bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimising future rhino population management strategies using insights from genetic health assessments across India
Authors: Ghosh Tista , Kakati Parikshit , Sharma Amit , Mondol Samrat 
Published: August 2024

AbstractVarious species conservation paradigms are facing enormous challenges during the ongoing Anthropocene. While the widely-used reintroduction/translocation-based approaches have supported many endangered species population recoveries, they seldom use detailed genetic information during initial planning. The Indian greater one-horned rhino typifies such assisted migration-driven species recovery, but currently facing long-term survival concerns due to their mostly small, isolated populations reaching respective carrying capacities. We assessed nation-wide rhino genetic health, identified suitable source populations and provided future translocation scenarios for all extant and proposed rhino habitats. Analyses with 504 unique rhino genotypes across all seven Indian rhino-bearing parks revealed six genetically-isolated populations with overall moderately low genetic diversity. Our results showed that Kaziranga and Manas NPs (Assam) to have the best rhino genetic health, whereas Jaldapara and Gorumara NPs (West Bengal) undergoing strong genetic erosions. Forward genetic simulations suggested that annual supplementation efforts from only few Assam rhino populations (Kaziranga NP, Orang NP and Pobitora WLS) are best suited for genetic rescue of most of the extant populations. Overall, the genetic diversity and differentiation patterns mimics the complex evolutionary history and individual recovery histories. We suggest park-specific management solutions (ranging from protection measures, grassland restoration, livestock and conflict management, regular supplementation events etc.) to ensure the species’ long-term persistence and prevent the alarming loss of grassland habitats and its associate biodiversity. We insist on utilising such genetic health indices-driven population management solutions to identify targeted mitigative measures in other species.
Rapid GIT transit time in volant vertebrates, with implications for convergence in microbiome composition
Authors: Cornelius Ruhs Emily , McFerrin Katherine , Jones Devin N. , Cortes-Delgado Natalia , Ravelomanantsoa Ny Anjara Fifi , Yeoman Carl J. , Plowright Raina K. , Brook Cara E. 
Published: August 2024

ABSTRACTFlying birds and bats have simplified gastrointestinal tracts (GITs) and low intestinal mass to facilitate flight. Previous work showed reduced GIT transit times in birds relative to other vertebrates—but GIT transit has never been collectively quantified for bats. Unique among mammals, bat GIT microbiomes are dominated by Pseudomonadota bacteria (previously Proteobacteria), which also dominate the microbiomes of flying birds – we hypothesized this convergence to result from rapid GIT transit times for both volant taxa. We conducted a meta-analysis of vertebrate GIT transit times which showed that bats and flying birds have significantly faster transit times relative to nonvolant vertebrates. Additionally, within the bat order (Chiroptera), we demonstrated decreasing transit times associated with increasing body mass, a pattern contrasting other vertebrates (including volant birds) and possibly influencing GIT microbiome composition. This inverted mass-transit association is likely driven by diet as fruit- and nectar-consuming Pteropodids are the largest of all bats.
Do transformers and CNNs learn different concepts of brain age?
Authors: Siegel Nys Tjade , Kainmueller Dagmar , Deniz Fatma , Ritter Kerstin , Schulz Marc-Andre 
Published: August 2024

Abstract“Predicted brain age” refers to a biomarker of structural brain health derived from machine learning analysis of T1-weighted brain magnetic resonance (MR) images. A range of machine learning methods have been used to predict brain age, with convolutional neural networks (CNNs) currently yielding state-of-the-art accuracies. Recent advances in deep learning have introduced transformers, which are conceptually distinct from CNNs, and appear to set new benchmarks in various domains of computer vision. However, transformers have not yet been applied to brain age prediction. Thus, we address two research questions: First, are transformers superior to CNNs in predicting brain age? Second, do conceptually different deep learning model architectures learn similar or different “concepts of brain age”? We adapted a Simple Vision Transformer (sViT) and a Shifted Window Transformer (SwinT) to predict brain age, and compared both models with a ResNet50 on 46,381 T1-weighted structural MR images from the UK Biobank. We found that SwinT and ResNet performed on par, while additional training samples will most likely give SwinT the edge in prediction accuracy. We identified that different model architectures may characterize different (sub-)sets of brain aging effects, representing diverging concepts of brain age. Thus, we systematically tested whether sViT, SwinT and ResNet focus on different concepts of brain age by examining variations in their predictions and clinical utility for indicating deviations in neurological and psychiatric disorders. Reassuringly, we did not find substantial differences in the structure of brain age predictions between model architectures. Based on our results, the choice of deep learning model architecture does not appear to have a confounding effect on brain age studies.
Hypoxia promotes airway differentiation in the human lung epithelium
Authors: Dong Ziqi , Wit Niek , Agarwal Aastha , Dubal Dnyanesh , van den Ameele Jelle , Reid Adam James , Nathan James A. , Rawlins Emma L. 
Published: August 2024

ABSTRACTHuman early embryos develop under physiological hypoxia, but how hypoxia regulates human organogenesis remains little known. We have investigated oxygen availability effects on the human lung epithelium using organoids. We find first-trimester lung epithelial progenitors remain undifferentiated under normoxia, but spontaneously differentiate towards multiple airway cell types and inhibit alveolar differentiation under hypoxia. Using chemical and genetic tools, we demonstrate that hypoxia-induced airway differentiation is dependent on HIF (Hypoxia-Inducible Factor) pathways, with HIF1α and HIF2α differentially regulating fate decisions. Transcription factors KLF4 and KLF5 are direct targets of the HIF pathway and promote progenitor differentiation to basal and secretory cells. Chronic hypoxia also induces transdifferentiation of human alveolar type 2 cells to airway cells via the HIF pathway, mimicking alveolar bronchiolization processes in lung disease. Our results reveal roles for hypoxia and HIF signalling during human lung development and have implications for aberrant cell fate decisions in chronic lung diseases.
Making the effect visible – OX40 targeting nanobodies forin vivoimaging of activated T cells
Authors: Frecot Desiree I. , Blaess Simone , Wagner Teresa R. , Kaiser Philipp D. , Traenkle Bjoern , Fandrich Madeleine , Jakobi Meike , Scholz Armin M. , Nueske Stefan , Schneiderhan-Marra Nicole , Gouttefangeas Cécile , Kneilling Manfred , Pichler Bernd J. , Sonanini Dominik , Rothbauer Ulrich 
Published: August 2024

AbstractPurposeHuman OX40 (hOX40/CD134), a member of the TNF receptor superfamily, is mainly expressed on activated T lymphocytes. Triggered by its ligand OX40L (CD252), it provides costimulatory signals that support the differentiation, proliferation and long-term survival of T cells. Besides being a relevant therapeutic target, hOX40 is also an important biomarker for monitoring the presence or infiltration of activated T cells within the tumor microenvironment (TME), the inflammatory microenvironment (IME) in immune-mediated diseases (IMIDs) and the lymphatic organs. Here, we developed novel single domain antibodies (nanobodies, Nbs) targeting hOX40 to monitor the activation status of T cells byin vivomolecular imaging.MethodsNbs against hOX40 (hOX40-Nbs) were selected from an immunized Nb-library by phage display. The identified hOX40-Nbs were characterizedin vitro, including determination of their specificity, affinity, stability, epitope recognition and their impact on OX40 signaling and T cell function. A lead candidate was site-specifically conjugated with a fluorophore via sortagging and applied for noninvasivein vivooptical imaging (OI) of hOX40-expressing cells in a xenograft mouse model.ResultsOur selection campaign revealed four unique Nbs that exhibit strong binding affinities and high stabilities under physiological conditions. Epitope binning and domain mapping indicated the targeting of at least two different epitopes on hOX40. When analyzing their impact on OX40 signaling, an agonistic effect was excluded for all validated Nbs. Incubation of activated T cells with hOX40-Nbs did not affect cell viability or proliferation patterns, whereas differences in cytokine release were observed.In vivoOI with a fluorophore-conjugated lead candidate in experimental mice with hOX40-expressing xenografts demonstrated its specificity and functionality as an imaging probe.ConclusionConsidering the need for advanced probes for noninvasivein vivomonitoring of T cell activation dynamics, we propose, that our hOX40-Nbs have a great potential as imaging probes for noninvasive and longitudinalin vivodiagnostics. Quantification of OX40+T cells in TME or IME will provide crucial insights into the activation state of infiltrating T cells, offering a valuable biomarker for assessing immune responses, predicting treatment efficacy, and guiding personalized immunotherapy strategies in patients with cancer or IMIDs.
dia-PASEF Proteomics of Tumor and Stroma LMD Enriched from Archived HNSCC Samples
Authors: Panigrahi Aswini , Hunt Allison L , Assis Diego , Willetts Matthew , Kallakury Bhaskar V , Davidson Bruce , Conrads Thomas P , Goldman Radoslav 
Published: August 2024

AbstractWe employed laser microdissection to selectively harvest tumor cells and stroma from the microenvironment of formalin-fixed, paraffin-embedded head and neck squamous cell carcinoma (HNSCC) tissues. The captured HNSCC tissue fractions were analyzed by quantitative mass spectrometry-based proteomics using a data independent analysis approach. In paired samples, we achieved excellent proteome coverage having quantified 6,668 proteins with a median quantitative coefficient of variation under 10%. We observed significant differences in relevant functional pathways between the spatially resolved tumor and stroma regions. Our results identified extracellular matrix (ECM) as a major component enriched in the stroma, including many cancer associated fibroblast signature proteins in this compartment. We demonstrate the potential for comparative deep proteome analysis from very low starting input in a scalable format that is useful to decipher the alterations in tumor and the stromal microenvironment. Correlating such results with clinical features or disease progression will likely enable identification of novel targets for disease classification and interventions.
Somatic mutation phasing and haplotype extension using linked-reads in multiple myeloma
Authors: Foltz Steven M. , Li Yize , Yao Lijun , Terekhanova Nadezhda V. , Weerasinghe Amila , Gao Qingsong , Dong Guanlan , Schindler Moses , Cao Song , Sun Hua , Jayasinghe Reyka G. , Fulton Robert S. , Fronick Catrina C. , King Justin , Kohnen Daniel R. , Fiala Mark A. , Chen Ken , DiPersio John F. , Vij Ravi , Ding Li 
Published: August 2024

AbstractSomatic mutation phasing informs our understanding of cancer-related events, like driver mutations. We generated linked-read whole genome sequencing data for 23 samples across disease stages from 14 multiple myeloma (MM) patients and systematically assigned somatic mutations to haplotypes using linked-reads. Here, we report the reconstructed cancer haplotypes and phase blocks from several MM samples and show how phase block length can be extended by integrating samples from the same individual. We also uncover phasing information in genes frequently mutated in MM, includingDIS3,HIST1H1E,KRAS,NRAS, andTP53, phasing 79.4% of 20,705 high-confidence somatic mutations. In some cases, this enabled us to interpret clonal evolution models at higher resolution using pairs of phased somatic mutations. For example, our analysis of one patient suggested that twoNRAShotspot mutations occurred on the same haplotype but were independent events in different subclones. Given sufficient tumor purity and data quality, our framework illustrates how haplotype-aware analysis of somatic mutations in cancer can be beneficial for some cancer cases.
Deep skin fibroblast-mediated macrophage recruitment supports acute wound healing
Authors: Amuso Veronica M. , Haas MaryEllen R. , Cooper Paula O. , Chatterjee Ranojoy , Hafiz Sana , Salameh Shatha , Gohel Chiraag , Mazumder Miguel F. , Josephson Violet , Khorsandi Khatereh , Horvath Anelia , Rahnavard Ali , Shook Brett A. 
Published: August 2024

ABSTRACTEpithelial and immune cells have long been appreciated for their contribution to the early immune response after injury; however, much less is known about the role of mesenchymal cells. Using single nuclei RNA-sequencing, we defined changes in gene expression associated with inflammation at 1-day post-wounding (dpw) in mouse skin. Compared to keratinocytes and myeloid cells, we detected enriched expression of pro-inflammatory genes in fibroblasts associated with deeper layers of the skin. In particular, SCA1+ fibroblasts were enriched for numerous chemokines, including CCL2, CCL7, and IL33 compared to SCA1-fibroblasts. Genetic deletion ofCcl2in fibroblasts resulted in fewer wound bed macrophages and monocytes during injury-induced inflammation with reduced revascularization and re-epithelialization during the proliferation phase of healing. These findings highlight the important contribution of deep skin fibroblast-derived factors to injury-induced inflammation and the impact of immune cell dysregulation on subsequent tissue repair.
Image-Guided Targeting of Mitochondrial Metabolism Sensitizes Pediatric Malignant Rhabdoid Tumors to Low Dose Radiotherapy
Authors: Xia Wenxi , Goff Matthew , Schiavone Carmine , Singh Neetu , Huang Jiemin , Need Esther , Cave Joseph , Gillespie David L. , Jensen Randy L. , Pagel Mark D. , Dogra Prashant , Shi Sixiang , Goel Shreya 
Published: August 2024

AbstractTumor hypoxia leads to radioresistance and markedly worse clinical outcomes for pediatric malignant rhabdoid tumors (MRT). Our transcriptomics and bioenergetic profiling data reveal that mitochondrial oxidative phosphorylation (OXPHOS) is a metabolic vulnerability of MRT and can be exploited to overcome consumptive hypoxia by repurposing an FDA-approved anti-malarial drug, Atovaquone (AVO). We then establish the utility of Oxygen-Enhanced-Multispectral Optoacoustic Tomography (OE-MSOT), a label-free, ionizing radiation-free imaging modality, to visualize and quantify spatiotemporal changes in tumor hypoxia in response to AVO. We show a potent but transient increase in tumor oxygenation upon AVO treatment which results in complete elimination of tumors in all tested mice when combined with 10 Gy radiotherapy, a dose several times lower than the current clinic standard. Finally, we use translational mathematical modeling for systematic evaluation of dosing regimens, administration timing, and therapeutic synergy in a virtual clinical patient population. Together, our work establishes a framework for safe and pediatric patient-friendly image-guided metabolic radiosensitization of rhabdoid tumors.
Physiological oxygen concentration during sympathetic primary neuron culture improves neuronal health and reduces HSV-1 reactivation
Authors: Dochnal Sara A. , Krakowiak Patryk A. , Whitford Abigail L. , Cliffe Anna R. 
Published: August 2024

AbstractHerpes simplex virus-1 (HSV-1) establishes a latent infection in peripheral neurons and periodically reactivates in response to a stimulus to permit transmission.In vitromodels using primary neurons are invaluable to studying latent infection because they use bona fide neurons that have undergone differentiation and maturationin vivo. However, culture conditionsin vitroshould remain as close to thosein vivoas possible. This is especially important when considering minimizing cell stress, as it is a well-known trigger of HSV reactivation. We recently developed an HSV-1 model system that requires neurons to be cultured for extended lengths of time. Therefore, we sought to refine culture conditions to optimize neuronal health and minimize secondary effects on latency and reactivation. Here, we demonstrate that culturing primary neurons under conditions closer to physiological oxygen concentrations (5% oxygen) results in cultures with features consistent with reduced stress. Furthermore, culture in these lower oxygen conditions diminishes the progression to full HSV-1 reactivation despite minimal impacts on latency establishment and earlier stages of HSV-1 reactivation. We anticipate that our findings will be useful for the broader microbiology community as they highlight the importance of considering physiological oxygen concentration in studying host-pathogen interactions.
Predicting metal-binding proteins and structures through integration of evolutionary-scale and physics-based modeling
Authors: Dai Xin , Henderson Max , Yoo Shinjae , Liu Qun 
Published: August 2024

ABSTRACTMetals are essential elements in all living organisms, binding to approximately 50% of proteins. They serve to stabilize proteins, catalyze reactions, regulate activities, and fulfill various physiological and pathological functions. While there have been many advancements in determining the structures of protein-metal complexes, numerous metal-binding proteins still need to be identified through computational methods and validated through experiments. To address this need, we have developed the ESMBind workflow, which combines evolutionary scale modeling (ESM) for metal-binding prediction and physics-based protein-metal modeling. Our approach utilizes the ESM-2 and ESM-IF models to predict metal-binding probability at the residue level. In addition, we have designed a metal-placement method and energy minimization technique to generate detailed 3D structures of protein-metal complexes. Our workflow outperforms other models in terms of residue and 3D-level predictions. To demonstrate its effectiveness, we applied the workflow to 142 uncharacterized fungal pathogen proteins and predicted metal-binding proteins involved in fungal infection and virulence.
Bayesian Estimation of Allele-Specific Expression in the Presence of Phasing Uncertainty
Authors: Zou Xue , Gomez Zachary W. , Reddy Timothy E. , Allen Andrew S. , Majoros William H. 
Published: August 2024

AbstractMotivationAllele-specific expression (ASE) analyses aim to detect imbalanced expression of maternal versus paternal copies of an autosomal gene. Such allelic imbalance can result from a variety of cis-acting causes, including disruptive mutations within one copy of a gene that impact the stability of transcripts, as well as regulatory variants outside the gene that impact transcription initiation. Current methods for ASE estimation suffer from a number of shortcomings, such as relying on only one variant within a gene, assuming perfect phasing information across multiple variants within a gene, or failing to account for alignment biases and possible genotyping errors.ResultsWe developed BEASTIE, a Bayesian hierarchical model designed for precise ASE quantification at the gene level, based on given genotypes and RNA-Seq data. BEASTIE addresses the complexities of allelic mapping bias, genotyping error, and phasing errors by incorporating empirical phasing error rates derived from Genome-in-a-Bottle individual NA12878. BEASTIE surpasses existing methods in accuracy, especially in scenarios with high phasing errors. This improvement is critical for identifying rare genetic variants often obscured by such errors. Through rigorous validation on simulated data and application to real data from the 1000 Genomes Project, we establish the robustness of BEASTIE. These findings underscore the value of BEASTIE in revealing patterns of ASE across gene sets and pathways.Availability and ImplementationThe software is freely available fromhttps://github.com/x811zou/BEASTIE. BEASTIE is available as Python source code and as a Docker image.Supplementary informationAdditional information is available online.
microRNA-1 Regulates Metabolic Flexibility in Skeletal Muscle via Pyruvate Metabolism
Authors: Ismaeel Ahmed , Peck Bailey D. , Montgomery McLane M. , Burke Benjamin I. , Goh Jensen , Kang Gyumin , Franco Abigail B. , Xia Qin , Goljanek-Whysall Katarzyna , McDonagh Brian , McLendon Jared M. , Koopmans Pieter J. , Jacko Daniel , Schaaf Kirill , Bloch Wilhelm , Gehlert Sebastian , Wen Yuan , Murach Kevin A. , Peterson Charlotte A. , Boudreau Ryan L. , Fisher-Wellman Kelsey H. , McCarthy John J. 
Published: August 2024

AbstractMicroRNA-1 (miR-1) is the most abundant miRNA in adult skeletal muscle. To determine the function of miR-1 in adult skeletal muscle, we generated an inducible, skeletal muscle-specific miR-1 knockout (KO) mouse. Integration of RNA-sequencing (RNA-seq) data from miR-1 KO muscle with Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) from human skeletal muscle identified miR-1 target genes involved with glycolysis and pyruvate metabolism. The loss of miR-1 in skeletal muscle induced cancer-like metabolic reprogramming, as shown by higher pyruvate kinase muscle isozyme M2 (PKM2) protein levels, which promoted glycolysis. Comprehensive bioenergetic and metabolic phenotyping combined with skeletal muscle proteomics and metabolomics further demonstrated that miR-1 KO induced metabolic inflexibility as a result of pyruvate oxidation resistance. While the genetic loss of miR-1 reduced endurance exercise performance in mice and inC. elegans,the physiological down-regulation of miR-1 expression in response to a hypertrophic stimulus in both humans and mice causes a similar metabolic reprogramming that supports muscle cell growth. Taken together, these data identify a novel post-translational mechanism of adult skeletal muscle metabolism regulation mediated by miR-1.