bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-HLA Class II Antibodies Are the Most Resistant to Desensitization in Crossmatch-positive Living-donor Kidney Transplantations: A Patient Series
Authors: de Weerd Annelies E. , Roelen Dave L. , Betjes Michiel G.H. , Clahsen-van Groningen Marian C. , Haasnoot Geert W. , Kho Marcia M.L. , Reinders Marlies E.J. , Roodnat Joke I. , Severs David , Karahan Gonca E. , van de Wetering Jacqueline 
Published: August 2024

Background.
In HLA-incompatible kidney transplantation, the efficacy of desensitization in terms of anti-HLA antibody kinetics is not well characterized. We present an overview of the course of anti-HLA antibodies throughout plasma exchange (PE) desensitization in a series of crossmatch-positive patients.

Methods.
All consecutive candidates in the Dutch HLA-incompatible kidney transplantation program between November 2012 and January 2022 were included. The eligibility criteria were a positive crossmatch with a living kidney donor and no options for compatible transplantation. Desensitization consisted of 5–10 PE with low-dose IVIg.

Results.
A total of 16 patient-donor pairs were included. Patients had median virtual panel-reactive antibody of 99.58%. Cumulative donor-specific anti-HLA antibody (cumDSA) mean fluorescence intensity (MFI) was 31 399 median, and immunodominant DSA (iDSA) MFI was 18 677 for class I and 21 893 for class II. Median anti-HLA antibody MFI response to desensitization was worse in class II as compared with class I (P < 0.001), particularly for HLA-DQ. Class I cumDSA MFI decreased 68% after 4 PE versus 53% in class II. The decrease between the fifth and the 10th PE sessions was modest with 21% in class I versus 9% in class II. Antibody-mediated rejection occurred in 85% of patients, with the iDSA directed to the same mismatched HLA as before desensitization, except for 3 patients, of whom 2 had vigorous rebound of antibodies to repeated mismatches (RMMs). Rebound was highest (86%) in RMM-DSA with prior grafts removed (transplantectomy n = 7), lower (39%) in non-RMM-DSA (n = 30), and lowest (11%) for RMM-DSA with in situ grafts (n = 5; P = 0.018 for RMM-DSA transplantectomy versus RMM-DSA graft in situ). With a median follow-up of 59 mo, 1 patient had died resulting in a death-censored graft survival of 73%.

Conclusions.
Patients with class II DSA, and particularly those directed against HLA-DQ locus, were difficult to desensitize.
Endogamy and high prevalence of deleterious mutations in India: evidence from strong founder events
Authors: Machha Pratheusa , Gopalan Amirtha , Elangovan Yamini , Mouli Veeravalli Sarath Chandra , Sowpati Divya Tej , Thangaraj Kumarasamy 
Published: August 2024

AbstractFounder events influence recessive diseases in highly endogamous populations. Several Indian populations have experienced significant founder events and maintained strict endogamy. Genomic studies in Indian populations often lack in addressing clinical implications of these phenomena. We performed whole-exome sequencing of 281 individuals from four South Indian groups to evaluate population-specific disease causing mutations associated with founder events. Our study revealed a high inbreeding rate of 59% across the groups. We identified ∼29.2% of the variants to be exclusive to a single population and uncovered 1,284 novel exonic variants, underscoring the genetic underrepresentation of Indian populations. Among these, 23 predicted as deleterious were found in heterozygous state, suggesting they may be pathogenic in a homozygous state and are common in the endogamous groups. Approximately 40-68% of the identified pathogenic variants showed significantly higher occurrence rates. Pharmacogenomic analysis revealed distinct allele frequencies in CYP450 and non-CYP450 gene variants, highlighting heterogeneous drug responses and associated risks. We report a high prevalence of ankylosing spondylitis in Reddys, linked toHLA-B*27:04allele and strong founder effect. Our findings emphasize the need for expanded genomic research in understudied Indian populations to elucidate disease risk and medical profiles, eventually aiming towards precision medicine and mitigating disease burden.
StrIDR: a database of intrinsically disordered regions of proteins with experimentally resolved structures
Authors: Majila Kartik , Viswanath Shruthi 
Published: August 2024

AbstractMotivationIntrinsically disordered regions (IDRs) of proteins exist as an ensemble of conformations, and not as a single structure. Existing databases contain extensive, experimentally derived annotations of intrinsic disorder for millions of proteins at the sequence level. However, only a tiny fraction of these IDRs are associated with an experimentally determined protein structure. Moreover, even if a structure exists, parts of the disordered regions may still be unresolved.ResultsHere we organizeStructures ofIntrinsicallyDisorderedRegions (StrIDR), a database of IDRs confirmedviaexperimental or homology-based evidence, resolved in experimentally determined structures. The database can provide useful insights into the dynamics, folding, and interactions of IDRs. It can also facilitate computational studies on IDRs, such as those using molecular dynamics simulations and/or machine learning.AvailabilityStrIDR is available athttps://isblab.ncbs.res.in/stridr. The web UI allows for downloading PDB structures and SIFTS mappings of individual entries. Additionally, the entire database can be downloaded in a JSON format. The source code for creating and updating the database is available athttps://github.com/isblab/stridr.
Metagenomic insights into an enigmatic gammaproteobacterium that is important for carbon cycling in cave ecosystems worldwide
Authors: Jones Daniel S. , Green Katelyn M. , Brown Abigail , Havlena Zoë E. , Best Mackenzie B. , Northup Diana E. , Mainiero Maurizio , Auch Benjamin 
Published: August 2024

AbstractCaves are windows into the subsurface through which we can directly evaluate the microbiological processes responsible for rock weathering and biogeochemical cycling in more expansive areas of Earth’s subsurface. However, many cave microbial communities are dominated by microorganisms from uncultivated groups with unknown genomic capabilities that cannot be resolved from marker gene surveys alone. An example of this is a genus ofGammaproteobacteriaknown as “wb1-P19”, which are ubiquitous and abundant in rRNA gene surveys from limestone and volcanic caves around the world. We recovered a nearly complete metagenome-assembled genome (MAG) representing a population of wb1-P19 from Lehman Caves in Great Basin National Park, Nevada, USA, and used it to identify additional MAGs representing this group from the Frasassi Caves in Italy and in publicly available databases. Although members of the wb1-P19 group have often been thought to be autotrophs that oxidize inorganic nitrogen compounds, we show that wb1-P19 are actually obligate or facultative methanotrophs capable of aerobic and anaerobic growth. Based on genomic classification, wb1-P19 are members of upland soil cluster γ (USCγ; part of the newly proposed order “CandidatusMethyloligotrophales”), and are likely important for methane consumption and carbon cycling in caves and other subterranean ecosystems globally.
Industrializing yeast as a drug repurposing platform for inherited metabolic diseases
Authors: Thevandavakkam Mathuravani A. , Long Natalie E. , Roel Briannna M. , Kantautas Kristin A. , Zakin Shiri , Duesterberg Van , Perlstein Ethan O. 
Published: August 2024

SummaryThe development of therapies for rare diseases, particularly inherited metabolic disorders (IMDs), faces significant challenges due to the high cost and lengthy timelines involved. This study presents a yeast-based platform for drug repurposing that capitalizes on the remarkable similarity between yeast and human cellular pathways. This platform enables rapid, cost-effective screening of potential therapeutic compounds for rare diseases, offering a quick turnaround compared to traditional drug development processes. Utilizing a TargetMol library of comprising ∼50% nutraceuticals, our pipeline accelerates translation of promising drug repurposing hits into patient observational studies in as little as 6 months. We demonstrate the efficacy of this platform through three case studies in the context of IMDs, showcasing its potential to uncover novel treatments and reduce the time and expense associated with bringing therapies to patients with rare diseases.
tombRaider– improved species and haplotype recovery from metabarcoding data through artefact and pseudogene exclusion
Authors: Jeunen Gert-Jan , Fernandes Kristen , Dowle Eddy , Kroos Gracie C. , Mauvisseau Quentin , Torma Michal , Miller Allison K. , Lamare Miles , Gemmell Neil 
Published: August 2024

ABSTRACTEnvironmental DNA metabarcoding has revolutionized ecological surveys of natural systems. By amplifying and sequencing small gene fragments from environmental samples containing complex DNA mixtures, scientists are now capable of exploring biodiversity patterns across the tree of life in a time-efficient and cost-effective manner. However, the accuracy of species and haplotype identification can be compromised by sequence artefacts and pseudogenes. Despite various strategies developed over the years, effective removal of artefacts remains challenging and inconsistent data reporting standards hinder reproducibility in eDNA metabarcoding experiments. To address these issues, we introducetombRaider, an open-source command line software program (https://github.com/gjeunen/tombRaider) and R package (https://github.com/gjeunen/tombRaider_R) to remove artefacts and pseudogenes from metabarcoding data post clustering and denoising.tombRaiderfeatures a modular algorithm capable of evaluating multiple criteria, including sequence similarity, co-occurrence patterns, taxonomic assignment, and the presence of stop codons. We validatedtombRaiderusing various published data sets, including mock invertebrate communities, air eDNA from a zoo, and salmon haplotypes from aquatic eDNA. Our results demonstrate thattombRaidereffectively removed a higher proportion of artefacts while retaining authentic sequences, thus enhancing the accuracy and reliability of eDNA-derived diversity metrics. This user-friendly software program not only improves data quality in eDNA metabarcoding studies, but also contributes to standardised reporting practices, an aspect currently lacking in this emerging research field.
Differential Tractography: A Biomarker for Neuronal Function in Neurodegenerative Disease
Authors: Lewis Connor J. , Vardar Zeynep , Kühn Anna Luisa , Johnston Jean M. , D’Souza Precilla , Gahl William A. , Shazeeb Mohammed Salman , Tifft Cynthia J. , Acosta Maria T. 
Published: August 2024

AbstractGM1 gangliosidosis is an ultra-rare inherited neurodegenerative lysosomal storage disorder caused by biallelic mutations in theGLB1gene. GM1 is uniformly fatal and has no approved therapies, although clinical trials investigating gene therapy as a potential treatment for this condition are underway. Novel outcome measures or biomarkers demonstrating the longitudinal effects of GM1 and potential recovery due to therapeutic intervention are urgently needed to establish efficacy of potential therapeutics. One promising tool is differential tractography, a novel imaging modality utilizing serial diffusion weighted imaging (DWI) to quantify longitudinal changes in white matter microstructure. In this study, we present the novel use of differential tractography in quantifying the progression of GM1 alongside age-matched neurotypical controls. We analyzed 113 DWI scans from 16 GM1 patients and 32 age-matched neurotypical controls to investigate longitudinal changes in white matter pathology. GM1 patients showed white matter degradation evident by both the number and size of fiber tract loss. In contrast, neurotypical controls showed longitudinal white matter improvements as evident by both the number and size of fiber tract growth. We also corroborated these findings by documenting significant correlations between cognitive global impression (CGI) scores of clinical presentations and our differential tractography derived metrics in our GM1 cohort. Specifically, GM1 patients who lost more neuronal fiber tracts also had a worse clinical presentation. This result demonstrates the importance of differential tractography as an important biomarker for disease progression in GM1 patients with potential extension to other neurodegenerative diseases and therapeutic intervention.
A systematic evaluation of highly variable gene selection methods for single-cell RNA-sequencing
Authors: Zhao Ruzhang , Lu Jiuyao , Zhou Weiqiang , Zhao Ni , Ji Hongkai 
Published: August 2024

AbstractBackgroundSelecting highly variable features is a crucial step in most analysis pipelines of single-cell RNA-sequencing (scRNA-seq) data. Despite numerous methods proposed in recent years, a systematic understanding of the best solution is still lacking.ResultsHere, we systematically evaluate 47 highly variable gene (HVG) selection methods, consisting of 21 baseline methods developed based on different data transformations and mean-variance adjustment techniques and 26 hybrid methods developed based on mixtures of baseline methods. Across 19 diverse benchmark datasets, 18 objective evaluation criteria per method, and 5,358 analysis settings, we observe that no single baseline method consistently outperforms the others across all datasets and criteria. However, hybrid methods as a group robustly outperform individual baseline methods. Based on these findings, a new HVG selection approach, mixture HVG selection (mixHVG), that incorporates top-ranked features from multiple baseline methods is proposed as a better solution to HVG selection. An open source R packagemixhvgis developed to enable convenient use of mixHVG and its integration into users’ data analysis pipelines.ConclusionOur benchmark study not only provides a systematic comparison of existing methods, leading to a better HVG selection solution, but also creates a pipeline and resource consisting of diverse benchmark data and criteria for evaluating new methods in the future.
Integrating microscopy and transcriptomics from individual uncultured eukaryotic plankton
Authors: Gatt Catherine , Xie Yike , Wahi Kanu , Johansson Emma M. V. , Zanini Fabio 
Published: August 2024

ABSTRACTEukaryotic plankton comprises organisms as diverse as diatoms and pelagic larvae, covering a wide spectrum of shapes, molecular compositions, and ecological functions. Plankton research is often approached using either optical methods, especially for taxonomic purposes, or genomics, which excels at describing the biochemistry of microbial communities. This technological dichotomy hampers efforts to link the morpho-optical properties of each species with its genetic and biomolecular makeup, leading to fragmented information and limited reproducibility. Methods to simultaneously acquire multimodal, i.e. optical and genetic, information on planktonic organisms would provide a connection between organismal appearance and function, improve taxonomic prediction, and strengthen ecological analysis. Here we present Ukiyo-e-Seq, an approach to generate paired optical and transcriptomic data from individual eukaryotic plankton. We performed Ukiyo-e-Seq on 66 microscopic organisms from Coogee, NSW, Australia and assembled transcriptomic contigs using a merge-split strategy. While overall phylogenetic heterogeneity spanned hundreds of taxa, diversity in individual wells was low, enabling accurate classification of both microbial plankton and marine larvae. We then combined Ukiyo-e-Seq with AlphaFold 3, a protein language model, and could confidently infer (i) the joint structure and interactions of 34 photosynthesis proteins from a singleChaetocerosdiatom, and (ii) the cellular and developmental functions of novel proteins highly expressed in one trout larva. In summary, Ukiyo-e-Seq is a precise tool to connect morphological and genetic information of eukaryotic plankton.
Development and evaluation of an online training program for palliative care in India
Authors: Passi Varun Raj , Warrier Sreedevi , Balu Rajalekshmi , Sunilkumar MM , Sharma Parth 
Published: August 2024

ABSTRACTObjectivePalliative care training at the undergraduate level is poor in India. With the need for palliative care rising in India and globally, it is possible to train physicians in resource-limited settings in palliative care via online training programs owing to ease of access and convenience. However, there is limited evidence available from India on the development and implementation of such a training program. This study aims to describe the development of an online training program offered by the Trivandrum Institute of Palliative Sciences (TIPS), Kerala, and the impact of the program on the confidence of physicians in managing various palliative care needs of their patients.Material and MethodsThe course was developed by an interdisciplinary expert team from TIPS. The course content was made keeping in mind the local sociocultural factors in India and was peer-reviewed by two external experts. The program was started in 2018 and updated and revised over the years. Currently, the program has 20 sessions, each lasting for 90 minutes. The course content was disseminated using project-ECHO’s tele mentoring model. To assess the impact of the training program, self-reported change in confidence from twenty-two batches of physicians, trained from January 2020 to August 2023. Feedback from participants was also assessed to identify areas of improvement in the training program.ResultsA total of 1159 physicians were trained during the study period. At the end of the course, 51.2% of the participants completed the evaluation survey and had a statistically significant (p<0.05) improvement in confidence in pain, gastrointestinal symptoms and breathlessness management, morphine prescription, and psychosocial communication. The duration of each session and the entire course was reported to be ideal by 88.6% and 87.9% of participants, respectively.ConclusionOur results show that online training can be effectively used to build confidence in physicians in managing various palliative care needs.
Functional maps of a genomic locus reveal confinement of an enhancer by its target gene
Authors: Eder Mathias , Moene Christina J.I. , Dauban Lise , Leemans Christ , van Steensel Bas 
Published: August 2024

AbstractGenes are often activated by enhancers located at large genomic distances. The importance of this positioning is poorly understood. By relocating promoter-reporter constructs into >1,000 alternative positions within a single locus, we dissected the positional relationship between the mouseSox2gene and its distal enhancer. This revealed an intricate, sharply confined activation landscape, in which the nativeSox2gene occupies an optimal position for its activation. Deletion of the gene relaxes this confinement and broadly increases reporter activity. Surprisingly, the confining effect of theSox2gene is partially conferred by its ∼1 kb coding region. Our local relocation approach provides high-resolution functional maps of a genomic locus and reveals that a gene can strongly constrain the realm of influence of its enhancer.
Comparative analysis of trans-chromosomic rodent models reveals improved somatic hypermutation and class-switch recombination in rats
Authors: Satofuka Hiroyuki , Abe Satoshi , Moriwaki Takashi , Okada Akane , Kazuki Kanako , Hamamichi Shusei , Hiratsuka Masaharu , Hirabayashi Masumi , Nakamura Kazuomi , Sakuma Tetsushi , Yamamoto Takashi , Baba Yoshihiro , Tomizuka Kazuma , Kazuki Yasuhiro 
Published: August 2024

AbstractHumanized rodent models, especially humanization of genetic/genomic components involved in immunity have significantly advanced our understanding of human immune system. Here, we utilized trans-chromosomic (Tc) technology to generate a TC-mAb rat model that stably harbors a mouse artificial chromosome carrying full-length human immunoglobulin (Ig) heavy and kappa light chain genes (IGHK-NAC) in a rat Ig knockout background. In contrast with TC-mAb mice, serum human IgG concentration was found higher than IgM. Number of lymphocytes was recovered, and B cell population in the spleen was normal. Remarkably, repertoire analysis revealed similarities between the model and human PBMCs; somatic hypermutation and class-switch recombination also more closely resembled humans. Furthermore, immunization resulted in generation of antigen-specific human antibodies. Collectively, our strategy to generate both rat and mouse models through introduction of the identical IGHK-NAC offers unprecedented opportunities to comprehensively evaluate genomic regulation and its outcomes associated with genomic sequences and host-derived protein factors.
A sleep disturbance method by novel objects in the home cage to minimize stress
Authors: Egebjerg Christine , Kolmos Mie Gunni , Abelson Klas , Kornum Birgitte Rahbek 
Published: August 2024

AbstractBackgroundThe increasing prevalence of low sleep quality is a significant issue, particularly among adolescents, necessitating a deeper understanding of its biological consequences. In sleep research, various protocols are used for sleep deprivation or disturbance, each presenting its own set of confounding factors crucial to consider.New MethodWe developed a standardized seven-day sleep disturbance (SD) protocol using daily four-hour exposures to novel objects to minimize rodent stress. Objects were selected and characterized for wake-promoting properties, and exposure timing was structured to reduce variability and enhance experimental reliability and reproducibility.ResultsDuring the four hours of SD, the mice were efficiently sleep-deprived on the first and seventh day of SD. Thus, the selected objects efficiently sleep restricted the mice. On the first day of SD, the protocol induced sleep deprivation effect when measured over 24h, but by the seventh day, the mice recovered the sleep loss. Thus, this method is a sub-chronic sleep disturbance and not sleep deprivation. Fecal corticosterone concentrations remained unchanged during the seven days of SD.Comparison with existing methodsThis approach reduced the risk of stress through voluntary rather than forced wakefulness. Previously, novel objects have been exchanged randomly during mouse sleep initiation causing protocol variability and very frequent disturbances. Our protocol minimizes this by introducing the novel object in a structured manner.ConclusionWe effectively disturbed the sleep of the mice during seven days without inflicting substantial stress. We further demonstrate the value of validating the efficiency of an SD protocol with 24h recordings.HighlightsStandardized sleep disruption method by object exposure in miceMice are sleep-restricted during the four-hour SD intervention all 7 daysMice habituate to a subchronic sleep deprivation setup by recovering sleep outside of the SD periodFecal corticosterone samples showed no difference before and after SD intervention
Diarylamidine activation of a brachiopod DEG/ENaC/ASIC channel
Authors: Martí-Solans Josep , Børve Aina , Hejnol Andreas , Lynagh Timothy 
Published: August 2024

AbstractDiarylamidines are a group of widely used small molecule drugs. One common use of diarylamidines is their pharmacological inhibition of ligand-gated cation channels, including tetrameric ionotropic glutamate receptors and trimeric degenerin/epithelial sodium channel channel/acid-sensing ion channels (DEG/ENaC/ASICs). Here, we discover a DEG/ENaC/ASIC channel from the brachiopod (lamp shell)Novocrania anomala, at which diarylamidines act as agonists. The channel is closely related to bile acid-gated, pH-gated, and peptide-gated channels but is not activated by such stimuli. We describe activation of the channel by diminazene, DAPI, and pentamidine, examine several biophysical and pharmacological properties, and briefly explore the molecular determinants of channel activity with site-directed mutagenesis. We term this channel the diarylamidine-activated sodium channel (DiaaNaC).