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**9. References**

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(10,000 g, 30 min), 1.5 µl of supernatant was placed onto a nitrocellulose membrane (Bio-rad 162-147, 0.2 µm). Non-specific binding sites were saturated with 50 mM Tris buffer containing 2% bovine serum albumin. The protein was revealed using, in succession, a mouse monoclonal antibody to TH (10 ng/ml; Boehringer Mannheim), a 125I-labeled protein A (S.A: 1.11x 10-9 Bq/mg, 1850 Bq/ml, Amersham) and 3H-hyperfilms (Amersham). The radioimmunochemical labeling was calibrated using a scale of standard TH protein (extracted from adult rat adrenals and diluted in homogenates of cerebellum). One U of TH (UTH) is defined as the mean TH protein content of 10 µg (wet weight) of adult rat adrenal gland. Optical density measurements were converted into UTH/mg tissue by reference to the standards. Each reading provided the surface area (mm2) of the dot and the TH tissue concentration (UTH/mg tissue). Using the surface area and the TH tissue concentration, the amount of TH (UTH) in the region of interest was calculated and normalized by expressing

Rats were perfused transcardially with NaCl 9°/°° and PFA 4%. The brain was then removed and stored in PBS buffer containing 0.1% sodium azide pH 7.4 (PBSA). To evaluate the extent of the lesion in the SN and the extent of CPc denervation, TH immuno precipitation was performed on coronally sectioned slices (40–50 µm thickness). Brains were cut on a cryostat (HM440E, Microm); free-floating slices were collected and stored in PBSA. Sections were incubated in 3% H2O2 in PBS to block endogenous peroxidase activity and were then incubated overnight with the primary rabbit anti-TH antibody (Chemicon, Temecula, CA; 1/2500) in 10% normal swine serum, TBS, pH 7.4, containing 2% NGS and 0.2%Triton X-100 for 24 h at 4 °C on a platform shaker. After rinsing in PBS 0.1% plus triton X100, sections were incubated with biotinylated swine anti-rabbit secondary antibody for 30 min at room temperature. This was followed by incubation with Strept-ABC-HRP complex (Dako, Glostrup, Denmark). TH immunoreactive neurons were visualized using 3.3 diaminobenzidine (DAB) in N2+ 0.5% and H2O2. To test the specificity of the staining, control sections were processed in an identical manner but with omission of the primary or secondary antibody. All sections were then washed for 10 min in PBS, mounted on slides, dried, dehydrated in increasing grades of ethanol, cleared in toluene, and mounted with DPX and cover slipped. These sections were scanned and analyzed immediately using

The work described here was supported by the Institut National de la Santé et de la Recherché Médicale, le Centre National de la Recherche Scientifique et Rhone Alpes Région.

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the amount of TH as a percentage of values in the control rats.

Imagemaster Labscan V-3.00 (Pharmacia Biotech, Dzahini et al., 2010).

**7.12 Immunoprecipitation of TH enzyme**

**8. Acknowledgment**

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**12**

 *Australia*

**Activity-Dependent Regulation of the Dopamine**

The motor symptoms of Parkinson's disease (PD) are caused by degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and the resulting depletion of DA signaling in their target structure, the dorsal striatum (the nigrostriatal pathway). PD motor symptoms are successfully alleviated by systemic administration of a blood-brain barrier permeable DA precursor (levodopa) or DA receptor agonists (Olanow et al. 2001), however these treatments are marred by side-effects in some patients (Wood 2010), and increasingly unreliable response and shortened duration of effect coupled with the emergence of dyskinesias in most patients (Stocchi et al. 2010, Stocchi & Marconi 2010). These problems probably arise from loss of physiological storage, release and reuptake of nigrostriatal DA and ensuing down-stream changes in post-synaptic signaling, and from increased DA signaling in structures outside the nigrostriatal pathway, especially when D2 agonists are used. Targeted (nigrostriatal) reconstruction of physiological DA signaling, aimed at restoring nigrostriatal DA transmission to at least the level at disease outset, ought to alleviate PD motor symptoms without side-effects. However, attempts to achieve this by replacing SNc DA cells through transplantation or endogenous repair are often hampered by poor acquisition and maintenance of the DA phenotype in the microenvironment of the adult SNc (Brundin et al. 2000, Courtois et al. 2010, Torres et al. 2005, Bauer et al. 2000).

There is evidence that expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) by adult SNc and midbrain neurons is pliable. TH is down-regulated in cells that survive exposure to neurotoxins [6-hydroxy-dopamine (6-OHDA) or 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)], and can be up-regulated again, presumably in these same cells, by glial-derived neurotrophic factor (GDNF) (Bjorklund *et al.* 1997, Bowenkamp *et al.* 1996, Gash *et al.* 1996, Sauer & Oertel 1994). There is also a degree of spontaneous recovery in the number of TH immunoreactive (TH+) SNc cells following 6- OHDA, which occurs coincidentally with a decrease in the number of SNc cells that are not immunoreactive against TH (TH-) (Stanic *et al.* 2003), implying acquisition of DA phenotype by extant cells. The DA phenotype of SNc neurons also appears to be regulated in an activity-dependent way. Reduced SNc TH expression following striatal infarct is blocked by

**1. Introduction**

**Phenotype in the Adult Substantia Nigra:**

Mal Horne, Kate Lord and Tim Aumann

*Florey Neuroscience Institutes, The University of Melbourne,*

**Prospects for Treating Parkinson's Disease**


**1. Introduction**

One of the challenging goals of the field of nuclear structure physics is to model atomic nuclei, including their properties and their reactions—rooted in the fundamental forces at play between protons and neutrons—with predictive power also for the shortestlived nuclear species located near the driplines of the chart. With this ultimate vision to extrapolate towards the most neutron-rich nuclei that may elude experimental study in the near future, much can be gleaned from nuclei in regions that display the effects of structural evolution away from the valley of stability and so offer a window into the driving forces of structural change and our understanding of it [1–3]. Specifically, the complex interplay between single-particle and collective degrees of freedom can provide exciting experimental challenges and demanding theoretical benchmarks.

The region of rapid structural change of interest in this review is the so-called "*N* = 40 island of inversion" [4,5], where the neutron-rich Fe and Cr nuclei around neutron number 40 become the most deformed in the region. In nuclear models, this is theorized to be caused by the strong quadrupole-quadrupole interaction producing a nuclear shape transition in which highly-correlated many-particle–many-hole configurations become energetically more favored than the normal-order (spherical) ones [4]. Such islands of inversion are characterized by rapid structural changes and shape coexistence [5,6], providing insight into nuclear structure physics far from stability [7]. Large-scale shell-model calculations with the LNPS (Lenzi-Nowacki-Poves-Sieja) effective interaction [4] in the full *f p* shell for protons and the *f*5/2, *p*3/2, *p*1/2, *g*9/2, and *d*5/2 orbitals for neutrons have confirmed the picture described above, with many successful predictions that preceded experimental results [3].

**Citation:** Gade, A Reaching into the *N* = 40 Island of Inversion with Nucleon Removal Reactions. *Physics* **2021**, *3*, 1226–1236. https://doi.org/ 10.3390/physics3040077

Received: 29 October 2021 Accepted: 2 December 2021 Published: 8 December 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

A recent prediction extends this island of inversion to *N* = 50 [5] and includes nuclei that will only be reached at next-generation rare-isotope beam facilities. This exciting prospect of extending the island towards the magic neutron number *N* = 50 is based on extrapolations of calculations using the LNPS shell-model effective interaction and its monopole drifts [4,5]. These prediction together with advances in experimentation continue to push the field forward on the journey to the *N* = 50 island of inversion.

The furthest experimental reach into the Fe, Cr, and Ti isotopes has been afforded by inverse-kinematics nucleon removal studies induced by fast rare-isotope projectile beams [8,9] to probe the nuclei of interest via in-beam *γ*-ray spectroscopy [10]. Often, such reactions provide the first glimpse of the excitation level scheme [11] and, in some cases, the direct character of such reactions is used to conclude on wave function overlaps within the shell-model framework [8,9]. This paper reviews the recent results for the very neutron-rich nuclei 66,68,70,72Fe, 64,66Cr, and 60,62Ti, all located near the center of the *N* = 40 island of inversion or already on the path to *N* = 50, obtained with such experimental approaches which have provided pioneering information the furthest away from the line of stability; see Figure 1.

**Figure 1.** Portion of the nuclear chart that shows the *N* = 40 island of inversion. Nuclei discussed in this review are highlighted with a red outline. This chart was generated with [12] (half-life color coding based on NuBase2020 and corresponding extrapolations).

#### **2. Experimental Approaches**

Experimental techniques aimed at tracking the changes in the structure of nuclei are multi-pronged. They include measurements of ground-state properties such as masses, radii, *β*-decay properties, and electromagnetic moments as well as the study of properties of bound and unbound excited states. One way of probing specific nuclear structure aspects in quantitative ways is the use of nuclear reactions that selectively probe a specific degree of freedom. Inelastic scattering of nuclei, including Coulomb excitation, has long been used to probe nuclear collectivity, characterized by the coherent motion of several protons and neutrons. The single-particle degree of freedom, on the other hand, is commonly associated with the single-particle composition of the many-body wave function in a shell-model picture. Such single-particle properties can be studied rather selectively by using *direct* reactions that add or remove one or a few nucleons from the nucleus of interest. Intriguing possibilities now arise in the above mentioned islands of inversion, where the telltale onset of collectivity and the underlying migration of single-particle levels can be tracked to provide a consistent picture.

At in-flight rare-isotope facilities, short-lived nuclei away from stability can be efficiently produced by fragmentation (or fission) of stable, primary beams impinging upon stable targets at high beam energy. The resulting secondary beams of rare isotopes are then available for experiments at velocities typically exceeding a *v*/*c* of 30%, where *c* is the speed of light. Well-established experimental techniques used for decades to study stable nuclei are not readily applicable in inverse kinematics and at the low beam rates encountered for the shortest-lived nuclear species. Instead, powerful new experimental approaches have been developed to enable in-beam nuclear spectroscopy studies of fast rare-isotope beams with intensities that are several orders of magnitude less than needed for typical low-energy techniques.

The intensities of rare-isotope beams are lower than stable-beam rates by several orders of magnitude. However, the experimental approach of in-beam *γ*-ray spectroscopy compensates for the reduced intensities by enabling thick reaction targets, due to the high beam velocity, and realizing measurements with luminosities comparable to stable-beam experiments but at beam rates of up to a factor of 104 less. Reactions such as nucleon removal are induced in thick reaction targets (several hundred mg/cm2 to g/cm2) and with the detection of *γ* rays for the identification of the reaction residue's final state [10]. Since the residue's *γ*-ray emission occurs *in flight*, the *γ*-ray detection systems have to be granular or position-sensitive to allow for an angle-dependent event-by-event reconstruction of the Doppler-shifted *γ*-ray energies into the rest frame of the emitter. The choice of the target material depends on the desired reaction; one- and two-nucleon knockout reactions [8] are often induced by light targets, for example 9Be or 12C, while quasi-free scattering of the (*p*, 2*p*) or (*p*, *pn*) type are nowadays performed with MINOS, an extended liquid hydrogen target that allows reaction vertex-reconstruction and tracking following the concept of a time projection chamber [13]. The projectile-like reaction residues exiting the target has to be identified with magnetic spectrographs or advanced detector systems to cleanly select the reaction channel of interest. In-beam *γ*-ray spectroscopy programs with fast beams are pursued at a number of fragmentation facilities around the world, while the work using nucleon removal reactions in the *N* = 40 region has been performed largely at NSCL [14] in the US and RIBF/RIKEN [15] in Japan with the GRETINA [16,17] and DALI2 [18] arrays for *γ*-ray spectroscopy, respectively. A sketch of the experimental scheme is shown in Figure 2.

**Figure 2.** Experimental scheme for inverse-kinematics nucleon knockout reactions at rare-isotope beam facilities that provide fast beams of rare isotopes via projectile fragmentation or fission with velocities, *v*, exceeding 30% of the speed of light, *c*.

For 9Be- or 12C-induced one-nucleon knockout reactions, the exit channel of interest is one where—in a single step—one proton or neutron is removed from the fast rareisotope beam and the projectile-like residue with one less nucleon survives in a bound final state. This channel is characterized by swift, surface-grazing collisions of the projectile and the target nuclei. From a large body of experiments performed at energies from 50 MeV/nucleon to more than 1 GeV/nucleon at (rare-isotope) facilities around the world, it has been established that, with large cross sections, the dominant single-hole states relative to the projectile ground state are populated in the projectile-like reaction residue, unambiguously demonstrating the unmatched sensitivity to the single-particle degree of freedom. The residue parallel momentum distributions encode in their shape and width the information of the orbital angular momentum and separation energy of the removed

nucleon [8]. The cross section of the selectively populated single-hole configurations scale with the respective spectroscopic factor or wave-function overlap in a shell-model picture. Statistical descriptions of these reactions will not capture these features. Comparisons of such one-nucleon removal data with nuclear structure calculations have been enabled by a direct reaction model [8,19,20] that uses the sudden (short interaction time) and the spectator-core approximation to many-body eikonal (forward-scattering) theory [19] with a detailed prescription provided in [21]. The single-particle nuclear structure information then enters the calculations through spectroscopic factors, or wave-function overlaps, that scale the calculated cross sections for the removal of one nucleon from the corresponding orbital. With that, the measured knockout cross sections can serve as formidable probes of shell-model interactions on the quest to identify the single-particle makeup of the projectile ground state and the residue final states [8,22].

It has been shown also that two-proton and two-neutron removal from neutron-rich and neutron-deficient projectiles, respectively, also proceed as direct reactions [23–25]. By combining eikonal reaction dynamics, that assumes a sudden single-step removal of two nucleons and shell-model calculations of the two-nucleon amplitudes (TNAs), the cross sections for two-nucleon knockout from the parent-nucleus ground state to each of the final states in the daughter nucleus can be calculated [26]. Also, it was shown that the shape of the parallel momentum distribution of the two-nucleon knockout residues depends strongly on the total angular momentum of the two removed nucleons, allowing spin values to be assigned to populated final states [27–29]. One step further, it was proposed and confirmed that since the two-nucleon overlaps contain components with different values of the total orbital angular momentum, information beyond the total angular momentum can be probed. This opens up the possibility to uniquely explore this composition and couplings within the wave functions of rare isotopes [30,31].

More recently, quasi-free (*p*, 2*p*) and (*p*, *pn*) reactions, extensively used in normal kinematics with stable targets, have been successfully adapted for inverse-kinematics studies of rare-isotope beams on proton targets [9]. Just as the heavy-ion-induced knockout reactions sketched above, the proton-induced knockout reaction selectively probes the single-particle structure of the nucleus of interest. Also, the shape of the momentum distribution of the knockout residue is connected to the momentum distribution of the knocked-out nucleon.  In heavyion induced knockout, the orbital radii need to be modeled precisely due to their surface localization [21]. This experimental approach has been used recently at RIBF/RIKEN for measurements reviewed here. Various reaction models have been developed and their consistency remains a challenge for the future [32]. The different nucleon removal reactions were described and confronted with each other recently and extensive details on sensitivities and model dependencies can be found in reference [32].


**Part 4**

**Hematopoietic Stem Cell Therapy**

344 Advances in Hematopoietic Stem Cell Research

Zulli, A; Buxton, BF; Black, MJ & Hare, DL.. (2005). CD34 Class III positive cells are present

Zuo, F; Kaminski , N; Eugui, E; Allard, J; Yakhini, Z; Ben-Dor, A; Lollini, L; Morris, D;

*Cell Biology*, Vol. 124, pp: 517-522.

Vol.99, pp: 6292–6297.

in atherosclerotic plaques of the rabbit model of atherosclerosis. *Histochemestry and*

Kim, Y; DeLustro, B ; Sheppard D; Pardo, A; Selman, M & Heller, RA. (2002). Gene expression analysis reveals matrilysin as a key regulator of pulmonary brosis in mice and humans. *Proccedings of the National Academy of Sciences USA,*

**16**

*USA*

**Applications**

*Children's Mercy Hospital in Kansas City, MO,*

Carla McCrave

**Hematopoietic Stem Cells Therapeutic**

Hematopoietic stem cell transplantation (HSCT) has become an established treatment for malignant hematological diseases, solid malignancies and non-malignant diseases **(**figure 1). Newer indications for HSCT have emerged because of better understanding of human immunology, tumor biology and immunotherapy (table 1). Novel approaches have resulted in increase number of transplants as well as significant reductions in the morbidity and mortality associated with HSCT. These include more suitable donors with the addition of unrelated cord blood units (single & double) and partially matched family members; and novel conditioning regimens (reduced & non-myeloablative) that allow patients with significant co-morbidities to undergo transplantation. On the other hand, the introduction of alternative therapies, such as imatinib (tyrosine kinase inhibitor) for chronic myelogenous leukemia (CML), has challenged well established indications. This chapter summarizes the current indications for HSCT in pediatrics and address recent clinical developments in the

**1. Introduction**

field of HSCT.

Fig. 1. Indications for HSCT


**6. Acknowledgements**

The chapter has been done in connection with project Institute of clean technologies for mining and utilization of raw materials for energy use, reg. no. CZ.1.05/2.1.00/03.0082 supported by Research and Development for Innovations Operational Programme financed by Structural Founds of Europe Union and from the means of state budget of the Czech Republic. Presented work was also supported by the Academy of Sciences of the Czech Republic, project No. AV0Z30860518. Author is thankful for the support.


Contents

Preface

The recalcitrant and alarming title of Ioannidis' research article from 2005 (quoted above) addressed a growing concern that the current practice of statistics to a significant extent could be flawed. In his book Willful Ignorance: The Mismeasure of Uncertainty (2009), Herbert Weisberg pointed out the nearly abyssal difference in perspectives of quantitative and qualitative studies and reflected on the historical evolution of statistics, displeased by the fact that practical scientists nowadays systematically avoid discussing the meaning of probability, despite its being intensively debated for over two centuries. These claims of doubt were accompanied by Alex Reinhard, who in his book Statistics Done Wrong: The Woefully Complete Guide (2015) discussed a number of questionable ways statistical analyses of today are

The famous statistician R.A. Fisher stated in the early 20th century that: "The tendency of modern scientific teaching is to neglect the great books, to lay far too much stress upon relatively unimportant modern work, and to present masses of detail of doubtful truth and questionable weight in such a way as to obscure principles." In the modern society flooded not only by massive unleashed computational power but also by data-based artificial intelligence and unprecedented means to craft stunning graphics, it is not at all surprising that people at large are struggling to distinguish facts from fake. Fisher's concern from the 1930s suddenly appears more alive than ever before. The need to re-evaluate statistical practices thus steadily seem to grow

These observations suggest current statistical methodologies may have gone too far into an engineering practice with minimal questioning. As an example, multiple tests are often launched in scientific studies to enhance the likelihood of finding a

In the modern age pervaded by data in various forms, statistical processing affects almost everyone, whether we like it or not. Internet-based analyses operate on sample sets almost as big as the populations they are drawn from. Behavioral, political, and customer surveys are frequently made. Despite this, the basic principles and practices have remained remarkably intact over the years. In stark contrast stands the rapid evolution of computer programming methodologies and development of convenient, flexible, high-level, and broadly accessible software tools for statistical analysis and presentation, like Python, R, Matlab/Octave, etc. To fully utilize their potential rather than be distracted and paralyzed by their breathtaking performance, good statistical methodologies and practices are of greater value than

ever before. This context provided the basic motivation for this book.

A selection of various aspects of statistical methodologies are here presented by independent authors. The chapters are not meant to be exhaustive or representative, even though each contribution is self-contained and complete within the task

significant result, although this should be impossible …

"Why Most Published Research Findings Are False"

performed.

the more they are utilized.


**Recent Advancement of Thermal Fluid Engineering in the Supercritical CO**2 **Power Cycle**

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