Miracle-dz/UniFAR-FTUs huggingface dataset:
Genome-wide association study of susceptibility loci for T-cell acute lymphoblastic leukemia in children.

BACKGROUND Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts. METHODS We performed a genome-wide association study (GWAS) in 1,191 children with T-ALL and 12,178 control subjects, with independent replication using 117 cases and 5,518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two-sided. RESULTS A novel risk locus in the USP7 gene (rs74010351, odds ratio = 1.44, 95% CI = 1.27-1.65, P = 4.51 x 10-8) reached genome-wide significance in the discovery cohort, with independent validation (odds ratio = 1.51, 95% CI: 1.03-2.22, P = .04). The USP7 risk allele was over-represented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs. B-ALL pointed to distinctive etiology of these leukemias. CONCLUSIONS These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs. T-ALL).
Two forms of phosphomannomutase in gammaproteobacteria: The overlooked membrane-bound form of AlgC is required for twitching motility of Lysobacter enzymogenes

Lysobacter enzymogenes, a member of Xanthomonadaceae, is a promising tool to control crop-destroying fungal pathogens. One of its key antifungal virulence factors is the type IV pili that are required for twitching motility. Transposon mutagenesis of L. enzymogenes revealed that production of type IV pili required the presence of the Le2152 gene, which encodes an AlgC-type phosphomannomutase/phosphoglucomutase (PMM). However, in addition to the cytoplasmic PMM domain, the Le2152 gene product contains a ca. 200-aa N-terminal periplasmic domain that is anchored in the membrane by two transmembrane segments and belongs to the dCache superfamily of periplasmic sensor domains. Sequence analysis identified similar membrane-anchored PMMs, encoded in conserved coaBC-dut-algC gene clusters, in a variety of gammaproteobacteria, either as the sole PMM gene in the entire genome or in addition to the gene encoding the stand-alone enzymatic domain. Previously overlooked N-terminal periplasmic sensor domains were detected in the well-characterized PMMs of Pseudomonas aeruginosa and Xanthomonas campestris, albeit not in the enzymes from Pseudomonas fluorescens, Pseudomonas putida or Azotobacter vinelandii. It appears that after the initial cloning of the enzymatically active soluble part of P. aeruginosa AlgC in 1991, all subsequent studies utilized N-terminally truncated open reading frames. The N-terminal dCache sensor domain of AlgC is predicted to modulate the PMM activity of the cytoplasmic domain in response to as yet unidentified environmental signal(s). AlgC-like membrane-bound PMMs appear to comprise yet another environmental signaling system that regulates production of type IV pili and potentially other systems in certain gammaproteobacteria.
Orthographic connectivity in Arabic reading: a case study of an individual with deep dyslexia and letter-by-letter reading

ABSTRACT Arabic orthography is complex, partly as a consequence of variations in orthographic connectivity. In this article, we present the case study of CHS, an Arabic individual with deep dyslexia associated with letter-by-letter reading. In the experimental study, we specifically explored the influence of orthographic connectivity on CHS’s word recognition and reading abilities. Our results show that CHS’s performance was better preserved for words and non-words made up of connected letters than made up of non-connected letters. CHS demonstrated impairment of visuoperceptual mechanisms, which affected the processing of complex orthographic material. These results provide insight into the cognitive processes associated with reading Arabic.
Cultural Context in DSM Diagnosis: An American Indian Case Illustration of Contradictory Trends

Recent revisions of the Diagnostic and Statistical Manual of Mental Disorders (DSM) increasingly acknowledge the importance of cultural context for the diagnosis of mental illness. However, these same revisions include evolving diagnostic criteria that simultaneously decontextualize particular disorders such as Major Depressive Disorder (MDD) and Posttraumatic Stress Disorder (PTSD). As a result, the DSM reflects a contradictory role for context in psychiatric diagnosis. The case analysis presented here frames the consequences of this contradictory trend for an American Indian woman with a history of DSM-IV MDD and PTSD, whose diagnostic portrait is substantively altered in light of more recent DSM-5 criteria. Specifically, consideration of this respondent’s bereavement-related illness experience suggests that a sociocentric cultural frame of reference, which places high value on interdependent personal relationships, is not well-captured by DSM-5’s revised MDD or PTSD criteria, or the newly proposed categories of traumatic bereavement or Persistent Complex Bereavement Disorder. The respondent’s illness experience argues for greater recognition of this contradictory diagnostic trend, suggesting a need for future resolution of this tension toward more valid diagnosis for culturally diverse populations.
Relationship between microbial diversity and nitrogenase activity of Stipagrostis pennata rhizosheath

Nitrogen is the key factor for plant survival and growth, especially in the desert. Stipagrostis pennata, a sand born drought‐resistant plant, could colonize pioneerly in Gurbantunggut Desert during revegetation. One strategy for their environment adaptation was the rhizosheath formatted by root‐hair, mucilaginous exudates, microbial components, and soil particles, for which not only provides a favorable living microenvironment but also supplies essential nutrients. To understand the relationship between microorganisms living in rhizosheaths and the nitrogen nutrition supply, the microbial diversity and nitrogenase activity was estimated during the growth of S. pennata. Five samples of the rhizosheath, which based on the development periods of the plant, regreen, flowering, filling, seed maturating, and withering period, were collected. The nitrogenase activity was estimated by acetylene reduction and the microbial diversity was analyzed by 16S rRNA high‐throughput sequencing. The results showed that the nitrogenase activity was increased slowly during regreen to flowering, while reached a peak rapidly at filling sample and then decreased gradually. A total of 274 operational taxonomic units (OTUs) were identified and significant differences in community structure and composition at each growth period. Among them, the main phyla included Actinobacteria and Proteus, which were the most abundant phyla in all periods. In addition, the microbial diversity in the grain filling period was higher than other periods in view of the analysis of alpha diversity and beta diversity. Furthermore, principal component analysis (PCA) analysis showed that the microbial communities in the filling period was low in similarity with other periods. Most importantly, the OTUs associated with nitrogen fixation is the most during the filling period, involving Phagecidae and Fucoraceae. Overall, the study not only revealed the differences in nitrogenase activity among different developmental periods in S. pennata, but also explored the potential bridges between it and community structure and diversity of bacteria.
Depressive symptoms and age of alcohol use onset interact to predict suicidal ideation

Abstract Distal risk factors of alcohol use may increase suicidal ideation in the presence of proximal risk factors, such as depressive symptoms. We tested whether depressive symptoms and age at onset of alcohol use interact to predict suicidal ideation in 500 individuals (67% men; 68% Black/African American) under criminal justice supervision. Regression analysis revealed that age of onset negatively associated with suicidal ideation only at average and high levels of depressive symptoms while controlling for suicide attempt history. Clinicians may consider individuals with an early age of onset of alcohol use and current depressive symptoms at risk for suicidal ideation.
TGF‐β1‐activated type 2 dendritic cells promote wound healing and induce fibroblasts to express tenascin c following corneal full‐thickness hydrogel transplantation

We showed previously that 1‐ethyl‐3‐(3‐dimethylamino‐propyl)‐carbodiimide hydrochloride (EDC) cross‐linked recombinant human collagen III hydrogels promoted stable regeneration of the human cornea (continued nerve and stromal cell repopulation) for over 4 years. However, as EDC cross linking kinetics were difficult to control, we additionally tested a sterically bulky carbodiimide. Here, we compared the effects of two carbodiimide cross linkers—bulky, aromatic N‐cyclohexyl‐N0‐(2‐morpholinoethyl)‐carbodiimide (CMC), and nonbulky EDC—in a mouse corneal graft model. Murine corneas undergoing full‐thickness implantation with these gels became opaque due to dense retro‐corneal membranes (RCM). Corneal epithelial cytokeratin 12 and alpha smooth muscle actin indicative of functional tissue regeneration and wound contraction were observed in RCM surrounding both hydrogel types. However, quantitatively different levels of infiltrating CD11c+ dendritic cells (DC) were found, suggesting a hydrogel‐specific innate immune response. More DC infiltrated the stroma surrounding EDC‐N‐hydroxysuccinimide (NHS) hydrogels concurrently with higher fibrosis‐associated tenascin c expression. The opposite was true for CMC‐NHS gels that had previously been shown to be more tolerising to DC. In vitro studies showed that DC cultured with transforming growth factor β1 (TGF‐β1) induced fibroblasts to secrete more tenascin c than those cultured with lipopolysaccharide and this effect was blocked by TGF‐β1 neutralisation. Furthermore, tenascin c staining was found in 40‐ to 50μm long membrane nanotubes formed in fibroblast/DC cocultures. We suggest that TGF‐β1 alternatively activated (tolerising) DC regulate fibroblast‐mediated tenascin c secretion, possibly via local production of TGF‐β1 in early wound contraction, and that this is indirectly modulated by different hydrogel chemistries.
Reactivation of nonsense-mediated mRNA decay protects against C9orf72 dipeptide-repeat neurotoxicity

Impaired RNA metabolism has been implicated in amyotrophic lateral sclerosis (ALS). Xu et al. report that the nonsense-mediated mRNA decay (NMD) pathway is inhibited in C9orf72 hexanucleotide repeat expansion-associated ALS. Reactivation of the NMD pathway protects against neurodegeneration in ALS models, suggesting potential as a therapeutic strategy.
Human Cytomegalovirus Antigen Presentation by HLA-DR+ NKG2C+ Adaptive NK Cells Specifically Activates Polyfunctional Effector Memory CD4+ T Lymphocytes

Natural killer (NK) cells play a dual role in the defense against viral pathogens by directly lysing infected cells as well as by regulating anti-viral T cell immunity. Infection by human cytomegalovirus (HCMV) promotes a persistent expansion of NKG2C+ adaptive NK cells which have been shown to display enhanced antibody-dependent responses against infected targets and associated to viral control in transplanted patients. Based on gene expression data showing increased transcription of CIITA and several genes related to the MHC class II pathway in adaptive NK cells, we explored their putative capacity for antigen presentation to CD4+ T cells. Phenotypic analysis confirmed a preferential steady-state expression of HLA-DR by circulating NKG2C+ adaptive NK cells in healthy individuals. Expression of HLA-DR in NKG2C+ adaptive NK cells was variable and unrelated to the expression of activation (i.e., CD69 and CD25) or differentiation (i.e., FcRγ chain, CD57) markers, remaining stable over time at the individual level. Incubation of purified NK cells with HCMV complexed with serum specific antibodies induced an up-regulation of surface HLA-DR concomitant to CD16 loss whereas no changes in CD80/CD86 co-stimulatory ligands were detected. In addition, surface CX3CR1 decreased upon antigen-loading while HLA-DR+ NK cells maintained a CCR7-, CXCR3low homing profile. Remarkably, HCMV-loaded purified NK cells activated autologous CD4+ T cells in an HLA-DR dependent manner. The fraction of T lymphocytes activated by antigen-loaded NK cells was smaller than that stimulated by monocyte-derived dendritic cells, corresponding to CD28-negative effector-memory CD4+ T cells with cytotoxic potential. Antigen presentation by NK cells activated a polyfunctional CD4+ T cell response characterized by degranulation (CD107a) and the secretion of Th1 cytokines (IFNγ and TNFα). Overall, our data discloses the capacity of NKG2C+ adaptive NK cells to process and present HCMV antigens to memory CD4+ cytotoxic T cells, directly regulating their response to the viral infection.
Distribution Level Aggregator Platform for DSO Support—Integration of Storage, Demand Response, and Renewables

Modern era is full of renewable energy resources, particularly wind and solar that are installed at both Low and Medium voltage nodes of the distribution system. With the diffusion of new resources in the distribution grid, a new challenge for the system operators is to cope up with the introduced changes in the distribution network. These changes can be on voltage levels, magnitudes and direction of current, and changes in power factor. The reduced visibility of these additives to operators require provision of ancillary services to ensure power system reliability and stability. In order to give flexibility to operator, and in particular DSO for distribution grid, the paper suggests the use of distribution level aggregators to serve as sub-DSO (JDSO). These aggregators utilize the three main components: Electrical energy storage system, customers demand response, and the renewable resources (PV and wind). These aggregators utilize a platform where all these actors can participate. DSO-JDSOs interaction is possible through the platform, and the local problems at distribution can be resolved before it goes to TSO. Paper presents and simulates the platform, develop test cases, and validate the model.
Humble Leadership and Employee Resilience: Exploring the Mediating Mechanism of Work-Related Promotion Focus and Perceived Insider Identity

Although the topic of employee resilience has recently received increased attention, existing research has largely failed to explore its situational triggers. Drawing on social information processing theory, the current study integrates the literature of humility and resilience to theorize the underlying mechanism through which humble leadership facilitates employee resilience. This research proposes a potential heterogeneous effect that humble leadership catalyzes employee resilience through multiple pathways. Field (N = 434) and experimental studies (N = 104) conducted in Mainland China support hypotheses that humble leadership enhances employee resilience through simultaneous increases in work-related promotion focus and perceived insider identity. Research implications are discussed, and directions for future research are offered.
Molecular dynamic simulation of stress development during coalescence of grain in presence of depositing atoms

Three‐dimensional molecular dynamics simulations are carried out to study the evolution of stress during the deposition of atoms on the (100) plane of an fcc regular crystal, using the cubic system with x‐y periodic boundary conditions. In the present study, starting simulation box consists of a substrate and deposited layers forming regular strips. The interactions in the system are described by the Lennard‐Jones potential. The deposited atoms are in contact with two types of surfaces (substrate and strips/grains). The atoms in contact with the substrate generate the tensile stress, but atoms in contact with the grain generate the compressive stress. The melted grains increase the contact surface giving possibility the larger number of atoms to penetrate the grain boundaries and finally to produce a larger total compressive stress. This result is in agreement with the model proposed by Chason et al. (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Application of a Dual Internally Quenched Fluorogenic Substrate in Screening for D-Arginine Specific Proteases

The application of D-stereospecific proteases (DSPs) in resolution of racemic amino acids and in the semisynthesis of proteins has been a successful strategy. The main limitation for a broader application is, however, the accessibility of suitable DSPs covering multiple substrate specificities. To identify DSPs with novel primary substrate preferences, a fast specificity screening method using the easily accessible internally quenched fluorogenic substrate aminobenzoyl-D-arginyl-D-alanyl-p-nitroanilide was developed. By monitoring both UV/vis-absorbance and fluorescence signals at the same time it allows to detect two distinct D-amino acid substrate specificities simultaneously and separately with respect to the individual specificities. In order to identify novel DSP specificities for synthesis applications, DSPs specific for D-arginine were of special interest due to their potential ability as catalysts for substrate mimetics-mediated peptide and protein ligations. D-alanine in the substrate served as positive control and reference based on its known acceptance by numerous DSPs. In silico analysis suggested that DSPs are predominantly present in gram-positive microorganisms, therefore this study focused on the bacilli strains Bacillus thuringiensis and Bacillus subtilis as potential hosts of D-Arg-specific DSPs. While protease activities toward D-alanine were found in both organisms, a novel and so far unknown D-arginine specific DSP was detected within the culture supernatant of B. thuringiensis. Enrichment of this activity via cation exchange and size exclusion chromatography allowed isolation and further characterization of this novel enzyme consisting of a molecular mass of 37.7 kDa and an enzymatic activity of 8.3 U mg-1 for cleaving the D-Arg|D-Ala bond in the detecting substrate. Independent experiments also showed that the identified enzyme shows similarities to the class of penicillin binding proteins. In future applications this enzyme will be a promising starting point for the development of novel strategies for the semisynthesis of all-L-proteins.
Medroxyprogesterone Acetate Decreases Th1, Th17, and Increases Th22 Responses via AHR Signaling Which Could Affect Susceptibility to Infections and Inflammatory Disease

A synthetic progestin, medroxyprogesterone acetate (MPA), was used in a novel study to determine progestin effects on human purified macrophages and Th1, Th2, Th17, Th22 cells. MPA concentrations were equivalent to those in the serum of women after 6 and 9 months of progestin use. MPA has no effect on the proliferation of PBMCs and CD4+ T cell clones induced by immobilized anti-CD3 antibodies or by antigen (streptokinase). However, MPA decreases production and mRNA expression of IL-5, IL-13, IFN-γ, T-bet, RORC, and IL-17A but increases production and mRNA expression of IL-22 by CD4+ Th22 cell clones and decreases IL-22 production by Th17 cells. MPA inhibits RORC, but not T-bet and AHR, by Th17 cells but increases AHR mRNA and T-bet expression of established CD4+ Th22 cell clones. This suggests that MPA, at concentrations equivalent to those found in the serum of women after treatment for contraception and hormone replacement therapy, can directly inhibit Th1 responses (against intracellular bacteria and viruses), Th17 (against extracellular bacteria and fungi), Th2 (against parasites) but MPA therapy increases IL-22 produced by Th22 cells mediated by an increased expression of AHR and T-bet controlling inflammation. MPA could be responsible for the tissue damage limited by IL-22 in absence of IL-17A.
Rare Variants Imputation in Admixed Populations: Comparison Across Reference Panels and Bioinformatics Tools

Background Imputation has become a standard approach in genome-wide association studies (GWAS) to infer in silico untyped markers. Although feasibility for common variants imputation is well established, we aimed to assess rare and ultra-rare variants’ imputation in an admixed Caribbean Hispanic population (CH). Methods We evaluated imputation accuracy in CH (N=1,000), focusing on rare (0.1% ≤minor allele frequency (MAF) ≤ 1%) and ultra-rare (MAF < 0.1%) variants. We used two reference panels, the Haplotype Reference Consortium (HRC; N=27,165) and 1000 Genome Project (1000G phase 3; N=2,504) and multiple phasing (SHAPEIT, Eagle2) and imputation algorithms (IMPUTE2, MACH-Admix). To assess imputation quality, we reported: a) high-quality variant counts according to imputation tools’ internal indexes (e.g. IMPUTE2 “info”≥80%). b) Wilcoxon Signed-Rank Test comparing imputation quality for genotyped variants that were masked and imputed; c) Cohen’s kappa coefficient to test agreement between imputed and whole-exome sequencing (WES) variants; d) imputation of G206A mutation in the PSEN1 (ultra-rare in the general population an more frequent in CH) followed by confirmation genotyping. We also tested ancestry proportion (European, African and Native American) against WES-imputation mismatches in a Poisson regression fashion. Results SHAPEIT2 retrieved higher percentage of imputed high-quality variants than Eagle2 (rare: 51.02% vs. 48.60%; ultra-rare 0.66% vs 0.65%, Wilcoxon p-value < 0.001). SHAPEIT-IMPUTE2 employing HRC outperformed 1000G (64.50% vs. 59.17%; 1.69% vs 0.75% for high-quality rare and ultra-rare variants, respectively; Wilcoxon p-value < 0.001). SHAPEIT-IMPUTE2 outperformed MaCH-Admix. Compared to 1000G, HRC-imputation retrieved a higher number of high-quality rare and ultra-rare variants, despite showing lower agreement between imputed and WES variants (e.g. rare: 98.86% for HRC vs. 99.02% for 1000G). High Kappa (K = 0.99) was observed for both reference panels. Twelve G206A mutation carriers were imputed and all validated by confirmation genotyping. African ancestry was associated with higher imputation errors for uncommon and rare variants (p-value < 1e-05). Conclusion Reference panels with larger numbers of haplotypes can improve imputation quality for rare and ultra-rare variants in admixed populations such as CH. Ethnic composition is an important predictor of imputation accuracy, with higher African ancestry associated with poorer imputation accuracy.