bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections
Authors: Gantner Pierre , Buranapraditkun Supranee , Pagliuzza Amélie , Dufour Caroline , Pardons Marion , Mitchell Julie L. , Kroon Eugène , Sacdalan Carlo , Tulmethakaan Nicha , Pinyakorn Suteeraporn , Robb Merlin L. , Phanuphak Nittaya , Ananworanich Jintanat , Hsu Denise , Vasan Sandhya , Trautmann Lydie , Fromentin Rémi , Chomont Nicolas 
Published: May 2022

AbstractUpon infection, HIV disseminates throughout the human body within 1-2 weeks. However, its early cellular targets remain poorly characterized. We analyzed productively and latently infected cells in blood and lymphoid tissue from individuals in acute infection. The phenotype of productively infected cells rapidly evolved with time and differed between blood and lymph nodes. The TCR repertoire of productively infected cells was heavily biased, with preferential infection of previously expanded/disseminated cells, but composed almost exclusively of unique clonotypes, indicating that they were the product of independent infection events. Latent genetically intact proviruses were already archived early in infection. Hence, productive infection is initially established in a pool of phenotypically and clonotypically distinct T cells in blood and lymph nodes and latently infected cells are generated simultaneously.One-Sentence SummaryHIV initially infects phenotypically and clonotypically distinct T cells and establishes a latent reservoir concomitantly.
The recruitment of indirect-waves within primary motor cortex during motor imagery: A directional Transcranial Magnetic Stimulation study
Authors: Neige Cécilia , Ciechelski Valentin , Lebon Florent 
Published: May 2022

AbstractMotor imagery (MI) refers to the mental simulation of an action without any overt movement. While numerous transcranial magnetic stimulation (TMS) studies provided evidence for a modulation of corticospinal excitability and intracortical inhibition during MI, the neural signature within the primary motor cortex is not clearly established. In the current study, we used directional TMS to probe the modulation of the excitability of early and late indirect-waves (I-waves) generating pathways during MI. Corticospinal responses evoked by TMS with posterior-anterior (PA) and anterior-posterior (AP) current flow within primary motor cortex evoke preferentially early and late I-waves, respectively. Seventeen participants were instructed to stay at rest or to imagine isometric maximal contractions of the right flexor carpi radialis. We demonstrated that the increase of corticospinal excitability during MI is greater with PA than AP orientation. By using paired-pulse stimulations, we confirmed that short-interval intracortical inhibition (SICI) increased during MI in comparison to rest with PA orientation whereas we found that it decreased with AP orientation. Overall, these results indicate that the specific early I-waves generating pathway activated by PA orientation is probably more sensitive to the corticospinal excitability and intracortical inhibition modulations induced by MI.
Continuous sensing of IFNα by hepatic endothelial cells shapes a vascular antimetastatic barrier
Authors: Tran Ngoc Lan , Ferreira Lorena Maria , Alvarez-Moya Blanca , Buttiglione Valentina , Ferrini Barbara , Zordan Paola , Monestiroli Andrea , Fagioli Claudio , Bezzecchi Eugenia , Scotti Giulia Maria , Esposito Antonio , Leone Riccardo , Gnasso Chiara , Brendolan Andrea , Guidotti Luca G. , Sitia Giovanni 
Published: May 2022

AbstractHepatic metastases are a poor prognostic factor of colorectal carcinoma (CRC) and new strategies to reduce the risk of liver CRC colonization are highly needed. Herein, we used mouse models of hepatic metastatization to demonstrate that the continuous infusion of therapeutic doses of interferon-alpha (IFNα) controls CRC invasion by acting onhepatic endothelial cells (HECs). Mechanistically, IFNα promoted the development of a vascular antimetastatic niche characterized by liver sinusoidal endothelial cells (LSECs) defenestration extracellular matrix and glycocalyx deposition, thus strengthening the liver vascular barrier impairing CRC trans-sinusoidal migration, without requiring a direct action on tumor cells, hepatic stellate cells, hepatocytes, or liver dendritic cells (DCs), Kupffer cells (KCs) and liver capsular macrophages (LCMs). Moreover, IFNα endowed LSECs with efficient cross-priming potential that, along with the early intravascular tumor burden reduction, supported the generation of antitumor CD8+T cells and ultimately led to the establishment of a protective long-term memory T cell response. These findings provide a rationale for the use of continuous IFNα therapy in perioperative settings to reduce CRC metastatic spreading to the liver.
Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling
Authors: Álvarez-Merz Iris , Fomitcheva Ioulia V. , Sword Jeremy , Hernández-Guijo Jesús M. , Solís José M. , Kirov Sergei A. 
Published: May 2022

AbstractBleeding into cerebral parenchyma during hemorrhagic stroke or head trauma leads to ischemia and release of plasmatic content, including amino acids (AA). Although excitotoxic AA have been extensively studied, little is known about non-excitatory AA during hypoxic injury. Hypoxia-induced synaptic depression becomes irreversible after adding non-excitatory AA to hippocampal slices, alongside their intracellular accumulation and increased tissue electrical resistance. A combination of four non-excitatory AA (L-alanine, glycine, L-glutamine, L-serine: AGQS) at plasmatic concentrations was applied to brain slices from transgenic mice expressing EGFP in pyramidal neurons or astrocytes during normoxia or hypoxia. Two-photon imaging, changes in light transmittance (LT), and electrophysiological field recordings followed by electron microscopy in hippocampal CA1st. radiatumwere used to monitor synaptic function concurrently with cellular swelling and injury. During normoxia, AGQS-induced increase in LT was due to astroglial but not neuronal swelling. Fast LT raise during hypoxia and AGQS manifested neuronal and astroglial swelling accompanied by a permanent loss of synaptic transmission and irreversible dendritic beading, signifying acute tissue damage. Neuronal injury was not triggered by spreading depolarization which did not occur in our experiments. Hypoxia without AGQS did not cause cell swelling, leaving dendrites intact. Inhibition of NMDA receptors prevented neuronal damage and irreversible loss of synaptic function. Deleterious effects of AGQS during hypoxia were prevented by alanine-serine-cysteine transporters (ASCT2) and volume-regulated anion channels (VRAC) blockers. Our findings suggest that swelling induced by intracellular accumulation of non-excitatory AA and release of excitotoxins through antiporters and VRAC may exacerbate the hypoxia-induced neuronal injury.Significance StatementLittle is known if non-excitatory amino acids (AA) contribute to cellular injury when released during bleeding, as in hemorrhagic stroke and head trauma. Alanine, glycine, glutamine, and serine are one of the most abundant in plasma. Remarkably, during hypoxia, these non-excitatory AA caused severe neuronal and astroglial swelling and irreversible dendritic injury alongside a permanent loss of synaptic function. Activation of NMDA receptors was implicated in the onset of damage. Experimental evidence pointed to the involvement of alanine-serine-cysteine transporter 2 (ASCT2) and volume-regulated anion channels (VRAC) as molecular mechanisms underlying AA-induced damage during hypoxia. A detailed understanding of how brain injury evolves with non-excitatory AA during hypoxia will help design brain recovery treatments in neurological conditions involving bleeding.
Mechanism of Curaxin-dependent Nucleosome Unfolding by FACT
Authors: Volokh Olesya I. , Sivkina Anastasia L. , Moiseenko Andrey V. , Popinako Anna V. , Karlova Maria G. , Valieva Maria , Kotova Elena Y. , Kirpichnikov Mikhail P. , Formosa Timothy , Studitsky Vasily M. , Sokolova Olga S. 
Published: May 2022

AbstractHuman FACT (FACT) is a multifunctional histone chaperone involved in transcription, replication and DNA repair. Curaxins are anticancer compounds that induce FACT- dependent nucleosome unfolding and trapping of FACT in the chromatin of cancer cells (c-trapping) through an unknown molecular mechanism. Here, we analyzed the effects of curaxin CBL0137 on nucleosome unfolding by FACT using spFRET and electron microscopy. By itself, FACT adopted multiple conformations, including a novel, compact, four-domain state in which the previously unresolved NTD of the SPT16 subunit of FACT was localized, apparently stabilizing a compact configuration. Multiple, primarily open conformations of FACT-nucleosome complexes were observed during curaxin-supported nucleosome unfolding. The structures of intermediates suggest “decision points” in the unfolding/folding pathway where FACT can either promote disassembly or assembly of nucleosomes, with the outcome possibly being influenced by additional factors. The data suggest novel mechanisms of nucleosome unfolding by FACT and c-trapping by curaxins.
Identification of a novel deFADding activity in 5’ to 3’ exoribonucleases
Authors: Sharma Sunny , Yang Jun , Doamekpor Selom K. , Grudizen-Nogalska Ewa , Tong Liang , Kiledjian Megerditch 
Published: May 2022

ABSTRACTIdentification of metabolite caps including FAD on the 5’ end of RNA has uncovered a previously unforeseen intersection between cellular metabolism and gene expression. To understand the function of FAD caps in cellular physiology, we characterised the proteins interacting with FAD caps in budding yeast. Here we demonstrate that highly conserved 5’-3’ exoribonucleases, Xrn1 and Rat1, physically interact with the RNA 5’ FAD cap and both possess FAD cap decapping (deFADding) activity and subsequently degrade the resulting RNA. Xrn1 deFADding activity was also evident in human cells indicating its evolutionary conservation. Furthermore, we report that the recently identified bacterial 5’-3’ exoribonuclease RNase AM also possesses deFADding activity that can degrade FAD-capped RNAs in vitro and in E. coli cells. To gain a molecular understanding of the deFADding reaction, an RNase AM crystal structure with three manganese ions coordinated by a sulfate molecule and the active site amino acids was generated that provided details underlying hydrolysis of the FAD cap. Our findings reveal a general propensity for 5’-3’ exoribonucleases to hydrolyse and degrade RNAs with 5’ end noncanonical caps in addition to their well characterized 5’ monophosphate RNA substrates indicating an evolutionarily conserved intrinsic property of 5’-3’ exoribonucleases.
Small-angle x-ray microdiffraction from fibrils embedded in tissue thin sections
Authors: Nepal Prakash , Bashit Abdullah Al , Yang Lin , Makowski Lee 
Published: May 2022

AbstractSmall-angle x-ray scattering (SAXS) from fibrils embedded in a fixed, thin section of tissue includes contributions from the fibrils; the polymeric matrix surrounding the fibrils; other constituents of the tissue; and cross-terms due to the spatial correlation between fibrils and neighbouring molecules. This complex mixture severely limits the amount of information that can be extracted from scattering studies. However, availability of micro- and nano-beams has made possible measurement of scattering from very small volumes which, in some cases, may be dominated by a single fibrillar constituent. In those cases, information about the predominant species may be accessible. Nevertheless, even in these cases, the correlations between the positions of fibrils and other constituents have significant impact on the observed scattering. Here, we propose strategies to extract partial information about fibril structure and tissue organization on the basis of SAXS from samples of this type. We show that the spatial correlation function of the fibril in the direction perpendicular to the fibril axis can be computed and contains information about the predominant fibril structure and the organization of the surrounding tissue matrix. It has significant advantages over approaches based on techniques developed for x-ray solution scattering. We present examples of the calculation of correlation in different types of samples to demonstrate the kinds of information that can be obtained from these measurements.SynopsisThe availability of micro- and nano- x-ray beams is making possible measurement of scattering from very small volumes, opening possibilities for derivingin situstructural information on fibrillar constituents in complex materials and tissues. This work outlines a set of strategies for confronting the formidable technical obstacles to extracting useful structural information from scattering derived from these materials.
A Commercial ARHGEF17/TEM4 antibody cross-reacts with Nuclear Mitotic Apparatus protein 1 (NuMA)
Authors: Prifti Diogjena Katerina , Lauzier Annie , Elowe Sabine 
Published: May 2022

AbstractThe Rho family Guanine nucleotide exchange factor (GEF) ARHGEF17 (also known as TEM4) is a large protein with only 3 annotated regions: an N-terminal actin-binding domain, a Rho-specific dbl homology (DH)- pleckstrin homology (PH) type GEF domain and a seven bladed β propeller fold at the C-terminus with unknown function. TEM4 has been implicated in numerous activities that rely on regulation of the cytoskeleton including cell migration, cell-cell junction formation and the spindle assembly checkpoint during mitosis. Here we have assessed the specificity of a TEM4 polyclonal antibody that has been commonly used as a Western blotting and immunocytochemistry probe for TEM4 in mammalian cells. We find that this antibody, in addition to its intended target, cross-reacts with the Nuclear Mitotic Apparatus Protein 1 (NuMA) in Western blotting and immunoprecipitation, and detects NuMA preferentially in immunocytochemistry. This cross-reactivity, with an abundant chromatin- and mitotic spindle-associated factor, is likely to affect the interpretation of experiments that make use of this antibody probe, in particular by immunocytochemistry and immunoprecipitation.
Phylogenetic trees of closely related bacterial species and subspecies based on frequencies of short nucleotide sequences
Authors: Nakano Yoshio , Domon Yusaku , Yamagishi Kenji 
Published: May 2022

AbstractBacterial phylogenetic analyses are commonly performed to explore relationships among various bacterial species and genera based on their 16S rRNA gene sequences; however, the results are limited by mosaicism, intragenomic heterogeneity, and difficulty in distinguishing between related species. In this study, we aimed to perform genome-wide comparisons of different bacterial species, namely Escherichia coli and Shigella and Yersinia, Klebsiella, and Neisseria spp. or serotypes of Listeria monocytogenes, based on their K-mer profiles to construct phylogenetic trees. Pentanucleotide frequency analysis (512 patterns of 5 nucleotides each) was performed to distinguish highly similar species from each other, such as Yersinia species, along with Shigella spp. and E. coli. Moreover, Escherichia albertii strains were clearly distinguished from E. coli and Shigella, despite being closely related to enterohemorrhagic E. coli in the phylogenetic tree. In addition, the phylogenetic tree of Ipomoea species based on pentamer frequency in chloroplast genomes correlated with previously reported morphological similarities. Furthermore, a support vector machine clearly classified E. coli and Shigella genomes based on pentanucleotide profiles. These results suggest that phylogenetic analysis based on penta- or hexamer profiles is a useful alternative for microbial phylogenetic studies. In addition, we introduced an R application, Phy5, which generates a phylogenetic tree based on genome-wide comparisons of pentamer profiles. The online version of Phy5 can be accessed at https://phy5.shinyapps.io/Phy5R/.
Fast and Accurate Bayesian Polygenic Risk Modeling with Variational Inference
Authors: Zabad Shadi , Gravel Simon , Li Yue 
Published: May 2022

AbstractThe recent proliferation of large scale genome-wide association studies (GWASs) has motivated the development of statistical methods for phenotype prediction using single nucleotide polymorphism (SNP) array data. These polygenic risk score (PRS) methods formulate the task of polygenic prediction in terms of a multiple linear regression framework, where the goal is to infer the joint effect sizes of all genetic variants on the trait. Among the subset of PRS methods that operate on GWAS summary statistics, sparse Bayesian methods have shown competitive predictive ability. However, most existing Bayesian approaches employ Markov Chain Monte Carlo (MCMC) algorithms for posterior inference, which are computationally inefficient and do not scale favorably with the number of SNPs included in the analysis. Here, we introduce Variational Inference of Polygenic Risk Scores (VIPRS), a Bayesian summary statistics-based PRS method that utilizes Variational Inference (VI) techniques to efficiently approximate the posterior distribution for the effect sizes. Our experiments with genome-wide simulations and real phenotypes from the UK Biobank (UKB) dataset demonstrated that variational approximations to the posterior are competitively accurate and highly efficient. When compared to state-of-the-art PRS methods, VIPRS consistently achieves the best or second best predictive accuracy in our analyses of 36 simulation configurations as well as 12 real phenotypes measured among the UKB participants of “White British” background. This performance advantage was higher among individuals from other ethnic groups, with an increase in R2 of up to 1.7-fold among participants of Nigerian ancestry for Low-Density Lipoprotein (LDL) cholesterol. Furthermore, given its computational efficiency, we applied VIPRS to a dataset of up to 10 million genetic markers, an order of magnitude greater than the standard HapMap3 subset used to train existing PRS methods. Modeling this expanded set of variants conferred significant improvements in prediction accuracy for a number of highly polygenic traits, such as standing height.
A molecular phenology scale of fruit development
Authors: Tornielli Giovanni Battista , Sandri Marco , Fasoli Marianna , Amato Alessandra , Pezzotti Mario , Zuccolotto Paola , Zenoni Sara 
Published: May 2022

AbstractFruit growth and development consists of a continuous succession of physical, biochemical, and physiological changes driven by a genetic program that dynamically responds to environmental cues. Establishing recognizable stages over the whole fruit lifetime represents a fundamental requirement for research and fruit crop cultivation. This is especially relevant in perennial crops like the grapevine to scale the development of its fruit across genotypes and growing conditions.In this work, molecular-based information from several grape berry transcriptomic datasets was exploited to build a molecular phenology scale (MPhS) and to map the ontogenic development of the fruit. The proposed statistical pipeline consisted in an unsupervised learning procedure yielding an innovative combination of semiparametric, smoothing and dimensionality reduction tools. The transcriptomic distance between fruit samples was precisely quantified by means of the MPhS that also enabled to highlight the winding dynamics of the transcriptional program over berry development through the calculation of the rate of variation of MPhS stages by time.The MPhS allowed the alignment of time-series fruit samples proving to be a step forward in mapping the progression of grape berry development with higher precision compared to classic time- or phenotype-based approaches and inspiring the use of the transcriptional information to scale the developmental progression of any organ in any plant species.
Sex differences in islet stress responses support female beta cell resilience
Authors: Brownrigg George P. , Xia Yi Han , Chu Chieh Min Jamie , Wang Su , Chao Charlotte , Zhang Jiashuo Aaron , Skovsø Søs , Panzhinskiy Evgeniy , Hu Xiaoke , Johnson James D. , Rideout Elizabeth J. 
Published: May 2022

ABSTRACTObjectivePancreatic β cells play a key role in glucose homeostasis; dysfunction of this critical cell type causes type 2 diabetes (T2D). Emerging evidence points to sex differences in β cells, but few studies have examined male-female differences in β cell stress responses and resilience across multiple contexts, including diabetes. Here, we address the need for high-quality information on sex differences in β cell/islet gene expression and function using both human and rodent samples.MethodsWe compared β cell gene expression and insulin secretion in donors living with T2D to non-diabetic donors in both males and females. In mice, we generated a well-powered islet RNAseq dataset from 20-week-old male and female siblings with equivalent insulin sensitivity. Because on our unbiased analysis of gene expression pointed to sex differences in endoplasmic reticulum (ER) stress response, we subjected islets isolated from age-matched male and female mice to thapsigargin treatment and monitored protein synthesis, cell death, and β cell insulin production and secretion. Transcriptomic and proteomic analyses were used to characterize sex differences in islet responses to ER stress.ResultsOur single-cell analysis of human β cells revealed sex-specific changes to gene expression and function in T2D, correlating with more robust insulin secretion in islets isolated from female donors living with T2D compared to male T2D donors. In mice, RNA sequencing revealed differential enrichment of unfolded protein response pathway-associated genes, where female islets showed higher expression of genes linked with protein synthesis, folding, and processing. This differential expression was biologically significant, as female islets were more resilient to ER stress induction with thapsigargin. Specifically, female islets maintained better insulin secretion and showed a distinct transcriptional response under ER stress compared with males.ConclusionsOur data demonstrate that physiologically significant sex differences in β cell gene expression exist in both humans and mice, and that female β cells maintain better insulin production and secretion across multiple physiological and pathological contexts.