title: Early Growth Response Gene-1 Suppresses Foot-and-Mouth Disease Virus Replication by Enhancing Type I Interferon Pathway Signal Transduction

text: Early growth response gene-1 (EGR1) is a multifunctional transcription factor that is implicated in viral infection. In this study, we observed that foot-and-mouth disease virus (FMDV) infection significantly triggered EGR1 expression. Overexpression of EGR1 suppressed FMDV replication in porcine cells, and knockdown of EGR1 considerably promoted FMDV replication. A previously reported FMDV mutant virus (with two amino acids mutations in SAP domain) that displays a strong type I interferon (IFN) induction activity was used in this study. We found that SAP mutant FMDV infection induced a higher expression of EGR1 than wildtype FMDV infection, and also triggered higher IFN-β and IFN-stimulated genes (ISGs) expression than wildtype FMDV infection. This implied a link between EGR1 and type I IFN signaling. Further study showed that overexpression of EGR1 resulted in Sendai virus (SeV)-induced IFN-stimulated response element (ISRE) and NF-κB promoter activation. In addition, the SeV-induced ISGs expression was impaired in EGR1 knockdown cells. EGR1 upregulation promoted type I IFN signaling activation and suppressed FMDV and Seneca Valley virus replication. Suppression of the transcriptional activity of EGR1 did not affect its antiviral effect against FMDV. This study reveals a new mechanism evolved by EGR1 to enhance type I IFN signaling and suppress FMDV replication.


title: Characterization of the structure, cells, and cellular mechanobiological response of human plantar fascia

text: In this study, we report that human plantar fascia consists of two distinct tissues with differential structural properties. These tissues also contain stem/progenitor cells with differential biological properties. The mechanobiological responses of these two plantar fascia stem cells also differ in terms of expression of collagen I and IV, non-ligament-related genes, and proinflammatory genes. The production of inflammatory agents (prostaglandin E(2), interleukin-6) and matrix degradative enzymes (matrix metalloproteinase-1, matrix metalloproteinase-2) are also different between the two types of plantar fascia stem cells. Based on the findings from this study, we suggest that plantar fasciitis results from the aberrant mechanobiological responses of the stem cells from plantar fascia sheath and core tissues. Our findings may also be used to devise tissue engineering approaches to treat plantar fascia injury effectively.


title: Role of extracellular matrix and microenvironment in regulation of tumor growth and LAR-mediated invasion in glioblastoma

text: The cellular dispersion and therapeutic control of glioblastoma, the most aggressive type of primary brain cancer, depends critically on the migration patterns after surgery and intracellular responses of the individual cancer cells in response to external biochemical cues in the microenvironment. Recent studies have shown that miR-451 regulates downstream molecules including AMPK/CAB39/MARK and mTOR to determine the balance between rapid proliferation and invasion in response to metabolic stress in the harsh tumor microenvironment. Surgical removal of the main tumor is inevitably followed by recurrence of the tumor due to inaccessibility of dispersed tumor cells in normal brain tissue. In order to address this complex process of cell proliferation and invasion and its response to conventional treatment, we propose a mathematical model that analyzes the intracellular dynamics of the miR-451-AMPK- mTOR-cell cycle signaling pathway within a cell. The model identifies a key mechanism underlying the molecular switches between proliferative phase and migratory phase in response to metabolic stress in response to fluctuating glucose levels. We show how up- or down-regulation of components in these pathways affects the key cellular decision to infiltrate or proliferate in a complex microenvironment in the absence and presence of time delays and stochastic noise. Glycosylated chondroitin sulfate proteoglycans (CSPGs), a major component of the extracellular matrix (ECM) in the brain, contribute to the physical structure of the local brain microenvironment but also induce or inhibit glioma invasion by regulating the dynamics of the CSPG receptor LAR as well as the spatiotemporal activation status of resident astrocytes and tumor-associated microglia. Using a multi-scale mathematical model, we investigate a CSPG-induced switch between invasive and non-invasive tumors through the coordination of ECM-cell adhesion and dynamic changes in stromal cells. We show that the CSPG-rich microenvironment is associated with non-invasive tumor lesions through LAR-CSGAG binding while the absence of glycosylated CSPGs induce the critical glioma invasion. We illustrate how high molecular weight CSPGs can regulate the exodus of local reactive astrocytes from the main tumor lesion, leading to encapsulation of non-invasive tumor and inhibition of tumor invasion. These different CSPG conditions also change the spatial profiles of ramified and activated microglia. The complex distribution of CSPGs in the tumor microenvironment can determine the nonlinear invasion behaviors of glioma cells, which suggests the need for careful therapeutic strategies.


title: Burkitt lymphoma of the ovaries mimicking sepsis: a case report and review of the literature

text: BACKGROUND: It is not unusual for systemic diseases to mimic sepsis and, in any case, the clinician should thoroughly investigate this possibility. CASE PRESENTATION: We present the case of a 21-year-old Greek woman who presented to the Intensive Care Unit of our hospital with severe septic shock – multiple organ failure as a result of a suspected gynecological infection of the ovaries. An immediate improvement of her clinical condition in combination with strong clinical suspicion and negative cultures led to the differential diagnosis of diseases other than sepsis. Based on the results of the biopsies that were obtained by research laparotomy, our patient suffered from primary Burkitt ovarian lymphoma. Her clinical condition improved with supportive treatment and chemotherapy. Chemotherapy is the dominant treatment for Burkitt’s lymphoma, while surgery or radiotherapy has no place. CONCLUSIONS: All intensivists should be aware of clinical conditions that mimic sepsis as early diagnosis can lead to appropriate therapy and avoid unnecessary diagnostic tests and antibiotic abuse.


title: Quantifying the value of surveillance data for improving model predictions of lymphatic filariasis elimination

text: BACKGROUND: Mathematical models are increasingly being used to evaluate strategies aiming to achieve the control or elimination of parasitic diseases. Recently, owing to growing realization that process-oriented models are useful for ecological forecasts only if the biological processes are well defined, attention has focused on data assimilation as a means to improve the predictive performance of these models. METHODOLOGY AND PRINCIPAL FINDINGS: We report on the development of an analytical framework to quantify the relative values of various longitudinal infection surveillance data collected in field sites undergoing mass drug administrations (MDAs) for calibrating three lymphatic filariasis (LF) models (EPIFIL, LYMFASIM, and TRANSFIL), and for improving their predictions of the required durations of drug interventions to achieve parasite elimination in endemic populations. The relative information contribution of site-specific data collected at the time points proposed by the WHO monitoring framework was evaluated using model-data updating procedures, and via calculations of the Shannon information index and weighted variances from the probability distributions of the estimated timelines to parasite extinction made by each model. Results show that data-informed models provided more precise forecasts of elimination timelines in each site compared to model-only simulations. Data streams that included year 5 post-MDA microfilariae (mf) survey data, however, reduced each model’s uncertainty most compared to data streams containing only baseline and/or post-MDA 3 or longer-term mf survey data irrespective of MDA coverage, suggesting that data up to this monitoring point may be optimal for informing the present LF models. We show that the improvements observed in the predictive performance of the best data-informed models may be a function of temporal changes in inter-parameter interactions. Such best data-informed models may also produce more accurate predictions of the durations of drug interventions required to achieve parasite elimination. SIGNIFICANCE: Knowledge of relative information contributions of model only versus data-informed models is valuable for improving the usefulness of LF model predictions in management decision making, learning system dynamics, and for supporting the design of parasite monitoring programmes. The present results further pinpoint the crucial need for longitudinal infection surveillance data for enhancing the precision and accuracy of model predictions of the intervention durations required to achieve parasite elimination in an endemic location.


title: Monitoring the age-specificity of measles transmissions during 2009-2016 in Southern China

text: BACKGROUND: Despite several immunization efforts, China saw a resurgence of measles in 2012. Monitoring of transmissions of individuals from different age groups could offer information that would be valuable for planning adequate disease control strategies. We compared the age-specific effective reproductive numbers (R) of measles during 2009–2016 in Guangdong, China. METHODS: We estimated the age-specific R values for 7 age groups: 0–8 months, 9–18 months, 19 months to 6 years, 7–15 years, 16–25 years, 26–45 years, and ≥46 years adapting the contact matrix of China. The daily numbers of laboratory and clinically confirmed cases reported to the Center for Disease Control and Prevention of Guangdong were used. RESULTS: The peak R values of the entire population were above unity from 2012 to 2016, indicating the persistence of measles in the population. In general, children aged 0–6 years and adults aged 26–45 years had larger values of R when comparing with other age groups after 2012. While the peaks of R values for children aged 0–6 years dropped steadily after 2013, the peaks of R values for adults aged 26–45 years kept at a high range every year. CONCLUSIONS: Although the provincial supplementary immunization activities (SIAs) conducted in 2009 and 2010 were able to reduce the transmissions from 2009 to 2011, larger values of R for children aged 0–6 years were observed after 2012, indicating that the benefits of the SIAs were short-lived. In addition, the transmissions from adults aged between 26 and 45 years increased over time. Disease control strategies should target children and adult groups that carry high potential for measles transmission.


title: Insights into the genetic and host adaptability of emerging porcine circovirus 3

text: Porcine circovirus 3 (PCV3) was found to be associated with reproductive disease in pigs, and since its first identification in the United States, it subsequently spread worldwide, especially in China, where it might pose a potential threat to the porcine industry. However, no exhaustive analysis was performed to understand its evolution in the prospect of codon usage pattern. Here, we performed a deep codon usage analysis of PCV3. PCV3 sequences were classified into two clades: PCV3a and PCV3b, confirmed by principal component analysis. Additionally, the degree of codon usage bias of PCV3 was slightly low as inferred from the analysis of the effective number of codons. The codon usage pattern was mainly affected by natural selection, but there was a co-effect of mutation pressure and dinucleotide frequency. Moreover, based on similarity index analysis, codon adaptation index analysis and relative codon deoptimization index analysis, we found that PCV3 might pose a potential risk to public health though with unknow pathogenicity. In conclusion, this work reinforces the systematic understanding of the evolution of PCV3, which was reflected by the codon usage patterns and fitness of this novel emergent virus.


Histopathological Features and Viral Antigen Distribution in the Lung of Fatal Patients with Enterovirus 71 Infection


title: Monomeric Camelus dromedarius GSTM1 at low pH is structurally more thermostable than its native dimeric form

text: Glutathione S‒transferases (GSTs) are multifunctional enzymes that play an important role in detoxification, cellular signalling, and the stress response. Camelus dromedarius is well-adapted to survive in extreme desert climate and it has GSTs, for which limited information is available. This study investigated the structure-function and thermodynamic properties of a mu-class camel GST (CdGSTM1) at different pH. Recombinant CdGSTM1 (25.7 kDa) was expressed in E. coli and purified to homogeneity. Dimeric CdGSTM1 dissociated into stable but inactive monomeric subunits at low pH. Conformational and thermodynamic changes during the thermal unfolding pathway of dimeric and monomeric CdGSTM1 were characterised via a thermal shift assay and dynamic multimode spectroscopy (DMS). The thermal shift assay based on intrinsic tryptophan fluorescence revealed that CdGSTM1 underwent a two-state unfolding pathway at pH 1.0–10.0. Its Tm value varied with varying pH. Another orthogonal technique based on far-UV CD also exhibited two-state unfolding in the dimeric and monomeric states. Generally, proteins tend to lose structural integrity and stability at low pH; however, monomeric CdGSTM1 at pH 2.0 was thermally more stable and unfolded with lower van't Hoff enthalpy. The present findings provide essential information regarding the structural, functional, and thermodynamic properties of CdGSTM1 at pH 1.0–10.0.


title: Nanoparticle Vaccines Against Infectious Diseases

text: Due to emergence of new variants of pathogenic micro-organisms the treatment and immunization of infectious diseases have become a great challenge in the past few years. In the context of vaccine development remarkable efforts have been made to develop new vaccines and also to improve the efficacy of existing vaccines against specific diseases. To date, some vaccines are developed from protein subunits or killed pathogens, whilst several vaccines are based on live-attenuated organisms, which carry the risk of regaining their pathogenicity under certain immunocompromised conditions. To avoid this, the development of risk-free effective vaccines in conjunction with adequate delivery systems are considered as an imperative need to obtain desired humoral and cell-mediated immunity against infectious diseases. In the last several years, the use of nanoparticle-based vaccines has received a great attention to improve vaccine efficacy, immunization strategies, and targeted delivery to achieve desired immune responses at the cellular level. To improve vaccine efficacy, these nanocarriers should protect the antigens from premature proteolytic degradation, facilitate antigen uptake and processing by antigen presenting cells, control release, and should be safe for human use. Nanocarriers composed of lipids, proteins, metals or polymers have already been used to attain some of these attributes. In this context, several physico-chemical properties of nanoparticles play an important role in the determination of vaccine efficacy. This review article focuses on the applications of nanocarrier-based vaccine formulations and the strategies used for the functionalization of nanoparticles to accomplish efficient delivery of vaccines in order to induce desired host immunity against infectious diseases.


title: Zika Virus Infection at Different Pregnancy Stages: Anatomopathological Findings, Target Cells and Viral Persistence in Placental Tissues

text: Zika virus (ZIKV) infection in humans has been associated with congenital malformations and other neurological disorders, such as Guillain-Barré syndrome. The mechanism(s) of ZIKV intrauterine transmission, the cell types involved, the most vulnerable period of pregnancy for severe outcomes from infection and other physiopathological aspects are not completely elucidated. In this study, we analyzed placental samples obtained at the time of delivery from a group of 24 women diagnosed with ZIKV infection during the first, second or third trimesters of pregnancy. Villous immaturity was the main histological finding in the placental tissues, although placentas without alterations were also frequently observed. Significant enhancement of the number of syncytial sprouts was observed in the placentas of women infected during the third trimester, indicating the development of placental abnormalities after ZIKV infection. Hyperplasia of Hofbauer cells (HCs) was also observed in these third-trimester placental tissues, and remarkably, HCs were the only ZIKV-positive fetal cells found in the placentas studied that persisted until birth, as revealed by immunohistochemical (IHC) analysis. Thirty-three percent of women infected during pregnancy delivered infants with congenital abnormalities, although no pattern correlating the gestational stage at infection, the IHC positivity of HCs in placental tissues and the presence of congenital malformations at birth was observed. Placental tissue analysis enabled us to confirm maternal ZIKV infection in cases where serum from the acute infection phase was not available, which reinforces the importance of this technique in identifying possible causal factors of birth defects. The results we observed in the samples from naturally infected pregnant women may contribute to the understanding of some aspects of the pathophysiology of ZIKV.


title: Genome Sequences of Rhinovirus Genotype C56 Detected in Three Patients with Acute Respiratory Illness, California, 2016 to 2017

text: We report here two genome sequences of a newly designated rhinovirus genotype, RV-C56, which were obtained from respiratory specimens of three patients with acute respiratory illness in 2016 and 2017. To our knowledge, these sequences represent the first near-complete genomes for RV-C56 strains.


title: Characterization of patients transported with extracorporeal respiratory and/or cardiovascular support in the State of São Paulo, Brazil

text: OBJECTIVE: To characterize the transport of severely ill patients with extracorporeal respiratory or cardiovascular support. METHODS: A series of 18 patients in the state of São Paulo, Brazil is described. All patients were consecutively evaluated by a multidisciplinary team at the hospital of origin. The patients were rescued, and extracorporeal membrane oxygenation support was provided on site. The patients were then transported to referral hospitals for extracorporeal membrane oxygenation support. Data were retrieved from a prospectively collected database. RESULTS: From 2011 to 2017, 18 patients aged 29 (25 - 31) years with a SAPS 3 of 84 (68 - 92) and main primary diagnosis of leptospirosis and influenza A (H1N1) virus were transported to three referral hospitals in São Paulo. A median distance of 39 (15 - 82) km was traveled on each rescue mission during a period of 360 (308 - 431) min. A median of one (0 - 2) nurse, three (2 - 3) physicians, and one (0 - 1) physical therapist was present per rescue. Seventeen rescues were made by ambulance, and one rescue was made by helicopter. The observed complications were interruption in the energy supply to the pump in two cases (11%) and oxygen saturation < 70% in two cases. Thirteen patients (72%) survived and were discharged from the hospital. Among the nonsurvivors, there were two cases of brain death, two cases of multiple organ dysfunction syndrome, and one case of irreversible pulmonary fibrosis. CONCLUSIONS: Transportation with extracorporeal support occurred without serious complications, and the hospital survival rate was high.


title: A polymorphic residue that attenuates the antiviral potential of interferon lambda 4 in hominid lineages

text: As antimicrobial signalling molecules, type III or lambda interferons (IFNλs) are critical for defence against infection by diverse pathogens, including bacteria, fungi and viruses. Counter-intuitively, expression of one member of the family, IFNλ4, is associated with decreased clearance of hepatitis C virus (HCV) in the human population; by contrast, a natural frameshift mutation that abrogates IFNλ4 production improves HCV clearance. To further understand how genetic variation between and within species affects IFNλ4 function, we screened a panel of all known extant coding variants of human IFNλ4 for their antiviral potential and identify three that substantially affect activity: P70S, L79F and K154E. The most notable variant was K154E, which was found in African Congo rainforest ‘Pygmy’ hunter-gatherers. K154E greatly enhanced in vitro activity in a range of antiviral (HCV, Zika virus, influenza virus and encephalomyocarditis virus) and gene expression assays. Remarkably, E154 is the ancestral residue in mammalian IFNλ4s and is extremely well conserved, yet K154 has been fixed throughout evolution of the hominid genus Homo, including Neanderthals. Compared to chimpanzee IFNλ4, the human orthologue had reduced activity due to amino acid K154. Comparison of published gene expression data from humans and chimpanzees showed that this difference in activity between K154 and E154 in IFNλ4 correlates with differences in antiviral gene expression in vivo during HCV infection. Mechanistically, our data show that the human-specific K154 negatively affects IFNλ4 activity through a novel means by reducing its secretion and potency. We thus demonstrate that attenuated activity of IFNλ4 is conserved among humans and postulate that differences in IFNλ4 activity between species contribute to distinct host-specific responses to—and outcomes of—infection, such as HCV infection. The driver of reduced IFNλ4 antiviral activity in humans remains unknown but likely arose between 6 million and 360,000 years ago in Africa.


‘Hajj: what it means for general practice’


title: A Simple Method to Detect Candidate Overlapping Genes in Viruses Using Single Genome Sequences

text: Overlapping genes in viruses maximize the coding capacity of their genomes and allow the generation of new genes without major increases in genome size. Despite their importance, the evolution and function of overlapping genes are often not well understood, in part due to difficulties in their detection. In addition, most bioinformatic approaches for the detection of overlapping genes require the comparison of multiple genome sequences that may not be available in metagenomic surveys of virus biodiversity. We introduce a simple new method for identifying candidate functional overlapping genes using single virus genome sequences. Our method uses randomization tests to estimate the expected length of open reading frames and then identifies overlapping open reading frames that significantly exceed this length and are thus predicted to be functional. We applied this method to 2548 reference RNA virus genomes and find that it has both high sensitivity and low false discovery for genes that overlap by at least 50 nucleotides. Notably, this analysis provided evidence for 29 previously undiscovered functional overlapping genes, some of which are coded in the antisense direction suggesting there are limitations in our current understanding of RNA virus replication.


title: Protective Effect and Mechanism of Alprostadil in Acute Respiratory Distress Syndrome Induced by Oleic Acid in Rats

text: BACKGROUND: This study investigated the role and mechanism of alprostadil in acute respiratory distress syndrome (ARDS) induced by oleic acid (OA) in rats. MATERIAL/METHODS: Sprague-Dawley rats were randomly divided into control, OA model, and OA + Alprostadil (2.5, 5, and 10 μg/kg, respectively) groups. The ARDS model was induced by femoral vein injection of OA, and alprostadil was administrated immediately. Lung injury was evaluated by lung wet-dry weight ratio (W/D) and histological analyses. Expressions of ACE, inflammatory mediators, apoptotic-related proteins, and proteins in the MAPKs and NF-κB signaling pathways were determined by Western blot or immunohistochemical staining. RESULTS: Compared with the control group, the OA model group had significantly increased W/D, lung injury score, and collagen deposition at 3 h after OA injection. However, alprostadil (10 μg/kg) treatment significantly reduced OA-induced elevation of these indicators. Additionally, OA-induced expression of TNF-α and IL-1β were suppressed by alprostadil. The OA-induced activation of nuclear factor (NF) κB p65 was also reduced by alprostadil. Furthermore, we found that Alprostadil had an inhibitory effect on the phosphorylation of JNK, ERK1/2, and p38 MAPKs. Alprostadil inhibited Bax but increased Bcl-2, indicating a suppressive role in apoptosis. Remarkably increased expression of ACE in the OA model group was observed, which was decreased by alprostadil. CONCLUSIONS: Alprostadil has a protective effect on ARDS induced by OA in rats, possibly through inhibiting apoptosis, suppressing the activation of MAPKs and NF-κB signaling pathways, and decreasing ACE protein expression. Therefore, the use of alprostadil in clinical ARDS treatment is promising.


title: Review of global sanitation development

text: The implementation of the United Nations (UN) Millennium Development Goals (MDGs) and Sustainable Development Goals (SDGs) has resulted in an increased focus on developing innovative, sustainable sanitation techniques to address the demand for adequate and equitable sanitation in low-income areas. We examined the background, current situation, challenges, and perspectives of global sanitation. We used bibliometric analysis and word cluster analysis to evaluate sanitation research from 1992 to 2016 based on the Science Citation Index EXPANDED (SCI-EXPANDED) and Social Sciences Citation Index (SSCI) databases. Our results show that sanitation is a comprehensive field connected with multiple categories, and the increasing number of publications reflects a strong interest in this research area. Most of the research took place in developed countries, especially the USA, although sanitation problems are more serious in developing countries. Innovations in sanitation techniques may keep susceptible populations from contracting diseases caused by various kinds of contaminants and microorganisms. Hence, the hygienization of human excreta, resource recovery, and removal of micro-pollutants from excreta can serve as effective sustainable solutions. Commercialized technologies, like composting, anaerobic digestion, and storage, are reliable but still face challenges in addressing the links between the political, social, institutional, cultural, and educational aspects of sanitation. Innovative technologies, such as Microbial Fuel Cells (MFCs), Microbial Electrolysis Cells (MECs), and struvite precipitation, are at the TRL (Technology readiness levels) 8 level, meaning that they qualify as “actual systems completed and qualified through test and demonstration.” Solutions that take into consideration economic feasibility and all the different aspects of sanitation are required. There is an urgent demand for holistic solutions considering government support, social acceptability, as well as technological reliability that can be effectively adapted to local conditions.


title: Spatial infectious disease epidemiology: on the cusp

text: Infectious diseases continue to pose a significant public health burden despite the great progress achieved in their prevention and control over the last few decades. Our ability to disentangle the factors and mechanisms driving their propagation in space and time has dramatically advanced in recent years. The current era is rich in mathematical and computational tools and detailed geospatial information, including sociodemographic, geographic, and environmental data, which are essential to elucidate key drivers of infectious disease transmission from epidemiological and genetic data. Indeed, this paradigm shift was driven by dramatic advances in complex systems approaches along with substantial improvements in data availability and computational power. The burgeoning output of infectious disease spatial modeling suggests that we are close to a fully integrated approach for early epidemic detection and intervention. This special collection in BMC Medicine aims to bring together a broad range of quantitative investigations that improve our understanding of the spatiotemporal transmission dynamics of infectious diseases in order to mitigate their impact on the human population.


title: Therapeutic Efficacy and Safety of Prolonged Macrolide, Corticosteroid, Doxycycline, and Levofloxacin against Macrolide-Unresponsive Mycoplasma pneumoniae Pneumonia in Children

text: BACKGROUND: We aimed to compare the therapeutic efficacy of prolonged macrolide (PMC), corticosteroids (CST), doxycycline (DXC), and levofloxacin (LFX) against macrolide-unresponsive Mycoplasma pneumoniae (MP) pneumonia in children and to evaluate the safety of the secondary treatment agents. METHODS: We retrospectively analyzed the data of patients with MP pneumonia hospitalized between January 2015 and April 2017. Macrolide-unresponsiveness was clinically defined with a persistent fever of ≥ 38.0°C at ≥ 72 hours after macrolide treatment. The cases were divided into four groups: PMC, CST, DXC, and LFX. We compared the time to defervescence (TTD) after secondary treatment and the TTD after initial macrolide treatment in each group with adjustment using propensity score-matching analysis. RESULTS: Among 1,165 cases of MP pneumonia, 190 (16.3%) were unresponsive to macrolides. The proportion of patients who achieved defervescence within 48 hours in CST, DXC, and LFX groups were 96.9% (31/33), 85.7% (12/14), and 83.3% (5/6), respectively. The TTD after initial macrolide treatment did not differ between PMC and CST groups (5.1 vs. 4.2 days, P = 0.085), PMC and DXC groups (4.9 vs. 5.7 days, P = 0.453), and PMC and LFX groups (4.4 vs. 5.0 days, P = 0.283). No side effects were observed in the CST, DXC, and LFX groups. CONCLUSION: The change to secondary treatment did not show better efficacy compared to PMC in children with macrolide-unresponsive MP pneumonia. Further studies are needed to guide appropriate treatment in children with MP pneumonia.


title: Surfactant protein D attenuates acute lung and kidney injuries in pneumonia-induced sepsis through modulating apoptosis, inflammation and NF-κB signaling

text: Pneumonia and sepsis are major risk factors for acute kidney injury (AKI). Patients with pneumonia and AKI are at increased risk for morbidity and mortality. Surfactant protein D (SP-D) expressed in lung and kidney plays important roles in innate immunity. However, little is known about the role of organ-specific SP-D in the sepsis. The current study uses wild type (WT), SP-D knockout (KO), and humanized SP-D transgenic (hTG, lung-specific SP-D expression) mice to study organ-specific role of SP-D in pneumonia-induced sepsis. Analyses demonstrated differential lung and kidney injury among three-type mice infected with Pseudomonas aeruginosa. After infection, KO mice showed higher injurious scores in both lung and kidney, and decreased renal function than WT and hTG mice. hTG mice exhibited comparable lung injury but more severe kidney injury compared to WT mice. Increased renal tubular apoptosis, NF-κB activation and proinflammatory cytokines in the kidney of KO mice were found when compared with WT and hTG mice. Furthermore, in vitro primary proximal tubular epithelial cells from KO mice showed more apoptosis with higher level of activated caspase-3 than those from WT mice after LPS treatment. Collectively, SP-D attenuates AKI in the sepsis by modulating renal apoptosis, inflammation and NF-κB signaling.


title: Evaluation of Data Exchange Process for Interoperability and Impact on Electronic Laboratory Reporting Quality to a State Public Health Agency

text: BACKGROUND: Past and present national initiatives advocate for electronic exchange of health data and emphasize interoperability. The critical role of public health in the context of disease surveillance was recognized with recommendations for electronic laboratory reporting (ELR). Many public health agencies have seen a trend towards centralization of information technology services which adds another layer of complexity to interoperability efforts. OBJECTIVES: The study objective was to understand the process of data exchange and its impact on the quality of data being transmitted in the context of electronic laboratory reporting to public health. This was conducted in context of Minnesota Electronic Disease Surveillance System (MEDSS), the public health information system for supporting infectious disease surveillance in Minnesota. Data Quality (DQ) dimensions by Strong et al., was chosen as the guiding framework for evaluation. METHODS: The process of assessing data exchange for electronic lab reporting and its impact was a mixed methods approach with qualitative data obtained through expert discussions and quantitative data obtained from queries of the MEDSS system. Interviews were conducted in an open-ended format from November 2017 through February 2018. Based on these discussions, two high level categories of data exchange process which could impact data quality were identified: onboarding for electronic lab reporting and internal data exchange routing. This in turn comprised of ten critical steps and its impact on quality of data was identified through expert input. This was followed by analysis of data in MEDSS by various criteria identified by the informatics team. RESULTS: All DQ metrics (Intrinsic DQ, Contextual DQ, Representational DQ, and Accessibility DQ) were impacted in the data exchange process with varying influence on DQ dimensions. Some errors such as improper mapping in electronic health records (EHRs) and laboratory information systems had a cascading effect and can pass through technical filters and go undetected till use of data by epidemiologists. Some DQ dimensions such as accuracy, relevancy, value-added data and interpretability are more dependent on users at either end of the data exchange spectrum, the relevant clinical groups and the public health program professionals. The study revealed that data quality is dynamic and on-going oversight is a combined effort by MEDSS Informatics team and review by technical and public health program professionals. CONCLUSION: With increasing electronic reporting to public health, there is a need to understand the current processes for electronic exchange and their impact on quality of data. This study focused on electronic laboratory reporting to public health and analyzed both onboarding and internal data exchange processes. Insights gathered from this research can be applied to other public health reporting currently (e.g. immunizations) and will be valuable in planning for electronic case reporting in near future.


title: Innate Immune Detection of Cardioviruses and Viral Disruption of Interferon Signaling

text: Cardioviruses are members of the Picornaviridae family and infect a variety of mammals, from mice to humans. Replication of cardioviruses produces double stranded RNA that is detected by helicases in the RIG-I-like receptor family and leads to a signaling cascade to produce type I interferon. Like other viruses within Picornaviridae, however, cardioviruses have evolved several mechanisms to inhibit interferon production. In this review, we summarize recent findings that have uncovered several proteins enabling efficient detection of cardiovirus dsRNA and discuss which cell types may be most important for interferon production in vivo. Additionally, we describe how cardiovirus proteins L, 3C and L(∗) disrupt interferon production and antagonize the antiviral activity of interferon effector molecules.


title: Glycyrrhizic acid activates chicken macrophages and enhances their Salmonella-killing capacity in vitro

text: OBJECTIVE: Salmonella enterica remains a major cause of food-borne disease in humans, and Salmonella Typhimurium (ST) contamination of poultry products is a worldwide problem. Since macrophages play an essential role in controlling Salmonella infection, the aim of this study was to evaluate the effect of glycyrrhizic acid (GA) on immune function of chicken HD11 macrophages. METHODS: Chicken HD11 macrophages were treated with GA (0, 12.5, 25, 50, 100, 200, 400, or 800 μg/ml) and lipopolysaccharide (LPS, 500 ng/ml) for 3, 6, 12, 24, or 48 h. Evaluated responses included phagocytosis, bacteria-killing, gene expression of cell surface molecules (cluster of differentiation 40 (CD40), CD80, CD83, and CD197) and antimicrobial effectors (inducible nitric oxide synthase (iNOS), NADPH oxidase-1 (NOX-1), interferon-γ (IFN-γ), LPS-induced tumor necrosis factor (TNF)-α factor (LITAF), interleukin-6 (IL-6), and IL-10), and production of nitric oxide (NO) and hydrogen peroxide (H(2)O(2)). RESULTS: GA increased the internalization of both fluorescein isothiocyanate (FITC)-dextran and ST by HD11 cells and markedly decreased the intracellular survival of ST. We found that the messenger RNA (mRNA) expression of cell surface molecules (CD40, CD80, CD83, and CD197) and cytokines (IFN-γ, IL-6, and IL-10) of HD11 cells was up-regulated following GA exposure. The expression of iNOS and NOX-1 was induced by GA and thereby the productions of NO and H(2)O(2) in HD11 cells were enhanced. Notably, it was verified that nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways were responsible for GA-induced synthesis of NO and IFN-γ gene expression. CONCLUSIONS: Taken together, these results suggested that GA exhibits a potent immune regulatory effect to activate chicken macrophages and enhances Salmonella-killing capacity. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available for this article at 10.1631/jzus.B1700506 and is accessible for authorized users.


title: Overlapping genes and the proteins they encode differ significantly in their sequence composition from non-overlapping genes

text: Overlapping genes represent a fascinating evolutionary puzzle, since they encode two functionally unrelated proteins from the same DNA sequence. They originate by a mechanism of overprinting, in which point mutations in an existing frame allow the expression (the "birth") of a completely new protein from a second frame. In viruses, in which overlapping genes are abundant, these new proteins often play a critical role in infection, yet they are frequently overlooked during genome annotation. This results in erroneous interpretation of mutational studies and in a significant waste of resources. Therefore, overlapping genes need to be correctly detected, especially since they are now thought to be abundant also in eukaryotes. Developing better detection methods and conducting systematic evolutionary studies require a large, reliable benchmark dataset of known cases. We thus assembled a high-quality dataset of 80 viral overlapping genes whose expression is experimentally proven. Many of them were not present in databases. We found that overall, overlapping genes differ significantly from non-overlapping genes in their nucleotide and amino acid composition. In particular, the proteins they encode are enriched in high-degeneracy amino acids and depleted in low-degeneracy ones, which may alleviate the evolutionary constraints acting on overlapping genes. Principal component analysis revealed that the vast majority of overlapping genes follow a similar composition bias, despite their heterogeneity in length and function. Six proven mammalian overlapping genes also followed this bias. We propose that this apparently near-universal composition bias may either favour the birth of overlapping genes, or/and result from selection pressure acting on them.


title: Characterization of murine CEACAM1 in vivo reveals low expression on CD8(+) T cells and no tumor growth modulating activity by anti-CEACAM1 mAb CC1

text: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) has been reported to mediate both tumorigenic and anti-tumor effects in vivo. Blockade of the CEACAM1 signaling pathway has recently been implicated as a novel mechanism for cancer immunotherapy. CC1, a mouse anti-CEACAM1 monoclonal antibody (mAb), has been widely used as a pharmacological tool in preclinical studies to inform on CEACAM1 pathway biology although limited data are available on its CEACAM1 blocking characteristics or pharmacodynamic-pharmacokinetic profiles. We sought to investigate CEACAM1 expression on mouse tumor and immune cells, characterize CC1 mAb binding, and evaluate CC1 in syngeneic mouse oncology models as a monotherapy and in combination with an anti-PD-1 mAb. CEACAM1 expression was observed at high levels on neutrophils, NK cells and myeloid-derived suppressor cells (MDSCs), while the expression on tumor-infiltrating CD8+ T cells was low. Unexpectedly, rather than blocking, CC1 facilitated binding of soluble CEACAM1 to CEACAM1 expressing cells. No anti-tumor effects were observed in CT26, MBT2 or A20 models when tested up to 30 mg/kg dose, a dose that was estimated to achieve >90% target engagement in vivo. Taken together, tumor infiltrating CD8+ T cells express low levels of CEACAM1 and CC1 Ab mediates no or minimal anti-tumor effects in vivo, as a monotherapy or in combination with anti-PD-1 treatment.


ESICM LIVES 2018: Paris, France. 20-24 October 2018


title: Deep sequencing of primary human lung epithelial cells challenged with H5N1 influenza virus reveals a proviral role for CEACAM1

text: Current prophylactic and therapeutic strategies targeting human influenza viruses include vaccines and antivirals. Given variable rates of vaccine efficacy and antiviral resistance, alternative strategies are urgently required to improve disease outcomes. Here we describe the use of HiSeq deep sequencing to analyze host gene expression in primary human alveolar epithelial type II cells infected with highly pathogenic avian influenza H5N1 virus. At 24 hours post-infection, 623 host genes were significantly upregulated, including the cell adhesion molecule CEACAM1. H5N1 virus infection stimulated significantly higher CEACAM1 protein expression when compared to influenza A PR8 (H1N1) virus, suggesting a key role for CEACAM1 in influenza virus pathogenicity. Furthermore, silencing of endogenous CEACAM1 resulted in reduced levels of proinflammatory cytokine/chemokine production, as well as reduced levels of virus replication following H5N1 infection. Our study provides evidence for the involvement of CEACAM1 in a clinically relevant model of H5N1 infection and may assist in the development of host-oriented antiviral strategies.


title: Epidemic spreading in localized environments with recurrent mobility patterns

text: The spreading of epidemics is very much determined by the structure of the contact network, which may be impacted by the mobility dynamics of the individuals themselves. In confined scenarios where a small, closed population spends most of its time in localized environments and has easily identifiable mobility patterns—such as workplaces, university campuses, or schools—it is of critical importance to identify the factors controlling the rate of disease spread. Here, we present a discrete-time, metapopulation-based model to describe the transmission of susceptible-infected-susceptible-like diseases that take place in confined scenarios where the mobilities of the individuals are not random but, rather, follow clear recurrent travel patterns. This model allows analytical determination of the onset of epidemics, as well as the ability to discern which contact structures are most suited to prevent the infection to spread. It thereby determines whether common prevention mechanisms, as isolation, are worth implementing in such a scenario and their expected impact.


title: Bilateral massive pneumonia as an unusual manifestation of Puumala hantavirus infection

text: Renal involvement due to European Puumala virus (PUUV) is frequent but pulmonary involvement is quite rare. We present here, a 24-year-old male with atypical clinical presentation of acute PUUV infection with gross pulmonary and minimal renal involvement. Severe pulmonary manifestations of PUUV infection, in this case, highlights that hantavirus infection should be considered in the differential diagnosis of atypical pneumonia.


title: SMS-based smartphone application for disease surveillance has doubled completeness and timeliness in a limited-resource setting – evaluation of a 15-week pilot program in Central African Republic (CAR)

text: BACKGROUND: It is a challenge in low-resource settings to ensure the availability of complete, timely disease surveillance information. Smartphone applications (apps) have the potential to enhance surveillance data transmission. METHODS: The Central African Republic (CAR) Ministry of Health and Médecins Sans Frontières (MSF) conducted a 15-week pilot project to test a disease surveillance app, Argus, for 20 conditions in 21 health centers in Mambéré Kadéi district (MK 2016). Results were compared to the usual paper-based surveillance in MK the year prior (MK 2015) and simultaneously in an adjacent health district, Nana-Mambére (NM 2016). Wilcoxon rank sum and Kaplan-Meier analyses compared report completeness and timeliness; the cost of the app, and users’ perceptions of its usability were assessed. RESULTS: Two hundred seventy-one weekly reports sent by app identified 3403 cases and 63 deaths; 15 alerts identified 28 cases and 4 deaths. Median completeness (IQR) for MK 2016, 81% (81–86%), was significantly higher than in MK 2015 (31% (24–36%)), and NM 2016 (52% (48–57)) (p < 0.01). Median timeliness (IQR) for MK 2016, 50% (39–57%) was also higher than in MK 2015, 19% (19–24%), and NM 2016 29% (24–36%) (p < 0.01). Kaplan-Meier Survival Analysis showed a significant progressive reduction in the time taken to transmit reports over the 15-week period (p < 0.01). Users ranked the app’s usability as greater than 4/5 on all dimensions. The total cost of the 15-week pilot project was US$40,575. It is estimated that to maintain the app in the 21 health facilities of MK will cost approximately US$18,800 in communication fees per year. CONCLUSIONS: The app-based data transmission system more than doubled the completeness and timeliness of disease surveillance reports. This simple, low-cost intervention may permit the early detection of disease outbreaks in similar low-resource settings elsewhere.


title: A comprehensive in silico analysis for identification of therapeutic epitopes in HPV16, 18, 31 and 45 oncoproteins

text: Human papillomaviruses (HPVs) are a group of circular double-stranded DNA viruses, showing severe tropism to mucosal tissues. A subset of HPVs, especially HPV16 and 18, are the primary etiological cause for several epithelial cell malignancies, causing about 5.2% of all cancers worldwide. Due to the high prevalence and mortality, HPV-associated cancers have remained as a significant health problem in human society, making an urgent need to develop an effective therapeutic vaccine against them. Achieving this goal is primarily dependent on the identification of efficient tumor-associated epitopes, inducing a robust cell-mediated immune response. Previous information has shown that E5, E6, and E7 early proteins are responsible for the induction and maintenance of HPV-associated cancers. Therefore, the prediction of major histocompatibility complex (MHC) class I T cell epitopes of HPV16, 18, 31 and 45 oncoproteins was targeted in this study. For this purpose, a two-step plan was designed to identify the most probable CD8+ T cell epitopes. In the first step, MHC-I and II binding, MHC-I processing, MHC-I population coverage and MHC-I immunogenicity prediction analyses, and in the second step, MHC-I and II protein-peptide docking, epitope conservation, and cross-reactivity with host antigens’ analyses were carried out successively by different tools. Finally, we introduced five probable CD8+ T cell epitopes for each oncoprotein of the HPV genotypes (60 epitopes in total), which obtained better scores by an integrated approach. These predicted epitopes are valuable candidates for in vitro or in vivo therapeutic vaccine studies against the HPV-associated cancers. Additionally, this two-step plan that each step includes several analyses to find appropriate epitopes provides a rational basis for DNA- or peptide-based vaccine development.


title: N-substituted phenylbenzamides of the niclosamide chemotype attenuate obesity related changes in high fat diet fed mice

text: Obesity and insulin resistance are primary risk factors for Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD is generally exhibited by non-progressive simple steatosis. However, a significant subset of patient’s progress to nonalcoholic steatohepatitis (NASH) that is defined by the presence of steatosis, inflammation and hepatocyte injury with fibrosis. Unfortunately, there are no approved therapies for NAFLD or NASH and therefore therapeutic approaches are urgently needed. Niclosamide is an U.S. Food and Drug Administration (FDA)-approved anthelmintic drug that mediates its effect by uncoupling oxidative phosphorylation. Niclosamide and its salt forms, Niclosamide Ethanolamine (NEN), and Niclosamide Piperazine (NPP) have shown efficacy in murine models of diet induced obesity characterized by attenuation of the prominent fatty liver disease phenotype and improved glucose metabolism. While the exact mechanism(s) underlying these changes remains unclear, the ability to uncouple oxidative phosphorylation leading to increased energy expenditure and lipid metabolism or attenuation of PKA mediated glucagon signaling in the liver have been proposed. Unfortunately, niclosamide has very poor water solubility, leading to low oral bioavailability. This, in addition to mitochondrial uncoupling activity and potential genotoxicity have reduced enthusiasm for its clinical use. More recently, salt forms of niclosamide, NEN and NPP, have demonstrated improved oral bioavailability while retaining activity. This suggests that development of safer more effective niclosamide derivatives for the treatment of NAFLD and Type 2 Diabetes may be possible. Herein we explored the ability of a series of N-substituted phenylbenzamide derivatives of the niclosamide salicylanilide chemotype to attenuate hepatic steatosis using a novel phenotypic in vitro model of fatty liver and the high fat diet-fed mouse model of diet induced obesity. These studies identified novel compounds with improved pre-clinical properties that attenuate hepatic steatosis in vitro and in vivo. These compounds with improved drug properties may be useful in alleviating symptoms and protection against disease progression in patients with metabolic syndrome and NAFLD.


title: Viral Respiratory Infections in the Neonatal Intensive Care Unit—A Review

text: Although infrequent, respiratory viral infections (RVIs) during birth hospitalization have a significant impact on short- and long-term morbidity in term and preterm neonates. RVI have been associated with increased length of hospital stay, severe disease course, unnecessary antimicrobial exposure and nosocomial outbreaks in the neonatal intensive care unit (NICU). Virus transmission has been described to occur via health care professionals, parents and other visitors. Most at risk are infants born prematurely, due to their immature immune system and the fact that they stay in the NICU for a considerable length of time. A prevalence of RVIs in the NICU in symptomatic infants of 6–30% has been described, although RVIs are most probably underdiagnosed, since testing for viral pathogens is not performed routinely in symptomatic patients in many NICUs. Additional challenges are the wide range of clinical presentation of RVIs, their similarity to bacterial infections and the unreliable detection methods prior to the era of molecular biology based technologies. In this review, current knowledge of early-life RVI in the NICU is discussed. Reviewed viral pathogens include human rhinovirus, respiratory syncytial virus and influenza virus, and discussed literature is restricted to reports based on modern molecular biology techniques. The review highlights therapeutic approaches and possible preventive strategies. Furthermore, short- and long-term consequences of RVIs in infants hospitalized in the NICU are discussed.


title: LincRNA-p21 promotes mesenchymal stem cell migration capacity and survival through hypoxic preconditioning

text: BACKGROUND: Mesenchymal stem cells (MSCs) derived from bone marrow have potent stabilizing effects for the treatment of acute respiratory distress syndrome (ARDS). However, low efficiency and survival in MSC homing to injured lung tissue remains to be solved. Therefore, the aim of this study was to assess whether large intergenic noncoding RNA (LincRNA)-p21 promote MSC migration and survival capacity through hypoxic preconditioning in vitro. METHODS: MSCs were cultured and divided into the normoxia culture group (20% O2) and hypoxia culture group (1% O2). To determine roles and mechanisms, lentivirus vector-mediated LincRNA-p21 knockdown of MSCs and hypoxia-inducible factor (HIF-1α) inhibitor KC7F2 were introduced. Additionally, MSC migration was analyzed by scratch test and transwell migration assays. MSC proliferation was tested by cell counting kit-8 and trypan blue dye. Apoptosis was detected by Annexin V-PE/7-AAD stained flow cytometry. Moreover, LincRNA-p21 and HIF-1α mRNA was measured by reverse transcription-polymerase chain reaction, and HIF-1α and CXCR4/7 protein were assayed by western blot (WB) or enzyme-linked immunosorbent assay (ELISA). Apoptosis protein caspase-3 and cleaved-caspase-3 were investigated by WB analysis. Considering interactions between VHL and HIF-1α under LincRNA-p21 effect, co-immunoprecipitation was detected. RESULTS: Hypoxic preconditioning MSC promoted migration capacity and MSC survival than normoxia culture group. MSCs induced by hypoxic preconditioning evoked an increase in expression of LincRNA-p21, HIF-1α, and CXCR4/7(both were chemokine stromal-derived factor-1(SDF-1) receptors). Contrarily, blockade of LincRNA-p21 by shRNA and HIF-1α inhibitor KC7F2 abrogated upregulation of hypoxic preconditioning induced CXCR4/7 in MSCs, cell migration, and survival. Furthermore, co-immunoprecipitation assay revealed that hypoxic preconditioning isolated VHL and HIF-1α protein by increasing HIF-1α expression. CONCLUSIONS: Hypoxic preconditioning was identified as a promoting factor of MSC migration and survival capacity. LincRNA-p21 promotes MSC migration and survival capacity through HIF-1α/CXCR4 and CXCR7 pathway under hypoxic preconditioning in vitro.


title: A novel framework for inferring parameters of transmission from viral sequence data

text: Transmission between hosts is a critical part of the viral lifecycle. Recent studies of viral transmission have used genome sequence data to evaluate the number of particles transmitted between hosts, and the role of selection as it operates during the transmission process. However, the interpretation of sequence data describing transmission events is a challenging task. We here present a novel and comprehensive framework for using short-read sequence data to understand viral transmission events, designed for influenza virus, but adaptable to other viral species. Our approach solves multiple shortcomings of previous methods for this purpose; for example, we consider transmission as an event involving whole viruses, rather than sets of independent alleles. We demonstrate how selection during transmission and noisy sequence data may each affect naive inferences of the population bottleneck, accounting for these in our framework so as to achieve a correct inference. We identify circumstances in which selection for increased viral transmission may or may not be identified from data. Applying our method to experimental data in which transmission occurs in the presence of strong selection, we show that our framework grants a more quantitative insight into transmission events than previous approaches, inferring the bottleneck in a manner that accounts for selection, both for within-host virulence, and for inherent viral transmissibility. Our work provides new opportunities for studying transmission processes in influenza, and by extension, in other infectious diseases.


Infection Prevention for The Emergency Department: Out of Reach or Standard of Care?


title: What happened to health service utilization, health care expenditures, and quality of care in patients with acute pancreatitis after implementation of global budgeting in Taiwan?

text: AIM: Acute pancreatitis is associated with significant morbidity and mortality. In the United States, more than 3,00,000 patients are admitted and about 20,000 die from acute pancreatitis per year. In Taiwan, the incidence rate of acute pancreatitis is 0.03% and the mortality rate among severe acute pancreatitis is 16.3%. The aim of the study was to evaluate the impact of the global budgeting system on health service utilization, health care expenditures, and quality of care among patients with acute pancreatitis in Taiwan. MATERIALS AND METHODS: The National Health Insurance Research Database (NHIRD) was used for analysis. Data on patients with acute pancreatitis diagnosed during the period 2000 and 2001 were used as baseline data, and data from 2004 and 2005 were used as post-intervention data. The length of stay (LOS), diagnostic costs, drug cost, therapy costs, total costs, risk of readmission within 14 days, and risk of revisiting the emergency department (ED) within 3 days of discharge before and after implementation of the global budgeting system were compared and analyzed. RESULTS: Data on 2810 patients with acute pancreatitis were analyzed in this study. There was a significant difference in mean LOS before and after introduction of the global budget system (7.34 ± 0.22 days and 7.82 ± 0.22 days, respectively; P < .001)). The mean total costs before and after implementation of the global budget system were Taiwan dollars (NT$) 28,290.66 ± 1576.32 and NT$ 42,341.83 ± 2285.23, respectively. The mean rate of revisiting the ED within 3 days decreased from 9.9 ± 0.9% before adoption of global budgeting to 7.2 ± 0.6% after implementation of the system. The mean 14-day re-admission rates before and after introduction of global budgeting were 11.6 ± 1.0% and 7.9 ± 0.7%, respectively. CONCLUSION: The global budget system was associated with significantly longer length of stay, higher health care expenditures, and better quality of care in patients treated for acute pancreatitis.


title: Fomite-mediated transmission as a sufficient pathway: a comparative analysis across three viral pathogens

text: BACKGROUND: Fomite mediated transmission can be an important pathway causing significant disease transmission in number of settings such as schools, daycare centers, and long-term care facilities. The importance of these pathways relative to other transmission pathways such as direct person-person or airborne will depend on the characteristics of the particular pathogen and the venue in which transmission occurs. Here we analyze fomite mediated transmission through a comparative analysis across multiple pathogens and venues. METHODS: We developed and analyzed a compartmental model that explicitly accounts for fomite transmission by including pathogen transfer between hands and surfaces. We consider two sub-types of fomite-mediated transmission: direct fomite (e.g., shedding onto fomites) and hand-fomite (e.g., shedding onto hands and then contacting fomites). We use this model to examine three pathogens with distinct environmental characteristics (influenza, rhinovirus, and norovirus) in four venue types. To parameterize the model for each pathogen we conducted a thorough literature search. RESULTS: Based on parameter estimates from the literature the reproductive number ([Formula: see text] ) for the fomite route for rhinovirus and norovirus is greater than 1 in nearly all venues considered, suggesting that this route can sustain transmission. For influenza, on the other hand, [Formula: see text] for the fomite route is smaller suggesting many conditions in which the pathway may not sustain transmission. Additionally, the direct fomite route is more relevant than the hand-fomite route for influenza and rhinovirus, compared to norovirus. The relative importance of the hand-fomite vs. direct fomite route for norovirus is strongly dependent on the fraction of pathogens initially shed to hands. Sensitivity analysis stresses the need for accurate measurements of environmental inactivation rates, transfer efficiencies, and pathogen shedding. CONCLUSIONS: Fomite-mediated transmission is an important pathway for the three pathogens examined. The effectiveness of environmental interventions differs significantly both by pathogen and venue. While fomite-based interventions may be able to lower [Formula: see text] for fomites below 1 and interrupt transmission, rhinovirus and norovirus are so infectious ([Formula: see text] ) that single environmental interventions are unlikely to interrupt fomite transmission for these pathogens. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12879-018-3425-x) contains supplementary material, which is available to authorized users.


title: An unusually high substitution rate in transplant-associated BK polyomavirus in vivo is further concentrated in HLA-C-bound viral peptides

text: Infection with human BK polyomavirus, a small double-stranded DNA virus, potentially results in severe complications in immunocompromised patients. Here, we describe the in vivo variability and evolution of the BK polyomavirus by deep sequencing. Our data reveal the highest genomic evolutionary rate described in double-stranded DNA viruses, i.e., 10(−3)–10(−5) substitutions per nucleotide site per year. High mutation rates in viruses allow their escape from immune surveillance and adaptation to new hosts. By combining mutational landscapes across viral genomes with in silico prediction of viral peptides, we demonstrate the presence of significantly more coding substitutions within predicted cognate HLA-C-bound viral peptides than outside. This finding suggests a role for HLA-C in antiviral immunity, perhaps through the action of killer cell immunoglobulin-like receptors. The present study provides a comprehensive view of viral evolution and immune escape in a DNA virus.


title: Test Paper for Colorimetric Inspection of Fatty Acids and Edible Oils

text: Fatty acids (FAs) are of interest to the areas of food science and medicine because they are important dietary sources of fuel for animals and play important roles in many biological processes. The health effects of FAs are different due to the diversity of olefinic bonds in the alkyl chains including number, position and configuration. However, the discrimination of FAs is difficult from a chemical sensing perspective due to the lack of diversity in terms of functional groups. Until now, only a few chemosensors have been developed for selective sensing of FAs based on their overall shape, however they are still limited in discrimination of FAs with subtle structural differences, moreover, they cannot be used for rapid and in situ inspections. Herein, for the first time, we designed a test paper for in situ colorimetric inspection for FAs based on the combination of the highly selective binding of Ag(+) to olefinic bonds and Ag(+) mediated color variation of 3,3′,5,5′,-tetramethylbenzidine. As a result, the sensor exhibited high sensitivity and good selectivity for five FAs with subtle structural differences. Furthermore, our method described herein was successfully applied to monitor the structural variations of FAs and quality changes in mixture edible hot pot oils with heat treatment in time course. Hence, the test paper presented herein holds great potential in the inspection of fats and edible oils in food industries.


title: A High-Throughput Screening Approach To Repurpose FDA-Approved Drugs for Bactericidal Applications against Staphylococcus aureus Small-Colony Variants

text: Drug repurposing offers an expedited and economical route to develop new clinical therapeutics in comparison to traditional drug development. Growth-based high-throughput screening is concomitant with drug repurposing and enables rapid identification of new therapeutic uses for investigated drugs; however, this traditional method is not compatible with microorganisms with abnormal growth patterns such as Staphylococcus aureus small-colony variants (SCV). SCV subpopulations are auxotrophic for key compounds in biosynthetic pathways, which result in low growth rate. SCV formation is also associated with reduced antibiotic susceptibility, and the SCV’s ability to revert to the normal cell growth state is thought to contribute to recurrence of S. aureus infections. Thus, there is a critical need to identify antimicrobial agents that are potent against SCV in order to effectively treat chronic infections. Accordingly, here we describe adapting an adenylate kinase (AK)-based cell death reporter assay to identify members of a Food and Drug Administration (FDA)-approved drug library that display bactericidal activity against S. aureus SCV. Four library members, daunorubicin, ketoconazole, rifapentine, and sitafloxacin, exhibited potent SCV bactericidal activity against a stable S. aureus SCV. Further investigation showed that sitafloxacin was potent against methicillin-susceptible and -resistant S. aureus, as well as S. aureus within an established biofilm. Taken together, these results demonstrate the ability to use the AK assay to screen small-molecule libraries for SCV bactericidal agents and highlight the therapeutic potential of sitafloxacin to be repurposed to treat chronic S. aureus infections associated with SCV and/or biofilm growth states. IMPORTANCE Conventional antibiotics fail to successfully treat chronic osteomyelitis, endocarditis, and device-related and airway infections. These recurring infections are associated with the emergence of SCV, which are recalcitrant to conventional antibiotics. Studies have investigated antibiotic therapies to treat SCV-related infections but have had little success, emphasizing the need to identify novel antimicrobial drugs. However, drug discovery is a costly and time-consuming process. An alternative strategy is drug repurposing, which could identify FDA-approved and well-characterized drugs that could have off-label utility in treating SCV. In this study, we adapted a high-throughput AK-based assay to identify 4 FDA-approved drugs, daunorubicin, ketoconazole, rifapentine, and sitafloxacin, which display antimicrobial activity against S. aureus SCV, suggesting an avenue for drug repurposing in order to effectively treat SCV-related infections. Additionally, this screening paradigm can easily be adapted for other drug/chemical libraries to identify compounds bactericidal against SCV.


title: Prediction of Antimicrobial Potential of a Chemically Modified Peptide From Its Tertiary Structure

text: Designing novel antimicrobial peptides is a hot area of research in the field of therapeutics especially after the emergence of resistant strains against the conventional antibiotics. In the past number of in silico methods have been developed for predicting the antimicrobial property of the peptide containing natural residues. This study describes models developed for predicting the antimicrobial property of a chemically modified peptide. Our models have been trained, tested and evaluated on a dataset that contains 948 antimicrobial and 931 non-antimicrobial peptides, containing chemically modified and natural residues. Firstly, the tertiary structure of all peptides has been predicted using software PEPstrMOD. Structure analysis indicates that certain type of modifications enhance the antimicrobial property of peptides. Secondly, a wide range of features was computed from the structure of these peptides using software PaDEL. Finally, models were developed for predicting the antimicrobial potential of chemically modified peptides using a wide range of structural features of these peptides. Our best model based on support vector machine achieve maximum MCC of 0.84 with an accuracy of 91.62% on training dataset and MCC of 0.80 with an accuracy of 89.89% on validation dataset. To assist the scientific community, we have developed a web server called “AntiMPmod” which predicts the antimicrobial property of the chemically modified peptide. The web server is present at the following link (http://webs.iiitd.edu.in/raghava/antimpmod/).


title: Comparison of conservative therapy and steroid therapy for Bell’s palsy in children

text: PURPOSE: Bell’s palsy is characterized by sudden onset of unilateral facial weakness. The use of corticosteroids for childhood Bell’s palsy is controversial. This study aimed to identify clinical characteristics, etiology, and laboratory findings in childhood Bell’s palsy, and to evaluate the efficacy of corticosteroid treatment. METHODS: We conducted a retrospective analysis of children under 19 years of age treated for Bell’s palsy between January 2009 and June 2017, and followed up for over 1 month. Clinical characteristics, neuroimaging data, laboratory findings, treatments, and outcomes were reviewed. Patients with Bell’s palsy were divided into groups with (group 1) and without (group 2) corticosteroid treatment. Differences in onset age, sex, laterality, infection and vaccination history, degree of facial nerve palsy, and prognosis after treatment between the groups were analyzed. RESULTS: One hundred patients were included. Mean age at presentation was 7.4±5.62 years. A total of 73 patients (73%) received corticosteroids with or without intravenous antiviral agents, and 27 (27%) received only supportive treatment. There was no significant difference in the severity, laboratory findings, or neuroimaging findings between the groups. Significant improvement was observed in 68 (93.2%) and 26 patients (96.3%) in groups 1 and 2, respectively; this rate was not significantly different between the groups (P=0.48). CONCLUSION: Childhood Bell’s palsy showed good prognosis with or without corticosteroid treatment; there was no difference in prognosis between treated and untreated groups. Steroid therapy in childhood Bell’s palsy may not significantly improve outcomes.


title: Inhibition of Tetraspanin Functions Impairs Human Papillomavirus and Cytomegalovirus Infections

text: Tetraspanins are suggested to regulate the composition of cell membrane components and control intracellular transport, which leaves them vulnerable to utilization by pathogens such as human papillomaviruses (HPV) and cytomegaloviruses (HCMV) to facilitate host cell entry and subsequent infection. In this study, by means of cellular depletion, the cluster of differentiation (CD) tetraspanins CD9, CD63, and CD151 were found to reduce HPV16 infection in HeLa cells by 50 to 80%. Moreover, we tested recombinant proteins or peptides of specific tetraspanin domains on their effect on the most oncogenic HPV type, HPV16, and HCMV. We found that the C-terminal tails of CD63 and CD151 significantly inhibited infections of both HPV16 and HCMV. Although CD9 was newly identified as a key cellular factor for HPV16 infection, the recombinant CD9 C-terminal peptide had no effect on infection. Based on the determined half-maximal inhibitory concentration (IC(50)), we classified CD63 and CD151 C-terminal peptides as moderate to potent inhibitors of HPV16 infection in HeLa and HaCaT cells, and in EA.hy926, HFF (human foreskin fibroblast) cells, and HEC-LTT (human endothelial cell-large T antigen and telomerase) cells for HCMV, respectively. These results indicate that HPV16 and HCMV share similar cellular requirements for their entry into host cells and reveal the necessity of the cytoplasmic CD151 and CD63 C-termini in virus infections. Furthermore, this highlights the suitability of these peptides for functional investigation of tetraspanin domains and as inhibitors of pathogen infections.


title: An Alanine-to-Valine Substitution in the Residue 175 of Zika Virus NS2A Protein Affects Viral RNA Synthesis and Attenuates the Virus In Vivo

text: The recent outbreaks of Zika virus (ZIKV), its association with Guillain–Barré syndrome and fetal abnormalities, and the lack of approved vaccines and antivirals, highlight the importance of developing countermeasures to combat ZIKV disease. In this respect, infectious clones constitute excellent tools to accomplish these goals. However, flavivirus infectious clones are often difficult to work with due to the toxicity of some flavivirus sequences in bacteria. To bypass this problem, several alternative approaches have been applied for the generation of ZIKV clones including, among others, in vitro ligation, insertions of introns and using infectious subgenomic amplicons. Here, we report a simple and novel DNA-launched approach based on the use of a bacterial artificial chromosome (BAC) to generate a cDNA clone of Rio Grande do Norte Natal ZIKV strain. The sequence was identified from the brain tissue of an aborted fetus with microcephaly. The BAC clone was fully stable in bacteria and the infectious virus was efficiently recovered in Vero cells through direct delivery of the cDNA clone. The rescued virus yielded high titers in Vero cells and was pathogenic in a validated mouse model (A129 mice) of ZIKV infection. Furthermore, using this infectious clone we have generated a mutant ZIKV containing a single amino acid substitution (A175V) in the NS2A protein that presented reduced viral RNA synthesis in cell cultures, was highly attenuated in vivo and induced fully protection against a lethal challenge with ZIKV wild-type. This BAC approach provides a stable and reliable reverse genetic system for ZIKV that will help to identify viral determinants of virulence and facilitate the development of vaccine and therapeutic strategies.


title: Role of Host Cell Secretory Machinery in Zika Virus Life Cycle

text: The high human cost of Zika virus infections and the rapid establishment of virus circulation in novel areas, including the United States, present an urgent need for countermeasures against this emerging threat. The development of an effective vaccine against Zika virus may be problematic because of the cross reactivity of the antibodies with other flaviviruses leading to antibody-dependent enhancement of infection. Moreover, rapidly replicating positive strand RNA viruses, including Zika virus, generate large spectrum of mutant genomes (quasi species) every replication round, allowing rapid selection of variants resistant to drugs targeting virus-specific proteins. On the other hand, viruses are ultimate cellular parasites and rely on the host metabolism for every step of their life cycle, thus presenting an opportunity to manipulate host processes as an alternative approach to suppress virus replication and spread. Zika and other flaviviruses critically depend on the cellular secretory pathway, which transfers proteins and membranes from the ER through the Golgi to the plasma membrane, for virion assembly, maturation and release. In this review, we summarize the current knowledge of interactions of Zika and similar arthropod-borne flaviviruses with the cellular secretory machinery with a special emphasis on virus-specific changes of the secretory pathway. Identification of the regulatory networks and effector proteins required to accommodate the trafficking of virions, which represent a highly unusual cargo for the secretory pathway, may open an attractive and virtually untapped reservoir of alternative targets for the development of superior anti-viral drugs.


title: CEACAM1 in Liver Injury, Metabolic and Immune Regulation

text: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a transmembrane glycoprotein that is expressed on epithelial, endothelial and immune cells. CEACAM1 is a differentiation antigen involved in the maintenance of epithelial polarity that is induced during hepatocyte differentiation and liver regeneration. CEACAM1 regulates insulin sensitivity by promoting hepatic insulin clearance, and controls liver tolerance and mucosal immunity. Obese insulin-resistant humans with non-alcoholic fatty liver disease manifest loss of hepatic CEACAM1. In mice, deletion or functional inactivation of CEACAM1 impairs insulin clearance and compromises metabolic homeostasis which initiates the development of obesity and hepatic steatosis and fibrosis with other features of non-alcoholic steatohepatitis, and adipogenesis in white adipose depot. This is followed by inflammation and endothelial and cardiovascular dysfunctions. In obstructive and inflammatory liver diseases, soluble CEACAM1 is shed into human bile where it can serve as an indicator of liver disease. On immune cells, CEACAM1 acts as an immune checkpoint regulator, and deletion of Ceacam1 gene in mice causes exacerbation of inflammation and hyperactivation of myeloid cells and lymphocytes. Hence, hepatic CEACAM1 resides at the central hub of immune and metabolic homeostasis in both humans and mice. This review focuses on the regulatory role of CEACAM1 in liver and biliary tract architecture in health and disease, and on its metabolic role and function as an immune checkpoint regulator of hepatic inflammation.


title: Nucleic Acid-Dependent Structural Transition of the Intrinsically Disordered N-Terminal Appended Domain of Human Lysyl-tRNA Synthetase

text: Eukaryotic lysyl-tRNA synthetases (LysRS) have an N-terminal appended tRNA-interaction domain (RID) that is absent in their prokaryotic counterparts. This domain is intrinsically disordered and lacks stable structures. The disorder-to-order transition is induced by tRNA binding and has implications on folding and subsequent assembly into multi-tRNA synthetase complexes. Here, we expressed and purified RID from human LysRS (hRID) in Escherichia coli and performed a detailed mutagenesis of the appended domain. hRID was co-purified with nucleic acids during Ni-affinity purification, and cumulative mutations on critical amino acid residues abolished RNA binding. Furthermore, we identified a structural ensemble between disordered and helical structures in non-RNA-binding mutants and an equilibrium shift for wild-type into the helical conformation upon RNA binding. Since mutations that disrupted RNA binding led to an increase in non-functional soluble aggregates, a stabilized RNA-mediated structural transition of the N-terminal appended domain may have implications on the functional organization of human LysRS and multi-tRNA synthetase complexes in vivo.


title: Ebola Virus Maintenance: If Not (Only) Bats, What Else?

text: The maintenance mechanisms of ebolaviruses in African forest ecosystems are still unknown, but indirect evidences point at the involvement of some bat species. Despite intense research, the main bat-maintenance hypothesis has not been confirmed yet. The alternative hypotheses of a non-bat maintenance host or a maintenance community including, or not, several bat and other species, deserves more investigation. However, African forest ecosystems host a large biodiversity and abound in potential maintenance hosts. How does one puzzle out? Since recent studies have revealed that several bat species have been exposed to ebolaviruses, the common denominator to these hypotheses is that within the epidemiological cycle, some bats species must be exposed to the viruses and infected by these potential alternative hosts. Under this constraint, and given the peculiar ecology of bats (roosting behaviour, habitat utilisation, and flight mode), we review the hosts and transmission pathways that can lead to bat exposure and infection to ebolaviruses. In contrast to the capacity of bats to transmit ebolaviruses and other pathogens to many hosts, our results indicate that only a limited number of hosts and pathways can lead to the transmission of ebolaviruses to bats, and that the alternative maintenance host, if it exists, must be amongst them. A list of these pathways is provided, along with protocols to prioritise and investigate these alternative hypotheses. In conclusion, taking into account the ecology of bats and their known involvement in ebolaviruses ecology drastically reduces the list of potential alternative maintenance hosts for ebolaviruses. Understanding the natural history of ebolaviruses is a health priority, and investigating these alternative hypotheses could complete the current effort focused on the role of bats.


title: Temperature Sensitive Mutations in Influenza A Viral Ribonucleoprotein Complex Responsible for the Attenuation of the Live Attenuated Influenza Vaccine

text: Live attenuated influenza vaccines (LAIV) have prevented morbidity and mortality associated with influenza viral infections for many years and represent the best therapeutic option to protect against influenza viral infections in humans. However, the development of LAIV has traditionally relied on empirical methods, such as the adaptation of viruses to replicate at low temperatures. These approaches require an extensive investment of time and resources before identifying potential vaccine candidates that can be safely implemented as LAIV to protect humans. In addition, the mechanism of attenuation of these vaccines is poorly understood in some cases. Importantly, LAIV are more efficacious than inactivated vaccines because their ability to mount efficient innate and adaptive humoral and cellular immune responses. Therefore, the design of potential LAIV based on known properties of viral proteins appears to be a highly appropriate option for the treatment of influenza viral infections. For that, the viral RNA synthesis machinery has been a research focus to identify key amino acid substitutions that can lead to viral attenuation and their use in safe, immunogenic, and protective LAIV. In this review, we discuss the potential to manipulate the influenza viral RNA-dependent RNA polymerase (RdRp) complex to generate attenuated forms of the virus that can be used as LAIV for the treatment of influenza viral infections, one of the current and most effective prophylactic options for the control of influenza in humans.


title: Non-Invasive Detection of Extracellular Matrix Metalloproteinase Inducer EMMPRIN, a New Therapeutic Target against Atherosclerosis, Inhibited by Endothelial Nitric Oxide

text: Lack of endothelial nitric oxide causes endothelial dysfunction and circulating monocyte infiltration, contributing to systemic atheroma plaque formation in arterial territories. Among the different inflammatory products, macrophage-derived foam cells and smooth muscle cells synthesize matrix metalloproteinases (MMPs), playing a pivotal role in early plaque formation and enlargement. We found increased levels of MMP-9 and MMP-13 in human endarterectomies with advanced atherosclerosis, together with significant amounts of extracellular matrix (ECM) metalloproteinase inducer EMMPRIN. To test whether the absence of NO may aggravate atherosclerosis through EMMPRIN activation, double NOS3/apoE knockout (KO) mice expressed high levels of EMMPRIN in carotid plaques, suggesting that targeting extracellular matrix degradation may represent a new mechanism by which endothelial NO prevents atherosclerosis. Based on our previous experience, by using gadolinium-enriched paramagnetic fluorescence micellar nanoparticles conjugated with AP9 (NAP9), an EMMPRIN-specific binding peptide, magnetic resonance sequences allowed non-invasive visualization of carotid EMMPRIN in NOS3/apoE over apoE control mice, in which atheroma plaques were significantly reduced. Taken together, these results point to EMMPRIN as a new therapeutic target of NO-mediated protection against atherosclerosis, and NAP9 as a non-invasive molecular tool to target atherosclerosis.


title: Characteristics and pregnancy outcomes of patients with severe pneumonia complicating pregnancy: a retrospective study of 12 cases and a literature review

text: BACKGROUND: Pneumonia during pregnancy has been proven to be associated with increased maternal and fetal morbidity and mortality. The management of severe pneumonia in gravid patients is even more challenging. Thus, we summarized the characteristics and pregnancy outcomes of these patients and explored the probable risk factors and predictive factors for pneumonia during pregnancy and the appropriate timing of delivery in severe pneumonia patients. METHODS: A retrospective cohort study was conducted with 12 patients who were diagnosed with severe pneumonia complicating pregnancy at Peking Union Medical College Hospital between January 2010 and June 2017. The clinical features, treatment strategies, and pregnancy outcomes were collected from medical records and telephone calls. RESULTS: All 12 patients were in their late second or third trimester. The patients had a higher prevalence of anemia (50%) and preeclampsia (25%) than ordinary pregnant women. Delayed diagnoses were not uncommon. Two mothers died in our series, resulting in a mortality rate of 17%. Two intrauterine deaths were observed. Elective delivery was not performed in any of the four patients in their second trimester. Six of the seven patients who presented after 28 weeks of gestation and had live fetuses underwent emergency deliveries. Preterm births (6/7) and cesarean sections (5/7) were the two leading adverse outcomes in newborns. CONCLUSIONS: Anemia, advanced gestational age, and preeclampsia might be associated with the severity of pneumonia. Chest radiographs should be taken as soon as pneumonia is highly suspected to facilitate an early diagnosis. High incidences of adverse fetal outcomes were observed; thus, termination of the pregnancy is recommended for patients in their third trimester when respiratory function deteriorates progressively. However, it might be reasonable to continue pregnancy for those in their first or second trimester.


title: Transcriptome–pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS

text: Sporadic amyotrophic lateral sclerosis (sALS) is the most common form of ALS, however, the molecular mechanisms underlying cellular damage and motor neuron degeneration remain elusive. To identify molecular signatures of sALS we performed genome-wide expression profiling in laser capture microdissection-enriched surviving motor neurons (MNs) from lumbar spinal cords of sALS patients with rostral onset and caudal progression. After correcting for immunological background, we discover a highly specific gene expression signature for sALS that is associated with phosphorylated TDP-43 (pTDP-43) pathology. Transcriptome–pathology correlation identified casein kinase 1ε (CSNK1E) mRNA as tightly correlated to levels of pTDP-43 in sALS patients. Enhanced crosslinking and immunoprecipitation in human sALS patient- and healthy control-derived frontal cortex, revealed that TDP-43 binds directly to and regulates the expression of CSNK1E mRNA. Additionally, we were able to show that pTDP-43 itself binds RNA. CK1E, the protein product of CSNK1E, in turn interacts with TDP-43 and promotes cytoplasmic accumulation of pTDP-43 in human stem-cell-derived MNs. Pathological TDP-43 phosphorylation is therefore, reciprocally regulated by CK1E activity and TDP-43 RNA binding. Our framework of transcriptome–pathology correlations identifies candidate genes with relevance to novel mechanisms of neurodegeneration. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00401-018-1870-7) contains supplementary material, which is available to authorized users.


title: Single‐cell transcriptomics reveals distinct inflammation‐induced microglia signatures

text: Microglia are specialized parenchymal‐resident phagocytes of the central nervous system (CNS) that actively support, defend and modulate the neural environment. Dysfunctional microglial responses are thought to worsen CNS diseases; nevertheless, their impact during neuroinflammatory processes remains largely obscure. Here, using a combination of single‐cell RNA sequencing and multicolour flow cytometry, we comprehensively profile microglia in the brain of lipopolysaccharide (LPS)‐injected mice. By excluding the contribution of other immune CNS‐resident and peripheral cells, we show that microglia isolated from LPS‐injected mice display a global downregulation of their homeostatic signature together with an upregulation of inflammatory genes. Notably, we identify distinct microglial activated profiles under inflammatory conditions, which greatly differ from neurodegenerative disease‐associated profiles. These results provide insights into microglial heterogeneity and establish a resource for the identification of specific phenotypes in CNS disorders, such as neuroinflammatory and neurodegenerative diseases.


title: The effects of in ovo administration of encapsulated Toll-like receptor 21 ligand as an adjuvant with Marek’s disease vaccine

text: Marek’s Disease Virus (MDV) is the causative agent of a lymphoproliferative disease, Marek’s disease (MD) in chickens. MD is only controlled by mass vaccination; however, immunity induced by MD vaccines is unable to prevent MDV replication and transmission. The herpesvirus of turkey (HVT) vaccine is one of the most widely used MD vaccines in poultry industry. Vaccines can be adjuvanted with Toll-like receptor ligands (TLR-Ls) to enhance their efficacy. In this study, we examined whether combining TLR-Ls with HVT can boost host immunity against MD and improve its efficacy. Results demonstrated that HVT alone or HVT combined with encapsulated CpG-ODN partially protected chickens from tumor incidence and reduced virus replication compared to the control group. However, encapsulated CpG-ODN only moderately, but not significantly, improved HVT efficacy and reduced tumor incidence from 53% to 33%. Further investigation of cytokine gene profiles in spleen and bursa of Fabricius revealed an inverse association between interleukin (IL)-10 and IL-18 expression and protection conferred by different treatments. In addition, the results of this study raise the possibility that interferon (IFN)-β and IFN-γ induced by the treatments may exert anti-viral responses against MDV replication in the bursa of Fabricius at early stage of MDV infection in chickens.


title: The Fourth International Neonatal and Maternal Immunization Symposium (INMIS 2017): Toward Integrating Maternal and Infant Immunization Programs

text: Prevention of serious infections in pregnant mothers, newborns, and young infants through immunization during pregnancy and in early life has the potential to further reduce maternal and neonatal morbidity and mortality worldwide. In the past decade, research in this field has advanced substantially, from the understanding of the biology and immunology of pregnancy and early life, to the active development of several candidate vaccines, for which challenges and opportunities for global implementation are under consideration. Experts from academia, industry, regulatory and funding agencies, public health, and international organizations met in Brussels (Belgium) from 10 to 12 September 2017, at the 4th International Neonatal and Maternal Immunization Symposium (INMIS), to review the most relevant advances in maternal and neonatal immunization. The overarching focus of the conference was to identify the path forward to achieve integration of maternal and early life immunization strategies for the successful implementation of vaccines in antenatal care and pediatric programs for reduction of maternal and infant mortality worldwide. IMPORTANCE This report provides an overview of the proceedings of the 4th International Maternal and Neonatal Immunization Symposium, where presentations focused on the state-of-the-art research on the development and implementation of vaccines given during pregnancy for the protection of mothers and infants.


title: A benchmark driven guide to binding site comparison: An exhaustive evaluation using tailor-made data sets (ProSPECCTs)

text: The automated comparison of protein-ligand binding sites provides useful insights into yet unexplored site similarities. Various stages of computational and chemical biology research can benefit from this knowledge. The search for putative off-targets and the establishment of polypharmacological effects by comparing binding sites led to promising results for numerous projects. Although many cavity comparison methods are available, a comprehensive analysis to guide the choice of a tool for a specific application is wanting. Moreover, the broad variety of binding site modeling approaches, comparison algorithms, and scoring metrics impedes this choice. Herein, we aim to elucidate strengths and weaknesses of binding site comparison methodologies. A detailed benchmark study is the only possibility to rationalize the selection of appropriate tools for different scenarios. Specific evaluation data sets were developed to shed light on multiple aspects of binding site comparison. An assembly of all applied benchmark sets (ProSPECCTs–Protein Site Pairs for the Evaluation of Cavity Comparison Tools) is made available for the evaluation and optimization of further and still emerging methods. The results indicate the importance of such analyses to facilitate the choice of a methodology that complies with the requirements of a specific scientific challenge.


title: A Comprehensive In Silico Method to Study the QSTR of the Aconitine Alkaloids for Designing Novel Drugs

text: A combined in silico method was developed to predict potential protein targets that are involved in cardiotoxicity induced by aconitine alkaloids and to study the quantitative structure–toxicity relationship (QSTR) of these compounds. For the prediction research, a Protein-Protein Interaction (PPI) network was built from the extraction of useful information about protein interactions connected with aconitine cardiotoxicity, based on nearly a decade of literature and the STRING database. The software Cytoscape and the PharmMapper server were utilized to screen for essential proteins in the constructed network. The Calcium-Calmodulin-Dependent Protein Kinase II alpha (CAMK2A) and gamma (CAMK2G) were identified as potential targets. To obtain a deeper insight on the relationship between the toxicity and the structure of aconitine alkaloids, the present study utilized QSAR models built in Sybyl software that possess internal robustness and external high predictions. The molecular dynamics simulation carried out here have demonstrated that aconitine alkaloids possess binding stability for the receptor CAMK2G. In conclusion, this comprehensive method will serve as a tool for following a structural modification of the aconitine alkaloids and lead to a better insight into the cardiotoxicity induced by the compounds that have similar structures to its derivatives.


Please cite this paper as: Hsieh Ying‐Hen. (2010) Pandemic influenza A (H1N1) during winter influenza season in the southern hemisphere. Influenza and Other Respiratory Viruses 4(4), 187–197. Background Countries in the southern hemisphere experienced sizable epidemics of pandemic influenza H1N1 in their winter season during May–August, 2009. Methods We make use of the Richards model to fit the publicly available epidemic data (confirmed cases, hospitalizations, and deaths) of six southern hemisphere countries (Argentina, Brazil, Chile, Australia, New Zealand, and South Africa) to draw useful conclusions, in terms of its reproduction numbers and outbreak turning points, regarding the new pH1N1 virus in a typical winter influenza season. Results The estimates for the reproduction numbers of these six countries range from a high of 1·53 (95% CI: 1·22, 1·84) for confirmed case data of Brazil to a low of 1·16 (1·09, 1·22) for pH1N1 hospitalizations in Australia. For each country, model fits using confirmed cases, hospitalizations, or deaths data always yield similar estimates for the reproduction number. Moreover, the turning points for these closely related outbreak indicators always follow the correct chronological order, i.e., case–hospitalization–death, whenever two or more of these three indicators are available. Conclusions The results suggest that the winter pH1N1 outbreaks in the southern hemisphere were similar to the earlier spring and later winter outbreaks in North America in its severity and transmissibility, as indicated by the reproduction numbers. Therefore, the current strain has not become more severe or transmissible while circulating around the globe in 2009 as some experts had cautioned. The results will be useful for global preparedness planning of possible tertiary waves of pH1N1 infections in the fall/winter of 2010.