bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of the ISR by AB5 subtilase cytotoxin drives type-I IFN expression in pDCs via STING activation
Authors: Barros Daniela , Ferreira Beatriz H. , Garcia-Gonzalez Paulina , Carbone Francesco , Luka Marine , Leite-Pinheiro Fátima , Antas Paulo , Mendes Andreia , Machado Mariana D. , Zhang Lichen , Cresci Marina , Galliot Lou , Gigan Julien , Reverendo Marisa , Su Bing , Paton Adrienne W. , Paton James C. , Rocchi Stéphane , Rieux-Laucat Frédéric , Argüello Rafael J. , Nal Béatrice , Liang Yinming , Ménager Mickaël , Gatti Evelina , Almeida Catarina R. , Pierre Philippe 
Published: October 2024

SUMMARYWe demonstrate that exposure to the AB5 subtilase cytotoxin (SubAB) induces the unfolded protein response (UPR) in human peripheral blood mononuclear cells, concomitant with a pro-inflammatory response across distinct cell subsets. Notably, SubAB selectively induces type-I interferon (IFN) expression in plasmacytoid dendritic cells, acting synergistically with Toll-like receptor 7 stimulation. The induction of type-I IFN in response to SubAB relies on stimulator of interferon genes (STING) activation, coupled with protein synthesis inhibition mediated by protein kinase R-like endoplasmic reticulum kinase and phosphorylation of the eukaryotic translation initiation factor 2 subunit-alpha. By impeding mRNA translation through the integrated stress response, SubAB precipitates the downregulation of the negative innate signaling feedback regulator Tax1-binding protein 1. This downregulation is necessary to unleash TANK-binding kinase 1 signaling associated with STING activation. These findings shed new light on how UPR-inducing conditions may regulate the immune system during infection or pathogenesis.
Linking candidate causal autoimmune variants to T cell networks using genetic and epigenetic screens in primary human T cells
Authors: Ho Ching-Huang , Dippel Maxwell A. , McQuade Meghan S. , Mishra Arpit , Pribitzer Stephan , Nguyen LeAnn P. , Hardy Samantha , Chandok Harshpreet , Chardon Florence , McDiarmid Troy A. , DeBerg Hannah A. , Buckner Jane H. , Shendure Jay , de Boer Carl G. , Guo Michael H. , Tewhey Ryan , Ray John P. 
Published: October 2024

AbstractGenetic variants associated with autoimmune diseases are highly enriched within putativecis-regulatory regions of CD4+T cells, suggesting that they alter disease risk via changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. We tested >18,000 autoimmune disease-associated variants for allele-specific expression using massively parallel reporter assays in primary human CD4+T cells. The 545 expression-modulating variants (emVars) identified greatly enrich for likely causal variants. We provide evidence that many emVars are mediated by common upstream regulatory conduits, and that putative target genes of primary T cell emVars are highly enriched within a lymphocyte activation network. Using bulk and single-cell CRISPR-interference screens, we confirm that emVar-containing T cellcis-regulatory elements modulate both known and novel target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk.
Cerebral Small Vessel Disease genetic determinant TRIM47 controls brain homeostasisviathe NRF2 antioxidant system
Authors: Duplàa Cécile , Delobel Valentin , Boulestreau Romain , Rubin Sébastien , Vaurs Juliette , Jaspard-Vinassa Béatrice , Busson Muriel , Combrouze Cloé , Proust Carole , Morel Jean- Luc , Bontempi Bruno , Mishra Aniket , Debette Stéphanie , Couffinhal Thierry , Peghaire Claire 
Published: October 2024

AbstractCerebral small vessel disease (cSVD) is a leading cause of stroke, cognitive decline and dementia, for which no specific mechanism-based treatments are available to date. Genome-wide and whole-exome association studies previously identified robust associations of common variants at chr17q25 with cSVD features on magnetic resonance imaging, with converging bioinformatic and experimental data for a causal involvement ofTRIM47. Preliminary functional evaluation of TRIM47, an ubiquitin ligase enriched in brain endothelial cells (ECs), suggested its potential role in blood brain barrier (BBB) integrity. Here, we show that TRIM47 regulates brain EC resilience and adaptive responses to oxidative stress by binding to KEAP1, stabilizing NRF2 protein levels and promoting the NRF2 antioxidant signaling pathway.In vivo,Trim47-deficient mice exhibit downregulation of NRF2 target genes, BBB dysfunction, astrogliosis and cognitive impairments. Endothelial-specific deletion ofTrim47recapitulates these phenotypes. Treatment with the NRF2 activator tert- butylhydroquinone normalized BBB integrity and cognitive function inTrim47-deficient mice, highlighting the role of endothelial TRIM47 in driving brain homeostasis through NRF2 pathway activation. This work indicates that loss of the protective TRIM47/NRF2 axis may increase the susceptibility to developing human cSVD and that targeting the TRIM47/NRF2 axis could be a promising therapeutic approach for vascular cognitive impairment and dementia.
MEDOC: A fast, scalable and mathematically exact algorithm for the site-specific prediction of the protonation degree in large disordered proteins
Authors: Fossat Martin J. 
Published: October 2024

AbstractIntrinsically disordered regions are found in most eukaryotic proteins and are enriched in positively and negatively charged residues. While it is often convenient to assume these residues follow their model-compound pKavalues, recent work has shown that local charge effects (charge regulation) can upshift or downshift sidechain pKavalues with major consequences for molecular function. Despite this, charge regulation is rarely considered when investigating disordered regions. The number of potential charge microstates that can be populated through acid/base regulation of a given number of ionizable residues in a sequence,N, scales as ∼2N. This exponential scaling makes the assessment of the full charge landscape of most proteins computationally intractable. To address this problem, we developed MEDOC (Multisite Extent of Deprotonation Originating from Context) to determine the degree of protonation of a protein based on the local sequence context of each ionizable residue. We show that we can drastically reduce the number of parameters necessary to determine the full, analytic, Boltzmann partition function of the charge landscape at both global and site-specific levels. Our algorithm applies the structure of theq-canonical ensemble, combined with novel strategies to rapidly obtain the minimal set of parameters, thereby circumventing the combinatorial explosion of the number of charge microstates even for proteins containing a large number of ionizable amino acids. We apply MEDOC to several sequences, including a global analysis of the distribution of pKavalues across the entire DisProt database. Our results show differences in the distribution of predicted pKavalues for different amino acids, in agreement with NMR-measured distributions in proteins.
vScreenML v2.0: Improved Machine Learning Classification for Reducing False Positives in Structure-Based Virtual Screening
Authors: Andrianov Grigorii V. , Haroldsen Emeline , Karanicolas John 
Published: October 2024

AbstractEnthusiastic adoption of make-on-demand chemical libraries for virtual screening has highlighted the need for methods that deliver improved hit-finding discovery rates. Traditional virtual screening methods are often inaccurate, with most compounds nominated in a virtual screen not engaging the intended target protein to any detectable extent. Emerging machine learning approaches have made significant progress in this regard, including our previously-described tool vScreenML. Broad adoption of vScreenML was hindered by its challenging usability and dependencies on certain obsolete or proprietary software packages. Here, we introduce vScreenML 2.0 (https://github.com/gandrianov/vScreenML2) to address each of these limitations with a streamlined Python implementation. Through careful benchmarks, we show that vScreenML 2.0 outperforms other widely-used tools for virtual screening hit discovery.
DigestR an open-source software tool for visualizing LC-MS proteomics data resulting from natural protein catabolism
Authors: de Lamache Dimitri Desmonts , Aburashed Raied , Wacker Soren , Lewis Ian A. 
Published: October 2024

AbstractProtein catabolism is an essential biological function supported by every living organism. Although liquid chromatography mass spectrometry proteomics has advanced considerably over the past decade, protein catabolism in natural systems is still difficult to study. One reason for this is the lack of software tools designed specifically for decoding the complex mixtures of peptides that result fromin vivoprotein digestion. To address this, we developed DigestR, an open-source software tool designed specifically for the analysis of LC-MS proteomics data. DigestR allows users to visualize naturally occurring peptides and align them to a reference proteome at display them at either a proteome-wide and protein-specific level. These visualization tools allow users to track the patters of peptides occurring in natural systems and map naturally-occurring proteolytic cut sites. To demonstrate these functions, we used DigestR to analyze a mixture of peptides resulting from thein vitrodigestion of human hemoglobin and bovine albumin with a cocktail of well characterized proteases. As expected, DigestR correctly identified both the proteins involved and the proteolytic cut sites produced by our protease cocktail. We then used DigestR to analyze the complex semi-ordered hemoglobin digestion pathway used by the malaria parasitePlasmodium falciparum.We show that DigestR successfully identified the proteolytic cut sites linked to the Plasmepsins, a protease known to be involved in hemoglobin digestion by the parasite. Collectively, these findings show that DigestR can be used to help visualize and interpret the complex mixtures of peptides occurring throughin vivoprotein catabolism. DigestR can be downloaded fromwww.lewisresearchgroup.org/software.
Polymer Model Integrates Super-Resolution Imaging and Epigenomic Sequencing to Elucidate the Role of Epigenetic Reactions in Shaping 4D Chromatin Organization
Authors: Vinayak Vinayak , Basir Ramin , Golloshi Rosela , Toth Joshua , Sant’Anna Lucas , Lakadamyali Melike , McCord Rachel Patton , Shenoy Vivek B 
Published: October 2024

AbstractChromatin, with its complex spatial and temporal organization, plays a crucial role in regulating gene expression. Recent advancements in super-resolution microscopy have revealed that nanoscale domains of heterochromatin (repressed segments) embedded within a euchromatin (active segments) background are fundamental units of 3D chromatin organization. In tissue-resident cells, the size of these heterochromatin domains varies with the microenvironment, particularly its stiffness, and chromatin organization is also influenced by pharmacological and epigenetic drugs. However, the mechanisms governing heterochromatin domain size under various conditions and their impact on gene expression remain unclear. To address this knowledge gap, we have developed a dynamic, next-generation sequencing informed chromatin copolymer model. Our model simulates the spatiotemporal evolution of chromatin, driven by passive diffusion and active epigenetic reactions, which interconvert euchromatin and heterochromatin. By integrating chromatin-chromatin interaction energetics and diffusion-reaction dynamics, we predict the formation of nanoscale heterochromatin-rich domains and establish a scaling relationship between their size and the modulation of epigenetic reaction rates. Additionally, our model predicts that epigenetic and chromatin compaction changes in response to changes in global reaction rates occur predominantly at domain boundaries. We validated these predictions via Hi-C contact map analysis and super-resolution imaging of hyperacetylated melanoma cells. Subsequent RNA-seq analysis suggested a pivotal role of these epigenetic shifts in influencing the metastatic potential of these cells. We further validated our mesoscale findings against chromatin rearrangement in hMSCs, which exhibit sensitivity of epigenetic reaction rates to changes in microenvironmental stiffness. Finally, we evaluated the effects of cycling of epigenetic reaction rates in silico, mimicking the cellular transition to different extracellular conditions, and back again. This finding reveals a cell-type invariant mechanism driven by domain boundaries, whereby chromatin organization guides epigenetic memory formation. Our findings show that chromatin reorganization in response to changes in epigenetic reaction rates resulting from alterations in the microenvironment, drug exposure and disease progression impacts both immediate cellular responses and long-term epigenetic memory.
Identification and predictive machine learning models construction of gut microbiota associated with lymph node metastasis in colorectal cancer
Authors: Wu Yongzhi , Huang Xiaoliang , Huang Yongqi , Huang Zigui , Chen Chuanbin , Qin Mingjian , Wang Zhen , He Fuhai , Tang Binzhe , Long Chenyan , Mo Xianwei , Liu Jungang , Tang Weizhong 
Published: October 2024

AbstractThis study focuses on the significant role between gut microbiota and lymph node metastasis (LNM) in colorectal cancer (CRC). By conducting 16S rRNA sequencing on fecal samples from 147 CRC patients and combining it with the linear discriminant analysis effect size (LEfSe) algorithm, we successfully identified significant differences in the gut microbiota between patients with LNM and those with none lymph node metastasis (NLNM). Furthermore, using transcriptome data from 9 CRC patients, we constructed an immune cell infiltration matrix to deeply explore the biological functions associated with LNM. Eventually, using the characteristics of the gut microbiota associated with LNM, we developed random forest (RF) and multilayer perceptron (MLP) machine learning models to predict the lymph node metastasis status of CRC patients. We identified 21 differentially abundant gut microbes between the two groups, among whichBacteroides plebeius, significantly enriched in LNM group, is closely related to the upregulation of resting NK cells and chemokine CXCL8 expression, and this bacterial species is also positively correlated with the enhancement of fructose metabolism. The RF and MLP models constructed based on the LNM-associated gut microbiota showed good predictive efficacy in predicting LNM status in CRC. This study reveals thatBacteroides plebeiusmay play an important role in the progression of CRC, with its mechanism potentially involving changes in immune modulation and metabolic pathways. The classification model constructed based on gut microbiota characteristics can predict LNM status of CRC, providing a new perspective for personalized and precision treatment of CRC patients.ImportanceThis study highlights the pivotal role of gut microbiota in lymph node metastasis (LNM) of CRC, identifying key microbial differences between LNM and NLNM patients. Our findings implicateBacteroides plebeiusin CRC progression via immune modulation and metabolic alterations. Moreover, machine learning models based on gut microbiota predict LNM status accurately, offering a novel approach for personalized CRC treatment.
Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-γ induced IRF1
Authors: Chang Tyron , Alvarez Jessica , Chappidi Sruthi , Crockett Stacey , Sorouri Mahsa , Orchard Robert C. , Hancks Dustin C. 
Published: October 2024

ABSTRACTInterferon (IFN) induced activities are critical, early determinants of immune responses and infection outcomes. A key facet of IFN responses is the upregulation of hundreds of mRNAs termed interferon-stimulated genes (ISGs) that activate intrinsic and cell-mediated defenses. While primary interferon signaling is well-delineated, other layers of regulation are less explored but implied by aberrant ISG expression signatures in many diseases in the absence of infection. Consistently, our examination of tonic ISG levels across uninfected human tissues and individuals revealed three ISG subclasses. As tissue identity and many comorbidities with increased virus susceptibility are characterized by differences in metabolism, we characterized ISG responses in cells grown in media known to favor either aerobic glycolysis (glucose) or oxidative phosphorylation (galactose supplementation). While these conditions over time had a varying impact on the expression of ISG RNAs, the differences were typically greater between treatments than between glucose/galactose. Interestingly, extended interferon-priming led to divergent expression of two ISG proteins: upregulation of IRF1 in IFN-γ/glucose and increased IFITM3 in galactose by IFN-α and IFN-γ. In agreement with a hardwired response, glucose/galactose regulation of interferon-γ induced IRF1 is conserved in unrelated mouse and cat cell types. In galactose conditions, proteasome inhibition restored interferon-γ induced IRF1 levels to that of glucose/interferon-γ. Glucose/interferon-γ decreased replication of the model poxvirus vaccinia at low MOI and high MOIs. Vaccinia replication was restored byIRF1KO. In contrast, but consistent with differential regulation of IRF1 protein by glucose/galactose, WT andIRF1KO cells in galactose media supported similar levels of vaccinia replication regardless of IFN-γ priming. Also associated with glucose/galactose is a seemingly second block at a very late stage in viral replication which results in reductions in herpes- and poxvirus titers but not viral protein expression. Collectively, these data illustrate a novel layer of regulation for the key ISG protein, IRF1, mediated by glucose/galactose and imply unappreciated subprograms embedded in the interferon response. In principle, such cellular circuitry could rapidly adapt immune responses by sensing changing metabolite levels consumed during viral replication and cell proliferation.
Arctic Ocean virus communities: seasonality, bipolarity, and prokaryotic interactions
Authors: Calayag Alyzza , Priest Taylor , Oldenburg Ellen , Muschiol Jan , Popa Ovidiu , Wietz Matthias , Needham David M. 
Published: October 2024

ABSTRACTViruses play important roles in ocean environments as agents of mortality and genetic transfer, influencing ecology, evolution and biogeochemical processes. However, we know little about the diversity, seasonality, and host interactions of viruses in polar waters. To address this, we studied dsDNA viruses in the Arctic Fram Strait across four years via 47 long-read metagenomes of the cellular size-fraction. Among 5,662 vOTUs, 69%, 30% and 1.4% were bacteriophages (Myoviridae, Podoviridae, and Siphoviridae), Unassigned, and Phycodnaviridae, respectively. Viral coverage was, on average, 5-fold higher than prokaryotic coverage, and 8-fold higher in summer. Viral community composition showed annual peaks in similarity and was strongly correlated with prokaryotic community composition. Using a Convergent Cross Mapping network, we identified putative virus-host interactions and six ecological modules, each associated with distinct environmental conditions. The network also revealed putative novel cyanophages with time-lagged correlations to their hosts (late summer) as well as diverse viruses correlated with Nitrososphaerales (winter). By comparison with global metagenomes, we found that 42% of Fram Strait vOTUs peaked in abundance in high latitude regions of both hemispheres (average 61°N and 51°S), and encoded proteins with biochemical signatures of cold adaptation. Our study reveals a rich diversity of polar viruses with pronounced seasonality, providing a foundation for understanding how they regulate and impact ecosystem functionality in changing polar oceans.
Defacing biases visual quality assessments of structural MRI
Authors: Provins Céline , Savary Élodie , Sanchez Thomas , Mullier Emeline , Barranco Jaime , Fischi-Gómez Elda , Alemán-Gómez Yasser , Richiardi Jonas , Poldrack Russell A. , Hagmann Patric , Esteban Oscar 
Published: October 2024

AbstractA critical requirement before data-sharing of human neuroimaging is removing facial features to protect individuals’ privacy. However, not only does this process redact identifiable information about individuals, but it also removes non-identifiable information. This introduces undesired variability into downstream analysis and interpretation. This registered report investigated the degree to which the so-calleddefacingaltered the quality assessment of T1-weighted images of the human brain from the openly available “IXI dataset”. The effect of defacing on manual quality assessment was investigated on a single-site subset of the dataset (N=185). By comparing two linear mixed-effects models, we determined that four trained human raters’ perception of quality was significantly influenced by defacing by comparing their ratings on the same set of images in two conditions: “nondefaced” (that is, preserving facial features) and “defaced”. In addition, we investigated these biases on automated quality assessments by applying repeated-measures multivariate ANOVA (rm-MANOVA) on the image quality metrics extracted withMRIQCon the full IXI dataset (N=581; three acquisition sites). This study found that defacing altered the quality assessments by humans and showed thatMRIQC’s quality metrics were mostly insensitive to defacing.
Isolated human Fos promoter in plasmid DNA is overactive
Authors: Andrei Gorbunov , Dmitrii Fedorov , Olga Kvitko , Olga Lopina , Elizaveta Klimanova 
Published: October 2024

AbstractChanges in intracellular concentrations of Na+and K+are shown to alterFosgene expression. Here, we obtained a genetic construct encodingTurboGFP-dest1gene under control of the humanFospromoter (−549; +155) and studied its expression in HEK293T. Amplification of theFospromoter sequence from genomic DNA was only efficient in the presence of Li+ions. Ouabain and medium with replacement of Na+with Li+ions resulted in the accumulation of Na+and Li+in cells, respectively. These stimuli increased the mRNA level of endogenousFosand the average fluorescence intensity of TurboGFP-dest1 in transfected cells. The mRNA level ofTurboGFP-dest1was extremely higher than the mRNA level of endogenousFosand was little affected by the stimuli.
Provirus deletion fromHaloferax volcaniiaffects motility, stress resistance and CRISPR RNA expression
Authors: Di Cianni Nadia , Bolsinger Simon , Brendel Jutta , Raabe Monika , König Sabine , Mitchell Laura , Bischler Thorsten , Gräfenhan Tom , Read Clarissa , Erdmann Susanne , Allers Thorsten , Walther Paul , Urlaub Henning , Dyall-Smith Mike , Pfeiffer Friedhelm , Marchfelder Anita 
Published: October 2024

AbstractHaloferax volcaniiharbours four putative proviruses: Halfvol1, Halfvol2, Halfvol3 and Halfvol4. In this study we successfully deleted all four provirus genomes, demonstrating, that they are not essential. Transcriptome comparison between this strain (ΔHalfvol1-4) and a wild type strain reveals an increase in archaella and chemotaxis gene expression, resulting in higher swarming motility in ΔHalfvol1-4. Furthermore, ΔHalfvol1-4 cells show an elongated cell shape and a higher resistance to H2O2stress compared to the wild type. RNA-seq also revealed down-regulation of CRISPR arrays in the provirus-free strain.Circularised genomes of Halfvol1, Halfvol2 and Halfvol3 were found in the culture supernatant. This confirms excision of the proviruses from the chromosome, which seems to happen more efficiently at low temperature (30°C). Electron microscopy revealed potential viral particles in the supernatant, and mass spectrometry analysis confirmed the presence of structural viral proteins of Halfvol1 and Halfvol3 in the isolated virus sample. These observations suggest that these proviruses are active and cause a chronic infection inHfx. volcanii.