bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expanding kinetoplastid genome annotation through protein structure comparison
Authors: Trinidad-Barnech J.M. , José Sotelo-Silveira J.R. , Fernandez Do Porto D. , Smircich P. 
Published: August 2024

AbstractKinetoplastids belong to the supergroup Discobids, an early divergent eukaryotic clade. Although the amount of genomic information on these parasites has grown substantially, assigning gene functions through traditional sequence-based homology methods remains challenging. Recently, significant advancements have been made inin silicoprotein structure prediction and algorithms for rapid and precise large-scale protein structure comparisons. In this work, we developed a protein structure-based homology search pipeline (ASC, Annotation by Structural Comparisons) and applied it to annotate all kinetoplastid proteins available in TriTrypDB. Our pipeline assigned functional annotation to 23,000 hypothetical proteins across all 35 kinetoplastid species in the database. Among these, we identified ubiquitous eukaryotic proteins that had not been previously detected in kinetoplastid genomes. The resulting annotations (KASC, Kinetoplastid Annotation by Structural Comparison) are openly available to the community (kasc.fcien.edu.uy).Author SummaryKinetoplastids are a group of parasites that cause severe diseases in the poorest regions of the world. Despite the increasing amount of genomic information available on these parasites, predicting the function of many of their genes using traditional methods has been difficult. Recently, there have been significant advancements in predicting protein structures and comparing them on a large scale. In this study, we created a new method called ASC (Annotation by Structural Comparisons) to find functions for all the kinetoplastid genes listed in the TriTrypDB database. Our strategy successfully assigned functions to 23,000 proteins in kinetoplastids. Among these, we discovered important proteins found in all eukaryotes that had not been previously identified in kinetoplastids. This information (KASC, Kinetoplastid Annotation by Structural Comparison) is freely available at kasc.fcien.edu.uy.
Mixed outcomes in recombination rates after domestication: Revisiting theory and data
Authors: Bursell Madeline , Rohilla Manav , Ramirez Lucia , Cheng Yuhuan , Schwarzkopf Enrique J. , Guerrero Rafael F. , Heil Caiti Smukowski 
Published: August 2024

AbstractThe process of domestication has altered many phenotypes. Selection on these phenotypes has long been hypothesized to indirectly select for increases in recombination rate. This hypothesis is consistent with theory on the evolution of recombination rate, but empirical support has been unclear. We review relevant theory, lab-based experiments, and data comparing recombination rates in wild progenitors and their domesticated counterparts. We utilize population sequencing data and a deep learning method to infer genome-wide recombination rates for new comparisons of chicken/red junglefowl, sheep/mouflon, and goat/bezoar. We find evidence of increased recombination in domestic goats compared to bezoars, but more mixed results in chicken, and generally decreased recombination in domesticated sheep compared to mouflon. Our results add to a growing body of literature in plants and animals that finds no consistent evidence of an increase in recombination with domestication.
Design of a Soluble Multivalent Notch Agonist
Authors: Mout Rubul , Jing Ran , Egan Emily D , Eisenach Helen , Najia Mohamad Ali Toufic , Hensch Luca , Bingham Trevor , Kononov Martin A. , Gunage Rajesh , Zhao Yunliang , Edman Natasha I , Schlaeger Thorsten M , Zon Leonard I , North Trista E , Lendahl Urban , Baker David , Blacklow Stephen C , Daley George Q 
Published: August 2024

AbstractDesigned protein agonists can enhance the efficiency of endogenous signaling pathways, and provide a powerful means to control cellular functions and develop disease therapeutics. Designing a soluble cytokine-like agonist for Notch signaling, an evolutionarily conserved pathway that regulates cell fate in embryonic and adult development, is especially challenging because Notch receptor activation requires a mechanical force that is typically mediated by cell-associated transmembrane ligands at sites of cell-cell contact. Moreover, free soluble Notch ligand is signal inhibitory. Here, we exploit computationally designed protein oligomers with precise geometries and valencies to generate cytokine-like, ‘protein only,’ multivalent soluble Notch agonists. These tools promote cell-cell contact, cluster Notch proteins in synapses at the cell surface, and activate Notch signaling in reporter cell lines and cells expressing endogenous receptors. We demonstrate the utility of these soluble Notch agonists in T cell differentiation from cord blood (CB) and human induced pluripotent stem cells (iPSCs), and in bioreactor production of T cells in liquid suspension. Soluble multivalent Notch agonists can be applied broadly toin vitrocellular differentiation methods to generate clinical cell products and to develop immunotherapies.
TRCompDB: A reference of human tandem repeat sequence and composition variation from long-read assemblies
Authors: Gu Bida , Chaisson Mark J.P. 
Published: August 2024

AbstractTandem repeats (TRs), including short tandem repeats (STRs) and variable-number tandem repeats (VN-TRs), are hypermutable genetic elements consisting of tandem arrays of repeated motifs. TR variation can modify gene expression and has been implicated in over 50 diseases through repeat mutation and pathogenic expansion. Recent advances in long-read sequencing (LRS) enable the comprehensive profiling of TR variation in large cohorts. We previously developedvamos, a tool for annotating motif count and composition in LRS samples. Here, we expanded the functionality ofvamoswith new methods to construct motif databases that enhanced motif consistency, and a toolsettryvamosfor rapid analysis using vamos output. We demonstrate that thevamosmotif composition annotations more accurately reflect underlying genomes than other approaches for TR annotation. By applyingvamosto 360 LRS assemblies of diverse ancestries, we constructed TRCompDB, a reference database of tandem repeat variation across 805,485 STR and 370,468 VNTR loci on the CHM13 reference genome. Usingtryvamosfor genome-wide testing, we identified 6,039 loci exhibiting strong signatures of population divergence in length or composition, yielding insight into stratification of TR loci.
GPR43 in eosinophils prevents the emergence of pathogenic Siglec-Fhineutrophils in allergic airway inflammation
Authors: Yu Jihyun , Kim Seongryong , Song Hyun-Sup , Kim Hye-Young , Kim You-Me 
Published: August 2024

AbstractEosinophils are major effector cells in type 2 immune responses, contributing to host defense and allergic diseases. They also play critical roles in maintaining tissue homeostasis by regulating various immune cell types. However, evidence of the crosstalk between eosinophils and neutrophils is limited. Here, we show that eosinophils directly associate with neutrophils in the lungs of asthma-induced mice. Eosinophil-specific deficiency of the short-chain fatty acid receptor GPR43 results in hyperactivation of eosinophils and increases the expression of neutrophil chemoattractants and PECAM-1, thus enhancing the interaction between eosinophils and neutrophils. This binding event exposes the neutrophils to eosinophil-derived IL-4 and GM-CSF, which induces the conversion of conventional neutrophils into more pathogenic Siglec-Fhineutrophils that strongly enhance Th17 cell differentiation and aggravate asthma symptoms. These results reveal GPR43 as a critical regulator of eosinophils and highlight that eosinophils have a hitherto little-known ability to directly modulate neutrophil differentiation and function.One Sentence SummaryEosinophils directly recruit neutrophils and induce their differentiation into a pathogenic Siglec-Fhisubset in allergic airway inflammation.
Rapid Nanopore cloud-based monitoring and analysis of commercial aquaculture microbiomes
Authors: Strutt James P. B. , Bessarab Irina , Min Jamine Goh Ying , Marican Hana , Summers Stephen 
Published: August 2024

AbstractAquaculture stands as a crucial component of global food security and sustainable development, yet it faces challenges in disease management and ecological balance. Here, we present a novel approach using rapid nanopore sequencing, cloud-based monitoring and analysis for aquaculture microbiomes. Our study aimed to perform untargeted, agnostic biological monitoring of a commercial aquaculture facility, emphasizing rapidity, specificity, and sensitivity. We employed Oxford Nanopore Technologies’ MinION sequencer with an optimised rapid sequencing protocol, enabling on-site operation by facility staff. Three separate sampling efforts resulting in thirteen sequencing runs were conducted, revealing a representative microbiome baseline across aquaculture system components within a 24-hour timeframe. Our results demonstrated the feasibility of rapid monitoring and analysis of nitrogen-associated organisms, essential for same-day water quality management and infection event detection. Notably, Moving Bed Biofilm Reactor (MBBR media) or BioDiscs exhibited the highest diversity and abundance of nitrogen-associated organisms, confirming a pivotal role in nitrification processes. Critically, our approach addressed challenges in metagenomic sample purity and false positives, offering insights for future refinement and application. Our findings underscore the potential of rapid sequencing technologies in enhancing aquaculture management and sustainability. This approach holds promise for mitigating disease outbreaks, optimizing productivity, and advancing ecological balance in aquaculture systems.
Probing Autism and ADHD subtypes using cortical signatures of the T1w/T2w-ratio and morphometry
Authors: Norbom Linn B. , Syed Bilal , Kjelkenes Rikka , Rokicki Jaroslav , Beauchamp Antoine , Nerland Stener , Kushki Azadeh , Anagnostou Evdokia , Arnold Paul , Crosbie Jennifer , Kelley Elizabeth , Nicolson Robert , Schachar Russell , Taylor Margot J. , Westlye Lars T. , Tamnes Christian K. , Lerch Jason P. 
Published: August 2024

AbstractAutism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental conditions that share genetic etiology and frequently co-occur. Given this comorbidity and well-established clinical heterogeneity, identifying individuals with similar brain signatures may be valuable for predicting clinical outcomes and tailoring treatment strategies. Cortical myelination is a prominent developmental process, and its disruption is a candidate mechanism for both disorders. Yet, no studies have attempted to identify subtypes using T1w/T2w-ratio, a magnetic resonance imaging (MRI) based proxy for intracortical myelin. Moreover, cortical variability arises from numerous biological pathways, and multimodal approaches can integrate cortical metrics into a single network. We analyzed data from 310 individuals aged 2.6-23.6 years, obtained from the Province of Ontario Neurodevelopmental (POND) Network consisting of individuals diagnosed with ASD (n=136), ADHD (n=100), and typically developing (TD) individuals (n=74). We first tested for differences in T1w/T2w-ratio between diagnostic categories and controls. We then performed unimodal (T1w/T2w-ratio) and multimodal (T1w/T2w-ratio, cortical thickness, and surface area) spectral clustering to identify diagnostic-blind subgroups. Linear models revealed no statistically significant case-control differences in T1w/T2w-ratio. Unimodal clustering mostly isolated single individual- or minority clusters, driven by image quality and intensity outliers. Multimodal clustering suggested three distinct subgroups, which transcended diagnostic boundaries, showing separate cortical patterns but similar clinical and cognitive profiles. T1w/T2w-ratio features were the most relevant for demarcation, followed by surface area. While our analysis revealed no significant case-control differences, multimodal clustering incorporating the T1w/T2w-ratio among cortical features holds promise for identifying biologically similar subsets of individuals with neurodevelopmental conditions.
Adverse events reported during weekly isoniazid-rifapentine (3HP) tuberculosis preventive treatment among people living with HIV in Uganda
Authors: Kadota Jillian L. , Musinguzi Allan , Aschmann Hélène E. , Akello Lydia , Welishe Fred , Nakimuli Jane , Berger Christopher A. , Kiwanuka Noah , Phillips Patrick PJ , Katamba Achilles , Dowdy David W. , Cattamanchi Adithya , Semitala Fred C. 
Published: August 2024

ABSTRACTBackgroundShort-course tuberculosis (TB) prevention regimens, including 12 weeks of isoniazid and rifapentine (3HP), are increasingly used in high TB-burden countries. Despite established safety and tolerability in efficacy trials, 3HP-related adverse events (AE) could differ in routine settings. Real-world data on AE type, frequency, and timing is crucial for health systems considering 3HP programmatic scale-up.MethodsWe reviewed AEs among people living with HIV (PLHIV) participating in a pragmatic implementation trial of facilitated 3HP taken by directly observed therapy (DOT) or self-administered therapy (SAT) in Kampala, Uganda, and classified them using the Common Terminology Criteria for Adverse Events. We assessed AE timing and summarized related clinical actions including lab tests, diagnoses made, medications prescribed, and treatment interruptions.ResultsAmong 1655 PLHIV treated between July 2020-September 2022, 270 (16.3%) reported 451 events; main issues included general (7%), nervous system (6%), musculoskeletal (5%), gastrointestinal (5%), and dermatologic (3%) disorders. Most (61%) occurred within 6 weeks of initiating 3HP. Among those with events, 211 (78%) required further clinician evaluation, 202 (75%) required laboratory testing, 102 (38%) had medications prescribed, 40 (15%) had treatment paused, and 14 (5%) discontinued 3HP. Women, those multidimensionally impoverished, and DOT recipients were more likely to report an AE. SAT users and later enrollees were more likely to have 3HP interrupted or stopped due to an AE.ConclusionsIn a routine setting, 3HP was safe with 16% of PLHIV reporting AEs and only 3% requiring temporary or permanent treatment interruption. These findings support 3HP expansion in routine HIV/AIDS care settings for TB prevention.Summary3HP is being rolled out for TB prevention in high burden countries. We describe the incidence and clinical management of adverse events in a real-world clinical setting among people living with HIV participating in a pragmatic implementation study in Uganda.
Biogenesis, engineering and function of membranes in the CO2-fixing pyrenoid
Authors: Hennacy Jessica H. , Atkinson Nicky , Kayser-Browne Angelo , Ergun Sabrina L. , Franklin Eric , Wang Lianyong , Kafri Moshe , Fauser Friedrich , Vilarrasa-Blasi Josep , Jinkerson Robert E. , McCormick Alistair J. , Jonikas Martin C. 
Published: August 2024

Summary ParagraphApproximately one-third of global CO2assimilation is performed by the pyrenoid1, a liquid-like organelle found in most algae and some plants2. Specialized membranes are hypothesized to drive CO2assimilation in the pyrenoid by delivering concentrated CO23,4, but their biogenesis and function have not been experimentally characterized. Here, we show that homologous proteins SAGA1 and MITH1 mediate the biogenesis of the pyrenoid membrane tubules in the model algaChlamydomonas reinhardtiiand are sufficient to reconstitute pyrenoid-traversing membranes in a heterologous system, the plantArabidopsis thaliana. SAGA1 localizes to the regions where thylakoid membranes transition into tubules and is necessary to initiate tubule formation. MITH1 localizes to the tubules and is necessary for their extension through the pyrenoid. Tubule-deficient mutants exhibit growth defects under CO2-limiting conditions, providing evidence for the function of membrane tubules in CO2delivery to the pyrenoid. Furthermore, these mutants form multiple aberrant condensates of pyrenoid matrix, indicating that a normal tubule network promotes the coalescence of a single pyrenoid. The reconstitution of pyrenoid-traversing membranes in a plant represents a key milestone toward engineering a functional pyrenoid into crops for improving crop yields. More broadly, our study demonstrates the functional importance of pyrenoid membranes, identifies key biogenesis factors, and paves the way for the molecular characterization of pyrenoid membranes across the tree of life.
Examining Fetal Sex-Specific Placental DNA Methylation Intensities and Variability PostIn VitroFertilization
Authors: Lemaire Melanie , Smith Keaton Warrick , Wilson Samantha L 
Published: August 2024

AbstractInfertility impacts up to 17.5% of reproductive-aged couples worldwide. To aid in conception, many couples turn to assisted reproductive technology, such asin vitrofertilization (IVF). IVF can introduce both physical and environmental stressors that may alter DNA methylation regulation, an important and dynamic process during early fetal development. This meta-analysis aims to assess the differences in the placental DNA methylome between spontaneous and IVF pregnancies. We identified three studies from NCBI GEO that measured DNA methylation with an Illumina Infinium Microarray in post-delivery placental tissue from both IVF and spontaneous pregnancies with a total of 575 samples for analysis (n = 96 IVF, n = 479 spontaneous). While there were no significant or differentially methylated CpGs in mixed or female stratified populations, we identified 9 CpGs that reached statistical significance (FDR <0.05) between IVF (n = 56) and spontaneous (n = 238) placentae. 7 autosomal CpGs and 1 X chromosome CpG was hypermethylated and 2 autosomal CpGs were hypomethylated in the IVF placentae compared to spontaneous. Autosomal CpGs closest toLIPJ,EEF1A2, andFBRSL1also met our criteria to be classified as biologically differentially methylated CpGs (FDR <0.05, |Δβ|>0.05). When analyzing variability differences in Δβvalues between IVF females, IVF males, spontaneous females and spontaneous males, we found a significant shift to greater variability in the both IVF males and females compared to spontaneous (p <2.2e-16, p <2.2e-16). Trends of variability were further analyzed in the biologically differentially methylated autosomal CpGs nearLIPJ EEF1A2, andFBRSL1, and while these regions were statistically significant in males, the female Δβs and ΔCoVs followed a similar trend that differed in magnitude. In males and females there was a statistically significant difference in proportions of endothelial cells, hofbauer cells, stromal cells and syncytiotrophoblasts between spontaneous andin vitroFertilization (IVF) populations. We also observed significant differences between sex within reproduction type in syncytiotrophoblasts and trophoblasts. The results of this study are critical to further understand the impact of IVF on tissue epigenetics which may help to investigate the connections between IVF and negative pregnancy outcomes. Additionally, our study supports sex specific differences in placental DNA methylation and cell composition should be considered as factors for future placental DNA methylation analyses.
Commensal Yeast PromotesSalmonellaTyphimurium Virulence
Authors: Jaswal Kanchan , Todd Olivia A , Flores Audelo Roberto C , Santus William , Paul Saikat , Singh Manmeet , Miao Jian , Underhill David M , Peters Brian M , Behnsen Judith 
Published: August 2024

AbstractEnteric pathogens engage in complex interactions with the host and the resident microbiota to establish gut colonization. Although mechanistic interactions between enteric pathogens and bacterial commensals have been extensively studied, whether and how commensal fungi affect pathogenesis of enteric infections remains largely unknown. Here we show that colonization with the common human gut commensal fungusCandida albicansworsened infections with the enteric pathogenSalmonella entericaserovar Typhimurium. Presence ofC. albicansin the mouse gut increasedSalmonellacecum colonization and systemic dissemination. We investigated the underlying mechanism and found thatSalmonellabinds toC. albicansvia Type 1 fimbriae and uses its Type 3 Secretion System (T3SS) to deliver effector proteins intoC. albicans. A specific effector, SopB, was sufficient to manipulateC. albicansmetabolism, triggering increased arginine biosynthesis inC. albicansand the release of millimolar amounts of arginine into the extracellular environment. The released arginine, in turn, induced T3SS expression inSalmonella, increasing its invasion of epithelial cells.C. albicansdeficient in arginine production was unable to increaseSalmonellavirulencein vitroorin vivo. In addition to modulating pathogen invasion, arginine also directly influenced the host response to infection. Arginine-producingC. albicansdampened the inflammatory response duringSalmonellainfection, whereasC. albicansdeficient in arginine production did not. Arginine supplementation in the absence ofC. albicansincreased the systemic spread ofSalmonellaand decreased the inflammatory response, phenocopying the presence ofC. albicans. In summary, we identifiedC. albicanscolonization as a susceptibility factor for disseminatedSalmonellainfection, and arginine as a central metabolite in the cross-kingdom interaction between fungi, bacteria, and host.
Organ Chips with integrated multifunctional sensors enable continuous metabolic monitoring at controlled oxygen levels
Authors: Izadifar Zohreh , Charrez Berenice , Almeida Micaela , Robben Stijn , Pilobello Kanoelani , van der Graaf-Mas Janet , Benz Max , Marquez Susan L. , Ferrante Thomas C. , Shcherbina Kostyantyn , Gould Russell , LoGrande Nina T. , Sesay Adama M. , Ingber Donald E. 
Published: August 2024

ABSTRACTDespite remarkable advances in Organ-on-a-chip (Organ Chip) microfluidic culture technology, recreating tissue-relevant physiological conditions, such as the region-specific oxygen concentrations, remains a formidable technical challenge, and analysis of tissue functions is commonly carried out using one analytical technique at a time. Here, we describe two-channel Organ Chip microfluidic devices fabricated from polydimethylsiloxane and gas impermeable polycarbonate materials that are integrated with multiple sensors, mounted on a printed circuit board and operated using a commercially available Organ Chip culture instrument. The novelty of this system is that it enables the recreation of physiologically relevant tissue-tissue interfaces and oxygen tension as well as non-invasive continuous measurement of transepithelial electrical resistance, oxygen concentration and pH, combined with simultaneous analysis of cellular metabolic activity (ATP/ADP ratio), cell morphology, and tissue phenotype. We demonstrate the reliable and reproducible functionality of this system in living human Gut and Liver Chip cultures. Changes in tissue barrier function and oxygen tension along with their functional and metabolic responses to chemical stimuli (e.g., calcium chelation, oligomycin) were continuously and noninvasively monitored on-chip for up to 23 days. A physiologically relevant microaerobic microenvironment that supports co-culture of human intestinal cells with livingLactococcus lactisbacteria also was demonstrated in the Gut Chip. The integration of multi-functional sensors into Organ Chips provides a robust and scalable platform for the simultaneous, continuous, and non-invasive monitoring of multiple physiological functions that can significantly enhance the comprehensive and reliable evaluation of engineered tissues in Organ Chip models in basic research, preclinical modeling, and drug development.