bluuebunny/crossref_metadata_2025_split huggingface dataset:
scEMB: Learning context representation of genes based on large-scale single-cell transcriptomics
Authors: Hsieh Kang-Lin , Chu Yan , Li Xiaoyang , Pilié Patrick G. , Dai Yulin 
Published: September 2024

ABSTRACTBackgroundThe rapid advancement of single-cell transcriptomic technologies has led to the curation of millions of cellular profiles, providing unprecedented insights into cellular heterogeneity across various tissues and developmental stages. This growing wealth of data presents an opportunity to uncover complex gene-gene relationships, yet also poses significant computational challenges.ResultsWe present scEMB, a transformer-based deep learning model developed to capture context-aware gene embeddings from large-scale single-cell transcriptomics data. Trained on over 30 million single-cell transcriptomes, scEMB utilizes an innovative binning strategy that integrates data across multiple platforms, effectively preserving both gene expression hierarchies and cell-type specificity. In downstream tasks such as batch integration, clustering, and cell type annotation, scEMB demonstrates superior performance compared to existing models like scGPT and Geneformer. Notably, scEMB excelsin silicocorrelation analysis, accurately predicting gene perturbation effects in CRISPR-edited datasets and microglia state transition, identifying a few known Alzheimer’s disease (AD) risks genes in top gene list. Additionally, scEMB offers robust fine-tuning capabilities for domain-specific applications, making it a versatile tool for tackling diverse biological problems such as therapeutic target discovery and disease modeling.ConclusionsscEMB represents a powerful tool for extracting biologically meaningful insights from complex gene expression data. Its ability to modelin silicoperturbation effects and conduct correlation analyses in the embedding space highlights its potential to accelerate discoveries in precision medicine and therapeutic development.
Membrane composition and curvature in SNX9-mediated actin polymerization
Authors: Vaishnav Pankti , Shimo Kondo Hanae , Gadsby Jonathan R , Dobramysl Ulrich , Mason Julia , Atherton Joseph , Gallop Jennifer L 
Published: September 2024

AbstractMembrane-binding adaptor protein Sorting nexin 9 (SNX9) contributes to viral uptake and inflammation and is associated with worse outcomes in several cancers. It is involved in endocytosis of epidermal growth factor receptors, β1-integrin and membrane type 1 matrix metalloprotease and in mitochondrial-derived vesicles. Its BAR-PX domain binds phosphatidylinositol phosphates (PIPs) and its SH3 domain interacts with dynamin and N-WASP to stimulate Arp2/3 complex actin polymerization during vesicle scission. Recent complexities have arisen in SNX9’s lipid specificity and its involvement both endocytic and filopodial membrane topologies. Here we use biolayer interferometry, cell-free reconstitution and superresolution microscopy to analyse the activities of SNX9. We find that more SNX9 binds membranes that contain PI(4,5)P2 and PI(3)P compared with PI(3,4)P2, despite having similar affinity, suggesting SNX9 can assemble into different macromolecular arrangements depending on the composition. Actin assembly requires the wider protein and lipid network provided by PX-BAR and SH3 interactions. 3D direct stochastic optical reconstruction microscopy on filopodia-like reconstitutions shows that SNX9 and related protein Transducer of Cdc42 activation-1 (TOCA-1) are competent to form both tubular and plaque-like organizations with the actin machinery. Finally, using cryo-electron tomography we show that SNX9 assembles both branched and bundled actin filaments demonstrating its multifunctional nature.
Interactions among Merlin, Arkadia, and SKOR2 mediate NF2-associated Schwann cell proliferation in human
Authors: Tang Pei-Ciao , Um Seyoung , Mayfield Anderson B. , Bracho Olena R. , Castillo Christian Del , Dinh Christine T. , Dykxhoorn Derek M. , Liu Xue Zhong 
Published: September 2024

SummaryNF2-Related Schwannomatosis (previously referred to as Neurofibromatosis Type 2, or NF2) is a genetic-associated disease resulting from mutations in the gene,NF2.NF2encodes the merlin protein, which acts as a tumor suppressor. Bilateral vestibular schwannoma (VS) is a hallmark of NF2. Although the exactly molecular mechanism mediating NF2-driven schwannomatosis remain unclear, it is known that defective Merlin protein functionality leads to abnormal cell proliferation. Herein, we utilized a human induced pluripotent stem cell (hiPSC)-based Schwann cell (SC) model to investigate the role of merlin in human SCs. SCs were derived from hiPSCs carrying aNF2mutation (c.191 T > C; p. L64P), its isogenic wild-type control cell line, and a NF2 patient-derived hiPSC line. NF2 mutant SCs showed abnormal cellular morphology and proliferation. Proteomic analyses identified novel interaction partners for Merlin – Arkadia and SKOR2. Our results established a new model in which merlin interacts with Arkadia and SKOR2 and this interaction is required for the proper activation of the SMAD-dependent pathway in TGFβ signaling.
Biosynthetic Origin of the Methoxy Group in Quinine and Related Cinchona Alkaloids
Authors: Lombe Blaise Kimbadi , Zhou Tingan , Caputi Lorenzo , Ploss Kerstin , O’Connor Sarah E. 
Published: September 2024

AbstractQuinine is a historically important natural product containing a methoxy group that is assumed to be incorporated at a late pathway stage. Here we show that the methoxy group in quinine and related Cinchona alkaloids is introduced onto the starting substrate tryptamine. Feeding studies with Cinchona plantlets definitively show that 5-methoxytryptamine is utilized as a quinine biosynthetic intermediatein planta. We discover the biosynthetic genes that encode the responsible oxidase and methyltransferase, and we use these genes to reconstitute the early steps of the Cinchona alkaloid biosynthetic pathway inNicotiana benthamianato produce a mixture of methoxylated and desmethoxylated Cinchona alkaloid intermediates. Importantly, we show that the co-occurrence of both tryptamine and 5-methoxytryptamine substrates, along with the substrate promiscuity of downstream pathway enzymes, enable parallel formation of both methoxylated and desmethoxylated alkaloids inCinchona pubescens.
Substrate stiffness dictates unique paths towards proliferative arrest in WI-38 cells
Authors: Kaiser Alyssa M. , Selahi Amirali , Kong Wenjun , Ruby J. Graham 
Published: September 2024

AbstractFinite replicative potential is a defining feature of non-transformed somatic cells, first established by Leonard Hayflickin vitrousing WI-38 human lung fibroblasts. Once proliferative capacity is exhausted due to telomere shortening, cells enter into a state called replicative senescence, which can be avoided through ectopic expression of telomerase reverse transcriptase (hTERT). As WI-38 cells approach replicative arrest, molecular pathways linked to mechanotransduction are induced, including YAP signaling, but the potential interplay between replicative lifespan and the mechanical environment of the cell remains unexplored. Here, we investigate the influence of mechanosensation on the trajectory towards replicative arrest taken by WI-38 cells by growing cells on substrates of varying stiffnesses. Matrix softening slowed proliferation, altered cellular phenotypes, and shortened proliferative lifespan while hTERT expression abrogated or reduced these responses. Our analyses of bulk and single-cell RNA-sequencing and ATAC-sequencing revealed the emergence of a unique G1 transcriptional state on soft substrates, characterized by an AP-1 transcription factor program, which failed to manifest with hTERT expression. Together, these findings reveal how the mechanical environment alters WI-38 cell proliferative lifespan and dictates unique paths towards growth arrest.
Pooled nanoparticle screening using a chemical barcoding approach
Authors: Vaidya Katherine , Regan Michael S. , Lin James , Houle Jenna , Stopka Sylwia A. , Agar Nathalie Y. R. , Hammond Paula T. , Boehnke Natalie 
Published: September 2024

AbstractWe report the development of a small molecule-based barcoding platform for pooled screening of nanoparticle delivery. Using aryl halide-based tags (halocodes), we achieve high-sensitivity detection via gas chromatography coupled with mass spectrometry or electron capture. This enables barcoding and tracking of nanoparticles with minimal halocode concentrations and without altering their physicochemical properties. To demonstrate the utility of our platform for pooled screening, we synthesized a halocoded library of polylactide-co-glycolide (PLGA) nanoparticles and quantified uptake in ovarian cancer cells in a pooled manner. Our findings correlate with conventional fluorescence-based assays. Additionally, we demonstrate the potential of halocodes for spatial mapping of nanoparticles using mass spectrometry imaging (MSI). Halocoding presents an accessible and modular nanoparticle screening platform capable of quantifying delivery of pooled nanocarrier libraries in a range of biological settings.
THOC1 complexes with SIN3A to regulate R-loops and promote glioblastoma progression
Authors: Budhiraja Shreya , Baisiwala Shivani , Cho Sia , Chojak Rafal , Kazi Hasaan A , Stepniak Amelia , Perrault Ella N , Chen Li , Park Cheol H. , Dmello Crismita , Lin Peiyu , Sonabend Adam M , Ahmed Atique U 
Published: September 2024

ABSTRACTGlioblastoma (GBM), the most common and aggressive malignant brain tumor in adults, has a median survival of 21 months. To identify drivers of GBM proliferation, we conducted a CRISPR-knockout screen, which revealed THO Complex 1 (THOC1) as a key driver. Knocking down THOC1 significantly reduced GBM cell viability across patient-derived xenograft (PDX) lines, enhancing survival (p<0.01) in primary PDX models. Conversely, overexpressing THOC1 in non-cancerous cells bolstered viability, decreasing survival and causing tumor engraftment in vivo (p<0.01). Further investigation revealed THOC1’s robust interaction with SIN3A, a histone deacetylase complex. Histone deacetylation has been previously shown to prevent the buildup of R-loops, structures that form normally during transcription but can be lethal in excess. We found that THOC1-knockdown leads to elevated R-loop levels and reduced histone deacetylation levels. Next, to understand the networks specifically regulated by THOC1-mediated R-loop prevention, we conducted unbiased RNA-sequencing on control and THOC1-knockdown GBM cells. We found that THOC1’s role in R-loop prevention primarily affects telomeres, critical regions for cell replication. We further show that THOC1-knockdown results in significantly increased telomeric R-loop levels and shortened telomeres. Ultimately, this study suggests that targeting THOC1 shows promise as a therapeutic strategy to disrupt the delicate R-loop landscape and undermine GBM’s replicative potential.
Distinct roles of the two BRCA2 DNA binding domains in DNA damage repair and replication fork preservation
Authors: Neal Francisco , Li Wenjing , Uhrig Mollie E. , Sharma Neelam , Syed Shahrez , Burma Sandeep , Hromas Robert , Mazin Alexander , Dray Eloise , Libich David , Olsen Shaun , Wasmuth Elizabeth , Zhao Weixing , Sørensen Claus S. , Wiese Claudia , Kwon Youngho , Sung Patrick 
Published: September 2024

AbstractHomologous recombination (HR) is a highly conserved tool for the removal of DNA double-strand breaks (DSBs) and the preservation of stalled and damaged DNA replication forks. Successful completion of HR requires the tumor suppressor BRCA2. Germline mutations in BRCA2 lead to familial breast, ovarian, and other cancers, underscoring the importance of this protein for maintaining genome stability. BRCA2 harbors two distinct DNA binding domains, one that possesses three oligonucleotide/oligosaccharide binding (OB) folds (known as the OB-DBD), and with the other residing in the C-terminal recombinase binding domain (termed the CTRB-DBD) encoded by the last gene exon. Here, we employ a combination of genetic, biochemical, and cellular approaches to delineate contributions of these two DNA binding domains toward HR and the maintenance of stressed DNA replication forks. We show that OB-DBD and CTRB-DBD confer ssDNA and dsDNA binding capabilities to BRCA2, respectively, and that BRCA2 variants mutated in either DNA binding domain are impaired in the ability to load the recombinase RAD51 onto ssDNA pre-occupied by RPA. While the CTRB-DBD mutant is modestly affected for HR, it exhibits a strong defect in the protection of stressed replication forks. In contrast, the OB-DBD is indispensable for both BRCA2 functions. Our study thus defines the unique contributions of the two BRCA2 DNA binding domains in genome maintenance.
Grey Pineapple Mealybug,Dysmicoccus neobrevipesBeardsley: A New Devastating Pest of Tuberose in India
Authors: Firake D. M. , Joshi Sunil , Kumar P. Naveen , Saha T. N. , Dantuluri V.S. Raju , Prasad K. V. 
Published: September 2024

AbstractTuberose (Agave amica) is a highly valued flower crop in India, known for its consistently high returns and ability to thrive in various climatic conditions. Severe outbreaks of the grey pineapple mealybug,Dysmicoccus neobrevipesBeardsley (Hemiptera: Pseudococcidae), have been observed in several villages of the Pune district, Maharashtra (India), since 2021, leading to significant economic losses. This report provides an illustrative morphological diagnosis ofD. neobrevipesand basic information on its field establishment, impact on tuberose crops, nature of the damage and field symptoms etc. Surveys conducted in major tuberose-growing areas of Pune district (Maharashtra) revealed that the mealybug primarily infests the underground and basal portion of tuberose plants, causing stunted growth, drooping, and ultimately death of the plants.D. neobrevipesproduces honeydew, fostering sooty mold growth that impairs photosynthesis, reduces flower yield. It also infests tuberose bulbs, spoiling them in storage. Based on primary scientific literature, this study represents the first scientifically confirmed record ofD. neobrevipesas a new pest of tuberose in India. The ant speciesSolenopsis geminatawas found attending to mealybug colonies, aiding their spread and creating a nuisance for farmers during routine field activities. A total of 87.09% of the surveyed fields (n=62) showed mealybug infestation, ranging from 68% to 97%. Raising awareness among the farmers and implementing regular monitoring in tuberose-growing areas are crucial steps for developing effective management practices and preventing the further spread of this pest to other regions.
Association between national action and trends in antibiotic resistance: an analysis of 73 countries from 2000 to 2023
Authors: Søgaard Jørgensen Peter , Nguyen Thanh Luong , Pehlivanoglu Ege , Klein Franziska , Wernli Didier , Jasovsky Dusan , Aktipis Athena , Dunn Robert R. , Gröhn Yrjo , Lhermie Guillaume , Scott H. Morgan , Klein Eili Y. 
Published: September 2024

AbstractBackgroundThe world’s governments have agreed both global and national actions to address the challenge of antimicrobial resistance. This raises the importance of understanding to what degree national action so far has been effective. Answering this question is challenged by variation in data availability and quality as well as disruptive events such as the COVID-19 pandemic. We investigate the association between a survey of self-reported action based on the first Global Database for Tracking Antimicrobial Resistance (TrACSS) survey and trends in multiple indicators related to the DPSEEA framework leading up to the survey.Methods and findingsWe apply regression methods across 73 countries between actions in 2016 and the trend in indicators of health system development (drivers), antibiotic use (pressures, ABU), absolute rates of resistance (state, ABR) and relative rates of resistance (exposure, Drug Resistance Index, DRI) from 2000 to 2016. We find that action is consistently associated with improved linear and categorical trend in health systems, ABU, ABR and DRI. Reductions are associated with relatively high levels of action (0-4) for ABU (median 2.8, 25-75% quartile 2.6-3.3), ABR (3.0, 2.4-3.4), and DRI (3.5, 3.1-3.6). These associations are robust to the inclusion of other contextual factors such as health system and socio-economic status, human population density, animal production and climate. Since 2016, a majority of both Low-Middle Income Countries (LMICs) and High-Income Countries (HICs) report increased action on repeated questions, while one third of countries report reduced action. The main limitations in interpretation are heterogeneity in data availability and the recency of action.ConclusionsOur findings highlight the importance of national action to address the domestic situation related to antibiotic resistance and indicate the value of both incremental changes in reducing adverse outcomes and the need for high levels of action in delivering improvements.
Ruminant-dense environments increase risk of Shiga toxin-producingEscherichia coliindependently of ruminant contact
Authors: Ward Caitlin , Finical William , Smith Kirk , Rounds Joshua M. , Klumb Carrie A. , Tarr Gillian A.M. 
Published: September 2024

AbstractCattle and other domestic ruminants are the primary reservoirs of O157 and non-O157 Shiga toxin-producingEscherichia coli(STEC). Living in areas with high ruminant density has been associated with excess risk of infection, which could be due to both direct ruminant contact and residual environmental risk, but the role of each is unclear. We investigated whether there is any meaningful risk to individuals living in ruminant-dense areas if they do not have direct contact with ruminants. Using a Bayesian spatial framework, we investigated the association between the density of ruminants on feedlots and STEC incidence in Minnesota from 2010 to 2019, stratified by serogroup and season, and adjusting for direct ruminant contact. For every additional head of cattle or sheep per 10 acres, the incidence of O157 STEC infection increased by 30% (IRR 1.30; 95% CrI 1.18, 1.42) or 135% (IRR 2.35; 95% CrI 1.14, 4.20), respectively, during the summer months. Sheep density was also associated with O157 STEC risk during winter (IRR 4.28; 95% CrI 1.40, 8.92). The risk of non-O157 STEC infection was only elevated in areas with goat operations during summer (IRR 19.6; 95% CrI 1.69, 78.8). STEC risk associated with ruminant density was independent of direct ruminant contact across serogroups and seasons. Our findings demonstrate that living in a ruminant-dense area increases an individual’s risk of O157 and non-O157 STEC infection even without direct ruminant contact, indicating that prevention efforts need to extend to community strategies for averting indirect transmission from local ruminant populations.ImportanceSTEC are zoonotic enteric bacteria responsible for 2.5 million illnesses each year. Infections in young children can be especially devastating, causing hemolytic uremic syndrome (HUS), a debilitating and sometimes fatal form of acute kidney injury. STEC’s primary reservoirs are cattle and other domestic ruminants, and transmission can occur through food, water, animal contact, and person-to-person. Living near ruminants poses a significant risk of STEC infection; however, the proportion of that risk due to direct ruminant contact or other routes of transmission is unknown. Our research demonstrates that direct ruminant contact is a substantial risk irrespective of location, and that individuals living in ruminant-rich regions are at high risk of STEC infection regardless of whether they come into contact with ruminants. These findings indicate a need for multi-pronged prevention efforts that emphasize control of contamination in the environments surrounding ruminant populations, in addition to biosafety precautions when contacting ruminants directly.
Neural correlates of β-lactam exposure in intensive care unit patients: an observational, prospective cohort study
Authors: Zalta Arnaud , Trébuchon Agnès , Daquin Géraldine , Velly Lionel , Leone Marc , Blin Olivier , Lagarde Stanislas , Guilhaumou Romain 
Published: September 2024

BackgroundΒ-Lactam-induced neurotoxicity in critical care patients can compromise clinical outcomes. Despite the growing use of therapeutic drug monitoring (TDM) for β-lactams, clear toxicity thresholds remain undefined, leaving clinicians uncertain about dosing adjustments when adverse effects occur. Identifying a relevant and easily detectable neurophysiological biomarker for β-lactam exposure would improve monitoring and prevent serious complications.MethodsIn a prospective multicenter, non-interventional study, we analysed electroencephalographic (EEG) signals of 56 patients hospitalized in intensive care units (ICUs) receiving continuous infusions of five β-lactams (meropenem, piperacillin/tazobactam, cefepime, cefotaxime, or ceftazidime). We applied a time frequency decomposition on these EEG data to investigate quantitatively the power of neural dynamics across frequencies ranging from 1 to 45 Hz. We used a multivariate pattern decoding method to correlate the β-lactam exposure and Sepsis-related Organ Failure Assessment (SOFA) scores with the neural activity.Resultsβ-lactam exposure correlated with increased β-low γ neural dynamics (20–40 Hz) (p < 0.001, FDR corrected), independent of other clinical factors or medications. Β neural activity was most pronounced in central electrodes (C3 : r = 0.20, p < 0.01; C4 : r = 0.26, p < 0.01) and the right frontal electrode (Fp2 : r = 0.12, p = 0.02). Lower θ-α activity (3.5-5 Hz and 12-18 Hz) was associated with higher SOFA scores (p < 0.001, FDR corrected). No significant correlations were observed between other drugs (opioids, antiseizure medications, psychotropics) and β or θ-α dynamics.ConclusionsThese results suggest that β neural dynamics represent a potential biomarker for β-lactam exposure in ICU patients. They highlight the potential of quantitative EEG and advanced multivariate decoding methods to identify subtle neurophysiological features that are otherwise difficult to detect.Trial registrationClinicalTrials.govIDNCT03339869. Registered 14 September 2017.
Arsenic exposure is associated with elevated sweat chloride concentration and airflow obstruction among adults in Bangladesh: a cross sectional study
Authors: Lee Mi-Sun S. , North Crystal M. , Choudhuri Irada , Biswas Subrata K. , Fleisch Abby F. , Farooque Afifah , Bao Diane , Afroz Sakila , Mow Sadia , Husain Nazmul , Islam Fuadul , Mostafa Md Golam , Biswas Partha Pratim , Ludwig David S. , Digumarthy Subba R. , Hug Christopher , Quamruzzaman Quazi , Christiani David C. , Mazumdar Maitreyi 
Published: September 2024

AbstractArsenic is associated with lung disease and experimental models suggest that arsenic-induced degradation of the chloride channel CFTR (cystic fibrosis transmembrane conductance regulator) is a mechanism of arsenic toxicity. We examined associations between arsenic exposure, sweat chloride concentration (measure of CFTR function), and pulmonary function among 285 adults in Bangladesh. Participants with sweat chloride ≥ 60 mmol/L had higher arsenic exposures than those with sweat chloride < 60 mmol/L (water: median 77.5 µg/L versus 34.0 µg/L,p= 0.025; toenails: median 4.8 µg/g versus 3.7 µg/g,p= 0.024). In linear regression models, a one-unit µg/g increment in toenail arsenic was associated with a 0.59 mmol/L higher sweat chloride concentration, p < 0.001. We found that toenail arsenic concentration was associated with increased odds of airway obstruction (OR: 1.97, 95%: 1.06, 3.67,p= 0.03); however, sweat chloride concentration did not mediate this association. Our findings suggest that sweat chloride concentration may be a novel biomarker for arsenic exposure and also that arsenic likely acts on the lung through mechanisms other than CFTR dysfunction.