bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell atlas of developing mouse palates reveals cellular and molecular transitions in periderm cell fate
Authors: Huang Wenbin , Qian Zhenwei , Zhang Jieni , Ding Yi , Wang Bin , Lin Jiuxiang , Zhang Xiannian , Zhao Huaxiang , Chen Feng 
Published: November 2024

AbstractCleft palate is one of the most common congenital craniofacial disorders that affects children’s appearance and oral functions. Investigating the transcriptomics during palatogenesis is crucial for comprehending the etiology of this disorder and facilitating prenatal molecular diagnosis. However, there is limited knowledge about the single-cell differentiation dynamics during mid- and late-palatogenesis, specifically regarding the subpopulations and developmental trajectories of periderm, a rare but critical cell population. Here we explore the single-cell landscape of mouse developing palates from E10.5 to E16.5. We systematically depict the single-cell transcriptomics of mesenchymal and epithelial cells during palatogenesis, including subpopulations and differentiation dynamics. Additionally, we identify four subclusters of palatal periderm and construct two distinct trajectories of cell fates for periderm cells. Our findings reveal thatClaudinsandArhgap29play a role in the non-stick function of the periderm before the palatal shelves contact, andPitx2mediates the adhesion of periderm during the contact of opposing palatal shelves. Furthermore, we demonstrate that epithelial-mesenchymal transition (EMT), apoptosis, and migration collectively contribute to the degeneration of periderm cells in the medial epithelial seam. Taken together, our study suggests a novel model of periderm development during palatogenesis and delineates the cellular and molecular transitions in periderm cell determination.
Platelets are Protective in Early Abdominal Aortic Aneurysm Formation
Authors: Russell Hannah M. , Spuzzillo Anthony R. , Benson Tyler W. , Jaworski James , Clément Marc , Boulaftali Yacine , Saum Keith , Conrad Kelsey A. , Howatt Deborah A. , Luyendyk James P. , Cameron Scott J. , Nieswandt Bernhard , Steinhubl Steven R. , Daugherty Alan , Bergmeier Wolfgang , Tong Wei , Damrauer Scott M. , Tsao Philip S. , Mallat Ziad , Edwards Todd L. , Mackman Nigel , Owens A. Phillip 
Published: November 2024

ABSTRACTBackgroundAbdominal aortic aneurysm (AAA) is a disease associated with the pathophysiologic degradation of the tunica media resulting in aortic dilatation, systemic inflammation, and dysregulated hemostasis. Beyond role its role in initiating primary hemostasis, platelets are a source of ROS, inflammatory cytokines and growth factors necessary for angiogenesis and vascular remodeling. Although platelets contribute to the progression of established aneurysms, their role in the initiation of AAA remains undefined.MethodsLow density lipoprotein receptor deficient (Ldlr−/−) mice were examined for platelet accumulation in the angiotensin II (AngII) model of AAA utilizing in vivo labeling techniques. Two platelet antagonists (clopidogrel and aspirin), a thrombin inhibitor (dabigatran) or genetic deficiencies (protease-activated receptor 4,P2Y12,Lnk) were administered to AngII-infused mice to determine the role of platelets in initiation of AAA. The effect of platelet depletion was examined in multiple mouse strains of AngII-induced AAA and two additional aneurysm models. PheWAS and meta-analysis was analyzed in humans for platelet gene SNPs associated with AAA.ResultsWe show that platelets are recruited rapidly to the aorta after the initiation of AngII infusion. Genetic deficiency of platelet receptors had no effect on abdominal aortic diameter, but augmented rupture-induced death in littermate versus placebo controls during AngII-induced AAA. Moreover,Ldlr−/−mice receiving anti-platelet inhibitors or a thrombin inhibitor also had augmented rupture-induced death. Platelet depletion preceding aneurysm formation resulted in pervasive rupture-induced death in several mouse strains and with three different mouse models of AAA.ConclusionsInhibition of platelet function is detrimental in an early expanding aortic lumen resulting in catastrophic rupture and hemodynamic failure in murine AAA models.
An Open Competition for Biomarkers of Aging
Authors: Ying Kejun , Paulson Seth , Reinhard Julian , de Lima Camillo Lucas Paulo , Träuble Jakob , Jokiel Stefan ,   Biomarkers of Aging Consortium, Gobel Dane , Herzog Chiara , Poganik Jesse R. , Moqri Mahdi , Gladyshev Vadim N. 
Published: November 2024

AbstractOpen scientific competitions have successfully driven biomedical advances but remain underutilized in aging research, where biological complexity and heterogeneity require methodological innovations. Here, we present the results from Phase I of the Biomarkers of Aging Challenge, an open competition designed to drive innovation in aging biomarker development and validation. The challenge leverages a unique DNA methylation dataset and aging outcomes from 500 individuals, aged 18 to 99. Participants are asked to develop novel models to predict chronological age, mortality, and multi-morbidity. Results from the chronological age prediction phase show important advances in biomarker accuracy and innovation compared to existing models. The winning models feature improved predictive power and employ advanced machine learning techniques, innovative data preprocessing, and the integration of biological knowledge. These approaches have led to the identification of novel age-associated methylation sites and patterns. This challenge establishes a paradigm for collaborative aging biomarker development, potentially accelerating the discovery of clinically relevant predictors of aging-related outcomes. This supports personalized medicine, clinical trial design, and the broader field of geroscience, paving the way for more targeted and effective longevity interventions.
PreDigs: a Database of Context-specific Cell-type Markers and Precise cell subtypes for Digestive Cell Annotation
Authors: Meng Jiayue , Han Mengyao , Huang Yuwei , Li Liang , Ju Yuanhu , Lv Daqing , Chen Xiaoyi , Yuan Liyun , Zhang Guoqing 
Published: November 2024

AbstractResearch on cell type markers aids investigators in exploring the diverse cellular compositions within gastrointestinal tumors, enhancing our understanding of tumor heterogeneity and its implications for disease progression and treatment response. However, issues such as the integration of large-scale datasets and the lack of standardized cell type identification hinder comprehensive characterization. Here, we developed a user-friendly web interface called PreDigs (Predicted Signatures in Digestive System), which offers 124 tailored scRNA-seq datasets available for download, encompassing over 3.4 million cells. After unsupervised clustering, we unified the identification and naming of subtype labels, ultimately constructing a cell ontology tree that includes 142 cell types, with up to eight hierarchical levels. Meanwhile, we calculated three different context-specific cell-type markers—’Cell Markers’, ‘Subtype Markers’, and ‘TPN Markers’—based on various application requirements within or across tissues. Through the integrated analysis of PreDigs gastrointestinal data, we identified distinct cell subpopulations exclusive to tumors, one of which corresponds to tumor-specific endothelial cells (TEC). Furthermore, PreDigs offers online cell annotation tools that empower users to perform single-cell classification with greater flexibility, accessible athttps://www.biosino.org/predigs/.
Salmonellaeffector SseL induces PD-L1 up-regulation and T cell inactivation via β-catenin signalling axis
Authors: Chopra Umesh , Sabu Maria Kondooparambil , Rajmani Raju S , Chaudhary Ayushi Devendrasingh , Gupta Shashi Kumar , Chakravortty Dipshikha 
Published: November 2024

AbstractThe upregulation of PD-L1 by various pathogens is a recognized strategy to evade the adaptive immune response.Salmonellainfection also upregulates PD-L1 levels causing culling of the activated T-cell; however, the underlying mechanism behind this upregulation is not known. Our findings indicate that the upregulation of PD-L1 is throughSalmonellapathogenicity island 2 (SPI-2) encoded effectors since PFA-fixed STM WT and STMΔssaV(which is unable to secrete effector proteins) did not alter PD-L1 levels. We have further investigated the role of the SPI-2 effector SseL (a deubiquitinase known to affect the NF-ĸB pathway) in PD-L1 upregulation. Our study identifies SPI-2 effector SseL to be crucial for upregulating PD-L1in vitroas well asin vivomurine models. The increase in PD-L1 levels induced by STM WT facilitates colonization in secondary infection sites in C57BL/6 mice, including the liver and spleen, while the STMΔsseLstrain exhibits significant colonization defects. Notably, despite the reduced colonization capacity of STMΔsseL, infected mice exhibit earlier mortality associated with heightened inflammation. We further elucidated the molecular mechanism behind PD-L1 upregulation and observed that bacterial effector SseL helps in the stabilization of β-catenin inside the cell. β-catenin thus translocates into the nucleus and directly regulates the transcriptional levels of PD-L1, which is abrogated upon using β-catenin/TCF inhibitor FH535. Collectively, our study elucidates the mechanism by whichSalmonellamediates immune suppression through PD-L1 upregulation.Abstract FigureAbstract figure: Schematic representation of SseL mediated PDL1 upregulation and further affecting the T cell proliferation
Phenotypic plasticity in a novel set of EGFR tyrosine kinase inhibitor-adapted non-small cell lung cancer cell lines
Authors: Nanthaprakash Tharsagini , Gourlay Campbell W. , Oehme Ina , Garrett Michelle D. , Cinatl Jindrich , Wass Mark N. , Michaelis Martin 
Published: November 2024

AbstractHere, we introduce sublines of the EGFR-mutant non-small cell lung cancer (NSCLC) cell lines HCC827 and HCC4006 adapted to the EGFR kinase inhibitors gefitinib (HCC827rGEFI2µM, HCC4006rGEFI1µM), erlotinib (HCC827rERLO2µM, HCC4006rERLO1µM), and afatinib (HCC827rAFA50nM, HCC4006rAFA100nM). All sublines displayed resistance to gefitinib, erlotinib, afatinib, and the third-generation EGFR kinase inhibitor osimertinib that overcomes T790M-mediated resistance. HCC4006rERLO1µMdisplayed a spindle-like morphology in agreement with previous findings that had detected epithelial-mesenchymal-transition (EMT) in its precursor cell line HCC4006rERLO0.5µM. EMT had also been reported for the HCC4006rGEFI1µMprecursor cell line HCC4006rGEFI0.5µMand for HCC4006rAFA100nM, but the morphologies of HCC4006rGEFI1µMor HCC4006rAFA100nMdid not support this, suggesting plasticity in EMT regulation during the drug adaptation process and in established resistant cell lines. Accordingly, HCC4006rERLO1µMdisplayed resistance to MEK and AKT inhibitors in contrast to its precursor HCC4006rERLO0.5µM. We also detected metabolic plasticity, i.e., a temporary Warburg metabolism, in HCC4006 and HCC827rGEFI2µM. Response profiles to cytotoxic anti-cancer drugs, kinase inhibitors, and HDAC inhibitors resulted in complex patterns that were specific for each individual subline without obvious overlaps, indicating individual resistance phenotypes. All resistant sublines remained sensitive or displayed collateral sensitivity to at least one of the investigated drugs. In conclusion, the comparison of EGFR kinase-resistant NSCLC sublines with their precursor cell lines that had been previously characterised at a lower resistance level and metabolic investigations indicated phenotypic plasticity during the resistance formation process and in established cell lines. This plasticity may contribute to the well-known variability in cell line phenotypes observed between different laboratories and in intra-laboratory experiments.
PSTP: Decoding Latent Sequence Grammar for Protein Phase Separation through Transfer Learning and Attention
Authors: Feng Mofan , Liu Liangjie , Xian Zhuo-Ning , Wei Xiaoxi , Li Keyi , Yan Wenqian , Lu Qing , Shi Yi , He Guang 
Published: November 2024

AbstractPhase separation (PS) is essential in various biological processes, necessitating high-accuracy predictive algorithms for studying numerous uncharacterized sequences, and accelerating experimental validation. However, many recent prediction methods face challenges in generalizability due to their reliance on engineered features. Furthermore, accurately identifying protein regions involved in PS remains challenging. To address this, we propose PSTP, a model employing a dual-language model embedding strategy and a lightweight attention module. The attention layer enables reliable residue-level phase separation predictions, identifying 84% of PS regions in PhaSePro and substantially improving correlation coefficient compared to existing models. PSTP also demonstrates robust performance in predicting PS propensity across various types of PS proteins and shows potential for predicting artificial proteins. By analyzing 160,000+ variants, PSTP characterizes the link between the incidence of pathogenic variants and residue-level PS propensities. PSTP’s predictive power and broad applicability make it a valuable tool for understanding biomolecular condensates and disease mechanisms.
The cold tolerance of the terrestrial slug,Ambigolimax valentianus
Authors: Gill Lauren T. , Udaka Hiroko , Marshall Katie E. 
Published: November 2024

AbstractTerrestrial molluscs living in temperate and polar environments must contend with cold winter temperatures. However, the physiological mechanisms underlying the survival of terrestrial molluscs in cold environments and the strategies employed by them are poorly understood. Here we investigated the cold tolerance ofAmbigolimax valentianus, an invasive, terrestrial slug that has established populations in Japan, Canada, and Europe. To do this, we acclimatedA. valentianusto different environmental conditions (differing day lengths and temperatures), then exposed them to sub-zero temperatures and measured overall survival. Then, we measured low molecular weight metabolites using1H NMR to see if they play a role in their cold tolerance as they do in other invertebrate species. We found thatA. valentianusis not strongly freeze tolerant but do become more cold-hardy after acclimation to shorter day lengths. We also found that no metabolites were strongly upregulated in response to winter conditions despite the change in cold hardiness, and instead saw evidence of metabolic suppression leading up to winter such as formate and L-glutamine being supressed in winter conditions.
PAL-AI reveals genetic determinants that control poly(A)-tail length during oocyte maturation with relevance to human fertility
Authors: Xiang Kehui , Bartel David P. 
Published: November 2024

AbstractIn oocytes of mammals and other animals, gene regulation is mediated primarily through changes in poly(A)-tail length1–9. Here, we introduce PAL-AI, an integrated neural network machine-learning model that accurately predicts tail-length changes in maturing oocytes of frogs and mammals. We show that PAL-AI learned known and previously unknown sequence elements and their contextual features that control poly(A)-tail length, enabling it to predict tail-length changes resulting from 3ʹ-UTR single-nucleotide substitutions. It also predicted tail-length-mediated translational changes, allowing us to nominate genes important for oocyte maturation. When comparing predicted tail-length changes in human oocytes with genomic datasets of the All of Us Research Program10and gnomAD11we found that genetic variants predicted to disrupt tail lengthening are under negative selection in the human population, thereby linking mRNA tail lengthening to human female fertility.
Antigen-specific T cell immunotherapy by in vivo mRNA delivery
Authors: Su Fang-Yi , Siebart Jamison C. , Chan Ching S. , Wang Matthew Y. , Yao Xinyi , Trenkle Aaron Silva , Sivakumar Avanti , Su Melanie , Harandi Rustin , Shahrawat Neha , Nguyen Chi H. , Goenka Anshika , Mun Jinhee , Dhodapkar Madhav V. , Kwong Gabriel A. 
Published: November 2024

AbstractImmunotherapy has shown promise for treating patients with autoimmune diseases or cancer, yet treatment is associated with adverse effects associated with global activation or suppression of T cell immunity. Here, we developed antigen-presenting nanoparticles (APNs) to selectively engineer disease antigen (Ag)-specific T cells byin vivomRNA delivery. APNs consist of a lipid nanoparticle core functionalized with peptide-major histocompatibility complexes (pMHCs), facilitating antigen-specific T cell transfection through cognate T cell receptor-mediated endocytosis. In mouse models of type 1 diabetes and multiple myeloma, APNs selectively deplete autoreactive T cells leading to durable control of glycemia, and engineer virus-specific T cells with anti-cancer chimeric antigen receptors (CARs), achieving comparable therapeutic outcome as virally transducedex vivoCAR. Overall, our work supports the use of APNs to engineer disease-relevant T cellsin vivoas Ag-specific immunotherapy for autoimmune disorders and cancer.
Improved pangenomic classification accuracy with chain statistics
Authors: Brown Nathaniel K. , Shivakumar Vikram S. , Langmead Ben 
Published: November 2024

AbstractCompressed full-text indexes enable efficient sequence classification against a pangenome or tree-of-life index. Past work on compressed-index classification used matching statistics or pseudo-matching lengths to capture the fine-grained co-linearity of exact matches. But these fail to capture coarse-grained information about whether seeds appear co-linearly in the reference. We present a novel approach that additionally obtains coarse-grained co-linearity (“chain”) statistics. We do this without using a chaining algorithm, which would require superlinear time in the number of matches. We start with a collection of strings, avoiding the multiple-alignment step required by graph approaches. We rapidly compute multi-maximal unique matches (multi-MUMs) and identify BWT sub-runs that correspond to these multi-MUMs. From these, we select those that can be “tunneled,” and mark these with the corresponding multi-MUM identifiers. This yields an ℴ(r+n/d)-space index for a collection ofdsequences having a length-nBWT consisting ofrmaximal equal-character runs. Using the index, we simultaneously compute fine-grained matching statistics and coarse-grained chain statistics in linear time with respect to query length. We found that this substantially improves classification accuracy compared to past compressed-indexing approaches and reaches the same level of accuracy as less efficient alignmentbased methods.
PNPLA3-I148M is a Neomorph that Interferes with Two Primary Hepatic Triglyceride Clearance Pathways
Authors: Sherman David J. , Liu Lei , LaGory Edward L. , Fordstrom Preston , Pruitt Danielle , Barreda Jose , Xie Jiansong , Ferbas John , Rulifson Ingrid C. , Deshaies Raymond J. 
Published: November 2024

AbstractA common variant ofPNPLA3, encoding PNPLA3-I148M, is the most significant genetic determinant of fatty liver disease worldwide. However, it is unclear precisely how PNPLA3-I148M drives disease risk. Here, we show that endogenous human PNPLA3-I148M impairs secretion of Apolipoprotein B (ApoB), the scaffolding protein of very low-density lipoproteins (VLDLs), from hepatocytes. This is not due to a generalized secretory pathway defect, nor is it equivalent to loss of function of PNPLA3. The VLDL secretory defect is conserved in mice expressing human I148M. Untargeted lipidomics reveal that I148M human cells are enriched in polyunsaturated fatty acid (PUFA)-containing triglycerides at the expense of PUFA-containing phosphatidylcholine, causing reduced membrane dynamics, concomitantly hindering biogenesis of secreted VLDLs. ApoB secretion is substantially rescued in I148M cells that overexpress ABHD5/CGI-58, an I148M binding partner that activates lipolysis by ATGL/PNPLA2 when not bound to I148M. Conversely, knocking down CGI-58 or PNPLA2 mimics I148M. We propose that neomorphic PNPLA3-I148M exacerbates fatty liver risk by simultaneously impeding two major CGI-58-dependent pathways for liver triglyceride clearance: lipolysis and secretion.
Embryonic Mast Cells Arise fromCpa3-expressing Precursors Independent of Granulocyte-Monocyte Progenitors
Authors: Ma Wei , Chen Huifang , Gao Fei , Zhao Han , Wu Ningbo , Zhang Shuangyan , Zhu Yiwen , Xu Zijian , Lan Yu , Liu Bing , Ye Youqiong , Liu Zhaoyuan , Ginhoux Florent , Su Bing 
Published: November 2024

SUMMARYMost of the mast cells (MCs) in connective tissues, such as skin, are long-lived embryonic-derived immune cells that play important roles in host defense and various immunological diseases, including allergies. Their embryonic origin and ontogeny remain to be fully studied since several overlapping waves of embryonic hematopoiesis have been shown to give rise to these cells. Here, combining single-cell RNA sequencing and new genetic fate mapping models, we identified aCpa3-expressing population sequentially appearing in the yolk sac, fetal liver, and peripheral tissues which gives rise to dermal MCs during embryonic days 11.5 to 14.5. Using in vitro differentiation and in vivo transplant methods, we identified a Ter119−F4/80−CD45+CD117+CD16/32+CD135−CD115−Ly6C−CD34lopopulation as potential fetal liver MC precursors. Fate mapping withCpa3CreERT2andZbtb16CreERT2models, as well as the granulocyte-monocyte progenitor (GMP) modelsMs4a3CreandElaneCre, demonstrated that MCs arise fromCpa3+progenitors rather thanMs4a3+orElane+GMPs. A corresponding population with a similar developmental trajectory was also identified in human early yolk sac and fetal liver, suggesting a conserved MC developmental program across species. These findings delineate the detailed developmental path of MCs in embryos, permitting future functional studies in immunity and development.HighlightsCpa3-expressing cells in the yolk sac and fetal liver contain mast cell precursorsCpa3CreERT2labels embryonic mast cells and their precursorsEmbryonic mast cells arise throughCpa3+mast cell precursors, but notElane+/Ms4a3+GMPsThe seeding of MCPs to embryonic skin slows down after E14.5
Aboral cell types ofClytiaand coral larvae have shared features and link taurine to the regulation of settlement
Authors: Ramon-Mateu Julia , Ferraioli Anna , Teixidó Núria , Domart-Coulon Isabelle , Houliston Evelyn , Copley Richard R. 
Published: November 2024

AbstractPlanktonic larvae of many marine invertebrates settle on a suitable substrate and metamorphose into bottom-dwelling adults. Larval settlement is of considerable interest both for ecologists and for evolutionary biologists, who have proposed that anterior sensory systems for substrate selection provided the basis for animal brains. Nevertheless the cellular and molecular regulation of larval settlement, including in Cnidaria (corals, jellyfish, sea anemones, hydroids) is not well understood. We generated and compared anterior (aboral) transcriptomes and single-cell RNA-seq datasets from the planula larvae of three cnidarian species: the hydrozoan jellyfishClytia hemisphaerica,and the scleractinian coralsAstroides calycularisandPocillopora acuta. Integrating these datasets and characterizing aboral cell types, we defined a common cellular architecture of the planula aboral end, and identified clade-specific specializations in cell types, including unique aboral neural cells in theClytiaplanula and neurosecretory cell types with distinct molecular signatures in bothClytiaand coral planulae. Among common planula aboral features were genes implicated in taurine uptake and catabolism expressed in distinct specialized cell types. In functional assays, exogenous taurine inhibited settlement of bothClytiaandAstroidesplanulae. These findings define a detailed molecular and cellular framework of the planula aboral pole, and implicate localized taurine destruction in defining settlement competence.