bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upright stance is controlled close to critical stability across different postures
Authors: Geng Yang , Bruijn Sjoerd M. , van Dieen Jaap H. 
Published: January 2025

AbstractFeedback stabilization of upright standing postures should be reflected by a time-lagged relationship between the ground reaction force (GRF) and the center of mass (COM) state. In this study, we propose a model relating corrective ground reaction forces (Fcorr) to preceding COM position (PCOM) and velocity (VCOM). We first checked the model’s validity by simulating an inverted pendulum model with known intrinsic and feedback parameters, to see if we could identify the feedback parameters. Next, we tested this model in 14 young adult volunteers standing in different postures.Our model effectively reconstructedFcorrin both simulations (R2: 0.50∼0.99) and human experimental data (R2: 0.76∼0.99). Strikingly, estimated position and velocity gains were similar across postures even between bipedal and unipedal standing, with the position gain slightly above critical stiffness. The estimated delay in normal standing (246±21ms) was significantly larger than that in unipedal standing and step posture (204±24ms and 193±29ms, respectively).In conclusion, our results support that an estimate of the COM state is used to generate corrective ground reaction forces to stabilize upright posture, and our feedback model can be used to characterize this control mechanism. The proposed model requires only easily measurable inputs which may yield value in assessment of balance disorders. Notably, our results showed that stability of upright stance is achieved by maintaining feedback gains at levels just above critical stability.
A delivered DNase toxin creates population heterogeneity through transient intoxication of siblings
Authors: Eriksson Hanna , Schlegel Susan , Kjellin Jonas , Koskiniemi Sanna 
Published: January 2025

AbstractPopulation heterogeneity is important for multicellular behavior and division of labor. Bacterial toxin delivery has been implicated in generating population heterogeneity, but the molecular mechanisms behind this are not well understood. Here we investigatehowCdiA toxins generate heterogeneity in isogenic populations. Using a DNase toxin as proxy, we find thatE. colipopulations able to deliver the toxin show a heterogeneous expression of the SOS-response genesulA. Heterogeneity results from excessive delivery of toxin into some cells, which become intoxicated due to insufficient immunity. Intoxication is transiently reversible, and intoxicated cells can be rescued byde novosynthesis of cognate immunity protein. Expression ofsulAis regulated by both DNA damage and redox status. Interestingly, kin-delivery changes redox status, whereas intoxicated non-kin cells induce the SOS DNA damage response. The former results in changed expression of metabolic genes whereas the latter induces prophage excision, which may promote horizontal gene transfer. In conclusion, we identify a molecular mechanism by which heterogeneity is generated through toxin delivery among kin, and the consequences of said heterogeneity.Significance statementBacteria communicate through secretion of chemical signaling molecules to perform multicellular behavior. Recent advances suggest that contact-mediated toxin delivery allow bacteria to participate also in direct cell-cell communication. How such toxin-mediated communication would work mechanistically is however unclear. Here we elucidate a molecular mechanism of a toxin-mediated communication, where kin-cells transiently intoxicate each other, resulting in physiological changes. These changes depend on the toxic activity, i.e. other toxins with different activities are likely to give rise to other responses. Thus, the arsenal of toxins that a bacterium harbors could affect their ability to communicate. Understanding the molecular mechanism of how toxins could mediate polyphenism is important for our understanding of what this signaling is used for.
Systematic functional assessment of antiphage systems in their native host
Authors: David Ellie , Plantady Clarisse , Poissonnier Sophiane , Le Boulch Justine , Gutierrez Arnaud , Chevallereau Anne 
Published: January 2025

SummaryBacterial resistance to bacteriophages (phages) relies on two primary strategies: preventing phage attachment and blocking post-attachment steps. These latter mechanisms are mediated by defence systems, including DNA-degrading systems such as Restriction- Modification (RM) and CRISPR-Cas, as well as abortive infection systems that induce cell death or dormancy. Computational studies suggest that bacterial genomes encode several defence systems, which may act synergistically to enhance phage resistance. However, the regulation, interactions, and ecological roles of these systems in native hosts remain poorly understood. This study explored the role of eight predicted defence systems in the clinical isolate NILS69 ofE. coliby testing its susceptibility to 93 phages. Infectivity and adsorption assays using mutants defective in these systems revealed that only PD-T4-3 and RM systems restricted phages able to adsorb. The RM system acted via a predicted Type IV endonuclease and was also able to limit plasmid conjugation if the plasmid was transferred from a donor strain lacking a methylase, which is the hallmark of Type I, II or III RM systems. Other defence systems showed no detectable activity, likely due to phage specificity, environmental regulation, or cofactor requirements. These findings underscore the need for further studies to investigate the regulation and ecological roles of bacterial defence systems in their native host contexts.
The Septin Cytoskeleton is a Novel Regulator of Intestinal Epithelial Barrier Integrity and Mucosal Inflammation
Authors: Naydenov Nayden G. , Hu Gaizun , Zafar Atif , Robak Dominik , Makhmudova Khosiyat , Lechuga Susana , Ohno Yuta , Sagwan Naseer , Bandyopadhyay Saikat , Musich Ryan , Jeffery Erin , Sun Lei , Marino-Melendez Armando , Rieder Florian , Sheynkman Gloria , Ivanov Andrei I. , Ebrahim Seham 
Published: January 2025

ABSTRACTBackground and AimsIntestinal epithelial barrier-integrity is essential for human health, and its disruption induces and exacerbates intestinal inflammatory disorders. While the cytoskeleton is critical for maintaining gut barrier-integrity, the role of the septins- the newest family of cytoskeletal proteins- is unknown. To address this knowledge gap, we evaluate the role of SEPT9- a critical component of the septin-cytoskeleton- in intestinal epithelial cell (IEC) barrier permeability and inflammation.MethodsWe developed SEPT9-NeonGreen knockin mice, inducible intestinal epithelial cell (IEC)-specific SEPT9 knockout (KO) mice, and SEPT9-KO human IEC lines. SEPT9 localization was analyzed using super-resolution microscopy. Barrier-integrity was assessed via transepithelial electrical resistance, FITC-dextran flux, and visualization of tight junction (TJ) and adherens junction (AJ) proteins. Dextran sodium sulfate-induced experimental colitis was evaluated in control and KO mice through measuring cytokine expression, immune cell infiltration, and IEC death. SEPT9 expression was examined in intestinal tissue of IBD patients.ResultsSEPT9 overlapped with TJs and AJs at IEC apical junctions. SEPT9 loss resulted in a leaky epithelial barrier due to mislocalization of junctional proteins. SEPT9 interacted with non-muscle myosin IIC (NMIIC) at the IEC apical-junctional actomyosin belt, and its ablation displaced NMIIC from IEC junctions. Loss of NMIIC also caused barrier disruption. SEPT9 KO mice exhibited increased susceptibility to experimental-colitis. SEPT9 expression was significantly reduced in intestinal mucosa of IBD patients.ConclusionSEPT9 regulates intestinal barrier integrity, supporting TJ and AJ assembly through NMIIC recruitment to the actomyosin belt. SEPT9 safeguards the intestinal mucosa during acute inflammation, and its reduced expression in IBD suggests a loss of this protective function.Graphical Abstract
Parp7 generates an ADP-ribosyl degron that controls negative feedback of androgen signaling
Authors: Wierbiłowicz Krzysztof , Yang Chun-Song , Almaghasilah Ahmed , Wesołowski Patryk A. , Pracht Philipp , Dworak Natalia M. , Masur Jack , Wijngaarden Sven , Filippov Dmitri V. , Wales David J. , Kelley Joshua B. , Ratan Aakrosh , Paschal Bryce M. 
Published: January 2025

AbstractThe androgen receptor (AR) tranduces the effects of circulating and tumor-derived androgens to the nucleus through ligand-induced changes in protein conformation, localization, and engagement with chromatin binding sites. Understanding these events and their integration with signal transduction is critical for defining how AR drives prostate cancer and unveiling pathway features that are amenable to therapeutic intervention. Here, we describe a novel post-transcriptional mechanism that controls AR protein levels on chromatin and associated gene output which is based on a highly selective, inducible degradation mechanism. We find that the mono-ADP-ribosyltransferase PARP7 generates an ADP-ribosyl degron on a single cysteine within the DNA binding domain of AR, which is then recognized by the ADP- ribose reader domain in the ubiquitin E3 ligase DTX2 and degraded by the proteasome. Mathematical modeling of the pathway suggested that PARP7 ADP-ribosylates chromatin-bound AR, a prediction that was validated in cells using an AR mutant that undergoes nuclear import but fails to bind DNA. Lysine- independent, non-conventional ubiquitin conjugation to ADP-ribosyl-cysteine and AR degradation by the proteasome forms the basis of a negative feedback loop that regulates specific modules of AR target genes. Our data expand the repertoire of mono-ADP-ribosyltransferase enzymes to include gene regulation based on highly selective protein degradation.One Sentence SummaryPARP7 mono-ADP-ribosylates the androgen receptor on Cys620 to mark the androgen receptor for ubiquitin conjugation by an E3 ligase with ADP-ribose reader function, resulting in in negative feedback of AR-dependent gene expression.
Click-linking: a cell-compatible protein crosslinking method based on click chemistry
Authors: Amaral Bruno C. , Michael Andrew R.M. , Brodie Nicholas I. , Crowder D. Alex , Eiriksson Kristen H. , Schriemer David C. 
Published: January 2025

AbstractCrosslinking mass spectrometry (XL-MS) has the potential to map the human interactome at high resolution and with high fidelity, replacing indirect, error prone sampling methods such as affinity pulldown MS. However, the sampling depth of XL-MS remains stubbornly low. We present a novel crosslinking strategy that splits the crosslinking reaction into two sequential and orthogonal coupling events. The method involves pre-stabilizing the spatial proteome with a fixation protocol inspired by immunofluorescence imaging, followed by a stepwise process that begins with extensively labeling surface-accessible lysines in the cell with N-hydroxysuccinimide (NHS)-modified click reagents. We show that a subsequent copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction of the installed precursors generates crosslinks at levels approaching 30% of the total signal, as demonstrated by a subtractive approach. The method generates no detectable side reactions or obvious distortions of the spatial proteome. Protein-protein interactions (PPIs) are detected at levels approximately 20 times higher than a conventional DSS-based method, outperforming even enrichable crosslinkers.
Agent-based modeling reveals impacts of cell adhesion and matrix remodeling on cancer collective cell migration phenotypes
Authors: Benson Temitope O. , Islam Mohammad Aminul , Liu Kailei , Ford Versypt Ashlee N. 
Published: January 2025

AbstractUnderstanding the phenotypic transitions of cancer cells is crucial for elucidating tumor progression mechanisms, particularly the transition from a non-invasive spheroid phenotype to an invasive network phenotype. We developed an agent-based model (ABM) using Compucell3D, an open-source biological simulation software, to investigate how varying biophysical and biochemical parameters influence emerging properties of cellular communities, including cell growth, division, and migration. Our focus was on cell-cell contact adhesion and matrix remodeling effects on cancer cell migration.We simplified enzymatic remodeling of the extracellular matrix and the subsequent enhancements to cellular chemotaxis or durotaxis as a combined effect of localized cellular secretion of a chemoattractant. By varying the chemoattractant secretion rate and contact adhesion energy, we simulated their effects on cellular behavior and driving the transition from a spheroid phenotype to a network phenotype. The model serves as a digital twin for 3D cancer cell culture, simulating cancer cell growth, division, and invasion over 1 week, validated against published data. The simulations track the emergent morphological and collective phenotype changes using key metrics such as cell circularity and invasion. Our findings indicate that increased chemoattractant secretion enhances the invasiveness of the collective cells, promoting the transition to a network phenotype. Additionally, changing cell-cell contact energy from a strong cell-cell adhesion to a weak cell-cell adhesion affects the compactness of the spheroids, resulting in lower circularity and increased collective cell invasion. Our work advances the understanding of tumor progression by providing insights into the biophysical mechanisms behind invasive cancer cell phenotypic transitions.
Missense mutations: Backbone structure positional effects
Authors: Perez Ivan , Stege Ulrike , Jabbari Hosna 
Published: January 2025

ABSTRACTHuman diversity often manifests through single nucleotide polymorphisms (SNPs). Among these, missense mutations, or SNPs that alter amino acids, can modify a protein’s three-dimensional (3D) structure. This impacts its function and can potentially elicit diseases or affect drug interactions. Thus, understanding protein single point mutations is crucial for precision medicine, as it helps tailor treatments based on individual genetic variations. As atomic locations can be susceptible to any number of changes that might or might not affect function, we focus on the secondary structure to provide concrete results on possible protein structural deformation that may occur from missense mutations.We assess state-of-the-art structure prediction methods regarding backbone deformations caused by missense mutations. We categorize these deformations aslocal, distant, orglobalbased on the proximity of structural changes to the mutation site. Our analysis utilizes a diverse dataset from the Protein Data Bank, comprising over 500 protein clusters with experimentally determined structures and documented mutations.Our findings indicate that missense mutations can significantly affect the accuracy of structure prediction methods. These mutations often lead to predicted structural changes even when the actual secondary structures remain unchanged, suggesting that current methods overestimate the impact of missense mutations. This issue is particularly evident in advanced prediction algorithms, which struggle to accurately model proteins with stable mutations. We also found that the addition of low-performing prediction methods during structural analysis can positively impact the results on some proteins, particularly those with low homology. Furthermore, proteins that form complexes or bind ligands—such as membrane and transport proteins—are inaccurately predicted due to the absence of extra-molecular interaction data in the models, highlighting how missense mutations can complicate accurate structure prediction. All code and data are available athttps://github.com/ivanpmartell/pdb-sam.
Tracking Progress: Trends in Surgical Indicator Reporting in the World Development Indicators
Authors: Torres Perez-Iglesias Carolina , Jensen Kennedy , Raguveer Vanitha , Hyman Gabriella Y. , Suzuki Emi , Meara John G. , Raykar Nakul P. 
Published: January 2025

ABSTRACTBackgroundThe Lancet Commission on Global Surgery (LCoGS) emphasized the need for six core indicators to track progress toward safe, affordable, and timely surgical care. In 2016, four of these indicators were integrated into the World Development Indicators (WDI) to facilitate global tracking of surgical system performance. However, the impact of these indicators relies on the accuracy and frequency of the reported data. We aimed to analyze trends in the reporting of the WDI surgical indicators and evaluate trends in the context of countries undertaking National Surgical Plans (NSPs).MethodsData were extracted from the World Bank WDI database and analyzed by WHO region from 2015-2020. Countries were categorized based on their engagement with NSPs. Trends in reporting for the four surgical indicators—surgical case volume (SV), surgical workforce density (SW), catastrophic health expenditure (CHE), and impoverishing expenditure (IE)—were assessed. Correlations between NSP implementation and reporting completeness were explored.ResultsFrom 2015 to 2020, reporting rates for the modeled indicators CHE and IE remained stable, with an average annual reporting rate of 62% for both. In contrast, the reporting of non-modeled indicators (SV, SW) declined over the study period. SV reporting dropped from 12% in 2015 to 0% in 2020, and SW reporting decreased from 18% to 0%. Regional disparities were significant: the European region had the highest reporting rates for non-modeled indicators, with 13.3% for SW and 3.7% for SV, while the African region reported only 5.4% for SW and 1.8% for SV. No significant correlation was found between NSP implementation and reporting rates (R² = 0.00014, p = 0.986).ConclusionsDespite integrating surgical indicators into the WDI, reporting rates remain low, particularly for non-modeled indicators. Strengthening data collection and reporting systems, particularly in low-resource settings, is essential for improving surgical care monitoring and addressing global disparities.
Genetic Insight into the Paradoxical Relationship among Diabetes, Coronary Artery Disease, and Abdominal Aortic Aneurysm
Authors: Zheng Shufen , Wu Yonglin , Li Aijie , Wu Zhuoyi , Liu Zhen , Wang Huawei , Jia Xiaoyan , Tsao Philip S. , Pan Cuiping 
Published: January 2025

AbstractType 2 diabetes (T2D) increases the risk of coronary artery disease (CAD) but decreases that for abdominal aortic aneurysm (AAA), forming an intriguing diabetes-atherosclerosis paradox. We investigate its genetic basis employing techniques such as genetic correlation, colocalization, gene annotation, functional enrichment, and pathway pairing on GWAS datasets. We discover a strong and positive correlation between T2D and CAD throughout the genome, with shared enrichment in immune signaling. The genetic correlation between CAD and AAA is weaker, with shared genetic components related to lipid metabolism. Conversely, T2D and AAA show the weakest genetic correlation, counter-balanced by two-thirds of genes and chromosomal segments with positive correlations and one-third with negative correlations. The positive correlations entail immune signaling, whereas the negative correlations are characteristic of beta-cell function and lipid metabolism. Our study suggests immune signaling contributes to the synergy between diabetes and atherosclerosis. By decoding the genetic interplay underlying these diseases, our findings provide a foundation for improving treatment strategies and advancing precision medicine.
The dark side of streaking: Examining the backfire potential of run streaking in recreational runners who broke a long-term streak
Authors: Ingalls Erin E. , Larade Nicholas , Ozakinci Gozde , Tymowski-Gionet Gabriela , Fleig Lena , Dombrowski Stephan U. 
Published: January 2025

ABSTRACTBackgroundRun streaking is running on consecutive days for a minimum of one mile per day. Despite its benefits for supporting habit formation and long-term behaviour change, some streak runners report potential unintended negative consequences of run streaking. The aim of the study is to examine the backfire potential of run streaking in recreational runners who ended a long-term streak.MethodsQualitative semi-structured interviews with 17 recreational adult runners (10 male, 6 female, 1 other gender). All runners ended a run streak of ≥100 consecutive days. Transcripts were analyzed using a hybrid deductive–inductive thematic analysis.ResultsPrior to streak cessation, some runners felt streak-related inconveniences and ran with injury to prolong the streak. Immediate consequences following the end of a streak included feelings of sadness, anger, disappointment and relief. Several run streakers described a ‘grieving process’ in the weeks and months following streak cessation. Unintended negative consequences were amplified in runners with higher levels of streak attachment. All physically capable runners continued to run regularly with most starting a new streak and all voiced positive views towards run streaking despite their streak ending.ConclusionRun streaking as a behaviour change technique has small backfire potential in some runners. Ending a long-term run streak can lead to short-term negative affect which can develop into experiences of grief, particularly in those with high levels of streak attachment. No long-term negative consequences were reported. All participants perceived run streaking as positive overall and remained physically active following the end of their long-term streak.
Development and clinical validation of a cross-sex translator of ECG drug responses
Authors: Shetty Roshni , Morotti Stefano , Sobota Vladimír , Bayer Jason D. , Ni Haibo , Grandi Eleonora 
Published: January 2025

AbstractSex differences in cardiac electrophysiology are a crucial factor affecting arrhythmia risk and treatment responses. It is well-documented that females are at a higher risk of drug-induced Torsade de Pointes and sudden cardiac death, largely due to longer QTc intervals compared to males. However, the underrepresentation of females in both basic and clinical research introduces biases that hinder our understanding of sex-specific arrhythmia mechanisms, risk metrics, disease progression, treatment strategies, and outcomes. To address this problem, we developed a quantitative tool that predicts ECG features in females based on data from males (and vice versa) by combining detailed biophysical models of human ventricular excitation-contraction coupling and statistical regression models. We constructed male and female ventricular tissue models incorporating transmural heterogeneity and sex-specific parameterizations and derived pseudo-ECGs from these models. Multivariable lasso regression was employed to generate sets of regression coefficients (a cross-sex translator) that map male ECG features to female ECG features. The predictive ability of the translator was evaluated using an independent dataset that simulates the effects of various drugs and pharmacological agents at different concentrations on male and female models. Furthermore, we demonstrated a proof-of-concept clinical application using ECG data from age-matched subjects of both sexes under various drug regimens. We propose our cross-sex ECG translator as a novel digital health tool that can facilitate sex-specific cardiac safety assessments, ensuring that pharmacotherapy is safe and effective for both sexes, which is a major step forward in addressing disparities in cardiac treatment for females.One Sentence Summary:We used biophysical and regression models for predicting ECG features across sexes to address disparities in sex-specific cardiac drug responses