bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sparse neural networks enable low-power, implantable neural interfaces
Authors: Costello Joseph T. , Temmar Hisham , Cubillos Luis , Mender Matthew J. , Wallace Dylan M. , Kelberman Madison , Benharush Omer , Simons Jeremy , Willsey Matthew S. , Kumar Nishant Ganesh , Kung Theodore A. , Patil Parag G. , Chestek Cynthia A. 
Published: December 2024

AbstractRecent advances in brain-machine interfaces (BMIs) using neural network decoders and increased channel count have improved the restoration of speech and motor function, but at the cost of higher power consumption. For wireless, implantable BMIs to be clinically viable, power consumption must be limited to prevent thermal tissue damage and enable long use without frequent charging. Here, we show how neural network “pruning” creates sparse decoders that require fewer computations and active channels for reduced power consumption. Across multiple movement decoding tasks using brain and muscle signals, recurrent neural network decoders can be compressed by over 100x while maintaining strong performance, enabling decoding on the implant with <1% power increase compared to decoding externally. Pruning also allows for deactivating up to 89% of channels, reducing BMI power by up to 5x. Counterintuitively, our findings suggest that BMIs employing a subset of a larger number of channels may achieve lower power consumption than BMIs with fewer channels, for a given performance level. These results suggest a path toward power-efficient, implantable BMIs suitable for long-term clinical use.
Periaqueductal gray passes over disappointment and signals continuity of remaining reward expectancy
Authors: Lee Hyunchan , Hikosaka Okihide 
Published: December 2024

AbstractDisappointment is a vital factor in the learning and adjustment of strategies in reward-seeking behaviors. It helps them conserve energy in environments where rewards are scarce, while also increasing their chances of maximizing rewards by prompting them to escape to environments where richer rewards are anticipated (e.g., migration). However, another key factor in obtaining the reward is the ability to monitor the remaining possibilities of obtaining the outcome and to tolerate the disappointment in order to continue with subsequent actions. The periaqueductal gray (PAG) has been reported as one of the key brain regions in regulating negative emotions and escape behaviors in animals. The present study suggests that the PAG could also play a critical role in inhibiting escape behaviors and facilitating ongoing motivated behaviors to overcome disappointing events. We found that PAG activity is tonically suppressed by reward expectancy as animals engage in a task to acquire a reward outcome. This tonic suppression of PAG activity was sustained during a series of sequential task procedures as long as the expectancy of reward outcomes persisted. Notably, the tonic suppression of PAG activity showed a significant correlation with the persistence of animals’ reward-seeking behavior while overcoming intermittent disappointing events. This finding highlights that the balance between distinct tonic signaling in the PAG, which signals remaining reward expectancy, and phasic signaling in the LHb, which signals disappointment, could play a crucial role in determining whether animals continue or discontinue reward-seeking behaviors when they encounter an unexpected negative event. This mechanism would be essential for animals to efficiently navigate complex environments with various reward volatilities and ultimately contributes to maximizing their reward acquisition.
Validation of the Baseline Recurrence Risk in Cellulitis (BRRISC) score and the added impact of acute clinical response
Authors: Cross Elizabeth LA , Hayward Gail N , Llewelyn Martin J , Walker A Sarah 
Published: December 2024

AbstractObjectivesThe BRRISC score predicts hospital-attended recurrence of cellulitis using baseline clinical data. In practice, clinicians assess treatment response when deciding antibiotic duration. We investigated whether markers of acute clinical response improved prognostic score performance within an external validation cohort.MethodsWe recruited adults with lower limb cellulitis attending hospital. Outcomes included ‘hospital-attended recurrence’ (primary outcome for validation) and ‘any recurrence’. We assessed clinical response from days 0-3 of treatment. Using multivariate logistic regression with backwards elimination, we identified response variables independently associated with either outcome for an extended score.ResultsOf 202 patients, 8% (n=17) experienced ‘hospital-attended recurrence’ and 23% (n=46) ‘any recurrence’. In this validation dataset, the BRRISC score had a C-index=0.75 (95%CI, 0.64-0.86) for predicting ‘hospital-attended recurrence’. There was weak evidence that an extended score, incorporating day-2/3 severity of skin blistering, improved the C-index to 0.83 (0.75-0.92). No acute clinical response variables were independently associated with ‘any recurrence’ after adjusting for BRRISC score.ConclusionOur measures of early clinical response did not add useful prognostic information to BRRISC score baseline risk. Further research should consider whether responses after day-3 add helpful information, whether risk stratification can personalise antibiotic duration, and explore non-antibiotic approaches to prevent recurrence.
25-Hydroxy Cholesterol Effectively Inhibits Japanese Encephalitis Virus infection in Vero Cells
Authors: Archana Km. , Bohra Babita , Tripathi Raj Kamal , Haldar Sourav 
Published: December 2024

AbstractThe Japanese encephalitis virus (JEV) is a mosquito-borne, enveloped flavivirus that causes acute encephalitis. Although JEV is increasingly recognized as a global threat, there is currently no FDA-approved treatment available for JEV. 25-hydroxycholesterol (25-HC) is an oxysterol produced through the oxidation of cholesterol, a process catalyzed by cholesterol 25-hydroxylase (CH25H), which is an interferon-stimulated gene that is upregulated during viral infections. In this study, we report for the first time that 25-HC effectively prevents JEV infection in cells. Our results show that 25-HC inhibits JEV infection in Vero cells with an IC50 of ∼ 3.7 μM, while displaying no cell toxicity (CC50 > 50 μM). Given the antiviral effects of 25HC against Zika and Dengue viruses, our findings suggest that 25-HC could be a promising candidate for the development of broad-spectrum anti-flaviviral therapeutics.
Scavenger receptor CD163 multimerises to allow uptake of diverse ligands
Authors: Zhou Richard X. , Higgins Matthew K. 
Published: December 2024

AbstractScavenger receptors mediate cellular uptake of diverse ligands. CD163 is an archetypal scavenger receptor with a primary role in haemoglobin detoxification. Haemoglobin released from lysed erythrocytes causes oxidative damage. This is countered by formation of haemoglobin-haptoglobin complexes and CD163-mediated uptake into macrophages for degradation. Different haptoglobin isoforms form stoichiometrically diverse haptoglobin-haemoglobin complexes which must all be recognised by CD163. We show that CD163 forms multimeric complexes, with calcium-mediated interactions forming a trimeric base. Arms emerge from this base, moulding around the ligand to form a single promiscuous ligand-binding site. The arms can also bind to arms of adjacent protomers, blocking the ligand-binding surfaces in an autoinhibited state. This results in a scavenger receptor that can recognise diverse haemoglobin-containing complexes, allowing physiologically important detoxification.
Spatio-temporal interaction of immune and renal cells determines glomerular crescent formation in autoimmune kidney disease
Authors: Sultana Zeba , Khatri Robin , Yousefi Behnam , Shaikh Nikhat , Jauch-Speer Saskia L. , Schaub Darius P. , Engesser Jonas , Hellmig Malte , Hube Arthur L. , Sivayoganathan Varshi , Borchers Alina , Peters Anett , Kaffke Anna , Paust Hans-Joachim , Goldbeck-Strieder Thiago , Wenzel Ulrich O. , Puelles Victor , Hoxha Elion , Wiech Thorsten , Huber Tobias B. , Panzer Ulf , Bonn Stefan , Krebs Christian F. 
Published: December 2024

AbstractRapidly progressive glomerulonephritis (RPGN) is the most aggressive group of autoimmune kidney disease with the worst prognosis. Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis, anti-glomerular basement membrane (anti-GBM) and lupus nephritis are the most common causes of RPGN and are characterized by the formation of glomerular crescents and infiltration of leukocytes that eventually lead to glomerulosclerosis and kidney failure.In this work, we used high-resolution spatial transcriptomics of 32 ANCA, 19 lupus nephritis, 6 anti-GBM, and 6 control patients to understand how intercellular signaling between immune and renal tissue cells leads to renal inflammation and glomerular injury. Using 3,218,210 immune and kidney cells, we observed that the biological pathways involved in the sequence of glomerular crescent formation are similar across the diseases. While innate immune cells infiltrated the glomerular compartment relatively early, later increases in adaptive immune cells were largely restricted to the periglomerular regions. These changes in immune cells temporally correlated with increases in glomerular parietal epithelial (PEC) and fibrotic mesangial cells, suggesting disease-relevant functional signaling between these immune and renal cells. Cell communication analysis revealed early disease PDGF signaling from epithelial and mesangial cells to PECs, causing their activation and proliferation. At later stages, TGF-β signaling from macrophages, T cells, epithelial cells, and mesangial cells to PECs triggered the expression of extracellular matrix components resulting in glomerulosclerosis.Our results highlight a spatio-temporally conserved progression into glomerular crescents and sclerosis for ANCA, lupus nephritis, and anti-GBM disease, which is driven by consecutive PDGF and TGF-β signaling to PECs.
BRAFV600and ErbB inhibitors directly activate GCN2 in an off-target manner to limit cancer cell proliferation
Authors: Ill C. Ryland , Marikar Nasreen C. , Nguyen Vu , Nangia Varuna , Darnell Alicia M. , Vander Heiden Matthew G. , Reigan Philip , Spencer Sabrina L. 
Published: December 2024

AbstractTargeted kinase inhibitors are well known for their promiscuity and off-target effects. Herein, we define an off-target effect in which several clinical BRAFV600inhibitors, including the widely used dabrafenib and encorafenib, interact directly with GCN2 to activate the Integrated Stress Response and ATF4. Blocking this off-target effect by co-drugging with a GCN2 inhibitor in A375 melanoma cells causes enhancement rather than suppression of cancer cell outgrowth, suggesting that the off-target activation of GCN2 is detrimental to these cells. This result is mirrored in PC9 lung cancer cells treated with erlotinib, an EGFR inhibitor, that shares the same off-target activation of GCN2. Using anin silicokinase inhibitor screen, we identified dozens of FDA-approved drugs that appear to share this off-target activation of GCN2 and ATF4. Thus, GCN2 activation may modulate the therapeutic efficacy of some kinase inhibitors, depending on the cancer context.
EpiAgent: Foundation model for single-cell epigenomic data
Authors: Chen Xiaoyang , Li Keyi , Cui Xuejian , Wang Zian , Jiang Qun , Lin Jiacheng , Li Zhen , Gao Zijing , Jiang Rui 
Published: December 2024

AbstractLarge-scale foundation models have recently opened new avenues for artificial general intelligence. Such a research paradigm has recently shown considerable promise in the analysis of single-cell sequencing data, while to date, efforts have centered on transcriptome. In contrast to gene expression, chromatin accessibility provides more decisive insights into cell states, shaping the chromatin regulatory landscapes that control transcription in distinct cell types. Yet, challenges also persist due to the abundance of features, high data sparsity, and the quasi-binary nature of these data. Here, we introduce EpiAgent, the first foundation model for single-cell epigenomic data, pretrained on a large-scale Human-scATAC-Corpus comprising approximately 5 million cells and 35 billion tokens. EpiAgent encodes chromatin accessibility patterns of cells as concise “cell sentences,” and employs bidirectional attention to capture cellular heterogeneity behind regulatory networks. With comprehensive benchmarks, we demonstrate that EpiAgent excels in typical downstream tasks, including unsupervised feature extraction, supervised cell annotation, and data imputation. By incorporating external embeddings, EpiAgent facilitates the prediction of cellular responses to both out-of-sample stimulated and unseen genetic perturbations, as well as reference data integration and query data mapping. By simulating the knockout of keycis-regulatory elements, EpiAgent enables in-silico treatment for cancer analysis. We further extended zero-shot capabilities of EpiAgent, allowing direct cell type annotation on newly sequenced datasets without additional training.
Sex-specific mate choice and mate change based on MHC-IIB dissimilarity in a genetically monogamous seabird
Authors: Thel Lucie , Pineaux Maxime , Ribeiro Léa , Danchin Etienne , Hatch Scott A. , Blanchard Pierrick , Leclaire Sarah 
Published: December 2024

AbstractAmong species reproducing sexually, mating strategies represent a major component of individual fitness. The Major Histocompatibility Complex (MHC) is an extremely diverse set of genes responsible for immunological recognition and defense against pathogens. Although MHC-dissimilarity between mates has been proposed to drive mate choice through increased offspring pathogen resistance, evidence is mixed, and evidence for other MHC-based mating strategies remains rare. We investigated whether MHC-IIB dissimilarity is associated with mate choice and mate change in the genetically monogamous black-legged kittiwake (Rissa tridactyla). We found that first-time male breeders are paired with females more MHC-IIB dissimilar to them than expected by chance. After a successful reproduction, the more males are MHC-IIB dissimilar to their mate, the less likely they are to change mate. When males change their mate, they tend to be more MHC-IIB dissimilar to the new mate compared to the previous mate. However, males are not more MHC-IIB dissimilar to their new mate than expected by chance. We did not find evidence for an effect of MHC-IIB dissimilarity on mating strategies when considering the female’s perspective. Male mate choice should not be overlooked in species with bi-parental care in which the male performs a significant part of parental care.
Viro3D: a comprehensive database of virus protein structure predictions
Authors: Litvin Ulad , Lytras Spyros , Jack Alexander , Robertson David L , Grove Joe , Hughes Joseph 
Published: December 2024

AbstractViruses are intracellular parasites of organisms from all domains of life. They infect and cause disease in humans, animals and plants but also play crucial roles in the ecology of microbial communities. Tolerance to genetic change, high-mutation rates, adaptations to hosts and immune escape has driven high divergence of viral genes, hampering their functional annotation and phylogenetic inference. The protein structure is more conserved than sequence and can be used for searches of distant homologs and evolutionary analysis of divergent proteins. Structures of viral proteins are traditionally underrepresented in public databases, but recent advances in protein structure prediction allows us to address this issue. Combining two state-of-the-art approaches, AlphaFold2-ColabFold and ESMFold, we predicted models for 85,000 proteins from 4,400 human and animal viruses, expanding the structural coverage for viral proteins by 30 times compared to experimental structures. We also performed structural and network analyses of the models to demonstrate their utility for functional annotation and inference of distant phylogenetic relationships. Taking this approach, we examined the deep evolutionary history of viral class-I fusion glycoproteins, gaining insights on the origins of coronavirus spike protein. To enable further discoveries, we have createdViro3D(https://viro3d.cvr.gla.ac.uk/), a virus species-centred protein structure database. It allows users to search, browse and download protein models from a virus of interest and explore similar structures present in other virus species. This resource will facilitate fundamental molecular virology, investigation of virus evolution, and may enable structure-informed design of therapies and vaccines.
Ongoing loss of viable neurons for weeks after mild perinatal hypoxia-ischemia
Authors: McNally Melanie A. , Lau Lauren A. , Granak Simon , Hike David , Liu Xiaochen , Yu Xin , Donahue Rachel A. , Chibnik Lori B. , Ortiz John V. , Che Alicia , Northington Frances , Staley Kevin 
Published: December 2024

ABSTRACTMild hypoxic-ischemic encephalopathy is common in neonates with no evidence-based therapies, and 30-40% of patients experience adverse outcomes. The nature and progression of mild injury is poorly understood. Thus, we studied the evolution of mild perinatal brain injury using longitudinal two-photon imaging of transgenic fluorescent proteins as a novel readout of neuronal viability and activity at cellular resolution. In vitro, perinatal murine organotypic hippocampal cultures underwent 15-20 minutes of oxygen-glucose deprivation. In vivo, mild hypoxia-ischemia was completed in post-natal day 10 mouse pups of both sexes with carotid ligation and 15 minutes of hypoxia. Consistent with a mild injury, minimal immediate neuronal death was seen and there was no volumetric evidence of injury by ex vivo MRI 2.5 weeks after injury. In both the hippocampus and neocortex, these mild injuries resulted in a significantly delayed and progressive neuronal loss in the second week after injury, measured by fluorophore quenching. Mild hypoxia-ischemia transiently suppressed cortical network activity followed by normal maturation. No post-injury seizures were seen. The participation in network activity of individual neurons destined to die was indistinguishable from those that survived for 4 days post-injury. In conclusion, our results showed that mild perinatal brain injury resulted in a prolonged increase of neuronal death. Neurons that died late were functioning normally for days after injury, suggesting a new pathophysiology of neuronal death. Critically, the neurons destined to die late demonstrated multiple biomarkers of viability long after mild injury, suggesting their later death may be modified with neuroprotective interventions.SIGNIFICANCE STATEMENTNeonatal encephalopathy due to peripartum hypoxia-ischemia (HI) is a major cause of neonatal mortality and morbidity worldwide. Of these infants, most are categorized as having mild HI. Infants with mild HI have significant long-term disabilities. There are currently no evidence-based therapies, largely because the progression and pathophysiology of mild injury is poorly understood. We have identified, for the first time, that mild perinatal HI results in a delayed and prolonged increase in neuronal death. The cortical and hippocampal neurons that die over a week after injury participate normally in neural network activity and exhibit robust viability for many days after injury, indicating a novel pathophysiology of neuronal death. Clinically, these data suggest an extended therapeutic window for mild perinatal HI.
Skeletal trait measurements for thousands of bird species
Authors: Weeks Brian C. , Zhou Zhizhuo , Probst Charlotte M. , Berv Jacob S. , O’Brien Bruce , Benz Brett W. , Skeen Heather R. , Ziebell Mark , Bodt Louise , Fouhey David F. 
Published: December 2024

AbstractLarge comparative datasets of avian functional traits have been used to address a wide range of questions in ecology and evolution. To date, this work has been constrained by the limited availability of skeletal trait datasets that include extensive inter- and intra-specific sampling. We use computer vision to identify and measure bones from photographs of museum skeletal specimens to assemble an extensive dataset of functionally important skeletal elements in birds. The dataset spans 2,057 species of birds (Aves: Passeriformes) and includes measurements of 12 skeletal elements from 14,419 individuals. In addition to the trait values directly measured from photographs, we leverage the multi-dimensional nature of our dataset and known phylogenetic relationships of the species to impute missing data under an evolutionary model. To facilitate use of the dataset, the taxonomy has been reconciled with an existing comprehensive avian phylogeny and an additional dataset of external functional traits for all birds.
HapCNV: A Comprehensive Framework for CNV Detection in Low-input DNA Sequencing Data
Authors: Yu Xuanxuan , Qin Fei , Liu Shiwei , Brown Noah J. , Lu Qing , Cai Guoshuai , Guler Jennifer L. , Xiao Feifei 
Published: December 2024

AbstractCopy number variants (CNVs) are prevalent in both diploid and haploid genomes, with the latter containing a single copy of each gene. Studying CNVs in genomes from single or few cells is significantly advancing our knowledge in human disorders and disease susceptibility. Low-input including low-cell and single-cell sequencing data for haploid and diploid organisms generally displays shallow and highly non-uniform read counts resulting from the whole genome amplification steps that introduce amplification biases. In addition, haploid organisms typically possess relatively short genomes and require a higher degree of DNA amplification compared to diploid organisms. However, most CNV detection methods are specifically developed for diploid genomes without specific consideration of effects on haploid genomes. Challenges also reside in reference samples or normal controls which are used to provide baseline signals for defining copy number losses or gains. In traditional methods, references are usually pre-specified from cells that are assumed to be normal or disease-free. However, the use of pre-defined reference cells can bias results if common CNVs are present. Here, we present the development of a comprehensive statistical framework for data normalization and CNV detection in haploid single- or low-cell DNA sequencing data called HapCNV. The prominent advancement is the construction of a novel genomic location specific pseudo-reference that selects unbiased references using a preliminary cell clustering method. This approach effectively preserves common CNVs. Using simulations, we demonstrated that HapCNV outperformed existing methods by generating more accurate CNV detection, especially for short CNVs. Superior performance of HapCNV was also validated in detecting known CNVs in a realP. falciparumparasite dataset. In conclusion, HapCNV provides a novel and useful approach for CNV detection in haploid low-input sequencing datasets, with easy applicability to diploids.