bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shared Transcriptomic Signatures Reveal Synaptic Pruning as a Link Between Alzheimer’s Disease and Epilepsy
Authors: Li Huihong , Xie Zhiran , Tian Yuxuan , Lin Bingying , Li Jianwei , Wu Jie , Chen Mingjie , Liu Xueke , Sun Yushan , Chen Si , Deng Zihan , Hong Mengqi , Huang Bing , Wei Naili , Ji Xiaoyu 
Published: October 2024

AbstractAlzheimer’s disease (AD) and epilepsy (EP) exhibit a complex, bidirectional relationship, however, the molecular mechanisms underlying their comorbidity remain poorly understood. To address this gap, we analyzed large-scale transcriptomic datasets from pilocarpine-induced EP mouse models (n = 200), two AD mouse models expressing human tau (rTg4510) or amyloid precursor protein (J20) (n = 141), and transcriptomic profiles from AD and EP patient cohorts. Differential expression and weighted gene co-expression network analyses identified a highly conserved immune-related module enriched in microglia-specific genes, particularlyTyrobp,Trem2, andC1qcomplement component genes (C1qa,C1qb,C1qc) implicated in the synaptic pruning pathway. Gene regulatory network analysis showed thatTyrobpregulates theseC1qcomponents gene throughTrem2. These hub genes were markedly upregulated in both models and human patient datasets, preserved their regulatory relationship across species, and displayed strong diagnostic value. Cell composition deconvolution and single-cell transcriptomics confirmed their high, cell-type-specific expression in microglia from both animal model and human patient datasets. Moreover, computational modeling indicated that excessive synaptic pruning, particularly of inhibitory synapses, alters the excitation/inhibition (E/I) balance toward excitability that increases neural network synchrony. Collectively, our findings reveal how microglial complement-driven synapse elimination may promote both seizure activity and cognitive decline. We suggest that microglia play a central role in the comorbidity of EP and AD, and further exploration of this synaptic pruning pathway in the context of EP may provide promising insights into the treatment of AD and EP comorbidity.Graphic abstractHighlightsTranscriptomic analysis across epilepsy (EP) and Alzheimer’s disease (AD) models and patient datasets revealed a conserved immune gene module.Shared transcriptomic signatures identified in animal models show strong diagnostic value in both AD and EP patient datasets.Tyrobp-Trem2-C1qmicroglial synaptic pruning pathway was identified as a central shared molecular mechanism across model and patient datasets.Computational modeling revealed that excessive synaptic pruning, particularly of inhibitory synapses, alters E/I balance toward excitability and increases synchrony in neural network.
WAVE1 and WAVE2 facilitate human papillomavirus-driven actin polymerization during cellular entry
Authors: Fernandez DJ , Cheng Stephanie , Prins Ruben , Hamm-Alvarez Sarah F , Kast W Martin 
Published: October 2024

AbstractHuman Papillomavirus Type 16 (HPV16) is an etiological agent of human cancers that requires endocytosis to initiate infection. HPV16 entry into epithelial cells occurs through a non-canonical endocytic pathway that is actin-driven, but it is not well understood how HPV16-cell surface interactions trigger actin reorganization in a way that facilitates entry. This study provides evidence that Wiskott-Aldrich syndrome protein family verprolin-homologous proteins 1 and 2 (WAVE1 and WAVE2) are molecular mediators of the actin polymerization that facilitates HPV endocytosis and intracellular trafficking. We demonstrate through post-transcriptional gene silencing and genome editing that WAVE1 and WAVE2 are critical for efficient HPV16 infection, and that restoration of each in knockout cells rescues HPV16 infection. Cells lacking WAVE1, WAVE2, or both, internalize HPV16 at a significantly reduced rate. Analysis of fluorescently labeled cells exposed to HPV16 and acquired by confocal fluorescence microscopy revealed that HPV16, WAVE1, WAVE2, and actin are all colocalized at the cellular dorsal surface. We also found that HPV16 stimulates WAVE1 and WAVE2-mediated cellular dorsal surface filopodia formation during the viral endocytic process. Taken together, this study provides evidence that the HPV endocytic process needed for infection is controlled by actin reorganization into filopodial protrusions and that this process is mediated by WAVE1 and WAVE2.Author SummaryHuman Papillomavirus (HPV) is the most common sexually transmitted infection in the United States. While its mode of entry into cells has yet to be fully described, extensive studies indicate HPV entry occurs via a macropinocytosis-like pathway. Interestingly, more than 10 viruses enter cells via macropinocytosis-like entry, with no two viruses utilizing identical factors for entry. It is unclear whether these viruses are entering cells via the same pathway, or if the term “macropinocytosis” describes a subset of endocytic pathways. One unifying feature of entry for each of these viruses is their requirement of actin polymerization. In this study, we identify the cellular factors necessary for actin polymerization to participate in HPV endocytosis. The findings of this study are of importance to the field of virology as they may extend to the infection of other viruses. It is also of interest in cancer studies as macropinocytosis has been associated with the scavenging of nutrients and methuosis, a form of cell death in cancer cells that occurs from over- scavenging. Nanoparticle delivery can also occur via macropinocytosis. Therefore, the contribution of WAVE proteins to macropinocytosis and macropinocytosis-like endocytic events is informative to a broad audience.
Cross-Species Analysis Reveals No Universal Programmed Aging Mechanism: Insights from Single-Cell Transcriptomics in Zebrafish, Fruit Fly, and Nematode
Authors: Niu Yunhui , Wu Dongzhi , Zhang Sen , Zheng Hong , Wu Xing , Chen Jiansong , Zhang Yunze , Zhang Tao , He Wenhui , Chen Li 
Published: October 2024

AbstractThe question of whether aging follows a universal programmed process has been a topic of debate for a long time. Previous arguments, either supporting or refuting programmed aging, were mainly based on different evolutionary biology theories. In this study, we analysed single-cell RNA sequencing data from zebrafish, fruit fly, and nematode at various stages of development to explore gene co-expression modules across these species. We successfully identified a co-expression module related to ribosomal protein genes that is shared across the early development stages in multiple tissues of all three species. However, we did not find any cross-species shared gene co-expression modules related to aging. Further analysis of gene regulatory networks (GRNs) demonstrated that although certain aging-related genes are conserved, their regulatory mechanisms vary significantly between species. These findings suggest that aging is not governed by a conserved universal program but rather by species-specific adaptations to damage and environmental conditions.
A mitochondrial redox switch licenses the onset of morphogenesis in animals
Authors: Kahlon Updip , Ricca Francesco Dalla , Pillai Saraswathi J. , Olivetta Marine , Tharp Kevin M. , Jao Li-En , Dudin Omaya , McDonald Kent , Aydogan Mustafa G. 
Published: October 2024

AbstractEmbryos undergo pre-gastrulation cleavage cycles to generate a critical cell mass before transitioning to morphogenesis. The molecular underpinnings of this transition have traditionally centered on zygotic chromatin remodeling and genome activation1,2, as their repression can prevent downstream processes of differentiation and organogenesis. Despite precedents that oxygen depletion can similarly suspend development in early embryos3–6, hinting at a pivotal role for oxygen metabolism in this transition, whether there is abona fidechemical switch that licenses the onset of morphogenesis remains unknown. Here we discover that a mitochondrial oxidant acts as a metabolic switch to license the onset of animal morphogenesis. Concomitant with the instatement of mitochondrial membrane potential, we found a burst-like accumulation of mitochondrial superoxide (O2-) during fly blastoderm formation.In vivochemistry experiments revealed that an electron leak from site IIIQoat ETC Complex III is responsible for O2-production. Importantly, depleting mitochondrial O2-fully mimics anoxic conditions and, like anoxia, induces suspended animation prior to morphogenesis, but not after. Specifically, H2O2, and not ONOO-, NO, or HO•, can single-handedly account for this mtROS-based response. We demonstrate that depleting mitochondrial O2-similarly prevents the onset of morphogenetic events in vertebrate embryos and ichthyosporea, close relatives of animals. We postulate that such redox-based metabolic licensing of morphogenesis is an ancient trait of holozoans that couples the availability of oxygen to development, conserved from early-diverging animal relatives to vertebrates.
Structure, dynamics and evolution of theCandida albicansmulti-drug resistance ABC transporter CDR1
Authors: Shin Jeeeun , Jin Ruitao , Gall Barnabas , Jobichen Chacko , Jackson Colin , Rug Melanie , Corry Ben , Brock Joseph 
Published: October 2024

AbstractThe pleiotropic drug resistance transporter Cdr1 fromCandida albicansplays a crucial role in antifungal resistance. Here, we present high-resolution cryo-electron microscopy structures ofC. albicansCdr1 in multiple functional states: nucleotide-bound, substrate-bound, and apo forms. The 3.5 Å resolution structure of Cdr1 in complex with ATP and ADP reveals the molecular details of its asymmetric nucleotide-binding sites (NBS), with ATP bound to the deviant NBS1 and ADP to the canonical NBS2. Structures of Cdr1 bound to rhodamine 6G (3.4 Å) and Oregon Green 488 (3.5 Å) in complex with these nucleotides elucidate the pleiotropic substrate-binding pocket and highlight how nucleotide exchange drives conformational change required for transport. Additionally, we determined a 3.7 Å resolution structure of Cdr1 in the detergent LMNG without nucleotides, as well as a 3.5 Å resolution structure with nucleotides but no substrate, representing an apo state. We complemented these structural insights with molecular dynamics simulations to understand substrate binding dynamics, ancestral sequence reconstruction to trace the evolution of key functional motifs, and analysis of clinical isolates from sequence databases to identify potential resistance-associated variations. Comparison of these structures provides new insights into the conformational changes associated with the transport cycle of this asymmetric ABC transporter, revealing how ATP binding at the deviant NBS1 allosterically regulates the canonical NBS2, driving ATPase activity. This work significantly advances our understanding of the molecular mechanisms underlying multidrug resistance in pathogenic fungi and provides a structural and evolutionary framework for the rational design of Cdr1 inhibitors to combat antifungal resistance.
Socio-Demographic Biases in Medical Decision-Making by Large Language Models: A Large-Scale Multi-Model Analysis
Authors: Omar Mahmud , Soffer Shelly , Agbareia Reem , Bragazzi Nicola Luigi , Apakama Donald U. , Horowitz Carol R , Charney Alexander W , Freeman Robert , Kummer Benjamin , Glicksberg Benjamin S , Nadkarni Girish N , Klang Eyal 
Published: October 2024

AbstractLarge language models (LLMs) are increasingly integrated into healthcare but concerns about potential socio-demographic biases persist. We aimed to assess biases in decision-making by evaluating LLMs’ responses to clinical scenarios across varied socio-demographic profiles. We utilized 500 emergency department vignettes, each representing the same clinical scenario with differing socio-demographic identifiers across 23 groups—including gender identity, race/ethnicity, socioeconomic status, and sexual orientation—and a control version without socio-demographic identifiers. We then used Nine LLMs (8 open source and 1 proprietary) to answer clinical questions regarding triage priority, further testing, treatment approach, and mental health assessment, resulting in 432,000 total responses. We performed statistical analyses to evaluate biases across socio-demographic groups, with results normalized and compared to control groups. We find that marginalized groups—including Black, unhoused, and LGBTQIA+ individuals—are more likely to receive recommendations for urgent care, invasive procedures, or mental health assessments compared to the control group (p < 0.05 for all comparisons). High-income patients were more often recommended advanced diagnostic tests such as CT scans or MRI, while low-income patients were more frequently advised to undergo no further testing. We observed significant biases across all models, both proprietary and open source regardless of the model’s size. The most pronounced biases emerged in mental health assessment recommendations. LLMs used in medical decision-making exhibit significant biases in clinical recommendations, perpetuating existing healthcare disparities. Neither model type nor size affects these biases. These findings underscore the need for careful evaluation, monitoring, and mitigation of biases in LLMs to ensure equitable patient care.
Cortical iron-related markers are elevated in mild Traumatic Brain Injury: An individual-level quantitative susceptibility mapping study
Authors: Essex Christi A. , Overson Devon K. , Merenstein Jenna L. , Truong Trong-Kha , Madden David J. , Bedggood Mayan J. , Morgan Catherine , Murray Helen , Holdsworth Samantha J. , Stewart Ashley W. , Faull Richard L. M. , Hume Patria , Theadom Alice , Pedersen Mangor 
Published: October 2024

ABSTRACTQuantitative susceptibility mapping (QSM) has been applied to map brain iron distribution after mild traumatic brain in-jury (mTBI), to understand properties of neural tissue which may be related to microstructural damage. However, mTBI is a heterogeneous injury associated with microstructural brain changes, and ‘traditional’ group-wise statistical approaches may lead to a loss of clinically relevant information, as subtle individual-level changes can be obscured by averages and confounded by within-group variability. More precise and individualised approaches are needed to characterise mTBI better and elucidate potential cellular mechanisms to improve intervention and rehabilitation. To address this issue, we build individualised profiles of regional positive (iron-related) magnetic susceptibility across 34 bilateral cortical regions of interest (ROIs) following mTBI. Healthy population templates were constructed for each cortical area using standardised z-scores derived from 25 age-matched male controls, serving as a reference against which z-scores of 35 males with acute (< 14 days) sports-related mTBI (sr-mTBI) were compared. Secondary analyses sensitive to cortical depth and curvature were also generated to approximate the location of iron accumulation in the cortical laminae and the effect of gyrification. Our primary analyses indicated that approximately one-third (11/35; 31%) of mTBI participants exhibited elevated positive sus-ceptibility indicative of abnormal iron profiles relative to the healthy control population, a finding that was mainly concentrated in ROIs within the temporal lobe. Injury severity was significantly higher (p < 0.01) for these mTBI participants than their iron-normal counterparts, suggesting a link between injury severity, symptom burden, and elevated cortical iron. Secondary analyses of cortical depth and curvature profiles revealed abnormal iron accumulation in 83% (29/35) of mTBI participants, enabling better localisation of mTBI-related changes in iron content to specific loci within each ROI and identifying effects that may be more subtle and lost in ROI-wise averaging. Our findings suggest that individualised approaches can further elucidate the clinical relevance of iron in mTBI. Differences in injury severity between iron-normal and iron-abnormal mTBI participants highlight not only why precise investigation is required to understand the link between objective changes in the brain and subjective symptomatology, but also identify iron as a candidate biomarker for tissue damage after mTBI.
Antibiotic lethality dictates mycobacterial infection outcomes
Authors: Jovanovic Alexander , Bright Frederick K. , Sadeghi Ahmad , Wicki Basil , Muñiz Santiago E. Caño , Toprak Sara , Sauteur Loïc , Rodoni Anna , Wüst Andreas , Lupien Andréanne , Borrell Sonia , Grogono Dorothy M. , Wheeler Nicole , Dehio Philippe , Nemeth Johannes , Pargger Hans , Thomson Rachel , Bell Scott C. , Gagneux Sebastien , Bryant Josephine M. , Peng Tingying , Diacon Andreas , Floto R. Andres , Abanto Michael , Boeck Lucas 
Published: October 2024

ABSTRACTAntibiotic development and treatment focus on bacterial growth inhibition, often with limited success. Here, we introduce Antimicrobial Single-Cell Testing (ASCT), an advanced imaging strategy to assess bacterial killing in real-time. By tracking 140 million bacteria and generating over 20,000in vitrotime-kill curves, we can predictMycobacterium tuberculosistreatment outcomes in mice and humans and link strain-specific survival (drug tolerance) inMycobacterium abscessusto clinical responses. Using ASCT, we reveal drug tolerance as a distinct genetically encoded bacterial trait conserved across drugs with similar targets and, via genome-wide associations, uncover molecular mechanisms that govern bacterial killing. This study establishes the technical framework andin vivovalidation for large-scale bacterial killing assessments to advance our understanding of bacterial survival, antibiotic development and clinical decision-making.
Sequence determinants of intron-mediated enhancement learned from thousands of random introns
Authors: Kowal Emma J. K. , Sakai Yuta , McGurk Michael P. , Pasetsky Zoe J. , Burge Christopher B. 
Published: October 2024

AbstractSpliceosomal introns are a ubiquitous feature of eukaryotic genes, whose presence often boosts the expression of their host gene, a phenomenon known as intron-mediated enhancement (IME). IME has been noted across diverse genes and organisms, but remains mysterious in many respects. For example, how does intron sequence affect the magnitude of IME? In this study, we performed a massively parallel reporter assay (MPRA) to assess the effect of varying intron sequence on gene expression in a high-throughput manner, in human cells, using tens of thousands of synthetic introns with natural splice sites and randomized internal sequence. We observe that most random introns splice efficiently and enhance gene expression as well as or better than fully natural introns. Nearly all introns stimulate gene expression ∼eight-fold above an intronless control, at both mRNA and protein levels, suggesting that the primary mechanism acts to increase mRNA levels. IME strength is positively associated with splicing efficiency and with the intronic content of poly-uridine stretches, which we confirm using reporter experiments. Together, this work elucidates sequence determinants of IME from tens of thousands of random introns, and confirms that enhancement of gene expression is a general property of splicing.
Phytochemical characterization and antimicrobial properties ofAzadirachtin indicaagainst selected bacterial human pathogens
Authors: Eka Idorenyin Idorenyin , Wilson Idongesit Udo , Ibuot Aniefon Alphonsus 
Published: October 2024

AbstractThe study was conducted to assess the phytochemical and antibacterial potentials ofAzadirechtin indicaagainstSalmonella typhi, Staphylococcus aureusandPseudomonas aeruginosausing microbiological techniques. Ethanol and water were used to extract the active components from theAzadirechtin indicaleaves.Salmonella typhishowed range of inhibition zone from 11mm to 16mm at 50% to 90% concentrations of the plant ethanolic extract.Staphylococcus aureushad a range of inhibition zone from 10mm to 13mm at 50% to 90 % concentrations of the plant ethanolic extract andPseudomonas aeruginosahad a range of inhibition zone from 10mm to 12mm at 50% to 90% concentrations of the plant ethanolic extract. Ethanol extract showed greater antibacterial activity against the test organisms when compared with the aqueous extract. Preliminary screening of phytochemicals in the leaf extract ofAzadirechtin indicarevealed the presence of alkaloids (7.376mg/100g), saponins (12.041mg/100g), flavonoids (2.641mg/100g), tannins (3.431mg/100g) and cyannogenic glycosides (0.952 mg/100g). This result provides scientific support forAzadirechtin indicato be further investigated and used as drug.
Structural enzymological studies of the long chain fatty acyl-CoA synthetase FadD5 from themce1operon ofMycobacterium tuberculosis
Authors: Rahman Mohammad Asadur , Dalwani Subhadra , Venkatesan Rajaram 
Published: October 2024

AbstractThe cell wall ofMycobacterium tuberculosis(Mtb), the causative agent of tuberculosis, is rich in complex lipids. During intracellular stage, Mtb depends on lipids for its survival. Mammalian cell-entry (Mce) 1 complex encoded by themce1operon is a mycolic/fatty acid importer.mce1operon also encodes a putative fatty acyl-CoA synthetase (FadD5; Rv0166), potentially responsible for the activation of fatty acids imported through the Mce1 complex by conjugating them to Coenzyme A. Here we report that FadD5 is associated to membrane although it can be purified as a soluble dimeric protein. ATP and CoA binding influence FadD5’s stability and conformation. Enzymatic studies with fatty acids of varying chain lengths show that FadD5 prefers long chain fatty acids as substrates. X-ray crystallographic studies on FadD5 and its variant reveal that the C-terminal domain (∼100 residues) is cleaved off during crystallization. Noteworthy, deletion of this domain renders FadD5 completely inactive. SAXS studies, however, confirm the presence of full length FadD5 as a dimer in solution. Further structural analysis and comparisons with homologs provide insights on the possible mode of membrane association and fatty acyl tail binding.
Improved limits on
n→n′
transformation from the Spallation Neutron Source
Authors: Gonzalez Francisco M. , Rock Cary , Broussard Leah J. , DeBeer-Schmitt Lisa , Frost Matthew J. , Heilbronn Lawrence , Iverson Erik B. , Kamyshkov Yuri , Kline Michael , Milstead David , Powers Devyn , Rogers James , Santoro Valentina , Vavra Shaun 
Published: October 2024

Conversions between neutrons n and dark matter candidate sterile neutrons n′ have been proposed as a mechanism for baryon number B violation. In the case that there is a small mass difference Δm between the n and the n′ states, oscillations can be induced by compensating for Δm with a magnetic field. A search for such neutron oscillations was performed at the Spallation Neutron Source by looking for anomalous neutron transmission through a strongly absorbing cadmium wafer inside of a 6.6 T magnet. The approach described here saw no regenerated neutrons above background, which provides an improved limit for neutron–sterile neutron transformations for a range of Δm between 0.1 and 1000 neV.

Published by the American Physical Society
2024