bluuebunny/crossref_metadata_2025_split huggingface dataset:
IsoBayes: a Bayesian approach for single-isoform proteomics inference
Authors: Bollon Jordy , Shortreed Michael R , Jordan Ben T , Miller Rachel , Jeffery Erin , Cavalli Andrea , Smith Lloyd M , Dewey Colin , Sheynkman Gloria M , Tiberi Simone 
Published: June 2024

AbstractStudying protein isoforms is an essential step in biomedical research; at present, the main approach for analyzing proteins is via bottom-up mass spectrometry proteomics, which return peptide identifications, that are indirectly used to infer the presence of protein isoforms. However, the detection and quantification processes are noisy; in particular, peptides may be erroneously detected, and most peptides, known as shared peptides, are associated to multiple protein isoforms. As a consequence, studying individual protein isoforms is challenging, and inferred protein results are often abstracted to the gene-level or to groups of protein isoforms. Here, we introduceIsoBayes, a novel statistical method to perform inference at the isoform level. Our method enhances the information available, by integrating mass spectrometry proteomics and transcriptomics data in a Bayesian probabilistic framework. To account for the uncertainty in the measurement process, we propose a two-layer latent variable approach: first, we sample if a peptide has been correctly detected (or, alternatively filter peptides); second, we allocate the abundance of such selected peptides across the protein(s) they are compatible with. This enables us, starting from peptide-level data, to recover protein-level data; in particular, we: i) infer the presence/absence of each protein isoform (via a posterior probability), ii) estimate its abundance (and credible interval), and iii) target isoforms where transcript and protein relative abundances significantly differ. We benchmarked our approach in simulations, and in two multi-protease real datasets: our method displays good sensitivity and specificity when detecting protein isoforms, its estimated abundances highly correlate with the ground truth, and can detect changes between protein and transcript relative abundances.IsoBayesis freely distributed as a Bioconductor R package, and is accompanied by an example usage vignette.
Benchmarking second-generation methods for cell-type deconvolution of transcriptomic data
Authors: Dietrich Alexander , Merotto Lorenzo , Pelz Konstantin , Eder Bernhard , Zackl Constantin , Reinisch Katharina , Edenhofer Frank , Marini Federico , Sturm Gregor , List Markus , Finotello Francesca 
Published: June 2024

AbstractIn silico cell-type deconvolution from bulk transcriptomics data is a powerful technique to gain insights into the cellular composition of complex tissues. While first-generation methods used precomputed expression signatures covering limited cell types and tissues, second-generation tools use single-cell RNA sequencing data to build custom signatures for deconvoluting arbitrary cell types, tissues, and organisms. This flexibility poses significant challenges in assessing their deconvolution performance. Here, we comprehensively benchmark second-generation tools, disentangling different sources of variation and bias using a diverse panel of real and simulated data. Our study highlights the strengths, limitations, and complementarity of state-of-the-art tools shedding light on how different data characteristics and confounders impact deconvolution performance. We provide the scientific community with an ecosystem of tools and resources,omnideconv, simplifying the application, benchmarking, and optimization of deconvolution methods.
Single-Cell and Spatial Transcriptomic Analyses Reveals the Dynamic Transcript Profiles of Myocardial Lymphangiogenesis post Myocardial Infarction
Authors: He Jiaqi , Zhang Dali , Song Haixu , Liu Ziqi , Liu Dan , Zhang Xiaolin , Zhao Xiaojie , Zhang Yan , Liu Jing , Xu Jiaxin , Yan Chenghui , Han Yaling 
Published: June 2024

AbstractCardiac lymphatics play an important role in myocardial edema and inflammation. This study integrated single-cell sequencing data and spatial transcriptome data from mouse heart tissue at different time points post-myocardial infarction (MI), and identified four transcriptionally distinct subtypes of lymphatic endothelial cells (LECs) and localized them in space. Interestingly, LECs subgroups was found to be localized in different zones of infarcted heart related to different functions. Additionally, LEC capillary III(LEC ca III) may be involved in the direct regulation of myocardial injuries in infarcted zone from the perspective of metabolic stress, while LEC ca II may be related to the rapid immune inflammatory responses of the border zone in the early stage of MI. LEC ca I, as well as LEC collection mainly participate in the regulation of myocardial tissue edema resolution in the middle and late stages post-MI. Cell trajectory and Cell-Chat analyses further identified that LECs may regulate myocardial edema through Aqp1, and might affect the infiltration of macrophages through the Galectin9-CD44 pathway. Collectively, our study revealed the dynamic transcriptional heterogeneity distribution of LECs in different regions of the infarcted heart, in detail; these LECs formed different functional subgroups, that might exhibit different bioeffects in myocardial tissue post-MI.
Morphometrics as a conservation tool for rapid in-situ distinction of native and introduced iguanas: comparingIguana delicatissimaandIguana iguana
Authors: van den Burg Matthijs P. , Kappelhof Jeroen , Mitchell Adam , Debrot Adolphe O. 
Published: June 2024

AbstractInvasive alien species severely impact native and endemic species, disproportionately affecting insular species, and this is especially true for Caribbean reptiles. The Lesser Antillean iguana (Iguana delicatissima) experienced a drastic range decline strongly driven by hybridization with non-native green iguanas (NNGI,Iguana iguanaspecies complex). With numerous NNGI populations within the Lesser Antilles, it is a matter of time before these arrive on the lastI. delicatisismainhabited islands, whereupon rapid in-situ identification of non-native and hybrid animals is essential. However, only a few scale and coloration characters allow in-situ identification of NNGI, which are compromised by introgression. Here we assessed the differentiating power of an additional 20 scale and length-dependent characteristics between theI. delicatissimapopulation on St. Eustatius and the established NNGI population on St. Maarten, the main source of arriving stowaway iguanas on St. Eustatius. We identified 14 length-dependent characteristics that significantly differ betweenI. delicatissimaand NNGI’s, with multi-variate analysis showing clear morphospace separation and high assignment accuracy of predictive models (>91%). Additionally, the number of femorals and supra digital scales significantly differs between these iguanas. Morphospace knowledge of St. Eustatius’I. delicatissimanow allows rapid identification of any divergent iguanas using easy to obtain measurements and meristics. Given intraspecific variation inI. delicatissimaand green iguanas, we recommend that these characteristics are assessed and validated for other populations, including hybrid individuals. Our work demonstrates the urgent need to invest in baseline morphometric datasets to aid rapid in-situ conservation efforts once NNGI arrive and start to hybridize withI. delicatissima.
Daphnia-associated bacterial communities are influenced by infection status, environmental conditions and diet quantity across natural epidemics
Authors: Rajarajan Amruta , Wolinska Justyna , Walser Jean-Claude , Tardent Nadine , Käser Silvana , Keller Esther , Spaak Piet 
Published: June 2024

AbstractMicrobiomes associated with zooplankton play an important role for host health and contribute to ecosystem functions, such as nutrient cycling. Yet, few studies have assessed how environmental gradients and biotic interactions, such as parasitism and diet, shape the microbiome composition of wild zooplankton. Here, we used 16S rRNA gene sequencing and a long-term field dataset to investigate the microbiomes of water fleas belonging to theDaphnia longispinaspecies complex, across six sampling events spanning 13 years. Sampling coincided with epidemics of the virulent eukaryotic gut parasiteCaullerya mesnili.We further surveyed phytoplankton and zooplankton communities in the lake to explore associations betweenDaphniamicrobiome composition and diet (phytoplankton density), as well as zooplankton density and community composition. We observed temporal variation and infection-dependent shifts inDaphniamicrobiome composition. Importantly, host microbiome compositions co-varied with infection prevalence, indicating a correlation between host microbiome composition and epidemic size. Furthermore, environmental factors including temperature, dissolved oxygen and cyanobacterial abundance, previously found to driveCaulleryaepidemics, were associated with distinct host microbiome compositions. Dominant bacterial taxa in theDaphniamicrobiome correlated withDaphniadensity, whereas the phylogenetic composition of rare bacterial taxa correlated with total zooplankton density. Lastly,Daphniamicrobiome composition correlated with the density of green algae, protists and cyanobacteria in lake water, but not with their community composition. Our findings show the dynamic nature ofDaphnia-associated microbiomes and suggest potential mechanisms through which they may mediate host disease dynamics, including associations with temperature, host density and diet quantity.
Senescent fibroblasts support tumor growth by inducing immune cell death in humanized models
Authors: Cruz Monica , Dulong Joshua , Sonn Anthony , Moquin-Beaudry Gaël , Benabdallah Basma , Le Oanh , Beauséjour Christian 
Published: June 2024

ABSTRACTSyngeneic mouse models revealed that senescence influences the tumor immune response in many ways by, for example, inducing an immunosuppressive microenvironment or by favoring immune cell recruitment. Yet, the impact of senescence on the tumor immune response in a humanized setting is mostly unknown. Here, using tumor spheroids and humanized mice bearing tumors immunogenic to autologous human immune cells, we show that senescent fibroblasts exert a dual impact on the tumor immune response by attracting more immune cells but also by inducing the death of T and NK cells. Mechanistically, we demonstrate that this was mostly the result of increased Fas ligand (FasL) expression at the surface of senescent fibroblasts and that the deletion of FasL was sufficient to prevent immune cell death and increase tumor cell killing. Our results highlight the importance of evaluating the impact of therapy-induced senescence in humanized models to better understand and predict the outcome of cancer treatments.
Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells
Authors: Sinclair Linda V. , Youdale Tom , Spinelli Laura , Gakovic Milica , Langlands Alistair J. , Pathak Shalini , Howden Andrew J.M. , Ganley Ian G. , Cantrell Doreen A. 
Published: June 2024

AbstractAutophagy is important for CD8 T-cells but autophagy timing, triggers and targets are poorly defined. Herein, we show naïve CD8-T cells have high autophagic flux and identify an autophagy checkpoint whereby antigen receptor engagement represses autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Effector cytotoxic T cells with high levels of amino acid transporters driven by proinflammatory cytokines have low autophagic flux but rapidly reinduce autophagy when amino acid restricted. A census of proteins degraded and fuelled by autophagy shows how autophagy shapes CD8-T cell proteomes. In cytotoxic T-cells, dominant autophagy substrates include cytolytic effector molecules, amino acid and glucose transporters. In naïve T-cells mitophagy dominates and selective mitochondrial pruning supports the expression of molecules that coordinate T-cell migration and survival. Autophagy thus differentially prunes naive and effector T-cell proteomes and is dynamically repressed by antigen receptors and inflammatory cytokines to shape T-cell differentiation.
Local increases in admixture with hunter-gatherers followed the initial expansion of Neolithic farmers across continental Europe
Authors: Tsoupas Alexandros , Reyna-Blanco Carlos S. , Quilodrán Claudio S. , Blöcher Jens , Brami Maxime , Wegmann Daniel , Burger Joachim , Currat Mathias 
Published: June 2024

AbstractThe replacement of hunter-gatherer lifestyles by agriculture represents a pivotal change in human history. The initial stage of this Neolithic transition in Europe was instigated by the migration of farmers from Anatolia and the Aegean basin. In this study, we modeled the expansion of Neolithic farmers into Central Europe from Anatolia, along the Continental route of dispersal. We employed spatially explicit simulations of palaeogenomic diversity and high-quality palaeogenomic data from 67 prehistoric individuals to assess how population dynamics between indigenous European hunter-gatherers and incoming farmers varied across space and time. Our results demonstrate that admixture between the two groups increased locally over time at each stage of the Neolithic expansion along the Continental route. We estimate that the effective population size of farmers was about five times that of the hunter-gatherers. Additionally, we infer that sporadic long distance migrations of early farmers contributed to their rapid dispersal, while competitive interactions with hunter-gatherers were limited.TeaserThe first farmers of continental Europe increasingly admixed over time with indigenous hunter-gatherers.
Phosphorylation of disordered proteins tunes local and global intramolecular interactions
Authors: Usher Emery T. , Fossat Martin J. , Holehouse Alex S. 
Published: June 2024

ABSTRACTProtein post-translational modifications, such as phosphorylation, are important regulatory signals for diverse cellular functions. In particular, intrinsically disordered protein regions (IDRs) are subject to phosphorylation as a means to modulate their interactions and functions. Toward understanding the relationship between phosphorylation in IDRs and specific functional outcomes, we must consider how phosphorylation affects the IDR conformational ensemble. Various experimental techniques are suited to interrogate the features of IDR ensembles; molecular simulations can provide complementary insights and even illuminate ensemble features that may be experimentally inaccessible. Therefore, we sought to expand the tools available to study phosphorylated IDRs by all-atom Monte Carlo simulations. To this end, we implemented parameters for phosphoserine (pSer) and phosphothreonine (pThr) into the OPLS version of the continuum solvent model, ABSINTH, and assessed their performance in all-atom simulations compared to published findings. We simulated short (< 20 residues) and long (> 80 residues) phospho-IDRs that, collectively, survey both local and global phosphorylation-induced changes to the ensemble. Our simulations of four well-studied phospho-IDRs show near-quantitative agreement with published findings for these systems via metrics including changes to radius of gyration, transient helicity, and persistence length. We also leveraged the inherent advantage of sequence control in molecular simulations to explore the conformational effects of diverse combinations of phospho-sites in two multi-phosphorylated IDRs. Our results support and expand on prior observations that connect phosphorylation to changes in the IDR conformational ensemble. Herein, we describe phosphorylation as a means to alter sequence chemistry, net charge and charge patterning, and intramolecular interactions, which can collectively modulate the local and global IDR ensemble features.SIGNIFICANCESpatially and temporally controlled phosphorylation in disordered protein regions is critical to many facets of protein function and broader cellular health. Intrinsically disordered protein regions (IDRs) are overrepresented as targets of phosphorylation, but the structural and functional consequences of such modifications remain elusive for many systems. Toward rigorous modeling of phosphorylated IDRs using all-atom simulations, we present new parameters for phosphoserine and phosphothreonine for the ABSINTH implicit solvent paradigm. Through the study of four example phospho-IDRs, we demonstrate excellent agreement between our phospho-IDR simulations and published datasets.
Increased pathogenicity and transmission of SARS-CoV-2 Omicron XBB.1.9 sublineage, including HK.3 and EG.5.1
Authors: Jin Qiushi , Liu Ruixue , Wang Wenqi , Xie Jichen , Wang Tiecheng , Xiang Haiyang , Xia Xianzhu , Li Jianmin , Wang Xuefeng , Gao Yuwei 
Published: June 2024

AbstractWith the SARS-CoV-2 Omicron XBB.1.9 sublineage circulating worldwide, two XBB.1.9 variants, EG.5.1 and HK.3 spread rapidly and became dominant from middle 2023. However, the spike features, pathogenicity, and transmissibility of HK.3 are largely unknown. Here, we performed multiscale investigations to reveal the virological features of XBB.1.9 subvariants, especially the newly emerging HK.3. HK.3 revealed high replication efficiency in vitro. The HK.3 spike exhibited enhanced processing, although its infectivity, fusogenicity, and hACE2 binding affinity were comparable to those of the EG.5 and XBB.1 spikes. All XBB.1.9.1, EG.5.1 and HK.3 strains demonstrated efficient transmission in hamsters, although XBB.1.9.1 exhibited stronger fitness in the upper airways. HK.3 and EG.5.1 exhibited greater pathogenicity than XBB.1.9.1 and BA.2 in H11-K18-hACE2 hamsters. Our studies provide insight into the newly emerging pathogens HK.3 and EG.5.1.ImportanceIn animal models, the ongoing attenuated pathogenicity and poor transmission of Omicron subvariants seems to reach a consensus. However, our results revealed that Omicron XBB.1.9 subvariants, including one of the key variants of interest, EG.5 with its another key subvariant HK.3, universally exhibited both increased pathogenicity and highly transmission. This study reemphasized the importance of surveillance in characteristics of epidemic Omicron subvariants.
Longitudinal sex-at-birth and age analyses of cortical structure in the ABCD Study®
Authors: Marshall Andrew T. , Adise Shana , Kan Eric C. , Sowell Elizabeth R. 
Published: June 2024

AbstractWhile the brain continues to develop during adolescence, such development may depend on sex-at-birth. However, the elucidation of such differences may be hindered by analytical decisions (e.g., covariate selection to address body/brain-size differences) and the typical reporting of cross-sectional data. To further evaluate adolescent cortical development, we analyzed data from the Adolescent Brain Cognitive Development StudySM, whose cohort of 11,000+ youth participants with biannual neuroimaging data collection can facilitate understanding neuroanatomical change during a critical developmental window. Doubly considering individual differences in the context of group-level effects, we analyzed regional changes in cortical thickness, sulcal depth, surface area, and volume between two timepoints (∼2 years apart) in 9-to 12-year-olds assigned male or female sex-at-birth. First, we conducted linear mixed-effects models to gauge how controlling for intracranial volume, whole-brain volume (WBV), or a summary metric (e.g., mean cortical thickness) influenced interpretations of age-dependent cortical change. Next, we evaluated the relative changes in thickness and surface area as a function of sex-at-birth and age. Here, we showed that WBV (thickness, sulcal depth, volume) and total cortical surface area were more optimal covariates; controlling for different covariates would have substantially altered our interpretations of overall and sex-at-birth-specific neuroanatomical development. Further, we provided evidence to suggest that aggregate change in how cortical thickness is changing relative to surface area is generally comparable across those assigned male or female sex-at-birth, with corresponding change happening at slightly older ages in those assigned male sex-at-birth. Overall, these results help elucidate neuroanatomical developmental trajectories in early adolescence.Significance StatementWhile most of our brain’s development happens early in life, much of it still happens in adolescence. Because many factors can alter those developmental trajectories, it is important to evaluate the shape/timing of those trajectories (i.e., what generally constitutes typical brain development). Here, we showed that our understanding of those trajectories can be affected by how we choose to analyze them. First, we showed that the way researchers address differences in brain/body size affects how we interpret regional variation in brain change over time. Further, we showed that it is important to consider how similar patterns of development may simply be happening at different ages in different groups. These results support a relatively novel way of analyzing adolescent brain development.
Adjuvant Delivery Method and Nanoparticle Charge Influence Peptide Amphiphile Micelle Vaccine Bioactivity
Authors: Zhang Rui , Rygelski Brett T. , Kruse Luke E. , Smith Josiah D. , Wang Xiaofei , Allen Brittany N. , Kramer Jake S. , Seim Gracen F. , Faulkner Trent J. , Kuang Huihui , Kokkoli Efrosini , Schrum Adam G. , Ulery Bret D. 
Published: June 2024

AbstractVaccines are an indispensable public health measure that have enabled the eradication, near elimination, and prevention of a variety of pathogens. As research continues and our understanding of immunization strategies develops, subunit vaccines have emerged as exciting alternatives to existing whole vaccine approaches. Unfortunately, subunit vaccines often possess weak antigenicity, requiring delivery devices and adjuvant supplementation to improve their utility. Peptide amphiphile micelles have recently been shown to function as both delivery devices and self-adjuvanting systems that can be readily associated with molecular adjuvants to further improve vaccine-mediated host immunity. While promising, many “design rules” associated with the plethora of underlying adjustable parameters in the generation of a peptide amphiphile micelle vaccine have yet to be uncovered. This work explores the impact micellar adjuvant complexation method and incorporated antigen type have on their ability to activate dendritic cells and induce antigen specific responses. Interestingly, electrostatic complexation of CpG to micelles resulted in improvedin vitrodendritic cell activation over hydrophobic association and antigen|adjuvant co-localization influenced cell-mediated, but not antibody-mediated immune responses. These exciting results complement those previously published to build the framework of a micelle vaccine toolbox that can be leveraged for future disease-specific formulations.