes and often produces solutions many moves longer than the length of a shortest path. In contrast, DeepCubeA finds a shortest path to the goal for puzzles for which a shortest path is computationally verifiable: 60.3% of the time for the Rubik’s cube and over 90% of the time for the 15 puzzle, 24 puzzle and Lights Out. Deep approximate value iteration Value iteration 15 is a dynamic programming algorithm 14 , 16 that iteratively improves a cost-to-go function J . In traditional value iteration, J takes the form of a lookup table where the cost-to-go J ( s ) is stored in a table for all possible states s . However, this lookup table representation becomes infeasible for combinatorial puzzles with large state spaces like the Rubik’s cube. Therefore, we turn to approximate value iteration 16 , where J is represented by a parameterized function implemented by a DNN. The DNN is trained to minimize the mean squared error between its estimation of the cost-to-go of state s , J ( s ), and the updated cost-to-go estimation J ′( s ): $$J\prime (s) = {\mathrm{min}}_a(g^a(s,A(s,a)) + J(A(s,a)))$$ (1) where A ( s , a ) is the state obtained<|im_end|> <|im_start|>assistant Since its invention by a Hungarian architect in 1974, the Rubik's Cube has furrowed the brows of many who have tried to solve it, but the 3-D logic puzzle is no match for an artificial intelligence system created by researchers at the University of California, Irvine. DeepCubeA, a deep reinforcement learning algorithm programmed by UCI computer scientists and mathematicians, can find the solution in a fraction of a second, without any specific domain knowledge or in-game coaching from humans. This is no simple task considering that the cube has completion paths numbering in the billions but only one goal state—each of six sides displaying a solid color—which apparently can't be found through random moves. For a study published today in Nature Machine Intelligence, the researchers demonstrated that DeepCubeA solved 100 percent of all test configurations, finding the shortest path to the goal state about 60 percent of the time. The algorithm also works on other combinatorial games such as the sliding tile puzzle, Lights Out and Sokoban. "Artificial intelligence can defeat the world's best human chess and Go players, but some of the more difficult puzzles, such as the Rubik's Cube, had not been solved by computers, so we thought they were open for AI approaches," said senior author Pierre Baldi, UCI Distinguished Professor of computer science. "The solution to the Rubik's Cube involves more symbolic, mathematical and abstract thinking, so a deep learning machine that can crack such a puzzle is getting closer to becoming a system that can think, reason, plan and make decisions." The researchers were interested in understanding how and why the AI made its moves and how long it took to perfect its method. They started with a computer simulation of a completed puzzle and then scrambled the cube. Once the code was in place and running, DeepCubeA trained in isolation for two days, solving an increasingly difficult series of combinations. "It learned on its own," Baldi noted. There are some people, particularly teenagers, who can solve the Rubik's Cube in a hurry, but even they take about 50 moves. "Our AI takes about 20 moves, most of the time solving it in the minimum number of steps," Baldi said. "Right there, you can see the strategy is different, so my best guess is that the AI's form of reasoning is completely different from a human's." The veteran computer scientist said the ultimate goal of projects such as this one is to build the next generation of AI systems. Whether they know it or not, people are touched by artificial intelligence every day through apps such as Siri and Alexa and recommendation engines working behind the scenes of their favorite online services. "But these systems are not really intelligent; they're brittle, and you can easily break or fool them," Baldi said. "How do we create advanced AI that is smarter, more robust and capable of reasoning, understanding and planning? This work is a step toward this hefty goal." <|im_end|>

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1,959

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The alpha-2,8-linked form of the polysaccharide polysialic acid (PSA) has widespread implications in physiological and pathological processes, ranging from neurological development to disease progression. Though the high electronegativity and excluded volume of PSA often promotes interference of biomolecular interactions, PSA-binding ligands have important implications for both biological processes and biotechnological applications. As such, the design, identification, and characterisation of novel ligands towards PSA is critical for expanding knowledge of PSA interactions and achieving selective glycan targeting. Here, we report on a rational approach for the identification of alpha-2,8-PSA-binding peptides, involving design from the endogenous ligand Siglec-11 and multi-platform characterisation of peptide binding. Microarray-based examination of peptides revealed charge and sequence characteristics influencing peptide affinity to PSA, and carbohydrate–peptide binding was further quantified with a novel fluorescence anisotropy assay. PSA-binding peptides exhibited specific binding to polymeric SA, as well as different degrees of selective binding in various conditions, including competition with PSA of alternating 2,8/9-linkages and screening with PSA-expressing cells. A computational study of Siglec-11 and Siglec-11-derived peptides offered synergistic insight into ligand binding. These results demonstrate the potential of PSA-binding peptides for selective targeting and highlight the importance of the approaches described herein for the study of carbohydrate interactions. Introduction Polysialic acid (PSA) is a unique polysaccharide playing critical roles in a number of physiological and pathological processes. PSA occurs naturally in a variety of forms, comprising different sialic acid monomers and glycosidic linkages 1 , 2 . Of the three homopolymeric forms of N-acetylneuraminic acid (the most common sialic acid in humans), only α-2,8-linked PSA is found in our species 1 , 2 , 3 . The roles of PSAs across biology are diverse; humans display highest PSA expression on neural stem and progenitor cells, where expression primarily guides neurological development, but in other systems and organisms, this biopolymer is implicated in bypassing immune surveillance, promoting tissue development, enabling cell migration, and even possibly serving as a molecular reservoir 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . Changes in polysialylation on proteins and cell surfaces are often tied to functional states. For example, change in PSA expression during human embryonic development influences neuronal growth and migration, while in adults, long-chain PSA is largely restricted to regions of the nervous system undergoing remodelling 1 , 2 , 3 , 4 , 5 . In pathological context, PSA is of great interest due to its occurrence on pathogenic bacteria ( e.g ., Neisseria meningitidis groups B and C), where expression in the polysaccharide capsule enables evasion of the host immune system 1 , 2 , 9 , 10 , 11 , 12 . Additionally, PSA has been found on tumour cells, and its expression has been correlated with poorer prognosis of certain cancers, possibly due to an increase in metastatic potential 1 , 2 , 13 . Despite the broad diagnostic and therapeutic application space available with the ability to understand, target, and detect PSA, in vitro or in vivo , few studies have sought to develop and characterise robust ligands against PSA. Several naturally occurring proteins have been identified to bind to PSA, including neurotrophins and polysialyltransferases 1 , 2 . However, information ( e.g ., residue-level and structural) about direct interaction of PSA with endogenous ligands is limited 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . Additionally, challenges in protein isolation and stability deter characterisation and applicability of such ligands for PSA targeting. The generation of anti-PSA antibodies, together with their biochemical characterisation (as of mAb735), has proved useful 2 , 21 , 22 . Yet, as with native ligands, factors including production, size, and stability may limit the versatility of antibodies in applications; these factors comparatively promote the versatility of low molecular weight ligands. Besides such advantages for the latter ligands (described elsewhere 24 ), the identification of small targeting agents, like peptides, for PSA can add to basic knowledge of PSA molecular interactions, especially when rational design strategies are incorporated in ligand development. Furthermore, ligand design with a focus on elucidating binding characteristics can provide critical information for iterative design and future targeting efforts. In this study, we report on the design and identification of α-2,8-PSA-binding peptides, with biochemical and thermodynamic characterisation of peptide binding and insight into PSA interaction with the endogenous ligand Siglec-11 23 . We have previously identified peptide ligands binding to α-2,8-PSA, demonstrating the success of a high-throughput peptide microarray platform for evaluating design strategies and supporting preliminary peptide characterisation 25 . Here, we examined amino acid sequences derived from a naturally occurring lectin to PSA in tandem with previously identified peptides, while simultaneously expanding on peptide characterisation using a synergistic experimental and computational approach. Results Library-level examination of peptide–PSA interaction Peptides (762 unique sequences) were screened for binding to α-2,8-PSA using a high-throughput microarray screening platform 25 . A library of peptides was designed from linear epitope mapping of the protein Siglec-11 (all domains) with peptides 15 residues in length overlapping by 13 residues (329 peptides; 1 previously reported 25 ). Siglec-11 is a member of the highly homologous Siglec family of sialic acid binding-proteins with 2,8-linkage specificity 23 , 26 , 27 , 28 . An additional 172 peptides (1 previously reported 25 ) were designed based on Siglec-derived sequences. Modifications to these peptides included select rational mutations and sequence scrambling. Siglec-modified sequences designed with preliminary binding hypotheses were synthesized alongside the parent library; other sequences based on screening of the original library were synthesized iteratively, where binding and non-binding peptides were modified to study variation in target affinity and selectivity. Random sequences from de novo design and from prior reports in literature 29 (38 peptides), as well as PSA-binding and non-binding peptides previously designed from mAb735 and phage display screening (223 peptides) 25 , were concurrently screened for intra-assay comparison to binding of Siglec-derived peptides. Sequences of", "role": "user" }, { "content": "Chemically engineered peptides, designed and developed by a team of researchers at Rensselaer Polytechnic Institute, could prove valuable in the battle against some of the most persistent human health challenges. The team's findings, recently published in Nature Scientific Reports, demonstrate how researchers can engineer peptides capable of selectively and specifically binding to polysialic acid (PSA)—a carbohydrate that is present in many human cells and plays a key role in various physiological and pathological processes, including neurological development and disease progression. This foundational research lays the groundwork for further study into the ability of these peptides to provide an effective vehicle for therapeutics in the treatment of diseases such as Alzheimer's, Parkinson's, and cancer. The team's findings suggest the peptides may also prove valuable in providing a barrier between cells and viruses, such as the one that causes COVID-19—a possibility the research team now hopes to study. \"Because these peptides bind to PSA, they also mask PSA, and could potentially be used to inhibit the binding of viruses and their entry into cells,\" said Pankaj Karande, an associate professor of chemical engineering, a member of the Center for Biotechnology and Interdisciplinary Studies (CBIS), and one of the lead authors on this paper. \"The idea is to see if these peptides could inhibit that interaction and therefore inhibit the infectivity of those viruses.\" Taking inspiration from nature, Karande said the team modeled its peptides after proteins known as Sialic acid-binding immunoglobulin-type lectins, or Siglecs, which occur naturally and inherently bind to PSA. The research laid out in the paper was also led by Divya Shastry, a former doctoral student in biological sciences at Rensselaer. It was completed in collaboration with Robert Linhardt, an endowed professor of chemistry and chemical biology, and Mattheos Koffas, an endowed professor of chemical and biological engineering, both of whom are members of CBIS as well. The Rensselaer team also worked with a team from Syracuse University that used computational modeling to provide the Rensselaer researchers with a molecular-level look at the peptides they designed. \"These significant and promising research advances are a prime example of how a collaborative approach can solve persistent human health challenges,\" said Deepak Vashishth, the director of CBIS. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The alpha-2,8-linked form of the polysaccharide polysialic acid (PSA) has widespread implications in physiological and pathological processes, ranging from neurological development to disease progression. Though the high electronegativity and excluded volume of PSA often promotes interference of biomolecular interactions, PSA-binding ligands have important implications for both biological processes and biotechnological applications. As such, the design, identification, and characterisation of novel ligands towards PSA is critical for expanding knowledge of PSA interactions and achieving selective glycan targeting. Here, we report on a rational approach for the identification of alpha-2,8-PSA-binding peptides, involving design from the endogenous ligand Siglec-11 and multi-platform characterisation of peptide binding. Microarray-based examination of peptides revealed charge and sequence characteristics influencing peptide affinity to PSA, and carbohydrate–peptide binding was further quantified with a novel fluorescence anisotropy assay. PSA-binding peptides exhibited specific binding to polymeric SA, as well as different degrees of selective binding in various conditions, including competition with PSA of alternating 2,8/9-linkages and screening with PSA-expressing cells. A computational study of Siglec-11 and Siglec-11-derived peptides offered synergistic insight into ligand binding. These results demonstrate the potential of PSA-binding peptides for selective targeting and highlight the importance of the approaches described herein for the study of carbohydrate interactions. Introduction Polysialic acid (PSA) is a unique polysaccharide playing critical roles in a number of physiological and pathological processes. PSA occurs naturally in a variety of forms, comprising different sialic acid monomers and glycosidic linkages 1 , 2 . Of the three homopolymeric forms of N-acetylneuraminic acid (the most common sialic acid in humans), only α-2,8-linked PSA is found in our species 1 , 2 , 3 . The roles of PSAs across biology are diverse; humans display highest PSA expression on neural stem and progenitor cells, where expression primarily guides neurological development, but in other systems and organisms, this biopolymer is implicated in bypassing immune surveillance, promoting tissue development, enabling cell migration, and even possibly serving as a molecular reservoir 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . Changes in polysialylation on proteins and cell surfaces are often tied to functional states. For example, change in PSA expression during human embryonic development influences neuronal growth and migration, while in adults, long-chain PSA is largely restricted to regions of the nervous system undergoing remodelling 1 , 2 , 3 , 4 , 5 . In pathological context, PSA is of great interest due to its occurrence on pathogenic bacteria ( e.g ., Neisseria meningitidis groups B and C), where expression in the polysaccharide capsule enables evasion of the host immune system 1 , 2 , 9 , 10 , 11 , 12 . Additionally, PSA has been found on tumour cells, and its expression has been correlated with poorer prognosis of certain cancers, possibly due to an increase in metastatic potential 1 , 2 , 13 . Despite the broad diagnostic and therapeutic application space available with the ability to understand, target, and detect PSA, in vitro or in vivo , few studies have sought to develop and characterise robust ligands against PSA. Several naturally occurring proteins have been identified to bind to PSA, including neurotrophins and polysialyltransferases 1 , 2 . However, information ( e.g ., residue-level and structural) about direct interaction of PSA with endogenous ligands is limited 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . Additionally, challenges in protein isolation and stability deter characterisation and applicability of such ligands for PSA targeting. The generation of anti-PSA antibodies, together with their biochemical characterisation (as of mAb735), has proved useful 2 , 21 , 22 . Yet, as with native ligands, factors including production, size, and stability may limit the versatility of antibodies in applications; these factors comparatively promote the versatility of low molecular weight ligands. Besides such advantages for the latter ligands (described elsewhere 24 ), the identification of small targeting agents, like peptides, for PSA can add to basic knowledge of PSA molecular interactions, especially when rational design strategies are incorporated in ligand development. Furthermore, ligand design with a focus on elucidating binding characteristics can provide critical information for iterative design and future targeting efforts. In this study, we report on the design and identification of α-2,8-PSA-binding peptides, with biochemical and thermodynamic characterisation of peptide binding and insight into PSA interaction with the endogenous ligand Siglec-11 23 . We have previously identified peptide ligands binding to α-2,8-PSA, demonstrating the success of a high-throughput peptide microarray platform for evaluating design strategies and supporting preliminary peptide characterisation 25 . Here, we examined amino acid sequences derived from a naturally occurring lectin to PSA in tandem with previously identified peptides, while simultaneously expanding on peptide characterisation using a synergistic experimental and computational approach. Results Library-level examination of peptide–PSA interaction Peptides (762 unique sequences) were screened for binding to α-2,8-PSA using a high-throughput microarray screening platform 25 . A library of peptides was designed from linear epitope mapping of the protein Siglec-11 (all domains) with peptides 15 residues in length overlapping by 13 residues (329 peptides; 1 previously reported 25 ). Siglec-11 is a member of the highly homologous Siglec family of sialic acid binding-proteins with 2,8-linkage specificity 23 , 26 , 27 , 28 . An additional 172 peptides (1 previously reported 25 ) were designed based on Siglec-derived sequences. Modifications to these peptides included select rational mutations and sequence scrambling. Siglec-modified sequences designed with preliminary binding hypotheses were synthesized alongside the parent library; other sequences based on screening of the original library were synthesized iteratively, where binding and non-binding peptides were modified to study variation in target affinity and selectivity. Random sequences from de novo design and from prior reports in literature 29 (38 peptides), as well as PSA-binding and non-binding peptides previously designed from mAb735 and phage display screening (223 peptides) 25 , were concurrently screened for intra-assay comparison to binding of Siglec-derived peptides. Sequences of<|im_end|> <|im_start|>assistant Chemically engineered peptides, designed and developed by a team of researchers at Rensselaer Polytechnic Institute, could prove valuable in the battle against some of the most persistent human health challenges. The team's findings, recently published in Nature Scientific Reports, demonstrate how researchers can engineer peptides capable of selectively and specifically binding to polysialic acid (PSA)—a carbohydrate that is present in many human cells and plays a key role in various physiological and pathological processes, including neurological development and disease progression. This foundational research lays the groundwork for further study into the ability of these peptides to provide an effective vehicle for therapeutics in the treatment of diseases such as Alzheimer's, Parkinson's, and cancer. The team's findings suggest the peptides may also prove valuable in providing a barrier between cells and viruses, such as the one that causes COVID-19—a possibility the research team now hopes to study. "Because these peptides bind to PSA, they also mask PSA, and could potentially be used to inhibit the binding of viruses and their entry into cells," said Pankaj Karande, an associate professor of chemical engineering, a member of the Center for Biotechnology and Interdisciplinary Studies (CBIS), and one of the lead authors on this paper. "The idea is to see if these peptides could inhibit that interaction and therefore inhibit the infectivity of those viruses." Taking inspiration from nature, Karande said the team modeled its peptides after proteins known as Sialic acid-binding immunoglobulin-type lectins, or Siglecs, which occur naturally and inherently bind to PSA. The research laid out in the paper was also led by Divya Shastry, a former doctoral student in biological sciences at Rensselaer. It was completed in collaboration with Robert Linhardt, an endowed professor of chemistry and chemical biology, and Mattheos Koffas, an endowed professor of chemical and biological engineering, both of whom are members of CBIS as well. The Rensselaer team also worked with a team from Syracuse University that used computational modeling to provide the Rensselaer researchers with a molecular-level look at the peptides they designed. "These significant and promising research advances are a prime example of how a collaborative approach can solve persistent human health challenges," said Deepak Vashishth, the director of CBIS. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Uranium (U) is a ubiquitous element in the Earth’s crust at ~2 ppm. In anoxic environments, soluble hexavalent uranium (U(VI)) is reduced and immobilized. The underlying reduction mechanism is unknown but likely of critical importance to explain the geochemical behavior of U. Here, we tackle the mechanism of reduction of U(VI) by the mixed-valence iron oxide, magnetite. Through high-end spectroscopic and microscopic tools, we demonstrate that the reduction proceeds first through surface-associated U(VI) to form pentavalent U, U(V). U(V) persists on the surface of magnetite and is further reduced to tetravalent UO 2 as nanocrystals (~1–2 nm) with random orientations inside nanowires. Through nanoparticle re-orientation and coalescence, the nanowires collapse into ordered UO 2 nanoclusters. This work provides evidence for a transient U nanowire structure that may have implications for uranium isotope fractionation as well as for the molecular-scale understanding of nuclear waste temporal evolution and the reductive remediation of uranium contamination. Introduction Redox transformations from soluble uranium (U) hexavalent species (U(VI)) to insoluble tetravalent species (U(IV)) largely constrain uranium biogeochemical behavior. This redox reaction occurs in the remediation of soils and sediments where biologically generated minerals may immobilize contaminant U 1 , 2 , 3 , as well as in paleo-redox studies where the isotopic signature of uranium reduction may be used to indicate the presence of O 2 in the geological record 4 , 5 , 6 , 7 . Redox-active minerals, including Fe(II)- or sulfide-bearing minerals such as pyrite, mackinawite, magnetite, green rust, and Fe(II)-containing clays 1 , 2 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 are responsible for U(VI) reduction in ore deposits, anoxic aquifers, and marine sediments. Iron(II)-bearing minerals have gained attention also due to their importance in nuclear waste disposal where steel corrosion products may include magnetite (Fe 3 O 4 ) 12 , 17 , 18 , 19 . The molecular mechanism of U(VI) abiotic reduction by Fe(II)-bearing reducing agents, the electron transfer to U(VI), and the subsequent precipitation of U(IV) oxide have not been fully unraveled. Generally, studies to date have suggested that the reduction process consists of U(VI) adsorption followed by electron transfer by structural, adsorbed, or aqueous Fe(II) to result in the formation of U(IV) 3 , 18 , 20 . The reaction pathway and kinetics are controlled mainly by aqueous geochemistry conditions 12 , 21 , 22 and mineral characteristics, such as the availability of Fe(II) in either solid structures or aqueous phase 1 , 10 , 11 , 18 . Most laboratory studies report the final reduced product as U(IV), occurring as nanoparticulate uraninite (UO 2 ) 3 , 9 , 10 , 11 , 12 , 18 . Meanwhile, others have observed the formation of non-uraninite U(IV) 8 , 22 , or monomeric U(IV) species due to the presence of ligands or biomass that preclude the precipitation of UO 2 1 , 23 . Moreover, contradictory morphologies have been suggested, including the formation of a coating of UO 2 on the surface of mackinawite 2 , 23 , or individual UO 2 nanoparticles associated with the edge of green rust particles 9 and large magnetite crystals 12 , as well as stand-alone aggregates away from the magnetite surface 11 , 22 . Thus, a molecular-scale view of the process of formation of uraninite and its crystal growth process is still lacking. The presence of pentavalent U (U(V)), as an intermediate valence state, has been demonstrated in laboratory experiments 24 , 25 , 26 , and its importance as a long-lasting intermediate in the reductive process is starting to be recognized. However, uncertainty about its presence and of its role in reduction pathways involving iron oxides remains. The reduction of U(VI) to U(IV) can occur via (a) two single-electron transfer steps, from U(VI) to U(V), and U(V) to U(IV), or (b) from U(VI) to U(V) followed by disproportionation of two U(V) to U(VI) and U(IV) 22 , 27 , 28 , 29 . Theoretical calculations reported the reduction from U(VI) to U(V) by aqueous Fe(II) to be facile 29 and demonstrated that the incorporation of U in solid phases widens the stability field of U(V) species in the reduction by magnetite 16 . U(V) incorporation into iron oxide phases has been described experimentally in several scenarios. First, through the reduction of U(VI)-incorporated hematite by aqueous Fe(II) 30 or during the Fe(II)-induced transformation of iron oxides, from ferrihydrite to goethite or magnetite 21 , 31 , 32 . Second, it is well established that during the coprecipitation of U and magnetite, U(V) is incorporated into the iron oxides and persists for up to a year 33 . Third, the presence of U(V) has been detailed when U(VI) was reduced by pre-formed magnetite at relatively low pH values (<5) at which dissolution and recrystallization of iron oxides occur 16 , 26 , 34 . However, under neutral pH conditions, which is the more likely scenario in reducing soils and sediments, a single study showed the presence of U 3 O 8 (harboring U(V) and U(VI) 35 ) with X-ray photoelectron spectroscopy (XPS) 19 . In contrast, most other studies did not show direct evidence of U(V) on the pre-formed magnetite surface 11 , 22 . It should be noted that U(V) incorporated in iron oxides is considered to hold a uranate(V) structure because the first shell U–O bond distances are all ~2.0–2.1 Å 33 , 36 , as opposed to a uranyl(V) structure, which has short U–O trans-diaxo bonds (1.9 Å) and longer equatorial bonds (2.50 Å) 37 . Thus, while U(VI) reduction by minerals has been studied for decades, the molecular mechanism of formation of uraninite is mostly unknown. The role of U(V), the transfer of electrons to U from the mineral surface, and the formation of UO 2 are all poorly constrained. Furthermore, under some conditions, abiotic U(VI) reduction shows an isotope fractionation behavior deviating from equilibrium 38 , 39 . Depending on the reducing agent", "role": "user" }, { "content": "Most people are familiar with uranium as a fuel for nuclear power plants. And while that's the most common application, this element is also used in many other fields, such as dyes, medical devices, and weapons. Scientists at EPFL's Environmental Microbiology Laboratory (EML) have recently made an important discovery about uranium that could have major implications for soil and groundwater remediation as well as radioactive waste management. Their research has just been published in Nature Communications. Uranium is a radioactive heavy metal found in the Earth's crust and in tiny concentrations in water, air, plants and living organisms—humans have small amounts of uranium in their bones. The EML scientists studied the properties of uranium as it occurs naturally in the environment, and made significant breakthroughs in understanding how it goes from one oxidation state to the other, transitioning from a water-soluble compound to a stable mineral. \"At the +6 oxidation state, uranium is mostly soluble and can therefore spread uncontrolled in the environment,\" says Zezhen Pan, an EML scientist and the study's lead author. \"But at the +4 oxidation state, it is less soluble and less mobile. In our research we were able to pinpoint the nanoscale mechanisms of interaction between uranium and particles of magnetite, a magnetic iron oxide, to transition from one oxidation state to the other. We showed the persistence of Uranium at the +5 oxidation state, which is usually considered metastable.\" A nanowire structure Most interestingly, the scientists also identified a molecular phenomenon that occurs during the transformation from the +6 to the +4 oxidation state: they discovered the formation of novel nanowires composed of very small nanoparticles (~1-2 nm) that assembled spontaneously into chains. These chains eventually collapse as individual nanoparticles grow larger. The scientists were able to view the nanowires—which have a diameter of just 2–5 nm, or 100,000 times thinner than a human hair—thanks to the electron microscopes at EPFL's Interdisciplinary Center for Electron Microscopy (CIME). The identification of the nanowire structure could improve understanding of how radioactive compounds spread in the subsurface at contaminated sites. \"These findings hold a lot of promise because they provide insight into how nanoscale minerals form naturally through interactions at the water-mineral interface,\" says Rizlan Bernier-Latmani, the head of the EML. \"We now have a better understanding of the molecular mechanisms at work for this process.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Uranium (U) is a ubiquitous element in the Earth’s crust at ~2 ppm. In anoxic environments, soluble hexavalent uranium (U(VI)) is reduced and immobilized. The underlying reduction mechanism is unknown but likely of critical importance to explain the geochemical behavior of U. Here, we tackle the mechanism of reduction of U(VI) by the mixed-valence iron oxide, magnetite. Through high-end spectroscopic and microscopic tools, we demonstrate that the reduction proceeds first through surface-associated U(VI) to form pentavalent U, U(V). U(V) persists on the surface of magnetite and is further reduced to tetravalent UO 2 as nanocrystals (~1–2 nm) with random orientations inside nanowires. Through nanoparticle re-orientation and coalescence, the nanowires collapse into ordered UO 2 nanoclusters. This work provides evidence for a transient U nanowire structure that may have implications for uranium isotope fractionation as well as for the molecular-scale understanding of nuclear waste temporal evolution and the reductive remediation of uranium contamination. Introduction Redox transformations from soluble uranium (U) hexavalent species (U(VI)) to insoluble tetravalent species (U(IV)) largely constrain uranium biogeochemical behavior. This redox reaction occurs in the remediation of soils and sediments where biologically generated minerals may immobilize contaminant U 1 , 2 , 3 , as well as in paleo-redox studies where the isotopic signature of uranium reduction may be used to indicate the presence of O 2 in the geological record 4 , 5 , 6 , 7 . Redox-active minerals, including Fe(II)- or sulfide-bearing minerals such as pyrite, mackinawite, magnetite, green rust, and Fe(II)-containing clays 1 , 2 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 are responsible for U(VI) reduction in ore deposits, anoxic aquifers, and marine sediments. Iron(II)-bearing minerals have gained attention also due to their importance in nuclear waste disposal where steel corrosion products may include magnetite (Fe 3 O 4 ) 12 , 17 , 18 , 19 . The molecular mechanism of U(VI) abiotic reduction by Fe(II)-bearing reducing agents, the electron transfer to U(VI), and the subsequent precipitation of U(IV) oxide have not been fully unraveled. Generally, studies to date have suggested that the reduction process consists of U(VI) adsorption followed by electron transfer by structural, adsorbed, or aqueous Fe(II) to result in the formation of U(IV) 3 , 18 , 20 . The reaction pathway and kinetics are controlled mainly by aqueous geochemistry conditions 12 , 21 , 22 and mineral characteristics, such as the availability of Fe(II) in either solid structures or aqueous phase 1 , 10 , 11 , 18 . Most laboratory studies report the final reduced product as U(IV), occurring as nanoparticulate uraninite (UO 2 ) 3 , 9 , 10 , 11 , 12 , 18 . Meanwhile, others have observed the formation of non-uraninite U(IV) 8 , 22 , or monomeric U(IV) species due to the presence of ligands or biomass that preclude the precipitation of UO 2 1 , 23 . Moreover, contradictory morphologies have been suggested, including the formation of a coating of UO 2 on the surface of mackinawite 2 , 23 , or individual UO 2 nanoparticles associated with the edge of green rust particles 9 and large magnetite crystals 12 , as well as stand-alone aggregates away from the magnetite surface 11 , 22 . Thus, a molecular-scale view of the process of formation of uraninite and its crystal growth process is still lacking. The presence of pentavalent U (U(V)), as an intermediate valence state, has been demonstrated in laboratory experiments 24 , 25 , 26 , and its importance as a long-lasting intermediate in the reductive process is starting to be recognized. However, uncertainty about its presence and of its role in reduction pathways involving iron oxides remains. The reduction of U(VI) to U(IV) can occur via (a) two single-electron transfer steps, from U(VI) to U(V), and U(V) to U(IV), or (b) from U(VI) to U(V) followed by disproportionation of two U(V) to U(VI) and U(IV) 22 , 27 , 28 , 29 . Theoretical calculations reported the reduction from U(VI) to U(V) by aqueous Fe(II) to be facile 29 and demonstrated that the incorporation of U in solid phases widens the stability field of U(V) species in the reduction by magnetite 16 . U(V) incorporation into iron oxide phases has been described experimentally in several scenarios. First, through the reduction of U(VI)-incorporated hematite by aqueous Fe(II) 30 or during the Fe(II)-induced transformation of iron oxides, from ferrihydrite to goethite or magnetite 21 , 31 , 32 . Second, it is well established that during the coprecipitation of U and magnetite, U(V) is incorporated into the iron oxides and persists for up to a year 33 . Third, the presence of U(V) has been detailed when U(VI) was reduced by pre-formed magnetite at relatively low pH values (<5) at which dissolution and recrystallization of iron oxides occur 16 , 26 , 34 . However, under neutral pH conditions, which is the more likely scenario in reducing soils and sediments, a single study showed the presence of U 3 O 8 (harboring U(V) and U(VI) 35 ) with X-ray photoelectron spectroscopy (XPS) 19 . In contrast, most other studies did not show direct evidence of U(V) on the pre-formed magnetite surface 11 , 22 . It should be noted that U(V) incorporated in iron oxides is considered to hold a uranate(V) structure because the first shell U–O bond distances are all ~2.0–2.1 Å 33 , 36 , as opposed to a uranyl(V) structure, which has short U–O trans-diaxo bonds (1.9 Å) and longer equatorial bonds (2.50 Å) 37 . Thus, while U(VI) reduction by minerals has been studied for decades, the molecular mechanism of formation of uraninite is mostly unknown. The role of U(V), the transfer of electrons to U from the mineral surface, and the formation of UO 2 are all poorly constrained. Furthermore, under some conditions, abiotic U(VI) reduction shows an isotope fractionation behavior deviating from equilibrium 38 , 39 . Depending on the reducing agent<|im_end|> <|im_start|>assistant Most people are familiar with uranium as a fuel for nuclear power plants. And while that's the most common application, this element is also used in many other fields, such as dyes, medical devices, and weapons. Scientists at EPFL's Environmental Microbiology Laboratory (EML) have recently made an important discovery about uranium that could have major implications for soil and groundwater remediation as well as radioactive waste management. Their research has just been published in Nature Communications. Uranium is a radioactive heavy metal found in the Earth's crust and in tiny concentrations in water, air, plants and living organisms—humans have small amounts of uranium in their bones. The EML scientists studied the properties of uranium as it occurs naturally in the environment, and made significant breakthroughs in understanding how it goes from one oxidation state to the other, transitioning from a water-soluble compound to a stable mineral. "At the +6 oxidation state, uranium is mostly soluble and can therefore spread uncontrolled in the environment," says Zezhen Pan, an EML scientist and the study's lead author. "But at the +4 oxidation state, it is less soluble and less mobile. In our research we were able to pinpoint the nanoscale mechanisms of interaction between uranium and particles of magnetite, a magnetic iron oxide, to transition from one oxidation state to the other. We showed the persistence of Uranium at the +5 oxidation state, which is usually considered metastable." A nanowire structure Most interestingly, the scientists also identified a molecular phenomenon that occurs during the transformation from the +6 to the +4 oxidation state: they discovered the formation of novel nanowires composed of very small nanoparticles (~1-2 nm) that assembled spontaneously into chains. These chains eventually collapse as individual nanoparticles grow larger. The scientists were able to view the nanowires—which have a diameter of just 2–5 nm, or 100,000 times thinner than a human hair—thanks to the electron microscopes at EPFL's Interdisciplinary Center for Electron Microscopy (CIME). The identification of the nanowire structure could improve understanding of how radioactive compounds spread in the subsurface at contaminated sites. "These findings hold a lot of promise because they provide insight into how nanoscale minerals form naturally through interactions at the water-mineral interface," says Rizlan Bernier-Latmani, the head of the EML. "We now have a better understanding of the molecular mechanisms at work for this process." <|im_end|>

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2,054

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objectives The circadian clocks are internal timing mechanisms that drive ∼24-hour rhythms in a tissue-specific manner. Many aspects of the physiology of the intervertebral disc (IVD) show clear diurnal rhythms. However, it is unknown whether IVD tissue contains functional circadian clocks and if so, how their dysregulation is implicated in IVD degeneration. Methods Clock gene dynamics in ex vivo IVD explants (from PER2:: luciferase (LUC) reporter mice) and human disc cells (transduced with lentivirus containing Per2 ::luc reporters) were monitored in real time by bioluminescence photon counting and imaging. Temporal gene expression changes were studied by RNAseq and quantitative reverse transcription (qRT)-PCR. IVD pathology was evaluated by histology in a mouse model with tissue-specific deletion of the core clock gene Bmal1 . Results Here we show the existence of the circadian rhythm in mouse IVD tissue and human disc cells. This rhythm is dampened with ageing in mice and can be abolished by treatment with interleukin-1β but not tumour necrosis factor α. Time-series RNAseq revealed 607 genes with 24-hour patterns of expression representing several essential pathways in IVD physiology. Mice with conditional knockout of Bmal1 in their disc cells demonstrated age-related degeneration of IVDs. Conclusions We have established autonomous circadian clocks in mouse and human IVD cells which respond to age and cytokines, and control key pathways involved in the homeostasis of IVDs. Genetic disruption to the mouse IVD molecular clock predisposes to IVD degeneration. These results support the concept that disruptions to circadian rhythms may be a risk factor for degenerative IVD disease and low back pain. Low Back Pain Cytokines Arthritis Chondrocytes This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 18 news outlets Blogged by 2 Tweeted by 17 On 5 Facebook pages 119 readers on Mendeley 2 readers on CiteULike Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version=\"1.0\" encoding=\"UTF-8\" ? Request permissions Low Back Pain Cytokines Arthritis Chondrocytes Introduction The circadian clocks are internal timing mechanisms which drive ∼24-hour rhythms in physiology and behaviour. In mammals, the central pacemaker suprachiasmatic nuclei (SCN) in the hypothalamus synchronises peripheral clocks in most major body organs. 1–3 Circadian rhythms coordinate tissue-specific physiology with light/darkness, rest/activity, feeding cycles and body temperature fluctuations. 1 , 4 Disruptions to circadian rhythms (during ageing or in shift workers) have been linked to increased risk of diseases (eg, obesity, diabetes, cardiovascular disease and osteoarthritis). 5 , 6 At the molecular level, the circadian clock consists of a network of transcriptional activators ( Clock , Bmal1 ) and repressors ( Per1/2 and Cry1/2 ) organised in a negative feedback loop. 6 This core oscillator generates 24-hour rhythms in the expression of its core components and a myriad of clock-controlled genes. Depending on the tissue, expression of 3%–16% of the whole transcriptome exhibits a circadian rhythm. 7 The spine is comprised of bony vertebral bodies alternating with fibrocartilagenous intervertebral discs (IVD). IVD degeneration is among the most prevalent musculoskeletal disorders affecting one in five people under 60 and more than half of the people above 60 years of age. 8 Low back pain, which is often associated with IVD degeneration, is the number one cause of years lived with disability in the developed countries. 9 Existing evidence suggests that the IVD is a highly rhythmic tissue, experiencing a diurnal cycle of higher loading (activity phase), 10 , 11 followed by a period of low-load recovery (resting phase). Under high load, the pressurised interstitial fluid flows to regions of lower pressure through the outer annulus fibrosus (AF) and the cartilaginous end plate (CEP), resulting in decreased disc height, AF outward bulging and an increase in osmolarity of the central gelatinous nucleus pulposus (NP). During the recovery period, the process is reversed by high osmotic pressure inside the disc causing fluid flow to the NP. 12 Exchange of nutrients/metabolites that occurs with fluid flow during this cycle maintains disc cell homeostasis. 13 Consistent with the rhythmic nature of IVD tissue, shift work (a factor known to disrupt circadian rhythms) was reported to be associated with higher risk of low back pain (LBP) and IVD degeneration. 14–18 We have previously shown that environmental disruption of circadian rhythm in mice, when combined with high fat diet, leads to degeneration of the lumbar IVD tissue in mice. 19 More recently, changes in the expression of circadian clock genes have been identified in rat IVD tissues following passive smoking (a risk factor for LBP). 20 However, no studies have examined whether IVD cells express intrinsic circadian clocks, how these IVD clocks are regulated, what their targets are and whether genetic disruption to the IVD clock impact on tissue homeostasis and susceptibility to degeneration. In this study, we systemically characterised the molecular circadian clock mechanisms in mouse and human IVD tissue/cells. Moreover, by generating a tissue-specific Bmal1 KO mouse model, our study provides the first genetic evidence linking a core clock factor to IVD degeneration. Results Intervertebral disc possesses a functional, temperature entrainable circadian clock To test whether the IVD contains a molecular circadian clock capable of driving circadian rhythm of gene expression, we monitored the dynamics of PER2::Luc protein in IVD explant cultures isolated from PER2::Luc reporter mice. 21 Real-time bioluminescence photon counting demonstrated robust circadian rhythm of PER2::Luc activity which lasted for more than 5 days, with a period of 23.93±0.10 hours (mean±SEM, n=6, figure 1 A). As the IVD comprises two distinct cell types, the NP and AF cells, we wanted to know if both regions exhibit circadian", "role": "user" }, { "content": "New research by University of Manchester scientists has for the first time shown that our spinal discs have 24-hour body clocks which when they malfunction, can contribute to lower back pain. Lower back pain is amongst the most prevalent spinal diseases associated with increasing age, with over 80% of the UK population predicted to experience back pain within their lifetime. Progressive degeneration of the spine disc is a major contributing factor. The study led by Dr Qing-Jun Meng and Professor Judith Hoyland could have important implications on the understanding and treatment of the condition. Their findings have been published in the journal Annals of the Rheumatic Diseases today . Ageing and inflammation, say the scientists, are major causes of disc degeneration and lower back pain. In this research, both conditions were found to cause body clock malfunction. The team say getting a good night's sleep will protect our body clocks and potentially avoid disc problems later in life. Avoiding night working where possible, or working fixed regular hours, as opposed to rotating shift work, they say, will also help. Additionally, the non-steroidal anti-inflammatory drugs we take for back pain will be more effective if we take into account our natural body clock cycle, by timing treatment to anticipate pain, they add. Dr Meng, who is a Senior Research Fellow funded by Arthritis Research UK, said: \"It has been known for years that, as a consequence of the daily activity and resting cycle, we are taller in the mornings by up to 2cm more than when we go to bed. \"The discovery of body clocks in the disc may go some way to explain, for the first time, the science behind this rhythmic physiology of the spine. \"Our research shows that this system is regulated by our internal body clock and when the body clock ceases to work properly during ageing or in shift workers, lower back pain is more likely to become an issue.\" He added: \"Looking after your body clock will help manage or delay the onset of your back pain. \"And based on our findings, we hope that one day, we may be able to combine NSAIDs with clock targeting compounds to provide a more powerful solution.\" Dr Natalie Carter, head of research liaison and evaluation at the charity Arthritis Research UK, said: \"This research is very interesting and is a significant breakthrough in our understanding of lower back pain. Many people find that their symptoms get worse at certain times of the day and the results of this study reveal a likely biological basis to this effect. \"As a charity we know that living in pain, day in and day out, can have a devastating impact on people's lives, affecting their independence, mobility and ability to stay in work. If we are going to address this growing need, we need better pain management and better treatments to relieve pain. An exciting prospect is that it may be possible to use this new information improve treatments and pain relief for people affected by this debilitating condition.\" The 24-hour body clock was revealed to be present in the disc tissue of transgenic mice and human samples. Though the investigation of human disc cells was more complex, both results were consistent with each other. The team tracked a 'clock' protein which shows the presence of the body clock using bioluminescent markers, whose flashes correspond to clock activity of the disc. A fascinating video, made by the scientists, shows how inflammation disrupts the body clock in living disc tissue which then recovers following treatment. Professor Hoyland said: \"Our research shows that if you remove the body clock from cells in the disc in mice, within 6 months degeneration is very noticeable and the disc is thinner by 20 to 30%. \"Within 12 months, we found evidence of fibrosis, the thickening and scarring of connective tissue prevalent in human degenerative disc. \"This accelerated ageing of the disc in a \"clockless\" model indicates that having a robust body clock will help slow down spinal aging and associated spinal diseases.\" \"We were also excited to find 607 rhythmic genes which exist in in disc tissue. Many of these genes are implicated in key pathways involved in the health of the disc.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objectives The circadian clocks are internal timing mechanisms that drive ∼24-hour rhythms in a tissue-specific manner. Many aspects of the physiology of the intervertebral disc (IVD) show clear diurnal rhythms. However, it is unknown whether IVD tissue contains functional circadian clocks and if so, how their dysregulation is implicated in IVD degeneration. Methods Clock gene dynamics in ex vivo IVD explants (from PER2:: luciferase (LUC) reporter mice) and human disc cells (transduced with lentivirus containing Per2 ::luc reporters) were monitored in real time by bioluminescence photon counting and imaging. Temporal gene expression changes were studied by RNAseq and quantitative reverse transcription (qRT)-PCR. IVD pathology was evaluated by histology in a mouse model with tissue-specific deletion of the core clock gene Bmal1 . Results Here we show the existence of the circadian rhythm in mouse IVD tissue and human disc cells. This rhythm is dampened with ageing in mice and can be abolished by treatment with interleukin-1β but not tumour necrosis factor α. Time-series RNAseq revealed 607 genes with 24-hour patterns of expression representing several essential pathways in IVD physiology. Mice with conditional knockout of Bmal1 in their disc cells demonstrated age-related degeneration of IVDs. Conclusions We have established autonomous circadian clocks in mouse and human IVD cells which respond to age and cytokines, and control key pathways involved in the homeostasis of IVDs. Genetic disruption to the mouse IVD molecular clock predisposes to IVD degeneration. These results support the concept that disruptions to circadian rhythms may be a risk factor for degenerative IVD disease and low back pain. Low Back Pain Cytokines Arthritis Chondrocytes This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 18 news outlets Blogged by 2 Tweeted by 17 On 5 Facebook pages 119 readers on Mendeley 2 readers on CiteULike Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version="1.0" encoding="UTF-8" ? Request permissions Low Back Pain Cytokines Arthritis Chondrocytes Introduction The circadian clocks are internal timing mechanisms which drive ∼24-hour rhythms in physiology and behaviour. In mammals, the central pacemaker suprachiasmatic nuclei (SCN) in the hypothalamus synchronises peripheral clocks in most major body organs. 1–3 Circadian rhythms coordinate tissue-specific physiology with light/darkness, rest/activity, feeding cycles and body temperature fluctuations. 1 , 4 Disruptions to circadian rhythms (during ageing or in shift workers) have been linked to increased risk of diseases (eg, obesity, diabetes, cardiovascular disease and osteoarthritis). 5 , 6 At the molecular level, the circadian clock consists of a network of transcriptional activators ( Clock , Bmal1 ) and repressors ( Per1/2 and Cry1/2 ) organised in a negative feedback loop. 6 This core oscillator generates 24-hour rhythms in the expression of its core components and a myriad of clock-controlled genes. Depending on the tissue, expression of 3%–16% of the whole transcriptome exhibits a circadian rhythm. 7 The spine is comprised of bony vertebral bodies alternating with fibrocartilagenous intervertebral discs (IVD). IVD degeneration is among the most prevalent musculoskeletal disorders affecting one in five people under 60 and more than half of the people above 60 years of age. 8 Low back pain, which is often associated with IVD degeneration, is the number one cause of years lived with disability in the developed countries. 9 Existing evidence suggests that the IVD is a highly rhythmic tissue, experiencing a diurnal cycle of higher loading (activity phase), 10 , 11 followed by a period of low-load recovery (resting phase). Under high load, the pressurised interstitial fluid flows to regions of lower pressure through the outer annulus fibrosus (AF) and the cartilaginous end plate (CEP), resulting in decreased disc height, AF outward bulging and an increase in osmolarity of the central gelatinous nucleus pulposus (NP). During the recovery period, the process is reversed by high osmotic pressure inside the disc causing fluid flow to the NP. 12 Exchange of nutrients/metabolites that occurs with fluid flow during this cycle maintains disc cell homeostasis. 13 Consistent with the rhythmic nature of IVD tissue, shift work (a factor known to disrupt circadian rhythms) was reported to be associated with higher risk of low back pain (LBP) and IVD degeneration. 14–18 We have previously shown that environmental disruption of circadian rhythm in mice, when combined with high fat diet, leads to degeneration of the lumbar IVD tissue in mice. 19 More recently, changes in the expression of circadian clock genes have been identified in rat IVD tissues following passive smoking (a risk factor for LBP). 20 However, no studies have examined whether IVD cells express intrinsic circadian clocks, how these IVD clocks are regulated, what their targets are and whether genetic disruption to the IVD clock impact on tissue homeostasis and susceptibility to degeneration. In this study, we systemically characterised the molecular circadian clock mechanisms in mouse and human IVD tissue/cells. Moreover, by generating a tissue-specific Bmal1 KO mouse model, our study provides the first genetic evidence linking a core clock factor to IVD degeneration. Results Intervertebral disc possesses a functional, temperature entrainable circadian clock To test whether the IVD contains a molecular circadian clock capable of driving circadian rhythm of gene expression, we monitored the dynamics of PER2::Luc protein in IVD explant cultures isolated from PER2::Luc reporter mice. 21 Real-time bioluminescence photon counting demonstrated robust circadian rhythm of PER2::Luc activity which lasted for more than 5 days, with a period of 23.93±0.10 hours (mean±SEM, n=6, figure 1 A). As the IVD comprises two distinct cell types, the NP and AF cells, we wanted to know if both regions exhibit circadian<|im_end|> <|im_start|>assistant New research by University of Manchester scientists has for the first time shown that our spinal discs have 24-hour body clocks which when they malfunction, can contribute to lower back pain. Lower back pain is amongst the most prevalent spinal diseases associated with increasing age, with over 80% of the UK population predicted to experience back pain within their lifetime. Progressive degeneration of the spine disc is a major contributing factor. The study led by Dr Qing-Jun Meng and Professor Judith Hoyland could have important implications on the understanding and treatment of the condition. Their findings have been published in the journal Annals of the Rheumatic Diseases today . Ageing and inflammation, say the scientists, are major causes of disc degeneration and lower back pain. In this research, both conditions were found to cause body clock malfunction. The team say getting a good night's sleep will protect our body clocks and potentially avoid disc problems later in life. Avoiding night working where possible, or working fixed regular hours, as opposed to rotating shift work, they say, will also help. Additionally, the non-steroidal anti-inflammatory drugs we take for back pain will be more effective if we take into account our natural body clock cycle, by timing treatment to anticipate pain, they add. Dr Meng, who is a Senior Research Fellow funded by Arthritis Research UK, said: "It has been known for years that, as a consequence of the daily activity and resting cycle, we are taller in the mornings by up to 2cm more than when we go to bed. "The discovery of body clocks in the disc may go some way to explain, for the first time, the science behind this rhythmic physiology of the spine. "Our research shows that this system is regulated by our internal body clock and when the body clock ceases to work properly during ageing or in shift workers, lower back pain is more likely to become an issue." He added: "Looking after your body clock will help manage or delay the onset of your back pain. "And based on our findings, we hope that one day, we may be able to combine NSAIDs with clock targeting compounds to provide a more powerful solution." Dr Natalie Carter, head of research liaison and evaluation at the charity Arthritis Research UK, said: "This research is very interesting and is a significant breakthrough in our understanding of lower back pain. Many people find that their symptoms get worse at certain times of the day and the results of this study reveal a likely biological basis to this effect. "As a charity we know that living in pain, day in and day out, can have a devastating impact on people's lives, affecting their independence, mobility and ability to stay in work. If we are going to address this growing need, we need better pain management and better treatments to relieve pain. An exciting prospect is that it may be possible to use this new information improve treatments and pain relief for people affected by this debilitating condition." The 24-hour body clock was revealed to be present in the disc tissue of transgenic mice and human samples. Though the investigation of human disc cells was more complex, both results were consistent with each other. The team tracked a 'clock' protein which shows the presence of the body clock using bioluminescent markers, whose flashes correspond to clock activity of the disc. A fascinating video, made by the scientists, shows how inflammation disrupts the body clock in living disc tissue which then recovers following treatment. Professor Hoyland said: "Our research shows that if you remove the body clock from cells in the disc in mice, within 6 months degeneration is very noticeable and the disc is thinner by 20 to 30%. "Within 12 months, we found evidence of fibrosis, the thickening and scarring of connective tissue prevalent in human degenerative disc. "This accelerated ageing of the disc in a "clockless" model indicates that having a robust body clock will help slow down spinal aging and associated spinal diseases." "We were also excited to find 607 rhythmic genes which exist in in disc tissue. Many of these genes are implicated in key pathways involved in the health of the disc." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP–TRPV1) 1 . Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase–Cre mice, which express Cre in glucose-sensing neurons 2 . Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types. Main While electrode stimulation and lesioning studies suggest that hypothalamic neurons regulate blood glucose and feeding 3 , these methods affect both cells and fibres of passage 4 , 5 , 6 and do not define contributing cell types 7 . Previously we showed that radio waves or magnetic fields can control calcium (Ca 2+ ) entry and gene expression using ferritin nanoparticles tethered to the temperature-sensitive TRPV1 channel 1 . In this report, we tested the utility of our approach for neural activation and investigate the function of hypothalamic glucose-sensing neurons. A replication-deficient adenovirus with Cre-dependent expression of anti-GFP–TRPV1/GFP–ferritin (Ad-FLEX-anti-GFP-TRPV1/GFP-ferritin) was injected unilaterally into the ventromedial hypothalamus (VMH) of glucokinase–Cre (GK–Cre) mice, which express Cre in glucose-sensing neurons 2 ( Extended Data Fig. 1a ), targeting ~2,000 neurons (see Methods), similar to previous studies 8 , 9 . Radio frequency (RF) treatment (465 kHz) of these mice significantly increased blood glucose (change in blood glucose at 30 min: RF-treated, 48.9 ± 16.9 mg dl −1 versus untreated, −0.7 ± 12.9 mg dl −1 ; P < 0.05; at 45 min: RF-treated, 91.3 ± 28.2 mg dl −1 versus untreated, 8.7 ± 11.1 mg dl −1 ; P < 0.05) and the cumulative change in blood glucose (area under the curve (AUC; 0–90 min): RF-treated, 5,562 ± 1,977 mg dl −1 min versus untreated, 62 ± 1,184 mg dl −1 min; P < 0.05) ( Fig. 1b, c ). The time course and extent of glucose changes after RF treatment were almost superimposable with those after optogenetic activation of VMH GK–Cre neurons, albeit with a slight delay ( Fig. 1b, c ). RF treatment of GK–Cre mice with VMH injection of anti-GFP–TRPV1/GFP–ferritin halved plasma insulin, increased plasma glucagon threefold and significantly induced expression of the hepatic gluconeogenic enzyme 10 , glucose-6-phosphatase ( Fig. 1d ). Thus, remote activation of glucose-sensing neurons regulated pancreatic hormones to increase blood glucose. Blood glucose changes were dependent on RF field strength and duration ( Extended Data Fig. 2a–d ). RF treatment did not alter blood glucose in wild-type mice with VMH injection of anti-GFP–TRPV1/GFP–ferritin ( Extended Data Fig. 3 ). RF treatment induced c-Fos expression only in GFP-expressing neurons and not in RF-treated wild-type mice ( Extended Data Fig. 1d ). Anti-GFP–TRPV1/GFP–ferritin expression, with or without RF, did not alter apoptotic cell count compared to control virus expressing GFP ( Extended Data Fig. 1d, e ). Figure 1: Remote neural activation in vivo using radio waves. a , Schema of activation system. b , c , Change in blood glucose ( b ) and cumulative blood glucose ( c ) with RF treatment of GK–Cre mice (VMH injection Ad-FLEX-anti-GFP-TRPV1/GFP-ferritin, n = 13; VMH injection rAAV-FLEX-ChR2, n = 4). Values are mean ± s.e.m.; two-way ANOVA with Sidak’s multiple comparison test; * P < 0.05, ** P < 0.01, **** P < 0.0001. ChR2, channelrhodopsin 2. d , RF treatment of GK–Cre (GK) or wild-type (WT) mice with VMH Ad-FLEX-anti-GFP-TRPV1/GFP-ferritin on plasma insulin (GK–Cre, n = 8; wild type, n = 8), glucagon (GK–Cre, n = 6; wild type, n = 11) and hepatic glucose-6-phosphatase expression (GK–Cre, n = 12; wild type, n = 9).Values are mean ± s.e.m.; two-tailed, unpaired Student’s t -test or Mann–Whitney U -test; * P < 0.05, *** P < 0.005. WT nanoV1 refers to wild-type mice with VMH injection of Ad-FLEX-anti-GFP-TRPV1/GFP-ferritin, Gck NanoV1 indicates GK-Cre mice with VMH injection of Ad-FLEX-anti-GFP-TRPV1/GFP-ferritin. PowerPoint slide Full size image Consistent with these in vivo data, RF significantly increased the number of cells with raised intracellular Ca 2+ in a hypothalamic N38 cell line stably expressing anti-GFP–TRPV1/GFP–ferritin. These effects were blocked by the TRP channel inhibitor ruthenium red. The mode response time was 11–15 s after RF onset ( Extended Data Fig. 4a–c ). Calcium responses were proportional to RF field strength and a 10 s pulse significantly increased intracellular Ca 2+ ( Extended Data Fig. 4d–g ). RF treatment of N38 cells expressing anti-GFP–TRPV1/GFP–ferritin also significantly increased targets of Ca 2+ signalling, phosphorylated-cAMP-response element-binding protein (pCREB) 11 and c-Fos 12 , and these effects were blocked by ruthenium red ( Extended Data Fig. 4h, i ). RF treatment of N38 cells without anti-GFP–TRPV1/GFP–ferritin induced a small increase in c-Fos and no increase in pCREB ( Extended Data Fig. 6 ). Immunohistochemistry, electron microscopy and immuno-electron microscopy confirmed co-expression and co-localization of anti-GFP–TRPV1 and GFP–ferritin in vitro ( Extended Data Fig. 5 ). Non-invasive neural inhibition would provide a valuable research tool and potentially offer an alternative to deep brain stimulation which may act by neural inhibition 13 . An amino acid substitution, from isoleucine to lysine in the S6 pore region of TRPM2 and M8 changed ionic selectivity from cations to", "role": "user" }, { "content": "To learn what different cells do, scientists switch them on and off and observe what the effects are. There are many methods that do this, but they all have problems: too invasive, or too slow, or not precise enough. Now, a new method to control the activity of neurons in mice, devised by scientists at Rockefeller University and Rensselear Polytechnic Institute, avoids these downfalls by using magnetic forces to remotely control the flow of ions into specifically targeted cells. Jeffrey Friedman, Marilyn M. Simpson Professor and head of the Laboratory of Molecular Genetics, and colleagues successfully employed this system to study the role of the central nervous system in glucose metabolism. Published online today in Nature, the findings suggest a group of neurons in the hypothalamus play a vital role in maintaining blood glucose levels. \"These results are exciting because they provide a broader view of how blood glucose is regulated—they emphasize how crucial the brain is in this process,\" says Friedman. \"And having a new means for controlling neural activity, one that doesn't require an implant and allows you to elicit rapid responses, fills a useful niche between the methods that are already available.\" It may also be possible to adapt this method for clinical applications, says Jonathan Dordick of Rensselear. \"Depending on the type of cell we target, and the activity we enhance or decrease within that cell, this approach holds potential in development of therapeutic modalities, for example, in metabolic and neurologic diseases.\" Magnetic mind control Previous work led by Friedman and Dordick tested a similar method to turn on insulin production in diabetic mice. The system couples a natural iron storage particle, ferritin, and a fluorescent tag to an ion channel called TRPV1, also known as the capsaicin chili pepper receptor. Ferritin can be affected by forces such as radio waves or magnetic fields, and its presence tethered to TRPV1 can change the conformation of the ion channel. \"Normally radio waves or magnetic fields, at these strengths, will pass through tissue without having any effect,\" says first author Sarah Stanley (now Assistant Professor of Medicine, Endocrinology, Diabetes and Bone Disease at Icahn School of Medicine at Mount Sinai). \"But when this modified ferritin is present, it responds and absorbs the energy of the radiofrequency or magnetic fields, producing motion. This motion opens the channel and allows ions into the cell. Depending on the ions flowing through the channel, this can either activate or inhibit the cells' activity.\" This study is the first to turn neurons on and off remotely with radio waves and magnetic fields. TRPV1 normally allows positive ions—such as calcium or sodium—to flow in, which activates neurons and transmits neuronal signals. The researchers were also able to achieve the opposite effect, neuronal inhibition, by mutating the TRPV1 channel to only allow negative chloride ions to flow through. \"The modified TRPV1 channel was targeted specifically to glucose sensing neurons using a genetic technique known as Cre-dependent expression,\" says Stanley. \"To test whether a magnetic field could remotely modulate these neurons, we simply placed the mice near the electromagnetic coil of an MRI machine.\" Blood sugar switch Using this novel method, the researchers investigated the role these glucose sensing neurons play in blood glucose metabolism. Hormones released by the pancreas, including insulin, maintain stable levels of glucose in the blood. A region of the brain called the ventromedial hypothalamus was thought to play a role in regulating blood glucose, but it was not possible with previous methods to decipher which cells were actually involved. Friedman and colleagues found that when they switched these neurons on with magnetic forces, blood glucose increased, insulin levels decreased, and behaviorally, the mice ate more. When they inhibited the neurons, on the other hand, the opposite occurred, and blood glucose decreased. \"We tend to think about blood glucose being under the control of the pancreas, so it was surprising that the brain can affect blood glucose in either direction to the extent that it can,\" says Friedman. \"It's been clear for a while that blood glucose can increase if the brain senses that it's low, but the robustness of the decrease we saw when these neurons were inhibited was unexpected.\" Polar possibilities The researchers' system has several advantages that make it ideal for studies on other circuits in the brain, or elsewhere. It can be applied to any circuit, including dispersed cells like those involved in the immune system. It has a faster time scale than similar chemogenetic tools, and it doesn't require an implant as is the case with so-called optogenetic techniques. In addition to its utility as a research tool, the technique may also have clinical applications. \"Although it is a long ways off, this technique may offer an alternative to deep brain stimulation or trans-magnetic stimulation,\" says Friedman. \"We'd like to explore the possibility that this could provide some of the benefits of these without such an invasive procedure or cumbersome device.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP–TRPV1) 1 . Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase–Cre mice, which express Cre in glucose-sensing neurons 2 . Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types. Main While electrode stimulation and lesioning studies suggest that hypothalamic neurons regulate blood glucose and feeding 3 , these methods affect both cells and fibres of passage 4 , 5 , 6 and do not define contributing cell types 7 . Previously we showed that radio waves or magnetic fields can control calcium (Ca 2+ ) entry and gene expression using ferritin nanoparticles tethered to the temperature-sensitive TRPV1 channel 1 . In this report, we tested the utility of our approach for neural activation and investigate the function of hypothalamic glucose-sensing neurons. A replication-deficient adenovirus with Cre-dependent expression of anti-GFP–TRPV1/GFP–ferritin (Ad-FLEX-anti-GFP-TRPV1/GFP-ferritin) was injected unilaterally into the ventromedial hypothalamus (VMH) of glucokinase–Cre (GK–Cre) mice, which express Cre in glucose-sensing neurons 2 ( Extended Data Fig. 1a ), targeting ~2,000 neurons (see Methods), similar to previous studies 8 , 9 . Radio frequency (RF) treatment (465 kHz) of these mice significantly increased blood glucose (change in blood glucose at 30 min: RF-treated, 48.9 ± 16.9 mg dl −1 versus untreated, −0.7 ± 12.9 mg dl −1 ; P < 0.05; at 45 min: RF-treated, 91.3 ± 28.2 mg dl −1 versus untreated, 8.7 ± 11.1 mg dl −1 ; P < 0.05) and the cumulative change in blood glucose (area under the curve (AUC; 0–90 min): RF-treated, 5,562 ± 1,977 mg dl −1 min versus untreated, 62 ± 1,184 mg dl −1 min; P < 0.05) ( Fig. 1b, c ). The time course and extent of glucose changes after RF treatment were almost superimposable with those after optogenetic activation of VMH GK–Cre neurons, albeit with a slight delay ( Fig. 1b, c ). RF treatment of GK–Cre mice with VMH injection of anti-GFP–TRPV1/GFP–ferritin halved plasma insulin, increased plasma glucagon threefold and significantly induced expression of the hepatic gluconeogenic enzyme 10 , glucose-6-phosphatase ( Fig. 1d ). Thus, remote activation of glucose-sensing neurons regulated pancreatic hormones to increase blood glucose. Blood glucose changes were dependent on RF field strength and duration ( Extended Data Fig. 2a–d ). RF treatment did not alter blood glucose in wild-type mice with VMH injection of anti-GFP–TRPV1/GFP–ferritin ( Extended Data Fig. 3 ). RF treatment induced c-Fos expression only in GFP-expressing neurons and not in RF-treated wild-type mice ( Extended Data Fig. 1d ). Anti-GFP–TRPV1/GFP–ferritin expression, with or without RF, did not alter apoptotic cell count compared to control virus expressing GFP ( Extended Data Fig. 1d, e ). Figure 1: Remote neural activation in vivo using radio waves. a , Schema of activation system. b , c , Change in blood glucose ( b ) and cumulative blood glucose ( c ) with RF treatment of GK–Cre mice (VMH injection Ad-FLEX-anti-GFP-TRPV1/GFP-ferritin, n = 13; VMH injection rAAV-FLEX-ChR2, n = 4). Values are mean ± s.e.m.; two-way ANOVA with Sidak’s multiple comparison test; * P < 0.05, ** P < 0.01, **** P < 0.0001. ChR2, channelrhodopsin 2. d , RF treatment of GK–Cre (GK) or wild-type (WT) mice with VMH Ad-FLEX-anti-GFP-TRPV1/GFP-ferritin on plasma insulin (GK–Cre, n = 8; wild type, n = 8), glucagon (GK–Cre, n = 6; wild type, n = 11) and hepatic glucose-6-phosphatase expression (GK–Cre, n = 12; wild type, n = 9).Values are mean ± s.e.m.; two-tailed, unpaired Student’s t -test or Mann–Whitney U -test; * P < 0.05, *** P < 0.005. WT nanoV1 refers to wild-type mice with VMH injection of Ad-FLEX-anti-GFP-TRPV1/GFP-ferritin, Gck NanoV1 indicates GK-Cre mice with VMH injection of Ad-FLEX-anti-GFP-TRPV1/GFP-ferritin. PowerPoint slide Full size image Consistent with these in vivo data, RF significantly increased the number of cells with raised intracellular Ca 2+ in a hypothalamic N38 cell line stably expressing anti-GFP–TRPV1/GFP–ferritin. These effects were blocked by the TRP channel inhibitor ruthenium red. The mode response time was 11–15 s after RF onset ( Extended Data Fig. 4a–c ). Calcium responses were proportional to RF field strength and a 10 s pulse significantly increased intracellular Ca 2+ ( Extended Data Fig. 4d–g ). RF treatment of N38 cells expressing anti-GFP–TRPV1/GFP–ferritin also significantly increased targets of Ca 2+ signalling, phosphorylated-cAMP-response element-binding protein (pCREB) 11 and c-Fos 12 , and these effects were blocked by ruthenium red ( Extended Data Fig. 4h, i ). RF treatment of N38 cells without anti-GFP–TRPV1/GFP–ferritin induced a small increase in c-Fos and no increase in pCREB ( Extended Data Fig. 6 ). Immunohistochemistry, electron microscopy and immuno-electron microscopy confirmed co-expression and co-localization of anti-GFP–TRPV1 and GFP–ferritin in vitro ( Extended Data Fig. 5 ). Non-invasive neural inhibition would provide a valuable research tool and potentially offer an alternative to deep brain stimulation which may act by neural inhibition 13 . An amino acid substitution, from isoleucine to lysine in the S6 pore region of TRPM2 and M8 changed ionic selectivity from cations to<|im_end|> <|im_start|>assistant To learn what different cells do, scientists switch them on and off and observe what the effects are. There are many methods that do this, but they all have problems: too invasive, or too slow, or not precise enough. Now, a new method to control the activity of neurons in mice, devised by scientists at Rockefeller University and Rensselear Polytechnic Institute, avoids these downfalls by using magnetic forces to remotely control the flow of ions into specifically targeted cells. Jeffrey Friedman, Marilyn M. Simpson Professor and head of the Laboratory of Molecular Genetics, and colleagues successfully employed this system to study the role of the central nervous system in glucose metabolism. Published online today in Nature, the findings suggest a group of neurons in the hypothalamus play a vital role in maintaining blood glucose levels. "These results are exciting because they provide a broader view of how blood glucose is regulated—they emphasize how crucial the brain is in this process," says Friedman. "And having a new means for controlling neural activity, one that doesn't require an implant and allows you to elicit rapid responses, fills a useful niche between the methods that are already available." It may also be possible to adapt this method for clinical applications, says Jonathan Dordick of Rensselear. "Depending on the type of cell we target, and the activity we enhance or decrease within that cell, this approach holds potential in development of therapeutic modalities, for example, in metabolic and neurologic diseases." Magnetic mind control Previous work led by Friedman and Dordick tested a similar method to turn on insulin production in diabetic mice. The system couples a natural iron storage particle, ferritin, and a fluorescent tag to an ion channel called TRPV1, also known as the capsaicin chili pepper receptor. Ferritin can be affected by forces such as radio waves or magnetic fields, and its presence tethered to TRPV1 can change the conformation of the ion channel. "Normally radio waves or magnetic fields, at these strengths, will pass through tissue without having any effect," says first author Sarah Stanley (now Assistant Professor of Medicine, Endocrinology, Diabetes and Bone Disease at Icahn School of Medicine at Mount Sinai). "But when this modified ferritin is present, it responds and absorbs the energy of the radiofrequency or magnetic fields, producing motion. This motion opens the channel and allows ions into the cell. Depending on the ions flowing through the channel, this can either activate or inhibit the cells' activity." This study is the first to turn neurons on and off remotely with radio waves and magnetic fields. TRPV1 normally allows positive ions—such as calcium or sodium—to flow in, which activates neurons and transmits neuronal signals. The researchers were also able to achieve the opposite effect, neuronal inhibition, by mutating the TRPV1 channel to only allow negative chloride ions to flow through. "The modified TRPV1 channel was targeted specifically to glucose sensing neurons using a genetic technique known as Cre-dependent expression," says Stanley. "To test whether a magnetic field could remotely modulate these neurons, we simply placed the mice near the electromagnetic coil of an MRI machine." Blood sugar switch Using this novel method, the researchers investigated the role these glucose sensing neurons play in blood glucose metabolism. Hormones released by the pancreas, including insulin, maintain stable levels of glucose in the blood. A region of the brain called the ventromedial hypothalamus was thought to play a role in regulating blood glucose, but it was not possible with previous methods to decipher which cells were actually involved. Friedman and colleagues found that when they switched these neurons on with magnetic forces, blood glucose increased, insulin levels decreased, and behaviorally, the mice ate more. When they inhibited the neurons, on the other hand, the opposite occurred, and blood glucose decreased. "We tend to think about blood glucose being under the control of the pancreas, so it was surprising that the brain can affect blood glucose in either direction to the extent that it can," says Friedman. "It's been clear for a while that blood glucose can increase if the brain senses that it's low, but the robustness of the decrease we saw when these neurons were inhibited was unexpected." Polar possibilities The researchers' system has several advantages that make it ideal for studies on other circuits in the brain, or elsewhere. It can be applied to any circuit, including dispersed cells like those involved in the immune system. It has a faster time scale than similar chemogenetic tools, and it doesn't require an implant as is the case with so-called optogenetic techniques. In addition to its utility as a research tool, the technique may also have clinical applications. "Although it is a long ways off, this technique may offer an alternative to deep brain stimulation or trans-magnetic stimulation," says Friedman. "We'd like to explore the possibility that this could provide some of the benefits of these without such an invasive procedure or cumbersome device." <|im_end|>

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814, 30975, 1521, 34313, 389, 449, 24924, 8603, 11, 6680, 34323, 7319, 11, 32152, 5990, 25983, 11, 323, 7865, 750, 11, 279, 24548, 30912, 810, 13, 3277, 814, 99669, 279, 34313, 11, 389, 279, 1023, 1450, 11, 279, 14329, 10222, 11, 323, 6680, 34323, 25983, 13, 330, 1687, 8541, 311, 1781, 922, 6680, 34323, 1694, 1234, 279, 2585, 315, 279, 62268, 300, 11, 779, 433, 574, 15206, 430, 279, 8271, 649, 7958, 6680, 34323, 304, 3060, 5216, 311, 279, 13112, 430, 433, 649, 1359, 2795, 62458, 13, 330, 2181, 596, 1027, 2867, 369, 264, 1418, 430, 6680, 34323, 649, 5376, 422, 279, 8271, 38207, 430, 433, 596, 3428, 11, 719, 279, 22514, 2136, 315, 279, 18979, 584, 5602, 994, 1521, 34313, 1051, 99669, 574, 16907, 1210, 56996, 24525, 578, 12074, 6, 1887, 706, 3892, 22934, 430, 1304, 433, 10728, 369, 7978, 389, 1023, 46121, 304, 279, 8271, 11, 477, 18403, 13, 1102, 649, 387, 9435, 311, 904, 16622, 11, 2737, 77810, 7917, 1093, 1884, 6532, 304, 279, 22852, 1887, 13, 1102, 706, 264, 10819, 892, 5569, 1109, 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2,720

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objectives To evaluate the existing evidence for associations between coffee consumption and multiple health outcomes. Design Umbrella review of the evidence across meta-analyses of observational and interventional studies of coffee consumption and any health outcome. Data sources PubMed, Embase, CINAHL, Cochrane Database of Systematic Reviews, and screening of references. Eligibility criteria for selecting studies Meta-analyses of both observational and interventional studies that examined the associations between coffee consumption and any health outcome in any adult population in all countries and all settings. Studies of genetic polymorphisms for coffee metabolism were excluded. Results The umbrella review identified 201 meta-analyses of observational research with 67 unique health outcomes and 17 meta-analyses of interventional research with nine unique outcomes. Coffee consumption was more often associated with benefit than harm for a range of health outcomes across exposures including high versus low, any versus none, and one extra cup a day. There was evidence of a non-linear association between consumption and some outcomes, with summary estimates indicating largest relative risk reduction at intakes of three to four cups a day versus none, including all cause mortality (relative risk 0.83, 95% confidence interval 0.83 to 0.88), cardiovascular mortality (0.81, 0.72 to 0.90), and cardiovascular disease (0.85, 0.80 to 0.90). High versus low consumption was associated with an 18% lower risk of incident cancer (0.82, 0.74 to 0.89). Consumption was also associated with a lower risk of several specific cancers and neurological, metabolic, and liver conditions. Harmful associations were largely nullified by adequate adjustment for smoking, except in pregnancy, where high versus low/no consumption was associated with low birth weight (odds ratio 1.31, 95% confidence interval 1.03 to 1.67), preterm birth in the first (1.22, 1.00 to 1.49) and second (1.12, 1.02 to 1.22) trimester, and pregnancy loss (1.46, 1.06 to 1.99). There was also an association between coffee drinking and risk of fracture in women but not in men. Conclusion Coffee consumption seems generally safe within usual levels of intake, with summary estimates indicating largest risk reduction for various health outcomes at three to four cups a day, and more likely to benefit health than harm. Robust randomised controlled trials are needed to understand whether the observed associations are causal. Importantly, outside of pregnancy, existing evidence suggests that coffee could be tested as an intervention without significant risk of causing harm. Women at increased risk of fracture should possibly be excluded. Introduction Coffee is one of the most commonly consumed beverages worldwide. 1 As such, even small individual health effects could be important on a population scale. There have been mixed conclusions as to whether coffee consumption is beneficial or harmful to health, and this varies between outcomes. 2 Roasted coffee is a complex mixture of over 1000 bioactive compounds, 3 some with potentially therapeutic antioxidant, anti-inflammatory, antifibrotic, or anticancer effects that provide biological plausibility for recent epidemiological associations. Key active compounds include caffeine, chlorogenic acids, and the diterpenes, cafestol and kahweol. The biochemistry of coffee has been documented extensively elsewhere. 4 Coffee undergoes a chemical metamorphosis from the unroasted green bean, and the type of bean (Arabica versus Robusta), degree of roasting, and preparation method including coffee grind setting and brew type, will all have an influence on the biochemical composition of the final cup. 5 6 7 An individual’s genotype and gut microbiome will then determine the bioavailability and type of coffee metabolites to which that individual is exposed. 8 Existing research has explored the associations between coffee as an exposure and a range of outcomes including all cause mortality, cancer, and diseases of the cardiovascular, metabolic, neurological, musculoskeletal, gastrointestinal, and liver systems, as well as outcomes associated with pregnancy. Most of this research has been observational in design, relying on evidence from cross sectional, case-control, or cohort studies, and often summarised by outcome through systematic review and meta-analysis. We have previously explored the relation between coffee consumption and liver cirrhosis 9 and hepatocellular carcinoma 10 and found significant beneficial associations for both. Observational evidence can suggest association but is unable to make causative claims, though methods based on Mendelian randomisation are less prone to confounding. Interventional research, ideally in the form of randomised controlled trials, is essential before we can fully understand coffee’s potential to prevent specific health outcomes. Before an interventional approach is taken, however, it is important to systematically assess the totality of higher level evidence of the effects of coffee consumption on all health outcomes. This approach can help contextualise the magnitude of the association across health outcomes and importantly assess the existing research for any harm that could be associated with increased consumption. To assimilate the vast amount of research available on coffee consumption and health outcomes, we performed an umbrella review of existing meta-analyses. Methods Umbrella review methods Umbrella reviews systematically search, organise, and evaluate existing evidence from multiple systematic reviews and/or meta-analyses on all health outcomes associated with a particular exposure. 11 We conducted a review of coffee consumption and multiple health outcomes by systematically searching for meta-analyses in which coffee consumption was all or part of the exposure of interest or where coffee consumption had been part of a subgroup analysis. Consumption, usually measured by cups a day, lends itself to combined estimates of effect in meta-analyses and we decided to include only meta-analyses in the umbrella review. Specifically, we excluded systematic reviews without meta-analysis. Literature search We searched PubMed, Embase, CINAHL, and the Cochrane Database of Systematic Reviews from inception to July 2017 for meta-analyses of observational or interventional studies that investigated the association between coffee consumption and any health outcome. We used the following search strategy: (coffee OR caffeine) AND (systematic review OR meta-analysis) using truncated terms for all fields, and following the SIGN guidance recommended search terms for systematic reviews and meta-analyses. 12 Two researchers (RP and OJK) independently screened the titles and abstracts and selected articles for full text review. They then independently reviewed full text articles for eligibility. A third researcher, PR, arbitrated any differences that could not be", "role": "user" }, { "content": "Drinking coffee is \"more likely to benefit health than to harm it\" for a range of health outcomes, say researchers in The BMJ today. They bring together evidence from over 200 studies and find that drinking three to four cups of coffee a day is associated with a lower risk of death and getting heart disease compared with drinking no coffee. Coffee drinking is also associated with lower risk of some cancers, diabetes, liver disease and dementia. However, they say drinking coffee in pregnancy may be associated with harms, and may be linked to a very small increased risk of fracture in women. The included studies used mainly observational data, providing lower quality evidence, so no firm conclusions can be drawn about cause and effect, but their findings back up other recent reviews and studies of coffee intake. As such, they say, excluding pregnancy and women at risk of fracture, \"coffee drinking appears safe within usual patterns of consumption\" and they suggest that coffee could be safely tested in randomised trials. Coffee is one of the most commonly consumed beverages worldwide and could have positive health benefits. But existing evidence is of lower quality from observational research and randomised controlled trials are needed to strengthen the evidence of benefits. To better understand the effects of coffee consumption on health, a team led by Dr Robin Poole, Specialist Registrar in Public Health at the University of Southampton, with collaborators from the University of Edinburgh, carried out an umbrella review of 201 studies that had aggregated data from observational research and 17 studies that had aggregated data from clinical trials across all countries and all settings. Umbrella reviews synthesise previous meta-analyses and provide a high-level summary of research on a particular topic Drinking coffee was consistently associated with a lower risk of death from all causes and from heart disease, with the largest reduction in relative risk of death at three cups a day, compared with non-coffee drinkers. Increasing consumption to above three cups a day was not associated with harm, but the beneficial effect was less pronounced. Coffee was also associated with a lower risk of several cancers, including prostate, endometrial, skin and liver cancer, as well as type 2 diabetes, gallstones and gout. The greatest benefit was seen for liver conditions, such as cirrhosis of the liver. Finally, there seemed to be beneficial associations between coffee consumption and Parkinson's disease, depression and Alzheimer's disease. There was less evidence for the effects of drinking decaffeinated coffee but it had similar benefits for a number of outcomes. Many of the included studies may have adjusted for factors that may be associated with both the health outcome and with coffee drinking, such as smoking. This was not comprehensive and varied from study to study. The authors can therefore not rule out the effect of such factors on the apparent harmful or beneficial associations. The authors conclude that coffee drinking \"seems safe within usual patterns of consumption, except during pregnancy and in women at increased risk of fracture.\" And they call for robust randomised controlled trials \"to understand whether the key observed associations are causal.\" In a linked editorial, Eliseo Guallar at the Johns Hopkins Bloomberg School of Public Health says, although we can be reassured that coffee intake is generally safe, doctors should not recommend drinking coffee to prevent disease - and people should not start drinking coffee for health reasons. As this study shows, some people may be at higher risk of adverse effects, he writes, and there is \"substantial uncertainty\" about the effects of higher levels of intake. Finally, coffee is often consumed with products rich in refined sugars and unhealthy fats, \"and these may independently contribute to adverse health outcomes,\" he adds. However, even with these caveats, \"moderate coffee consumption seems remarkably safe, and it can be incorporated as part of a healthy diet by most of the adult population,\" he concludes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objectives To evaluate the existing evidence for associations between coffee consumption and multiple health outcomes. Design Umbrella review of the evidence across meta-analyses of observational and interventional studies of coffee consumption and any health outcome. Data sources PubMed, Embase, CINAHL, Cochrane Database of Systematic Reviews, and screening of references. Eligibility criteria for selecting studies Meta-analyses of both observational and interventional studies that examined the associations between coffee consumption and any health outcome in any adult population in all countries and all settings. Studies of genetic polymorphisms for coffee metabolism were excluded. Results The umbrella review identified 201 meta-analyses of observational research with 67 unique health outcomes and 17 meta-analyses of interventional research with nine unique outcomes. Coffee consumption was more often associated with benefit than harm for a range of health outcomes across exposures including high versus low, any versus none, and one extra cup a day. There was evidence of a non-linear association between consumption and some outcomes, with summary estimates indicating largest relative risk reduction at intakes of three to four cups a day versus none, including all cause mortality (relative risk 0.83, 95% confidence interval 0.83 to 0.88), cardiovascular mortality (0.81, 0.72 to 0.90), and cardiovascular disease (0.85, 0.80 to 0.90). High versus low consumption was associated with an 18% lower risk of incident cancer (0.82, 0.74 to 0.89). Consumption was also associated with a lower risk of several specific cancers and neurological, metabolic, and liver conditions. Harmful associations were largely nullified by adequate adjustment for smoking, except in pregnancy, where high versus low/no consumption was associated with low birth weight (odds ratio 1.31, 95% confidence interval 1.03 to 1.67), preterm birth in the first (1.22, 1.00 to 1.49) and second (1.12, 1.02 to 1.22) trimester, and pregnancy loss (1.46, 1.06 to 1.99). There was also an association between coffee drinking and risk of fracture in women but not in men. Conclusion Coffee consumption seems generally safe within usual levels of intake, with summary estimates indicating largest risk reduction for various health outcomes at three to four cups a day, and more likely to benefit health than harm. Robust randomised controlled trials are needed to understand whether the observed associations are causal. Importantly, outside of pregnancy, existing evidence suggests that coffee could be tested as an intervention without significant risk of causing harm. Women at increased risk of fracture should possibly be excluded. Introduction Coffee is one of the most commonly consumed beverages worldwide. 1 As such, even small individual health effects could be important on a population scale. There have been mixed conclusions as to whether coffee consumption is beneficial or harmful to health, and this varies between outcomes. 2 Roasted coffee is a complex mixture of over 1000 bioactive compounds, 3 some with potentially therapeutic antioxidant, anti-inflammatory, antifibrotic, or anticancer effects that provide biological plausibility for recent epidemiological associations. Key active compounds include caffeine, chlorogenic acids, and the diterpenes, cafestol and kahweol. The biochemistry of coffee has been documented extensively elsewhere. 4 Coffee undergoes a chemical metamorphosis from the unroasted green bean, and the type of bean (Arabica versus Robusta), degree of roasting, and preparation method including coffee grind setting and brew type, will all have an influence on the biochemical composition of the final cup. 5 6 7 An individual’s genotype and gut microbiome will then determine the bioavailability and type of coffee metabolites to which that individual is exposed. 8 Existing research has explored the associations between coffee as an exposure and a range of outcomes including all cause mortality, cancer, and diseases of the cardiovascular, metabolic, neurological, musculoskeletal, gastrointestinal, and liver systems, as well as outcomes associated with pregnancy. Most of this research has been observational in design, relying on evidence from cross sectional, case-control, or cohort studies, and often summarised by outcome through systematic review and meta-analysis. We have previously explored the relation between coffee consumption and liver cirrhosis 9 and hepatocellular carcinoma 10 and found significant beneficial associations for both. Observational evidence can suggest association but is unable to make causative claims, though methods based on Mendelian randomisation are less prone to confounding. Interventional research, ideally in the form of randomised controlled trials, is essential before we can fully understand coffee’s potential to prevent specific health outcomes. Before an interventional approach is taken, however, it is important to systematically assess the totality of higher level evidence of the effects of coffee consumption on all health outcomes. This approach can help contextualise the magnitude of the association across health outcomes and importantly assess the existing research for any harm that could be associated with increased consumption. To assimilate the vast amount of research available on coffee consumption and health outcomes, we performed an umbrella review of existing meta-analyses. Methods Umbrella review methods Umbrella reviews systematically search, organise, and evaluate existing evidence from multiple systematic reviews and/or meta-analyses on all health outcomes associated with a particular exposure. 11 We conducted a review of coffee consumption and multiple health outcomes by systematically searching for meta-analyses in which coffee consumption was all or part of the exposure of interest or where coffee consumption had been part of a subgroup analysis. Consumption, usually measured by cups a day, lends itself to combined estimates of effect in meta-analyses and we decided to include only meta-analyses in the umbrella review. Specifically, we excluded systematic reviews without meta-analysis. Literature search We searched PubMed, Embase, CINAHL, and the Cochrane Database of Systematic Reviews from inception to July 2017 for meta-analyses of observational or interventional studies that investigated the association between coffee consumption and any health outcome. We used the following search strategy: (coffee OR caffeine) AND (systematic review OR meta-analysis) using truncated terms for all fields, and following the SIGN guidance recommended search terms for systematic reviews and meta-analyses. 12 Two researchers (RP and OJK) independently screened the titles and abstracts and selected articles for full text review. They then independently reviewed full text articles for eligibility. A third researcher, PR, arbitrated any differences that could not be<|im_end|> <|im_start|>assistant Drinking coffee is "more likely to benefit health than to harm it" for a range of health outcomes, say researchers in The BMJ today. They bring together evidence from over 200 studies and find that drinking three to four cups of coffee a day is associated with a lower risk of death and getting heart disease compared with drinking no coffee. Coffee drinking is also associated with lower risk of some cancers, diabetes, liver disease and dementia. However, they say drinking coffee in pregnancy may be associated with harms, and may be linked to a very small increased risk of fracture in women. The included studies used mainly observational data, providing lower quality evidence, so no firm conclusions can be drawn about cause and effect, but their findings back up other recent reviews and studies of coffee intake. As such, they say, excluding pregnancy and women at risk of fracture, "coffee drinking appears safe within usual patterns of consumption" and they suggest that coffee could be safely tested in randomised trials. Coffee is one of the most commonly consumed beverages worldwide and could have positive health benefits. But existing evidence is of lower quality from observational research and randomised controlled trials are needed to strengthen the evidence of benefits. To better understand the effects of coffee consumption on health, a team led by Dr Robin Poole, Specialist Registrar in Public Health at the University of Southampton, with collaborators from the University of Edinburgh, carried out an umbrella review of 201 studies that had aggregated data from observational research and 17 studies that had aggregated data from clinical trials across all countries and all settings. Umbrella reviews synthesise previous meta-analyses and provide a high-level summary of research on a particular topic Drinking coffee was consistently associated with a lower risk of death from all causes and from heart disease, with the largest reduction in relative risk of death at three cups a day, compared with non-coffee drinkers. Increasing consumption to above three cups a day was not associated with harm, but the beneficial effect was less pronounced. Coffee was also associated with a lower risk of several cancers, including prostate, endometrial, skin and liver cancer, as well as type 2 diabetes, gallstones and gout. The greatest benefit was seen for liver conditions, such as cirrhosis of the liver. Finally, there seemed to be beneficial associations between coffee consumption and Parkinson's disease, depression and Alzheimer's disease. There was less evidence for the effects of drinking decaffeinated coffee but it had similar benefits for a number of outcomes. Many of the included studies may have adjusted for factors that may be associated with both the health outcome and with coffee drinking, such as smoking. This was not comprehensive and varied from study to study. The authors can therefore not rule out the effect of such factors on the apparent harmful or beneficial associations. The authors conclude that coffee drinking "seems safe within usual patterns of consumption, except during pregnancy and in women at increased risk of fracture." And they call for robust randomised controlled trials "to understand whether the key observed associations are causal." In a linked editorial, Eliseo Guallar at the Johns Hopkins Bloomberg School of Public Health says, although we can be reassured that coffee intake is generally safe, doctors should not recommend drinking coffee to prevent disease - and people should not start drinking coffee for health reasons. As this study shows, some people may be at higher risk of adverse effects, he writes, and there is "substantial uncertainty" about the effects of higher levels of intake. Finally, coffee is often consumed with products rich in refined sugars and unhealthy fats, "and these may independently contribute to adverse health outcomes," he adds. However, even with these caveats, "moderate coffee consumption seems remarkably safe, and it can be incorporated as part of a healthy diet by most of the adult population," he concludes. <|im_end|>

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420, 3495, 706, 1027, 90380, 304, 2955, 11, 39661, 389, 6029, 505, 5425, 93460, 11, 1162, 4565, 11, 477, 41944, 7978, 11, 323, 3629, 29385, 4147, 555, 15632, 1555, 37538, 3477, 323, 8999, 56536, 13, 1226, 617, 8767, 36131, 279, 12976, 1990, 11033, 15652, 323, 26587, 30570, 41196, 10934, 220, 24, 323, 58259, 511, 54230, 89468, 220, 605, 323, 1766, 5199, 24629, 30257, 369, 2225, 13, 31943, 1697, 6029, 649, 4284, 15360, 719, 374, 12153, 311, 1304, 25540, 1413, 8349, 11, 3582, 5528, 3196, 389, 46211, 70664, 4288, 8082, 527, 2753, 38097, 311, 2389, 13900, 13, 71678, 278, 3495, 11, 50663, 304, 279, 1376, 315, 4288, 4147, 14400, 19622, 11, 374, 7718, 1603, 584, 649, 7373, 3619, 11033, 753, 4754, 311, 5471, 3230, 2890, 20124, 13, 13538, 459, 958, 44322, 5603, 374, 4529, 11, 4869, 11, 433, 374, 3062, 311, 60826, 8720, 279, 2458, 2786, 315, 5190, 2237, 6029, 315, 279, 6372, 315, 11033, 15652, 389, 682, 2890, 20124, 13, 1115, 5603, 649, 1520, 66251, 1082, 279, 26703, 315, 279, 15360, 4028, 2890, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Face coverings have been key in reducing the spread of COVID-19. At the same time, they have hindered interpersonal communication, particularly for those who rely on speechreading to aid communication. The available research indicated that deaf/hard of hearing (HoH) people experienced great difficulty communicating with people wearing masks and negative effects on wellbeing. Here we extended these findings by exploring which factors predict deaf/HoH people’s communication difficulties, loss of information, and wellbeing. We also explored the factors predicting perceived usefulness of transparent face coverings and alternative ways of communicating. We report the findings from an accessible survey study, released in two written and three signed languages. Responses from 395 deaf/HoH UK and Spanish residents were collected online at a time when masks were mandatory. We investigated whether onset and level of deafness, knowledge of sign language, speechreading fluency, and country of residence predicted communication difficulties, wellbeing, and degree to which transparent face coverings were considered useful. Overall, deaf/HoH people and their relatives used masks most of the time despite greater communication difficulties. Late-onset deaf people were the group that experienced more difficulties in communication, and also reported lower wellbeing. However, both early- and late-onset deaf people reported missing more information and feeling more disconnected from society than HoH people. Finally, signers valued transparent face shields more positively than non-signers. The latter suggests that, while seeing the lips is positive to everyone, signers appreciate seeing the whole facial expression. Importantly, our data also revealed the importance of visual communication other than speechreading to facilitate face-to-face interactions. Highlights Late-onset deaf people experienced more difficulties in communication and low wellbeing. Severely/profoundly deaf people missed more information and felt disconnected from society. Signers preferred completely transparent face coverings. More frequent use of masks doesn’t necessarily imply more difficulty communicating. Visual communication, pro-social behaviour, and societal structure might help easing communication. Significance statement The present study is a tight collaboration between deaf and hearing researchers in the fields of cognitive psychology and language processing in deaf people. We investigate the communication challenges faced by deaf and hard of hearing (HoH) people due to the community-wide use of face masks to help stopping the spread of COVID-19. Previous knowledge of basic research on language processing in deaf people informed both the survey’s design and the selection of predictors for the regression analyses. For example, level and onset of deafness were included as separate predictors because basic research shows that they result in different levels of reliance on speechreading to aid communication. Similarly, sign languages (SLs) are the first language of many deaf/HoH people. Knowing a SL could equip the signer with visual-communication strategies other than speechreading. Our findings highlight the importance of acknowledging the diversity in the deaf/HoH population and hence tailor interventions to their specific needs. We found that late-onset severely and profoundly deaf people experienced more difficulties communicating and lower wellbeing. However, it was signers who thought they had missed more information and felt more disconnected from society. Clear window masks, while better than opaque masks for all deaf/HoH people, might be most effective for fluent speechreaders and for non-signers. Interactions with signers could be improved by using completely transparent face coverings, paired with increased ventilation and social distancing for safety. Finally, other ways of communication such as using SL as much as possible, gesturing, writing or a combination of them can be particularly useful for deaf people. Introduction Face masks have been shown to effectively reduce the risk of COVID-19 infection (Chu et al., 2020 ). This meant that by the summer of 2020 most countries required use of masks in public locations (Howard et al., 2021 ). Furthermore, it is likely that the use of face coverings will persist to some degree in the near future (Ballard, 2022 ; BBC, 2021 ; Wisconsin Public Radio, 2022 ). Facial coverings have been essential to control the spread of the virus and therefore to save lives. At the same time, masks hinder interpersonal communication as they attenuate the vocal sounds and cover facial expressions and lip movements (Mheidly et al., 2020 ). Masks add to the communication challenges faced by deaf and hard-of-hearing (HoH) people, who often rely on speechreading (lipreading Footnote 1 ) to aid communication. The deaf and HoH communities warned early in the pandemic that use of face masks was likely to have a negative impact on communication (see e.g. jewishnews.timesofisrael.com, 2020 ; Lavanguardia.com, 2021 ; NDCS, 2021 ; RNID, 2021b ; Saiz et al., 2022 ) because it impedes speechreading. Similar warnings were issued from the medical community (Chodosh et al., 2020 ), highlighting that masks negatively affect speech perception in hospitals (particularly for older people) and that the lack of visual cues from the face was likely to have a major impact on deaf people (see Tavanai et al., 2021 ). The present survey study investigated the impact of face masks on loss of information, wellbeing, and how communication could be improved. According to the World Health Organisation (WHO), approximately 430 million people worldwide have hearing loss (WHO, 2021 ), 12 million in the UK (RNID, 2021a ), and over one million in Spain (see e.g. INE, 2021 ). It is well known that the deaf and HoH population is extremely heterogeneous. For example, in the UK approximately 28% of deaf/HoH people became deaf/HoH at birth or early childhood, and around 71% became deaf/HoH later in life, most of them as a result of ageing (see e.g. ONS, 2018 ). People with different onset of deafness are likely to adopt different communication strategies (Garstecki & Erler, 1999 ). For instance, it has been shown that people with late-onset deafness might be reluctant to disclose their deafness, reducing the number of social interactions they experience altogether (Barker et al., 2017 ). Conversely, early-onset deaf people are likely to have developed more efficient visual communication strategies (including learning sign language, developing better speechreading ability, use of manually coded speech, cued speech, increased use of pointing and gesturing, etc., see e.g.", "role": "user" }, { "content": "Mandatory mask wearing saw more than 90% of deaf people struggle to communicate during the pandemic, University of Essex research has revealed. It also discovered that 76% missed vital information and 59% felt disconnected from society due to the face coverings. This is because masks restrict the ability to read lips and judge expressions. It also emerged that over-55s who became deaf later in life found communication using masks more challenging. And profoundly deaf people and signers experienced more disconnection from society and negative effects on their well-being. Dr. Eva Gutierrez-Sigut, from the Department of Psychology, led a team of deaf and hearing researchers who made sure that the survey was accessible in different sign languages. Nearly 400 people were surveyed to discover how COVID-19 hit the deaf community and the researcher hopes the findings will now help shape public policy in health emergencies. Dr. Gutierrez-Sigut says that \"mask mandates were vital in fighting the spread of the deadly coronavirus but meant some of our most vulnerable communities were left isolated. The pandemic lockdowns were hard for everyone but even more so for the deaf and hard-of-hearing.\" This research exposes the unexpected consequences policies can have in a fast-moving international emergency and how people can fall through the cracks. \"If the world is gripped by a pandemic again Governments need to do more to be inclusive and engage with communities to find out what they need to thrive and survive.\" The paper—published in Cognitive Research: Principles and Implications—also uncovered cultural differences in how masks affected understanding, with Brits struggling more than Spanish people across the board. It is speculated that this is due to differences in mask regulations and that Spaniards made more of an effort to use other means than speaking, such as gesturing, writing, or \"some other creative alternatives.\" The research also showed that there is no one size fits all approach for the deaf or hard-of-hearing with masks. Signing, speech reading, and other communication techniques affect comprehension in combination with levels of deafness, whether they can use sign language, and when hearing loss started. However, a clear mask which made the entire mouth and lower face visible was the preferred option for many. Dr. Gutierrez-Sigut says that \"most deaf people we spoke to agreed these masks made a real difference and made everything from a trip to the shops to a vital doctor's appointment easier. It is worth remembering though that there isn't a one-size fits all solution for these communities. The deaf and hard-of-hearing are not a homogenous group and have different needs.\" \"One thing is clear though, more needs to be done to engage with them. To do this we made a real effort to create an accessible study using sign language to reach them. We are so thankful deaf and hard of hearing shared their experiences and we hope we can make their voices heard and seen.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Face coverings have been key in reducing the spread of COVID-19. At the same time, they have hindered interpersonal communication, particularly for those who rely on speechreading to aid communication. The available research indicated that deaf/hard of hearing (HoH) people experienced great difficulty communicating with people wearing masks and negative effects on wellbeing. Here we extended these findings by exploring which factors predict deaf/HoH people’s communication difficulties, loss of information, and wellbeing. We also explored the factors predicting perceived usefulness of transparent face coverings and alternative ways of communicating. We report the findings from an accessible survey study, released in two written and three signed languages. Responses from 395 deaf/HoH UK and Spanish residents were collected online at a time when masks were mandatory. We investigated whether onset and level of deafness, knowledge of sign language, speechreading fluency, and country of residence predicted communication difficulties, wellbeing, and degree to which transparent face coverings were considered useful. Overall, deaf/HoH people and their relatives used masks most of the time despite greater communication difficulties. Late-onset deaf people were the group that experienced more difficulties in communication, and also reported lower wellbeing. However, both early- and late-onset deaf people reported missing more information and feeling more disconnected from society than HoH people. Finally, signers valued transparent face shields more positively than non-signers. The latter suggests that, while seeing the lips is positive to everyone, signers appreciate seeing the whole facial expression. Importantly, our data also revealed the importance of visual communication other than speechreading to facilitate face-to-face interactions. Highlights Late-onset deaf people experienced more difficulties in communication and low wellbeing. Severely/profoundly deaf people missed more information and felt disconnected from society. Signers preferred completely transparent face coverings. More frequent use of masks doesn’t necessarily imply more difficulty communicating. Visual communication, pro-social behaviour, and societal structure might help easing communication. Significance statement The present study is a tight collaboration between deaf and hearing researchers in the fields of cognitive psychology and language processing in deaf people. We investigate the communication challenges faced by deaf and hard of hearing (HoH) people due to the community-wide use of face masks to help stopping the spread of COVID-19. Previous knowledge of basic research on language processing in deaf people informed both the survey’s design and the selection of predictors for the regression analyses. For example, level and onset of deafness were included as separate predictors because basic research shows that they result in different levels of reliance on speechreading to aid communication. Similarly, sign languages (SLs) are the first language of many deaf/HoH people. Knowing a SL could equip the signer with visual-communication strategies other than speechreading. Our findings highlight the importance of acknowledging the diversity in the deaf/HoH population and hence tailor interventions to their specific needs. We found that late-onset severely and profoundly deaf people experienced more difficulties communicating and lower wellbeing. However, it was signers who thought they had missed more information and felt more disconnected from society. Clear window masks, while better than opaque masks for all deaf/HoH people, might be most effective for fluent speechreaders and for non-signers. Interactions with signers could be improved by using completely transparent face coverings, paired with increased ventilation and social distancing for safety. Finally, other ways of communication such as using SL as much as possible, gesturing, writing or a combination of them can be particularly useful for deaf people. Introduction Face masks have been shown to effectively reduce the risk of COVID-19 infection (Chu et al., 2020 ). This meant that by the summer of 2020 most countries required use of masks in public locations (Howard et al., 2021 ). Furthermore, it is likely that the use of face coverings will persist to some degree in the near future (Ballard, 2022 ; BBC, 2021 ; Wisconsin Public Radio, 2022 ). Facial coverings have been essential to control the spread of the virus and therefore to save lives. At the same time, masks hinder interpersonal communication as they attenuate the vocal sounds and cover facial expressions and lip movements (Mheidly et al., 2020 ). Masks add to the communication challenges faced by deaf and hard-of-hearing (HoH) people, who often rely on speechreading (lipreading Footnote 1 ) to aid communication. The deaf and HoH communities warned early in the pandemic that use of face masks was likely to have a negative impact on communication (see e.g. jewishnews.timesofisrael.com, 2020 ; Lavanguardia.com, 2021 ; NDCS, 2021 ; RNID, 2021b ; Saiz et al., 2022 ) because it impedes speechreading. Similar warnings were issued from the medical community (Chodosh et al., 2020 ), highlighting that masks negatively affect speech perception in hospitals (particularly for older people) and that the lack of visual cues from the face was likely to have a major impact on deaf people (see Tavanai et al., 2021 ). The present survey study investigated the impact of face masks on loss of information, wellbeing, and how communication could be improved. According to the World Health Organisation (WHO), approximately 430 million people worldwide have hearing loss (WHO, 2021 ), 12 million in the UK (RNID, 2021a ), and over one million in Spain (see e.g. INE, 2021 ). It is well known that the deaf and HoH population is extremely heterogeneous. For example, in the UK approximately 28% of deaf/HoH people became deaf/HoH at birth or early childhood, and around 71% became deaf/HoH later in life, most of them as a result of ageing (see e.g. ONS, 2018 ). People with different onset of deafness are likely to adopt different communication strategies (Garstecki & Erler, 1999 ). For instance, it has been shown that people with late-onset deafness might be reluctant to disclose their deafness, reducing the number of social interactions they experience altogether (Barker et al., 2017 ). Conversely, early-onset deaf people are likely to have developed more efficient visual communication strategies (including learning sign language, developing better speechreading ability, use of manually coded speech, cued speech, increased use of pointing and gesturing, etc., see e.g.<|im_end|> <|im_start|>assistant Mandatory mask wearing saw more than 90% of deaf people struggle to communicate during the pandemic, University of Essex research has revealed. It also discovered that 76% missed vital information and 59% felt disconnected from society due to the face coverings. This is because masks restrict the ability to read lips and judge expressions. It also emerged that over-55s who became deaf later in life found communication using masks more challenging. And profoundly deaf people and signers experienced more disconnection from society and negative effects on their well-being. Dr. Eva Gutierrez-Sigut, from the Department of Psychology, led a team of deaf and hearing researchers who made sure that the survey was accessible in different sign languages. Nearly 400 people were surveyed to discover how COVID-19 hit the deaf community and the researcher hopes the findings will now help shape public policy in health emergencies. Dr. Gutierrez-Sigut says that "mask mandates were vital in fighting the spread of the deadly coronavirus but meant some of our most vulnerable communities were left isolated. The pandemic lockdowns were hard for everyone but even more so for the deaf and hard-of-hearing." This research exposes the unexpected consequences policies can have in a fast-moving international emergency and how people can fall through the cracks. "If the world is gripped by a pandemic again Governments need to do more to be inclusive and engage with communities to find out what they need to thrive and survive." The paper—published in Cognitive Research: Principles and Implications—also uncovered cultural differences in how masks affected understanding, with Brits struggling more than Spanish people across the board. It is speculated that this is due to differences in mask regulations and that Spaniards made more of an effort to use other means than speaking, such as gesturing, writing, or "some other creative alternatives." The research also showed that there is no one size fits all approach for the deaf or hard-of-hearing with masks. Signing, speech reading, and other communication techniques affect comprehension in combination with levels of deafness, whether they can use sign language, and when hearing loss started. However, a clear mask which made the entire mouth and lower face visible was the preferred option for many. Dr. Gutierrez-Sigut says that "most deaf people we spoke to agreed these masks made a real difference and made everything from a trip to the shops to a vital doctor's appointment easier. It is worth remembering though that there isn't a one-size fits all solution for these communities. The deaf and hard-of-hearing are not a homogenous group and have different needs." "One thing is clear though, more needs to be done to engage with them. To do this we made a real effort to create an accessible study using sign language to reach them. We are so thankful deaf and hard of hearing shared their experiences and we hope we can make their voices heard and seen." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract During influenza A virus (IAV) infections, viral proteins are targeted by cellular E3 ligases for modification with ubiquitin. Here, we decipher and functionally explore the ubiquitination landscape of the IAV polymerase proteins during infection of human alveolar epithelial cells by applying mass spectrometry analysis of immuno-purified K-ε-GG (di-glycyl)-remnant-bearing peptides. We have identified 59 modified lysines across the three subunits, PB2, PB1 and PA of the viral polymerase of which 17 distinctively affect mRNA transcription, vRNA replication and the generation of recombinant viruses via non-proteolytic mechanisms. Moreover, further functional and in silico analysis indicate that ubiquitination at K578 in the PB1 thumb domain is mechanistically linked to dynamic structural transitions of the viral polymerase that are required for vRNA replication. Mutations K578A and K578R differentially affect the generation of recombinant viruses by impeding cRNA and vRNA synthesis, NP binding as well as polymerase dimerization. Collectively, our results demonstrate that the ubiquitin-mediated charge neutralization at PB1-K578 disrupts the interaction to an unstructured loop in the PB2 N-terminus that is required to coordinate polymerase dimerization and facilitate vRNA replication. This provides evidence that IAV exploits the cellular ubiquitin system to modulate the activity of the viral polymerase for viral replication. Introduction Influenza A viruses (IAV) are respiratory pathogens of the Orthomyxoviridae family that pose a substantial threat to global health through seasonal epidemics and recurring pandemics. The IAV genome consists of eight segments of negative-sense single-strand RNA (vRNA). Each vRNA is encapsidated by multiple copies of the nucleoprotein (NP) and one copy of the trimeric viral RNA-dependent RNA polymerase (RdRP), composed of the subunits PB2, PB1, and PA 1 , 2 to form viral ribonucleoprotein (vRNPs) complexes 3 . Transcription of viral mRNAs and replication of the viral genome is mediated by RdRPs and occurs in the cell nucleus. While incoming vRNPs are capable to directly perform mRNA synthesis following cap-snatching from host-derived pre-mRNAs 4 , 5 , 6 , vRNA replication depends on newly produced viral proteins and polymerase complexes. It proceeds in a primer-independent manner that involves the generation of full-length positive-sense complementary RNA (cRNA) intermediates, which serve as templates for vRNA synthesis 7 . Structural investigations revealed that the IAV RdRP is a flexible and highly dynamic protein complex that adopts different conformations during mRNA transcription and vRNA replication 5 , 8 . The current model for vRNA replication suggests that the transition from the transcriptase to the replicase is promoted by the interaction with a second viral polymerase forming an asymmetric dimer 9 , 10 . Moreover, the formation of the asymmetric dimer facilitates encapsidation of the nascent cRNA strand. In the second step of genome replication, initiation of vRNA synthesis from cRNA templates requires formation of a symmetric polymerase dimer through interaction with a trans-activating polymerase 11 , 12 . To maintain the optimal balance between mRNA transcription and vRNA replication during the viral life cycle chronologic assembly of the two dimers is critical and is suggested to be influenced by viral as well as cellular factors. In particular, host-mediated post-translational modifications (PTM) of viral proteins were proposed as dynamic molecular switches to fine-tune the actions of the RdRP 13 , 14 . Indeed, phosphorylation 15 , 16 , 17 , 18 , 19 , ADP-ribosylation or acetylation 19 , 20 , 21 as well as linkage of ubiquitin (UB) 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 and ubiquitin-like modifiers (UBL), such as SUMO 1–3 32 , 33 , NEDD8 34 , or ISG15 35 to the polymerase subunits and NP have been reported. Among these modifiers, ubiquitination is the most abundant in human cells and regulates the functionality and longevity of a wide range of proteins and has been described for all subunits of the IAV RdRP with both pro- and antiviral outcomes. Conjugation of PTMs such as UB confers several effects. It introduces a binding surface for other UBL-binding proteins, but can also shield protein binding sites on the modified protein. In addition, UB transfers biological signals, e.g., the degradation by the cellular proteasome or translocation to a different cellular compartment. A less reported consequence of UB-linkage is the neutralization of the positive charge in the side chain of the acceptor lysine by formation of the dipeptide bond, which can result in structural alterations and affect interactions with other proteins 36 . Until today, the biological impact of site-specific modifications in the IAV polymerase proteins for the processes of viral mRNA transcription and genome replication has remained largely unknown. In this study, we have performed mass spectrometry (MS) analyses of immuno-selected, K-ε-GG-(di-glycyl)-enriched viral proteins purified from infected human lung epithelial cells to unravel the ubiquitination landscape of the IAV polymerase during infection. We have identified 59 modified lysines across the subunits of the IAV RdRP, with UB being the most abundant UBL. Mutational analysis and generation of recombinant viruses by reverse genetics reveal that ubiquitination at position PB1-K578 in the PB1-thumb domain regulates the spatio-temporal positioning of an unstructured N-terminal loop in the PB2 subunit and thereby participates in the coordination of polymerase dimerization, NP binding and vRNA replication. Results Unraveling the ubiquitination landscape of the IAV polymerase during infection Western blot analysis of co-precipitated strep-tagged RdRP subunits, PB2, PB1, and PA, with co-expressed UBLs revealed abundant UB modifications on all three subunits (Fig. 1a and Supplementary Fig. 1 ), which is in line with previous reports 27 . In contrast, NEDD8 was only detected on PA, while ISG15 was absent for all three subunits (Fig. 1b, c ). Fig. 1: Identification of site-specific UB modifications in the IAV polymerase. a – c Western blot analysis of ubiquitin (UB), NEDD8 and ISG15 modification of the IAV polymerase subunits. A549 (UB) or HEK293-T (NEDD8, ISG15) were transfected with expression plasmids for strep-tagged polymerase subunits (PB2, PB1, or PA), respectively, together with plasmids for the expression of ubiquitin-like modifiers (UBLs) bearing an HA- or His-tag. UBL-modified polymerase subunits were precipitated under denaturing conditions using Strep-Tactin®", "role": "user" }, { "content": "Influenza viruses are becoming increasingly resilient to medicines. For this reason, new active ingredients are needed. Important findings in this regard have been provided by researchers at the University of Münster: for the virus to proliferate, the polymerase of the influenza A virus has to be modified many times through enzymes in the host cells. The team of researchers was able to produce a comprehensive map of the types of modification. Medicines directed against the enzymes would be resilient to rapid mutations in the virus, thus offering great potential for the future. The study results have now been published in the journal Nature Communications. Every year, the influenza season presents a challenge to hospitals. Despite having been vaccinated, older people and patients with health problems run a heightened risk of falling prey to a severe bout of influenza. What is especially insidious about influenza viruses is their ability to mutate rapidly, which makes them increasingly resilient to medicines. For this reason, there is an urgent need for new active ingredients in order to be able to continue providing effective treatment for the illness in future. Researchers at the University of Münster have taken an important step in this direction by providing evidence of 59 specific modifications to the polymerase of the influenza A virus, in other words the decisive enzyme responsible for the production of copies of the virus genome. What is special about the modifications described in the study is that they are transmitted by proteins in the host cells—and, in contrast to virus proteins, they cannot mutate rapidly. They therefore represent a promising approach for the production of new medicines. The influenza A virus polymerase (IAV polymerase) is a highly complex protein which has more than just one function. One of these is that after a structural change it can also make copies of the virus genome (cRNA and vRNA). Without this \"switch\" of functions, the virus is not able to proliferate. Lead author Dr. Franziska Günl (left) and the head of the study, Dr. Linda Brunotte Credit: Saskia Hinse As Dr. Linda Brunotte and Dr. Franziska Günl and a team of colleagues have now discovered, the IAV polymerase needs proteins from the host cell to act as \"molecular switches\" and carry out its diverse functions. These proteins are enzymes that dock so-called ubiquitin proteins onto specific places in the polymerase and, as a result, trigger the signal for the switch of functions. \"We were able to produce a map showing 59 positions on the viral polymerase to which ubiquitin was attached through the host cell. These are completely new findings which reveal the Achilles' heel of the influenza A virus,\" explains Dr. Brunotte, who heads a team of researchers at the Institute of Molecular Virology and also initiated the study. This ubiquitination had a definite influence on the activity of the polymerase at 17 spots. Moreover, one specific position was discovered whose modification represents the signal for the conversion and the associated switch of functions in the polymerase. As a result, Dr. Günl, the lead author of the study, is now looking ahead: \"On the basis of our mapping of the ubiquitination, further studies can now research into which enzymes are specifically responsible for the modification of the IAV polymerase. Medicines which are directed against these enzymes would be resistant to mutations in influenza viruses, thus displaying great potential for future treatments.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract During influenza A virus (IAV) infections, viral proteins are targeted by cellular E3 ligases for modification with ubiquitin. Here, we decipher and functionally explore the ubiquitination landscape of the IAV polymerase proteins during infection of human alveolar epithelial cells by applying mass spectrometry analysis of immuno-purified K-ε-GG (di-glycyl)-remnant-bearing peptides. We have identified 59 modified lysines across the three subunits, PB2, PB1 and PA of the viral polymerase of which 17 distinctively affect mRNA transcription, vRNA replication and the generation of recombinant viruses via non-proteolytic mechanisms. Moreover, further functional and in silico analysis indicate that ubiquitination at K578 in the PB1 thumb domain is mechanistically linked to dynamic structural transitions of the viral polymerase that are required for vRNA replication. Mutations K578A and K578R differentially affect the generation of recombinant viruses by impeding cRNA and vRNA synthesis, NP binding as well as polymerase dimerization. Collectively, our results demonstrate that the ubiquitin-mediated charge neutralization at PB1-K578 disrupts the interaction to an unstructured loop in the PB2 N-terminus that is required to coordinate polymerase dimerization and facilitate vRNA replication. This provides evidence that IAV exploits the cellular ubiquitin system to modulate the activity of the viral polymerase for viral replication. Introduction Influenza A viruses (IAV) are respiratory pathogens of the Orthomyxoviridae family that pose a substantial threat to global health through seasonal epidemics and recurring pandemics. The IAV genome consists of eight segments of negative-sense single-strand RNA (vRNA). Each vRNA is encapsidated by multiple copies of the nucleoprotein (NP) and one copy of the trimeric viral RNA-dependent RNA polymerase (RdRP), composed of the subunits PB2, PB1, and PA 1 , 2 to form viral ribonucleoprotein (vRNPs) complexes 3 . Transcription of viral mRNAs and replication of the viral genome is mediated by RdRPs and occurs in the cell nucleus. While incoming vRNPs are capable to directly perform mRNA synthesis following cap-snatching from host-derived pre-mRNAs 4 , 5 , 6 , vRNA replication depends on newly produced viral proteins and polymerase complexes. It proceeds in a primer-independent manner that involves the generation of full-length positive-sense complementary RNA (cRNA) intermediates, which serve as templates for vRNA synthesis 7 . Structural investigations revealed that the IAV RdRP is a flexible and highly dynamic protein complex that adopts different conformations during mRNA transcription and vRNA replication 5 , 8 . The current model for vRNA replication suggests that the transition from the transcriptase to the replicase is promoted by the interaction with a second viral polymerase forming an asymmetric dimer 9 , 10 . Moreover, the formation of the asymmetric dimer facilitates encapsidation of the nascent cRNA strand. In the second step of genome replication, initiation of vRNA synthesis from cRNA templates requires formation of a symmetric polymerase dimer through interaction with a trans-activating polymerase 11 , 12 . To maintain the optimal balance between mRNA transcription and vRNA replication during the viral life cycle chronologic assembly of the two dimers is critical and is suggested to be influenced by viral as well as cellular factors. In particular, host-mediated post-translational modifications (PTM) of viral proteins were proposed as dynamic molecular switches to fine-tune the actions of the RdRP 13 , 14 . Indeed, phosphorylation 15 , 16 , 17 , 18 , 19 , ADP-ribosylation or acetylation 19 , 20 , 21 as well as linkage of ubiquitin (UB) 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 and ubiquitin-like modifiers (UBL), such as SUMO 1–3 32 , 33 , NEDD8 34 , or ISG15 35 to the polymerase subunits and NP have been reported. Among these modifiers, ubiquitination is the most abundant in human cells and regulates the functionality and longevity of a wide range of proteins and has been described for all subunits of the IAV RdRP with both pro- and antiviral outcomes. Conjugation of PTMs such as UB confers several effects. It introduces a binding surface for other UBL-binding proteins, but can also shield protein binding sites on the modified protein. In addition, UB transfers biological signals, e.g., the degradation by the cellular proteasome or translocation to a different cellular compartment. A less reported consequence of UB-linkage is the neutralization of the positive charge in the side chain of the acceptor lysine by formation of the dipeptide bond, which can result in structural alterations and affect interactions with other proteins 36 . Until today, the biological impact of site-specific modifications in the IAV polymerase proteins for the processes of viral mRNA transcription and genome replication has remained largely unknown. In this study, we have performed mass spectrometry (MS) analyses of immuno-selected, K-ε-GG-(di-glycyl)-enriched viral proteins purified from infected human lung epithelial cells to unravel the ubiquitination landscape of the IAV polymerase during infection. We have identified 59 modified lysines across the subunits of the IAV RdRP, with UB being the most abundant UBL. Mutational analysis and generation of recombinant viruses by reverse genetics reveal that ubiquitination at position PB1-K578 in the PB1-thumb domain regulates the spatio-temporal positioning of an unstructured N-terminal loop in the PB2 subunit and thereby participates in the coordination of polymerase dimerization, NP binding and vRNA replication. Results Unraveling the ubiquitination landscape of the IAV polymerase during infection Western blot analysis of co-precipitated strep-tagged RdRP subunits, PB2, PB1, and PA, with co-expressed UBLs revealed abundant UB modifications on all three subunits (Fig. 1a and Supplementary Fig. 1 ), which is in line with previous reports 27 . In contrast, NEDD8 was only detected on PA, while ISG15 was absent for all three subunits (Fig. 1b, c ). Fig. 1: Identification of site-specific UB modifications in the IAV polymerase. a – c Western blot analysis of ubiquitin (UB), NEDD8 and ISG15 modification of the IAV polymerase subunits. A549 (UB) or HEK293-T (NEDD8, ISG15) were transfected with expression plasmids for strep-tagged polymerase subunits (PB2, PB1, or PA), respectively, together with plasmids for the expression of ubiquitin-like modifiers (UBLs) bearing an HA- or His-tag. UBL-modified polymerase subunits were precipitated under denaturing conditions using Strep-Tactin®<|im_end|> <|im_start|>assistant Influenza viruses are becoming increasingly resilient to medicines. For this reason, new active ingredients are needed. Important findings in this regard have been provided by researchers at the University of Münster: for the virus to proliferate, the polymerase of the influenza A virus has to be modified many times through enzymes in the host cells. The team of researchers was able to produce a comprehensive map of the types of modification. Medicines directed against the enzymes would be resilient to rapid mutations in the virus, thus offering great potential for the future. The study results have now been published in the journal Nature Communications. Every year, the influenza season presents a challenge to hospitals. Despite having been vaccinated, older people and patients with health problems run a heightened risk of falling prey to a severe bout of influenza. What is especially insidious about influenza viruses is their ability to mutate rapidly, which makes them increasingly resilient to medicines. For this reason, there is an urgent need for new active ingredients in order to be able to continue providing effective treatment for the illness in future. Researchers at the University of Münster have taken an important step in this direction by providing evidence of 59 specific modifications to the polymerase of the influenza A virus, in other words the decisive enzyme responsible for the production of copies of the virus genome. What is special about the modifications described in the study is that they are transmitted by proteins in the host cells—and, in contrast to virus proteins, they cannot mutate rapidly. They therefore represent a promising approach for the production of new medicines. The influenza A virus polymerase (IAV polymerase) is a highly complex protein which has more than just one function. One of these is that after a structural change it can also make copies of the virus genome (cRNA and vRNA). Without this "switch" of functions, the virus is not able to proliferate. Lead author Dr. Franziska Günl (left) and the head of the study, Dr. Linda Brunotte Credit: Saskia Hinse As Dr. Linda Brunotte and Dr. Franziska Günl and a team of colleagues have now discovered, the IAV polymerase needs proteins from the host cell to act as "molecular switches" and carry out its diverse functions. These proteins are enzymes that dock so-called ubiquitin proteins onto specific places in the polymerase and, as a result, trigger the signal for the switch of functions. "We were able to produce a map showing 59 positions on the viral polymerase to which ubiquitin was attached through the host cell. These are completely new findings which reveal the Achilles' heel of the influenza A virus," explains Dr. Brunotte, who heads a team of researchers at the Institute of Molecular Virology and also initiated the study. This ubiquitination had a definite influence on the activity of the polymerase at 17 spots. Moreover, one specific position was discovered whose modification represents the signal for the conversion and the associated switch of functions in the polymerase. As a result, Dr. Günl, the lead author of the study, is now looking ahead: "On the basis of our mapping of the ubiquitination, further studies can now research into which enzymes are specifically responsible for the modification of the IAV polymerase. Medicines which are directed against these enzymes would be resistant to mutations in influenza viruses, thus displaying great potential for future treatments." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)—a multikinase inhibitor—encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities. Main Nanoscale drug delivery systems enable controlled drug release with increased tumour selectivity and reduced toxicity 1 . Recently, multifunctional nanoparticles activated by external stimuli have emerged to enhance tumour-selective drug release 1 . These activable delivery vehicles include optically responsive nanomaterials that support a broad range of biophotonic therapy and imaging applications 2 , 3 , 4 , offering great promise for facilitating multimodal therapies of cancer. However, a fundamental challenge in oncology is that a number of resistance mechanisms and escape pathways ultimately limit treatment efficacy 5 , 6 . Here, we report near-infrared (NIR) light-activated PMILs that impart photocytotoxicity to multiple tumour compartments and enable photoinitiated, sustained release of a multimolecular inhibitor with potent antiangiogenic activity and suppression of prominent treatment escape pathways ( Fig. 1a ). This unique approach impairs multiple, distinct molecular targets and is motivated by a three-way mechanistic interaction to combine: (i) photodynamic therapy (PDT)-induced tumour cell apoptotic signalling with XL184 inhibition of anti-apoptotic signalling pathways that promote cell survival; (ii) PDT-induced microvessel damage with sustained XL184 inhibition of vascular endothelial growth factor (VEGF) signalling to suppress tumour angiogenesis and vascular regrowth; and (iii) exploiting a second molecular target of XL184, sustained inhibition of MET—the receptor tyrosine kinase for hepatocyte growth factor—signalling to suppress cancer cell motility, invasion and metastatic escape in response to tumour hypoxia induced by vascular damage and antiangiogenic therapy 7 , 8 . We show that BPD–XL184 PMILs realize these complementary interactions, resulting in enhanced tumour reduction in vivo in two mouse models of human pancreatic ductal adenocarcinoma (PDAC). In contrast to the corresponding monotherapies and combination therapy using conventional drug formulations, a single treatment cycle using PMILs results in prolonged local tumour control in a subcutaneous and in an orthotopic PDAC mouse model. Figure 1: Concepts of spatiotemporal-synchronized combination therapy using PMILs. a , NIR light activates PMILs within the tumour microvasculature and parenchyma for simultaneous neovascular damage, tumour cell apoptosis and necrosis as well as liposome disruption with initiation of sustained multikinase inhibition. The PMIL delivery system is tuneable for simultaneous delivery of photodynamic, chemotherapeutics and small-molecular inhibitors. b , Schematic of a three-way interactive combination therapy with photodynamic tumour cell death and microvasculature damage and inhibition of treatment escape pathways. VEGFR signalling stimulates tumour angiogenesis and preparation of the premetastatic niche via supporting endothelial cell survival, migration and proliferation as well as increased vessel permeability and chemotaxis of bone marrow derived progenitor cells. MET signalling promotes escape from cytotoxic and antiangiogenic therapy via supporting cancer cell survival, motility and metastasis as well as cancer stem-like cell maintenance and tumour angiogenesis via cross talk with the VEGFR pathway. XL184 inhibits activation of both the MET and VEGF signalling pathways to suppress tumour cell survival, metastasis and regrowth following cytotoxic therapy. Full size image VEGF and MET are prime examples of tumour signalling pathways that promote treatment escape. VEGF and its receptors (for example VEGFR2) represent key targets for antiangiogenic therapy, and upregulation of VEGF signalling has been observed in response to radiotherapy 9 , chemotherapy 10 , cytoreductive surgery 11 and PDT 12 , 13 . MET is frequently expressed by cancer stem-like cells thought to drive tumour recurrence 14 , and abnormal MET signalling has been shown to promote the epithelial–mesenchymal transition 15 , cancer cell stemness 15 as well as tumour growth, invasion and metastasis 5 , 15 . Moreover, MET signalling is also observed in response to anti-VEGF therapy and comprises a prominent escape mechanism from antiangiogenic treatments 5 . When the tumour vasculature is pruned by anti-VEGF therapy, the hypoxic tumour microenvironment stimulates MET expression 7 , 8 , 16 . McDonald and colleagues elegantly demonstrated that concurrent inhibition of the VEGF and MET signalling pathways results in the favourable benefits of antiangiogenic therapy in slowing tumour growth while mitigating the unwanted consequences of increased intratumoural hypoxia—cancer cell migration and tumour growth along remaining, functional vessels as well as via lymphatic routes 16 , 17 . Here, we demonstrate that PDAC tumours transiently upregulate MET signalling in response to PDT in vivo ( Supplementary Fig. 1 ), which closes the triangle to motivate a three-way interactive therapy ( Fig. 1b )—suggesting a compelling rationale to combine concurrent anti-VEGF and -MET therapy with PDT—and motivated development of the PMIL. This approach—utilizing liposomes loaded with a lipophilic therapeutic agent and encapsulating a PLGA nanoparticle that releases a second, complementary agent—is supported by the reported successes of nanoliposome-based delivery of chemotherapeutics 18 , 19 ( Supplementary Note 1 ). An advantage of this hybrid drug delivery vehicle is that its lipid 18 and polymer components 20 , 21 are all in clinical use and are biodegradable, nontoxic chemicals that can be metabolized by the body. PMILs build on these advances by utilizing light activation not only for photodynamic action but also as a drug release mechanism to enable tumour-focused, spatiotemporally synchronized combination therapies. This opens the door to a number of combination therapies for which capturing and suppressing bursts in molecular signalling dynamics is key. PMIL design, synthesis and", "role": "user" }, { "content": "A nanoparticle drug-delivery system that combines two complementary types of anticancer treatment could improve outcomes for patients with pancreatic cancer and other highly treatment-resistant tumors while decreasing toxicity. In their report that has received advance online publication in Nature Nanotechnology, a research team based at the Wellman Center for Photomedicine at Massachusetts General Hospital (MGH) describes how a nanomedicine that combines photodynamic therapy - the use of light to trigger a chemical reaction - with a molecular therapy drug targeted against common treatment resistance pathways reduced a thousand-fold the dosage of the molecular therapy drug required to suppress tumor progression and metastatic outgrowth in an animal model. \"A broad challenge in cancer treatment is that tumor cells use a network of cellular signaling pathways to resist and evade treatment,\" says Bryan Spring, PhD, of the Wellman Center, co-lead author of the report. \"The new optically active nanoparticle we have developed is able both to achieve tumor photodamage and to suppress multiple escape pathways, opening new possibilities for synchronized multidrug combination therapies and tumor-focused drug release.\" Photodynamic therapy (PDT), involves the use of chemicals called photosensitizers that are activated by exposure to specific wavelengths of light to release reactive molecules that can damage nearby cells. In cancer treatment, PDT damages both tumor cells and their blood supply, directly killing some tumor cells and starving those that remain of nutrients. But as with many other types of treatments, treating tumors with PDT can stimulate molecular signaling pathways that support tumor survival. The nanomedicine developed by the Wellman-based team is made up of nanoliposomes - spherical lipid membrane structures - enclosing a polymer nanoparticle that has been loaded with a targeted molecular therapy drug. The lipid membrane of these photoactivable multi-inhibitor nanoliposomes (PMILs) contains a FDA-approved photosensitizer called BPD (benzoporphyrin derivative), and the nanoparticles are loaded with a molecular therapy drug called XL184 or cabozantinib. XL184 inhibits two important treatment escape pathways, VEGF and MET, but while it has FDA approval to treat thyroid cancer and is being tested against pancreatic cancer and several other tumors, it is quite toxic requiring dose restrictions or treatment interruption. Since XL184 is delivered to every part of the body and not just to the tumor when administered orally, enclosing it in the PMIL could reduce toxicity by confining its action to the area of the tumor. Led by Tayyaba Hasan, PhD, of the Wellman Center, the investigators first confirmed in laboratory experiments that exposing PMILs to near-infrared light both activated the antitumor action of BPD and, by disrupting the lipid membrane envelope, released the XL184-containing nanoparticles. In two mouse models of pancreatic cancer, a single treatment consisting of intravenous delivery of the PMILs followed by localized delivery of near-infrared light to the tumor site via optical fibers resulted in significantly greater reduction in tumor size than did either treatment with XL184 or PDT with BPD alone. PMIL treatment also was significantly more effective than treatment with both XL184 and BPD-PDT given as separate agents. Along with prolonged tumor reduction, PMIL treatment also almost completely suppressed metastasis in the mouse models. While the VEGF treatment escape pathway is known to be induced and sensitized by PDT, the research team found that PDT also induces signaling via the MET pathway. The ability to deliver XL184 and PDT almost simultaneously allowed the two therapeutics to be \"at the right place at the right time\" to cut off the rapid initiation of escape signaling that usually follows PDT. This was reflected in how much more efficient PMIL-delivered treatment was in the animal models compared to either treatment alone, since PDT simultaneously sensitized the tumor to the second therapy. Delivery of XL184 directly to the tumor site produced these promising results at a dosage level less than one thousandth of what is used in oral therapy, with little or no toxicity. \"Right now we can say this approach has tremendous potential for patients with locally advanced pancreatic cancer, for whom surgery is not possible,\" says Hasan. \"In our Phase I/II clinical studies with PDT alone, tumor destruction was achieved in all cases, and we've seen at least one case where PDT alone induced enough tumor shrinkage to enable follow-up surgery. The more robust tumor reduction and suppression of escape pathways possible with PMILs might enable curative surgery or improve the outcome of chemotherapy to enhance patient survival. But while we are encouraged by these results, this combination in a new nanoconstruct needs more validation before becoming a clinical treatment option\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)—a multikinase inhibitor—encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities. Main Nanoscale drug delivery systems enable controlled drug release with increased tumour selectivity and reduced toxicity 1 . Recently, multifunctional nanoparticles activated by external stimuli have emerged to enhance tumour-selective drug release 1 . These activable delivery vehicles include optically responsive nanomaterials that support a broad range of biophotonic therapy and imaging applications 2 , 3 , 4 , offering great promise for facilitating multimodal therapies of cancer. However, a fundamental challenge in oncology is that a number of resistance mechanisms and escape pathways ultimately limit treatment efficacy 5 , 6 . Here, we report near-infrared (NIR) light-activated PMILs that impart photocytotoxicity to multiple tumour compartments and enable photoinitiated, sustained release of a multimolecular inhibitor with potent antiangiogenic activity and suppression of prominent treatment escape pathways ( Fig. 1a ). This unique approach impairs multiple, distinct molecular targets and is motivated by a three-way mechanistic interaction to combine: (i) photodynamic therapy (PDT)-induced tumour cell apoptotic signalling with XL184 inhibition of anti-apoptotic signalling pathways that promote cell survival; (ii) PDT-induced microvessel damage with sustained XL184 inhibition of vascular endothelial growth factor (VEGF) signalling to suppress tumour angiogenesis and vascular regrowth; and (iii) exploiting a second molecular target of XL184, sustained inhibition of MET—the receptor tyrosine kinase for hepatocyte growth factor—signalling to suppress cancer cell motility, invasion and metastatic escape in response to tumour hypoxia induced by vascular damage and antiangiogenic therapy 7 , 8 . We show that BPD–XL184 PMILs realize these complementary interactions, resulting in enhanced tumour reduction in vivo in two mouse models of human pancreatic ductal adenocarcinoma (PDAC). In contrast to the corresponding monotherapies and combination therapy using conventional drug formulations, a single treatment cycle using PMILs results in prolonged local tumour control in a subcutaneous and in an orthotopic PDAC mouse model. Figure 1: Concepts of spatiotemporal-synchronized combination therapy using PMILs. a , NIR light activates PMILs within the tumour microvasculature and parenchyma for simultaneous neovascular damage, tumour cell apoptosis and necrosis as well as liposome disruption with initiation of sustained multikinase inhibition. The PMIL delivery system is tuneable for simultaneous delivery of photodynamic, chemotherapeutics and small-molecular inhibitors. b , Schematic of a three-way interactive combination therapy with photodynamic tumour cell death and microvasculature damage and inhibition of treatment escape pathways. VEGFR signalling stimulates tumour angiogenesis and preparation of the premetastatic niche via supporting endothelial cell survival, migration and proliferation as well as increased vessel permeability and chemotaxis of bone marrow derived progenitor cells. MET signalling promotes escape from cytotoxic and antiangiogenic therapy via supporting cancer cell survival, motility and metastasis as well as cancer stem-like cell maintenance and tumour angiogenesis via cross talk with the VEGFR pathway. XL184 inhibits activation of both the MET and VEGF signalling pathways to suppress tumour cell survival, metastasis and regrowth following cytotoxic therapy. Full size image VEGF and MET are prime examples of tumour signalling pathways that promote treatment escape. VEGF and its receptors (for example VEGFR2) represent key targets for antiangiogenic therapy, and upregulation of VEGF signalling has been observed in response to radiotherapy 9 , chemotherapy 10 , cytoreductive surgery 11 and PDT 12 , 13 . MET is frequently expressed by cancer stem-like cells thought to drive tumour recurrence 14 , and abnormal MET signalling has been shown to promote the epithelial–mesenchymal transition 15 , cancer cell stemness 15 as well as tumour growth, invasion and metastasis 5 , 15 . Moreover, MET signalling is also observed in response to anti-VEGF therapy and comprises a prominent escape mechanism from antiangiogenic treatments 5 . When the tumour vasculature is pruned by anti-VEGF therapy, the hypoxic tumour microenvironment stimulates MET expression 7 , 8 , 16 . McDonald and colleagues elegantly demonstrated that concurrent inhibition of the VEGF and MET signalling pathways results in the favourable benefits of antiangiogenic therapy in slowing tumour growth while mitigating the unwanted consequences of increased intratumoural hypoxia—cancer cell migration and tumour growth along remaining, functional vessels as well as via lymphatic routes 16 , 17 . Here, we demonstrate that PDAC tumours transiently upregulate MET signalling in response to PDT in vivo ( Supplementary Fig. 1 ), which closes the triangle to motivate a three-way interactive therapy ( Fig. 1b )—suggesting a compelling rationale to combine concurrent anti-VEGF and -MET therapy with PDT—and motivated development of the PMIL. This approach—utilizing liposomes loaded with a lipophilic therapeutic agent and encapsulating a PLGA nanoparticle that releases a second, complementary agent—is supported by the reported successes of nanoliposome-based delivery of chemotherapeutics 18 , 19 ( Supplementary Note 1 ). An advantage of this hybrid drug delivery vehicle is that its lipid 18 and polymer components 20 , 21 are all in clinical use and are biodegradable, nontoxic chemicals that can be metabolized by the body. PMILs build on these advances by utilizing light activation not only for photodynamic action but also as a drug release mechanism to enable tumour-focused, spatiotemporally synchronized combination therapies. This opens the door to a number of combination therapies for which capturing and suppressing bursts in molecular signalling dynamics is key. PMIL design, synthesis and<|im_end|> <|im_start|>assistant A nanoparticle drug-delivery system that combines two complementary types of anticancer treatment could improve outcomes for patients with pancreatic cancer and other highly treatment-resistant tumors while decreasing toxicity. In their report that has received advance online publication in Nature Nanotechnology, a research team based at the Wellman Center for Photomedicine at Massachusetts General Hospital (MGH) describes how a nanomedicine that combines photodynamic therapy - the use of light to trigger a chemical reaction - with a molecular therapy drug targeted against common treatment resistance pathways reduced a thousand-fold the dosage of the molecular therapy drug required to suppress tumor progression and metastatic outgrowth in an animal model. "A broad challenge in cancer treatment is that tumor cells use a network of cellular signaling pathways to resist and evade treatment," says Bryan Spring, PhD, of the Wellman Center, co-lead author of the report. "The new optically active nanoparticle we have developed is able both to achieve tumor photodamage and to suppress multiple escape pathways, opening new possibilities for synchronized multidrug combination therapies and tumor-focused drug release." Photodynamic therapy (PDT), involves the use of chemicals called photosensitizers that are activated by exposure to specific wavelengths of light to release reactive molecules that can damage nearby cells. In cancer treatment, PDT damages both tumor cells and their blood supply, directly killing some tumor cells and starving those that remain of nutrients. But as with many other types of treatments, treating tumors with PDT can stimulate molecular signaling pathways that support tumor survival. The nanomedicine developed by the Wellman-based team is made up of nanoliposomes - spherical lipid membrane structures - enclosing a polymer nanoparticle that has been loaded with a targeted molecular therapy drug. The lipid membrane of these photoactivable multi-inhibitor nanoliposomes (PMILs) contains a FDA-approved photosensitizer called BPD (benzoporphyrin derivative), and the nanoparticles are loaded with a molecular therapy drug called XL184 or cabozantinib. XL184 inhibits two important treatment escape pathways, VEGF and MET, but while it has FDA approval to treat thyroid cancer and is being tested against pancreatic cancer and several other tumors, it is quite toxic requiring dose restrictions or treatment interruption. Since XL184 is delivered to every part of the body and not just to the tumor when administered orally, enclosing it in the PMIL could reduce toxicity by confining its action to the area of the tumor. Led by Tayyaba Hasan, PhD, of the Wellman Center, the investigators first confirmed in laboratory experiments that exposing PMILs to near-infrared light both activated the antitumor action of BPD and, by disrupting the lipid membrane envelope, released the XL184-containing nanoparticles. In two mouse models of pancreatic cancer, a single treatment consisting of intravenous delivery of the PMILs followed by localized delivery of near-infrared light to the tumor site via optical fibers resulted in significantly greater reduction in tumor size than did either treatment with XL184 or PDT with BPD alone. PMIL treatment also was significantly more effective than treatment with both XL184 and BPD-PDT given as separate agents. Along with prolonged tumor reduction, PMIL treatment also almost completely suppressed metastasis in the mouse models. While the VEGF treatment escape pathway is known to be induced and sensitized by PDT, the research team found that PDT also induces signaling via the MET pathway. The ability to deliver XL184 and PDT almost simultaneously allowed the two therapeutics to be "at the right place at the right time" to cut off the rapid initiation of escape signaling that usually follows PDT. This was reflected in how much more efficient PMIL-delivered treatment was in the animal models compared to either treatment alone, since PDT simultaneously sensitized the tumor to the second therapy. Delivery of XL184 directly to the tumor site produced these promising results at a dosage level less than one thousandth of what is used in oral therapy, with little or no toxicity. "Right now we can say this approach has tremendous potential for patients with locally advanced pancreatic cancer, for whom surgery is not possible," says Hasan. "In our Phase I/II clinical studies with PDT alone, tumor destruction was achieved in all cases, and we've seen at least one case where PDT alone induced enough tumor shrinkage to enable follow-up surgery. The more robust tumor reduction and suppression of escape pathways possible with PMILs might enable curative surgery or improve the outcome of chemotherapy to enhance patient survival. But while we are encouraged by these results, this combination in a new nanoconstruct needs more validation before becoming a clinical treatment option" <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The acidity and antioxidant activity of cold brew coffee were investigated using light roast coffees from Brazil, two regions of Ethiopia, Columbia, Myanmar, and Mexico. The concentrations of three caffeoylquinic acid (CQA) isomers were also determined. Cold brew coffee chemistry was compared to that of hot brew coffee prepared with the same grind-to-coffee ratio. The pH values of the cold and hot brew samples were found to be comparable, ranging from 4.85 to 5.13. The hot brew coffees were found to have higher concentrations of total titratable acids, as well as higher antioxidant activity, than that of their cold brew counterparts. It was also noted that both the concentration of total titratable acids and antioxidant activity correlated poorly with total CQA concentration in hot brew coffee. This work suggests that the hot brew method tends to extract more non-deprotonated acids than the cold brew method. These acids may be responsible for the higher antioxidant activities observed in the hot brew coffee samples. Introduction Cold brew coffee is a popular phenomenon that has recently invigorated the coffee industry, particularly in the warm summer months 1 . The domestic cold brew coffee market grew 580% from 2011 to 2016 2 . Roast Magazine reports a 460% increase in retail sales of refrigerated cold brew coffee in the United States from 2015 to 2017, generating $38 million in 2017 alone 3 . Cold brew coffee is made through a low-temperature, long-contact brewing method. Regional coffee vendors, such as Starbucks and Dunkin Donuts have marketed the product as tasting smoother and less bitter than traditional hot brewed coffees 4 . Consumer interest has also been spurred by a range of online health and lifestyle blogs publishing recipes and specific health claims for cold brew coffee. A recent article in Healthy Living Made Simple , a bimonthly publication with 4 million readers, states that “coffee brewed hot is far more acidic than cold-brewed, according to a number of scientific studies, and some say cold-brewed coffee even has a sweeter taste because of its lower acidity” 5 . A blog post on Coffee Brewing Methods makes several claims regarding the decreased acidity, decreased caffeine levels, and increased antioxidant content of cold brew coffee 6 . At the time of publication, there was very little published research on the chemistry of cold brew coffee and no published research on the health effects of cold brew coffee. In fact, the health benefits and risks of traditional hot brew coffee consumption remain controversial. Coffee has long been associated with indigestion, heartburn, and other gastrointestinal symptoms. Epidemiological meta-analyses and patient-based experimentation have led to conflicting outcomes regarding the relationship between coffee consumption and gastrointestinal disorders. Early work by Thomas et al . 7 found that coffee consumption in 20 healthy individuals and 16 patients with reflux esophagitis resulted in the decrease of lower esophageal sphincter (LES) pressure. The reduction of LES pressure, found in both cohorts following consumption of coffee with pH values of 4.5 and 7.0, could lead to aggravated heartburn symptoms 7 . Because the decrease in LES pressure occurred at both an acidic and neutral pH, acidity may not be the inciting factor in heartburn following coffee consumption. Two studies by Wendl et al . 8 and Pehl et al . 9 observed gastro-oesophageal reflux in asymptomatic individuals (n = 16) and patients with gastro-oesophageal disease (GERD) (n = 17), respectively, and found that both cohorts experienced decreased oesophageal reflux after consuming decaffeinated coffee, indicating that caffeine may responsible for coffee-related heartburn symptoms 8 , 9 . A recent population-based study of GERD patients (n = 317) and asymptomatic individuals (n = 182) found no association between GERD symptom frequency or severity and coffee consumption 10 . Kubo et al .’s work is in agreement with other meta-analyses that use patient-reported symptoms. Shimamato et al . 11 used a large-scale multivariate analysis (n = 8,013) to evaluate coffee consumption as a contributor to the occurrence of gastric ulcers, duodenal ulcers, reflux esophagitis, and non-erosive reflux disease. Shimamato et al . 11 found no significant relationships between coffee consumption and these four major acid-related gastrointestinal disorders 11 . Given the disagreement found in the literature regarding the health impacts of traditional hot coffee, it is understandable that the general public views coffee as a potential health risk despite significant evidence to the contrary. Beyond gastrointestinal symptoms, coffee has been shown to correlate to multiple potential health benefits. A substantial umbrella review of numerous meta-analyses found no consistent evidence of harmful associations between coffee consumption and diverse health outcomes, with the exception of issues related to pregnancy and risk of bone fractures in women 12 . This work by Poole et al . 12 evaluated previous research relating coffee consumption to cardiovascular health (including cardiovascular disease, coronary heart disease, and stroke), and found a reduction in health risks when three cups of coffee per day were consumed 13 , 14 , 15 , 16 . Poole et al . 12 also found coffee consumption to be associated with decreased risk of liver 17 , 18 , metabolic 19 , 20 , and neurologic diseases 21 , 22 . The causal pathways for these chemoprotective associations between coffee consumption and disease are not well understood; however, recent studies of coffee have shown the beverage to exhibit high antioxidant capacity and anti-inflammatory effects. Work by Bakuradze et al . 23 showed compounds present in coffee roast products - notably 5-caffeoylquinic acid, a type of chlorogenic acid, and caffeic acid - demonstrated direct antioxidant activity in HT-29 (human colon) cells 23 . The role of antioxidant compounds as radical-scavengers in the body is well-researched 24 , 25 , 26 , but the relationship between coffee consumption, antioxidant activity, and brewing methods is largely uncharacterized. A recent review by Naveed et al . 27 further highlighted the therapeutic roles of chlorogenic acids in human health and called for further research in the area 27 . Work by Chu et al . 28", "role": "user" }, { "content": "In a new study, Jefferson (Philadelphia University + Thomas Jefferson University) researchers found chemical differences between hot and cold brew coffee that may have health impacts. In particular, the researchers found that hot-brewed coffee has higher levels of antioxidants, which are believed to be responsible for some of the health benefits of coffee. The study, published Oct. 30 in Scientific Reports, also found that the pH levels of both hot and cold coffee were similar, ranging from 4.85 to 5.13 for all coffee samples tested. Coffee companies and lifestyle blogs have tended to tout cold brew coffee as being less acidic than hot coffee and thus less likely to cause heartburn or gastrointestinal problems. The study was done by Niny Rao, Ph.D., associate professor of chemistry, and Megan Fuller, Ph.D., assistant professor of chemistry, both of them coffee drinkers who wondered whether the chemical make-up of cold brew differed from that of hot coffee. While the popularity of cold brew coffee has soared in recent years—the U.S. market grew 580 percent from 2011 to 2016—they found almost no studies on cold brew, which is a no-heat, long-steeping method of preparation. At the same time, there is well-documented research that hot-brewed coffee has some measurable health benefits, including lower risk of some cancers, diabetes and depression. While the overall pH levels were similar, Fuller and Rao found that the hot-brewed coffee method had more total titratable acids, which may be responsible for the hot cup's higher antioxidant levels. \"Coffee has a lot of antioxidants, if you drink it in moderation, research shows it can be pretty good for you,\" Fuller said. \"We found the hot brew has more antioxidant capacity.\" And considering hot and cold brews have comparable pH levels, Rao said, coffee drinkers should not consider cold brew a \"silver bullet\" for avoiding gastrointestinal distress. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The acidity and antioxidant activity of cold brew coffee were investigated using light roast coffees from Brazil, two regions of Ethiopia, Columbia, Myanmar, and Mexico. The concentrations of three caffeoylquinic acid (CQA) isomers were also determined. Cold brew coffee chemistry was compared to that of hot brew coffee prepared with the same grind-to-coffee ratio. The pH values of the cold and hot brew samples were found to be comparable, ranging from 4.85 to 5.13. The hot brew coffees were found to have higher concentrations of total titratable acids, as well as higher antioxidant activity, than that of their cold brew counterparts. It was also noted that both the concentration of total titratable acids and antioxidant activity correlated poorly with total CQA concentration in hot brew coffee. This work suggests that the hot brew method tends to extract more non-deprotonated acids than the cold brew method. These acids may be responsible for the higher antioxidant activities observed in the hot brew coffee samples. Introduction Cold brew coffee is a popular phenomenon that has recently invigorated the coffee industry, particularly in the warm summer months 1 . The domestic cold brew coffee market grew 580% from 2011 to 2016 2 . Roast Magazine reports a 460% increase in retail sales of refrigerated cold brew coffee in the United States from 2015 to 2017, generating $38 million in 2017 alone 3 . Cold brew coffee is made through a low-temperature, long-contact brewing method. Regional coffee vendors, such as Starbucks and Dunkin Donuts have marketed the product as tasting smoother and less bitter than traditional hot brewed coffees 4 . Consumer interest has also been spurred by a range of online health and lifestyle blogs publishing recipes and specific health claims for cold brew coffee. A recent article in Healthy Living Made Simple , a bimonthly publication with 4 million readers, states that “coffee brewed hot is far more acidic than cold-brewed, according to a number of scientific studies, and some say cold-brewed coffee even has a sweeter taste because of its lower acidity” 5 . A blog post on Coffee Brewing Methods makes several claims regarding the decreased acidity, decreased caffeine levels, and increased antioxidant content of cold brew coffee 6 . At the time of publication, there was very little published research on the chemistry of cold brew coffee and no published research on the health effects of cold brew coffee. In fact, the health benefits and risks of traditional hot brew coffee consumption remain controversial. Coffee has long been associated with indigestion, heartburn, and other gastrointestinal symptoms. Epidemiological meta-analyses and patient-based experimentation have led to conflicting outcomes regarding the relationship between coffee consumption and gastrointestinal disorders. Early work by Thomas et al . 7 found that coffee consumption in 20 healthy individuals and 16 patients with reflux esophagitis resulted in the decrease of lower esophageal sphincter (LES) pressure. The reduction of LES pressure, found in both cohorts following consumption of coffee with pH values of 4.5 and 7.0, could lead to aggravated heartburn symptoms 7 . Because the decrease in LES pressure occurred at both an acidic and neutral pH, acidity may not be the inciting factor in heartburn following coffee consumption. Two studies by Wendl et al . 8 and Pehl et al . 9 observed gastro-oesophageal reflux in asymptomatic individuals (n = 16) and patients with gastro-oesophageal disease (GERD) (n = 17), respectively, and found that both cohorts experienced decreased oesophageal reflux after consuming decaffeinated coffee, indicating that caffeine may responsible for coffee-related heartburn symptoms 8 , 9 . A recent population-based study of GERD patients (n = 317) and asymptomatic individuals (n = 182) found no association between GERD symptom frequency or severity and coffee consumption 10 . Kubo et al .’s work is in agreement with other meta-analyses that use patient-reported symptoms. Shimamato et al . 11 used a large-scale multivariate analysis (n = 8,013) to evaluate coffee consumption as a contributor to the occurrence of gastric ulcers, duodenal ulcers, reflux esophagitis, and non-erosive reflux disease. Shimamato et al . 11 found no significant relationships between coffee consumption and these four major acid-related gastrointestinal disorders 11 . Given the disagreement found in the literature regarding the health impacts of traditional hot coffee, it is understandable that the general public views coffee as a potential health risk despite significant evidence to the contrary. Beyond gastrointestinal symptoms, coffee has been shown to correlate to multiple potential health benefits. A substantial umbrella review of numerous meta-analyses found no consistent evidence of harmful associations between coffee consumption and diverse health outcomes, with the exception of issues related to pregnancy and risk of bone fractures in women 12 . This work by Poole et al . 12 evaluated previous research relating coffee consumption to cardiovascular health (including cardiovascular disease, coronary heart disease, and stroke), and found a reduction in health risks when three cups of coffee per day were consumed 13 , 14 , 15 , 16 . Poole et al . 12 also found coffee consumption to be associated with decreased risk of liver 17 , 18 , metabolic 19 , 20 , and neurologic diseases 21 , 22 . The causal pathways for these chemoprotective associations between coffee consumption and disease are not well understood; however, recent studies of coffee have shown the beverage to exhibit high antioxidant capacity and anti-inflammatory effects. Work by Bakuradze et al . 23 showed compounds present in coffee roast products - notably 5-caffeoylquinic acid, a type of chlorogenic acid, and caffeic acid - demonstrated direct antioxidant activity in HT-29 (human colon) cells 23 . The role of antioxidant compounds as radical-scavengers in the body is well-researched 24 , 25 , 26 , but the relationship between coffee consumption, antioxidant activity, and brewing methods is largely uncharacterized. A recent review by Naveed et al . 27 further highlighted the therapeutic roles of chlorogenic acids in human health and called for further research in the area 27 . Work by Chu et al . 28<|im_end|> <|im_start|>assistant In a new study, Jefferson (Philadelphia University + Thomas Jefferson University) researchers found chemical differences between hot and cold brew coffee that may have health impacts. In particular, the researchers found that hot-brewed coffee has higher levels of antioxidants, which are believed to be responsible for some of the health benefits of coffee. The study, published Oct. 30 in Scientific Reports, also found that the pH levels of both hot and cold coffee were similar, ranging from 4.85 to 5.13 for all coffee samples tested. Coffee companies and lifestyle blogs have tended to tout cold brew coffee as being less acidic than hot coffee and thus less likely to cause heartburn or gastrointestinal problems. The study was done by Niny Rao, Ph.D., associate professor of chemistry, and Megan Fuller, Ph.D., assistant professor of chemistry, both of them coffee drinkers who wondered whether the chemical make-up of cold brew differed from that of hot coffee. While the popularity of cold brew coffee has soared in recent years—the U.S. market grew 580 percent from 2011 to 2016—they found almost no studies on cold brew, which is a no-heat, long-steeping method of preparation. At the same time, there is well-documented research that hot-brewed coffee has some measurable health benefits, including lower risk of some cancers, diabetes and depression. While the overall pH levels were similar, Fuller and Rao found that the hot-brewed coffee method had more total titratable acids, which may be responsible for the hot cup's higher antioxidant levels. "Coffee has a lot of antioxidants, if you drink it in moderation, research shows it can be pretty good for you," Fuller said. "We found the hot brew has more antioxidant capacity." And considering hot and cold brews have comparable pH levels, Rao said, coffee drinkers should not consider cold brew a "silver bullet" for avoiding gastrointestinal distress. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Climate change is affecting thermal regimes globally, and organisms relying on their environment to regulate biological processes face unknown consequences. In ectotherms, temperature affects development rates, body condition, and performance. Embryonic stages may be the most vulnerable life history stages, especially for oviparous species already living at the warm edge of their distribution, as embryos cannot relocate during this developmental window. We reared 27 epaulette shark ( Hemiscyllium ocellatum ) embryos under average summer conditions (27 °C) or temperatures predicted for the middle and end of the twenty-first century with climate change (i.e., 29 and 31 °C) and tracked growth, development, and metabolic costs both in ovo and upon hatch. Rearing sharks at 31 °C impacted embryonic growth, yolk consumption, and metabolic rates. Upon hatch, 31 °C-reared sharks weighed significantly less than their 27 °C-reared counterparts and exhibited reduced metabolic performance. Many important growth and development traits in this species may peak after 27 °C and start to become negatively impacted nearing 31 °C. We hypothesize that 31 °C approximates the pejus temperature (i.e., temperatures at which performance of a trait begin to decline) for this species, which is alarming, given that this temperature range is well within ocean warming scenarios predicted for this species’ distribution over the next century. Introduction Ocean warming, resulting from global climate change, is already causing unprecedented changes to aquatic ecosystems worldwide 1 . The oceans absorb the Earth’s excess trapped heat that comes from anthropogenic emissions, and as such, sea surface temperatures are predicted to increase by as much as 4.0 °C under continued high emission scenarios 1 . These shifts are thought to have the most impact on tropical ecosystems where many species are adapted to narrow temperature ranges and also because seasonal temperature changes are small in comparison to those experienced in temperate zones 2 , 3 . Therefore, an organism’s ability to adapt to a change, whether by phenotypic or transgenerational plasticity, will become increasingly more important to surviving the changing conditions over the next century 2 . As most aquatic organisms are ectotherms, water temperatures regulate the biological and physiological processes that are crucial for survival 4 . Consequently, performance traits that reflect fitness (e.g., growth rates) exhibit thermal dependence, and this relationship can typically be depicted as a thermal performance curve 2 , 5 . In the context of ocean warming, establishing thermal performance curves for traits and species can help determine the suitability of future thermal habitats and help to predict both acute and chronic effects of warming on populations and ecosystems 6 , 7 . The embryonic life stage in ectotherms represents a thermal bottleneck when it comes to climate change vulnerability 8 , 9 . Across ectotherms, embryos are generally less thermally tolerant than juveniles and non-reproducing adults. For example, embryos exhibit a narrower thermal performance curve—the difference between their maximum and minimum critical temperatures—and a lower thermal safety margin, which is the difference between their optimal temperature and their mean habitat temperature 9 , 10 . However, embryos, particularly of oviparous species, must also possess mechanisms to tolerate temperature changes throughout development because they cannot freely move and/or choose temperatures that are more favourable while in ovo 11 . Consequently, the mismatch between an increase in thermal vulnerability and the inability to behaviourally thermoregulate during the embryonic stages will likely have negative consequences for many aquatic ectotherm species in the face of ocean warming. Chondrichthyan fishes (i.e., the class including sharks, rays, skates, and chimaera of which are mostly ectothermic) present a challenge in relation to ocean warming vulnerability, as many species are globally threatened (i.e., mainly from fisheries) 12 , poorly characterized in terms of basic life history 13 , have slow generation times and low reproductive output, and are logistically challenging for controlled laboratory experiments. However, these fishes have ecological, economical, and cultural significance worldwide, and require proper assessment and management, particularly with the rapidly changing marine environment 14 . Given that there are more than 1000 species of Chondrichthyans 12 , it is impractical to assume that comprehensive research investigating the effects of climate change can be conducted broadly. Therefore, we argue for a strategic focus on studies that investigate physiological tolerance limits and thresholds and to identify bioindicator species. Indeed, the indicator species concept is common in fields that include ecological and environmental monitoring to track the health of an ecosystem or to monitor the effectiveness of management 15 , 16 . However, it is less common to study an indicator species’ physiology—particularly via a thermal performance lens—for extrapolation within a taxonomic group, but that is the aim. Because oviparous (egg-laying) chondrichthyans tend to be smaller in comparison to viviparous (live-bearing) species within this taxonomic group and are well suited to captivity, climate change impacts on in ovo growth and development have been studied in several species 17 , 18 , 19 , 20 . In fact, in ovo incubation time negatively correlates with increasing water temperatures in 28 species of sharks, skates, and chimaera that have been investigated to date 11 . Indeed, the maximum thermal limits for growth and development are imperative to understanding species and population level vulnerabilities. Therefore, given the similarities with regard to growth and development patterns, at least within oviparous species, an oviparous chondrichthyan may be ideal as an indicator species, especially for investigating physiological thermal tolerance with respect to climate change. The epaulette shark ( Hemiscyllium ocellatum ), one such small oviparous shark endemic only to the Great Barrier Reef (GBR), Australia 21 , has been the focus of many climate change related laboratory studies 20 , 22 , 23 , 24 , 25 because this species thrives in captivity and is considered of least concern in the wild by the International Union for Conservation of Nature (IUCN) Red List Criteria 26 . Additionally, H. ocellatum possess unique morphological and physiological traits that allow them to hunt in isolated tidal pools and survive extreme and repeated hypoxia conditions 27 , 28 . Therefore,", "role": "user" }, { "content": "New research has found as climate change causes the world's oceans to warm, baby sharks are born smaller, exhausted, undernourished and into environments that are already difficult for them to survive in. Lead author of the study Carolyn Wheeler is a Ph.D. candidate at the ARC Centre of Excellence for Coral Reef Studies at James Cook University (Coral CoE at JCU) and the University of Massachusetts. She examined the effects of increased temperatures on the growth, development and physiological performance of epaulette sharks—an egg-laying species found only on the Great Barrier Reef. She and her team studied the sharks as embryos and as hatchlings. \"We tested shark embryos in waters up to 31°C,\" Ms Wheeler said. \"The hotter the conditions, the faster everything happened, which could be a problem for the sharks. The embryos grew faster and used their yolk sac quicker, which is their only source of food as they develop in the egg case. This led to them hatching earlier than usual.\" This meant hatchlings were not only smaller, they needed to feed almost straight away—while lacking significant energy. Co-author Associate Professor Jodie Rummer, also from Coral CoE at JCU, says the waters of the Great Barrier Reef will likely experience summer averages close to or even in excess of 31°C by the end of the century. Since sharks don't care for their eggs after they are laid, a shark egg must be able to survive unprotected for up to four months. Dr. Rummer flags rising ocean temperatures as a major concern for the future of all sharks—both egg-laying and live-bearing species. \"The epaulette shark is known for its resilience to change, even to ocean acidification,\" Dr. Rummer said. \"So, if this species can't cope with warming waters then how will other, less tolerant species fare?\" she said. Sharks and the class of animals they belong to, which includes rays and skates, are slow growing. They also don't reproduce that often compared to other fishes. The populations of these creatures are already threatened across the globe. The study suggests the sharks of the future will be born—or hatch, in this case—not only at a disadvantage but into environments that are already at the warmest they can tolerate. \"The study presents a worrying future given that sharks are already threatened,\" Ms Wheeler said. \"Sharks are important predators that keep ocean ecosystems healthy. Without predators, whole ecosystems can collapse, which is why we need to keep studying and protecting these creatures.\" \"Our future ecosystems depend us taking urgent action to limit climate change,\" Dr. Rummer said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Climate change is affecting thermal regimes globally, and organisms relying on their environment to regulate biological processes face unknown consequences. In ectotherms, temperature affects development rates, body condition, and performance. Embryonic stages may be the most vulnerable life history stages, especially for oviparous species already living at the warm edge of their distribution, as embryos cannot relocate during this developmental window. We reared 27 epaulette shark ( Hemiscyllium ocellatum ) embryos under average summer conditions (27 °C) or temperatures predicted for the middle and end of the twenty-first century with climate change (i.e., 29 and 31 °C) and tracked growth, development, and metabolic costs both in ovo and upon hatch. Rearing sharks at 31 °C impacted embryonic growth, yolk consumption, and metabolic rates. Upon hatch, 31 °C-reared sharks weighed significantly less than their 27 °C-reared counterparts and exhibited reduced metabolic performance. Many important growth and development traits in this species may peak after 27 °C and start to become negatively impacted nearing 31 °C. We hypothesize that 31 °C approximates the pejus temperature (i.e., temperatures at which performance of a trait begin to decline) for this species, which is alarming, given that this temperature range is well within ocean warming scenarios predicted for this species’ distribution over the next century. Introduction Ocean warming, resulting from global climate change, is already causing unprecedented changes to aquatic ecosystems worldwide 1 . The oceans absorb the Earth’s excess trapped heat that comes from anthropogenic emissions, and as such, sea surface temperatures are predicted to increase by as much as 4.0 °C under continued high emission scenarios 1 . These shifts are thought to have the most impact on tropical ecosystems where many species are adapted to narrow temperature ranges and also because seasonal temperature changes are small in comparison to those experienced in temperate zones 2 , 3 . Therefore, an organism’s ability to adapt to a change, whether by phenotypic or transgenerational plasticity, will become increasingly more important to surviving the changing conditions over the next century 2 . As most aquatic organisms are ectotherms, water temperatures regulate the biological and physiological processes that are crucial for survival 4 . Consequently, performance traits that reflect fitness (e.g., growth rates) exhibit thermal dependence, and this relationship can typically be depicted as a thermal performance curve 2 , 5 . In the context of ocean warming, establishing thermal performance curves for traits and species can help determine the suitability of future thermal habitats and help to predict both acute and chronic effects of warming on populations and ecosystems 6 , 7 . The embryonic life stage in ectotherms represents a thermal bottleneck when it comes to climate change vulnerability 8 , 9 . Across ectotherms, embryos are generally less thermally tolerant than juveniles and non-reproducing adults. For example, embryos exhibit a narrower thermal performance curve—the difference between their maximum and minimum critical temperatures—and a lower thermal safety margin, which is the difference between their optimal temperature and their mean habitat temperature 9 , 10 . However, embryos, particularly of oviparous species, must also possess mechanisms to tolerate temperature changes throughout development because they cannot freely move and/or choose temperatures that are more favourable while in ovo 11 . Consequently, the mismatch between an increase in thermal vulnerability and the inability to behaviourally thermoregulate during the embryonic stages will likely have negative consequences for many aquatic ectotherm species in the face of ocean warming. Chondrichthyan fishes (i.e., the class including sharks, rays, skates, and chimaera of which are mostly ectothermic) present a challenge in relation to ocean warming vulnerability, as many species are globally threatened (i.e., mainly from fisheries) 12 , poorly characterized in terms of basic life history 13 , have slow generation times and low reproductive output, and are logistically challenging for controlled laboratory experiments. However, these fishes have ecological, economical, and cultural significance worldwide, and require proper assessment and management, particularly with the rapidly changing marine environment 14 . Given that there are more than 1000 species of Chondrichthyans 12 , it is impractical to assume that comprehensive research investigating the effects of climate change can be conducted broadly. Therefore, we argue for a strategic focus on studies that investigate physiological tolerance limits and thresholds and to identify bioindicator species. Indeed, the indicator species concept is common in fields that include ecological and environmental monitoring to track the health of an ecosystem or to monitor the effectiveness of management 15 , 16 . However, it is less common to study an indicator species’ physiology—particularly via a thermal performance lens—for extrapolation within a taxonomic group, but that is the aim. Because oviparous (egg-laying) chondrichthyans tend to be smaller in comparison to viviparous (live-bearing) species within this taxonomic group and are well suited to captivity, climate change impacts on in ovo growth and development have been studied in several species 17 , 18 , 19 , 20 . In fact, in ovo incubation time negatively correlates with increasing water temperatures in 28 species of sharks, skates, and chimaera that have been investigated to date 11 . Indeed, the maximum thermal limits for growth and development are imperative to understanding species and population level vulnerabilities. Therefore, given the similarities with regard to growth and development patterns, at least within oviparous species, an oviparous chondrichthyan may be ideal as an indicator species, especially for investigating physiological thermal tolerance with respect to climate change. The epaulette shark ( Hemiscyllium ocellatum ), one such small oviparous shark endemic only to the Great Barrier Reef (GBR), Australia 21 , has been the focus of many climate change related laboratory studies 20 , 22 , 23 , 24 , 25 because this species thrives in captivity and is considered of least concern in the wild by the International Union for Conservation of Nature (IUCN) Red List Criteria 26 . Additionally, H. ocellatum possess unique morphological and physiological traits that allow them to hunt in isolated tidal pools and survive extreme and repeated hypoxia conditions 27 , 28 . Therefore,<|im_end|> <|im_start|>assistant New research has found as climate change causes the world's oceans to warm, baby sharks are born smaller, exhausted, undernourished and into environments that are already difficult for them to survive in. Lead author of the study Carolyn Wheeler is a Ph.D. candidate at the ARC Centre of Excellence for Coral Reef Studies at James Cook University (Coral CoE at JCU) and the University of Massachusetts. She examined the effects of increased temperatures on the growth, development and physiological performance of epaulette sharks—an egg-laying species found only on the Great Barrier Reef. She and her team studied the sharks as embryos and as hatchlings. "We tested shark embryos in waters up to 31°C," Ms Wheeler said. "The hotter the conditions, the faster everything happened, which could be a problem for the sharks. The embryos grew faster and used their yolk sac quicker, which is their only source of food as they develop in the egg case. This led to them hatching earlier than usual." This meant hatchlings were not only smaller, they needed to feed almost straight away—while lacking significant energy. Co-author Associate Professor Jodie Rummer, also from Coral CoE at JCU, says the waters of the Great Barrier Reef will likely experience summer averages close to or even in excess of 31°C by the end of the century. Since sharks don't care for their eggs after they are laid, a shark egg must be able to survive unprotected for up to four months. Dr. Rummer flags rising ocean temperatures as a major concern for the future of all sharks—both egg-laying and live-bearing species. "The epaulette shark is known for its resilience to change, even to ocean acidification," Dr. Rummer said. "So, if this species can't cope with warming waters then how will other, less tolerant species fare?" she said. Sharks and the class of animals they belong to, which includes rays and skates, are slow growing. They also don't reproduce that often compared to other fishes. The populations of these creatures are already threatened across the globe. The study suggests the sharks of the future will be born—or hatch, in this case—not only at a disadvantage but into environments that are already at the warmest they can tolerate. "The study presents a worrying future given that sharks are already threatened," Ms Wheeler said. "Sharks are important predators that keep ocean ecosystems healthy. Without predators, whole ecosystems can collapse, which is why we need to keep studying and protecting these creatures." "Our future ecosystems depend us taking urgent action to limit climate change," Dr. Rummer said. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Albedo—a primary control on surface melt—varies considerably across the Greenland Ice Sheet yet the specific surface types that comprise its dark zone remain unquantified. Here we use UAV imagery to attribute seven distinct surface types to observed albedo along a 25 km transect dissecting the western, ablating sector of the ice sheet. Our results demonstrate that distributed surface impurities—an admixture of dust, black carbon and pigmented algae—explain 73% of the observed spatial variability in albedo and are responsible for the dark zone itself. Crevassing and supraglacial water also drive albedo reduction but due to their limited extent, explain just 12 and 15% of the observed variability respectively. Cryoconite, concentrated in large holes or fluvial deposits, is the darkest surface type but accounts for <1% of the area and has minimal impact. We propose that the ongoing emergence and dispersal of distributed impurities, amplified by enhanced ablation and biological activity, will drive future expansion of Greenland's dark zone. Introduction The Greenland Ice Sheet has become the largest cryospheric contributor to global sea-level rise predominantly through increased surface melt and runoff, which accounts for over half of its mass loss since 1991 1 , 2 , 3 , 4 . The dominant energy source for snow and ice melt is direct solar shortwave radiation, the absorption and reflection of which is predominantly modulated by surface albedo 5 , 6 , 7 . Accurately constraining spatiotemporal patterns of albedo across the ice sheet is hence fundamental to understanding and predicting surface melt and runoff along with their impact on ice sheet flow dynamics and sea-level rise. A conspicuous feature of Greenland’s ablation area is its dark zone, an area of bare ice with particularly low albedo that appears across the west and southwest sectors of the ice sheet each summer 8 , 9 , 10 . At the Arctic Circle, in the vicinity of the Kangerlussuaq (K-) sector, the dark zone extends between 20 and 75 km from the land-terminating margin where Moderate Resolution Imaging Spectroradiometer (MODIS) data indicate a regional albedo minimum of ~0.34 8 . From 2000 to 2012, the spatial extent of the dark zone increased by 12% but also exhibited considerable interannual variability 11 , 12 . The extent of the dark zone is weakly positively correlated with air temperature and negatively correlated with solar radiation during June, July and August (JJA) 11 , 12 . This suggests that the ongoing albedo decrease observed during the melt season is not simply driven by melting of the winter snowpack to reveal the darker bare ice surface beneath, but, following exposure, there are changes in the nature of the bare ice itself 11 , 12 . However, the surface characteristics of the dark zone remain unquantified because the spatial resolution of satellite imagery is insufficient to fully resolve the specific surface types that comprise it, and how these surfaces evolve through time, distinguishing the dark zone from brighter ice surfaces adjacent to it. Previous field-based, in situ observations indicate that western Greenland’s ablation zone is characterized by highly variable non-ice constituents and surface structures 8 , 13 , 14 , 15 . These include features such as crevasses, fractures and foliations 16 , 17 ; supraglacial hydrological features, including streams, rivers, ponds and lakes 18 , 19 ; snow patches and fracture cornices; cryoconite, concentrated in holes or in supraglacial fluvial deposits 20 , 21 ; microbes and their humic by-products 22 , 23 , 24 ; mineral dust and aerosols from outcropping or contemporary aeolian deposition including black carbon from wildfires 10 , 25 , 26 and other aerosols. While the highest resolution optical satellite imagery currently available has facilitated the examination of crevasse fields 16 and surficial hydrology 19 , a quantitative assessment of the specific ice surface types that comprise the dark zone, and how they combine to yield observed albedo patterns across the ablation zone of the ice sheet, has yet to be made. Here, we utilize high-resolution (15 cm pixel size) imagery acquired from an unmanned aerial vehicle (UAV) to characterize the specific ice surfaces across the dark zone and determine their impact on the mesoscale (1–10 km) albedo distribution during peak melt season, as represented by the MODIS albedo product, MOD10A1. On 8 August 2014, a fixed-wing UAV equipped with a digital camera and upward and downward facing pyranometers was deployed from a field camp based in the vicinity of the K-transect, S6 automated weather station (AWS) on a 25 km east-west transect dissecting the dark zone (Fig. 1 ). Seven distinct surface types were visually identified on the ground by an expert and automatically classified based on their reflectance and roughness properties. The survey transect was divided into sixty 500 × 500 m segments, co-located to the footprints of corresponding MODIS pixels, and the fractional area of each surface type in each segment was determined using a supervised k-nearest neighbours (k-NN) classification (see Methods section: Surface Classification for more information) (Figs. 1 , 2 ). Finally, the mean albedo of each surface type was derived from the digital imagery and the relative contribution of different surface types to mesoscale albedo variability (defined by MOD10A1 pixels) was calculated using principal component regression (PCR). Fig. 1 Overview map showing location of UAV survey transect. The background is a Landsat 8 Operational Land Imager (OLI) true colour image of the Kangerlussuaq sector of the Greenland Ice Sheet from 6 August 2014. The transect was divided into sixty 0.25 km 2 segments for comparison with the MODIS albedo product, MOD10A1. High-resolution aerial imagery and surface classification of six segments (coloured red) are shown in Figs. 5 and 6 Full size image Fig. 2 Schematic summarizing the aims of the study. Aerial digital imagery are used to characterize the surface types that are found in the ablation zone and assess their impact on mesoscale spatial albedo patterns as represented by MODIS Full size image Results Surface type variation along the transect Analysis of all UAV imagery allowed us", "role": "user" }, { "content": "The Dark Zone of Greenland ice sheet is a large continuous region on the western flank of the ice sheet; it is some 400 kilometers wide stretching about 100 kilometres up from the margin of the ice. Some previous theories have attributed this darkening to water on top of the ice sheet – often seen as strikingly sapphire blue ponds, rivers and lakes. But a new study in Nature Communications provides a new hypothesis based on the character of the impurities on the ice surface itself. \"What we show is that the Dark Zone is covered in a finely distributed layer of dust, and black carbon, which provide nutrition for dark coloured algae. These are the main cause of the darkening.\" says professor Alun Hubbard, the co-author of the study and professor at CAGE—Centre for Arctic Gas Hydrate, Environment and Climate at UiT The Arctic University of Norway. A dirt belt in the melt zone The Dark Zone is a literally dirty belt of the melting area – the ablation zone – of the ice sheet. The darker this ablation zone is, the more of the sun's energy it absorbs, and the faster the ice melts. Albedo is a measure of the reflectance of the ice sheet. It is the major factor governing how much incoming solar radiation is used to melt the ice and is the main positive feedback in Arctic climate change. Bright white surfaces, like snow or pure ice, reflect the sun's energy, but dark surfaces absorb it. \"The fact that a large portion of the western flank of the Greenland ice sheet has become dark means that the melt is up to five times as much as if it was a brilliant snow surface. \" says Hubbard. Algae – a major player The ice algae seem to be one of the major players in this scheme – even the slight increase of the atmospheric temperature and liquid water production seems to promote algae colonization across the ice surface. \"The algae need nutrients and food, essentially dust, organic carbon, and water. In summer, these are plentiful and the algal bloom takes off. Because algae are dark in colour – they reinforce the dark zone. Thereby you get a positive feedback effect where the ice sheet absorbs even more solar radiation producing yet more melt.\" Innovative drone study The Dark Zone of the Greenland ice sheet is vast and previously observed by satellites such as MODIS. But for this study the scientists employed relatively modest drones – or unmanned aerial vehicles (UAV) – to survey the darkened ice belt in unprecedented detail. While satellite data are great for the big picture of what's happening across the entire Greenland ice sheet, they only work at really coarse pixel resolutions. \"If we compare it to camera pixels, even the best satellites for the ice sheet imaging have resolution of tens of metres. They can't see the detail of what's happening on the ground. Our fixed-wing UAVs can take hundreds of images with pixel resolutions on the centimeter scale with an operating range of hundreds of kilometres.\" says Hubbard. Scientists could see in real detail what the dark zone is made up of. In effect, this UAV survey across the ablation zone of the ice sheet perfectly bridges the gap between people on the ground studying what's under their feet in just one part of the ice sheet, and the satellite data that shows what's going on across the entire ice sheet. \"The UAV survey, with its amazing detail, allows us to identify and characterize all the different surface types and impurities across the entire dark zone, not just a small local little part of it.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Albedo—a primary control on surface melt—varies considerably across the Greenland Ice Sheet yet the specific surface types that comprise its dark zone remain unquantified. Here we use UAV imagery to attribute seven distinct surface types to observed albedo along a 25 km transect dissecting the western, ablating sector of the ice sheet. Our results demonstrate that distributed surface impurities—an admixture of dust, black carbon and pigmented algae—explain 73% of the observed spatial variability in albedo and are responsible for the dark zone itself. Crevassing and supraglacial water also drive albedo reduction but due to their limited extent, explain just 12 and 15% of the observed variability respectively. Cryoconite, concentrated in large holes or fluvial deposits, is the darkest surface type but accounts for <1% of the area and has minimal impact. We propose that the ongoing emergence and dispersal of distributed impurities, amplified by enhanced ablation and biological activity, will drive future expansion of Greenland's dark zone. Introduction The Greenland Ice Sheet has become the largest cryospheric contributor to global sea-level rise predominantly through increased surface melt and runoff, which accounts for over half of its mass loss since 1991 1 , 2 , 3 , 4 . The dominant energy source for snow and ice melt is direct solar shortwave radiation, the absorption and reflection of which is predominantly modulated by surface albedo 5 , 6 , 7 . Accurately constraining spatiotemporal patterns of albedo across the ice sheet is hence fundamental to understanding and predicting surface melt and runoff along with their impact on ice sheet flow dynamics and sea-level rise. A conspicuous feature of Greenland’s ablation area is its dark zone, an area of bare ice with particularly low albedo that appears across the west and southwest sectors of the ice sheet each summer 8 , 9 , 10 . At the Arctic Circle, in the vicinity of the Kangerlussuaq (K-) sector, the dark zone extends between 20 and 75 km from the land-terminating margin where Moderate Resolution Imaging Spectroradiometer (MODIS) data indicate a regional albedo minimum of ~0.34 8 . From 2000 to 2012, the spatial extent of the dark zone increased by 12% but also exhibited considerable interannual variability 11 , 12 . The extent of the dark zone is weakly positively correlated with air temperature and negatively correlated with solar radiation during June, July and August (JJA) 11 , 12 . This suggests that the ongoing albedo decrease observed during the melt season is not simply driven by melting of the winter snowpack to reveal the darker bare ice surface beneath, but, following exposure, there are changes in the nature of the bare ice itself 11 , 12 . However, the surface characteristics of the dark zone remain unquantified because the spatial resolution of satellite imagery is insufficient to fully resolve the specific surface types that comprise it, and how these surfaces evolve through time, distinguishing the dark zone from brighter ice surfaces adjacent to it. Previous field-based, in situ observations indicate that western Greenland’s ablation zone is characterized by highly variable non-ice constituents and surface structures 8 , 13 , 14 , 15 . These include features such as crevasses, fractures and foliations 16 , 17 ; supraglacial hydrological features, including streams, rivers, ponds and lakes 18 , 19 ; snow patches and fracture cornices; cryoconite, concentrated in holes or in supraglacial fluvial deposits 20 , 21 ; microbes and their humic by-products 22 , 23 , 24 ; mineral dust and aerosols from outcropping or contemporary aeolian deposition including black carbon from wildfires 10 , 25 , 26 and other aerosols. While the highest resolution optical satellite imagery currently available has facilitated the examination of crevasse fields 16 and surficial hydrology 19 , a quantitative assessment of the specific ice surface types that comprise the dark zone, and how they combine to yield observed albedo patterns across the ablation zone of the ice sheet, has yet to be made. Here, we utilize high-resolution (15 cm pixel size) imagery acquired from an unmanned aerial vehicle (UAV) to characterize the specific ice surfaces across the dark zone and determine their impact on the mesoscale (1–10 km) albedo distribution during peak melt season, as represented by the MODIS albedo product, MOD10A1. On 8 August 2014, a fixed-wing UAV equipped with a digital camera and upward and downward facing pyranometers was deployed from a field camp based in the vicinity of the K-transect, S6 automated weather station (AWS) on a 25 km east-west transect dissecting the dark zone (Fig. 1 ). Seven distinct surface types were visually identified on the ground by an expert and automatically classified based on their reflectance and roughness properties. The survey transect was divided into sixty 500 × 500 m segments, co-located to the footprints of corresponding MODIS pixels, and the fractional area of each surface type in each segment was determined using a supervised k-nearest neighbours (k-NN) classification (see Methods section: Surface Classification for more information) (Figs. 1 , 2 ). Finally, the mean albedo of each surface type was derived from the digital imagery and the relative contribution of different surface types to mesoscale albedo variability (defined by MOD10A1 pixels) was calculated using principal component regression (PCR). Fig. 1 Overview map showing location of UAV survey transect. The background is a Landsat 8 Operational Land Imager (OLI) true colour image of the Kangerlussuaq sector of the Greenland Ice Sheet from 6 August 2014. The transect was divided into sixty 0.25 km 2 segments for comparison with the MODIS albedo product, MOD10A1. High-resolution aerial imagery and surface classification of six segments (coloured red) are shown in Figs. 5 and 6 Full size image Fig. 2 Schematic summarizing the aims of the study. Aerial digital imagery are used to characterize the surface types that are found in the ablation zone and assess their impact on mesoscale spatial albedo patterns as represented by MODIS Full size image Results Surface type variation along the transect Analysis of all UAV imagery allowed us<|im_end|> <|im_start|>assistant The Dark Zone of Greenland ice sheet is a large continuous region on the western flank of the ice sheet; it is some 400 kilometers wide stretching about 100 kilometres up from the margin of the ice. Some previous theories have attributed this darkening to water on top of the ice sheet – often seen as strikingly sapphire blue ponds, rivers and lakes. But a new study in Nature Communications provides a new hypothesis based on the character of the impurities on the ice surface itself. "What we show is that the Dark Zone is covered in a finely distributed layer of dust, and black carbon, which provide nutrition for dark coloured algae. These are the main cause of the darkening." says professor Alun Hubbard, the co-author of the study and professor at CAGE—Centre for Arctic Gas Hydrate, Environment and Climate at UiT The Arctic University of Norway. A dirt belt in the melt zone The Dark Zone is a literally dirty belt of the melting area – the ablation zone – of the ice sheet. The darker this ablation zone is, the more of the sun's energy it absorbs, and the faster the ice melts. Albedo is a measure of the reflectance of the ice sheet. It is the major factor governing how much incoming solar radiation is used to melt the ice and is the main positive feedback in Arctic climate change. Bright white surfaces, like snow or pure ice, reflect the sun's energy, but dark surfaces absorb it. "The fact that a large portion of the western flank of the Greenland ice sheet has become dark means that the melt is up to five times as much as if it was a brilliant snow surface. " says Hubbard. Algae – a major player The ice algae seem to be one of the major players in this scheme – even the slight increase of the atmospheric temperature and liquid water production seems to promote algae colonization across the ice surface. "The algae need nutrients and food, essentially dust, organic carbon, and water. In summer, these are plentiful and the algal bloom takes off. Because algae are dark in colour – they reinforce the dark zone. Thereby you get a positive feedback effect where the ice sheet absorbs even more solar radiation producing yet more melt." Innovative drone study The Dark Zone of the Greenland ice sheet is vast and previously observed by satellites such as MODIS. But for this study the scientists employed relatively modest drones – or unmanned aerial vehicles (UAV) – to survey the darkened ice belt in unprecedented detail. While satellite data are great for the big picture of what's happening across the entire Greenland ice sheet, they only work at really coarse pixel resolutions. "If we compare it to camera pixels, even the best satellites for the ice sheet imaging have resolution of tens of metres. They can't see the detail of what's happening on the ground. Our fixed-wing UAVs can take hundreds of images with pixel resolutions on the centimeter scale with an operating range of hundreds of kilometres." says Hubbard. Scientists could see in real detail what the dark zone is made up of. In effect, this UAV survey across the ablation zone of the ice sheet perfectly bridges the gap between people on the ground studying what's under their feet in just one part of the ice sheet, and the satellite data that shows what's going on across the entire ice sheet. "The UAV survey, with its amazing detail, allows us to identify and characterize all the different surface types and impurities across the entire dark zone, not just a small local little part of it." <|im_end|>

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128257, 198 ]

2,088

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Ex vivo manufactured red blood cells (RBC) generated from immortalized erythroid cell lines which can continuously grow are expected to become a significant alternative in future transfusion therapies. The ectopic expression of human papilloma virus (HPV) E6/E7 gene has successfully been employed to establish these cell lines. To induce differentiation and maturation of the immortalized cell lines, terminating the HPV-E6/E7 expression through a gene induction system has been believed to be essential. Here, we report that erythroid cell lines established from human bone marrow using simple expression of HPV-E6/E7 are capable of normal erythroid differentiation, without turning gene expression off. Through simply changing cell culture conditions, a newly established cell line, Erythroid Line from Lund University (ELLU), is able to differentiate toward mature cells, including enucleated reticulocytes. ELLU is heterogeneous and, unexpectedly, clones expressing adult hemoglobin rapidly differentiate and produce fragile cells. Upon differentiation, other ELLU clones shift from fetal to adult hemoglobin expression, giving rise to more mature cells. Our findings propose that it is not necessary to employ gene induction systems to establish immortalized erythroid cell lines sustaining differentiation potential and describe novel cellular characteristics for desired functionally competent clones. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction The large-scale ex vivo production of red blood cells (RBCs) has been maybe a future alternative approach to provide enormous numbers of RBCs, thus solving the problem of shortage of blood supply in transfusion therapies [ 1 , 2 ]. Immortalized human erythroid cell lines are one of the most promising sources with the potential to achieve such a large-scale RBC production. A major advantage of using these cell lines is that they are already committed to the erythroid lineage, thereby requiring only a few steps to differentiate toward mature RBCs. E6 and E7 proteins of high-risk Human papilloma virus (HPV), such as HPV16, immortalize cells through transactivating pRb and degrading p53 proteins [ 3 ]. By ectopically expressing HPV-E6/E7 gene in CD36 + or CD34 + hematopoietic cells derived from various sources, immortalized human erythroid cell lines have successfully been established [ 4 , 5 , 6 , 7 ]. These cell lines grow continuously, express erythroid specific cell surface markers (e.g., Glycophorin-A), and synthesize functional hemoglobin, and some are capable of giving rise to enucleated reticulocytes [ 5 , 6 , 7 , 8 ]. It has been assumed that to induce maturation of these cells, HPV-E6/E7 genes must be shut down using a gene induction system such as Tet-On system [ 5 , 6 , 7 ], in the absence of treatment with specific histone deacetylase inhibitors (HDACi) [ 8 ]. However, in the case of two cell lines, we have previously generated (Human Umbilical Cord Blood-Derived Erythroid Progenitor: HUDEP, and Human iPS cell-Derived Erythroid Progenitor: HiDEP) [ 5 ], the termination of HPV-E6/E7 gene by removing doxycycline significantly reduced cell viability and the resulting yield of enucleated cells was very low. Thus, shutting HPV-E6/E7 expression down might be a double-edged sword for the differentiation of erythroid cell lines. However, the necessity of terminating HPV-E6/E7 to induce differentiation has not been verified. Here, we report the establishment of a new immortalized erythroid cell line from human bone marrow by a simple expression of HPV-E6/E7. The new cell line, Erythroid Line from Lund University (ELLU), can differentiate into more mature cells, including enucleated cells, without terminating HPV-E6/E7 expression. Although ELLU clones are all derived from the same source, variability is found between clones in their erythroid traits and properties. Diverse hemoglobin expression is observed and, unexpectedly, clones expressing high adult hemoglobin (HBB) rapidly differentiate to mature cells; however, viability of generated cells quickly reduced. In contrast, clones expressing high fetal hemoglobin (HBG1) and low levels of HBB under maintenance conditions differentiate slowly. However, upon differentiation, these cells start expressing HBB and give rise to relatively more stable mature cells. Our findings propose an alternative, simpler method of establishing immortalized erythroid cell lines. In addition, we demonstrate the functional diversity of established clones, potentially correlated to hemoglobin expression. Materials and methods Vector HPV16-E6/E7 gene was subcloned into CSII-EF-RfA-IRES2-Venus plasmid vector (provided by the Gene Engineering Division, RIKEN BioResource Research Center through the National BioResource Project of the MEXT/AMED, Japan) to produce CSII-EF-HPV16-E6/E7-IRES2-Venus. Lentiviruses were produced by co-transfecting 293T cells with CSII-EF-HPV16-E6/E7-IRES2-Venus, pCAG-HIVgp and pCMV-VSV-G-RSC-Rev plasmid vectors. Produced lentiviruses were then ultracentrifuged to produce concentrated viral solution. Establishment of ELLU Human bone marrow was donated from a healthy donor with a written informed consent. Mononuclear cells were isolated using Lymphoprep™ solution (Alere Technologies AS) from the bone marrow. CD34 + cells were purified using CD34 MicroBead Kit (Miltenyi). CD34 + cells were cultured in 1° medium [StemSpan™ SFEM (SFEM) supplemented with 6 IU/ml erythropoietin (EPO), 50 ng/ml human stem cell factor (SCF), and 50 ng/ml human interleukin-3 (IL-3)] for 24 h, and then, lentiviral vectors for HPV16-E6/E7 expression were added. After 24 h incubation, cells were washed and transferred into a culture dish containing 2° medium [SFEM supplemented with 50 ng/ml SCF, 6 IU/ml EPO, and 10 –6 M dexamethasone (DEX)]. After 2 weeks of culture, EPO concentration was reduced to 3 IU/ml. Cells were then cultured for more than 90 days with regular passaging. After 11 month culture that was considered to be beyond the Hayflick’s limit, cells were then single cell sorted and each clone was individually cultured. To induce differentiation, ELLU clones were transferred to a differentiation medium, consisting of SFEM supplemented with 6 IU EPO and 500 μg/ml holo-transferrin (Sigma-Aldrich). Cell line and cell culture HiDEP-1 (HiDEP) and HUDEP-2 (HUDEP) were obtained from the RIKEN Cell Bank (Tsukuba, Ibaraki, Japan), and maintained in SFEM supplemented with 1% penicillin/streptomycin (Invitrogen), 3 IU/ml erythropoietin (EPO), 1 μM dexamethasone (Sigma-Aldrich), and 1 μg/ml doxycycline (Dox, Sigma-Aldrich). Cells were maintained in normoxic (21% O 2 ) incubator with 5% CO 2 at 37 °C. To improve cell viability during differentiation, 5% of human serum (Sigma-Aldrich) was added.", "role": "user" }, { "content": "Recently developed cell line is a potential source for generating endless amounts of red blood cells outside the body. A collaborative research team from Kumamoto University (Japan), the Japanese Red Cross Society and Lund University (Sweden), has established a new cell line from human adult bone marrow that can grow infinitely and differentiate toward red blood cells (RBCs). This cell line has the potential to contribute to future transfusion therapies. Transfusion is an essential clinical treatment for treating dozens, if not hundreds, of maladies and medical procedures ranging from anemia to surgical operations. Currently, the transfusion system relies heavily on blood donated from volunteers. However, the number of donors is inadequate and has been decreasing yearly even though the requirements for transfusions constantly remains high. In particular, less common blood types are always at a risk of shortage. Furthermore, contamination of donated blood (by viral infection or other factors) further reduces availability. To solve these burdens, producing RBCs outside of the body has been considered an alternative to increase the blood supply available for transfusion. Industrially produced RBCs are clean, and their production can be controlled to stably provide desired blood types. It is important to note that RBCs are the most abundant type of cell (>80% of all cells) in the body. Thus, sources that are able to continuously provide enormous amounts of RBCs are required. Immortalized cell lines that can limitlessly proliferate and generate RBCs are therefore expected to become significant alternatives to compensate a serious blood supply shortage for therapies that require transfusion. Hematopoietic stem cells isolated from various sources such as bone marrow and umbilical cord blood are differentiated to erythroblasts, immature red blood cells that still hold a nucleus. These cells are then transduced with virus expressing HPV-E6/E7 to be immortalized. Established cell lines can be easily maintained and expanded infinitely. At a desired time, those cells are placed into a different culture condition to mature toward RBCs, which are then used for transfusion. Credit: Kumamoto University It is here where the research team headed by Prof. Miharada from Kumamoto University succeeded in establishing a new RBC generating cell line. Their creation, which they named Erythroid Line from Lund University (ELLU), was developed from isolated human bone marrow cells (CD34+ hematopoietic stem and progenitor cells) and can grow infinitely and differentiate into RBCs. The researchers previously established cell lines using erythroid cells differentiated from human umbilical cord blood CD34+ cells and human induced pluripotent stem (iPS) cells, both of which contain fetal (γ) globin. However, cells having adult (β) globin are more desired for use in transfusion therapies. Maturation of an immortalized human erythroid cell line, ELLU, toward an enucleated reticulocyte. ELLU was established by ectopic expression of HPV-E6/E7 genes, and it wasn’t necessary to turn-off expression of those genes but rather change the culture conditions to trigger the differentiation toward mature cells. In this image, a number of ELLU cells at various stages of differentiation can be seen. Credit: Ms. Svetlana Soboleva Previously, human papillomavirus (HPV) E6/E7 genes are frequently used to immortalize cells. It has been believed that turning off the HPV-E6/E7 is essential when the cells begin differentiation to RBCs. However, Prof. Miharada's team demonstrated that ELLU cells can differentiate without such a complicated system. Interestingly, ELLU cells showed considerable variation in their hemoglobin expression, with some clones expressing adult globin adult (β) globin while others mainly containing fetal (γ) globin, despite the fact that all of the cells were derived from adult bone marrow. They also unexpectedly found that clones expressing adult type hemoglobin started dying upon differentiation. In contrast however, clones with fetal hemoglobin gradually started expressing adult globin and generated more stable cells. \"We believe that our findings will contribute to simplifying the methods used to establish immortalized cell lines, and allow us to select clones that have the maximum potential for producing RBCs,\" Prof. Miharada stated. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Ex vivo manufactured red blood cells (RBC) generated from immortalized erythroid cell lines which can continuously grow are expected to become a significant alternative in future transfusion therapies. The ectopic expression of human papilloma virus (HPV) E6/E7 gene has successfully been employed to establish these cell lines. To induce differentiation and maturation of the immortalized cell lines, terminating the HPV-E6/E7 expression through a gene induction system has been believed to be essential. Here, we report that erythroid cell lines established from human bone marrow using simple expression of HPV-E6/E7 are capable of normal erythroid differentiation, without turning gene expression off. Through simply changing cell culture conditions, a newly established cell line, Erythroid Line from Lund University (ELLU), is able to differentiate toward mature cells, including enucleated reticulocytes. ELLU is heterogeneous and, unexpectedly, clones expressing adult hemoglobin rapidly differentiate and produce fragile cells. Upon differentiation, other ELLU clones shift from fetal to adult hemoglobin expression, giving rise to more mature cells. Our findings propose that it is not necessary to employ gene induction systems to establish immortalized erythroid cell lines sustaining differentiation potential and describe novel cellular characteristics for desired functionally competent clones. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction The large-scale ex vivo production of red blood cells (RBCs) has been maybe a future alternative approach to provide enormous numbers of RBCs, thus solving the problem of shortage of blood supply in transfusion therapies [ 1 , 2 ]. Immortalized human erythroid cell lines are one of the most promising sources with the potential to achieve such a large-scale RBC production. A major advantage of using these cell lines is that they are already committed to the erythroid lineage, thereby requiring only a few steps to differentiate toward mature RBCs. E6 and E7 proteins of high-risk Human papilloma virus (HPV), such as HPV16, immortalize cells through transactivating pRb and degrading p53 proteins [ 3 ]. By ectopically expressing HPV-E6/E7 gene in CD36 + or CD34 + hematopoietic cells derived from various sources, immortalized human erythroid cell lines have successfully been established [ 4 , 5 , 6 , 7 ]. These cell lines grow continuously, express erythroid specific cell surface markers (e.g., Glycophorin-A), and synthesize functional hemoglobin, and some are capable of giving rise to enucleated reticulocytes [ 5 , 6 , 7 , 8 ]. It has been assumed that to induce maturation of these cells, HPV-E6/E7 genes must be shut down using a gene induction system such as Tet-On system [ 5 , 6 , 7 ], in the absence of treatment with specific histone deacetylase inhibitors (HDACi) [ 8 ]. However, in the case of two cell lines, we have previously generated (Human Umbilical Cord Blood-Derived Erythroid Progenitor: HUDEP, and Human iPS cell-Derived Erythroid Progenitor: HiDEP) [ 5 ], the termination of HPV-E6/E7 gene by removing doxycycline significantly reduced cell viability and the resulting yield of enucleated cells was very low. Thus, shutting HPV-E6/E7 expression down might be a double-edged sword for the differentiation of erythroid cell lines. However, the necessity of terminating HPV-E6/E7 to induce differentiation has not been verified. Here, we report the establishment of a new immortalized erythroid cell line from human bone marrow by a simple expression of HPV-E6/E7. The new cell line, Erythroid Line from Lund University (ELLU), can differentiate into more mature cells, including enucleated cells, without terminating HPV-E6/E7 expression. Although ELLU clones are all derived from the same source, variability is found between clones in their erythroid traits and properties. Diverse hemoglobin expression is observed and, unexpectedly, clones expressing high adult hemoglobin (HBB) rapidly differentiate to mature cells; however, viability of generated cells quickly reduced. In contrast, clones expressing high fetal hemoglobin (HBG1) and low levels of HBB under maintenance conditions differentiate slowly. However, upon differentiation, these cells start expressing HBB and give rise to relatively more stable mature cells. Our findings propose an alternative, simpler method of establishing immortalized erythroid cell lines. In addition, we demonstrate the functional diversity of established clones, potentially correlated to hemoglobin expression. Materials and methods Vector HPV16-E6/E7 gene was subcloned into CSII-EF-RfA-IRES2-Venus plasmid vector (provided by the Gene Engineering Division, RIKEN BioResource Research Center through the National BioResource Project of the MEXT/AMED, Japan) to produce CSII-EF-HPV16-E6/E7-IRES2-Venus. Lentiviruses were produced by co-transfecting 293T cells with CSII-EF-HPV16-E6/E7-IRES2-Venus, pCAG-HIVgp and pCMV-VSV-G-RSC-Rev plasmid vectors. Produced lentiviruses were then ultracentrifuged to produce concentrated viral solution. Establishment of ELLU Human bone marrow was donated from a healthy donor with a written informed consent. Mononuclear cells were isolated using Lymphoprep™ solution (Alere Technologies AS) from the bone marrow. CD34 + cells were purified using CD34 MicroBead Kit (Miltenyi). CD34 + cells were cultured in 1° medium [StemSpan™ SFEM (SFEM) supplemented with 6 IU/ml erythropoietin (EPO), 50 ng/ml human stem cell factor (SCF), and 50 ng/ml human interleukin-3 (IL-3)] for 24 h, and then, lentiviral vectors for HPV16-E6/E7 expression were added. After 24 h incubation, cells were washed and transferred into a culture dish containing 2° medium [SFEM supplemented with 50 ng/ml SCF, 6 IU/ml EPO, and 10 –6 M dexamethasone (DEX)]. After 2 weeks of culture, EPO concentration was reduced to 3 IU/ml. Cells were then cultured for more than 90 days with regular passaging. After 11 month culture that was considered to be beyond the Hayflick’s limit, cells were then single cell sorted and each clone was individually cultured. To induce differentiation, ELLU clones were transferred to a differentiation medium, consisting of SFEM supplemented with 6 IU EPO and 500 μg/ml holo-transferrin (Sigma-Aldrich). Cell line and cell culture HiDEP-1 (HiDEP) and HUDEP-2 (HUDEP) were obtained from the RIKEN Cell Bank (Tsukuba, Ibaraki, Japan), and maintained in SFEM supplemented with 1% penicillin/streptomycin (Invitrogen), 3 IU/ml erythropoietin (EPO), 1 μM dexamethasone (Sigma-Aldrich), and 1 μg/ml doxycycline (Dox, Sigma-Aldrich). Cells were maintained in normoxic (21% O 2 ) incubator with 5% CO 2 at 37 °C. To improve cell viability during differentiation, 5% of human serum (Sigma-Aldrich) was added.<|im_end|> <|im_start|>assistant Recently developed cell line is a potential source for generating endless amounts of red blood cells outside the body. A collaborative research team from Kumamoto University (Japan), the Japanese Red Cross Society and Lund University (Sweden), has established a new cell line from human adult bone marrow that can grow infinitely and differentiate toward red blood cells (RBCs). This cell line has the potential to contribute to future transfusion therapies. Transfusion is an essential clinical treatment for treating dozens, if not hundreds, of maladies and medical procedures ranging from anemia to surgical operations. Currently, the transfusion system relies heavily on blood donated from volunteers. However, the number of donors is inadequate and has been decreasing yearly even though the requirements for transfusions constantly remains high. In particular, less common blood types are always at a risk of shortage. Furthermore, contamination of donated blood (by viral infection or other factors) further reduces availability. To solve these burdens, producing RBCs outside of the body has been considered an alternative to increase the blood supply available for transfusion. Industrially produced RBCs are clean, and their production can be controlled to stably provide desired blood types. It is important to note that RBCs are the most abundant type of cell (>80% of all cells) in the body. Thus, sources that are able to continuously provide enormous amounts of RBCs are required. Immortalized cell lines that can limitlessly proliferate and generate RBCs are therefore expected to become significant alternatives to compensate a serious blood supply shortage for therapies that require transfusion. Hematopoietic stem cells isolated from various sources such as bone marrow and umbilical cord blood are differentiated to erythroblasts, immature red blood cells that still hold a nucleus. These cells are then transduced with virus expressing HPV-E6/E7 to be immortalized. Established cell lines can be easily maintained and expanded infinitely. At a desired time, those cells are placed into a different culture condition to mature toward RBCs, which are then used for transfusion. Credit: Kumamoto University It is here where the research team headed by Prof. Miharada from Kumamoto University succeeded in establishing a new RBC generating cell line. Their creation, which they named Erythroid Line from Lund University (ELLU), was developed from isolated human bone marrow cells (CD34+ hematopoietic stem and progenitor cells) and can grow infinitely and differentiate into RBCs. The researchers previously established cell lines using erythroid cells differentiated from human umbilical cord blood CD34+ cells and human induced pluripotent stem (iPS) cells, both of which contain fetal (γ) globin. However, cells having adult (β) globin are more desired for use in transfusion therapies. Maturation of an immortalized human erythroid cell line, ELLU, toward an enucleated reticulocyte. ELLU was established by ectopic expression of HPV-E6/E7 genes, and it wasn’t necessary to turn-off expression of those genes but rather change the culture conditions to trigger the differentiation toward mature cells. In this image, a number of ELLU cells at various stages of differentiation can be seen. Credit: Ms. Svetlana Soboleva Previously, human papillomavirus (HPV) E6/E7 genes are frequently used to immortalize cells. It has been believed that turning off the HPV-E6/E7 is essential when the cells begin differentiation to RBCs. However, Prof. Miharada's team demonstrated that ELLU cells can differentiate without such a complicated system. Interestingly, ELLU cells showed considerable variation in their hemoglobin expression, with some clones expressing adult globin adult (β) globin while others mainly containing fetal (γ) globin, despite the fact that all of the cells were derived from adult bone marrow. They also unexpectedly found that clones expressing adult type hemoglobin started dying upon differentiation. In contrast however, clones with fetal hemoglobin gradually started expressing adult globin and generated more stable cells. "We believe that our findings will contribute to simplifying the methods used to establish immortalized cell lines, and allow us to select clones that have the maximum potential for producing RBCs," Prof. Miharada stated. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract R-loops are by-products of transcription that must be tightly regulated to maintain genomic stability and gene expression. Here, we describe a mechanism for the regulation of the R-loop-specific helicase, senataxin (SETX), and identify the ubiquitin specific peptidase 11 (USP11) as an R-loop regulator. USP11 de-ubiquitinates SETX and its depletion increases SETX K48-ubiquitination and protein turnover. Loss of USP11 decreases SETX steady-state levels and reduces R-loop dissolution. Ageing of USP11 knockout cells restores SETX levels via compensatory transcriptional downregulation of the E3 ubiquitin ligase, KEAP1. Loss of USP11 reduces SETX enrichment at KEAP1 promoter, leading to R-loop accumulation, enrichment of the endonuclease XPF and formation of double-strand breaks. Overexpression of KEAP1 increases SETX K48-ubiquitination, promotes its degradation and R-loop accumulation. These data define a ubiquitination-dependent mechanism for SETX regulation, which is controlled by the opposing activities of USP11 and KEAP1 with broad applications for cancer and neurological disease. Introduction DNA:RNA hybrids (R-loops) are natural byproducts of transcription. Structural studies suggest a ‘thread back model’ of R-loop formation, whereby a nascent RNA invades the DNA duplex and anneals to the template DNA strand, causing the non-template DNA strand to be left un-annealed 1 . R-loop formation is promoted over G-rich regions and at sites of RNA polymerase stalling 2 , 3 . R-loops occupy ~5% of human and mouse genomes, and are usually found over promoter and termination regions 4 . As R-loops are more thermodynamically stable than double-stranded DNA, they persist until enzymatically resolved 5 . There are positive and negative consequences of R-loops. For example, R-loops facilitate class switch recombination, transcription-associated homologous recombination and transcription termination 6 , 7 , 8 , regulate gene expression 9 and DNA methylation 10 . On the other hand, aberrant accumulation of R-loops causes genome instability 11 , 12 , 13 , 14 , 15 , 16 , 17 . Thus, a tight control of R-loop homeostasis is essential to promote their beneficial effects and avoid their deleterious consequences. Human cells possess R-loop-specific nucleases such as RNase H1, RNase H2 and R-loop-specific helicases, such as DHX9, DDX19, DDX21 and senataxin (SETX) 18 , 19 , 20 . RNA-binding proteins were also shown to prevent R-loop formation 11 , 21 . In human mitochondria, mtEXO degradosome, which contains a ribonuclease and a helicase, controls R-loop levels 22 . SETX was shown to resolve R-loops at transcription termination sites of RNA Polymerase II (RNAPII) 8 and more recently at sites of double-strand breaks 23 . The importance of SETX function is highlighted by non-sense loss-of-function mutations of SETX , which cause ataxia with oculomotor apraxia type 2, and missense gain-of-function mutations, which cause a juvenile form of amyotrophic lateral sclerosis type 4 (ALS4) 24 , 25 . The ALS4 SETX L389S variant was shown to resolve R-loops at 1200 human promoters leading to transcriptional misregulation 26 . Furthermore, we recently reported a role for SETX in cancer, by protecting cells from R-loop-mediated DNA damage in hypoxia, which is a major cause of resistance to anti-cancer therapeutics 27 . Although much is known about R-loop metabolizing enzymes, little is known about the mechanisms that regulate their homeostasis. Protein homeostasis is controlled by many processes such as ubiquitination and deubiquitination. Ubiquitination is a process of conjugating small ubiquitin peptides (8.5 kDa) to lysine residues of target proteins. As ubiquitin itself possesses lysine residues, ubiquitin chains and branches can be formed by E3 ligases and trimmed by deubiquitinases (DUBs). Ubiquitination has been shown to signal for proteasomal degradation, influence subcellular localization and alter protein–protein interactions or enzymatic activities 28 . DUBs have been shown to promote DNA damage signalling and repair mechanisms. For example, USP1 has been suggested to inhibit translesion synthesis 29 . USP47 regulates the steady-state levels of DNA polymerase-β, which is essential for base excision repair 30 . USP3 and USP16 control cell cycle progression via deubiquitination of histone 2A (H2A) 31 , 32 . UCHL3 fine tunes topoisomerase-linked DNA break repair via deubiquitination of TDP1 33 , 34 . The activity of p53 is also regulated by DUBs 35 , which further highlights the role of deubiquitination in the maintenance of genome integrity. Here we conducted an unbiased genetic screen coupled with cellular and biochemical analyses to reveal the ubiquitin-specific peptidase 11 (USP11) as an R-loop regulator via controlling SETX proteostasis. USP11-deficient cells exhibit high levels of R-loops, which are reduced by expression of wild-type but not catalytically inactive USP11. Depletion of USP11 or SETX alone increases detectable R-loops and causes hypersensitivity to topoisomerase I poisons, and depletion of both does not exacerbate the R-loop and hypersensitivity phenotypes, indicating that USP11 and SETX are in the same pathway. Consistent with this, SETX interacts with USP11 and the interaction is increased by R-loop induction in a transcription-dependent manner. Depletion of USP11 increases SETX K48-ubiquitination and degradation, which leads to accumulation of R-loops that are converted to double-strand breaks. Finally, we describe a mechanism of cellular adaptation to USP11 loss through transcriptional downregulation of the E3 ligase, KEAP1, which counteracts USP11 to maintain SETX protein levels. Results Proteasomal inhibition perturbs R-loop homeostasis R-loop homeostasis is controlled by helicases and ribonucleases; however, little is known about how R-loop-metabolizing enzymes are regulated. To examine this, we first set out to validate the specificity of the widely employed R-loop detection method using S9.6 antibodies in MRC-5 cells. Cells were incubated with the topoisomerase inhibitor camptothecin (CPT) for 10 min and S9.6 signal was examined by immunofluorescence (Fig. 1a ). The co-localization of S9.6 with α-nucleolin suggests nucleolar enrichment of R-loops (Fig. 1a ), as CPT treatment did not change the number of nucleolin foci (Supplementary Fig. 1a ). The number and intensity of nucleolar S9.6 foci increased after 10 min CPT treatment (Fig. 1b ), which is consistent with previous findings 3 , 36 . By masking the nucleolar S9.6 foci, we observed ~40% increase in nuclear S9.6 signal intensity (Fig. 1b ). The CPT-dependent increase of S9.6 signal was specific to R-loops, as it was ablated by pre-treatment", "role": "user" }, { "content": "Researchers from the University of Sheffield have discovered a new gene therapy pathway that has uncovered an important regulatory mechanism to keep our genome healthy. This pathway has the potential to protect us against serious life-limiting diseases such as cancer and dementia. Cancer and neurodegeneration are two major health challenges currently affecting the population, and they constitute two sides of the same coin - one is caused by uncontrolled cell proliferation due to genome damage, and the other is caused by excessive genome damage that causes cell death. This new pathway impacts both and offers new therapeutic opportunities to help the fight against disease. Published in Nature Communications, the research found that when cells in our body read DNA to build proteins, they often make mistakes that can damage our genome, causing disease such as cancer and dementia. However, by investigating how cells fix damage in the DNA to keep us healthy, scientists have discovered the benefits of three proteins working together as a team. The three proteins, called USP11, KEAP1 and SETX, receive instructions from their coach to direct their function in space and time with remarkable harmony, to keep our DNA healthy. By understanding how cells protect themselves from these mistakes and thus preventing diseases, scientists are able to modify the behavior of these proteins to promote the health and wellbeing of people. Findings from this study will enable scientists to develop diagnostic tests and drugs to target one or more of the proteins in the pathway for the early detection and treatment of certain types of cancer and neurological disease. Developing new drugs to regulate the level of one or more of these proteins is expected to offer new treatments for cancer and dementia. \"The findings are important and significant, this is because we are now at the stage where we could make drugs to control this modification. This would be useful in killing cells, which is what we do when we treat elderly people for cancer. The other application would be to reduce the level of genome damage, which could be beneficial for other aging associated disorders like dementia,\" says Professor Sherif El-Khamisy, Co-Founder and Deputy Director of the Healthy Lifespan Institute at the University of Sheffield and a professor from the University's School of Biosciences and the Neuroscience Institute at the University of Sheffield ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract R-loops are by-products of transcription that must be tightly regulated to maintain genomic stability and gene expression. Here, we describe a mechanism for the regulation of the R-loop-specific helicase, senataxin (SETX), and identify the ubiquitin specific peptidase 11 (USP11) as an R-loop regulator. USP11 de-ubiquitinates SETX and its depletion increases SETX K48-ubiquitination and protein turnover. Loss of USP11 decreases SETX steady-state levels and reduces R-loop dissolution. Ageing of USP11 knockout cells restores SETX levels via compensatory transcriptional downregulation of the E3 ubiquitin ligase, KEAP1. Loss of USP11 reduces SETX enrichment at KEAP1 promoter, leading to R-loop accumulation, enrichment of the endonuclease XPF and formation of double-strand breaks. Overexpression of KEAP1 increases SETX K48-ubiquitination, promotes its degradation and R-loop accumulation. These data define a ubiquitination-dependent mechanism for SETX regulation, which is controlled by the opposing activities of USP11 and KEAP1 with broad applications for cancer and neurological disease. Introduction DNA:RNA hybrids (R-loops) are natural byproducts of transcription. Structural studies suggest a ‘thread back model’ of R-loop formation, whereby a nascent RNA invades the DNA duplex and anneals to the template DNA strand, causing the non-template DNA strand to be left un-annealed 1 . R-loop formation is promoted over G-rich regions and at sites of RNA polymerase stalling 2 , 3 . R-loops occupy ~5% of human and mouse genomes, and are usually found over promoter and termination regions 4 . As R-loops are more thermodynamically stable than double-stranded DNA, they persist until enzymatically resolved 5 . There are positive and negative consequences of R-loops. For example, R-loops facilitate class switch recombination, transcription-associated homologous recombination and transcription termination 6 , 7 , 8 , regulate gene expression 9 and DNA methylation 10 . On the other hand, aberrant accumulation of R-loops causes genome instability 11 , 12 , 13 , 14 , 15 , 16 , 17 . Thus, a tight control of R-loop homeostasis is essential to promote their beneficial effects and avoid their deleterious consequences. Human cells possess R-loop-specific nucleases such as RNase H1, RNase H2 and R-loop-specific helicases, such as DHX9, DDX19, DDX21 and senataxin (SETX) 18 , 19 , 20 . RNA-binding proteins were also shown to prevent R-loop formation 11 , 21 . In human mitochondria, mtEXO degradosome, which contains a ribonuclease and a helicase, controls R-loop levels 22 . SETX was shown to resolve R-loops at transcription termination sites of RNA Polymerase II (RNAPII) 8 and more recently at sites of double-strand breaks 23 . The importance of SETX function is highlighted by non-sense loss-of-function mutations of SETX , which cause ataxia with oculomotor apraxia type 2, and missense gain-of-function mutations, which cause a juvenile form of amyotrophic lateral sclerosis type 4 (ALS4) 24 , 25 . The ALS4 SETX L389S variant was shown to resolve R-loops at 1200 human promoters leading to transcriptional misregulation 26 . Furthermore, we recently reported a role for SETX in cancer, by protecting cells from R-loop-mediated DNA damage in hypoxia, which is a major cause of resistance to anti-cancer therapeutics 27 . Although much is known about R-loop metabolizing enzymes, little is known about the mechanisms that regulate their homeostasis. Protein homeostasis is controlled by many processes such as ubiquitination and deubiquitination. Ubiquitination is a process of conjugating small ubiquitin peptides (8.5 kDa) to lysine residues of target proteins. As ubiquitin itself possesses lysine residues, ubiquitin chains and branches can be formed by E3 ligases and trimmed by deubiquitinases (DUBs). Ubiquitination has been shown to signal for proteasomal degradation, influence subcellular localization and alter protein–protein interactions or enzymatic activities 28 . DUBs have been shown to promote DNA damage signalling and repair mechanisms. For example, USP1 has been suggested to inhibit translesion synthesis 29 . USP47 regulates the steady-state levels of DNA polymerase-β, which is essential for base excision repair 30 . USP3 and USP16 control cell cycle progression via deubiquitination of histone 2A (H2A) 31 , 32 . UCHL3 fine tunes topoisomerase-linked DNA break repair via deubiquitination of TDP1 33 , 34 . The activity of p53 is also regulated by DUBs 35 , which further highlights the role of deubiquitination in the maintenance of genome integrity. Here we conducted an unbiased genetic screen coupled with cellular and biochemical analyses to reveal the ubiquitin-specific peptidase 11 (USP11) as an R-loop regulator via controlling SETX proteostasis. USP11-deficient cells exhibit high levels of R-loops, which are reduced by expression of wild-type but not catalytically inactive USP11. Depletion of USP11 or SETX alone increases detectable R-loops and causes hypersensitivity to topoisomerase I poisons, and depletion of both does not exacerbate the R-loop and hypersensitivity phenotypes, indicating that USP11 and SETX are in the same pathway. Consistent with this, SETX interacts with USP11 and the interaction is increased by R-loop induction in a transcription-dependent manner. Depletion of USP11 increases SETX K48-ubiquitination and degradation, which leads to accumulation of R-loops that are converted to double-strand breaks. Finally, we describe a mechanism of cellular adaptation to USP11 loss through transcriptional downregulation of the E3 ligase, KEAP1, which counteracts USP11 to maintain SETX protein levels. Results Proteasomal inhibition perturbs R-loop homeostasis R-loop homeostasis is controlled by helicases and ribonucleases; however, little is known about how R-loop-metabolizing enzymes are regulated. To examine this, we first set out to validate the specificity of the widely employed R-loop detection method using S9.6 antibodies in MRC-5 cells. Cells were incubated with the topoisomerase inhibitor camptothecin (CPT) for 10 min and S9.6 signal was examined by immunofluorescence (Fig. 1a ). The co-localization of S9.6 with α-nucleolin suggests nucleolar enrichment of R-loops (Fig. 1a ), as CPT treatment did not change the number of nucleolin foci (Supplementary Fig. 1a ). The number and intensity of nucleolar S9.6 foci increased after 10 min CPT treatment (Fig. 1b ), which is consistent with previous findings 3 , 36 . By masking the nucleolar S9.6 foci, we observed ~40% increase in nuclear S9.6 signal intensity (Fig. 1b ). The CPT-dependent increase of S9.6 signal was specific to R-loops, as it was ablated by pre-treatment<|im_end|> <|im_start|>assistant Researchers from the University of Sheffield have discovered a new gene therapy pathway that has uncovered an important regulatory mechanism to keep our genome healthy. This pathway has the potential to protect us against serious life-limiting diseases such as cancer and dementia. Cancer and neurodegeneration are two major health challenges currently affecting the population, and they constitute two sides of the same coin - one is caused by uncontrolled cell proliferation due to genome damage, and the other is caused by excessive genome damage that causes cell death. This new pathway impacts both and offers new therapeutic opportunities to help the fight against disease. Published in Nature Communications, the research found that when cells in our body read DNA to build proteins, they often make mistakes that can damage our genome, causing disease such as cancer and dementia. However, by investigating how cells fix damage in the DNA to keep us healthy, scientists have discovered the benefits of three proteins working together as a team. The three proteins, called USP11, KEAP1 and SETX, receive instructions from their coach to direct their function in space and time with remarkable harmony, to keep our DNA healthy. By understanding how cells protect themselves from these mistakes and thus preventing diseases, scientists are able to modify the behavior of these proteins to promote the health and wellbeing of people. Findings from this study will enable scientists to develop diagnostic tests and drugs to target one or more of the proteins in the pathway for the early detection and treatment of certain types of cancer and neurological disease. Developing new drugs to regulate the level of one or more of these proteins is expected to offer new treatments for cancer and dementia. "The findings are important and significant, this is because we are now at the stage where we could make drugs to control this modification. This would be useful in killing cells, which is what we do when we treat elderly people for cancer. The other application would be to reduce the level of genome damage, which could be beneficial for other aging associated disorders like dementia," says Professor Sherif El-Khamisy, Co-Founder and Deputy Director of the Healthy Lifespan Institute at the University of Sheffield and a professor from the University's School of Biosciences and the Neuroscience Institute at the University of Sheffield <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract DOI Classify Address Funds Advanced Search ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' Journal Information ngIf: newsColumn.subColumns.length > 0 ngIf: newsColumn.abbreviation == 'journals' ngIf: newsColumn.subColumns.length > 0 end ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' For Authors ngIf: newsColumn.subColumns.length > 0 ngIf: newsColumn.abbreviation == 'journals' ngIf: newsColumn.subColumns.length > 0 end ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' For Referees ngIf: newsColumn.subColumns.length > 0 ngIf: newsColumn.abbreviation == 'journals' ngIf: newsColumn.subColumns.length > 0 end ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus E-mail Alert RSS 手机菜单 Opto-Electronic Advances <img src=\"/style/web/images/logo-new_03.png\" alt=\"\"> Advanced Search ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' Journal Information <ol class=\"data-show i-menu-journals\" ng-if=\"newsColumn.abbreviation == 'journals'\"></ol> <ol class=\"data-show\" ng-controller=\"j-content-journals\" ng-if=\"newsColumn.abbreviation == 'journals'\"> <li ng-repeat=\"journal in journalTypes\" > <a ng-if=\"journal.linkedWebsite != null && journal.linkedWebsite !=''\" href=\"{{journal.linkedWebsite}}\" target=\"_blank\"> {{journal.titleEn}} </a> <a ng-if=\"journal.dblLanguage != 1 && journal.language == 'cn' && (journal.linkedWebsite == null || journal.linkedWebsite =='')\" href=\" {{journal.titleEn}} </a> <a ng-if=\"journal.dblLanguage != 1 && journal.language == 'en' && (journal.linkedWebsite == null || journal.linkedWebsite =='')\" href=\" {{journal.titleEn}} </a> <a ng-if=\"journal.dblLanguage == 1 && (journal.linkedWebsite == null || journal.linkedWebsite =='')\" href=\"/{{journal.publisherId}}\"> {{journal.titleEn}} </a> </li> </ol> ngIf: newsColumn.subColumns.length > 0 end ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' For Authors <ol class=\"data-show i-menu-journals\" ng-if=\"newsColumn.abbreviation == 'journals'\"></ol> <ol class=\"data-show\" ng-controller=\"j-content-journals\" ng-if=\"newsColumn.abbreviation == 'journals'\"> <li ng-repeat=\"journal in journalTypes\" > <a ng-if=\"journal.linkedWebsite != null && journal.linkedWebsite !=''\" href=\"{{journal.linkedWebsite}}\" target=\"_blank\"> {{journal.titleEn}} </a> <a ng-if=\"journal.dblLanguage != 1 && journal.language == 'cn' && (journal.linkedWebsite == null || journal.linkedWebsite =='')\" href=\" {{journal.titleEn}} </a> <a ng-if=\"journal.dblLanguage != 1 && journal.language == 'en' && (journal.linkedWebsite == null || journal.linkedWebsite =='')\" href=\" {{journal.titleEn}} </a> <a ng-if=\"journal.dblLanguage == 1 && (journal.linkedWebsite == null || journal.linkedWebsite =='')\" href=\"/{{journal.publisherId}}\"> {{journal.titleEn}} </a> </li> </ol> ngIf: newsColumn.subColumns.length > 0 end ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' For Referees <ol class=\"data-show i-menu-journals\" ng-if=\"newsColumn.abbreviation == 'journals'\"></ol> <ol class=\"data-show\" ng-controller=\"j-content-journals\" ng-if=\"newsColumn.abbreviation == 'journals'\"> <li ng-repeat=\"journal in journalTypes\" > <a ng-if=\"journal.linkedWebsite != null && journal.linkedWebsite !=''\" href=\"{{journal.linkedWebsite}}\" target=\"_blank\"> {{journal.titleEn}} </a> <a ng-if=\"journal.dblLanguage != 1 && journal.language == 'cn' && (journal.linkedWebsite == null || journal.linkedWebsite =='')\" href=\" {{journal.titleEn}} </a> <a ng-if=\"journal.dblLanguage != 1 && journal.language == 'en' && (journal.linkedWebsite == null || journal.linkedWebsite =='')\" href=\" {{journal.titleEn}} </a> <a ng-if=\"journal.dblLanguage == 1 && (journal.linkedWebsite == null || journal.linkedWebsite =='')\" href=\"/{{journal.publisherId}}\"> {{journal.titleEn}} </a> </li> </ol> ngIf: newsColumn.subColumns.length > 0 end ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus Home 头部结束底部暂时渲染在这电脑端开始 Previous Article Next Article PDF Cite Share facebook twitter google LinkedIn weibo wechat Share the QR code with wechat scanning code to friends and circle of friends. All Title Author Keyword Abstract DOI Category Address Fund Article navigation > Opto-Electronic Advances > 2022 Vol. 5 > No. 9 > 210065 Next Article Previous Article Yu ZQ, Zhang N, Wang JX, Dai ZJ, Gong C et al. 0.35% THz pulse conversion efficiency achieved by Ti:sapphire femtosecond laser filamentation in argon at 1 kHz repetition rate. Opto-Electron Adv 5, 210065 (2022). doi: 10.29026/oea.2022.210065 Citation: Yu ZQ, Zhang N, Wang JX, Dai ZJ, Gong C et al. 0.35% THz pulse conversion efficiency achieved by Ti:sapphire femtosecond laser filamentation in argon at 1 kHz repetition rate. Opto-Electron Adv 5 , 210065 (2022). doi: 10.29026/oea.2022.210065 Original Article Open Access 0.35% THz pulse conversion efficiency achieved by Ti:sapphire femtosecond laser filamentation in argon at 1 kHz repetition rate Zhiqiang Yu 1,2,† , Nan Zhang 1,2,† , Jianxin Wang 1,2 , Zijie Dai 1,2 , Cheng Gong 1,2 , Lie Lin 1,3 , Lanjun Guo 1,2 , Weiwei Liu 1,2 , , 英文作者地址 1. Institute of Modern Optics, Nankai University, Tianjin 300350, China 2. Tianjin Key Laboratory of Micro-scale Optical Information Science and Technology, Tianjin 300350, China 3. Tianjin Key Laboratory of Optoelectronic Sensor and Sensing Network Technology, Tianjin 300350, China More Information † These authors contributed equally to this work 作者简介和通讯作者 Corresponding author: WW Liu, E-mail: [email protected] <li class=\"com-author-info\"> </li> 稿件日期和基金项目11 稿件日期 Received Date 16 May 2021 Accepted Date 27 July 2021 Available Online 27 July 2022 Published Date 25 September 2022 摘要 Abstract Abstract In this study, an optical setup for generating terahertz (THz) pulses through a two-color femtosecond laser filament was carefully designed to achieve a precise overlap of two-color laser pulses in space and time. β-barium borate (BBO), α-BBO, and a dual-wavelength plate were used to compensate the phase delay of the two-color lasers. Tilting of α-BBO could further realize the precise spatial overlap of the two beams by counteracting the walk-off effect. The maximum output THz pulse energy reached 21 μJ in argon gas when using a commercial Ti:sapphire laser with a pulse energy of 6 mJ at a 1 kHz repetition rate. The corresponding conversion efficiency exceeded 0.35%. Keywords: femtosecond laser filaments / walk-off effect / conversion efficiency 全文 FullText(HTML) 遍历章节列表输出章节标题 start Introduction The availability of terahertz (THz) waves has enabled unprecedented research on the properties of matter 1 . To achieve further control over matter and light by using THz transients, the interaction of intense femtosecond lasers with nonlinear materials 2 has received considerable research interest. THz radiations with pulse energies of 436 μJ have been generated through optical rectification in lithium niobate (LN) 3 with an energy conversion efficiency of 0.77%. Recently, the output THz pulse energy was boosted to 1.4 mJ by pumping a large-area LN crystal (80 mm× 26.5 mm) with a 214 mJ Ti:sapphire laser pulse 4 and the energy conversion efficiency is 0.65%. Furthermore, when the organic crystals 5 , 6 are used, the THz energy conversion efficiency via the optical rectification can be up to 3%. On", "role": "user" }, { "content": "A new publication from Opto-Electronic Advances considers an over 20 μJ THz laser pulse generated at 1 kHz in gas media. Terahertz (THz) science and technology has received extensive attention from scientific researchers from all around the world over the past 20 years because of its prospective application potential in security imaging, medical diagnosis, military, wireless communications and astronomy. However, the development of high-power broadband THz radiation source has been a challenging task in the above-mentioned fields. Among various THz radiation sources, THz radiation source based on femtosecond laser filament has the advantages of broadband (~200 THz), high amplitude (100 MV/cm) and no limitation of damage threshold. In addition, the THz generation method based on the femtosecond laser filamentation confines the THz wave inside the filament, which can eliminate the diffraction and absorption during the propagation of the THz wave in the atmosphere and make the remote delivery of the THz wave become possible. The THz generation scheme based on the dual-color femtosecond laser filamentation has higher energy conversion efficiency than that using single-color femtosecond laser. In this scheme, the intensity, bandwidth, polarization and other characteristics of the THz radiation can be affected by many laser parameters including the temporal delay, dispersion, polarization, wavelength, spatial departure of the dual-color fields. Even the ambient gas species play a crucial role too. In order to develop an efficient THz radiation source, all these parameters need to be carefully designed and manipulated. The research group led by Prof. Weiwei Liu from Nankai university used femtosecond laser with single pulse energy of 6 mJ to generate the dual-color laser filamentation by frequency doubling the fundamental laser via a β-BBO crystal. The dual-color laser beams achieve the perfect spatial-temporal overlap through a tilted α-BBO crystal. Meanwhile, a dual-wavelength plate was used to make the dual-color laser beams have the identical polarization. The energy of the THz pulse generated from the laser filament in argon can be up to 21 μJ and the corresponding THz conversion efficiency reaches 0.35%. In this work, the ambient gas species' influence on the THz generation efficiency by the dual-color laser filamentation was investigated experimentally. The experimental results show that the highest conversion efficiency of THz radiation is achieved in argon gas. The relationship between the tilting angle of α-BBO and the generated THz power in argon was also investigated. α-BBO with optimal tilting angle and pre-designed thickness can simultaneously compensate the time delay and spatial walk-off of the two-color laser beams, playing the critical role in improving the generation efficiency of THz wave. This research work achieved a breakthrough in the energy conversion efficiency of THz wave generated by the two-color femtosecond laser filamentation, which is of great significance for the study of high-intensity THz sources and the exploration of the interaction between strong THz beam and materials. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract DOI Classify Address Funds Advanced Search ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' Journal Information ngIf: newsColumn.subColumns.length > 0 ngIf: newsColumn.abbreviation == 'journals' ngIf: newsColumn.subColumns.length > 0 end ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' For Authors ngIf: newsColumn.subColumns.length > 0 ngIf: newsColumn.abbreviation == 'journals' ngIf: newsColumn.subColumns.length > 0 end ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' For Referees ngIf: newsColumn.subColumns.length > 0 ngIf: newsColumn.abbreviation == 'journals' ngIf: newsColumn.subColumns.length > 0 end ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus E-mail Alert RSS 手机菜单 Opto-Electronic Advances <img src="/style/web/images/logo-new_03.png" alt=""> Advanced Search ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' Journal Information <ol class="data-show i-menu-journals" ng-if="newsColumn.abbreviation == 'journals'"></ol> <ol class="data-show" ng-controller="j-content-journals" ng-if="newsColumn.abbreviation == 'journals'"> <li ng-repeat="journal in journalTypes" > <a ng-if="journal.linkedWebsite != null && journal.linkedWebsite !=''" href="{{journal.linkedWebsite}}" target="_blank"> {{journal.titleEn}} </a> <a ng-if="journal.dblLanguage != 1 && journal.language == 'cn' && (journal.linkedWebsite == null || journal.linkedWebsite =='')" href=" {{journal.titleEn}} </a> <a ng-if="journal.dblLanguage != 1 && journal.language == 'en' && (journal.linkedWebsite == null || journal.linkedWebsite =='')" href=" {{journal.titleEn}} </a> <a ng-if="journal.dblLanguage == 1 && (journal.linkedWebsite == null || journal.linkedWebsite =='')" href="/{{journal.publisherId}}"> {{journal.titleEn}} </a> </li> </ol> ngIf: newsColumn.subColumns.length > 0 end ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' For Authors <ol class="data-show i-menu-journals" ng-if="newsColumn.abbreviation == 'journals'"></ol> <ol class="data-show" ng-controller="j-content-journals" ng-if="newsColumn.abbreviation == 'journals'"> <li ng-repeat="journal in journalTypes" > <a ng-if="journal.linkedWebsite != null && journal.linkedWebsite !=''" href="{{journal.linkedWebsite}}" target="_blank"> {{journal.titleEn}} </a> <a ng-if="journal.dblLanguage != 1 && journal.language == 'cn' && (journal.linkedWebsite == null || journal.linkedWebsite =='')" href=" {{journal.titleEn}} </a> <a ng-if="journal.dblLanguage != 1 && journal.language == 'en' && (journal.linkedWebsite == null || journal.linkedWebsite =='')" href=" {{journal.titleEn}} </a> <a ng-if="journal.dblLanguage == 1 && (journal.linkedWebsite == null || journal.linkedWebsite =='')" href="/{{journal.publisherId}}"> {{journal.titleEn}} </a> </li> </ol> ngIf: newsColumn.subColumns.length > 0 end ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' For Referees <ol class="data-show i-menu-journals" ng-if="newsColumn.abbreviation == 'journals'"></ol> <ol class="data-show" ng-controller="j-content-journals" ng-if="newsColumn.abbreviation == 'journals'"> <li ng-repeat="journal in journalTypes" > <a ng-if="journal.linkedWebsite != null && journal.linkedWebsite !=''" href="{{journal.linkedWebsite}}" target="_blank"> {{journal.titleEn}} </a> <a ng-if="journal.dblLanguage != 1 && journal.language == 'cn' && (journal.linkedWebsite == null || journal.linkedWebsite =='')" href=" {{journal.titleEn}} </a> <a ng-if="journal.dblLanguage != 1 && journal.language == 'en' && (journal.linkedWebsite == null || journal.linkedWebsite =='')" href=" {{journal.titleEn}} </a> <a ng-if="journal.dblLanguage == 1 && (journal.linkedWebsite == null || journal.linkedWebsite =='')" href="/{{journal.publisherId}}"> {{journal.titleEn}} </a> </li> </ol> ngIf: newsColumn.subColumns.length > 0 end ngIf: newsColumn.columnNewsShowLocation == '1' && newsColumn.abbreviation !='journals' end ngRepeat: newsColumn in topMenus Home 头部结束底部暂时渲染在这电脑端开始 Previous Article Next Article PDF Cite Share facebook twitter google LinkedIn weibo wechat Share the QR code with wechat scanning code to friends and circle of friends. All Title Author Keyword Abstract DOI Category Address Fund Article navigation > Opto-Electronic Advances > 2022 Vol. 5 > No. 9 > 210065 Next Article Previous Article Yu ZQ, Zhang N, Wang JX, Dai ZJ, Gong C et al. 0.35% THz pulse conversion efficiency achieved by Ti:sapphire femtosecond laser filamentation in argon at 1 kHz repetition rate. Opto-Electron Adv 5, 210065 (2022). doi: 10.29026/oea.2022.210065 Citation: Yu ZQ, Zhang N, Wang JX, Dai ZJ, Gong C et al. 0.35% THz pulse conversion efficiency achieved by Ti:sapphire femtosecond laser filamentation in argon at 1 kHz repetition rate. Opto-Electron Adv 5 , 210065 (2022). doi: 10.29026/oea.2022.210065 Original Article Open Access 0.35% THz pulse conversion efficiency achieved by Ti:sapphire femtosecond laser filamentation in argon at 1 kHz repetition rate Zhiqiang Yu 1,2,† , Nan Zhang 1,2,† , Jianxin Wang 1,2 , Zijie Dai 1,2 , Cheng Gong 1,2 , Lie Lin 1,3 , Lanjun Guo 1,2 , Weiwei Liu 1,2 , , 英文作者地址 1. Institute of Modern Optics, Nankai University, Tianjin 300350, China 2. Tianjin Key Laboratory of Micro-scale Optical Information Science and Technology, Tianjin 300350, China 3. Tianjin Key Laboratory of Optoelectronic Sensor and Sensing Network Technology, Tianjin 300350, China More Information † These authors contributed equally to this work 作者简介和通讯作者 Corresponding author: WW Liu, E-mail: [email protected] <li class="com-author-info"> </li> 稿件日期和基金项目11 稿件日期 Received Date 16 May 2021 Accepted Date 27 July 2021 Available Online 27 July 2022 Published Date 25 September 2022 摘要 Abstract Abstract In this study, an optical setup for generating terahertz (THz) pulses through a two-color femtosecond laser filament was carefully designed to achieve a precise overlap of two-color laser pulses in space and time. β-barium borate (BBO), α-BBO, and a dual-wavelength plate were used to compensate the phase delay of the two-color lasers. Tilting of α-BBO could further realize the precise spatial overlap of the two beams by counteracting the walk-off effect. The maximum output THz pulse energy reached 21 μJ in argon gas when using a commercial Ti:sapphire laser with a pulse energy of 6 mJ at a 1 kHz repetition rate. The corresponding conversion efficiency exceeded 0.35%. Keywords: femtosecond laser filaments / walk-off effect / conversion efficiency 全文 FullText(HTML) 遍历章节列表输出章节标题 start Introduction The availability of terahertz (THz) waves has enabled unprecedented research on the properties of matter 1 . To achieve further control over matter and light by using THz transients, the interaction of intense femtosecond lasers with nonlinear materials 2 has received considerable research interest. THz radiations with pulse energies of 436 μJ have been generated through optical rectification in lithium niobate (LN) 3 with an energy conversion efficiency of 0.77%. Recently, the output THz pulse energy was boosted to 1.4 mJ by pumping a large-area LN crystal (80 mm× 26.5 mm) with a 214 mJ Ti:sapphire laser pulse 4 and the energy conversion efficiency is 0.65%. Furthermore, when the organic crystals 5 , 6 are used, the THz energy conversion efficiency via the optical rectification can be up to 3%. On<|im_end|> <|im_start|>assistant A new publication from Opto-Electronic Advances considers an over 20 μJ THz laser pulse generated at 1 kHz in gas media. Terahertz (THz) science and technology has received extensive attention from scientific researchers from all around the world over the past 20 years because of its prospective application potential in security imaging, medical diagnosis, military, wireless communications and astronomy. However, the development of high-power broadband THz radiation source has been a challenging task in the above-mentioned fields. Among various THz radiation sources, THz radiation source based on femtosecond laser filament has the advantages of broadband (~200 THz), high amplitude (100 MV/cm) and no limitation of damage threshold. In addition, the THz generation method based on the femtosecond laser filamentation confines the THz wave inside the filament, which can eliminate the diffraction and absorption during the propagation of the THz wave in the atmosphere and make the remote delivery of the THz wave become possible. The THz generation scheme based on the dual-color femtosecond laser filamentation has higher energy conversion efficiency than that using single-color femtosecond laser. In this scheme, the intensity, bandwidth, polarization and other characteristics of the THz radiation can be affected by many laser parameters including the temporal delay, dispersion, polarization, wavelength, spatial departure of the dual-color fields. Even the ambient gas species play a crucial role too. In order to develop an efficient THz radiation source, all these parameters need to be carefully designed and manipulated. The research group led by Prof. Weiwei Liu from Nankai university used femtosecond laser with single pulse energy of 6 mJ to generate the dual-color laser filamentation by frequency doubling the fundamental laser via a β-BBO crystal. The dual-color laser beams achieve the perfect spatial-temporal overlap through a tilted α-BBO crystal. Meanwhile, a dual-wavelength plate was used to make the dual-color laser beams have the identical polarization. The energy of the THz pulse generated from the laser filament in argon can be up to 21 μJ and the corresponding THz conversion efficiency reaches 0.35%. In this work, the ambient gas species' influence on the THz generation efficiency by the dual-color laser filamentation was investigated experimentally. The experimental results show that the highest conversion efficiency of THz radiation is achieved in argon gas. The relationship between the tilting angle of α-BBO and the generated THz power in argon was also investigated. α-BBO with optimal tilting angle and pre-designed thickness can simultaneously compensate the time delay and spatial walk-off of the two-color laser beams, playing the critical role in improving the generation efficiency of THz wave. This research work achieved a breakthrough in the energy conversion efficiency of THz wave generated by the two-color femtosecond laser filamentation, which is of great significance for the study of high-intensity THz sources and the exploration of the interaction between strong THz beam and materials. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract A better understanding of the features that define the interaction between cancer cells and immune cells is important for the development of new cancer therapies 1 . However, focus is often given to interactions that occur within the primary tumour and its microenvironment, whereas the role of immune cells during cancer dissemination in patients remains largely uncharacterized 2 , 3 . Circulating tumour cells (CTCs) are precursors of metastasis in several types of cancer 4 , 5 , 6 , and are occasionally found within the bloodstream in association with non-malignant cells such as white blood cells (WBCs) 7 , 8 . The identity and function of these CTC-associated WBCs, as well as the molecular features that define the interaction between WBCs and CTCs, are unknown. Here we isolate and characterize individual CTC-associated WBCs, as well as corresponding cancer cells within each CTC–WBC cluster, from patients with breast cancer and from mouse models. We use single-cell RNA sequencing to show that in the majority of these cases, CTCs were associated with neutrophils. When comparing the transcriptome profiles of CTCs associated with neutrophils against those of CTCs alone, we detect a number of differentially expressed genes that outline cell cycle progression, leading to more efficient metastasis formation. Further, we identify cell–cell junction and cytokine–receptor pairs that define CTC–neutrophil clusters, representing key vulnerabilities of the metastatic process. Thus, the association between neutrophils and CTCs drives cell cycle progression within the bloodstream and expands the metastatic potential of CTCs, providing a rationale for targeting this interaction in treatment of breast cancer. Main CTCs are precursors of metastasis in various solid cancers, including breast cancer 6 , and are occasionally found in association with WBCs 7 . The role of CTC–WBC clusters in the development of metastasis as well as the principles that govern the interactions between CTCs and WBCs during blood-borne dissemination are largely uncharacterized. We first sought to determine the number and composition of CTC–WBC clusters in patients with breast cancer and mouse models. We obtained blood samples from 70 patients with invasive breast cancer who discontinued their treatment owing to progressive disease, as well as from five different breast cancer mouse models, and enriched for CTCs using the Parsortix microfluidic device 9 (Extended Data Fig. 1a–e ). We stained CTCs for cancer-associated cell-surface markers EpCAM, HER2 and EGFR or imaged directly for the expression of GFP, and labelled for CD45 to identify WBCs (Fig. 1a , Extended Data Fig. 1f ). Among 70 patients, 34 (48.6%) had detectable CTCs, with a mean number of 22 CTCs per 7.5 ml of blood (Supplementary Tables 1 , 2). Whereas the majority of CTCs were single (88.0%), we also detected CTC clusters (8.6%) and CTC–WBC clusters (3.4%) (Fig. 1b , Extended Data Fig. 1g, h ). Similarly, we observed that CTC–WBC clusters were present in all of the mouse models we tested, including those with immunodeficient or immunocompetent backgrounds, ranging from 0.05% to 61% of the total CTC population (Fig. 1b , Extended Data Fig. 1i, j ). Of note, CTC abundance and ratios markedly changed when drawing blood upstream of capillary beds as opposed to locations further downstream, which indicates that clustered CTCs are shed early yet may be trapped in capillaries before reaching the periphery (Extended Data Fig. 1k–n ). Thus, CTC–WBC clusters are rare in the peripheral circulation yet consistently found in patients with breast cancer and in mouse models. Fig. 1: CTC–neutrophil clusters are highly efficient metastatic precursors. a , Representative images of a CTC–WBC cluster, a CTC cluster and a single CTC from NSG-CDX-BR16- GFP mice. CTCs are expressing GFP (green) and CTC-associated WBCs are labelled with anti-CD45 antibodies (red) ( n = 8). b , Pie charts displaying the mean percentage of single CTCs (grey), CTC clusters (green) and CTC–WBC clusters (red) in patients with breast cancer and in mouse models. The number of independent biological replicates ( n ) is shown for each model. c , Schematic of the experimental design. CTC–WBC clusters are dissociated into individual cells and processed for RNA sequencing (RNA-seq). The transcriptome of CTC-associated WBCs is then compared to reference (ref.) WBCs. d , Reference component analysis clustering of CTC-associated WBCs and reference WBCs from patients with breast cancer, displaying projection scores of cells (columns ; n = 50) on the immune reference panel (rows). e , Representative images of CTC–WBC clusters stained for Ly-6G (neutrophils, gold) together with GFP (cancer cells, green) (top) or processed with the Wright–Giemsa (WG) assay to define nuclear morphology (bottom) ( n = 8). f , Pie charts showing the mean percentage of CTC–neutrophil clusters and CTC–monocyte clusters in individual models. The number of independent biological replicates ( n ) is shown for each model. g , Kaplan–Meier plot showing progression-free survival of patients with breast cancer ( n = 9 for patients with one or more CTC–neutrophil clusters and n = 10 for patients with five or more CTCs); P value by two-sided log-rank test is shown. h , Schematic of the experimental design. One hundred CTCs from CTC–neutrophil clusters or CTCs alone are injected in the tail vein of recipient mice to measure their metastatic potential (left). Kaplan–Meier plot showing overall survival of mice (right). n = 5 for CTC–neutrophil clusters and n = 10 for CTCs alone; P value by two-sided log-rank test is shown. Source data Full size image We then determined the type of WBCs found in CTC–WBC clusters. We used a robotic micromanipulator to dissociate CTC–WBC clusters (Supplementary Video 1 ), enabling single-cell RNA sequencing analysis of cluster-associated WBCs and their comparison to reference WBCs from matched donors (Fig. 1c ) using reference component analysis 10 . In patients, we found that 75% of CTC-associated WBCs were related to the myeloid lineage, whereas the remaining (25%) were similar to T cells (Fig. 1d , Extended Data Fig. 2a, b ). Likewise, we found that 93% of CTC-associated WBCs from mouse models were also characterized by a myeloid-cell-like expression profile (Extended", "role": "user" }, { "content": "Tumor cells use a certain type of immune cell, so-called neutrophils, to enhance their ability to form metastases. Scientists from the University of Basel and the University Hospital of Basel have deciphered the mechanisms of this collaboration and found strategies for blocking them. The results are published in Nature. A better understanding of the features that define the interplay between cancer cells and immune cells is key to identifying new cancer therapies. Yet, focus is often given to those interactions that occur within the primary tumor and its microenvironment, while the role of immune cells during cancer dissemination in patients remains largelyuncharacterized. For example, certain immune cells, the so-called neutrophils, often enter into an alliance with tumor cells that contributes significantly to the development of metastases. This was reported by Prof. Nicola Aceto's interdisciplinary research team at the Department of Biomedicine of the University of Basel and the University Hospital of Basel. Neutrophils escort circulating tumor cells Circulating tumor cells (CTCs) are cancer cells that leave a primary tumor and enter the bloodstream on their way to distant organs. These CTCs are regarded as precursors of metastases. They can be found in the blood of patients as single cells, cell clusters or in groups with neutrophils. The researchers discovered that CTCs in close contact to neutrophils proliferate much more than other circulating cancer cells. \"Surprisingly, the patient's own neutrophils act by protecting CTCs in circulation, allowing CTCs to more efficiently seed metastasis,\" says Prof. Aceto. Indeed, the presence of CTC-neutrophil clusters in the bloodstream also correlates with a poor prognosis of breast cancer patients. Blocking the alliance between tumor cells and neutrophils \"We undertook a number of experiments to fully characterize CTC-neutrophil clusters from patients and mouse models, aiming to find strategies to suppress their ability to form metastasis,\" says Prof. Aceto. To this end, the researchers combined state-of-the-art single cell sequencing techniques, microfluidic technologies and genetic knockout experiments to gain insights into the biology of CTC-neutrophil clusters. They found that the neutrophils enhance the metastasis-seeding ability of CTCs by releasing specific messenger substances, such as cytokines. When in turn this release of cytokines was blocked, the pro-metastatic effects of neutrophils were abrogated. Altogether, the researchers were able not only to uncover the role of CTC-neutrophil clusters, but also to identify their vulnerabilities. These results may lead to the development of new anti-metastatic drugs. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract A better understanding of the features that define the interaction between cancer cells and immune cells is important for the development of new cancer therapies 1 . However, focus is often given to interactions that occur within the primary tumour and its microenvironment, whereas the role of immune cells during cancer dissemination in patients remains largely uncharacterized 2 , 3 . Circulating tumour cells (CTCs) are precursors of metastasis in several types of cancer 4 , 5 , 6 , and are occasionally found within the bloodstream in association with non-malignant cells such as white blood cells (WBCs) 7 , 8 . The identity and function of these CTC-associated WBCs, as well as the molecular features that define the interaction between WBCs and CTCs, are unknown. Here we isolate and characterize individual CTC-associated WBCs, as well as corresponding cancer cells within each CTC–WBC cluster, from patients with breast cancer and from mouse models. We use single-cell RNA sequencing to show that in the majority of these cases, CTCs were associated with neutrophils. When comparing the transcriptome profiles of CTCs associated with neutrophils against those of CTCs alone, we detect a number of differentially expressed genes that outline cell cycle progression, leading to more efficient metastasis formation. Further, we identify cell–cell junction and cytokine–receptor pairs that define CTC–neutrophil clusters, representing key vulnerabilities of the metastatic process. Thus, the association between neutrophils and CTCs drives cell cycle progression within the bloodstream and expands the metastatic potential of CTCs, providing a rationale for targeting this interaction in treatment of breast cancer. Main CTCs are precursors of metastasis in various solid cancers, including breast cancer 6 , and are occasionally found in association with WBCs 7 . The role of CTC–WBC clusters in the development of metastasis as well as the principles that govern the interactions between CTCs and WBCs during blood-borne dissemination are largely uncharacterized. We first sought to determine the number and composition of CTC–WBC clusters in patients with breast cancer and mouse models. We obtained blood samples from 70 patients with invasive breast cancer who discontinued their treatment owing to progressive disease, as well as from five different breast cancer mouse models, and enriched for CTCs using the Parsortix microfluidic device 9 (Extended Data Fig. 1a–e ). We stained CTCs for cancer-associated cell-surface markers EpCAM, HER2 and EGFR or imaged directly for the expression of GFP, and labelled for CD45 to identify WBCs (Fig. 1a , Extended Data Fig. 1f ). Among 70 patients, 34 (48.6%) had detectable CTCs, with a mean number of 22 CTCs per 7.5 ml of blood (Supplementary Tables 1 , 2). Whereas the majority of CTCs were single (88.0%), we also detected CTC clusters (8.6%) and CTC–WBC clusters (3.4%) (Fig. 1b , Extended Data Fig. 1g, h ). Similarly, we observed that CTC–WBC clusters were present in all of the mouse models we tested, including those with immunodeficient or immunocompetent backgrounds, ranging from 0.05% to 61% of the total CTC population (Fig. 1b , Extended Data Fig. 1i, j ). Of note, CTC abundance and ratios markedly changed when drawing blood upstream of capillary beds as opposed to locations further downstream, which indicates that clustered CTCs are shed early yet may be trapped in capillaries before reaching the periphery (Extended Data Fig. 1k–n ). Thus, CTC–WBC clusters are rare in the peripheral circulation yet consistently found in patients with breast cancer and in mouse models. Fig. 1: CTC–neutrophil clusters are highly efficient metastatic precursors. a , Representative images of a CTC–WBC cluster, a CTC cluster and a single CTC from NSG-CDX-BR16- GFP mice. CTCs are expressing GFP (green) and CTC-associated WBCs are labelled with anti-CD45 antibodies (red) ( n = 8). b , Pie charts displaying the mean percentage of single CTCs (grey), CTC clusters (green) and CTC–WBC clusters (red) in patients with breast cancer and in mouse models. The number of independent biological replicates ( n ) is shown for each model. c , Schematic of the experimental design. CTC–WBC clusters are dissociated into individual cells and processed for RNA sequencing (RNA-seq). The transcriptome of CTC-associated WBCs is then compared to reference (ref.) WBCs. d , Reference component analysis clustering of CTC-associated WBCs and reference WBCs from patients with breast cancer, displaying projection scores of cells (columns ; n = 50) on the immune reference panel (rows). e , Representative images of CTC–WBC clusters stained for Ly-6G (neutrophils, gold) together with GFP (cancer cells, green) (top) or processed with the Wright–Giemsa (WG) assay to define nuclear morphology (bottom) ( n = 8). f , Pie charts showing the mean percentage of CTC–neutrophil clusters and CTC–monocyte clusters in individual models. The number of independent biological replicates ( n ) is shown for each model. g , Kaplan–Meier plot showing progression-free survival of patients with breast cancer ( n = 9 for patients with one or more CTC–neutrophil clusters and n = 10 for patients with five or more CTCs); P value by two-sided log-rank test is shown. h , Schematic of the experimental design. One hundred CTCs from CTC–neutrophil clusters or CTCs alone are injected in the tail vein of recipient mice to measure their metastatic potential (left). Kaplan–Meier plot showing overall survival of mice (right). n = 5 for CTC–neutrophil clusters and n = 10 for CTCs alone; P value by two-sided log-rank test is shown. Source data Full size image We then determined the type of WBCs found in CTC–WBC clusters. We used a robotic micromanipulator to dissociate CTC–WBC clusters (Supplementary Video 1 ), enabling single-cell RNA sequencing analysis of cluster-associated WBCs and their comparison to reference WBCs from matched donors (Fig. 1c ) using reference component analysis 10 . In patients, we found that 75% of CTC-associated WBCs were related to the myeloid lineage, whereas the remaining (25%) were similar to T cells (Fig. 1d , Extended Data Fig. 2a, b ). Likewise, we found that 93% of CTC-associated WBCs from mouse models were also characterized by a myeloid-cell-like expression profile (Extended<|im_end|> <|im_start|>assistant Tumor cells use a certain type of immune cell, so-called neutrophils, to enhance their ability to form metastases. Scientists from the University of Basel and the University Hospital of Basel have deciphered the mechanisms of this collaboration and found strategies for blocking them. The results are published in Nature. A better understanding of the features that define the interplay between cancer cells and immune cells is key to identifying new cancer therapies. Yet, focus is often given to those interactions that occur within the primary tumor and its microenvironment, while the role of immune cells during cancer dissemination in patients remains largelyuncharacterized. For example, certain immune cells, the so-called neutrophils, often enter into an alliance with tumor cells that contributes significantly to the development of metastases. This was reported by Prof. Nicola Aceto's interdisciplinary research team at the Department of Biomedicine of the University of Basel and the University Hospital of Basel. Neutrophils escort circulating tumor cells Circulating tumor cells (CTCs) are cancer cells that leave a primary tumor and enter the bloodstream on their way to distant organs. These CTCs are regarded as precursors of metastases. They can be found in the blood of patients as single cells, cell clusters or in groups with neutrophils. The researchers discovered that CTCs in close contact to neutrophils proliferate much more than other circulating cancer cells. "Surprisingly, the patient's own neutrophils act by protecting CTCs in circulation, allowing CTCs to more efficiently seed metastasis," says Prof. Aceto. Indeed, the presence of CTC-neutrophil clusters in the bloodstream also correlates with a poor prognosis of breast cancer patients. Blocking the alliance between tumor cells and neutrophils "We undertook a number of experiments to fully characterize CTC-neutrophil clusters from patients and mouse models, aiming to find strategies to suppress their ability to form metastasis," says Prof. Aceto. To this end, the researchers combined state-of-the-art single cell sequencing techniques, microfluidic technologies and genetic knockout experiments to gain insights into the biology of CTC-neutrophil clusters. They found that the neutrophils enhance the metastasis-seeding ability of CTCs by releasing specific messenger substances, such as cytokines. When in turn this release of cytokines was blocked, the pro-metastatic effects of neutrophils were abrogated. Altogether, the researchers were able not only to uncover the role of CTC-neutrophil clusters, but also to identify their vulnerabilities. These results may lead to the development of new anti-metastatic drugs. <|im_end|>

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