Miracle-dz/UniFAR-FTUs huggingface dataset:
FUNCTIONAL EFFECTS OF POLYMORPHISMS IN THE HUMAN GENE ENCODING 11β-HSD1: A SEQUENCE VARIANT AT THE TRANSLATION START OF 11β-HSD1 ALTERS ENZYME LEVELS

Regeneration of active glucocorticoids within liver and adipose tissue by the enzyme 11βhydroxysteroid dehydrogenase type 1 (11β-HSD1) may be of pathophysiological importance in obesity and Metabolic Syndrome and is a therapeutic target in type 2 diabetes. Polymorphisms in HSD11B1, the gene encoding 11β-HSD1, have been associated with metabolic phenotype in humans, including type 2 diabetes and hypertension. Here we have tested the functional consequences of 2 single nucleotide polymorphisms located in contexts that potentially affect tissue levels of 11β-HSD1. We report no effect of allelic variation at rs846910, a polymorphism within the 5′-flanking region of the gene on HSD11B1 promoter activity in vitro. However, compared to the common G allele, the A allele of rs13306421, a polymorphism located 2 nucleotides 5′ to the translation initiation site, gave higher 11β-HSD1 expression and activity in vitro and was translated at higher levels in in vitro translation reactions, possibly associated with a lower frequency of “leaky scanning”. These data suggest that this polymorphism may have direct functional consequences on levels of 11β-HSD1 enzyme activity in vivo. However, the rs13306421 A sequence variant originally reported in other ethnic groups may be of low prevalence as it was not detected in a population of 600 European caucasian women.
Some studies on solar optical flares reported under new classification.

Solar optical flares, numbering 8230, reported during the period September 1967 to November 1969,which covers the peak phase of the current solar cycle, were examined in relation to (1) percentage occurrences under different classes, (2) position on the solar disk, (3) risetime and duration, and (4) associated visual indications, numbering 26. From the study of the relative percentage occurrences of flares, it has been found that maximum occurrences under different classifications are as follows: 58% normal (n), 82% subflares (8), and 47% dual importance (8n). Percentage occurrences of flares under classes 2 and 3 increase with higher order of the intensity range and class 3 flares appear to be mostly bright. Regarding the distribution of flares on the solar disk, a strong north-south asymmetry (over 60% occurring in the northern hemisphere) exists for all classes of flares. East-west asymmetry is, however, ne~li~ible. Bright flares (b) are found to be inherently more impulsive in nature and the explosive phase (V) is mostly associated with these. Percentages of flares having some form of visual indications increase with increasing importance. Brilliant points (D and E), high velocity dark surges (H), and eruptive centres (F) are found to be relatively more important in all classes of flares.
Predictors and Outcomes of Variability in Subjective Alcohol Intoxication among College Students: An Event-Level Analysis across Four Years

Background—Individual differences in subjective alcohol intoxication, as measured by laboratory-based alcohol challenge, have been identified as a phenotypic risk factor for alcohol use disorders. Further, recent evidence indicates that subjective alcohol response is also associated with event-level physiological consequences among college students, including blackouts and hangovers. Methods—The current investigation tested predictors of and outcomes associated with subjective intoxication in the natural drinking environment. In a preliminary laboratory alcohol-challenge study (N = 53), we developed a brief measure of subjective alcohol intoxication for use in event level research. Participating students in the principal study (N = 1,867; 63% female; 54% Caucasian) completed 30 days of Web-based self-monitoring in each of the four college years. Results—In the principal study, Generalized Estimating Equation analyses revealed that both lighter drinking and a family history of alcohol problems predicted greater subjective intoxication after accounting for estimated blood alcohol concentration (eBAC). Moreover, greater subjective intoxication during a given drinking episode was associated with negative alcohol-related consequences, illicit drug use, and unsafe sex, and at higher eBACs, was associated with aggression, sex, and property crime. Students who on average experienced greater subjective intoxication were also more likely to experience negative consequences and engage in illicit drug use, sex, unsafe sex, and aggression. Conclusions—These findings suggest that both within-person variability and between-person individual differences in subjective intoxication may be risk factors for adverse drinking outcomes at the event level. Intervention efforts aimed at reducing problems associated with collegiate drinking may benefit from consideration both of who experiences greater subjective intoxication and of the situations in which they are more likely to do so.
Role of Parent-Reported Executive Functioning and Anxiety inInsistence on Sameness in Individuals with Germline PTENMutations

No studies to date have explored the correlates of insistence on sameness (IS) in individuals with germline pathogenic mutations in PTEN. This study aimed to characterize the relationship between IS and executive functioning (EF) and anxiety as well as with age, sex and Full-Scale IQ (FSIQ) among individuals with PTEN mutations. The sample included 38 individuals with PTEN mutation and ASD diagnosis (PTEN-ASD; n = 38; Mage= 8.93 years, SDage= 4.75), 25 with
Current Role of fMRI in diagnosis of movement disorders

The emergence of functional magnetic resonance techniques for the purpose of brain mapping serves as a valuable tool for understanding both normal physiology and the dysfunction taking place in disorders of the brain. This article provides an overview of fMRI methods and their applications in the study of neurological movement disorders. We then review the current neuroimaging literature regarding Parkinsonisms, Dystonia, Essential Tremor, and Huntington’s disease, including discussion of current methodological limitations and future directions for this exciting field.
Motion in Migrating Neutrophils

The relationship between cytosolic free calcium concentration ([Ca2+]i) and human neutrophil motility was studied by video microscopy. Neutrophils stimulated by a uniform concentration of an Nformylated peptide chemoattractant (f-MetLeu-Phe) were tracked during chemokinetic migration on albumin, fibronectin, and vitronectin. [Ca2+]i buffering with quin2 resulted in significant decreases in mean speed on albumin. To further characterize the relationship between [Ca2+]i changes and motility we carried out a cross-correlation analysis of [Ca2+]i with several motility parameters. Cross-correlations between [Ca2+]i and each cell's speed, angle changes, turn strength, and persistent forward motion revealed (i) a positive correlation between [Ca2+]i and cell speed (p < 0.05), (ii) no significant correlation between turns and calcium spikes, and (iii) the occurrence of turns during periods of low speed. Significant negative correlations between [Ca2+]i and angle change were noted on the high adhesion substrates vitronectin and fibronectin but not on the low adhesion substrate albumin. These data imply that there is a general temporal relationship between [Ca2+]j, speed, and persistent motion. However, the correlations are not sufficiently strong to imply that changes in [Ca>2+] are required proximal signals for velocity changes.
Cutting Edge: Heterogeneity in cell age contributes to functional diversity of natural killer cells

Heterogeneity among naïve adaptive lymphocytes determines their individual functions and fate decisions during an immune response. Natural killer (NK) cells are innate lymphocytes capable of generating ‘adaptive’ responses during infectious challenges. However, the factors that govern various NK cell functions are not fully understood. Here, we use a reporter mouse model to permanently ‘time-stamp’ NK cells and type 1 innate lymphoid cells (ILC1s) in order to characterize the dynamics of their homeostatic turnover. We found that the homeostatic turnover of tissue-resident ILC1s is much slower than that of circulating NK cells. NK cell homeostatic turnover is further accelerated without the transcription factor Eomes. Finally, heterogeneity in NK cell age diversifies NK cell function, with ‘older’ NK cells exhibiting more potent IFN-γ production to activating stimuli, and more robust adaptive responses during cytomegalovirus infection. These results provide insight into how the functional response of an NK cell varies over its lifespan.
Cross-regulation of Signaling and Immune Responses by IFN-γ and STAT1

IFN-γ is an important mediator of immunity and inflammation that utilizes the Jak-STAT pathway to activate STAT1. Many functions of IFN-γ have been ascribed to direct STAT1-mediated induction of immune effector genes, but recently it has become clear that key IFN-γ functions are mediated by crossregulation of cellular responses to other cytokines and inflammatory factors. Here we review mechanisms by which IFN-γ and STAT1 regulate signaling by TLRs, inflammatory factors, tissue destructive cytokines, anti-inflammatory cytokines, and cytokines that activate opposing STATs. These signaling mechanisms reveal insights about how IFN-γ regulates macrophage activation, inflammation, tissue remodeling, and Th and Treg differentiation, and how Th1 and Th17 responses are integrated in autoimmune diseases.
von Willebrand factor antigen, von Willebrand factor propeptide and ADAMTS13 in carotid stenosis and their relationship with cerebral micro-emboli

SJX Murphy, PhD, MRCPI, MRCP (UK)1,2, ST Lim, MRCPI1,2,3, F Hickey, PhD4, JA Kinsella, FRCPI5, S Tierney, FRCSI7, B Egan, FRCSI7, TM Feeley, FRCSI7,8, SM Murphy, FRCPI1,2,9, RA Walsh, MD2,15, DR Collins, MD2,10, T Coughlan, FRCPI2,10, D O’Neill, FRCPI2,10, JA Harbison, FRCPI11, P Madhavan, FRCS (Ed)12, SM O’Neill, FRCSI12, MP Colgan, MD12, JM O’Sullivan, PhD14,15, JS O’Donnell, PhD, FRCPI13,14,15, G Hamilton, FRCS16, DJH McCabe, PhD, FRCPI, FESO1,2,3,6,9,15
Kinetic Evidence for Inter-Domain Communication in the Allosteric Regulation of α-Isopropylmalate Synthase from M. tuberculosis†

The enzyme α-isopropylmalate synthase from Mycobacterium tuberculosis (MtIPMS) has been identified as a possible target for design of new anti-tubercular therapeutics. Recently it was shown that MtIPMS is subject to slow-onset, feedback inhibition by L-leucine, the first instance of an allosteric regulator utilizing this mechanism. Structural studies are inconsistent with allosteric mechanisms including changes to the quarternary structure or large, rigid-body conformational changes to the enzyme upon L-leucine binding. Thus, the allosteric regulation may result from a discrete inhibitory signal transmitted to the active site upon L-leucine binding in the regulatory domain, a distance of over 50 Å In order to test this mechanism, site-directed mutagenesis was employed to construct enzymes with substitutions at phylogenetically conserved active site residues near the interface of the catalytic and linker domains. The substitutions had wide ranging effects on the kinetics of L-leucine inhibition, with some modest effects on the kinetic parameters of catalysis. The most dramatic result was the finding that the Y410F mutant form of MtIPMS is insensitive to L-leucine inhibition, suggesting that this residue has completely uncoupled the inhibitory signal to the active site. Overall, the data are consistent with a mechanism of allosteric regulation described by the inter-domain communication of the inhibitory signal from the regulatory to catalytic domain and implicate the interaction between the linker and catalytic domains as critical determinants of inhibitory signal transmission.
In Vivo P-NMR Diffusion Spectroscopy of ATP and Phosphocreatine in Rat Skeletal Muscle

The aim of this study was to measure the diffusion of ATP and phosphocreatine (PCr) in intact rat skeletal muscle, using P-NMR. The acquisition of the diffusion-sensitized spectra was optimized in terms of the signal-to-noise ratio for ATP by using a frequency-selective stimulated echo sequence in combination with adiabatic radio-frequency pulses and surface coil signal excitation and reception. Diffusion restriction was studied by measuring the apparent diffusion coefficients of ATP and PCr as a function of the diffusion time. Orientation effects were eliminated by determining the trace of the diffusion tensor. The data were fitted to a cylindrical restriction model to estimate the unbounded diffusion coefficient and the radial dimensions of the restricting compartment. The unbounded diffusion coefficients of ATP and PCr were ;90% of their in vitro values at 37°C. The diameters of the cylindrical restriction compartment were ;16 and ;22 mm for ATP and PCr, respectively. The diameters of rat skeletal muscle fibers are known to range from 60 to 80 mm. The modelling therefore suggests that the in vivo restriction of ATP and PCr diffusion is not imposed by the sarcolemma but by other, intracellular structures with an overall cylindrical orientation.
Two-photon image-scanning microscopy with SPAD array and blind image reconstruction

: Two-photon excitation (2PE) laser scanning microscopy is the imaging modality of choice when one desires to work with thick biological samples. However, its spatial resolution is poor, below confocal laser scanning microscopy. Here, we propose a straightforward implementation of 2PE image scanning microscopy (2PE-ISM) that, by leveraging our recently introduced single-photon avalanche diode (SPAD) array detector and a novel blind image reconstruction method, is shown to enhance the eﬀective resolution, as well as the overall image quality of 2PE microscopy. With our adaptive pixel reassignment procedure ∼ 1.6 times resolution increase is maintained deep into thick semi-transparent samples. The integration of Fourier ring correlation based semi-blind deconvolution is shown to further enhance the eﬀective resolution by a factor of ∼ 2 – and automatic background correction is shown to boost the image quality especially in noisy images. Most importantly, our 2PE-ISM implementation requires no calibration measurements or other input from the user, which is an important aspect in terms of day-to-day usability of the technique.
The selective RhoA inhibitor Rhosin promotes stress resiliency through enhancing D1-MSN plasticity and reducing hyperexcitability

Background: Nucleus Accumbens (NAc) dopamine 1 receptor medium spiny neurons (D1MSNs) play a critical role in the development of depression-like behavior in mice. Social defeat stress causes dendritic morphological changes on this MSN subtype through expression and activation of early growth response 3 (EGR3) and the Rho GTPase RhoA. However, it is unknown how RhoA inhibition affects electrophysiological properties underlying stress-induced susceptibility. Methods: A novel RhoA specific inhibitor, Rhosin, was utilized to inhibit RhoA activity following chronic social defeat stress. Whole-cell electrophysiological recordings of D1-MSNs were performed to assess synaptic and intrinsic consequences of Rhosin treatment on stressed mice. Additionally, recorded cells were filled and analyzed for their morphological properties. Results: We found RhoA inhibition prevents both D1-MSN hyperexcitability and reduced excitatory input to D1-MSNs caused by social defeat stress. NAc specific RhoA inhibition is capable of blocking susceptibility caused by D1-MSN EGR3 expression. Lastly, we found Rhosin enhances spine density, which correlates with D1-MSN excitability, without affecting overall dendritic branching. Conclusions: These findings demonstrate pharmacological inhibition of RhoA during stress drives an enhancement of total spine number in a subset of NAc neurons that prevents stressrelated electrophysiological deficits and promotes stress resiliency. Correspondence to: Mary Kay Lobo, Ph.D., University of Maryland School of Medicine, Department of Anatomy and Neurobiology, 20 Penn Street, HSF2, Rm 265, Baltimore, MD 21201, mklobo@som.umaryland. edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosures The authors report no biomedical financial interests or potential conflicts of interest. HHS Public Access Author manuscript Biol Psychiatry. Author manuscript; available in PMC 2020 July 18. Published in final edited form as: Biol Psychiatry. 2019 June 15; 85(12): 1001–1010. doi:10.1016/j.biopsych. 2019.02. 007. A uhor M anscript
NEW CONCEPTS Antiaging Compounds: (–)Deprenyl (Selegiline) and (–)1-(Benzofuran-2-yl)-2-propylaminopentane, [(–)BPAP], a Selective Highly Potent Enhancer of the Impulse Propagation Mediated Release of Catecholamines and Serotonin in the Brain

Hundreds of millions of people now die over the age of 80 years primarily due to twentieth century progress in hygiene, chemotherapy, and immunology. With a longer average lifespan, the need to improve quality of life during the latter decades is more compelling. “Aging — The Epidemic of the New Millenium,” a recent international conference (Monte Carlo, June 17–18, 2000), showed with peculiar clarity that a safe and efficient drug strategy to slow the age-related decay of brain performance is still missing. This review summarizes the physiologic and pharmacologic arguments in favor of a peculiar lifelong prophylactic medication with reasonable chances to keep in check brain aging and decrease the precipitation of age-related neurological diseases. 317 CNS Drug Reviews Vol. 7, No. 3, pp. 317–345 © 2001 Neva Press, Branford, Connecticut Address correspondence and reprint requests to: Prof. J. Knoll, Department of Pharmacology, Faculty of General Medicine, Semmelweis University, Budapest, P.O. B. , H-1445, Hungary. Tel. Fax: +36 (1) 210-4405; E-mail: joszefknoll@hotmail.com.
HIV infection alters energy metabolism in the brain: contributions to HIV-associated neurocognitive disorders

The brain is particularly sensitive to changes in energy supply. Defects in glucose utilization and mitochondrial dysfunction are hallmarks of nearly all neurodegenerative diseases and are also associated with the cognitive decline that occurs as the brain ages. Chronic neuroinflammation driven by glial activation is commonly implicated as a contributing factor to neurodegeneration and cognitive impairment. Human immunodeficiency virus (HIV) disrupts normal brain homeostasis and leads to a spectrum of HIV-associated neurocognitive disorders (HAND). HIV activates stress responses in the brain and triggers a state of chronic neuroinflammation. Growing evidence suggests that inflammatory processes and bioenergetics are interconnected in the propagation of neuronal dysfunction. Clinical studies of HIV-infected individuals and basic research support the notion that HIV creates an environment in the CNS that interrupts normal metabolic processes at the cellular level and collectively alter whole brain metabolism. In this review, we highlight reports of abnormal brain metabolism from clinical studies and animal models. We also describe diverse CNS cell-specific changes in bioenergetics associated with HIV. Moreover, we propose that attention should be given to adjunctive therapies that combat sources of metabolic dysfunction as a mean to improve and prevent neurocognitive impairments.
Human Leukocyte Antigen-G Is Frequently Expressed in Glioblastoma and May Be Induced inVitro by Combined 5-Aza-2-Deoxycytidine and Interferon- Treatments

From the Commissariat à l’Energie Atomique et aux Energies Alternatives,* Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, and the Université Paris-Diderot,y Sorbonne Paris-Cité, UMR E5, Institut Universitaire d’Hématologie, Hôpital SaintLouis, Paris, France; the Divisão de Imunologia Clínica,z Departamento de Clínica Médica, and Departamento de Cirurgia,yy Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brasil; the Centre National de la Recherche Scientifique,x and the Université de Caen BasseNormandie,k and Commissariat à l’Energie Atomique et aux Energies Alternatives,{ Institut d’Imagerie Biomédicale, UMR 6301 ISTCT, UMR 6301 ISTCT, CERVOxy group, GIP CYCERON, Caen, France; the Centre Hospitalier Universitaire de Caen,** Service d’Anatomie Pathologique, Caen, France; the Department of Pathology,zz Odense University Hospital and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; and the Departments of Surgery, Immunology, and Pathology,xx University of Pittsburgh Cancer Institute, Pittsburgh, Pennsyvania
Satisfaction with Life after Mild Traumatic Brain Injury: A TRACK-TBI Study

Identifying the principal determinants of life satisfaction following mild TBI (mTBI) may inform efforts to improve subjective well-being in this population. We examined life satisfaction among participants in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study who presented with mTBI (Glasgow Coma Scale [GCS] score = 13–15; n = 1152). An L1-regularization path algorithm was used to select optimal sets of baseline and concurrent symptom measures for prediction of scores on the Satisfaction with Life Scale (SWLS) at 2 weeks and 3, 6, and 12 months post-injury. Multi-variable linear regression models (all n = 744–894) were then fit to evaluate associations between the empirically selected predictors and SWLS scores at each follow-up visit. Results indicated that emotional post-TBI symptoms (all b = -1.27 to -0.77, all p < 0.05), anhedonia (all b = -1.59 to -1.08, all p < 0.01), and pain interference (all b = -1.38 to -0.89, all p < 0.001) contributed to the prediction of lower SWLS scores at all follow-ups. Insomnia predicted lower SWLS scores at 2 weeks, 3 months, and 6 months (all b = -1.11 to -0.83, all ps < 0.01); and negative affect predicted lower SWLS scores at 2 weeks, 3 months, and 12 months (all b = -1.38 to -0.80, all p < 0.005). Other post-TBI symptom domains and baseline socio-demographic, injury-related, and clinical characteristics did not emerge as robust predictors of SWLS scores during the year after mTBI. Efforts to improve satisfaction with life following mTBI may benefit from a focus on the detection and treatment of affective symptoms, pain, and insomnia. The results reinforce the need for tailoring of evidence-based treatments for these conditions to maximize efficacy in patients with mTBI.
The macromolecular architecture of the extracellular domain of αNRXN1: domain organization, flexibility, and insights into trans-synaptic disposition

Neurexins are multi-domain synaptic cell-adhesion proteins that associate with multiple partnering proteins. Genetic evidence indicates that neurexins may contribute to autism, schizophrenia and nicotine dependence. Using analytical ultracentrifugation, single particle electron microscopy, and solution X-ray scattering, we obtained a three-dimensional structural model of the entire extracellular domain of neurexin-1α. This protein adopts a dimensionally asymmetric conformation that is monomeric in solution with a maximum dimension of ~170Å. The extracellular domain of α-neurexin maintains a characteristic “Y” shape, whereby LNS domains 1–4 form an extended base of the “Y” and LNS5–6 the shorter arms. Moreover, two major regions of flexibility are present: one between EGF1 and LNS2, corresponding to splice site 1, another between LNS5 and 6. We thus provide the first structural insights into the architecture of the extracellular region of neurexin-1α, show how the protein may fit in the synaptic cleft, and how partnering proteins could bind simultaneously.