bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fibroblast contractility drives network reorganization and epithelial proliferation in intestinal polyposis
Authors: Li Mei-Lan , Wang Yuying , Figetakis Maria , Gonzalez David , Jin Jason , McDonald Elizabeth S. , Ameen Nadia A. , Sumigray Kaelyn 
Published: January 2025

SummaryFibroblasts are critical regulators of epithelial homeostasis through mechanics and signaling. However, the regulatory principles governing fibroblast behaviors are largely unknown. Fibroblast dysregulation has emerged as a pathological contributor in epithelial diseases such as intestinal polyposis. Here, using an inducible Bmp-loss-of-function polyposis model, we define stepwise mechanisms unraveling how dysregulated signaling perturbs fibroblast behaviors, which in turn, disrupt their function to regulate epithelial homeostasis. Intriguingly, the first initiating event leading to epithelial polyps was architectural and impacted the fibroblasts, not the epithelium. Bmp signaling inhibition caused fibroblasts to become hypercontractile, leading to their reorganization from an elaborate network into collapsed clusters beneath crypts. Disrupted fibroblast mechanics and compartmentalization preceded epithelial hyperproliferation in polyps. Using in vitro models, we show that fibroblast hypercontractility not only disrupted fibroblast organization, but also enhanced the ability of fibroblasts to support epithelial growth, leading to epithelial dysregulation. Overall, our studies reveal stepwise regulatory mechanisms underlying fibroblast signaling, mechanics and organization critical for their function to regulate epithelial homeostasis.
Using a Pharmacokinetic Model to Design and Evaluate an Early ctDNA Biomarker for Response to Targeted Therapy
Authors: Li Aaron 
Published: January 2025

AbstractEarly prediction of response to therapy or lack thereof can help physicians plan treatment more efficiently. Biomarkers based on circulating tumor DNA (ctDNA) are promising. However, biomarkers beyond direct comparison to baseline have not been thoroughly explored. We develop a model for ctDNA shedding under targeted therapy that incorporates pharmacokinetics. Using a simulated cohort of virtual patients with varied parameters, we define and analyze a biomarker based on ctDNA samples at baseline, 12 hours, and 24 hours after initiation of treatment. The biomarker identified patients who would achieve partial or complete response with high sensitivity and specificity and was able to match the performance of a neural network classifier. Our result highlights the potential of ctDNA as a biomarker and underlines the importance of early ctDNA data collection.
A Machine Learning-based Approach for Quantification of Protein Secondary Structures from Discrete Frequency Infrared Images
Authors: Edmonds Harrison , Mukherjee Sudipta S. , Holcombe Brooke , Yeh Kevin , Bhargava Rohit , Ghosh Ayanjeet 
Published: January 2025

AbstractDiscrete frequency infrared (IR) imaging is an exciting experimental technique that has shown promise in various applications in biomedical science. This technique often involves acquiring IR absorptive images at specific frequencies of interest that enable pathologically relevant chemical contrast. However, certain applications, such as tracking the spatial variations in protein secondary structure of tissue specimens, necessary for the characterization of neurodegenerative diseases, require deeper analysis of spectral data. In such cases, the conventional analytical approach involves band fitting the hyperspectral data to extract the relative populations of different structures through their fitted areas under the curve (AUCs). While Gaussian spectral fitting for one spectrum is viable, expanding that to an image with millions of pixels, as often applicable for tissue specimens, becomes a computationally expensive process. Alternatives like Principal Component Analysis (PCA) are less structurally interpretable and incompatible with sparsely sampled data. Furthermore, this detracts from the key advantages of discrete frequency imaging by necessitating acquisition of a more finely sampled spectral data that is optimal for curve fitting, resulting in significantly longer data acquisition times, larger datasets and additional computational overhead. In this work we demonstrate that a simple two-step regressive neural network model can be utilized to mitigate these challenges and employ discrete frequency imaging for retrieving the results from band fitting without significant loss of fidelity. Our model reduces the data acquisition time nearly 6-fold by requiring only seven wavenumbers to accurately interpolate spectral information at a higher resolution, and subsequently using the upscaled spectra to accurate predict the component AUCs, which is more than 3000 times faster than spectral fitting. Our approach thus drastically cuts down the data acquisition and analysis time and predicts key differences in protein structure that can be vital towards broadening potential applications of discrete frequency imaging.
The influence of reproductive mode on resource competition and diversity patterns in Ediacaran early animal communities
Authors: Mitchell Emily G. , Manica Andrea 
Published: January 2025

SummaryThe appearance of the oldest known animals during the late Ediacaran (∼574 million years ago [Ma])1–4was followed by a phase of little change5. This period, which lasted ∼14 million years, ended with a burst of rapid diversification known as the Ediacaran “Second Wave”. The reasons for these diversity patterns are poorly understood. Here we investigate how reproductive mode mediated community dynamics, and in turn macroevolutionary change, in the Ediacaran. We show that widespread reproduction via stolon (namely via filaments connecting clones) in the first animals limited intra-specific competition among neighbours, leading to inter-specific competition acting at smaller-spatial scales than intra-specific competition, a phenomenon called heteromyopia6. Heteromyopia enables co-existence of sub-optimal competitors because the dispersal limitation of the dominant species means that they do not inhabit all the optimal habitat, so that lesser competitors can still exist within the same community, operating under reduced selection pressure. We explored the consequences of this dispersal limitation on community diversity using Approximate Bayesian Computation to estimate the posterior distributions of dispersal with a spatially explicit model fitted to the three Ediacaran assemblages and showed that the change from stoloniferous to sexual reproduction that coincided with the Second Wave could explain the sudden increase in alpha diversity observed in the fossil record. We conclude that widespread asexual reproduction via stolon likely constrained early animal evolution, limiting diversification until the onset of mobility and widespread sexual reproduction7–9.
Chromosomal inversions mediated by tandem insertions of transposable elements
Authors: Araya Robin Aasegg , Reinar William B , Tørresen Ole K , Goubert Clément , Daughton Tara J , Hoff Siv Nam Khang , Baalsrud Helle T , Brieuc Marine Servane Ono , Komisarczuk Anna , Jentoft Sissel , Cerca José , Jakobsen Kjetill S 
Published: January 2025

AbstractChromosomal inversions play a crucial role in evolution by influencing phenotypes through the linkage of co-adapted alleles. While inversions have been found across a large number of taxa, mapping and characterizing inversion breakpoint regions remains challenging, often due to the presence of complex tandem repeats and transposable elements (TEs). Here, we identify and quantify TEs in the breakpoints of the four large-scale inversions previously reported in Atlantic cod, leveraging on three high-quality long-read-based reference genome assemblies for the Norwegian Coastal cod, the Northeast Arctic cod and Celtic cod ecotypes. We detected a significant enrichment of TE orders and superfamilies with terminal inverted repeats (TIRs) within the inversion breakpoints of chromosomes 1, 7 and 12. Notably, we discovered a tandem accumulation of miniature inverted-repeat transposable elements (MITEs) belonging to a family ofhATtransposons, exclusively residing in the breakpoints of the inverted haplotype on chromosomes 1 and 7 found in the Northeast Arctic cod. The accumulation of tandemly arranged TEs in breakpoint regions suggests that they have driven the appearance of inversions through ectopic recombination, further supporting the potential of TEs in facilitating chromosomal reorganizations with large evolutionary implications.
30-Color Longitudinal Full-Spectrum Immunophenotyping and Sorting of Human Circulating Immune Cell Subsets Implicated in Systemic Autoimmune Rheumatic Diseases
Authors: Jiwrajka Nikhil , Tuluc Florin , Jaimes Maria C. , Murray Jennifer , Anguera Montserrat C. 
Published: January 2025

Purpose and Appropriate Sample TypesThis 30-color panel was developed to enable the enumeration and purification of distinct circulating immune cell subsets implicated in the pathogenesis of systemic autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc; scleroderma), Sjögren’s disease (SjD), idiopathic inflammatory myopathy (IIM), and others. While designed for application to peripheral blood mononuclear cells, the inclusion of CD45 coupled with the ability to extract cellular autofluorescence spectral signatures enables the application of this panel to other tissue types. Of the 30 total markers, this panel employs 18 markers to profile T cell subsets consisting of different memory subsets and T helper polarities,>10 markers to profile B cell subsets including double-negative B cells, and a total of 8 lineage markers to identify immune lineages including monocyte and natural killer cell subsets, conventional dendritic cells, plasmacytoid dendritic cells, and basophils. This panel reproducibly identifies target populations with excellent resolution over several months of data acquisition with minimal batch effects, offering investigators a practical approach to sort immune cell subsets of interest for downstream applications while simultaneously collecting high parameter immunophenotypic information using a limited sample quantity.
Palmitate-induced mitochondrial damage restricts histone acetylation in CD8+T cells to impair anti-tumor immunity
Authors: Tiberti Silvia , Romeo Martina , Rumiano Letizia , Nava Lauson Carina B , Sheraj Ilir , Catozzi Carlotta , Noberini Roberta , Olivari Davide , Dallavilla Tiziano , Galie’ Serena , Ballerini Mattia , Loffreda Alessia , Schaefer Martin H. , Bonaldi Tiziana , Nezi Luigi , Sdelci Sara , Manzo Teresa 
Published: January 2025

ABSTRACTAccumulation of lipids in the tumor microenvironment (TME) is a feature of several solid tumors and increased palmitate (PA) availability fosters tumor progression and metastases. The intrinsic effects of PA on cancer cells are well understood, but its role in modulating CD8+T cells (CTL) functional performances remains elusive. Here, we found that PA alters the mitochondrial metabolism of CTL and prevents their effector functions in an irreversible manner, resulting in impaired antitumoral immunity. Mechanistically, PA-induced mitochondrial block demotes histone acetylation and chromatin accessibility and decrease transcription of genes promoting DNA replication and production of effector molecules. We identified the metabolic enzyme Sphingosine Kinase 2 (SPHK2) as a molecular target of PA in establishing CTL dysfunction. Consistently, pharmacological inhibition of SPHK2 restored CTL mitochondrial fitness, effector functions and anti-tumor potential. Thus, we reveal a critical function of PA in tumor progression by undermining CTL antitumor immunity and highlight the therapeutic potential of inhibiting SPHK2 activity to optimize T cell functionality.
Determining off-target effects of splice-switching antisense oligonucleotides using short read RNAseq in neuronally differentiated human induced pluripotent stem cells
Authors: Kuijper EC , van der Graaf L , Pepers BA , Guimarães Ramos M , Korhorn S , Toonen LJA , Cats D , Buijsen RAM , Mina E , Mei H , van Roon-Mom WMC 
Published: January 2025

AbstractAntisense oligonucleotides (AONs) are small pieces of chemically modified DNA or RNA that bind to RNA in a sequence-specific manner based on Watson-Crick base-pairing. Splice-switching AONs are designed to modulate pre-mRNA splicing, thereby for instance restoring protein expression or modifying the eventual protein to restore its function or reduce its toxicity. Given the current lack ofin silicomethods that adequately predict off-target splicing events, assessment of off-target effects of AONs in human cells using RNAseq could be a promising approach. The identification and prioritization of potential off-target effects for validation and further investigation into the biological relevance would contribute to the development of safe and effective AONs. In this study, we used three different splice-switching AONs targeting three different human transcripts to study their transcriptome-wide, hybridization-dependent off-target effects with short read RNAseq. Using the computational tools rMATS and Whippet, we identified differential splicing events of which only a minority could be explained by hybridization, illustrating the difficulty of predicting off-target effects based on sequence homology. The main splicing events could all be validated with RT-PCR. Furthermore, from the three AONs studied, one AON induced considerably more changes in gene expression and splicing compared to the two other AONs assessed, which was confirmed in a validation experiment. Our study demonstrates that the interpretation of short read RNAseq data to determine off-target effects is challenging. Nonetheless, we showed that valuable results can be obtained as it allows the comparison of toxicity between different AONs within an experiment and identification of AON-specific off-target profiles.
Applying a conservation-based approach for predicting novel phosphorylation sites in eukaryotes and evaluating their functional relevance
Authors: Kalyuzhnyy Anton , Eyers Patrick A , Eyers Claire E , Deutsch Eric W , Jones Andrew R 
Published: January 2025

AbstractProtein phosphorylation, a key post-translational modification, is central to cellular signalling and disease pathogenesis. The development of high-throughput proteomics pipelines has led to the discovery of large numbers of phosphorylated protein motifs and sites (phosphosites) across many eukaryotic species. However, the majority of phosphosites are reported from human cellular sources, with most species having only a few experimentally confirmed or computationally predicted phosphosites. Furthermore, only a small fraction of the characterised human phosphoproteome has an annotated functional role. A common method of predicting functionally relevant phosphosites is conservation analysis. However, extensive evolutionary studies involving large numbers of species are scarce. In this study, we explore the conservation of 20,751 confident human phosphosites across 100 eukaryotic species. We link the observed conservation patterns to the functional relevance of phosphosites and investigate the evolution of associated protein domains and kinases. We identify several protein functions that are likely regulated by phosphorylation, including ancient functions conserved across all life and relatively new functions only conserved in species closely related to humans. We demonstrate the importance of conservation analysis in identifying organisms suitable as biological models for studying conserved signalling pathways relevant to human biology and disease. Finally, we use human protein sequences as a reference to apply conservation analysis and predict over 1,000,000 potential phosphosites in analysed eukaryotes. Our results can ultimately be used to improve proteome annotations of several species and direct downstream research surrounding the evolution and functional relevance of eukaryotic phosphosites.
AI-Driven Toolset for IPF and Aging Research Associates Lung Fibrosis with Accelerated Aging
Authors: Galkin Fedor , Chen Shan , Aliper Alex , Zhavoronkov Alex , Ren Feng 
Published: January 2025

AbstractIdiopathic pulmonary fibrosis (IPF) is a condition predominantly affecting the elderly and leading to a decline in lung function. Our study investigates the aging-related mechanisms in IPF using artificial intelligence (AI) approaches. We developed a pathway-aware proteomic aging clock using UK Biobank data and applied it alongside a specialized version of Precious3GPT (ipf-P3GPT) to demonstrate an AI-driven mode of IPF research. The aging clock shows great performance in cross-validation (R2=0.84) and its utility is validated in an independent dataset to show that severe cases of COVID-19 are associated with an increased aging rate. Computational analysis using ipf-P3GPT revealed distinct but overlapping molecular signatures between aging and IPF, suggesting that IPF represents a dysregulation rather than mere acceleration of normal aging processes. Our findings establish novel connections between aging biology and IPF pathogenesis while demonstrating the potential of AI-guided approaches in therapeutic development for age-related diseases.
Cadmium tolerance is associated with tissue-specific plasticity of metallothionein gene expression inGammarus fossarumfield populations
Authors: Lalouette Auréline , Chaumot Arnaud , Lepeule Louveline , Gaget Karen , Delorme Nicolas , Garnero Laura , Calevro Federica , Degli Esposti Davide 
Published: January 2025

AbstractThe metallothionein gene family codes for proteins involved in metal homeostasis and acute detoxification of non-essential toxic metal ions across the tree of life. We have previously documented increased cadmium (Cd) tolerance in field populations of the crustaceanGammarus fossarumexposed to chronic metallic contamination of geochemical origin. This tolerance is lost during maintenance of organisms in the laboratory, and is transmitted to offspring via parental effects. This study investigated whether the expression of the Cd-responsive metallothionein genemt1could be related to Cd-tolerance plasticity inG. fossarum. In eleven populations with different chronic Cd exposure history, we simultaneously assessed Cd-tolerance (mortality tests) andG. fossarum mt1expression levels by RT-qPCR in the gills and caeca of adult males and in neonates.mt1expression levels in the two organs were correlated to Cd-tolerance in field organisms and a loss of tolerance was observed in parallel with a decreased expression ofmt1in the caeca after maintenance in uncontaminated water. We also recorded a greater inducibility ofmt1expression in offspring of tolerant populations in the laboratory when re-exposed to Cd along with the bi-parental transmission of Cd-tolerance. These results suggest that the control ofmt1expression is involved in the plasticity of Cd-tolerance in gammarid populations with different histories of Cd exposure.Highlights-mt1gene expression in the gills and in the hepatopancreatic caeca is associated with Cd tolerance inGammarus fossarumpopulations.-Plasticity ofG. fossarum mt1gene expression is associated to loss of Cd tolerance.-Parental effect in Cd tolerance is supported by transgenerational control ofmt1expression, underlid by an increased induction ofmt1during Cd exposure.
Altered RNA-processing provides a mechanistic framework delineating human sex-reversal associated with pathogenic variants in the RNA-helicase DHX37
Authors: Elzaiat Maëva , Talouarn Estelle , Wankanit Somboon , Schlick Laurène , Eozenou Caroline , Bignon-Topalovic Joëlle , Kornobis Etienne , Commere Pierre-Henri , Baum Chloé , Seffer Valérie , McElreavey Ken , Bashamboo Anu 
Published: January 2025

AbstractRecurrent heterozygous missense variants in the highly conserved RNA-helicaseDHX37,which is required for ribosome biogenesis, are a frequent cause of 46,XY sex-reversal or testis regression syndrome. How these missense variants specifically disrupt testis formation is unknown. Here, we demonstrate that mutant DHX37 proteins retain their ATPase activity and are not associated with stabilization of cellular β-catenin. Transfection of DHX37 p.R674Q mutant protein in anin-vitrocellular model recapitulating human Sertoli cell formation, showed a reduced activation of pro-testis genes compared to the WT protein. The expression of a DHX37 mutant protein inin-vitroderived human Sertoli-like cells (iSLCs) was also associated with global changes in gene expression, predicted to impact basic cellular functions. To define RNA transcripts interacting with either the WT or a mutant (p.R674Q) protein, we combined HyperTRIBE and single-cell full-length RNA-sequencing approaches using iSLCs. Gene ontology analysis indicated that transcripts targeted by WT DHX37 were primarily associated with cytoskeleton organization, including cell motility and cell adhesion. However, in contrast transcripts targeted by the mutated DHX37 protein, were not only associated with cytoskeleton organization but also with protein degradation and cell death. These data provide mechanistic framework that may explain how variants in the DHX37 protein can result in 46,XY sex-reversal through altered RNA networks that are required for the formation and maintenance of the supporting cell lineages of the human testis.
The PST repeat region of MDC1 is a tunable multivalent chromatin tethering domain
Authors: Heyza Joshua R. , Mikhova Maria , Perez Gloria I. , Broadbent David G. , Schmidt Jens C. 
Published: January 2025

ABSTRACTDNA double strand breaks (DSBs) are widely considered the most cytotoxic DNA lesions occurring in cells because they physically disrupt the connectivity of the DNA double helix. Homologous recombination (HR) is a high-fidelity DSB repair pathway that copies the sequence spanning the DNA break from a homologous template, most commonly the sister chromatid. How both DNA ends, and the sister chromatid are held in close proximity during HR is unknown. Here we demonstrate that the PST repeat region of MDC1 is a mutlivalent nucleosome binding domain, sufficient to tether chromatin in multiple contexts. In mitotic cells the affinity of the PST repeats for chromatin is downregulated by phosphorylation to prevent chromosome missegregation, while still contributing to DNA break tethering by the MDC1-TOPBP1-CIP2A complex. In interphase, the PST repeat region is critical for RAD51 focus formation but not the recruitment of 53BP1 to DNA breaks, consistent with a chromatin tethering function. In total, this work demonstrates that the PST repeat region of MDC1 is a multivalent chromatin binding domain with tunable affinity that contributes to DNA break tethering during HR and in mitosis.