bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elastin-derived peptides favor type 2 innate lymphoid cells in COPD
Authors: Lahire Sarah , Fichel Caroline , Rubaszewski Océane , Lerévérend Cédric , Audonnet Sandra , Visneux Vincent , Perotin Jeanne-Marie , Deslée Gaëtan , Le Jan Sébastien , Potteaux Stéphane , Le Naour Richard , Pommier Arnaud 
Published: September 2023

ABSTRACTChronic obstructive pulmonary disease (COPD) is a condition characterized by chronic airway inflammation and obstruction, primarily caused by tobacco smoking. Although the involvement of immune cells in COPD pathogenesis is well established, the contribution of innate lymphoid cells (ILC) remains poorly understood. ILC are a type of innate immune cells that participate in tissue remodeling processes, but their specific role in COPD has not been fully elucidated. During COPD, the breakdown of pulmonary elastin generates elastin peptides that elicit biological activities on immune cells. This study aimed to investigate the presence of ILC in COPD patients and examine the impact of elastin peptides on their functionality.Our findings revealed an elevated proportion of ILC2 in the peripheral blood of COPD patients, and a general activation of ILC as indicated by an increase in their cytokine secretion capacity. Notably, our study demonstrated that serum from COPD patients promotes ILC2 phenotype, likely due to the elevated concentration of IL-5, a cytokine known to favor ILC2 activation. Furthermore, we uncovered that this increase in IL-5 secretion is partially attributed to its secretion by macrophages upon stimulation by elastin peptides, suggesting an indirect role of elastin peptides on ILC in COPD.These findings shed light on the involvement of ILC in COPD and provide insights into the potential interplay between elastin breakdown, immune cells, and disease progression. Further understanding of the mechanisms underlying ILC activation and their interaction with elastin peptides could contribute to the development of novel therapeutic strategies for COPD management.
Comparative analysis of metabolic models of microbial communities reconstructed from automated tools and consensus approaches
Authors: Hsieh Yunli Eric , Tandon Kshitij , Verbruggen Heroen , Nikoloski Zoran 
Published: September 2023

AbstractGenome-scale metabolic models (GEMs) of microbial communities offer valuable insights into the functional capabilities of their members and facilitate the exploration of microbial interactions. These models are generated using different automated reconstruction tools, each relying on different biochemical databases that may affect the conclusions drawn from thein silicoanalysis. One way to address this problem is to employ a consensus reconstruction method that combines the outcomes of different reconstruction tools. Here, we conducted a comparative analysis of community models reconstructed from three automated tools, i.e. CarveMe, gapseq, and KBase, alongside a consensus approach, utilizing data from two marine bacterial communities. Our analysis revealed that these reconstruction approaches, while based on the same genomes, resulted in GEMs with varying numbers of genes and reactions as well as metabolic functionalities, attributed to the different databases employed. Further, our results indicated that the set of exchanged metabolites was more influenced by the reconstruction approach rather than the specific bacterial community investigated. This observation suggests a potential bias in predicting metabolite interactions using community GEMs. We also showed that consensus models encompassed a larger number of reactions and metabolites while concurrently reducing the presence of dead-end metabolites. Therefore, the usage of consensus models allows making full and unbiased use from aggregating genes from the different reconstructions in assessing the functional potential of metabolic communities.ImportanceOur study contributes significantly to the field of microbial community modeling through a comprehensive comparison of genome-scale metabolic models (GEMs) generated via various automated tools, including: CarveMe, gapseq, KBase, and a consensus approach. We revealed substantial structural disparities in model outcomes, primarily attributed to variations in the employed databases. A key finding underscored the substantial impact of the reconstruction approach on the set of exchanged metabolites, emphasizing the necessity for enhanced data integration strategies. The consensus models emerge as a powerful solution, exhibiting improved functional capabilities by encompassing a greater number of reactions, metabolites, and genes. This not only offers a more comprehensive representation of metabolic networks within bacterial communities but also shows promise in reducing variability for more accurate predictions of exchange metabolites. Overall, our research provides a critical framework for refining microbial community simulations, impacting fields from ecology to synthetic biology.
eDAVE - extension of GDC Data Analysis, Visualization, and Exploration Tools
Authors: Bińkowski Jan , Taryma-Leśniak Olga , Sokolowska Katarzyna Ewa , Przybylowicz Patrycja Kamila , Staszewski Melanie , Wojdacz Tomasz Kazimierz 
Published: September 2023

AbstractPublicly available repositories such as Genomic Data Commons or Gene Expression Omnibus are a valuable research resource useful for hypothesis driven research as well as validation of the results of new experiments. Unfortunately, frequently advanced computational skills are required to mine those repositories making the use of those opulent research resources challenging, especially for researchers without bioinformatics expertise. To address this challenge, we have developed eDAVE, a user-friendly, web and desktop interface enabling intuitive and robust analysis of almost 12 000 methylomes and transcriptomes from over 200 types of cells and tissues deposited in the Genomic Data Commons repository.Web app implemented in Python, is supported for major browsers and available at:https://edave.pum.edu.pl/
Global impact of aberrant splicing on human gene expression levels
Authors: Fair Benjamin , Abad Najar Carlos Buen , Zhao Junxing , Lozano Stephanie , Reilly Austin , Mossian Gabriela , Staley Jonathan P , Wang Jingxin , Li Yang I 
Published: September 2023

AbstractAlternative splicing (AS) is pervasive in human genes, yet the specific function of most AS events remains unknown. It is widely assumed that the primary function of AS is to diversify the proteome, however AS can also influence gene expression levels by producing transcripts rapidly degraded by nonsense-mediated decay (NMD). Currently, there are no precise estimates for how often the coupling of AS and NMD (AS-NMD) impacts gene expression levels because rapidly degraded NMD transcripts are challenging to capture. To better understand the impact of AS on gene expression levels, we analyzed population-scale genomic data in lymphoblastoid cell lines across eight molecular assays that capture gene regulation before, during, and after transcription and cytoplasmic decay. Sequencing nascent mRNA transcripts revealed frequent aberrant splicing of human introns, which results in remarkably high levels of mRNA transcripts subject to NMD. We estimate that ∼15% of all protein-coding transcripts are degraded by NMD, and this estimate increases to nearly half of all transcripts for lowly-expressed genes with many introns. Leveraging genetic variation across cell lines, we find that GWAS trait-associated loci explained by AS are similarly likely to associate with NMD-induced expression level differences as with differences in protein isoform usage. Additionally, we used the splice-switching drug risdiplam to perturb AS at hundreds of genes, finding that ∼3/4 of the splicing perturbations induce NMD. Thus, we conclude that AS-NMD substantially impacts the expression levels of most human genes. Our work further suggests that much of the molecular impact of AS is mediated by changes in protein expression levels rather than diversification of the proteome.
Synergistic anti-tumor activity, reduced pERK, and immuno-stimulatory cytokine profiles with 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in CRC and pancreatic cancer cells independent of G12D mutation
Authors: Tajiknia Vida , Pinho-Schwermann Maximilian , Srinivasan Praveen R. , Hernandez Borrero Liz , Zhang Leiqing , Huntington Kelsey E. , El-Deiry Wafik S. 
Published: September 2023

AbstractKRAS mutations occur in ∼40-50% of mCRC and are associated with aggressive disease that is refractory to anti-EGFR therapies. Pancreatic cancer harbors ∼90% KRAS driver gene mutation frequency. Small molecules targeting KRAS G12C gained FDA approval for KRAS G12C-mutated NSCLC. ONC212, a fluorinated imipridone with nM anti-cancer activity has preclinical efficacy against pancreatic cancer and other malignancies. MRTX1133, identified as a noncovalent selective KRAS G12D inhibitor that suppresses G12D signaling by binding to the switch II pocket thereby inhibiting protein-protein interactions. We investigated cell viability, drug synergies, pERK suppression and cytokine, chemokine or growth factor alterations following treatment with 5-Fluorouracil (5-FU) or ONC212 plus MRTX1133 in 6 human CRC and 4 human pancreatic cancer cell lines. IC50 sensitivities ranged from 7 to 12 μM for 5-FU, 0.2-0.8 μM for ONC212, and >100 nM to >5,000 nM for MRTX1133 (G12D N=4: LS513 >100, HPAF-II >1,000, SNUC2B >5,000, PANC-1 >5,000). For non-G12D, the range of IC50 for MRTX1133 was >1,000 to >5,000 nM for CRC lines with G12V, G13D, or WT KRAS (N=7). Synergies between MRTX1133 plus 5-FU or ONC212 were observed regardless of KRAS G12D mutation with combination indices of <0.5 indicating strong synergy. Observed synergies were greater with MRTX1133 plus ONC212 compared to MRTX1133 plus 5-FU. pERK was suppressed with mutant but not wild-type KRAS at nM MRTX1133 doses. Immunostimulatory profiles included reduction in IL8/CXCL8, MICA, Angiopoietin 2, VEGF and TNF-alpha and increase in IL-18/IL-1F4 with MRTX treatments and combinations. Our studies reveal preclinical activity of MRTX1133 alone or synergies when combined with 5-FU or ONC212 against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation. The results suggest that KRAS G12V and KRAS G13D should be further considered in clinical trials including combination therapies involving MRTX1133 and 5-FU or ONC212.
A phylogenomic approach, combined with morphological characters gleaned via machine learning, uncovers the hybrid origin and biogeographic diversification of the plum genus
Authors: Hodel Richard G. J. , Winslow Sundre K. , Liu Bin-Bin , Johnson Gabriel , Trizna Michael , White Alex E. , Dikow Rebecca B. , Potter Daniel , Zimmer Elizabeth A. , Wen Jun 
Published: September 2023

ABSTRACTThe evolutionary histories of species have been shaped by genomic, environmental, and morphological variation. Understanding the interactions among these sources of variation is critical to infer accurately the biogeographic history of lineages. Here, using the geographically widely distributed plum genus (Prunus, Rosaceae) as a model, we investigate how changes in genomic and environmental variation drove the diversification of this group, and we quantify the morphological features that facilitated or resulted from diversification. We sequenced 610 nuclear loci and complete chloroplast genomes from 75 species representing all major lineages inPrunus, with a special focus on the understudied tropical racemose group. The environmental variation in extant species was quantified by synthesizing bioclimatic variables into principal components of environmental variation using thousands of georeferenced herbarium specimens. We used machine learning algorithms to classify and measure morphological variation present in thousands of digitized herbarium sheet images. Our phylogenomic and biogeographic analyses revealed that ancient hybridization and/or allopolyploidy spurred the initial rapid diversification of the genus in the early Eocene, with subsequent diversification in the north temperate zone, Neotropics, and Paleotropics. This diversification involved successful transitions between tropical and temperate biomes, an exceedingly rare event in woody plant lineages, accompanied by morphological changes in leaf and reproductive morphology. The machine learning approach detected morphological variation associated with ancient hybridization and quantified the breadth of morphospace occupied by major lineages within the genus. The paleotropical lineages ofPrunushave diversified steadily since the late Eocene/early Oligocene, while the neotropical lineages diversified much later. Critically, both the tropical and temperate lineages have continued to diversify. We conclude that the genomic rearrangements created by reticulation deep in the phylogeny ofPrunusmay explain why this group has been more successful than other groups with tropical origins that currently persist only in either tropical or temperate regions, but not both.
Plasma cell differentiation, antibody quality, and initial germinal center B cell population depend on glucose influx rate
Authors: Brookens Shawna K. , Cho Sung Hoon , Paik Yeeun , Meyer Kaylor , Raybuck Ariel L. , Park Chloe , Greenwood Dalton L. , Rathmell Jeffrey C. , Boothby Mark R. 
Published: September 2023

ABSTRACTAntibody secretion into sera, selection for higher affinity BCR, and the generation of higher Ab affinities are important elements of immune response optimization, and a core function of germinal center reactions. B cell proliferation requires nutrients to support the anabolism inherent in clonal expansion. Glucose usage by GC B cells has been reported to contribute little to their energy needs, with questions raised as to whether or not glucose uptake or glycolysis increases in GC B cells compared to their naïve precursors. Indeed, metabolism can be highly flexible, such that supply shortage along one pathway may be compensated by increased flux on others. We now show that elimination of the glucose transporter GLUT1 after establishment of a pre-immune B cell repertoire, even after initiation of the GC B cell gene expression program, decreased initial GC B cell population numbers, affinity maturation, and PC outputs. Glucose oxidation was heightened in GC B cells, but this hexose flowed more into the pentose phosphate pathway (PPP), whose activity was important in controlling reactive oxygen (ROS) and ASC production. In modeling how glucose usage by B cells promotes the Ab response, the control of ROS appeared insufficient. Surprisingly, the combination of galactose, which mitigated ROS, with provision of mannose - an efficient precursor to glycosylation - supported robust production of and normal Ab secretion by ASC under glucose-free conditions. Collectively, the findings indicate that GC depend on normal glucose influx, especially in PC production, but reveal an unexpected metabolic flexibility in hexose requirements.KEY POINTSGlucose influx is critical for GC homeostasis, affinity maturation and the generation of Ab-secreting cells.Plasma cell development uses the Pentose Phosphate Pathway, and hexose sugars maintain redox homeostasis.PCs can develop and achieve robust Ab secretion in the absence of glucose using a combination of hexose alternatives.
Computational Assessment of Aromatase: Unmasking Therapeutic Avenues for Female Hormonal Disorders
Authors: Koirala Sandesh P. , Magar Bhawana S. , Yadav Amit K. , Regmi Anisha , Pokharel Aashish , Subedi Samiran , Aryal Pramod 
Published: September 2023

AbstractWomen of reproductive age widely experience the physical, mental, and emotional effects of hormonal imbalances. The levels of two hormones, estrogen, and progesterone, were particularly high. When these two hormones are unbalanced, symptoms such as irregular menstrual cycles, pelvic pain, and uterine fibroids can appear. Statistics show that 80 percent of women have hormonal imbalances. The creation of novel disease-containing drug candidates may be facilitated by computer-aided drug design (CADD), as many drugs and surgical treatments have unique adverse effects. Achieving good data coverage requires an optimized process for protein identification and enhanced selection techniques for medicinal compounds, including their metabolic characterization. In this study, aromatase is the prioritized protein that acted as a rate-limiting enzyme in steroidogenesis. To maintain its expression and regulation to control estrogen production, natural compounds were retrieved from the ZINC15 database through ADME/TOX property filtration. Compound B, specifically designated as (1R,3S,6S,7S,10S,11R)-7-[(dimethylamino)methyl]-3,12-dimethyl-2,9-dioxatetracyclo [9.3.0.01,3.06,10] tetradec-12-en-8-one, exhibits remarkable therapeutic potential, as evidenced by its inability to inhibit S-adenosyl methionine (SAM) biosynthesis, the observed stability of molecular interactions based on Density Functional Theory (DFT), and a favorable energy gap between molecular orbital stages. This research can be employed as a utility module for fast screening of drug-like molecules and taking these leads forward to clinical trials, assessing their value as potential suitors for drug repurposing against female hormonal disorders.
RapTCR: Rapid exploration and visualization of T-cell receptor repertoires
Authors: Van Deuren Vincent M.L. , Valkiers Sebastiaan , Laukens Kris , Meysman Pieter 
Published: September 2023

AbstractMotivationThe acquisition of T-cell receptor (TCR) repertoire sequence data has become faster and cheaper due to advancements in high-throughput sequencing. However, fully exploiting the diagnostic and clinical potential within these TCR repertoires requires a thorough understanding of the inherent repertoire structure. Hence, visualizing the full space of TCR sequences could be a key step towards enabling exploratory analysis of TCR repertoire, driving their enhanced interrogation. Nonetheless, current methods remain limited to rough profiling of TCR V and J gene distributions. Addressing this need, we developed RapTCR, a tool for rapid visualization and post-analysis of TCR repertoires.ApproachTo overcome computational complexity, RapTCR introduces a novel, simple embedding strategy that represents TCR amino acid sequences as short vectors while retaining their pairwise alignment similarity. RapTCR then applies efficient algorithms for indexing these vectors and constructing their nearest neighbor network. It provides multiple visualization options to map and interactively explore a TCR network as a two-dimensional representation. Benchmarking analyses using epitope-annotated datasets demonstrate that these RapTCR visualizations capture TCR similarity features on a global level (e.g., J gene) and locally (e.g., epitope reactivity). RapTCR is available as a Python package, implementing the intuitive scikit-learn syntax to easily generate insightful, publication-ready figures for TCR repertoires of any size.Availability and ImplementationRapTCR was written in Python 3. It is available as an anaconda package (https://anaconda.org/vincentvandeuren/raptcr), and on github (https://github.com/vincentvandeuren/RapTCR). Documentation and example notebooks are available at vincentvandeuren.github.io/rapTCR_docs/.Contactpieter.meysman@uantwerpen.be
Signatures of transposon-mediated genome inflation, host specialization, and photoentrainment inEntomophthora muscaeand allied entomophthoralean fungi
Authors: Stajich Jason E. , Lovett Brian , Lee Emily , Macias Angie M. , Hajek Ann E. , de Bivort Benjamin L. , Kasson Matt T. , De Fine Licht Henrik H. , Elya Carolyn 
Published: September 2023

AbstractDespite over a century of observations, the obligate insect parasites within the order Entomophthorales remain poorly characterized at the genetic level. This is in part due to their large genome sizes and difficulty in obtaining sequenceable material. In this manuscript, we leveraged a recently-isolated, laboratory-tractableEntomophthora muscaeisolate and improved long-read sequencing to obtain a largely-complete entomophthoralean genome. OurE. muscaeassembly is 1.03 Gb, consists of 7,810 contigs and contains 81.3% complete fungal BUSCOs. Using a comparative approach with other available (transcriptomic and genomic) datasets from entomophthoralean fungi, we provide new insight into the biology of these understudied pathogens. We offer a head-to-head comparison of morphological and molecular data for species within theE. muscaespecies complex. Our findings suggest that substantial taxonomic revision is needed to define species within this group and we provide recommendations for differentiating strains and species in the context of the existing body ofE. muscaescientific literature. We show that giant genomes are the norm within Entomophthoraceae owing to extensive, but not recent, Ty3 retrotransposon activity, despite the presence of machinery to defend against transposable elements(RNAi). In addition, we find thatE. muscaeand its closest allies are enriched for M16A peptidases and possess genes that are likely homologs to the blue-light sensorwhite-collar 1, aNeurospora crassagene that has a well-established role in maintaining circadian rhythms. We find thatE. muscaehas an expanded group of acid-trehalases, consistent with trehalose being the primary sugar component of fly (and insect) hemolymph. We uncover evidence thatE. muscaediverged from other entomophthoralean fungi by expansion of existing families, rather than loss of particular domains, and possesses a potentially unique suite of secreted catabolic enzymes, consistent withE. muscae’s species-specific, biotrophic lifestyle. Altogether, we provide a genetic and molecular foundation that we hope will provide a platform for the continued study of the unique biology of entomophthoralean fungi.