bluuebunny/crossref_metadata_2025_split huggingface dataset:
Severus: accurate detection and characterization of somatic structural variation in tumor genomes using long reads
Authors: Keskus Ayse , Bryant Asher , Ahmad Tanveer , Yoo Byunggil , Aganezov Sergey , Goretsky Anton , Donmez Ataberk , Lansdon Lisa A. , Rodriguez Isabel , Park Jimin , Liu Yuelin , Cui Xiwen , Gardner Joshua , McNulty Brandy , Sacco Samuel , Shetty Jyoti , Zhao Yongmei , Tran Bao , Narzisi Giuseppe , Helland Adrienne , Cook Daniel E. , Chang Pi-Chuan , Kolesnikov Alexey , Carroll Andrew , Molloy Erin K. , Pushel Irina , Guest Erin , Pastinen Tomi , Shafin Kishwar , Miga Karen H. , Malikic Salem , Day Chi-Ping , Robine Nicolas , Sahinalp Cenk , Dean Michael , Farooqi Midhat S. , Paten Benedict , Kolmogorov Mikhail 
Published: March 2024

AbstractMost current studies rely on short-read sequencing to detect somatic structural variation (SV) in cancer genomes. Long-read sequencing offers the advantage of better mappability and long-range phasing, which results in substantial improvements in germline SV detection. However, current long-read SV detection methods do not generalize well to the analysis of somatic SVs in tumor genomes with complex rearrangements, heterogeneity, and aneuploidy. Here, we present Severus: a method for the accurate detection of different types of somatic SVs using a phased breakpoint graph approach. To benchmark various short- and long-read SV detection methods, we sequenced five tumor/normal cell line pairs with Illumina, Nanopore, and PacBio sequencing platforms; on this benchmark Severus showed the highest F1 scores (harmonic mean of the precision and recall) as compared to long-read and short-read methods. We then applied Severus to three clinical cases of pediatric cancer, demonstrating concordance with known genetic findings as well as revealing clinically relevant cryptic rearrangements missed by standard genomic panels.
Screening and characterization of 133 physiologically-relevant environmental chemicals for reproductive toxicity
Authors: Ulaganathan Gurugowtham , Jiang Hui , Canio Noah , Oke Ashwini , Armstrong Sujit Silas , Abrahamsson Dimitri , Varshavsky Julia R. , Lam Juleen , Cooper Courtney , Robinson Joshua F. , Fung Jennifer C. , Woodruff Tracey J. , Allard Patrick 
Published: March 2024

ABSTRACTReproduction is a functional outcome that relies on complex cellular, tissue, and organ interactions that span the developmental period to adulthood. Thus, the assessment of its disruption by environmental chemicals is remarkably painstaking in conventional toxicological animal models and does not scale up to the number of chemicals present in our environment and requiring testing.We adapted a previously described low-throughputin vivochromosome segregation assay usingC. eleganspredictive of reproductive toxicity and leveraged available public data sources (ToxCast, ICE) to screen and characterize 133 physiologically-relevant chemicals in a high-throughput manner. The screening outcome was further validated in a second, independentin vivoassay assessing embryonic viability. In total, 13 chemicals were classified as reproductive toxicants with the two most active chemicals belonging to the large family of Quaternary Ammonium Compounds (QACs) commonly used as disinfectants but with limited available reproductive toxicity data. We compared the results from theC. elegansassay with ToxCastin vitrodata compiled from 700+ cell response assays and 300+ signaling pathways-based assays. We did not observe a difference in the bioactivity or in average potency (AC50) between the top and bottom chemicals. However, the intended target categories were significantly different between the classified chemicals with, in particular, an over-representation of steroid hormone targets for the high Z-score chemicals.Taken together, these results point to the value ofin vivomodels that scale to high-throughput level for reproductive toxicity assessment and to the need to prioritize the assessment of QACs impacts on reproduction.
Characterizing the Binding Mechanism of Sparsentan to the Type-2 Angiotensin II Receptor Using AutoDock Vina
Authors: Geng Peter X. 
Published: March 2024

AbstractThe angiotensin II type-2 receptor (AT2R) is known to have a significant impact on cardiovascular physiology, and the elucidation of its drug interactions is crucial for advancing therapeutic interventions. Sparsentan is an antagonist of angiotensin II, which has received FDA approval due to its demonstrated efficacy in ameliorating proteinuria. While sparsentan exhibits a preferential affinity for angiotensin II type-1 receptor (AT1R) and may primarily target it, DrugBank identifies it as a drug that targets AT2R. Present databases lack detailed structural data on the interaction mechanism between sparsentan and AT2R, leaving no definitive evidence to confirm or refute an interaction with AT2R. This study aimed to explore the potential for an interaction between sparsentan and AT2R. Molecular docking simulations were conducted using AutoDock Vina to predict the binding conformation. The docking parameters were meticulously optimized to ensure the accuracy and reliability of the simulation results. Subsequently, the most stable sparsentan-AT2R complex was determined. We identified four primary types of interactions at the binding site containing hydrogen bonds, hydrophobic interactions, π-cation interactions, and π-stacking, that are likely to contribute to the affinity of sparsentan for AT2R. Our study indicates that sparsentan may potentially interact with AT2R, our results may serve as a valuable reference for elucidating the mechanism of sparsentan action and for guiding the design of AT2R-targeted drugs.
Microdissected tumor cuboids: a microscale cancer model for large-scale testing that retains a complex tumor microenvironment
Authors: Horowitz Lisa F , Rodriguez-Mias Ricard , Chan Marina , Zhu Songli , Gottshall Noah R , Stepanov Ivan , Stiles Casey , Yeung Marcus , Nguyen Tran NH , Lockhart Ethan J , Yeung Raymond S , Villen Judit , Gujral Taranjit S , Folch Albert 
Published: March 2024

AbstractTo bridge the gap between bench and bedside, there is a need for more faithful models of human cancers that can recapitulate key features of the human tumor microenvironment (TME) and simultaneously facilitate large-scale drug tests. Our recently developed microdissection method optimizes the yield of large numbers of cuboidal microtissues (“cuboids”, ∼(400 µm)3) from a tumor biopsy. Here we demonstrate that cuboids from syngeneic mouse tumor models and human tumors retain a complex TME, making them amenable for drug and immunotherapy evaluation. We characterize relevant TME parameters, such as cellular architecture, cytokine secretion, proteomics profiles, and response to drug panels in multi-well arrays. Despite the cutting procedure and the time spent in culture (up to 7 days), the cuboids display strong cytokine expression and drug responses, including to immunotherapy. Overall, our results suggest that cuboids could provide essential therapeutic information for personalized oncology applications and could help the development of TME-dependent therapeutics and cancer disease models, including for clinical trials.
Connectomic reconstruction of a cortical column
Authors: Sievers Meike , Motta Alessandro , Schmidt Martin , Yener Yagmur , Loomba Sahil , Song Kun , Bruett Johannes , Helmstaedter Moritz 
Published: March 2024

ABSTRACTThe cerebral cortex of mammals has long been proposed to comprise unit-modules, so-called cortical columns. The detailed synaptic-level circuitry of such a neuronal network of about 104neurons is still unknown. Here, using 3-dimensional electron microscopy, AI-based image processing and automated proofreading, we report the connectomic reconstruction of a defined cortical column in mouse barrel cortex. The cortical column appears as a structural feature in the connectome, without need for geometrical or morphological landmarks. We then used the connectome for definition of neuronal cell types in the column, to determine intracolumnar circuit modules, analyze the logic of inhibitory circuits, investigate the circuits for combination of bottom-up and top-down signals in the column and the specificity of bottom-up and top-down cortical input, search for higher-order circuit structure within homogeneous neuronal populations, and estimate the degree and symmetry of Hebbian learning in the various connection types. With this, we provide a first column-level connectomic description of the cerebral cortex, the likely substrate for a synaptic-level mechanistic understanding of sensory-conceptual integration and learning.
Mass spectrometry-based top-down proteomics in nanomedicine: proteoform-specific measurement of protein corona
Authors: Sadeghi Seyed Amirhossein , Ashkarran Ali Akbar , Mahmoudi Morteza , Sun Liangliang 
Published: March 2024

AbstractConventional mass spectrometry (MS)-based bottom-up proteomics (BUP) analysis of protein corona [i.e., an evolving layer of biomolecules, mostly proteins, formed on the surface of nanoparticles (NPs) during their interactions with biomolecular fluids] enabled nanomedicine community to partly identify the biological identity of NPs. Such an approach, however, fails pinpoint the specific proteoforms—distinct molecular variants of proteins, which is essential for prediction of the biological fate and pharmacokinetics of nanomedicines. Recognizing this limitation, this study pioneers a robust and reproducible MS-based top-down proteomics (TDP) technique for precisely characterizing proteoforms in the protein corona. Our TDP approach has successfully identified hundreds of proteoforms in the protein corona of polystyrene NPs, ranging from 3-70 kDa, revealing over 20 protein biomarkers with combinations of post-translational modifications, signal peptide cleavages, and/or truncations—details that BUP could not fully discern. This advancement in MS-based TDP offers a more comprehensive and exact characterization of NP protein coronas, deepening our understanding of NPs’ biological identities and potentially revolutionizing the field of nanomedicine.
Single cell approaches define forebrain neural stem cell niches and identify microglial ligands that enhance precursor-mediated remyelination
Authors: Willis Ashleigh , Jeong Danielle , Liu Yunlong , Lithopoulos Marissa A. , Yuzwa Scott , Frankland Paul W. , Kaplan David R. , Miller Freda D. 
Published: March 2024

SUMMARYHere we used single cell RNA-sequencing and single cell spatial transcriptomics to characterize the forebrain neural stem cell (NSC) niche under homeostatic and injury conditions. We define the dorsal and lateral ventricular-subventricular zones (V-SVZ) as two distinct neighborhoods, and show that following white matter injury, dorsal NSCs are locally activated to make oligodendrocytes for remyelination. This activation is coincident with a robust increase in transcriptionally-distinct microglia in the dorsal V-SVZ niche. We modeled ligand-receptor interactions within this changing niche and identified two remyelination-associated microglial ligands, IGF1 and OSM, that promote precursor proliferation and oligodendrogenesis in culture. Infusion of either ligand into the lateral ventricles also enhanced oligodendrogenesis, even in the lateral V-SVZ, where NSCs normally make neuroblasts. These data support a model where gliogenesis versus neurogenesis is determined by the local NSC neighborhood and where injury-induced niche alterations promote NSC activation, local oligodendrogenesis, and likely contribute to myelin repair.
Implantable Bioelectronics for Real-timein vivoRecordings of Enteric Neural Activity
Authors: Boys Alexander J. , Güemes Amparo , Gupta Rohit A. , Uhlig Friederike H. , Hyland Niall P. , Bulmer David C. , Malliaras George G. , Owens Róisín M. 
Published: March 2024

AbstractThe enteric nervous system represents a primary point of contact for a host of factors that influence bodily health and behavior. This division of the autonomic nervous system is unique in both its extensivity, with neurons distributed throughout the gastrointestinal tract from the esophagus to the rectum, and its capability for local information processing. Here, we show the construction and validation of a bioelectronic device to access neural information produced and processed in the gastrointestinal tract. We designed an implant and concurrent surgical procedure to place a neural recording device within the wall of the colon of rodents. We captured complex multi-frequency electrophysiological responses to neural stimulants and show that we can record activity in the context of mechanical activity mimicking gut motility. We also show the feasibility of utilizing this device for recording colonic activity in freely-moving animals. This work represents a step forward in devising functional bioelectronic devices for understanding the complex pathways of the gut-brain axis.One-Sentence SummaryBioelectronic device for real-time collection of neural information from the enteric nervous system.
PhosX: data-driven kinase activity inference from phosphoproteomics experiments
Authors: Lussana Alessandro , Petsalaki Evangelia 
Published: March 2024

AbstractMotivationThe inference of kinase activity from phosphoproteomics data can point to causal mechanisms driving signalling processes and potential drug targets. Identifying the kinases whose change in activity explains the observed phosphorylation profiles, however, remains challenging, and constrained by the manually curated knowledge of kinase-substrate associations. Recently, experimentally determined substrate sequence specificities of human kinases have become available, but robust methods to exploit this new data for kinase activity inference are still missing.ResultsWe present PhosX, a method to estimate differential kinase activity from phosphoproteomics data that combines stateof-the art statistics in enrichment analysis with kinases’ substrate sequence specificity information. Using a large phosphoproteomics dataset with known differentially regulated kinases we show that our method identifies upregulated and downregulated kinases by only relying on the input phosphopeptides’ sequences and intensity changes. We find that PhosX outperforms the currently available approach to perform the same task, and we therefore recommend its use for data-driven kinase activity inference.Availability and implementationPhosX is implemented in Python, open-source under the Apache-2.0 licence, and distributed on the Python Package Index. The code is available on GitHub (https://github.com/alussana/phosx).
CD4+T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model
Authors: Vereertbrugghen Alexia , Pizzano Manuela , Cernutto Agostina , Sabbione Florencia , Keitelman Irene A , Vera Aguilar Douglas , Podhorzer Ariel , Fuentes Federico , Corral-Vázquez Celia , Guzmán Mauricio , Giordano Mirta N , Trevani Analía , de Paiva Cintia S , Galletti Jeremías G 
Published: March 2024

AbstractDry eye disease (DED) is characterized by a dysfunctional tear film in which the cornea epithelium and its abundant nerves are affected by ocular desiccation and inflammation. Although adaptive immunity and specifically CD4+T cells play a role in DED pathogenesis, the exact contribution of these cells to corneal epithelial and neural damage remains undetermined. To address this, we explored the progression of a surgical DED model in wild-type (WT) and T cell-deficient mice. We observed that adaptive immune-deficient mice developed all aspects of DED comparably to WT mice except for the absence of functional and morphological corneal nerve changes, nerve damage-associated transcriptomic signature in the trigeminal ganglia, and sustained tear cytokine levels. Adoptive transfer of CD4+T cells from WT DED mice to T cell-deficient mice reproduced corneal nerve damage but not epitheliopathy. Conversely, T cell-deficient mice reconstituted solely with naive CD4+T cells developed corneal nerve impairment and epitheliopathy upon DED induction, thus replicating the WT DED phenotype. Collectively, our data show that while corneal neuropathy is driven by CD4+T cells in DED, corneal epithelia damage develops independently of the adaptive immune response. These findings have implications for T cell-targeting therapies currently in use for DED.Graphical abstractSignificance StatementDry eye is a frequent ocular disorder in which damage to the corneal epithelium and nerves is triggered by inadequate lubrication. The local CD4+T cell-predominant immune response aggravates ocular surface impairment but the exact contribution of these cells to corneal epithelial and neural disease remains undetermined. Using adoptive transfer of T cells into T cell-deficient mice, trigeminal transcriptomics, and tear cytokine analysis, we delineate the pathogenic role of CD4+T cells, revealing that they drive corneal nerve damage but are dispensable for epithelial disease to develop in response to desiccation. CD4+T cells promote corneal neuropathy possibly by releasing proinflammatory cytokines onto the ocular surface. These findings have implications for T cell-targeting therapies currently used for dry eye.
Taxonize-gb: A tool for filtering GenBank non-redundant databases based on taxonomy
Authors: Sarhan Mohamed S. , Filosi Michele , Maixner Frank , Fuchsberger Christian 
Published: March 2024

AbstractAnalyzing taxonomic diversity and identification in diverse ecological samples has become a crucial routine in various research and industrial fields. While DNA barcoding marker-gene approaches were once prevalent, the decreasing costs of next-generation sequencing have made metagenomic shotgun sequencing more popular and feasible. In contrast to DNA-barcoding, metagenomic shotgun sequencing offers possibilities for in-depth characterization of structural and functional diversity. However, analysis of such data is still considered a hurdle due to absence of taxa-specific databases. Here we present taxonize-gb, a command-line software tool to extract GenBank non-redundant nucleotide and protein databases, related to one or more input taxonomy identifier. Our tool allows the creation of taxa-specific reference databases tailored to specific research questions, which reduces search times and therefore represents a practical solution for researchers analyzing large metagenomic data on regular basis. Taxonize-gb is an open-source command-line Python-based tool freely available for installation athttps://pypi.org/project/taxonize-gb/and on GitHubhttps://github.com/msabrysarhan/taxonize_genbank. It is released under Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
Mutation of negative regulatory geneCEHC1encoding an FBXO3 protein results in normoxic expression ofHYDAgenes inChlamydomonas reinhardtii
Authors: Sun Xiaoqing , LaVoie Matthew , Lefebvre Paul A. , Gallaher Sean D. , Glaesener Anne G. , Strenkert Daniela , Mehta Radhika , Merchant Sabeeha S. , Silflow Carolyn D. 
Published: March 2024

AbstractOxygen is known to prevent hydrogen production in Chlamydomonas, both by inhibiting the hydrogenase enzyme and by preventing the accumulation of HYDA-encoding transcripts. We developed a screen for mutants showing constitutive accumulation ofHYDA1transcripts in the presence of oxygen. A reporter gene required for ciliary motility, placed under the control of theHYDA1promoter, conferred motility only in hypoxic conditions. By selecting for mutants able to swim even in the presence of oxygen we obtained strains that express the reporter gene constitutively. One mutant identified a gene encoding an F-box only protein 3 (FBXO3), known to participate in ubiquitylation and proteasomal degradation pathways in other eukaryotes. Transcriptome profiles revealed that the mutation, termedcehc1-1, leads to constitutive expression ofHYDA1and other genes regulated by hypoxia, and of many genes known to be targets of CRR1, a transcription factor in the nutritional copper signaling pathway.CRR1was required for the constitutive expression of theHYDA1reporter gene incehc1-1mutants. The CRR1 protein, which is normally degraded in Cu-supplemented cells, was stabilized incehc1-1cells, supporting the conclusion thatCEHC1acts to facilitate the degradation of CRR1. Our results reveal a novel negative regulator in theCRR1pathway and possibly other pathways leading to complex metabolic changes associated with response to hypoxia.
Autophagy at Crossroads: Modulating Responses to Combined Heat Stress and Bacterial Infection
Authors: Seybold Heike , Katz Ella , Soroka Yoram , Avin-Wittenberg Tamar 
Published: March 2024

AbstractPlants face diverse stresses in natural environments, necessitating complex responses for survival. Abiotic and biotic stress responses are typically counteractive, posing challenges for breeding crops resilient to multiple stresses. Autophagy, a cellular transport process, plays a vital role in plant stress response, facilitating the degradation of cellular components and enabling nutrient recycling. Here, we asked what the role of autophagy is in combined abiotic (heat) and biotic (bacterial infection byXanthomonas campestrispv.vesicatoria) stress. We introduce a conceptual framework based on assays monitoring autophagy activation, bacterial infection, and metabolic profiling.We observed that heat stress facilitates bacterial growth in an autophagy-dependent manner. Bacterial effectors facilitate this phenomenon. We also demonstrate the engagement of the autophagy-related 8 (ATG8) protein family members in stress-specific activation. Metabolic profiling highlights effector-dependent shifts in nutrient availability during stress, influencing bacterial performance. Our study challenges the assumption that combined stresses are simply the sum of individual responses as exemplified by activation of the autophagic pathway. Instead, it establishes autophagy as a link connecting environmental factors and plant-microbe interactions. Insights for our study can present a novel perspective for designing strategies to enhance crop resilience in the face of multifaceted challenges.