bluuebunny/crossref_metadata_2025_split huggingface dataset:
A functional Bayesian model for hydrogen-deuterium exchange mass-spectrometry
Authors: Crook Oliver M. , Chung Chun-wa , Deane Charlotte M. 
Published: July 2022

AbstractProteins often undergo structural perturbations upon binding to other proteins or ligands or when they are subject to environmental changes. Hydrogen deuterium exchange mass-spectrometry (HDX-MS) can be used to explore conformational changes in proteins by examining differences in the rate of deuterium incorporation in different contexts. To determine deuterium incorporation rates, HDX-MS measurements are typically made over a time course. Recently introduced methods show that incorporating the temporal dimension into the statistical analysis improves power and interpretation. However, these approaches have technical assumptions which hinder their flexibility. Here, we propose a more flexible methodology by reframing these methods in a Bayesian framework. Our proposed framework has improved algorithmic stability, allows us to perform uncertainty quantification, and can calculate statistical quantities that are inaccessible to other approaches. We demonstrate the general applicability of the method by showing it can perform rigorous model selection on a spike-in HDX-MS experiment and improved interpretation in an epitope mapping experiment. Bayesian analysis of an HDX experiment with an antibody dimer bound to an E3 ubiquitin ligase identifies at least two interaction interfaces where previous methods obtained confounding results due to the complexities of conformation change on binding. Our findings are consistent with the co-crystal structure of these proteins, demonstrating a bayesian approach can identify important binding epitopes from HDX data.
Pyruvate carboxylation identifies Glioblastoma Stem-like Cells opening new metabolic strategy to prevent tumor recurrence
Authors: Renoult Ophélie , Gratas Catherine , Joalland Noémie , Laurent--Blond Mélanie , Awada Hala , Bourgeois Marine , Oliver Lisa , Chiavassa Sophie , Croyal Mikaël , Paris François , Pecqueur Claire 
Published: July 2022

SummaryGlioblastoma (GBM) are currently associated with a dismal prognosis due to therapeutic resistance. Within the diverse tumor subpopulations, Glioblastoma Stem-like Cells (GSC) have been involved in GBM recurrence. In our study, we demonstrated that these tumor cells can be identified through singular mitochondrial alternative metabolisms. Combining state-of-the-art metabolic studies and the development of a straightforward tumoroid model recapitulating key features of primary GBM cultures, we uncovered a significant use of α-ketoglutarate reductive carboxylation and pyruvate carboxylation in tumoroid GBM cells, catalyzed respectively by isocitrate dehydrogenase and pyruvate carboxylase enzymes. We demonstrated that these singular metabolic features are shared by GBM cells from the mesenchymal subtype and radiation-escaping cells, also involved in recurrence. Finally, we demonstrated that pyruvate carboxylation is required for GBM cell survival in hypoxic niches where glutamine is restricted. Thus, besides providing a new way to identify GSC, our study also opens new therapeutic strategy to limit GBM recurrence.
Core-shell DNA-cholesterol nanoparticles exert lysosomolytic activity in African trypanosomes
Authors: Knieß Robert , Leeder Wolf-Matthias , Reißig Paul , Geyer Felix Klaus , Göringer H. Ulrich 
Published: July 2022

AbstractTrypanosoma bruceiis the causal infectious agent of African trypanosomiasis in humans and Nagana in livestock. Both diseases are currently treated with a small number of chemotherapeutics, which are hampered by a variety of limitations reaching from efficacy and toxicity complications to drug-resistance problems. Here, we explore the forward design of a new class of synthetic trypanocides based on nanostructured, core-shell DNA-lipid particles. In aqueous solution, the particles self-assemble into micelle-type structures consisting of a solvent-exposed, hydrophilic DNA shell and a hydrophobic lipid core. DNA-lipid nanoparticles have membrane-adhesive qualities and can permeabilize lipid membranes. We report the synthesis of DNA-cholesterol nanoparticles, which specifically subvert the membrane integrity of theT. bruceilysosome, killing the parasite with nanomolar potencies. Furthermore, we provide an example of the programmability of the nanoparticles. By functionalizing the DNA shell with a spliced leader (SL)-RNA-specific DNAzyme, we target a second trypanosome-specific pathway (dual-target approach). The DNAzyme provides a backup to counteract the recovery of compromised parasites, which reduces the risk of developing drug resistance.
Epstein-Barr virus nuclear antigen proteins deploy diverse mechanisms to bind the human genome
Authors: Haque Md. Redwanul , Tushar Abdur Rashid , Park Minjun , Moon Chang In , Rahman M. Sohel , Samee Md. Abul Hassan 
Published: July 2022

AbstractViral transcription factors (vTFs) are known to bind the human genome and impact critical biological processes. However, a vTF can infect multiple cell-types, and the extent to which they deploy the same mechanisms for DNA binding across different cell-types is poorly understood. We used the Epstein-Barr virus Nuclear Antigen Proteins 2 and 3 (EBNA2 and EBNA3) to address this gap, the two widely studied vTFs associated with cancers, as case studies. We analyze multiple ChIP-seq datasets of these vTFs from different human cell-lines using a state-of-the-art convolutional neural network model. We show that each vTF uses both cell-type specific and cell-type independent cofactors to bind the human genome. Interestingly, each vTF requires ∼10 cofactors consistently across all binding peaks. Such dependency on a large number of cofactors is in contrast to human TFs since human TFs typically co-bind with 2-3 cofactors. Our de novo motif finding approach also reveals novel sequence motifs at the ChIP peaks of these vTFs. These critical signals were missed by previous studies doing enrichment analysis using known human TFs. Finally, we find that although a vTF impacts similar biological processes across cell-types, it also impacts distinct biological processes in a cell-type specific manner. Our study provides a roadmap for integrative analysis of vTF binding and pinpointing their diverse mechanisms of targeting the human genome across different human cell-types.
Transcriptome responses of the aphid vectorMyzus persicaeare shaped by identities of the host plant and the virus
Authors: Chesnais Quentin , Golyaev Victor , Velt Amandine , Rustenholz Camille , Verdier Maxime , Brault Véronique , Pooggin Mikhail M. , Drucker Martin 
Published: July 2022

AbstractBackgroundNumerous studies have documented modifications in vector orientation behavior, settling and feeding behavior, and/or fecundity and survival due to virus infection in host plants. These alterations are often expected to enhance virus transmission, which has led to the hypothesis that such effects are vector manipulations by the virus. However, until now, the gene expression changes correlating with these effects and indicative of modified vector pathways and mechanisms are mostly unknown.ResultsTranscriptome profiling ofMyzus persicaeaphids feeding on turnip yellows virus (TuYV) and cauliflower mosaic virus (CaMV) infectedArabidopsis thalianaandCamelina sativarevealed a substantial proportion of commonly deregulated genes, amongst them many with general functions in plant-virus-aphid interactions. We identified also aphid genes specifically deregulated by CaMV or TuYV infection, which might be related to the viral transmission mode. Furthermore, we observed strong host-specific differences in the gene expression patterns with plant virus infection causing more deregulations of aphid genes onA. thalianathan onC. sativa, likely related to the differences in susceptibility of the plant hosts to these viruses. Finally, stress-related aphid genes were downregulated inM. persicaeon both infected plants, regardless of the virus.ConclusionsTuYV, relying on the circulative persistent mode of transmission, tended to affect developmental genes. This could increase the proportion of alate aphids, but also affect their locomotion, neuronal activity, and lifespan. CaMV, using the non-circulative non-persistent mode of transmission, had a strong impact on feeding-related genes and in particular those related to salivary proteins. In general, these transcriptome alterations targeted pathways that seem to be particularly adapted to the transmission mode of the corresponding virus and could be evidence of vector manipulation by the virus.
Reduced parasite burden in feral honeybee colonies
Authors: Kohl Patrick L. , D’Alvise Paul , Rutschmann Benjamin , Roth Sebastian , Remter Felix , Steffan-Dewenter Ingolf , Hasselmann Martin 
Published: July 2022

AbstractBee parasites are the main threat to apiculture, and since many parasite taxa can spill over from honeybees (Apis mellifera) to other bee species, honeybee disease management is important for pollinator conservation in general. It is unknown whether honeybees that escaped from apiaries (i.e., feral colonies) benefit from natural parasite-reducing mechanisms like swarming or suffer from high parasite pressure due to the lack of medical treatment. In the latter case, they could function as parasite reservoirs and pose a risk to the health of managed honeybees (spillback) and wild bees (spillover). We compared the occurrence of 18 microparasites among managed (N=74) and feral (N=64) honeybee colony samples from four regions in Germany using qPCR. We distinguished five colony types representing differences in colony age and management histories, two variables potentially modulating parasite prevalence. Besides strong regional variation in parasite communities, parasite burden was consistently lower in feral than in managed colonies. The overall number of detected parasite taxa per colony was lower, and Trypanosomatidae, chronic bee paralysis virus, and deformed wing viruses A and B were less prevalent and abundant in feral colonies than in managed colonies. Parasite burden was lowest in newly founded feral colonies, intermediate in overwintered feral colonies and managed nucleus colonies, and highest in overwintered managed colonies and hived swarms. Our study confirms the hypothesis that the natural mode of colony reproduction and dispersal by swarming temporally reduces parasite pressure in honeybees. We conclude that feral colonies are unlikely to contribute significantly to the spread of bee diseases.
Basal type I interferon signaling has only modest effects on neonatal and juvenile hematopoiesis
Authors: Li Yanan , Yang Wei , Wang Helen C. , Patel Riddhi M. , Casey Emily B. , Denby Elisabeth , Magee Jeffrey A. 
Published: July 2022

ABSTRACTType I interferon (IFN-1) regulates gene expression and hematopoiesis both during development and in response to inflammatory stress. We previously showed that during development, hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) induce IFN-1 target genes shortly before birth in mice. This coincides with the onset of a transition to adult hematopoiesis, and it drives expression of genes associated with antigen presentation. However, it is not clear whether perinatal IFN-1 modulates hematopoietic output, as has been observed in contexts of inflammation. We have characterized hematopoiesis at several different stages of blood formation, from HSCs to mature blood cells, and found that loss of the IFN-1 receptor (IFNAR1) leads to depletion of several phenotypic HSC and MPP subpopulations in neonatal and juvenile mice. Committed lymphoid and myeloid progenitor populations simultaneously expand. These changes had surprisingly little effect on production of more differentiated blood cells. Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) resolved the discrepancy between the extensive changes in progenitor numbers and modest changes in hematopoiesis, revealing stability in most MPP populations in Ifnar1-deficient neonates when the populations were identified based on gene expression rather than surface marker phenotype. Thus, basal IFN-1 signaling has only modest effects on hematopoiesis. Discordance between transcriptionally- and phenotypically-defined MPP populations may impact interpretations of how IFN-1 shapes hematopoiesis in other contexts, such as aging or inflammation.KEY POINTSLoss of type I Interferon signaling in neonatal mice depletes immature blood progenitors without compromising postnatal hematopoiesisProgenitor populations remain intact when measured by single cell transcriptomes rather than surface marker phenotypes
Canonical Wnt Signaling Maintains Human Mesenchymal Progenitor Cell Multipotency During Adipose Tissue Development
Authors: Loureiro Zinger Yang , Joyce Shannon , Solivan-Rivera Javier , Desai Anand , Skritakis Pantos , Yang Qin , DeSouza Tiffany , Nguyen Tammy , MacDougald Ormond A , Corvera Silvia 
Published: July 2022

ABSTRACTTissue development and repair throughout life depends on the availability of multipotent mesenchymal stem/progenitor cells capable of differentiating into specialized cell types. How an appropriately sized pool of such multipotent progenitors is maintained under varied signals for tissue growth and repair is unknown. We addressed this question by monitoring fate trajectories of human adipose tissue-derived multipotent progenitor cells using single-cell transcriptomics. Homogenous multipotent progenitors underwent two distinct fate trajectories rapidly upon induction of adipose differentiation– one toward the adipocyte fate, and the other towards a distinct, non-differentiated state characterized by up-regulation of canonical Wnt target genes. Upon isolation, this latter cell population was able to resume proliferation and display multipotency. Using canonical Wnt agonists and antagonists we find Wnt signaling is required for the maintenance of this multipotent pool under differentiation stimulus.In vivo, these cells are retained in adipose tissue developed from human multipotent progenitor cells in immunocompromised mice, and their transcriptomic signature is detected in human adult adipose tissue. Our study reveals a previously unrecognized mechanism for maintaining a functional pool of human mesenchymal progenitor cells under conditions of differentiation pressure, driven by Wnt signaling.
SRSF6 balances mitochondrial-driven innate immune outcomes through alternative splicing of BAX
Authors: Wagner Allison R. , Weindel Chi G. , West Kelsi O. , Scott Haley M. , Watson Robert O. , Patrick Kristin L. 
Published: July 2022

SUMMARYTo mount a protective response to infection while preventing hyperinflammation, gene expression in innate immune cells must be tightly regulated. Despite the importance of pre-mRNA splicing in shaping the proteome, its role in balancing immune outcomes remains understudied. Transcriptomic analysis of murine macrophage cell lines identified Serine/Arginine Rich Splicing factor 6 (SRSF6) as a gatekeeper of mitochondrial homeostasis. SRSF6 orchestrates this by directing alternative splicing of the mitochondrial pore-forming protein BAX. Loss of SRSF6 promotes accumulation of BAX-κ, a variant that sensitizes macrophages to undergo cell death and triggers upregulation of interferon stimulated genes through cGAS sensing of cytosolic mitochondrial DNA. Upon pathogen sensing, macrophages regulate SRSF6 expression to control the liberation of immunogenic mtDNA and adjust the threshold for entry into programmed cell death. This work defines BAX alternative splicing by SRSF6 as a critical node not only in mitochondrial homeostasis, but also in the macrophage’s response to pathogens.
X chromosome factor Kdm6a enhances memory independent of its demethylase function in the aging XY male brain
Authors: Shaw Cayce K. , Abdulai-Saiku Samira , Marino Francesca , Wang Dan , Davis Emily J. , Panning Barbara , Dubal Dena B. 
Published: July 2022

ABSTRACTMales exhibit shorter lifespan and more cognitive deficits in aging human populations. In mammals, the X chromosome is enriched for neural genes and is a major source of biologic sex difference, in part, because males show decreased expression of select X factors. While each sex (XX and XY) harbors one active X due to X chromosome inactivation in females, some genes, such asKdm6a, transcriptionally escape silencing in females – resulting in lower levels in males. Kdm6a is a known histone demethylase (H3K27me2/3) with multiple functional domains that is linked with synaptic plasticity and cognition. Whether elevatingKdm6acould benefit the aging male brain and whether this requires its demethylase function remains unknown. We used lentiviral-mediated overexpression of the X factor in the hippocampus of aging male mice and tested their cognition and behavior in the Morris water maze. We found that acutely increasingKdm6a– in a form without demethylase function – selectively improved learning and memory, without altering total activity or anxiety-like measures, in the aging XY brain. Further understanding the demethylase-independent downstream mechanisms of Kdm6a may lead to novel therapies for treating age-induced cognitive deficits in both sexes.
Proteome coverage after simultaneous proteo-metabolome liquid-liquid extraction
Authors: van Pijkeren A , Egger AS , Hotze M , Zimmermann E , Grander J , Gollowitzer A , Koeberle A , Bischoff R , Thedieck K , Kwiatkowski M 
Published: July 2022

AbstractProteo-metabolomics is essential in systems biology and simultaneous proteo-metabolome extraction by liquid-liquid extraction (SPM-LLE) allows extraction of the metabolome and proteome from the same sample. Since the proteome is present as a pellet in SPM-LLE it must be solubilized for quantitative proteomics. Solubilization and proteome extraction is a critical factor in the information that can be obtained at the proteome level. In this study, we investigated the performance of two surfactants (sodium deoxycholate (SDC), sodium dodecyl sulfate (SDS)) and urea with respect to proteome coverage and extraction efficiency of an interphase proteome pellet generated by methanol-chloroform based SPM-LLE. We also investigated the extent to which the performance differs when the proteome is extracted from the interphase pellet or by direct cell lysis. Our study reveals that the proteome coverages between the two surfactants and urea for the SPM-LLE interphase pellet were very similar, but the extraction efficiencies differed significantly. While SDS led to enrichment of basic proteins, which were mainly ribosomal and ribonuclear proteins, urea was the most efficient extraction agent for simultaneous proteo-metabolome analysis. The results of our study also show that the performance of surfactants (SDC, SDS) for quantitative proteomics is better when the proteome was extracted by direct cell lysis and not from an interphase pellet. In contrast, the performance of urea for quantitative proteomics was significantly better when the proteome was extracted from an interphase pellet and by direct cell lysis.
Optimal mating ofPinus taedaL. under different scenarios using differential evolution algorithm
Authors: Goda Khushi , Isik Fikret 
Published: July 2022

AbstractA newly developed software, AgMate, was used to perform optimized mating for monoeciousPinus taedaL. breeding. Using a computational optimization procedure called differential evolution (DE), AgMate was applied under different breeding population sizes scenarios (50, 100, 150, 200, 250) and candidate contribution scenarios (max use of each candidate was set to 1 or 8), to assess its efficiency in maximizing the genetic gain while controlling inbreeding. Real pedigree data set from North Carolina State University Tree Improvement Co-op with 962Pinus taedawere used to optimize objective functions accounting for coancestry of parents and expected genetic gain and inbreeding of the future progeny. AgMate results were compared with those from another widely used mating software called MateSel (Kinghorn, 1999). For the proposed mating list for 200 progenies, AgMate resulted in an 83.7% increase in genetic gain compared with the candidate population. There was evidence that AgMate performed similarly to MateSel in managing coancestry and expected genetic gain, but MateSel was superior in avoiding inbreeding in proposed mate pairs. The developed algorithm was computationally efficient in maximizing the objective functions and flexible for practical application in monoecious diploid conifer breeding.Study implicationsA dataset from a breeding population of loblolly pine (Pinus taedaL.) was analyzed using an optimal mating software, AgMate (developed by the authors), to optimize the selection, contribution, and mating of candidates simultaneously. The software helps breeders make decisions on which tree to cross with which tree and how many times, such that the trees are not related to each other and would result in the best performing progenies. AgMate is effective in meeting the breeding objectives for monoecious species. The open-source, easy-to-use, and flexible AgMate software, also available as a website, is invaluable in helping breeders to create optimal matings for future generations, which balance the pursuit of maximizing genetic gain while maintaining genetic diversity.
A comprehensive prediction of transcript isoforms in 19 chicken tissues by Oxford Nanopore long-read sequencing
Authors: Guan Dailu , Halstead Michelle M. , Islas-Trejo Alma D. , Goszczynski Daniel E. , Cheng Hans H. , Ross Pablo , Zhou Huaijun 
Published: July 2022

AbstractTo comprehensively identify and annotate transcript isoforms in the chicken genome, we generated Nanopore long-read sequencing data from a diverse set of 19 chicken tissues comprising 68 samples collected from experimental line 6 × line 7 F1 adult males and females. More than 23.8 million reads with mean read length of 790 bases and average quality of 18.2 were generated. The annotation and subsequent filtering resulted in identification of 55,382 transcripts with mean length of 1,700 bases at 40,547 loci, representing ∼1.4 transcripts per locus. Among them, we predicted 30,967 potential coding transcripts at 19,461 loci and 16,495 potential lncRNA transcripts at 15,512 loci. Compared to reference annotations, we found 52% of annotated transcripts could partially to fully match while 47% were novel and potentially transcribed from lncRNA loci. Based on our annotation, we quantified transcript expression across tissues and found brain tissues (i.e. cerebellum, cortex) expressed highest number of transcripts and loci. The further tissue specificity revealed that ∼22% of the transcripts displaying tissue specificity. Of them, the reproductive tissues (i.e. testis, ovary) contained the most tissue-specific transcripts. Despite sequencing 68 transcriptomes derived from 19 tissues, still ∼20% of Ensembl reference loci were not detected. This suggests that including additional samples from different cell types, developmental and physiological conditions, is needed to fully annotate the chicken genome. The application of Nanopore sequencing transcriptomes in this study demonstrated the usefulness of long-read data in discovering additional novel loci (e.g., lncRNA loci) and resolving complex transcripts (e.g., the longest transcript for the TTN locus).