bluuebunny/crossref_metadata_2025_split huggingface dataset:
A RUNX3 enhancer polymorphism associated with ankylosing spondylitis influences recruitment of Interferon Regulatory Factor 5 and factors of the Nucleosome Remodelling Deacetylase Complex in CD8+ T-cells
Authors: Vecellio Matteo , Cortes Adrian , Bonham Sarah , Selmi Carlo , Knight Julian C , Fischer Roman , Brown Matthew A , Wordsworth B Paul , Cohen Carla J 
Published: November 2019

ABSTRACTObjectivesTo investigate the functional consequences of the single nucleotide polymorphism rs4648889 in a putative enhancer upstream of the RUNX3 promoter strongly associated with ankylosing spondylitis (AS).MethodsThe effects of rs4648889 on transcription factor (TF) binding were tested by DNA pull-down and quantitative mass spectrometry. The results were validated by electrophoretic mobility gel shift assays (EMSA), Western blot (WB) analysis of the pulled-down eluates, and chromatin immuno-precipitation (ChIP)-qPCR.ResultsSeveral TFs showed differential allelic binding to a 50bp DNA probe spanning rs4648889. Binding was increased to the AS-risk A allele for IKZF3 (aiolos) in nuclear extracts from CD8+ T-cells (3.7-fold, p<0.03) and several components of the NUcleosome Remodeling Deacetylase (NuRD) complex, including Chromodomain-Helicase-DNA-binding protein 4 (3.6-fold, p<0.05) and Retinoblastoma-Binding Protein 4 (4.1-fold, p<0.02). In contrast, binding of interferon regulatory factor (IRF) 5 was increased to the AS-protective G allele. These results were confirmed by EMSA, WB and ChIP-qPCR.ConclusionsThe association of AS with rs4648889 most likely results from its influence on the binding of this enhancer-like region to TFs, including IRF5, IKZF3 and members of the NuRD complex. Further investigation of these factors and RUNX3-related pathways may reveal important new therapeutic possibilities in AS.
Clonally distinct differentiation trajectories shape CD8+ memory T cell heterogeneity after acute viral infections in humans
Authors: Mold Jeff E. , Modolo Laurent , Hård Joanna , Zamboni Margherita , Larsson Anton J.M. , Eriksson Carl-Johan , Ståhl Patrik L. , Borgström Erik , Picelli Simone , Reinius Björn , Sandberg Rickard , Réu Pedro , Talavera-Lopez Carlos , Andersson Björn , Blom Kim , Sandberg Johan K. , Picard Franck , Michaëlsson Jakob , Frisén Jonas 
Published: November 2019

AbstractCD8+ T cells play essential roles in immunity to viral and bacterial infections, and to guard against malignant cells. The CD8+ T cell response to an antigen is composed of many T cell clones with unique T cell receptors, together forming a heterogenous repertoire of phenotypically and functionally distinct effector and memory cells1, 2. How individual T cell clones contribute to this heterogeneity during an immune response is key to understand immunity but remains largely unknown. Here, we longitudinally tracked CD8+ T cell clones expanding in response to yellow fever virus vaccination at the single cell level in humans. We show that only a fraction of the clones detected in the acute response persists as circulating memory T cells, indicative of clonal selection. Clones persisting in the memory phase displayed biased differentiation trajectories along a gradient of stem cell memory (SCM) towards terminally differentiated effector memory (EMRA) fates. Reactivation of single memory CD8+ T cells revealed that they were poised to recapitulate skewed differentiation trajectories in secondary responses, and this was generalizable across individuals for both yellow fever and influenza virus. Together, we show that the sum of distinct clonal differentiation repertoires results in the multifaceted T cell response to acute viral infections in humans.
“GPress: a framework for querying General Feature Format (GFF) files and feature expression files in a compressed form”
Authors: Meng Qingxi , Ochoa Idoia , Hernaez Mikel 
Published: November 2019

1Abstract1.1MotivationSequencing data are often summarized at different annotation levels for further analysis. The general feature format (GFF) and its descendants, the gene transfer format (GTF) and GFF3, are the most commonly used data formats for genomic annotations. These files are extensively updated, queried and shared, and hence as the number of generated GFF files increases, efficient data storage and retrieval are becoming increasingly important. Existing GFF utilities for accessing these files, like gffutils and gffread, do not focus on reducing the storage space, significantly increasing it in some cases. Hence, we propose GPress, a framework for querying GFF files in a compressed form. In addition, GPress can also incorporate and compress feature expression files, supporting simultaneous queries on both files.1.2ResultsWe tested GPress on several GFF files of different organisms, and showed that it achieves on average a 98% reduction in size, while being able to retrieve all annotations for a given identifier or a range of coordinates in a few seconds. For example, on a Human GFF file, GPress can find all items with a unique identifier in 2.47 seconds and all items with coordinates within the range of 1,000 to 100,000 in 4.61 seconds. In contrast, gffutils provides faster retrieval but doubles the size of the GFF files. When additionally linking an expression file, we show that GPress can reduce the size of the expression file by more than 92%, while still retrieving the information within seconds. GPress is freely available at https://github.com/qm2/gpress.
JMJD6 participates in the maintenance of ribosomal DNA integrity in response to DNA damage
Authors: Fages Jérémie , Chailleux Catherine , Humbert Jonathan , Jang Suk-Min , Loehr Jérémy , Lambert Jean-Philippe , Côté Jacques , Trouche Didier , Canitrot Yvan 
Published: November 2019

AbstractRibosomal DNA (rDNA) is the most transcribed genomic region and contains hundreds of tandem repeats. Maintaining these rDNA repeats as well as the level of rDNA transcription is essential for cellular homeostasis. DNA damages generated in rDNA need to be efficiently and accurately repaired as rDNA repeats instability has been reported in cancer, aging and neurological diseases. Here, we describe that the histone demethylase JMJD6 is rapidly recruited at nucleolar DNA damage and is crucial for the relocalisation of rDNA in nucleolar caps. Yet, JMJD6 is dispensable for rDNA transcription inhibition. Mass spectrometry study revealed that JMJD6 interacts with the nucleolar protein Treacle and modulates its interaction with NBS1. Moreover, cells deficient for JMJD6 show increased sensitivity to nucleolar DNA damage as well as loss and rearrangements of rDNA repeats upon irradiation. Altogether our data reveals that rDNA transcription inhibition is uncoupled from rDNA relocalisation into nucleolar caps and that JMJD6 is required for rDNA stability upon the rDNA damage response through its role in nucleolar caps formation.Author summaryRibosomal DNA is the most transcribed genomic region composed of repeated sequences. Transcribed rDNA is essential for cellular homeostasis and cell proliferation. Numerous pathologies such as cancer and neurological disorders are described to present defective rDNA repeats maintenance. The mechanisms involved in the control of rDNA integrity involve major DNA repair pathways such as NonHomologous End-Joining and Homologous Recombination. However, how they are controlled and orchestrated is poorly understood. Here, we identified JMJD6 as a new member of the maintenance of rDNA integrity. We observed that JMJD6 controls the recruitment of NBS1 in the nucleolus in order to lead to the proper response to DNA damage at rDNA repeats.Author contributionsYC and DT wrote the manuscript with input from their coauthors. JF, CC, JH, S-KM, JL, J-PL and YC performed the experiments. JC supervised JF and JH during purification and mass spectrometry analysis. YC and DT conceived the project, designed research and coordinated the studies.
Brief report: Mutations in SIV Nef that disrupt and restore tetherin downregulation
Authors: Maness Nicholas J , Schouest Blake 
Published: November 2019

AbstractThe H196residue in SIVmac239 Nef is conserved across nearly all HIV and SIV isolates, lies immediately adjacent to the AP-2 (adaptor protein 2) interacting domain (ExxxLM195), and is critical for several described AP-2 dependent Nef functions, including the downregulation of tetherin (BST-2/CD317). Surprisingly, many stocks of the closely related SIVmac251 swarm virus harbor anefallele encoding a Q196, which is associated with loss of multiple AP-2 dependent functions in SIVmac239. Publicly available sequences for SIVmac251 stocks were mined for variants linked to Q196that might compensate for functional defects associated with this mutation. Variants were engineered into the SIVmac239 parental plasmid and mutant viruses were used to test tetherin downregulatory capacity in primary CD4 T cells using flow cytometry. SIVmac251 stocks that encode a Q196residue in Nef uniformly also encode an upstream R191residue. We show that R191restores the ability of Nef to downregulate tetherin in the presence of Q196. However, a published report showed Q196commonly evolves to H196in vivo, suggesting a fitness cost. R191may represent compensatory evolution to restore the ability to downregulate tetherin lost in viruses harboring Q196.
Genetic alteration of ferredoxin NADP+-reductase or cysteine desulfurase in piperaquine-resistant Plasmodium berghei restores susceptibility to lumefantrine and abolishes the impact of probenecid, verapamil, and cyproheptadine
Authors: Bara Fagdéba David , Ndung’u Loise , Onchieku Noah Machuki , Irungu Beatrice , Karou Simplice Damintoti , Kimani Francis , Matoke-Muhia Damaris , Mwitari Peter , Magoma Gabriel , Nzila Alexis , Kiboi Daniel 
Published: November 2019

AbstractChemotherapy remains central in the control of malaria; however, resistance has consistently thwarted these efforts. Currently, lumefantrine (LM), and piperaquine (PQ) drugs, are essential components in the mainstay artemisinin-based therapies used for the treatment of malaria globally. Using LM and PQ-resistant Plasmodium berghei, we measured the effect of known chemosensitizers: probenecid, verapamil, or cyproheptadine on the activity of LM or PQ. Using PlasmoGEM vectors, we then evaluated the impact of deleting cysteine desulfurase (SufS) or over-expressing Ferredoxin NADP+ reductase (FNR), genes that mediate drug action. Our data showed that, only cyproheptadine at 5mgkg−1 restored LM activity by above 65% against the LM-resistant parasites (LMR) but failed to reinstate PQ activity against the PQ-resistant parasites (PQR). Whereas the PQR had lost significant susceptibility to LM, the three chemosensitizers; cyproheptadine, probenecid, and verapamil, restored LM potency against the PQR by above 70%, 60%, and 55% respectively. We thus focused on LM resistance in PQR. Deletion of the SufS or overexpression of the FNR genes in the PQR abolished the impact of the chemosensitizers on the LM activity, and restored the susceptibility of the PQR parasites to LM. Taken together, we demonstrate the association between SufS or FNR genes with the action of LM and chemosensitizers in PQR parasites. There is, however, need to interrogate the impact of the chemosensitizers and the role of SufS or FNR genes on LM action in the human malaria parasite, Plasmodium falciparum.
BeamDelta: simple alignment tool for optical systems
Authors: Hall Nicholas J. , Pinto David Miguel Susano , Dobbie Ian M. 
Published: November 2019

AbstractBeamDelta is a tool to help align optical systems. It greatly assists in assembling bespoke optical systems by providing a live view of the current laser beam position and a reference position.Even a simple optical setup has multiple degrees of freedom that affect the alignment of beam paths. These degrees of freedom rise exponentially with the complexity of the system. The process of aligning all the optical components for a specific system is often esoteric and poorly documented, if it is documented at all.Alignment methods used often rely on visual inspection of beams impinging on pinholes in the beam path. Typically requiring an experienced operator staring at diffuse reflections for extended periods of time. This can lead to a decline in accuracy due to eye strain, flash blindness as well as symptoms such as headaches and, possibly, more serious retinal damage.Here we present BeamDelta a simple alignment tool and accompanying software interface which allows users to obtain accurate alignment as well as removing the necessity of staring at diffuse laser reflections. BeamDelta is a robust alignment tool as it doesn’t require any precise alignment itself.
MicroRNA 1253 regulation of WAVE2 and its relevance to health disparities in hypertension
Authors: Arkorful Mercy A. , Hooten Nicole Noren , Zhang Yongqing , Hewitt Amirah N. , Sanchez Lori Barrientos , Evans Michele K. , Dluzen Douglas F. 
Published: November 2019

AbstractThe prevalence of hypertension among African Americans (AAs) in the US is among the highest of any demographic and affects over two-thirds of AA women. Previous data from our laboratory suggests substantial differential gene expression (DGE) of mRNAs and microRNAs (miRNAs) exists within peripheral blood mononuclear cells (PBMCs) isolated from AA and white women with or without hypertension. We hypothesized that DGE by race may contribute to racial differences in hypertension. We found that the Wiskott-Aldrich syndrome protein Verprolin homologous-2 (WAVE2) is differentially-expressed in AA women with hypertension, along with several other members of the actin cytoskeleton signaling pathway that plays a role in cell shape and branching of actin filaments. We performed an in silico miRNA target prediction analysis that suggested miRNA miR-1253 regulates WAVE2. Transfection of miR-1253 mimics into human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) significantly repressed WAVE2 mRNA and protein levels (P<0.05), and a luciferase reporter assay confirmed that miR-1253 regulates the WAVE2 3’ UTR (P<0.01). miR-1253 over-expression in HUVECs significantly increased HUVEC lamellipodia formation (P<0.01), suggesting the miR-1253/WAVE2 interaction may play a role in endothelial cell shape and actin cytoskeleton function. Together, we have identified novel roles for miR-1253 and WAVE2 in a hypertension-related disparities context. This may ultimately lead to the discovery of additional actin-related genes which are important in the vascular-related complications of hypertension and influence the disproportionate susceptibility to hypertension among AAs in general and AA women in particular.
Serine and glycine are essential for human muscle progenitor cell population expansion
Authors: Gheller Brandon J. , Blum Jamie E. , Bender Erica L. , Gheller Mary E. , Lim Esther W. , Handzlik Michal K. , Stover Patrick J. , Field Martha S. , Cosgrove Benjamin D. , Metallo Christian M. , Thalacker-Mercer Anna E. 
Published: November 2019

SummarySkeletal muscle regeneration is reliant on a population of muscle specific adult stem cells (muscle progenitor cells; MPCs). During regeneration, the MPC population undergoes a transient and rapid period of population expansion, which is necessary to repair damaged myofibers and restore muscle homeostasis. Much research has focused on the age-related accumulation of negative regulators of regeneration, while the age-related decline of nutrient and metabolic determinants of the regenerative process needs examination. We hypothesized that older individuals, a population that is at risk for protein malnutrition, have diminished availability of amino acids that are necessary for MPC function. Here, we identified that levels of the non-essential amino acid serine are reduced in the skeletal muscle of healthy, older individuals. Furthermore, using stable-isotope tracing studies, we demonstrate that primary, human MPCs (hMPCs) exhibit a limited capacity forde novobiosynthesis of serine and the closely related amino acid glycine. We identified that serine and glycine are essential forhMPC proliferation and, therefore, population expansion. Serine and glycine were necessary to support synthesis of the intracellular antioxidant glutathione, and restriction of serine and glycine was sensed in an EIF2α-dependent manner resulting in cell cycle arrest in G0/G1. In conclusion, we elucidate that, despite an absolute requirement of serine/glycine forhMPC proliferation, availability of serine in the skeletal muscle microenvironment is limited to thehMPCs of healthy older adults and is a likely underlying mechanism for impaired skeletal muscle regeneration with advancing age.Graphical Abstract
A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of Diffuse Large B-cell Lymphoma
Authors: Miyawaki Kohta , Kato Koji , Sugio Takeshi , Sasaki Kensuke , Miyoshi Hiroaki , Semba Yuichiro , Kikushige Yoshikane , Mori Yasuo , Kunisaki Yuya , Iwasaki Hiromi , Miyamoto Toshihiro , Kuo Frank C. , Aster Jon C. , Ohshima Koichi , Maeda Takahiro , Akashi Koichi 
Published: November 2019

AbstractDiffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using highly-sensitive transcriptome profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of “unfavorable” molecular signatures.
Conformational heterogeneity in apo and drug-bound structures of Toxoplasma gondii prolyl-tRNA synthetase
Authors: Mishra Siddhartha , Malhotra Nipun , Kumari Shreya , Sato Mizuki , Kikuchi Haruhisa , Yogavel Manickam , Sharma Amit 
Published: November 2019

Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase family that drives protein translation in cells. The apicomplexan PRSs are validated targets of febrifugine (FF) and its halogenated derivative halofuginone (HF). PRSs are of great interest for drug development against Plasmodium falciparum and Toxoplasma gondii. In this study, structures of apo and FF-bound T. gondii (TgPRS) are revealed and the dynamic nature of the conformational changes that occur upon FF binding is unraveled. In addition, this study highlights significant conformational plasticity within two different crystal structures of apo PRSs but not within drug-bound PRSs. The apo PRSs exist in multi-conformational states and manifest pseudo-dimeric structures. In contrast, when FF is bound the PRS dimer adopts a highly symmetrical architecture. It is shown that TgPRS does not display extant fold switching, in contrast to P. falciparum PRS, despite having over 65% sequence identity. Finally, structure-comparison analyses suggest the utility of r.m.s.d. per residue (r.m.s.d./res) as a robust tool to detect structural alterations even when the r.m.s.d. is low. Apo TgPRS reveals FF/HF-induced rigidity and this work has implications for drug-design studies that rely on the apo structures of target proteins.
Field work supervision through open and distance learning: an Indian perspective
Authors: Guin Sayantani 
Published: November 2019

Purpose
The purpose of this paper is to highlight the method of field work supervision in BSW and MSW programmes offered through open and distance learning (ODL) at the Indira Gandhi National Open University (IGNOU). The key argument of the paper will focus on the fact that despite various challenges, field work supervision through ODL provides lot of scope and flexibility to students, generating a cadre of trained social work professionals.

Design/methodology/approach
The paper adopts a case study approach in presenting the various methods employed for field work supervision by the University. This section will highlight the achievements in terms of developing indigenous theory course and the best practices adopted by IGNOU to train social work professionals through adequate and timely supervision in the ODL mode.

Findings
Field work supervision in the ODL mode poses many challenges, especially when compared to that in the conventional universities. Some of these include irregular meeting of supervisor and student, inability of students to meet supervisor due to several reasons like remote location, poor economic background, lack of leave for working professionals, etc.

Research limitations/implications
There is a need for developing a mechanism to regularly orient field work supervisors in supervising students in the ODL mode. It is recommended that regular field work practicum workshops be conducted for supervisors and students. Viva for field work could be made mandatory at different regional centres. Field work supervision could be enhanced through the use of technology, namely, Skype, e-mail, WhatsApp, etc.

Originality/value
The paper describes the various nuances of field work supervision through ODL system. It is an original work and is of great value in understanding the challenges and difficulties encountered by learners and academic counsellors throughout the process of supervision. The paper highlights important recommendations by the stakeholders themselves in mitigating the challenges faced during field work supervision through ODL.