bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineering affinity-matured variants of an anti-polysialic acid monoclonal antibody with superior cytotoxicity-mediating potency
Authors: Wang Weiyao , Bunyatov Mehman , Lopez-Barbosa Natalia , DeLisa Matthew P. 
Published: February 2025

ABSTRACTMonoclonal antibodies (mAbs) that specifically recognize cell surface glycans associated with cancer and infectious disease hold tremendous value for both basic research and clinical applications. However, high-quality anti-glycan mAbs, especially those with sufficiently high affinity and specificity, remain scarce, highlighting the need for protein engineering approaches based on rational design or directed evolution that enable optimization of antigen-binding properties. To this end, we sought to enhance the affinity of a polysialic acid (polySia)-specific antibody called mAb735, which was raised by animal immunization and possesses only modest affinity, using a combination of rational design and directed evolution. The application of these approaches led to the discovery of affinity-matured IgG variants with up to ∼7-fold stronger affinity for polySia relative to the parental antibody. The higher affinity IgG variants were observed to opsonize polySia- positive cancer cells more avidly, which in turn resulted in significantly greater cytotoxicity as determined by both antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays. Collectively, these results demonstrate the effective application of both rational and random molecular evolution techniques to an important anti-glycan antibody, providing insights into its carbohydrate recognition while at the same time uncovering variants with greater therapeutic promise due to their enhanced affinity and potency.
Improved Graph-Based Antibody-Aware Epitope Prediction with Protein Language Model-Based Embeddings
Authors: Ahmed Mansoor , Ali Sarwan , Jan Avais , Khan Imdad Ullah , Patterson Murray 
Published: February 2025

AbstractThe accurate identification of B-cell epitopes is critical in antibody design, diagnostics, and immunotherapies. Manyin silicoapproaches have recently been proposed to predict epitopes, but these approaches struggle primarily because of the variational and conformational nature of epitopes. However, deep learning-based approaches have recently shown great promise in achieving better performance at the epitope prediction task. In this paper, we employ a graph convolutional network (GCN) coupled with pre-trained protein language model (PLM)-based embeddings for epitope prediction on a benchmark antibody-specific epitope prediction (AsEP) dataset. We explore the use of different PLM-embedding methods on the epitope prediction task and show that the choice of PLM embeddings impacts the performance. Specifically, we find that antibody-specific PLMs such as AntiBERTy and general PLMs such as ProtTrans and ESM-2 for antigens provide improved epitope prediction performance with an AUCROC of 0.65, precision of 0.28, and recall of 0.46. The source code is available at:https://github.com/mansoor181/walle-pp.git.
Single-cell multiome and spatial profiling reveals pancreas cell type-specific gene regulatory programs driving type 1 diabetes progression
Authors: Melton Rebecca , Jimenez Sara , Elison Weston , Tucciarone Luca , Howell Abigail , Wang Gaowei , Berti Denise , Beebe Elisha , Miller Michael , Zeng Chun , McGrail Carolyn , VanderStel Kennedy , Korgaonkar Katha , Elgamal Ruth , Mummey Hannah , Chiou Joshua , Griffin Emily , Kusmartseva Irina , Atkinson Mark , Preissl Sebastian , Theis Fabian J. , Sander Maike , Gaulton Kyle J. 
Published: February 2025

AbstractCell type-specific regulatory programs that drive type 1 diabetes (T1D) in the pancreas are poorly understood. Here we performed single nucleus multiomics and spatial transcriptomics in up to 32 non-diabetic (ND), autoantibody-positive (AAB+), and T1D pancreas donors. Genomic profiles from 853,005 cells mapped to 12 pancreatic cell types, including multiple exocrine sub-types. Beta, acinar, and other cell types, and related cellular niches, had altered abundance and gene activity in T1D progression, including distinct pathways altered in AAB+ compared to T1D. We identified epigenomic drivers of gene activity in T1D and AAB+ which, combined with genetic association, revealed causal pathways of T1D risk including antigen presentation in beta cells. Finally, single cell and spatial profiles together revealed widespread changes in cell-cell signaling in T1D including signals affecting beta cell regulation. Overall, these results revealed drivers of T1D progression in the pancreas, which form the basis for therapeutic targets for disease prevention.
Bilateral neuromuscular adaptation to acute unilateral resistance exercise in healthy older adults
Authors: Gamage Nishadi N. , Altheyab Abdulmajeed , Guo Yuxiao , Phillips Bethan E. , Opie George M. , Semmler John G. , Atherton Philip , Piasecki Mathew 
Published: February 2025

ABSTRACTIntroductionResistance exercise (RE) enhances functionality in older adults and has proven effective as a means of cross-education in scenarios of unilateral disuse. However, the extent to which older adults demonstrate cross-limb transfer at the motor unit (MU) level following a single bout of unilateral RE is unclear.MethodsThirteen healthy older adults (74.9 ± 4.8 years; 5 females) underwent bilateral neuromuscular assessments pre- and post- a single bout of unilateral RE consisting of 3-4 sets of 8-12 repetitions of leg extension of the dominant (exercise) leg, at 75% of 1 repetition maximum, performed to failure. Maximum voluntary contraction (MVC) and force steadiness (FS) were measured. Central and peripheral features of individual MU were recorded using high-density surface electromyography and intramuscular electromyography (HDs/iEMG), during contractions normalised to 25% MVC.ResultsFollowing unilateral RE, MVC reduced in exercise (-14.8%,p< 0.001) and control (-6.9%,p= 0.003) legs, with reduced FS performance in the exercise leg compared to the control(p= 0.002). MU firing rate increased during contractions normalised to 25% baseline MVC in the exercised leg (p< 0.05), with no adaptation in the control leg (p> 0.05). All iEMG recorded measures of MU potentials remained unchanged in both legs (allp> 0.05).ConclusionAcute unilateral RE leads to bilateral MVC reduction in older males and females, demonstrating the cross-limb transfer effect. However, adaptation of MU features was only apparent in the exercised limb, and mechanisms underlying the force decline in the non- exercised limb remain uncertain.
Accuracy and Scalability of Machine Learning Methods for Genotype-Phenotype Association Data
Authors: Collienne Kieran , Zhang Lilin , Gavryushkin Alex 
Published: February 2025

AbstractMany machine learning methods can be applied to predicting phenotypes from genetic data. Which of these methods work best remains an open question, however. To answer this question, we propose to compare a variety of approaches’ ability to predict a simulated non-linear complex trait. Specifically, we evaluate these methods on their accuracy and scalability with respect to the amount training data available, the noise present in the data, the complexity of the simulated (trait) functions, and their ability to provide insight into the simulated trait. We then compare the best approach to state-of-the-art models in real data, predicting gout in the UK Biobank. We find that transformer encoders outperform all other methods in simulations, and perform comparably to the state-of-the-art with real data, with a promise to scale to significantly larger datasets.
A mixture of endocrine disrupting chemicals linked to lower birth weight induces adipogenesis and transcriptional changes related to birth weight alterations and diabetes
Authors: Lizunkova Polina , Caporale Nicolò , Engdahl Elin , Cheroni Cristina , Germain Pierre-Luc , Borbély Gábor , Lindh Christian , Gennings Chris , Bornehag Carl-Gustaf , Testa Giuseppe , Rüegg Joëlle 
Published: February 2025

AbstractThere is increasing evidence that endocrine disrupting chemicals (EDCs) are contributing to the rise in metabolic disorders and obesity. Humans are constantly exposed to numerous EDCs, thus human exposure entails complex EDC mixtures. In this study, we examined the effects of an EDC mixture, mixture G, composed of four phthalate esters, triclosan, and three poly- och perfluorinated alkyl substances. Mixture G had previously been defined based on its association with lower birth weight in a pregnancy cohort, where low birth weight is an early risk factor for metabolic morbidities later in life. Here, we studied its effects on adipogenesis and uncovered their underlying transcriptional changes. Human mesenchymal stem cells (hMSCs) were exposed to mixture G in concentrations and mixing ratios that reflect those measured in human serum. Mixture G induced adipogenesis in hMSCs, as evidenced by a dose-dependent increase in lipid droplet accumulation after 14-21 days. Notably, significant adipogenic effects were observed at concentrations comparable to those detected in humans. RNA-sequencing upon exposure for 48 h revealed dose-dependent transcriptional changes in over 1000 genes. Mixture G-induced differentially expressed genes (DEGs) showed significant overlap with genes involved in osteogenesis, with glucocorticoid-regulated genes, and with genes associated with birth weight alterations and diabetes type II. These results indicate that exposure to an environmentally relevant EDC mixture induces adipogenesis and leads to transcriptional alterations that might change the balance between adipogenic and osteogenic differentiation as well as the functionality of MSCs, possibly via interference with glucocorticoid signalling. Thus our findings underscore the role of EDCs as metabolic disruptors and shed light on the molecular mechanisms underlying their potential contribution to the development of metabolic disorders.HighlightsAn endocrine disruptor mixture linked to lower birth weight increases adipogenesisThe mixture induced transcriptomic changes at low dosesAffected genes are associated with birth weight and diabetes type IIGraphical abstract
Single-Cell Sequencing Identifies the Crucial Role of Mitochondrial Fission-Fusion Balance in Cardiac Hypertrophy Progression
Authors: He Tao , Sha Jianmei , Hu Yuxin , Shao Caihong , Zhou Yi , Chen Lu , Yao Jianhua , Gao Junli 
Published: February 2025

AbstractBackgroundThe heart undergoes growth in response to both pathological and physiological stimuli. Pathological hypertrophy often leads to cardiomyocyte loss and heart failure (HF), whereas physiological hypertrophy paradoxically protects the heart and enhances cardiomyogenesis. The molecular mechanisms that distinguish these two forms of hypertrophy remain unclear.MethodsIn this study, we utilized single-cell transcriptomics from transverse aortic constriction (TAC) models at 2, 5, 8, and 11 weeks (GSE120064), along with bulk RNA sequencing from mice subjected to 12 months of exercise-induced physiological hypertrophy and cardiomyogenesis (CRA007207), to investigate the molecular differences between pathological and physiological hypertrophy.ResultsOur results reveal the following. Mitochondrial-related pathways are the primary drivers of the pathological changes that occur following TAC. The mitochondrial fission and fusion pathways exhibited increased activity at 2 weeks but decreased activity at 5, 8, and 11 weeks post TAC. The expression pattern of exercise-induced physiological hypertrophy was similar to that of 2-week TAC-induced changes, indicating that the early stage of TAC represents an adaptive physiological response or physiological hypertrophy. Notably, during HF, the fission genes Fis1 and Dnm1l increase, in contrast to the expected decrease in fusion genes. These findings were experimentally validated, indicating that the mitochondrial fission genes Fis1 and Dnm1l are key promoters of HF.ConclusionsOur data indicate that the balance between mitochondrial fission and fusion plays a critical role in the transition from physiological to pathological hypertrophy. The fission-related genes Fis1 and Dnm1l have emerged as key drivers of pathological hypertrophy and heart failure. These findings suggest that targeting fission genes, particularly Fis1 and Dnm1l, may represent promising therapeutic strategies for managing heart failure.
Mathematical Modeling of Neural Stem Cell Migration within Brain using Multi-Fiber Tractography
Authors: Hansen Austin , Rockne Russell , Adhikarla Vikram , Gutova Margarita , Cho Heyrim 
Published: February 2025

AbstractAn agent-based model of therapeutic neural stem cell (NSC) migration is developed and used to predict the migration of NSCs in naïve mouse brain. The model utilizes generalized q-sampling imaging which resolves white matter fibers that cross in the brain and is shown to better account for variations in NSC migration patterns as compared to diffusion tensor imaging. In calibrating the model to experimental data, we show that the model is able to reproduce the distribution of NSCs in the mouse brain. In addition, we show that the distribution of NSCs in the mouse brain is sensitive to the location of NSC injection. Persistent distribution of NSCs to the olfactory bulb, consistent with developmental pathways including the rostral migratory stream, suggests that future models of therapeutic NSCs in the naïve brain may need to include other factors such as chemotaxis or blood flow to account for variations in NSC migration paths. The results highlight the usefulness of the model in predicting which injection locations may provide the best distribution of NSCs to a given target location.
No Disconnection Syndrome after Near-Complete Callosotomy
Authors: Bekir Selin , Hopf Johanna L. , Paul Theresa , Wiemer Valerie M. , Santander Tyler , Skinner Henri E. , Rada Anna , Woermann Friedrich G. , Kalbhenn Thilo , Giesbrecht Barry , Bien Christian G. , Sporns Olaf , Gazzaniga Michael S. , Volz Lukas J. , Miller Michael B. 
Published: February 2025

AbstractMuch of the sensory-motor processing in the human brain is lateralized to either hemisphere, with the corpus callosum integrating these distinct processes into a seemingly unified conscious experience. The corpus callosum is thought to be topographically organized, with different subregions along its anterior-to-posterior axis involved in integrating information across different sensory modalities and cognitive domains. In complete callosotomy patients, where the corpus callosum is fully severed, this integration is typically disrupted across these domains. But which types of inter-hemispheric integration can still be preserved with small posterior callosal remnants? We studied four callosotomy patients—three complete and one partial with approximately 1 cm of preserved splenium—using an array of lateralized visual, tactile, visuospatial, and language tasks. While complete callosotomy patients showed the expected behavioral disconnection effects—performing poorly on tasks requiring inter-hemispheric integration but well on intra-hemispheric ones—the partial callosotomy patient with a preserved portion of the splenium showed no disconnection effects across all tasks. The splenium is traditionally implicated in visual transfer, yet our findings show that minimal splenial preservation maintains functional integration across multiple perceptual and cognitive domains. This is at odds with the presumed topographical organization of the corpus callosum, suggesting a broader inter-hemispheric integrative capacity of the posterior callosal fibers. Structure-function relationships in brain networks are known to be complex and nonlinear— these findings provide novel insights into flexible structural mechanisms for inter-hemispheric communication enabling a variety of integrated behaviors.
In-feed bacitracin methylene disalicylate alters microbiota function and increases antibiotic resistance in a dose-dependent manner
Authors: Oladele Paul , Wickware Carmen L. , Trachsel Julian , Looft Torey , Johnson Timothy A. 
Published: February 2025

AbstractAntibiotics are commonly used in turkey production to prevent and treat infection which can improve animal growth and efficiency, but the mechanism by which antibiotics improve animal performance, and the resistance risks associated with the antibiotic inclusion levels remain unclear, particularly in turkey production. Therefore, we investigated the longitudinal effect of subtherapeutic and therapeutic doses of bacitracin methylene disalicylate (BMD) on antibiotic resistance genes, mobile genetic elements, and metabolism genes by analyzing the turkey cecal metagenome. The therapeutic dose of BMD increased a vast array of antibiotic resistant genes (ARGs), conjugation-related genes of type IV secretion system and transduction-related genes for the length of the experiment (78 days), while a smaller, transient effect was observed due to the subtherapeutic dose. Estimated bacterial growth rate, estimated by metagenome assembled genome sequence coverage, decreased after 7 days of in-feed BMD, but increased in the therapeutic group over time. Tryptophan synthesis from chorismate increased in a dose-dependent manner between days 7 - 35. Overall, the effects of subtherapeutic BMD on the turkey cecal microbiota was temporary while those of a therapeutic dose were longer lasting. This study shows that antimicrobial resistance genes belonging to multiple antibiotic classes, and mobile genetic elements (MGEs) were increased after BMD administration. The enrichment these genes by BMD shows the risk associated with antimicrobial feed additives. BMD’s effect on tryptophan synthesis provides a potential metabolic target for developing non-antibiotic microbiome modulatory growth promoters for turkey production.ImportanceAntibiotic use in agricultural animals remains a hotly debated and important topic to human, animal, and environmental health. The dose-dependent responses to BMD, an antibiotic fed additive allowed at both therapeutic and subtherapeutic doses, are not well understood. This study highlights that therapeutic use of BMD is a stronger selective pressure than the subtherapeutic dose for antibiotic resistance genes and genes related to horizontal gene transfer. This indicates that use of BMD could select for antibiotic resistant bacteria that may pose a risk to animal, human and environmental health. Additionally, this study highlighted that BMD decreased the activity of beneficially bacteria, and therefore may be associated with a decreased concentration of bacterial metabolites (especially tryptophan related) in the cecum. This may indicate that growth promoting antibiotics suppress bacterial activity generally, rather than allowing beneficial bacteria to generate beneficial metabolites.
Targeting the Protein-Protein Interaction Between the CDC37 Co-Chaperone and Client Kinases by an Allosteric RAF Dimer Breaker
Authors: Yu Alison , Banerjee Shrhea , Malasani Sravani , Towolawi Bamidele , Liu Zhiwei , Wang Zhihong 
Published: February 2025

AbstractBraftide, originally designed as a potent allosteric RAF kinase dimer disruptor, was intended to inhibit RAF dimerization by targeting the conserved RAF dimer interface. Intriguingly, Braftide has also been observed to trigger proteasome-mediated protein degradation with an unclear mechanism of action. This study elucidates the mechanism underlying Braftide’s dual functionality and assesses its potential as a chemical probe to target kinase-chaperone interaction. CDC37, a selectivity co-chaperone in the HSP90 chaperone machinery, plays a crucial role in facilitating the recognition of client kinase. The RAF dimer interface overlaps with the CDC37-kinase client recognition motif, known as the αC helix-β4 loop. Using co-immunoprecipitation and NanoBiT assays, we confirmed Braftide’s ability to selectively disrupt the CDC37-client kinase interaction while sparing HSP90. Through deuterium exchange mass spectrometry, molecular dynamic simulations, andin vitrocrosslinking analyses, we mapped Braftide’s binding region within the BRAF kinase domain, as well as the CDC37 region implicated in the association of CDC37-client kinase complex. Consequently, this disruption destabilizes RAF kinase clients, resulting in proteasomal degradation, reduced cellular proliferation, and increased apoptosis in cancer cell lines. Furthermore, Braftide exhibits synergy with HSP90 inhibitors, jointly destabilizing both the CDC37-RAF complex and HSP90. Our work demonstrates the feasibility of disrupting the CDC37-client kinase interaction as an innovative therapeutic strategy and identifies the αC helix-β4 loop as a novel allosteric site with significant potential for the development of next-generation therapeutics.
Path integration impairments reveal early cognitive changes in Subjective Cognitive Decline
Authors: Segen Vladislava , Kabir Md Rysul , Streck Adam , Slavik Jakub , Glanz Wenzel , Butryn Michaela , Newman Ehren , Tiganj Zoran , Wolbers Thomas 
Published: February 2025

AbstractPath integration, the ability to track one’s position using self-motion cues, is critically dependent on the grid cell network in the entorhinal cortex, a region vulnerable to early Alzheimer’s disease pathology. In this study, we examined path integration performance in individuals with subjective cognitive decline (SCD), a group at increased risk for Alzheimer’s disease, and healthy controls using an immersive virtual reality task. We developed a Bayesian computational model to decompose path integration errors into distinct components. SCD participants exhibited significantly higher path integration error, primarily driven by increased memory leak, while other modelling-derived error sources, such as velocity gain, sensory and reporting noise, remained comparable across groups. Our findings suggest that path integration deficits, specifically memory leak, may serve as an early marker of neurodegeneration in SCD and highlight the potential of self-motion-based navigation tasks for detecting pre-symptomatic Alzheimer’s disease-related cognitive changes.TeaserVirtual reality, computational modelling, and biomarkers uncover path integration deficits, distinguishing pre-symptomatic Alzheimer’s from normal aging.
InHyphomicrobium denitrificanstwo related sulfane-sulfur responsive transcriptional repressors regulate thiosulfate oxidation and have a deep impact on nitrate respiration and anaerobic biosyntheses
Authors: Li Jingjing , Schmitte Nora E. , Törkel Kaya , Dahl Christiane 
Published: February 2025

AbstractBacteria have evolved multiple strategies to sense and respond to the availability of inorganic reduced sulfur compounds such as thiosulfate. InHyphomicrobium denitrificans, an obligately chemoorganoheterotrophic Alphaproteobacterium, the use of thiosulfate as a supplemental electron donor is regulated by two homologous sulfane-sulfur-responsive ArsR-type transcriptional repressors, sHdrR and SoxR. Here, we provide information on the distribution and phylogeny of sHdrR, the relevance of its two conserved cysteines in vivo, and identify the genes controlled by SoxR and sHdrR not only by targeted qRT-PCR but also by global RNA-Seq-based analyses of regulator-deficient mutant strains.The absence of sHdrR and SoxR affected 165 and 170 genes, respectively, with 138 genes overlapping. SoxR affects thesoxgenes for periplasmic thiosulfate oxidation and sulfane sulfur import into the cytoplasm, as well as thelip-shdr-lbpAgenes encoding the cytoplasmic enzymes essential for sulfite formation. sHdrR affects only a subset of these genes. The transcription ofsoxgenes remains unaltered in its absence. sHdrR and SoxR act cooperatively, possibly involving heterodimer formation, and their activity also involves interaction with other transcriptional regulators. Most importantly, sHdrR/SoxR regulation extends far beyond sulfur oxidation and deeply affects anaerobic metabolism, particularly denitrification inH. denitrificans.