bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiviral defence systems in the rumen microbiome
Authors: Sáenz Johan S. , Rios-Galicia Bibiana , Seifert Jana 
Published: April 2024

AbstractThe continuous interaction between phages and their respective hosts has resulted in the evolution of multiple bacterial immune mechanism. However, the diversity and prevalence of antiviral defence systems in complex communities is still unknown. We therefore investigated the diversity and abundance of viral defence systems in 3038 high-quality bacterial and archaeal genomes from the rumen. In total, 14,241 defence systems and 31,948 antiviral-related genes were identified. Those genes represented 114 unique system types grouped into 49 families. We observed a high prevalence of defence systems in the genomes. However, the number of defence systems, defence system families and systems density varied widely from genome to genome. Additionally, the number of defence system correlated positively with the number of defence systems families and the genome size. Restriction modification, Abi and cas system families were the most common, but many rare systems were present in only 1% of the genomes. Antiviral defence systems are prevalent and diverse in the rumen, but only a few are dominant, indicating that most systems are rarely present. However, the collection of systems throughout the rumen may represent a pool of mechanisms that can be shared by different members of the community and modulate the phage-host interaction.ImportancePhages may act antagonistically at the cell level but have a mutualistic interaction at the microbiome level. This interaction shapes the structure of microbial communities and is mainly driven by defence mechanism. However, the diversity of such mechanism is larger than previously thought. Because of that, we described the abundance and diversity of antiviral defence system of a collection of genomes, from the rumen. While defence mechanisms seem to be prevalent among bacteria and archaea, only a few were common. This suggests that most of these defence mechanisms are not present in many rumen microbes but could be shared among different members of the microbial community. This aligned with the ’pan-immune system’ model, which appears to be common across different environments.
Structural Models for a Series of Allosteric Inhibitors of IGF1R Kinase
Authors: Verma Jyoti , Vashisth Harish 
Published: April 2024

AbstractThe allosteric inhibition of Insulin-like Growth Factor Receptor 1 Kinase (IGF1RK) is a potential strategy to overcome selectivity barriers in targeting receptor tyrosine kinases. We constructed structural models of a series of 12 indole-butyl-amine derivatives which have been reported as allosteric inhibitors of IGF1RK. We further studied dynamics and interactions of each inhibitor in the allosteric pocket via all-atom explicit-solvent molecular dynamics (MD) simulations. We discovered that a bulky carbonyl substitution at the R1 indole ring is structurally unfavorable for inhibitor binding in the IGF1RK allosteric pocket. Moreover, we found that the most potent derivative (termed C11) acquires a distinct conformation, forming an allosteric pocket channel with better shape complementarity and interactions with the receptor. In addition to a hydrogen bonding interaction with V1063, the cyano derivative C11 forms a stable hydrogen bond with M1156, which is responsible for its unique binding conformation in the allosteric pocket. Our findings show that the position of chemical substituents at the R1 indole ring with different pharmacophore features influences molecular interactions and binding conformations of the indole-butyl-amine derivatives, hence dramatically affecting their potencies. Our results provide a structural framework for the design of allosteric inhibitors with improved affinities and specificities against IGF1RK.
BindCompare: A Novel Integrated Protein-Nucleic Acid Binding Analysis Platform
Authors: Mahableshwarkar Pranav , Shum Jasmine , Ray Mukulika , Larschan Erica 
Published: April 2024

AbstractSummaryAdvanced genomic technologies have generated thousands of Protein-Nucleic acid binding datasets that have the potential to identify testable gene regulatory network (GRNs) models governed by combinatorial associations between factors. Transcription factors (TFs) and RNA binding proteins (RBPs) are nucleic-acid binding proteins regulating gene expression and are key drivers of GRN function. However, the combinatorial mechanisms by which the interactions between specific TFs and RBPs regulate gene expression remain largely unknown. To identify possible combinations of TFs and RBPs that may function together, developing a tool that compares and contrasts the interactions of multiple TFs and RBPs with nucleic acids to identify their common and unique targets is necessary. Therefore, we introduce BindCompare, a user-friendly tool that can be run locally to predict new combinatorial relationships between TFs and RBPs. BindCompare can analyze data from any organism with known annotated genome information and outputs files with detailed genomic locations and gene information for targets for downstream analysis. Overall, BindCompare is a new tool that identifies TFs and RBPs that co-bind to the same DNA and/or RNA loci, generating testable hypotheses about their combinatorial regulation of target genes.Availability and ImplementationBindCompare is an open-source package that is available on the Python Packaging Index (PyPI,https://pypi.org/project/bindcompare/) with the source code available on GitHub (https://github.com/pranavmahabs/bindcompare). Complete documentation for the package can be found at both of these links.
Single-cell RNA-Seq data have prevalent blood contamination but can be rescued by Originator, a computational tool separating single-cell RNA-Seq by genetic and contextual information
Authors: Unjitwattana Thatchayut , Huang Qianhui , Yang Yiwen , Tao Leyang , Yang Youqi , Zhou Mengtian , Du Yuheng , Garmire Lana X. 
Published: April 2024

AbstractSingle-cell RNA sequencing (scRNA-Seq) data from complex human tissues have prevalent blood cell contamination during the sample preparation process. They may also comprise cells of different genetic makeups. These issues demand rigorous preprocessing and filtering prior to the downstream functional analysis, to avoid biased conclusions due to cell types not of interest. Towards this, we propose a new computational framework, Originator, which deciphers single cells by the genetic origin and separates immune cells of blood contamination from those of expected tissue-resident cells. We demonstrate the accuracy of Originator at separating immune cells from the blood and tissue as well as cells of different genetic origins, using a variety of artificially mixed and real datasets. We show the prevalence of blood contamination in scRNA-Seq data of many tissue types. We alert the significant consequences if failing to adjust for these confounders, using scRNA-Seq data of pancreatic cancer and placentas as examples.
EMERGENCE OF OXA-48-LIKE CARBAPENEMASES IN CLINICAL ENTEROBACTERALES FROM GUATEMALA
Authors: Mazariegos Carmen J. , Quinto Anna , Herrera Andres , Barillas Sara E. , Valenzuela Laura R. , Ordóñez Gabriela , Sierra Paola , Arevalo Carolina , Seah Christine , Melano Roberto G. 
Published: April 2024

ABSTRACTFive isolates (fourKlebsiella pneumoniaeand oneEscherichia coli) displaying resistance to piperacillin/tazobactam and ertapenem and reduced susceptibility to imipenem were found positive forblaOXA-48-like genes (blaOXA-181andblaOXA-232) carried on plasmids described previously. Although twoK. pneumoniaerecovered in 2020 were clonally related, the results suggest thatblaOXA-48-like genes have been circulating in Guatemala since 2019. This is the first report of this type of carbapenemase in Central America.
Transiently restricting individual amino acids protectsD. melanogasteragainst multiple stressors
Authors: Fulton Tahlia L. , Johnstone Joshua J. , Tan Jing J. , Balagopal Krithika , Dedman Amy , Johnson Travis K. , Chan Andrea Y. , Mirth Christen K. , Piper Matthew D. W. 
Published: April 2024

AbstractNutrition and resilience are linked, though it is not yet clear how diet confers stress resistance or the breadth of stressors that it can protect against. We have previously shown that transiently restricting an essential amino acid can extend lifespan and also protect against nicotine exposure inDrosophila melanogaster, raising the possibility that amino acid restriction is geroprotective because of elevated detoxification capacity. Here, we sought to characterise the nature of this dietary mediated protection, and determine whether it was sex, amino acid, and/or nicotine specific. When we compared between sexes, we found that isoleucine deprivation increases female, but not male, nicotine resistance. Surprisingly, we found that this protection afforded to females was not replicated by dietary protein restriction and was instead specific to individual amino acid restriction. Other studies have documented methionine or leucine restriction conferring stress resistance, though we previously found that individually depriving them did not increase nicotine resistance. We therefore wondered whether reducing the severity of restriction of these amino acids could confer nicotine resistance. This was true for methionine restriction, and we found that flies fed a diet containing 25% methionine for 7 days protected against subsequent nicotine poisoning (∼30% longer lived than controls with all amino acids). However, when dietary leucine was altered, nicotine resistance changed, but no single diet was protective. To understand whether these beneficial effects of diet were specific to nicotine or were generalisable across stressors, we pre-treated with amino acid restriction diets and exposed them to other types of stress. We did not find any diets that protected against heat stress or infection with the bacteriumEnterococcus faecalis. However, we found that some of the diets that protected against nicotine also protected against oxidative and starvation stress, and improved survival following cold shock. Interestingly, we found that a diet lacking isoleucine was the only diet to protect against all these stressors. These data point to isoleucine as a critical determinant of robustness in the face of environmental challenges.
Viscoelastic high-molecular-weight hyaluronic acid hydrogels support rapid glioblastoma cell invasion with leader-follower dynamics
Authors: Carvalho Emily M. , Ding Erika A. , Saha Atul , Weldy Anna , Zushin Peter-James H. , Stahl Andreas , Aghi Manish K. , Kumar Sanjay 
Published: April 2024

AbstractHyaluronic acid (HA), the primary component of brain extracellular matrix, is increasingly used to model neuropathological processes, including glioblastoma (GBM) tumor invasion. While elastic hydrogels based on crosslinked low-molecular-weight (LMW) HA are widely exploited for this purpose and have proven valuable for discovery and screening, brain tissue is both viscoelastic and rich in high-MW (HMW) HA, and it remains unclear how these differences influence invasion. To address this question, hydrogels comprised of either HMW (1.5 MDa) or LMW (60 kDa) HA are introduced, characterized, and applied in GBM invasion studies. Unlike LMW HA hydrogels, HMW HA hydrogels relax stresses quickly, to a similar extent as brain tissue, and to a greater extent than many conventional HA-based scaffolds. GBM cells implanted within HMW HA hydrogels invade much more rapidly than in their LMW HA counterparts and exhibit distinct leader-follower dynamics. Leader cells adopt dendritic morphologies, similar to invasive GBM cells observed in vivo. Transcriptomic, pharmacologic, and imaging studies suggest that leader cells exploit hyaluronidase, an enzyme strongly enriched in human GBMs, to prime a path for followers. This study offers new insight into how HA viscoelastic properties drive invasion and argues for the use of highly stress-relaxing materials to model GBM.
Determining the Young’s Modulus of the Bacterial Cell Envelope
Authors: Lee Junsung , Jha Karan , Harper Christine E. , Zhang Wenyao , Ramsukh Malissa , Bouklas Nikolaos , Dörr Tobias , Chen Peng , Hernandez Christopher J. 
Published: April 2024

ABSTRACTBacteria experience substantial physical forces in their natural environment including forces caused by osmotic pressure, growth in constrained spaces, and fluid shear. The cell envelope is the primary load-carrying structure of bacteria, but the mechanical properties of the cell envelope are poorly understood; reports of Young’s modulus of the cell envelope ofE. coliare widely range from 2 MPa to 18 MPa. We have developed a microfluidic system to apply mechanical loads to hundreds of bacteria at once and demonstrated the utility of the approach for evaluating whole-cell stiffness. Here we extend this technique to determine Young’s modulus of the cell envelope ofE. coliand of the pathogensV. choleraeandS. aureus.An optimization-based inverse finite element analysis was used to determine the cell envelope Young’s modulus from observed deformations. The Young’s modulus of the cell envelope was 2.06 ± 0.04 MPa forE. coli, 0.84 ± 0.02 MPa forE. colitreated with a chemical known to reduce cell stiffness, 0.12 ± 0.03 MPa forV. cholerae, and 1.52 ± 0.06 MPa forS. aureus(mean ± SD). The microfluidic approach allows examining hundreds of cells at once and is readily applied to Gram-negative and Gram-positive organisms as well as rod-shaped and cocci cells, allowing further examination of the structural causes of differences in cell envelope Young’s modulus among bacteria species and strains.
Structural insights into the human P2X1 receptor and ligand interactions
Authors: Bennetts Felix M. , Venugopal Hariprasad , Glukhova Alisa , Mobbs Jesse I. , Ventura Sabatino , Thal David M. 
Published: April 2024

AbstractThe P2X1 receptor is a trimeric ligand-gated ion channel that plays a pivotal role in urogenital and immune functions. Consequently, it offers numerous potential indications for novel drug treatments. Unfortunately, the progress of drug discovery targeting the P2X1 receptor has been impeded by the absence of structural information. To gain deeper insights into the binding site of the P2X1 receptor, we employed cryogenic electron microscopy (cryo-EM) to elucidate the structures of the P2X1 receptor in both an ATP-bound desensitised state and an NF449-bound closed state. NF449 is a potent P2X1 receptor antagonist and engages with the receptor in a distinctive manner. To gain insights into the molecular machinery governing receptor inhibition and activation and better understand P2X1 receptor ligand subtype selectivity, critical P2X1 receptor residues involved in ligand binding were mutated. Radioligand binding assays with [3H]-α,β-methylene ATP and intracellular calcium influx were employed to assess the effect of these mutations on ligand binding and receptor activation, thereby validating key ligand-receptor interactions. This research expands our understanding of the P2X1 receptor structure at a molecular level and opens new avenues forin silicodrug design targeting the P2X1 receptor.
Effects of spontaneous mutations on survival and reproduction ofDrosophila serratainfected with Drosophila C virus
Authors: Mendel Bonita M. , Asselin Angelique K. , Johnson Karyn N. , McGuigan Katrina 
Published: April 2024

AbstractThe impact of selection on host immune function genes has been widely documented. However, it remains essentially unknown how mutation influences the quantitative immune traits that selection acts on. Applying a classical mutation accumulation (MA) experimental design inDrosophila serrata, we found the mutational variation in susceptibility (median time of death, LT50) to Drosophila C virus (DCV) was of similar magnitude to that reported for intrinsic survival traits. However, the mean LT50 did not change as mutations accumulated, suggestion no directional bias in mutational effects. Maintenance of genetic variance in immune function is hypothesised to be influenced by pleiotropic effects on immunity and other traits that contribute to fitness. To investigate this, we assayed female reproductive output for a subset of MA lines with relatively long or short survival times under DCV infection. Longer survival time tended to be associated with lower reproductive output, suggesting that mutations affecting susceptibility to DCV had pleiotropic effects on investment in reproductive fitness. Further studies are needed to uncover the general patterns of mutational effect on immune responses and other fitness traits, and to determine how selection might typically act on new mutations via their direct and pleiotropic effects.
Effectiveness of BNT162b2 XBB vaccine in the US Veterans Affairs Healthcare System
Authors: Caffrey Aisling R. , Appaneal Haley J. , Lopes Vrishali V. , Puzniak Laura , Zasowski Evan J. , Jodar Luis , LaPlante Kerry L. , McLaughlin John M. 
Published: April 2024

ABSTRACTData evaluating effectiveness of XBB.1.5-adapted vaccines against JN.1-related endpoints are scarce. We performed a nationwide test-negative case-control study within the US Veterans Affairs Healthcare System to estimate vaccine effectiveness (VE) of BNT162b2 XBB.1.5-adapted vaccine compared to not receiving an XBB vaccine of any kind against COVID-19 hospitalization, emergency department or urgent care visits (ED/UC), and outpatient visits. Between September 25, 2023 and January 31, 2024, effectiveness was 24–35% during a period of JN.1 predominance and 50–61% during XBB predominance across all outcomes. VE within 60 days of vaccination during the likely JN.1 period was 32% (95% confidence interval 3-52%) against hospitalization, 41% (23–54%) against ED/UC visits, and 31% (1–52%) against outpatient visits. Corresponding VE during the likely XBB period was 62% (44–74%), 52% (37–63%), and 50% (25–66%) by setting, respectively. These data underscore the importance of strain match to maximize the public health impact of COVID-19 vaccination.
Unveiling Associations Between Retinal Microvascular Architecture and Phenotypes Across Thousands of Healthy Subjects
Authors: Shapira Michal , Shilo Smadar , Talmor-Barkan Yeela , Aviv Yaron , Reisner Yotam , Godneva Anastasia , Weinberger Adina , Skaat Alon , Loewenstein Anat , Segal Eran , Rossman Hagai 
Published: April 2024

AbstractFundus imaging has emerged as a powerful tool, allowing high-resolution and non-invasive visualization of the fundus microvasculature. Recent advancements in artificial intelligence (AI) have enabled the quantification of fundus microvascular characteristics, paving the way for the development of predictive markers for systemic conditions. In this study, we characterize the fundus microvasculature among 8467 healthy individuals, aged 40-70 years. We employ a fully automated segmentation tool to calculate 12 distinct vessel measures, including tortuosity density, vessel density, average width, fractal dimension, distance tortuosity, and curvature tortuosity for both arteries and veins. We provide reference values for these measures by age and sex, and explore the associations between these fundus vessel measures and various clinical features. Our analysis reveals numerous significant correlations, including connections between fundus arterial measures and cardiovascular measurements, lipid profile, sleep apnea indices, glycemic profile, body composition, and smoking status. This comprehensive analysis of fundus microvasculature anatomy in a large healthy population contributes to the growing field of oculomics and highlights the potential of fundus imaging for earlier detection and monitoring of systemic diseases such as metabolic syndrome, cardiovascular diseases and sleep disorders.
Analytical Validation of a Highly Accurate and Reliable Next-Generation Sequencing-Based Urine Assay
Authors: Couto-Rodriguez Mara , Danko David C , Wells Heather L , Rey Sol , Jirau Serrano Xavier , Papciak John , Combs P Ford , Fidler Gabor , Mason Christopher E. , Otto Caitlin , O’Hara Niamh B. , Nagy-Szakal Dorottya 
Published: April 2024

ABSTRACTCulture is currently the gold standard for diagnosis of urinary tract infections (UTIs); however, it has poor sensitivity detecting urogenital pathogens, especially if patients have already initiated antimicrobial therapy, or have an infection from an organism that is not commonly cultured. False negative urine culture results can lead to the inappropriate use of antimicrobial therapies or to the progression to urosepsis in high-risk patients. Though not commonly applied to urine in a clinical setting, Next-generation sequencing (NGS)-based metagenomics offer a solution as a precision diagnostic. We developed and validated BIOTIA-ID, a clinical-grade NGS-based diagnostic pipeline for the detection and identification of pathogens in urine specimens. Remnant clinical urine specimens, and contrived sterile urine spiked with common UTI pathogens, were processed with our end-to-end assay including extraction, metagenomic library preparation and Illumina NextSeq 550 sequencing. We trained and applied a bioinformatic pipeline that uses machine learning (ML) to identify pathogens. Internal controls and other quality control measures were incorporated into the process to provide rigorous and standardized results. The assay was tested on 1,470 urine specimens and achieved 99.92% sensitivity, 99.95% specificity and a limit of detection (LoD) of <25,000 CFU/mL and <5,000 CFU/mL in bacteria and fungi, respectively. Discordant results were reconciled with additional testing by target-specific qPCR or 16S Sanger sequencing; 87% of the NGS results were ultimately determined to be the correct result. Overall, these data demonstrate that BIOTIA-ID is a highly accurate clinical-grade diagnostic tool with notable advantages over current culture- based diagnostics.Conflict of Interest StatementMCR, DCD, HLW, SR, XJS, JP, PFC, GF, CEM, CO, NBO and DNS are employees at Biotia, Inc.
A Fast Nonparametric Sampling (NPS) Method for Time-to-Event in Individual-Level Simulation Models
Authors: Garibay-Treviño David U. , Jalal Hawre , Alarid-Escudero Fernando 
Published: April 2024

AbstractPurposeIndividual-level simulation models often require sampling times to events, however efficient parametric distributions for many processes may often not exist. For example, time to death from life tables cannot be accurately sampled from existing parametric distributions. We propose an efficient nonparametric method to sample times to events that does not require any parametric assumption on the hazards.MethodsWe developed a nonparametric sampling (NPS) approach that simultaneously draws multiple time-to-event samples from a categorical distribution. This approach can be applied to univariate and multivariate processes. We discretize the entire period into equal-length time intervals and then derived the interval-specific probabilities. The times to events can then be used directly in individual-level simulation models. We compared the accuracy of our approach in sampling time-to-events from common parametric distributions, including exponential, gamma, and Gompertz. In addition, we evaluated the method’s performance in sampling age to death from US life tables and sampling times to events from parametric baseline hazards with time-dependent covariates.ResultsThe NPS method estimated similar expected times to events from 1 million draws for the three parametric distributions, 100,000 draws for the homogenous cohort, 200,000 draws from the heterogeneous cohort, and 1 million draws for the parametric distributions with time-varying covariates, all in less than a second.ConclusionOur method produces accurate and computationally efficient samples for time-to-events from hazards without requiring parametric assumptions.