bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glutamatergic synaptic resilience to overexpressed human alpha-synuclein
Authors: Santos Patrícia I. , García-Plaza Inés Hojas , Shaib Ali , Rhee Jeong Seop , Chouaib Abed Alrahman , Rizzoli Silvio O. , Daniel James , Outeiro Tiago F. 
Published: February 2025

ABSTRACTAlpha synuclein (aSyn) is an abundant protein that, in the brain, is concentrated in neuronal presynaptic boutons and associates with synaptic vesicles. aSyn is strongly linked with Parkinson’s disease (PD) due to its accumulation in pathognomonic inclusions in neuronal cells, including in glutamatergic neurons. While increased expression of wild-type (WT) aSyn due to multiplications of the SNCA gene, or the expression of mutant forms of aSyn, can cause familial forms of PD, it is still unclear whether increased levels of aSyn alone are sufficient to impair synaptic function. Previous studies have used experimental systems that do not allow systematic characterisation of presynaptic physiology. To address this gap in research, we used lentiviral vectors to overexpress human aSyn (haSyn) in continental and autaptic glutamatergic neurons from rodent hippocampus and systematically analysed their presynaptic function. Virally-transduced neurons exhibited levels of expression of haSyn that mimic those associated with triplications of the SNCA gene in PD patients (2-fold increase in total aSyn), as determined using quantitative immunofluorescence imaging and immunoblots. Neuronal toxicity, neuronal morphology, and SNAP-25, a presynaptic protein, were not altered in continental cultures. Finally, a systematic characterization of autaptic neurons expressing haSyn exhibited no significant difference in any parameter of synaptic function, including basal properties of evoked and spontaneous neurotransmitter release, and synaptic plasticity compared to neurons infected with a control virus. These results indicate that rodent glutamatergic neurons are resilient to aSyn overexpression. In conclusion, our findings suggest neurotoxicity associated with aSyn overexpression is not universal, and that a deeper understanding of aSyn biology and pathobiology is necessary.
Cell signaling pathways discovery from multi-modal data
Authors: He Changhan , Simpson Claire , Cossentino Ian , Zhang Bin , Tkachev Sasha , Eddins Devon J. , Kosters Astrid , Yang Junkai , Sheth Shivani , Levy Tyler , Possemato Anthony , Huang Linglin , Tabatsky Evgeniy , Gregoretti Ivan , Ariss Majd , Dandekar Deepti , Ausekar Aniket , Ghosn Eliver E. B. , Colonna Marco , Rikova Klarisa , Nie Qing , Orlova Darya 
Published: February 2025

AbstractDeciphering cell signaling pathways is essential for advancing our understanding of basic biology, disease mechanisms, and the development of innovative therapeutic interventions. Recent advancements in multi-omics technologies enable us to capture cell signaling information in a more meaningful context. However, omics data is inherently complex—high-dimensional, heterogeneous, and extensive—making it challenging for human interpretation. Currently, computational tools capable of inferring cell signaling pathways from multi-omics data are very limited, underscoring the urgent need to develop such methods.To address this challenge, we developed Incytr, a method that facilitates the efficient discovery of cell signaling pathways by integrating diverse data modalities, including transcriptomics, proteomics, phosphoproteomics, and kinomics. We demonstrate Incytr’s application in elucidating cell signaling within the contexts of COVID-19, Alzheimer’s disease, and cancer. Incytr successfully rediscovered known subpathways in these diseases and generated novel hypotheses for cell-type-specific signaling pathways supported by multiple data modalities. We illustrate how overlaying Incytr-identified pathways with prior knowledge from biomarker and small molecule drug databases can be used to facilitate target and drug discovery. Overall, as we demonstrated here, with the use of simple natural language processing AI models, these pathways could serve as a discovery tool to deepen our understanding of cell-cell communication semantics and co-evolution.
Kinase-Inhibitor Binding Affinity Prediction with Pretrained Graph Encoder and Language Model
Authors: Guo Xudong , Ran Zixu , Li Fuyi 
Published: February 2025

AbstractMotivationThe accurate prediction of inhibitor-kinase binding affinity is crucial in drug discovery and medical applications, especially in the treatment of diseases such as cancer. Existing methods for predicting inhibitor-kinase affinity still face challenges including insufficient data expression, limited feature extraction, and low performance. Despite the progress made through artificial intelligence (AI) methods, especially deep learning technology, many current methods fail to capture the intricate interactions between kinases and inhibitors. Therefore, it is necessary to develop more advanced methods to solve the existing problems in inhibitor-kinase binding prediction.ResultsThis study proposed Kinhibit, a novel framework for inhibitor-kinase binding affinity predictor. Kinhibit integrates self-supervised pre-trained molecular encoders and protein language models (ESM-S) to extract features effectively. Kinhibit also employed a feature fusion approach to optimize the fusion of inhibitor and kinase features. Experimental results demonstrate the superiority of this method, achieving an accuracy of 92.6% in inhibitor prediction tasks of three MAPK signaling pathway kinases: Raf protein kinase (RAF), Mitogen-activated protein kinase kinase (MEK), and Extracellular Signal-Regulated Kinase (ERK). Furthermore, the framework achieves an impressive accuracy of 93.4% on a dataset containing over 200 kinases. This study provides promising and effective tools for drug screening and biological sciences.
Beyond Blacklists: A Critical Assessment of Exclusion Set Generation Strategies and Alternative Approaches
Authors: Wall Brydon P. G. , Ogata Jonathan D. , Nguyen My , McClay Joseph L. , Harrell J. Chuck , Dozmorov Mikhail G. 
Published: February 2025

AbstractShort-read sequencing data can be affected by alignment artifacts in certain genomic regions. Removing reads overlapping these exclusion regions, previously known as Blacklists, help to potentially improve biological signal. Tools like the widely used Blacklist software facilitate this process, but their algorithmic details and parameter choices are not always clearly documented, affecting reproducibility and biological relevance. We examined the Blacklist software and found that pre-generated exclusion sets were difficult to reproduce due to variability in input data, aligner choice, and read length. We also identified and ad- dressed a coding issue that led to over-annotation of high-signal regions. We further explored the use of “sponge” sequences—unassembled genomic regions such as satellite DNA, ribosomal DNA, and mitochondrial DNA—as an alternative approach. Aligning reads to a genome that includes sponge sequences reduced signal correlation in ChIP-seq data comparably to Blacklist-derived exclusion sets while preserving biological signal. Sponge-based alignment also had minimal impact on RNA-seq gene counts, suggesting broader applicability beyond chromatin profiling. These results highlight the limitations of fixed exclusion sets and suggest that sponge sequences offer a flexible, alignment-guided strategy for reducing artifacts and improving functional genomics analyses.
The impact of ambient contamination on demultiplexing methods for single-nucleus multiome experiments
Authors: Li Terence , Alvarez Marcus , Liu Cuining , Abuhanna Kevin , Sun Yu , Ernst Jason , Plath Kathrin , Balliu Brunilda , Luo Chongyuan , Zaitlen Noah 
Published: February 2025

AbstractSample multiplexing has become an increasingly common design choice in droplet-based single-nucleus multi-omic sequencing experiments to reduce costs and remove technical variation. Genotype-based demultiplexing is one popular class of methods that was originally developed for single-cell RNA-seq, but has not been rigorously benchmarked in other assays, such as snATAC-seq and joint snRNA/snATAC assays, especially in the context of variable ambient RNA/DNA contamination. To address this, we develop ambisim, a genotype-aware read-level simulator that can flexibly control ambient molecule proportions and generate realistic joint snRNA/snATAC data. We use ambisim to evaluate demultiplexing methods across several important parameters: doublet rate, number of multiplexed donors, and coverage levels. Our simulations reveal that methods are variably impacted by ambient contamination in both modalities. We then applied the demultiplexing methods to two joint snRNA/snATAC datasets and found highly variable concordance between methods in both modalities. Finally, we develop a new metric,variant consistency, which we show is correlated with cell-level ambient molecule fractions in singlets. Applying our metric to two multiplexed joint snRNA/snATAC datasets reveals variable ambient contamination across experiments and modalities. We conclude that improved modelling of ambient material in demultiplexing algorithms will increase both sensitivity and specificity.
Loss of 5-HT2CReceptor Function Alters Motor Behavior in Male and Female Mice With and Without Spinal Cord Injury
Authors: Sim Margaret I. , Birch Derin , Mahrous Amr A. , Heckman C.J. , Tysseling Vicki M. 
Published: February 2025

AbstractThe 5-HT2Creceptor is involved in the regulation of spinal motor function, specifically in both volitional and involuntary motor behavior. It contributes to various aspects of voluntary movement, such as locomotion, gait, coordination, and muscle contraction, as well as to involuntary motor behavior like spasms, which affect many individuals with spinal cord injury. Despite its known involvement in motor function, little is known about the physiological role of the 5-HT2Creceptor and the changes it undergoes after spinal cord injury. In this study, we have investigated the volitional and involuntary motor behavior of male and female uninjured and spinal cord injured knock-out mice that lack the functional 5-HT2Creceptor by comparing these genetically manipulated mice to typical-functioning sex-matched wildtype mice. Behavioral assessments revealed differences in volitional muscle strength and coordination, as well as hyperreflexia, between the groups observed. Additionally,ex vivosacral cord preparation data suggest that 5-HT2Creceptor knock-out mice exhibit less spasm-like activity than wildtype mice, corroborating our results from behavioral testing in which the flexor withdrawal reflex of the hindlimbs was assessed. To investigate potential compensatory changes in 5-HT2Creceptor expression following spinal cord injury, western blot analysis was performed on lumbar and sacral spinal cord tissue from wildtype and 5-HT2Creceptor knock-out mice before and after injury. Both sex and injury status significantly influenced 5-HT2Creceptor relative expression and distribution of these receptors in both spinal cord regions. Through a comprehensive approach combining behavioral assessments, electrophysiological experiments, and whole-tissue protein analysis, our findings provide strong evidence that the 5-HT2Creceptor plays a critical role in both volitional motor function and involuntary motor behavior, and the relative expression of the 5-HT2Creceptor is influenced by both sex and injury status.
A biological growth curve is a sum of two distinct S-curves
Authors: Shruti I S 
Published: February 2025

AbstractA growing population consists of successive generations of individuals interacting with each other and the environment. At every instant, these individual interactions can lead to either promotion or restriction of the population growth. Thus, within a growing population, differences arise over time due to both extrinsic and intrinsic factors such as resource utilization, competition, age distribution etc. These differences can lead to divergence within the population growth. The sum of these differences is manifested as the net population growth. In this work, we propose that these differences that arise over time within a growing population can be represented as two distinct S-curves. The sum of these two S-curves results in the growth curve of a population. These differences also arise in the growth curves of mean individual attributes such as height or weight. We demonstrate this by applying thea−mbiological growth model on (i) the population growth curves ofDrosophilaand yeast and (ii) the growth curves of mean individual height of sunflower plants and the mean individual body weight of male white rats. Finally, we also discuss the results using a coordinate system with the two distinct S-curves as the axes.
Nucleotide-specific RNA conformations and dynamics within ribonucleoprotein condensates
Authors: Wang Tong , Hu Qingyue , Fronhofer Scout , Pollack Lois 
Published: February 2025

AbstractRibonucleoprotein (RNP) condensates have distinct physiological and pathological significance, but the structure of RNA within them is not well understood. Using contrast-variation solution X-ray scattering, which discerns only the RNA structures within protein-RNA complexes, alongside ensemble-based structural modeling we characterize the conformational changes of flexible poly-A, poly-U and poly-C single stranded RNA as it interacts with polybasic peptides, eventually forming condensed coacervate mixtures. At high salt concentrations, where macromolecular association is weak, we probe association events that precede the formation of liquid-like droplets. Structural changes occur in RNA that reflect charge screening by the peptides as well asπ−πinteractions of the bases with basic residues. At lower salt concentrations, where association is enhanced, poly-A RNA within phase separated RNP mixtures exhibit a broad scattering peak, suggesting subtle ordering. Coarse-grained molecular dynamics simulations are used to elucidate the nucleotide-specific dynamics within RNP condensates. While adenine-rich condensates behave like stable semidilute solutions, uracil-rich RNA condensates appear to be compositionally fluctuating. This approach helps understand how RNA sequence contributes to the molecular grammar of RNA-protein phase separation.
Determinants of cholera fatalities in Malawi: A case-control study of patient-level and clinical management factors in the 2022-23 outbreak
Authors: Chitatanga Ronald , Thawani Alex , Chadwala Hope , Chirwa Amon , Mitambo Collins 
Published: February 2025

ABSTRACTMalawi experienced its deadliest cholera outbreak in 2022, reporting over 50,000 cases and more than 1,700 deaths, resulting in a case fatality rate of 3.1%. The outbreak was exacerbated by the devastation caused by Tropical Cyclones Freddy, Ana, and Gombe, which strained healthcare resources. Despite the severity of the outbreak, no real-time evaluations of patient-level risk factors influencing cholera mortality among hospitalized patients were conducted. This study characterizes patient-level factors and treatment practices associated with cholera mortality in Malawi. A multisite case-control study was conducted in August 2023 across four cholera treatment units. A retrospective review of 174 medical records (confirmed by rapid antigen test or stool culture) was performed by a team led by trained medical officers. Cases (deceased) and controls (survivors) were matched based on age and district of diagnosis. Conditional logistic regression was used to assess associations between patient characteristics and mortality. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for all predictors, with statistical significance set at p < 0.05. The strongest predictor of mortality was inadequate intravenous (IV) fluid management, with 95% of deceased patients classified as inadequately managed. Inadequate fluid management was associated with significantly higher odds of mortality (OR = 117, 95% CI: 14.3–959, p < 0.001). This study highlights critical gaps in adherence to cholera treatment protocols in Malawi’s treatment units, emphasizing the need for timely and adequate IV fluid management to reduce cholera-related deaths.
OTULIN Interactome Reveals Immune Response and Autophagy Associated with Tauopathy in a Mouse Model
Authors: Li Ling , Li Mingqi , Zhou Yuyang , Kakhniashvili David , Wang Xusheng , Liao Francesca-Fang 
Published: February 2025

AbstractTauopathies are neurodegenerative diseases that are pathologically characterized by accumulation of misfolded microtubule-associated protein tau aggregates in the brain. Deubiquitination, particularly by OTULIN, a unique deubiquitinase targeting methionine-1 (M1) linkages from linear ubiquitin chain assembly complex (LUBAC)), is reportedly associated with the accumulation of neurotoxic proteins in several neurodegenerative diseases, likely including tauopathies. To investigate the potential roles of OTULIN in tauopathies, we analyzed the OTULIN interactome in hippocampal tissues from PS19 transgenic (Tg) mice and their non-transgenic (nTg) littermate controls using affinity purification-mass spectrometry (AP-MS). We identified 705 and 800 proteins enriched in Tg and nTg samples, respectively, with a protein false discovery rate (FDR) of <1%. Of these, 189 and 205 proteins were classified as probable OTULIN interactors in Tg and nTg groups, respectively, based on Significance Analysis of INTeractome (SAINT) score of ≥0.80 and FDR of ≤ 5%. A total of 84 proteins were identified as OTULIN interactors in the PS19 Tg group, while 100 proteins were associated with OTULIN in the nTg controls. Functional enrichment analyses revealed that OTULIN-interacting proteins in the nTg group were enriched in pathways related to spliceosome, complement and coagulation cascades, and ribosome, whereas those in the Tg group were associated with immune response and autophagy. These findings suggest that OTULIN-interacting proteins may play a critical role in the pathogenesis of tauopathy in this mouse model.HighlightsOTULIN interactome in hippocampal tissues from PS19 transgenic (Tg) mice and their non-transgenic (nTg) littermate controls is analyzed.OTULIN-interacting proteins in the nTg group are enriched in pathways related to spliceosome, complement and coagulation cascades, and ribosome.OTULIN-interacting proteins in Tg are implicated in immune response and autophagy.ATP2A2 is identified as an OTULIN-interacting protein specifically enhanced in Tg mice.
In vivobase editing reduces liver cysts in autosomal dominant polycystic kidney disease
Authors: Ibel Antonia , Bhardwaj Rishi , Yilmaz Duygu Elif , Kong Shuhan , Wendlinger Sarah , Papaioannou Dimitra , Diezemann Claudia , Eckardt Kai-Uwe , Hasan Fatima , Klämbt Verena , Halbritter Jan , Fedeles Sorin , Krappitz Matteus , Kaminski Michael M. 
Published: February 2025

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disorder, affecting over 10 million individuals worldwide. Cystic expansion typically progresses to kidney failure and also involves the liver with limited treatment options. Pathogenic variants inPKD1orPKD2account for 85-90% of cases. Genetic re-expression ofPkd1orPkd2has been shown to partially reverse key characteristics of the disease phenotype in mice. Despite advancements in the understanding of the genetic basis, it remains unclear whether the correction of underlying pathogenic variants can effectively prevent, modify, or reverse the disease. Additionally, the feasibility of extrinsically delivered genome editing as a treatment option for ADPKD remains largely unexplored. In this study, we employed CRISPR base editing to correct a spectrum of representative pathogenicPKD1variants selected from a patient cohort achieving precise and efficient editingin vitro. Correction of a representative murine missense variant (c.6646C>T (R2216W)) in primary renal epithelial cells successfully increased polycystin-1 expression and reduced levels of the endoplasmic reticulum stress marker sXBP1.In vivo, base editor delivery to the c.6646C>T (R2216W) knock-in mouse enabled correction of the pathogenic variant, resulting in a significant reduction in liver cysts. These findings provide the first evidence of ADPKD reversibility through genome editing, opening promising novel therapeutic perspectives for affected patients and their families.
Motion processing in visual cortex of maculopathy patients
Authors: Michaud Célia , Guénot Jade , Faurite Cynthia , Gallice Mathilde , Chiquet Christophe , Vayssière Nathalie , Berry Isabelle , Trotter Yves , Soler Vincent , Peyrin Carole , Cottereau Benoit R. 
Published: February 2025

AbstractPrevious studies on animal models suggested that visual areas involved in motion processing could undergo important cortical reorganizations following retinal damages. This could have major implications for patients suffering from macular degeneration (MD), one leading cause of vision loss. Here, we performed fMRI recordings in a group of maculopathy patients (including individuals suffering from age-related macular degeneration or from Stargardt’s Disease) and a control group to characterize the motion processing cortical network in MD patients and determine whether this network undergoes significant large-scale reorganizations following the onset of the scotoma. We used an experimental protocol based on random-dot kinematograms (RDKs) classically employed to characterize motion-selective areas in the brain. To ensure that the visual information processed by the two groups was equivalent, the visual field in each control participant was masked using an artificial scotoma directly derived from clinical measurements in their paired patient. We found that in MD patients, translational motion elicited significant and robust activations in a restricted cortical network which included the human V5/MT+ complex (hMT+), areas V3A and V6, and a portion of primary visual areas (V1, V2 and V3) connected to peripheral vision. Importantly, the same patterns of responses were also observed in control participants. Moreover, the extent and strength of activation within these motion-selective areas did not differ significantly between the two groups. Altogether, these results suggest that in humans, the motion-selective network does not undergo significant large-scale cortical reorganizations following the onset of MD.Significance statementMotion processing in the visual cortex of patients with macular degeneration has never been characterized. Here, we performed fMRI recordings in 7 maculopathy patients and found robust motion-selective activations in a cortical network which included the human V5/MT+ complex (hMT+), areas V3A and V6, and a portion of primary visual areas connected to peripheral vision. These activations are in very good agreement with those reported in participants with normal vision in the literature and do not significantly differ from those measured in a group of age and gender-matched control participants. Altogether, our results suggest that the motion-selective network does not undergo significant large-scale reorganizations in maculopathy patients following the onset of the scotoma.