bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic clocks, sex markers, and age-class diagnostics in three harvested large mammals
Authors: Czajka Natalie , Northrup Joseph M. , Jones Meaghan J. , Shafer Aaron B.A. 
Published: November 2023

AbstractThe development of epigenetic clocks, or the DNA methylation-based inference of age, is an emerging tool for ageing in free ranging populations. In this study, we developed epigenetic clocks for three species of large mammals that are the focus of extensive management throughout their range: white-tailed deer, black bear, and mountain goat. We quantified differential DNA methylation patterns at over 30,000 cytosine-guanine sites (CpGs) from tissue samples (N=141) of all three species. We used a penalized regression model (elastic net) to build highly explanatory (black bearr= 0.95; white-tailed deerr= 0.99; mountain goatr= 0.97) and robust (black bear Median Absolute Error or MAE = 1.33; white-tailed deer MAE = 0.29; mountain goat MAE = 0.61) models of age (clocks). We also characterized individual CpG sites within each species that demonstrated clear differences in methylation levels between age classes and sex, which can be used to develop a suite of accessible diagnostic markers. Our results demonstrate promising tools for the large-scale estimation of age in wild animals, which have the potential to contribute to wildlife monitoring by providing easily obtainable representations of age structure in managed populations.
Comparingin vitrocytotoxic drug sensitivity in colon and pancreatic cancer using 2D and 3D cell models: contrasting viability and growth inhibition in clinically relevant dose and repeated drug cycles
Authors: Tidwell Tia R. , Røsland Gro , Tronstad Karl Johan , Søreide Kjetil , Hagland Hanne R. 
Published: November 2023

AbstractIn vitrodrug screening that is more translatable to thein vivotumor environment can reduce both time and cost of cancer drug development. Here we address some of the shortcomings in screening and show how treatment with 5-fluorouracil (5-FU) in 2D and 3D culture models of colorectal cancer (CRC) and pancreatic ductal adenocarcinomas (PDAC) give different responses regarding growth inhibition.The sensitivity of the cell lines at clinically relevant 5-FU concentrations was monitored over 4 days of treatment in both 2D and 3D cultures for CRC (SW948 and HCT116) and PDAC (Panc-1 and MIA-Pa-Ca-2) cell lines. The 3D cultures were maintained beyond this point to enable a second treatment cycle at day 14, following the timeline of a standard clinical 5-FU regimen. Evaluation after one cycle did not reveal significant growth inhibition in any of the CRC or PDAC 2D models. By the end of the second cycle of treatment the CRC spheroids reached 50% inhibition at clinically achievable concentrations in the 3D model, but not in the 2D model. The PDAC models were not sensitive to clinical doses even after two cycles. High content viability metrics point to even lower response in the resistant PDAC models.This study reveals the limitations of testing drugs in 2D cancer models and short exposure in 3D models, and the importance of using appropriate growth inhibition analysis. We found that screening with longer exposure and several cycles of treatment in 3D models suggests a more reliable way to assess drug sensitivity.
Adaptive Coding Explains the Paradoxical Relationship between hippocampus size and memory function in Alzheimer’s Disease, Autism Spectrum Disorder, and PTSD
Authors: Stocco Andrea , Hake Holly S. , Leonard Bridget , Li Xinyue 
Published: November 2023

AbstractThe relationship between hippocampal volume and memory function has produced mixed results in neuroscience research, which suggests an additional influencing mechanism. To explore the role of an experience-dependent encoding mechanism, we developed an autoencoder model of the cortex-hippocampus loop and examined how its memory representation is affected by a penalty that prioritizes sparseness. We trained our model with the Fashion MNIST database and a loss function to modify synapses via backpropagation of mean squared recall error. The model exhibited experience-dependent efficient encoding, representing frequently-repeated objects with fewer neurons and smaller loss penalties; representations of similar sizes were found for objects repeated equally. Our findings clarify perplexing results from neurodevelopmental studies by linking increased hippocampal size and memory impairments in autism spectrum disorder (ASD) to decreased sparseness, and explaining dementia symptoms of forgetting with varied neuronal integrity. Our findings propose a novel model that connects observed relationships between hippocampal size and memory to the environmental demands and the underlying biological constraints, contributing to the development of a larger theory on experience-dependent encoding and storage and its failure.Author SummaryThe hippocampus is the brain region where memories are initially formed. A larger hippocampus seems to be associated with better memory performance, but this is not a static relationship; studies suggest that its size might grows with demand (e.g., the need to memorize more information) and that, in certain conditions, larger or smaller volumes of the hippocampus are not associated with better or worse memory. We demonstrate that it is possible to make sense of these findings by assuming that the hippocampus balances the need to correctly remember with the need to minimize resources used to store it, and that the hippocampal size might change as a function of memory demands (the characteristics of the information to memorize) and the underlying biology (e.g., the presence of hippocampal cell damage, or a reduction in hippocampal GABA receptors). We test this hypothesis by building a neural network model; the model correctly predicts existing, puzzling findings in the literature, and can even capture subtle interactions between different phenomena, such as predicting that individuals with Autism Spectrum Disorder would be more susceptible to memory loss in dementia.
Effective High-Accuracy Prediction of Protein Structures from Easily Obtainable Artificial Homologous Sequences by Structure-Stability-Based Selection
Authors: Tang Jinle , Zhang Zhe , Zhan Jian , Zhou Yaoqi 
Published: November 2023

ABSTRACTHigh-resolution protein structure determination by experimental techniques is notoriously costly and labor intensive. This problem is mostly solved with arrival of deep-learning-based computational prediction by AlphaFold2 but only for those proteins with enough naturally occurring homologous sequences. Here, we attempt to close the remaining gap by employing artificially generated, structure-stability-selected homologous sequences as an input for AlphaFold2. We showed that only one round of selection of deeply mutated sequences of a few mutations is sufficient to bring the accuracy of predicted structures to better than 2 Å RMSD from their respective native structures for four of the five proteins experimented. The performance for three out of five proteins is even better than AlphaFold2 with naturally occurring sequences. The only protein with predicted structure of >2 Å (at 2.92 Å) RMSD is due to a fully exposed (i.e., likely flexible) β-hairpin. The result supports a future of determining protein structures at low cost and fast turnaround by integrating simple molecular biology experiments (deep mutational scanning andin vivoorin vitroselection) with high-throughput sequencing. The technique proposed here can be further extended to predict structures of protein complexes as well as proteins with posttranslational modifications.
Charm is a flexible pipeline to simulate chromosomal rearrangements on Hi-C-like data
Authors: Nuriddinov M.A. , Belokopytova P.S. , Fishman V.S. 
Published: November 2023

AbstractIdentifying structural variants (SVs) remains a pivotal challenge within genomic studies. The recent advent of chromosome conformation capture (3C) techniques has emerged as a promising avenue for the accurate identification of SVs. However, development and validation of computational methods leveraging 3C data necessitate comprehensive datasets of well-characterized chromosomal rearrangements, which are presently lacking. In this study, we introduce Charm (https://zenodo.org/doi/10.5281/zenodo.10653353): a robust computational framework tailored for Hi-C data simulation. Our findings demonstrate Charm’s efficacy in benchmarking both novel and established tools for SV detection. Additionally, we furnish an extensive dataset of simulated Hi-C maps, paving the way for subsequent benchmarking endeavors.
Genome sequence and cell biological toolbox of the highly regenerative, coenocytic green feather algaBryopsis
Authors: Ochiai Kanta K. , Hanawa Daiki , Ogawa Harumi A. , Tanaka Hiroyuki , Uesaka Kazuma , Edzuka Tomoya , Shirae-Kurabayashi Maki , Toyoda Atsushi , Itoh Takehiko , Goshima Gohta 
Published: November 2023

AbstractGreen feather algae (Bryopsidales) undergo a unique life cycle in which a single cell repeatedly executes nuclear division without cytokinesis, resulting in the development of a thallus (> 100 mm) with characteristic morphology called coenocyte.Bryopsisis a representative coenocytic alga that has exceptionally high regeneration ability: extruded cytoplasm aggregates rapidly in seawater, leading to the formation of protoplasts. However, the genetic basis of the unique cell biology ofBryopsisremains poorly understood. Here, we present a high-quality assembly and annotation of the nuclear genome ofBryopsissp. (90.7 Mbp, 27 contigs, N50 = 6.7 Mbp, 14,034 protein-coding genes). Comparative genomic analyses indicate that the genes encoding BPL-1/Bryohealin, the aggregation-promoting lectin, are heavily duplicated inBryopsis, whereas homologous genes are absent in other Ulvophycean algae, suggesting the basis of regeneration capability ofBryopsis.Bryopsissp. possesses >30 kinesins but only a single myosin, which differs from other green algae that have multiple types of myosin genes. Consistent with this biased motor toolkit, we observed that the bidirectional motility of chloroplasts in the cytoplasm was dependent on microtubules but not actin inBryopsissp. Unexpectedly, most genes required for cytokinesis in plants are present inBryopsis, including those in the SNARE or kinesin superfamily. Nevertheless, a kinesin crucial for cytokinesis initiation in plants (NACK/Kinesin-7II) is hardly expressed in the coenocytic part of the thallus, possibly underlying the lack of cytokinesis in this portion. The present genome sequence lays the foundation for experimental biology in coenocytic macroalgae.Significance statementThe exceptionally coenocytic body and remarkable regeneration ability ofBryopsishave attracted biologists for years. However, molecular biological tools remain underdeveloped, partly due to the lack of genome information. Here, we report high-quality assembly and annotation of the genome, providing a crucial resource for experimental biology and genomics studies ofBryopsis. Furthermore, comparative genomic analysis reveals a unique gene repertoire that possibly underlies the highly regenerative coenocytic body.
Immuno-informatics Study Identifies Conserved T Cell Epitopes in Non-structural Proteins of Bluetongue Virus Serotypes: Formulation of Computationally Optimized Next-Generation Broad-spectrum Multiepitope Vaccine
Authors: Kolla Harish Babu , Dutt Mansi , Kumar Anuj , Nanjunadappa Roopa Hebbandi , Karakach Tobias , Singh Karam Pal , Kelvin David , Clement Mertens Peter Paul , Umeshappa Channakeshava Sokke 
Published: November 2023

AbstractBluetongue (BT) is a significant arboviral disease affecting sheep, cattle, goats, and wild ruminants, posing serious economic challenges to livestock industry. Control efforts have been hampered by the existence of over 32 distinct BT virus (BTV) serotypes and the absence of broad-spectrum vaccines. Some key non-structural proteins of BTV, including NS1, NS2, and NS3, exhibit notable amino acid sequence conservation. Our findings reveal that mouse MHC class I (MHC-I) CD8+ T cell epitopes are highly conserved in NS1 and NS3, while MHC-II epitopes are prevalent in all the three non-structural NS 1-3 proteins. Similarly, both class I and II Bovine Leukocyte antigen-restricted CD8+ and CD4+ T cell epitopes are conserved within NS1, NS2, and NS3 proteins. To constructin silicobroad-spectrum vaccine, we subsequently screened these conserved epitopes based on antigenicity, allergenicity, toxicity, and solubility. Modeling and Refinement of the 3D structure models of vaccine constructs were achieved using protein modeling web servers. Our analysis revealed promising epitopes that exhibit strong binding affinities with low energies against two TLR receptors (TLR3 and TLR4). To ensure atomic-level stability, we evaluated the docking complexes of epitopes and receptors through all-atom molecular dynamics simulations (MDS). Encouragingly, our 100 nanoseconds MDS showed stable complexes with minimal RMSF values. Our study offers valuable insights into these conserved T cell epitopes as promising candidates for a broad-spectrum BT vaccine. We therefore encourage for their evaluation in animal models and natural hosts to assess their immunogenicity, safety, and efficacy for field use in the livestock.
Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart
Authors: Guevara Amanda , Smith Charlotte E.R. , Caldwell Jessica L. , Ngo Lena , Mott Lilian R. , Lee I-Ju , Tapa inivas , Wang Zhen , Wang Lianguo , Woodward William R. , Ng G. Andre , Habecker Beth A. , Ripplinger Crystal M. 
Published: November 2023

ABSTRACTNicotine is the primary addictive component in tobacco products. Through its actions on the heart and autonomic nervous system, nicotine exposure is associated with electrophysiological changes and increased arrhythmia susceptibility. However, the underlying mechanisms are unclear. To address this, we treated rabbits with transdermal nicotine (NIC, 21 mg/day) or control (CT) patches for 28 days prior to performing dual optical mapping of transmembrane potential (RH237) and intracellular Ca2+(Rhod-2 AM) in isolated hearts with intact sympathetic innervation. Sympathetic nerve stimulation (SNS) was performed at the 1st– 3rdthoracic vertebrae, and β-adrenergic responsiveness was additionally evaluated as changes in heart rate (HR) following norepinephrine (NE) perfusion. Baselineex vivoHR and SNS stimulation threshold were increased in NIC vs. CT (P= 0.004 andP= 0.003 respectively). Action potential duration alternans emerged at longer pacing cycle lengths (PCL) in NIC vs. CT at baseline (P= 0.002) and during SNS (P= 0.0003), with similar results obtained for Ca2+transient alternans. SNS reduced the PCL at which alternans emerged in CT but not NIC hearts. NIC exposed hearts also tended to have slower and reduced HR responses to NE perfusion. While fibrosis was unaltered, NIC hearts had lower sympathetic nerve density (P= 0.03) but no difference in NE content vs. CT. These results suggest both sympathetic hypo-innervation of the myocardium and diminished β-adrenergic responsiveness with NIC. This autonomic remodeling may underlie the increased risk of arrhythmias associated with nicotine exposure, which may be further exacerbated with continued long-term usage.NEW & NOTEWORTHYHere we show that chronic nicotine exposure was associated with increased heart rate, lower threshold for alternans and reduced sympathetic electrophysiological responses in the intact rabbit heart. We suggest that this was due to the sympathetic hypo-innervation of the myocardium and diminished β- adrenergic responsiveness observed following nicotine treatment. Though these differences did not result in increased arrhythmia propensity in our study, we hypothesize that prolonged nicotine exposure may exacerbate this pro-arrhythmic remodeling.
NanoLocz: Image analysis platform for AFM, high-speed AFM and localization AFM
Authors: Heath George R , Micklethwaite Emily , Storer Tabitha 
Published: November 2023

AbstractNanoLocz is an open-source computer program designed for high-throughput automatic processing and single-particle analysis of Atomic Force Microscopy (AFM) image data. High-Speed AFM and Localization AFM (LAFM) enable the study of single molecules with increasingly higher spatiotemporal resolution. However, efficient and rapid analysis of the images and movies produced by these techniques can be challenging, often requiring the use of multiple image processing software applications and scripts. Here, we introduce NanoLocz, an AFM and high-speed AFM analysis program that facilitates various single-particle analysis workflows through a simple, interactive interface. Workflows include but are not limited to: single-particle tracking, single-particle topographic feature analysis, single-molecule LAFM, time-resolved LAFM, and simulation LAFM. The source code and installation instructions for NanoLocz are available athttps://github.com/George-R-Heath/NanoLocz.
Taxometer: Improving taxonomic classification of metagenomics contigs
Authors: Kutuzova Svetlana , Nielsen Mads , Piera Pau , Nybo Nissen Jakob , Rasmussen Simon 
Published: November 2023

AbstractFor taxonomy based classification of metagenomics assembled contigs, current methods use sequence similarity to identify their most likely taxonomy. However, in the related field of metagenomics binning contigs are routinely clustered using information from both the contig sequences and their abundance. We introduce Taxometer, a neural network based method that improves the annotations and estimates the quality of any taxonomic classifier by combining contig abundance profiles and tetra-nucleotide frequencies. When applied to five short-read CAMI2 datasets, it increased the average share of correct species-level contig annotations of the MMSeqs2 tool from 66.6% to 86.2% and reduced the share of wrong species-level annotations in the CAMI2 Rhizosphere dataset two-fold on average for Metabuli, Centrifuge, and Kraken2. Finally, we applied Taxometer to two complex long-read metagenomics data sets for benchmarking taxonomic classifiers. Taxometer is available as open-source software and can enhance any taxonomic annotation of metagenomic contigs.
Genomic sequencing should extend to diverse priority pathogens for effective study and surveillance of antimicrobial resistance: a systematic review of whole-genome sequencing studies from India
Authors: Gheewalla Nazneen , Jagannadham Jaisri , Kutum Rintu , Karve Shraddha 
Published: November 2023

AbstractBackgroundAntimicrobial resistance (AMR) is a public health emergency in many low and middle-income countries, including India. To effectively tackle AMR, we need rapid diagnostics, effective surveillance and new antimicrobial drugs. Whole-genome sequencing of pathogens is the first definite step towards achieving these goals.MethodsIn this work, we review all the studies published till date that report whole-genome sequences of select priority AMR pathogens from India. We searched PubMed and Web of Science databases for the studies that involved whole-genome sequencing of AMR priority pathogens from India. For the top two highly sequenced pathogens,S. typhiandK. pneumoniae, we performed phylogenetic analyses to understand the geo-climatic distribution of genetically diverse strains.ResultsOur search reveals 94 studies that report 2547 unique whole-genome sequences. We find that most sequences are limited to select priority pathogens isolated from a couple of geo-climatic zones of India. Our phylogenetic analyses show that available data does not indicate systematic differences between the genomes of isolates from different geo-climatic zones. Our search also reveals complete absence of travel-related studies tracking possible movement of AMR pathogens within country. Lastly, we find very few studies that sequence AMR pathogens isolated from food, soil or other environments.ConclusionTogether, these observations suggest that lndia should prioritize sequencing of diverse AMR pathogens from clinics as well as from environments and travellers rather than extending the geo-climatic range of already-sequenced pathogens. Our recommendations can be potentially valuable for other low and middle-income countries with limited resources, high prevalence of AMR and diverse geo-climatic conditions.
A fungal endophyte induces local cell-wall mediated resistance in wheat roots against take-all disease
Authors: Chancellor Tania , Smith Daniel P. , Chen Wanxin , Clark Suzanne J. , Venter Eudri , Halsey Kirstie , Carrera Esther , McMillan Vanessa , Canning Gail , Armer Victoria , Hammond-Kosack Kim E. , Palma-Guerrero Javier 
Published: November 2023

AbstractTake-all disease, caused by the ascomycete fungusGaeumannomyces tritici, is one of the most important root diseases of wheat worldwide. The fungus invades the roots and destroys the vascular tissue, hindering the uptake of water and nutrients. Closely related non-pathogenic species in theMagnaporthaceaefamily, such asGaeumannomyces hyphopodioides, occur naturally in arable and grassland soils and have previously been reported to reduce take-all disease in field studies. However, the mechanism of take-all protection has remained unknown. Here, we characterise the root infection biologies ofG. triticiandG. hyphopodioidesin wheat. We investigate the ultrastructure of previously described “subepidermal vesicles” (SEVs), produced in wheat roots by non-pathogenicG. hyphopodioides,but not by pathogenicG. tritici.We show thatG. hyphopodioidesSEVs share key characteristics of fungal resting structures; containing a greater number of putative lipid bodies and a significantly thickened cell wall compared to infection hyphae. We demonstrate that take-all control is achieved via local but not systemic host changes in response to priorG. hyphopodioidesroot colonisation. A time-course wheat RNA sequencing analysis revealed extensive transcriptional reprogramming inG. hyphopodioidescolonised tissues, characterised by a striking downregulation of key cell-wall related genes, including cellulose synthase (CESA), and xyloglucan endotransglucosylase/hydrolase (XTH) genes. In the absence of take-all resistant wheat cultivars or non-virulentG. triticistrains, studying closely related non-pathogenicG. hyphopodioidesprovides a much-needed avenue to elucidate take-all resistance mechanisms in wheat.