bluuebunny/crossref_metadata_2025_split huggingface dataset:
Environmental stiffness restores mechanical homeostasis in vimentin-depleted cells
Authors: Grolleman Janine , Engeland Nicole C.A. van , Raza Minahil , Rasthi Sepinoud Azimi , Conte Vito , Sahlgren Cecilia M. , Bouten Carlijn V.C. 
Published: May 2023

AbstractRecent experimental evidence indicates a role for the intermediate filament vimentin in regulating cellular mechanical homeostasis, but its precise contribution remains to be discovered. Mechanical homeostasis requires a balanced bi-directional interplay between the cell’s microenvironment and the cellular morphological and mechanical state – this balance being regulated via processes of mechanotransduction and mechanoresponse, commonly referred to as mechanoreciprocity. Here, we systematically analyze vimentin-expressing and vimentin-depleted cells in a swatch ofin vitrocellular microenvironments varying in stiffness and/or ECM density. We find that vimentin-expressing cells maintain mechanical homeostasis by adapting cellular morphology and mechanics to micromechanical changes in the microenvironment. However, vimentin-depleted cells lose this mechanoresponse ability on short timescales, only to reacquire it on longer time scales. Indeed, we find that the morphology and mechanics of vimentin-depleted cell in stiffened microenvironmental conditions can get restored to the homeostatic levels of vimentin-expressing cells. Additionally, we observed vimentin-depleted cells increasing collagen matrix synthesis and its crosslinking, a phenomenon which is known to increase matrix stiffness, and which we now hypothesize to be a cellular compensation mechanism for the loss of vimentin. Taken together, our findings provide further insight in the regulating role of intermediate filament vimentin in mediating mechanoreciprocity and mechanical homeostasis.
G6PC2 controls glucagon secretion by defining the setpoint for glucose in pancreatic α-cells
Authors: Bahl Varun , Waite Eric , Rifkind Reut , Hamdan Zenab , May Catherine Lee , Manduchi Elisabetta , Voight Benjamin F. , Lee Michelle Y.Y. , Tigue Mark , Manuto Nicholas ,   the HPAP Consortium, Glaser Benjamin , Avrahami Dana , Kaestner Klaus H. 
Published: May 2023

AbstractImpaired glucose suppression of glucagon secretion (GSGS) is a hallmark of type 2 diabetes. A critical role for α-cell intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at theG6PC2locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c levels. Here, we find that trait-associated variants in theG6PC2promoter are located in open chromatin not just in β− but also in α-cells, and document allele-specificG6PC2expression of linked variants in human α– cells. Using α-cell specific gene ablation ofG6pc2in mice, we show that this gene plays a critical role in controlling glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology; findings we confirmed in primary human α-cells. Collectively, our data demonstrate thatG6PC2impacts glycemic control via its action in α-cells and suggest thatG6PC2inhibitors could help control blood glucose through a novel, bi-hormonal mechanism.
Full-length single-cell BCR sequencing paired with RNA sequencing reveals convergent responses to vaccination
Authors: Morgan Duncan M. , Zhang Yiming , Kim Jin-Hwan , Murillo MaryAnn , Singh Suddham , Loschko Jakob , Surendran Naveen , Patil Sarita U. , Kanevsky Isis , Chorro Laurent , Love J. Christopher 
Published: May 2023

AbstractSingle-cell RNA sequencing can to resolve transcriptional features from large numbers of individual immune cells, but techniques capable of resolving the variable regions of B cell receptors (BCR) – defining features that confer antigen specificity to B cells – remain limited, especially from widely-used 3′-barcoded libraries. Here, we report a method that for recovering paired, full-length variable region sequences of the BCRs from 3′-barcoded single-cell whole transcriptome libraries. We first verified this method could produce accurate, full-length BCR sequences. We then applied this method to profile antigen-specific B cell responses elicited against the capsular polysaccharide ofStreptococcus pneumoniaeserotype 3 (ST3) by glycoconjugate vaccines in infant rhesus macaques. Using our method, we defined features of the BCR associated with specificity for the ST3 antigen and showed that these sequence characteristics are present in multiple vaccinated monkeys, indicating a convergent response to vaccination. These results demonstrate the utility of our method to resolve key features of the B cell repertoire and for profiling antigen-specific responses elicited by vaccination.
Converging evidence that left extrastriate body area supports visual sensitivity to social interactions
Authors: Gandolfo Marco , Abassi Etienne , Balgova Eva , Downing Paul E. , Papeo Liuba , Koldewyn Kami 
Published: May 2023

AbstractNavigating our complex social world requires processing the interactions we observe. Recent psychophysical and neuroimaging studies provide parallel evidence that the human visual system may be attuned to efficiently perceive dyadic interactions. This work implies, but has not yet demonstrated, that activity in body-selective cortical regions causally supports efficient visual perception of interactions. We adopt a multi-method approach to close this important gap. First, using a large fMRI dataset (N=92), we found that the left-hemisphere Extrastriate Body Area (EBA) responds more to face-to-face than non-facing dyads. Second, we replicated a behavioural marker of visual sensitivity to interactions: categorisation of facing dyads is more impaired by inversion than non-facing dyads. Third, in a pre-registered experiment, we used fMRI-guided transcranial magnetic stimulation to show that online stimulation of the left EBA, but not a nearby control region, abolishes this selective inversion effect. Activity in left EBA, thus, causally supports the efficient perception of social interactions.
Model-X knockoffs reveal data-dependent limits on regulatory network identification
Authors: Kernfeld Eric , Keener Rebecca , Cahan Patrick , Battle Alexis 
Published: May 2023

SummaryComputational biologists have long sought to automatically infer transcriptional regulatory networks (TRNs) from gene expression data, but such approaches notoriously suffer from false positives. Two points of failure could yield false positives: faulty hypothesis testing, or erroneous assumption of a classic criterion calledcausal sufficiency. We show that a recent statistical development, model-X knockoffs, can effectively control false positives in tests of conditional independence in mouse andE. colidata, which rules out faulty hypothesis tests. Yet, benchmarking against ChIP and other gold standards reveals highly inflated false discovery rates. This identifies the causal sufficiency assumption as a key limiting factor in TRN inference.
The digestive system of a cricket pulverizes polyethylene microplastics
Authors: Ritchie Marshall W. , Provencher Jennifer F. , Allison Jane E. , Muzzatti Matthew J. , MacMillan Heath A. 
Published: May 2023

AbstractMicroplastics (MPs; <5 mm) are a growing concern and a poorly understood threat to biota. Despite a recent spike in research on MPs, most of this work has focused on marine systems, and less is known about interactions between terrestrial organisms. We used a generalist insect (a cricket;Gryllodes sigillatus) to examine whether individuals would ingest and physically degrade MPs in their food. We fed crickets a range of concentrations (0, 2.5, 5, and 10% w/w) of fluorescent MPs mixed into a standard diet and dissected the gut regions to isolate the MPs within. Comparing plastic content and fragment size within gut regions, we sought to identify whether and where crickets can fragment ingested MP particles. Given the digestive tract morphology of this species, we expected that the crickets would both ingest and egest the MPs. We also predicted that the MPs would be fragmented into smaller pieces during this digestive process. We found thatG. sigillatusegested much smaller pieces than they ingested (likely into the nanoplastic range), and this fragmentation occurs early in the digestive process of this insect. These findings suggest that generalist insects can act as agents of plastic transformation in their environment if/when encountering MPs.
A systemic approach allows to identify the pedoclimatic conditions most critical in the susceptibility of a grapevine cultivar to esca/Botryosphaeria dieback
Authors: Monod Vinciane , Zufferey Vivian , Wilhelm Matthieu , Viret Olivier , Gindro Katia , Croll Daniel , Hofstetter Valérie 
Published: May 2023

ABSTRACTEsca and/or Botryosphaeria dieback (esca-BD) are two of the most destructive grapevine trunk diseases in the world, disease complex which remains poorly understood. As some vine cultivars show highly variable susceptibility to esca-BD, we designed a four-year experiment to identify which environmental factors influence the expression of the disease. We collected epidemiological and physiological data once a year for four consecutive years in 19 vineyard plots located in four wine-growing regions of Western Switzerland. We compared these data with climatic data obtained from weather stations for these same plots for four years and over the long term. We also estimated the soil water holding capacity of each plot. Confounding factors were minimal because all vineyards were planted in 2003 with the same cultivar and all plants grafted in the same nursery with genetically homogeneous grafting material. Principal component and regression analyses of combined epidemiological, biotic and pedoclimatic data identified a positive correlation between soil water retention capacity and plant mortality due to esca-BD. These analyses also showed that leaf disease symptoms and apoplexy are more frequent when cold, wet periods are followed - or alternate with - hot, dry periods, and that apoplexy occurs more frequently when weather conditions change abruptly (cold, wet May followed by a hot June) and deviate significantly from long-term climatic conditions. Regression analyses show that the soil water holding capacity impacts less the disease expression when the climate is warm and dry, both at the regional and at year-specific levels. Having identified the most important environmental factors towards expression of esca-BD, this study allows recommendations to be given to the winegrowers for the cultivar studied but can also be used as a model to identify the environmental factors that influence the expression of fungal diseases in other grapevine cultivars, other grapevine trunk diseases and even in other woody plants.
Increased bleeding and thrombosis in myeloproliferative neoplasms mediated through altered expression of inherited platelet disorder genes
Authors: Mitchell Alan , Frontini Mattia , Islam Serajul , Sivapalaratnam Suthesh , Krishnan Anandi 
Published: May 2023

AbstractAn altered thrombo-hemorrhagic profile has long been observed in patients with myeloproliferative neoplasms (MPNs). We hypothesized that this observed clinical phenotype may result from altered expression of genes known to harbor genetic variants in bleeding, thrombotic, or platelet disorders. Here, we identify 32 genes from a clinically validated gene panel that were also significantly differentially expressed in platelets from MPN patients as opposed to healthy donors.This work begins to unravel previously unclear mechanisms underlying an important clinical reality in MPNs. Knowledge of altered platelet gene expression in MPN thrombosis/bleeding diathesis opens opportunities to advance clinical care by: (1) enabling risk stratification, in particular, for patients undergoing invasive procedures, and (2) facilitating tailoring of treatment strategies for those at highest risk, for example, in the form of antifibrinolytics, desmopressin or platelet transfusions (not current routine practice). Marker genes identified in this work may also enable prioritization of candidates in future MPN mechanistic as well as outcome studies.
csppinet: A Python package for context-specific biological network construction and analysis based on omics data
Authors: de Carvalho L.M. 
Published: May 2023

AbstractThe analysis of large-scale biological data, particularly omics data, has become essential for understanding complex biological systems. In this study, we present a Python package for the construction of context-specific biological networks based on gene expression activity and protein-protein interaction (PPI) data. The package leverages computational tools and the NetworkX library for network analysis. Through a case study focusing on yeast fermentation with glucose and xylose as carbon sources, we demonstrate the package’s capabilities. The context-specific networks derived from these fermentation conditions were compared to highlight the impact of different carbon sources and stages on network dynamics. Hub genes were identified within each network, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to understand their functional implications. The results revealed distinct hub genes and enriched biological processes in each context-specific network. In the glucose-specific network, the exclusively proteins in this network revealed enrichment in terms related tochromosome organization, biological regulation, MAPK signaling pathwayandmismatch repair pathway. Conversely, the exclusively proteins in xylose-specific network revealed enrichment ingeneration of precursor metabolites and energy), mitochondrion organization, response to extracellular stimulus, glutamate metabolic process, cellular response to alcohol, beta-Alanine metabolism, arginine and proline metabolism, glyoxylate and dicarboxylate metabolismandpyruvate metabolism. The developed Python package and context-specific networks provide researchers with a valuable framework to explore complex biological phenomena. By integrating gene expression profiles and PPI data, researchers can gain insights into context-dependent molecular interactions and regulatory mechanisms. These findings contribute to the understanding of cellular behavior and have potential implications in disease mechanisms, biomarker identification, and drug target discovery. The csppinet package is available athttps://github.com/lmigueel/csppinet.
Assessing Fairness of AlphaFold2 Prediction of Protein 3D Structures
Authors: Abbas Usman , Chen Jin , Shao Qing 
Published: May 2023

ABSTRACTAlphaFold2 is reshaping biomedical research by enabling the prediction of a protein’s 3D structure solely based on its amino acid sequence. This breakthrough reduces reliance on labor-intensive experimental methods traditionally used to obtain protein structures, thereby accelerating the pace of scientific discovery. Despite the bright future, it remains unclear whether AlphaFold2 can uniformly predict the wide spectrum of proteins equally well. Systematic investigation into the fairness and unbiased nature of its predictions is still an area yet to be thoroughly explored. In this paper, we conducted an in-depth analysis of AlphaFold2’s fairness using data comprised of five million reported protein structures from its open-access repository. Specifically, we assessed the variability in the distribution of PLDDT scores, considering factors such as amino acid type, secondary structure, and sequence length. Our findings reveal a systematic discrepancy in AlphaFold2’s predictive reliability, varying across different types of amino acids and secondary structures. Furthermore, we observed that the size of the protein exerts a notable impact on the credibility of the 3D structural prediction. AlphaFold2 demonstrates enhanced prediction power for proteins of medium size compared to those that are either smaller or larger. These systematic biases could potentially stem from inherent biases present in its training data and model architecture. These factors need to be taken into account when expanding the applicability of AlphaFold2.
Proteomic characterization of aging-driven changes in the mouse brain by co-expression network analysis
Authors: Tsumagari Kazuya , Sato Yoshiaki , Aoyagi Hirofumi , Okano Hideyuki , Kuromitsu Junro 
Published: May 2023

AbstractBrain aging causes a progressive decline in functional capacity and is a strong risk factor for dementias such as Alzheimer’s disease. To characterize age-related proteomic changes in the brain, we used quantitative proteomics to examine brain tissues, cortex and hippocampus, of mice at three age points (3, 15, and 24 months old), and quantified more than 7,000 proteins in total with high reproducibility. We found that many of the proteins upregulated with age were extracellular proteins, such as extracellular matrix proteins and secreted proteins, associated with glial cells. On the other hand, many of the significantly downregulated proteins were associated with synapses, particularly postsynaptic density, specifically in the cortex but not in the hippocampus. Our datasets will be helpful as resources for understanding the molecular basis of brain aging.
Inactive PARP1 causes embryonic lethality and genome instability in a dominant-negative manner
Authors: Shao Zhengping , Lee Brian J. , Zhang Hanwen , Lin Xiaohui , Li Chen , Jiang Wenxia , Chirathivat Napon , Gershik Steven , Shen Michael M. , Baer Richard , Zha Shan 
Published: May 2023

AbstractPARP1 is recruited and activated by DNA strand breaks, catalyzing the generation of poly-ADP-ribose (PAR) chains from NAD+. PAR relaxes chromatin and recruits other DNA repair factors, including XRCC1 and DNA Ligase 3, to maintain genomic stability. Here we show that, in contrast to the normal development of Parp1-null mice, heterozygous expression of catalytically inactive Parp1 (E988A,Parp1+/A) acts in a dominant-negative manner to disrupt murine embryogenesis. As such, all the surviving F1Parp1+/Amice are chimeras with mixedParp1+/AN(neoR retention) cells that act similarly toParp1+/-. Pure F2Parp1+/Aembryos were found at Mendelian ratios at the E3.5 blastocyst stage but died before E9.5. Compared toParp1-/-cells, genotype and expression-validated pureParp1+/Acells retain significant ADP-ribosylation and PARylation activities but accumulate markedly higher levels of sister chromatin exchange and mitotic bridges. Despite proficiency for homologous recombination and non-homologous end-joining measured by reporter assays and supported by normal lymphocyte and germ cell development,Parp1+/Acells are hypersensitive to base damages, radiation, and Topoisomerase I and II inhibition. The sensitivity ofParp1+/Acells to base damages and Topo inhibitors in particular exceedParp1-/-controls. The findings show that the enzymatically inactive PARP1 protein has a dominant negative role and establishes a clear physiological difference between PARP1 inactivation vs. deletion. As a result, the enzymatically inactive PARP1 has a much more deteriorating impact on normal tissues than previously estimated, providing a mechanism for the on-target side effect of PARP inhibitors used for cancer therapy.Significance StatementPARP1 is the primary target of PARP enzymatic inhibitors. The use of PARP inhibitors for cancer therapy is based not only on the extreme sensitivity of BRCA1/2-deficient cancer cells to PARP1 inhibition but also on the nonessential role of PARP1 in normal tissues. Here we show that in contrast to the normal development of Parp1-null mice, the mouse model expressing the catalytically inactive Parp1 on only one allele (E988A,Parp1+/A) dies embryonically with high levels of genomic instability. The results reveal the severe dominant-negative impact of catalytically inactive PARP1, indicating the presence of enzymatically inactive PARP1 is much more damaging to normal tissues than previously anticipated. These findings provide a mechanism for clinical PARP inhibitors’ unexpected normal tissue toxicity.
Study protocol for a systems evaluation of an infant mental health service: integration of ‘Little Minds Matter’ into the early years system
Authors: Masefield Sarah , Ellwood Alison , Blower Sarah , Dickerson Josie , Moss Rachael H. , Ahern Sara 
Published: May 2023

AbstractInfant Mental Health relates to how well a child develops socially and emotionally from birth to age three. There is a well-established link between parent-infant relationship quality, Infant Mental Health, and longer-term social and emotional development, however, there is a lack of evidence-based interventions that support the parent-infant relationship and/or protect against poor Infant Mental Health. Little Minds Matter is a specialist Infant Mental Health service developed in Bradford (UK) to support parent-infant relationships by providing training and consultation for professionals and direct clinical work to families. The efficacy of this intervention will depend upon how well it becomes embedded within the early years system. This study aims to apply a systems approach to evaluate this service and provide a perspective on the challenges to embedding a complex service within a healthcare system. Multiple methods will be used to investigate embeddedness within the wider early years system. Routine collected quantitative data about the service will be used to develop a system map showing interaction with related services. Qualitative data will be collected through interviews with individuals involved in the design and provision of the Little Minds Matter service, and professionals working within the early years system. Framework analysis will be used to analyse the data inductively and deductively within a systems approach. The findings from this study will provide evidence for the ongoing implementation of the Little Minds Matter Service for providers and commissioning bodies. Exploring this methodological approach to evaluation will have application more broadly for researchers evaluating complex interventions and services within a wider system.
Multi-modal cryo-EM reveals trimers of protein A10 to form the palisade layer in poxvirus cores
Authors: Datler Julia , Hansen Jesse M , Thader Andreas , Schlögl Alois , Hodirnau Victor-Valentin , Schur Florian KM 
Published: May 2023

AbstractPoxviruses are among the largest double-stranded DNA viruses with members such as Variola virus, Monkeypox virus and the famous vaccination strain Vaccinia virus (VACV). Knowledge about the structural proteins that form the viral core, found in all infectious poxvirus forms, has remained sparse. While major core proteins have been annotatedviaindirect experimental evidence, their structures have remained elusive and they could not be assigned to the individual architectural features of the core. Hence, which proteins constitute which layers of the core, such as the so-called palisade layer and the inner core wall has remained enigmatic.Here, we have performed a multi-modal cryo-electron microscopy (cryo-EM) approach to elucidate the structural determinants of the VACV core. In combination with molecular modeling using AlphaFold, we unambiguously identify trimers formed by the cleavage product of A10 as the key component of the palisade layer. This allows us to place previously-obtained descriptions of protein interactions within the core wall into perspective and to provide a substantially revised model of poxvirus core architecture. Importantly, we show that interactions within A10 trimers are likely identical amongPoxviridae, implying that our structural observations should be generalizable over most, if not all members of this important virus family.One sentence summarySingle-particle cryo-EM, cryo-electron tomography, and AlphaFold modeling reveal the structural architecture of the poxvirus core and identify trimers of protein A10 as the key component of the palisade layer.