Miracle-dz/UniFAR-FTUs huggingface dataset:
Phosphorylation Induced Conformational Transitions in DNA Polymerase β

DNA polymerase β (pol β) is a member of the X- family of DNA polymerases that catalyze the distributive addition of nucleoside triphosphates during base excision DNA repair. Previous studies showed that the enzyme was phosphorylated in vitro with PKC at two serines (44 and 55), causing loss of DNA polymerase activity but not DNA binding. In this work, we have investigated the phosphorylation-induced conformational changes in DNA polymerase β in the presence of Mg ions. We report a comprehensive atomic resolution study of wild type and phosphorylated DNA polymerase using molecular dynamics (MD) simulations. The results are examined via novel methods of internal dynamics and energetics analysis to reveal the underlying mechanism of conformational transitions observed in DNA pol β. The results show drastic conformational changes in the structure of DNA polymerase β due to S44 phosphorylation. Phosphorylation-induced conformational changes transform the enzyme from a closed to an open structure. The dynamic cross-correlation shows that phosphorylation enhances the correlated motions between the different domains. Centrality network analysis reveals that the S44 phosphorylation causes structural rearrangements and modulates the information pathway between the Lyase domain and base pair binding domain. Further analysis of our simulations reveals that a critical hydrogen bond (between S44 and E335) disruption and the formation of three additional salt bridges are potential drivers of these conformational changes. In addition, we found that two of these additional salt bridges form in the presence of Mg ions on the active sites of the enzyme. These results agree with our previous study of DNA pol β S44 phosphorylation without Mg ions which predicted the deactivation of DNA pol β. However, the phase space of structural transitions induced by S44 phosphorylation is much richer in the presence of Mg ions.
Biological Characteristics of HLA-G and Its Role in Solid Organ Transplantation

Organ transplantation is a lifesaving option for patients with advanced diseases. Rejection is regarded as one of the most severe risk factors post-transplantation. A molecule that contributes to immune tolerance and resisting rejection is human leukocyte antigen (HLA)-G, which belongs to the non-classical major histocompatibility complex class (MHC) I family. HLA-G was originally found to play a role during pregnancy to maintain immune tolerance between mother and child. It is expressed in the placenta and detected in several body fluids as soluble factor as well as different membrane isoforms on cells. Recent findings on HLA-G show that it can also play multifaceted roles during transplantation. This review will explain the general characteristics and biological function of HLA-G and summarize the views supporting the tolerogenic and other roles of HLA-G to better understand its role in solid organ transplantation (SOT) and its complications. Finally, we will discuss potential future research on the role of HLA-G in prevention, diagnosis, and treatment in SOT.
Water and Nitrogen Management at the Booting Stage Affects Yield, Grain Quality, Nutrient Uptake, and Use Efficiency of Fragrant Rice Under the Agro-Climatic Conditions of South China

The present study was conducted to assess the effects of water and nitrogen applications at the booting stage on yield, grain quality, and nutrient use efficiencies in fragrant rice in the early (March–July) and late (July–November) seasons of 2013. The experiment was comprised of two fragrant rice cultivars, i.e., Nongxiang 18 and Basmati; three nitrogen levels, i.e., 0 kg N ha−1 (N0), 30 kg N ha−1 (N1), and 60 kg N ha−1 (N2); and three water levels, i.e., 2–4 cm water layer well-watered (W0), water with a soil water potential of −15 ± 5 kPa (W1), and water with a soil water potential of −25 ± 5 kPa (W2), which were randomized in a split-split plot design. Results showed that Basmati produced a higher grain yield than Nongxiang 18 (16.20 and 9.61% in the early and late season, respectively), whereas the W1 exhibited the maximum grain yield and harvest index. The moderate application of nitrogen (N1) at the booting stage resulted in higher grain yield, nevertheless, cultivar, water, and nitrogen revealed different trends for some of the grain quality attributes, i.e., brown rice rate, milled rice rate, head milled rice rate, protein content, and amylose content as well as nutrient uptake and use efficiencies in the double rice production system. Basmati had a higher nitrogen harvest index (NHI; 18.28–20.23%) and P harvest index (PHI; 3.95–12.42%) but lower physiological P use efficiency for biomass (PPUEB; 7.66–23.66%) and physiological K use efficiency for biomass (PKUEB; 2.53–7.10%) than Nongxiang 18 in both seasons. Furthermore, the grain number per panicle, biomass yield, grain P uptake, and the whole plant P uptake were significantly related to the grain yield of fragrant rice. In both seasons, the interaction of water and nitrogen (W × N) had a significant effect on panicle number, grain quality attributes, and N, P uptake of straw, as well as the physiological N, P use efficiency for grain and the physiological N, K use efficiency for biomass. Overall, results suggest that moderate nitrogen and irrigation input at the booting stage could be feasible to improve the productivity and quality of the double rice production system with improved nutrient use efficiency under the agro-climatic conditions of South China.
DEAD-ly Affairs: The Roles of DEAD-Box Proteins on HIV-1 Viral RNA Metabolism

In order to ensure viral gene expression, Human Immunodeficiency virus type-1 (HIV-1) recruits numerous host proteins that promote optimal RNA metabolism of the HIV-1 viral RNAs (vRNAs), such as the proteins of the DEAD-box family. The DEAD-box family of RNA helicases regulates multiple steps of RNA metabolism and processing, including transcription, splicing, nucleocytoplasmic export, trafficking, translation and turnover, mediated by their ATP-dependent RNA unwinding ability. In this review, we provide an overview of the functions and role of all DEAD-box family protein members thus far described to influence various aspects of HIV-1 vRNA metabolism. We describe the molecular mechanisms by which HIV-1 hijacks these host proteins to promote its gene expression and we discuss the implications of these interactions during viral infection, their possible roles in the maintenance of viral latency and in inducing cell death. We also speculate on the emerging potential of pharmacological inhibitors of DEAD-box proteins as novel therapeutics to control the HIV-1 pandemic.
Déformation et construction de surfaces minimales

L'objet de cette these consiste en la construction de nouveaux exemples de surfaces (ou hypersurfaces) minimales dans les espaces euclidiens R^3, R^n x R avec n>2 ou dans l'espace homogene S^2 x R. Nous prouvons l'existence de surfaces minimales dans R^3 arbitrairement proches d'un polygone convexe. Nous prouvons egalement l'existence d'hypersurfaces minimales de type Riemann dans R^n x R, n>2. Celles-ci peuvent etre interpretees comme etant une famille d'hyperplans horizontaux (des bouts) relies les uns aux autres par des morceaux de catenoides deformes (des cous). Nous donnons un resultat general pour ce type d'objet quand il est periodique ou bien quand il a un nombre fini de bouts horizontaux. Cela se fait sous certaines hypotheses de contraintes sur les forces intervenant dans la construction. Nous finissons en donnant plusieurs exemples, notamment l'existence d'une hypersurface de type Wei verticale qui n'existe pas en dimension 3. Nous donnons aussi la preuve de l'existence d'une surface minimale de type Riemann dans S^2 x R telle que deux bouts spheriques sont relies entre eux alternativement par 1 cou et 2 cous. La aussi, nous mettons en evidence le role joue par les forces lors de la construction. De meme que dans le chapitre precedent, la methode repose sur un processus de recollement. Nous donnons une description tres precise de la catenoide et la surface de Riemann dans S^2 x R. Enfin, nous etablissons l'existence dans R^n x R d'hypersurfaces de type Scherk lorsque n>2
3D-Cultured Vascular-Like Networks Enable Validation of Vascular Disruption Properties of Drugs In Vitro

Vascular-disrupting agents are an interesting class of anticancer compounds because of their combined mode of action in preventing new blood vessel formation and disruption of already existing vasculature in the immediate microenvironment of solid tumors. The validation of vascular disruption properties of these drugs in vitro is rarely addressed due to the lack of proper in vitro angiogenesis models comprising mature and long-lived vascular-like networks. We herein report an indirect coculture model of human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts (HDFs) to form three-dimensional profuse vascular-like networks. HUVECs embedded and sandwiched in the collagen scaffold were cocultured with HDFs located outside the scaffold. The indirect coculture approach with the vascular endothelial growth factor (VEGF) producing HDFs triggered the formation of progressively maturing lumenized vascular-like networks of endothelial cells within less than 7 days, which have proven to be viably maintained in culture beyond day 21. Molecular weight-dependent Texas red-dextran permeability studies indicated high vascular barrier function of the generated networks. Their longevity allowed us to study the dose-dependent response upon treatment with the three known antiangiogenic and/or vascular disrupting agents brivanib, combretastatin A4 phosphate (CA4P), and 6´-sialylgalactose (SG) via semi-quantitative brightfield and qualitative confocal laser scanning microscopic (CLSM) image analysis. Compared to the reported data on in vivo efficacy of these drugs in terms of antiangiogenic and vascular disrupting effects, we observed similar trends with our 3D model, which are not reflected in conventional in vitro angiogenesis assays. High-vascular disruption under continuous treatment of the matured vascular-like network was observed at concentrations ≥3.5 ng·ml−1 for CA4P and ≥300 nM for brivanib. In contrast, SG failed to induce any significant vascular disruption in vitro. This advanced model of a 3D vascular-like network allows for testing single and combinational antiangiogenic and vascular disrupting effects with optimized dosing and may thus bridge the gap between the in vitro and in vivo experiments in validating hits from high-throughput screening. Moreover, the physiological 3D environment mimicking in vitro assay is not only highly relevant to in vivo studies linked to cancer but also to the field of tissue regeneration.
Three Physiological Components That Influence Regional Cerebral Tissue Oxygen Saturation

Near-infrared spectroscopy (NIRS) measurement of regional cerebral tissue oxygen saturation (rcStO2) has become a topic of high interest in neonatology. Multiple studies have demonstrated that rcStO2 measurements are feasible in the delivery room during immediate transition and resuscitation as well as after admission to the neonatal intensive care unit. Reference ranges for different gestational ages, modes of delivery, and devices have already been published. RcStO2 reflects a mixed tissue saturation, composed of arterial (A), venous (V), and capillary signals, derived from small vessels within the measurement compartment. The A:V signal ratio fluctuates based on changes in oxygen delivery and oxygen consumption, which enables a reliable trend monitoring of the balance between these two parameters. While the increasing research evidence supports its use, the interpretation of the absolute values of and trends in rcStO2 is still challenging, which halts its routine use in the delivery room and at the bedside. To visualize the influencing factors and improve the understanding of rcStO2 values, we have created a flowchart, which focuses on the three major physiological components that affect rcStO2: oxygen content, circulation, and oxygen extraction. Each of these has its defining parameters, which are discussed in detail in each section.
Extracellular Vesicles in Pathogenesis and Treatment of Metabolic Associated Fatty Liver Disease

Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide due to the sedentary and overeating lifestyle. Yet, the pathophysiology of MAFLD is still unclear and no drug has been approved for MAFLD treatment. Extracellular vesicles (EVs) are heterogenous membrane-bound particles released from almost all types of cells. These nano-sized particles mediate intercellular communication through their bioactive cargos including nucleic acids, proteins, and lipids. The EVs modulate metabolic homeostasis via communication between adipose tissue and liver. The dysregulation of lipid metabolism leads to inflammation in liver and the number and compounds of EVs are changed during MAFLD. The injured hepatocytes secrete EVs to induce the migration of bone marrow-derived monocytes and the activation of macrophages in liver. The EVs secreted by different cells regulate the alteration of hepatic stellate cell (HSC) phenotypes and HSC activation gives rise to liver fibrosis. Based on the participation of EVs in MAFLD progression, we discuss the prospects of EVs as a therapeutic target and their application in drug delivery.
The Human SCN9AR185H Point Mutation Induces Pain Hypersensitivity and Spontaneous Pain in Mice

The voltage-gated sodium channel Nav1.7 is encoded by SCN9A gene and plays a critical role in pain sensitivity. Several SCN9A gain-of-function (GOF) mutations have been found in patients with small fiber neuropathy (SFN) having chronic pain, including the R185H mutation. However, for most of these variants, their involvement in pain phenotype still needs to be experimentally elucidated. In order to delineate the impact of R185H mutation on pain sensitivity, we have established the Scn9aR185H mutant mouse model using the CRISPR/Cas9 technology. The Scn9aR185H mutant mice show no cellular alteration in the dorsal root ganglia (DRG) containing cell bodies of sensory neurons and no alteration of growth or global health state. Heterozygous and homozygous animals of both sexes were investigated for pain sensitivity. The mutant mice were more sensitive than the wild-type mice in the tail flick and hot plate tests, acetone, and von Frey tests for sensitivity to heat, cold, and touch, respectively, although with sexual dimorphic effects. The newly developed bioinformatic pipeline, Gdaphen is based on general linear model (GLM) and random forest (RF) classifiers as well as a multifactor analysis of mixed data and shows the qualitative and quantitative variables contributing the most to the pain phenotype. Using Gdaphen, tail flick, Hargreaves, hot plate, acetone, cold plate, and von Frey tests, sex and genotype were found to be contributing most to the pain phenotype. Importantly, the mutant animals displayed spontaneous pain as assessed in the conditioned place preference (CPP) assay. Altogether, our results indicate that Scn9aR185H mice show a pain phenotype, suggesting that the SCN9AR185H mutation identified in patients with SFN having chronic pain contributes to their symptoms. Therefore, we provide genetic evidence for the fact that this mutation in Nav1.7 channel plays an important role in nociception and in the pain experienced by patients with SFN who have this mutation. These findings should aid in exploring further pain treatments based on the Nav1.7 channel.
Effect of Cerebral Small Vessel Disease Burden on Outcomes in Patients With Acute Ischemic Stroke Receiving Endovascular Treatment

Background Cerebral small vessel disease (SVD) is common in the aging population. The study aimed to evaluate the effect of SVD on functional outcomes in patients with acute ischemic stroke (AIS) receiving endovascular treatment (EVT). Methods From a prospective registry, we selected patients with AIS receiving EVT. SVD features, including white matter hyperintensities (WMH), lacunes and brain atrophy, were assessed on MRI and a validated SVD score was calculated to reflect the total SVD burden. Results Among 137 patients included, 106 had none-mild SVD burden and 31 had moderate-severe SVD burden. The moderate-severe SVD burden group showed a significantly higher modified Rankin Scale score at 90 d (median, 4 versus 1 points, adjusted common odds ratio 0.32 [95% CI, 0.14–0.69], P < 0.01) and a significantly smaller improvement of NIHSS at 24 h (median, –3 versus –3 points, adjusted β coefficient 4.02 [95% CI, 0.57–7.48], P = 0.02) and 7 days (median, –4 versus –6 points, adjusted β coefficient 4.71 [95% CI, 1.06–8.36], P = 0.01) than the none-mild group. There was no significant difference in successful recanalization, death within 90 days, symptomatic intracranial hemorrhage within 24 h between two groups (all P > 0.05). Additionally, for each single SVD feature, brain atrophy and WMH, but not lacunes, were associated with the functional outcome. Conclusion Moderate-severe SVD burden was associated with poor early and late functional outcomes in patients with AIS receiving EVT. Our results suggest that SVD score may act as a good predictor of outcomes in these patients.
Different Patterns of Neural Activity Characterize Motor Skill Performance During Acquisition and Retention

Motor performance and learning have distinct behavioral and neural signatures and can be uniquely modulated by various informational and motivational factors. Contemporary frameworks describe four different motor learning mechanisms mapped onto specific neural regions which are key for motor skill acquisition: error-based learning (cerebellum), reinforcement learning (basal ganglia), cognitive strategies (prefrontal cortex), and use-dependent learning (motor cortex). However, little is known about the neural circuits engaged during skill acquisition that are modulated specifically by practice-based performance improvement and those that predict recall performance. Based on previous work, we hypothesize that brain activity during practice in primary motor cortex and basal ganglia (1) is associated with trial-by-trial practice performance and (2) is predictive of immediate recall performance. Leveraging the contemporary framework, we use a well-known task paradigm that primarily relies upon cognitive strategy, reinforcement, and use-based learning mechanisms to test our hypotheses. Forty neurotypical young adults were asked to practice a pinch force tracking task. Participants received performance feedback after each trial during practice. We used whole brain analysis of functional magnetic resonance imaging (fMRI) and behavioral performance measures (i.e., time-on-target and self-efficacy) during the practice phase to determine which brain activation patterns are (1) associated with trial-by-trial tracking performance and (2) predictive of immediate no-feedback retention performance. We observed brain activations in the frontal orbital cortex, putamen, amygdala, and insula correlated with tracking performance improvement during practice. In contrast, a different set of performance-related activated regions were observed that were associated with immediate retention performance that included the primary motor cortex, superior frontal gyrus, somatosensory cortex, angular gyrus, and parietal gyrus. Our findings demonstrate that improved practice performance and recall of a sensorimotor skill are correlated with distinct neural activity patterns during acquisition, drawing on different motor learning mechanisms during encoding. While motor performance improvements depend on both cortical and subcortical regions, motor skill recall depends primarily on prefrontal and motor cortices. We discuss possible interpretations for why our hypothesis regarding basal ganglia activity and retention performance was not supported. Understanding the different neural mechanisms engaged in motor performance and learning may inform novel interventions to enhance motor skill learning.
Movies, measurement, and modeling

Immunological phenomena that were once deduced from genetic, biochemical, and in situ approaches are now being witnessed in living color, in three dimensions, and in real time. The information in time-lapse imaging can provide valuable mechanistic insight into a host of processes, from cell migration to signal transduction. What we need now are methods to quantitate these new visual data and to exploit computational resources and statistical mechanical methods to develop mechanistic models.
Near Death Experience Cells Escaping a Non-MHC Gene-Controlled Enhanced Pathogenicity of Diabetogenic T

For unknown reasons, the common MHC class I variants encoded by the H2 g7 haplotype (K d , D b ) aberrantly elicit autoreactive CD8 T cell responses essential to type 1 diabetes development when expressed in NOD mice, but not other strains. In this study, we show that interactive non-MHC genes allow a NOD-derived diabetogenic CD8 T cell clonotype (AI4) to be negatively selected at far greater efﬁciency in C57BL/6 mice congenically expressing H2 g7 (B6. H2 g7 ). However, the few AI4 T cells escaping negative selection in B6. H2 g7 mice are exported from the thymus more efﬁciently, and are more functionally aggressive than those of NOD origin. This provides mechanistic insight to previous ﬁndings that resistant mouse strains carry some genes conferring greater diabetes susceptibility than the corresponding NOD allele. In the B6. H2 g7 stock, non-MHC gene-controlled elevations in TCR expression are associated with both enhanced negative selection of diabetogenic CD8 T cells and increased aggressiveness of those escaping this process. An implication of this ﬁnding is that the same phenotype, in this case relatively high TCR expression levels, could have double-edged sword effects, contributing to type 1 diabetes resistance at one level of T cell development, but at another actually promoting pathogenesis. The Journal of Immunology, 2004, 173: 3791–3800.
Proprotein convertase subtilisin/kexin type 9 inhibition after acute coronary syndrome or prior myocardial infarction

Purpose of review Lowering low-density lipoprotein cholesterol (LDL-C) with statins or ezetimibe reduces major adverse cardiovascular events (MACE) in patients with coronary heart disease. Additional treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may lower LDL-C to levels not achievable with conventional lipid-lowering agents. This review summarizes findings from two large, placebo-controlled trials that evaluated the cardiovascular efficacy of monoclonal antibodies directed against PCSK9, added to background statin therapy, in patients with established atherosclerotic cardiovascular disease (ASCVD) or recent acute coronary syndrome (ACS) and persistent elevation of atherogenic lipoproteins despite statin treatment. Recent findings The FOURIER trial with evolocumab and the ODYSSEY OUTCOMES trial with alirocumab demonstrated 15% overall reductions in MACE compared to placebo, associated with average achieved LDL-C levels as low as 30–40 mg/dl. Alirocumab treatment was associated with fewer deaths after ACS. Subgroups with large absolute treatment benefit included those with baseline LDL-C ≥100 mg/dl, diabetes, polyvascular or peripheral artery disease, prior coronary bypass surgery, statin intolerance, or elevated lipoprotein(a) levels. No safety concerns arose with use of PCSK9 monoclonal antibodies, even in patients who achieved LDL-C levels below 20 mg/dl. Summary In selected patients with established ASCVD or recent ACS, PCSK9 inhibitors can play an important role in reducing the risk of MACE, and may also reduce the risk of death after ACS.