bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA damage-induced lncRNA MEG9 impacts angiogenesis
Authors: Fraile-Bethencourt Eugenia , Khou Sokchea , Wilson RaeAnna , Baris Adrian , Ruhl Rebecca , Espinosa-Diez Cristina , Anand Sudarshan 
Published: December 2022

AbstractEndothelial cells are highly responsive to environmental changes that allow them to adapt to intrinsic and extrinsic stimuli and switch their transcriptome accordingly to go back to vascular homeostasis. Our previous data demonstrated that small non-coding-RNAs respond quickly to genotoxic stressors and determined endothelial cell fate and DNA damage response. To further understand the contribution of non-coding-RNAs, we profiled differentially expressed long non-coding RNAs in response to genotoxic stress and compared them to pro-angiogenic growth factor signaling. We identified the Maternally expressed gene 9 (MEG9) as a cytoprotective lncRNA in the endothelium. Gain and Loss-of-function studies indicate that MEG9 prevents endothelial cells from cell death, suggesting that MEG9 responses to genotoxic stress can be an adaptive and protective mechanism. Consistent with this phenotype, the knockdown of MEG9 decreases growth factor-dependent angiogenesis in a 3D fibrin gel angiogenesis assay. Deletion of the MEG9 ortholog, Mirg, in mice results in increased vascular leak in Matrigel plugs and a sex and age-dependent decrease in platelets. Mechanistically, we observed that both MEG9 knockdown in vitro andMirg-deleted mice in vivo activated common pathways, including apoptosis, clotting, and inflammation. Indeed, the proinflammatory adhesion molecule ICAM1 was significantly increased in human and mouse endothelial cells in a MEG9-dependent manner, supporting the increased vascular permeability observed on MEG9 deficient cells. Taken together, our findings illustrate how genotoxic stress responses through dynamic modulation of lncRNAs, such as MEG9, trigger adaptive mechanisms to maintain endothelial function, while loss of these molecules contributes to maladaptive responses and endothelial cell dysfunction.
TWAS coupled with eQTL analysis reveals the genetic connection between gene expression and flowering time in Arabidopsis
Authors: Chien Pei-Shan , Chen Pin-Hua , Lee Cheng-Ruei , Chiou Tzyy-Jen 
Published: December 2022

AbstractGenome-wide association study (GWAS) has improved our understanding of complex traits, but challenges exist in distinguishing causation versus association caused by linkage disequilibrium. Instead, the transcriptome-wide association study (TWAS) detects direct associations between expression levels and phenotypic variations, providing an opportunity to better prioritize candidate genes. To assess the feasibility of TWAS, we investigated the association among transcriptomes, genomes, and various traits, including flowering time inArabidopsis. First, the associated genes formerly known to regulate growth allometry or metabolite production were identified by TWAS. Then, for flowering time, six TWAS-newly identified genes were functionally validated. Analysis of expression quantitative trait locus (eQTL) further revealed atrans-regulatory hotspot affecting the expression of several TWAS-identified genes. The hotspot covers theFRIGIDA(FRI) gene body, which possesses multiple haplotypes differentially affecting the expression of downstream genes, such asFLOWERING LOCUS C(FLC) andSUPPRESSOR OF OVEREXPRESSION OF CO 1(SOC1). We also revealed multiple independent paths towards the loss ofFRIfunction in natural accessions. Altogether, this study demonstrates the potential of combining TWAS with eQTL analysis to identify important regulatory modules of theFRI-FLC-SOC1for quantitative traits in natural populations.HighlightCombining TWAS with eQTL analyses identifies haplotypes connecting flowering genes with their physiological trait, strengthening the importance ofFRI-FLC-SOC1regulatory module on flowering time among the Arabidopsis natural population.
Reactive myelopoiesis and FX-expressing monocyte-derived macrophages triggered by chemotherapy promote cancer lung metastasis
Authors: Wu Caijun , Zhong Qian , Shrestha Rejeena , Wang Jingzhi , Hu Xiaoling , Li Hong , Rouchka Eric C. , Yan Jun , Ding Chuanlin 
Published: December 2022

AbstractChemotherapy offers long-term clinical benefits to many cancer patients. However, several pre-clinical studies have demonstrated that certain cytotoxic drugs enhance metastasis via multiple mechanisms. These studies have mainly focused on tumor cell-derived inflammation. The importance of host responses triggered by chemotherapy in regulating cancer metastasis has not been fully explored. Here, we showed that multi-dose Gemcitabine (GEM) treatment promoted breast cancer lung metastasis in a transgenic spontaneous breast cancer animal model. Both CCR2+macrophages and monocytes were increased in the lungs of GEM-treated mice. Further, the increase of CCR2+macrophages and monocytes were observed in naïve (tumor-free) mice after GEM treatment. These changes were largely caused by chemotherapy-induced reactive myelopoiesis that are biased toward monocyte development. Mechanistically, enhanced production of mitochondrial ROS (mtROS) was observed in GEM-treated BM LSK cells and monocytes. Treatment with the mitochondrial targeted antioxidant abrogated GEM induced hyper differentiation of BM progenitors. In addition, GEM treatment induced up-regulation of host cell-derived CCL2, and CCL2/CCR2 axis played essential role in the pro-metastatic host response induced by chemotherapy. Further, GEM and Paclitaxel (PTX) in combination with Doxorubicin (DOX) treatment resulted in up-regulation of coagulation factor X (FX) in lung interstitial macrophages. Targeting activated FX (FXa) using FXa inhibitor or F10 gene knockdown reduced pro-metastatic effect of chemotherapy-triggered host response. Together, these studies suggest a novel mechanism for chemotherapy induced metastasis via the host response-induced accumulation of monocytes/macrophages and interplay between coagulation and inflammation in the lungs.
scEvoNet: a gradient boosting-based method for prediction of cell state evolution
Authors: Kotov Aleksandr , Zinovyev Andrei , Monsoro-Burq Anne-Helene 
Published: December 2022

Abstract•BackgroundExploring the function or the developmental history of cells in various organisms provides insights into a given cell type’s core molecular characteristics and putative evolutionary mechanisms. Numerous computational methods now exist for analyzing single-cell data and identifying cell states. These methods mostly rely on the expression of genes considered as markers for a given cell state. Yet, there is a lack of scRNA-seq computational tools to study the evolution of cell states, particularly how cell states change their molecular profiles. This can include novel gene activation or the novel deployment of programs already existing in other cell types, known as co-option.•ResultsHere we present scEvoNet, a Python tool for predicting cell type evolution in crossspecies or cancer-related scRNA-seq datasets. ScEvoNet builds the confusion matrix of cell states and a bipartite network connecting genes and cell states. It allows a user to obtain a set of genes shared by the characteristic signature of two cell states even between distantly-related datasets. These genes can be used as indicators of either evolutionary divergence or co-option occurring during organism or tumor evolution. Our results on cancer and developmental datasets indicate that scEvoNet is a helpful tool for the initial screening of such genes as well as for measuring cell state similarities.•ConclusionsThe scEvoNet package is implemented in Python and is freely available fromhttps://github.com/monsoro/scEvoNet. Utilizing this framework and exploring the continuum of transcriptome states between developmental stages and species will help explain cell state dynamics.
Genome comparison reveals inversions and alternative evolutionary history of nutritional endosymbionts in planthoppers (Hemiptera: Fulgoromorpha)
Authors: Deng Junchen , Bennett Gordon M. , Franco Diego C. , Prus-Frankowska Monika , Stroiński Adam , Michalik Anna , Łukasik Piotr 
Published: December 2022

SummaryThe evolutionary success of sap-feeding hemipteran insects in the suborder Auchenorrhyncha was enabled by nutritional contributions from their heritable endosymbiotic bacteria. However, the symbiont diversity, functions, and evolutionary origins in this large insect group have not been broadly characterized using genomic tools. In particular, the origins and relationships among ancient betaproteobacterial symbiontsVidania(in Fulgoromorpha) andNasuia/Zinderia(in Cicadomorpha) are uncertain. Here, we characterized the genomes ofVidaniaandSulciafrom threePyropsplanthoppers (family Fulgoridae) to understand their metabolic functions and evolutionary histories. Like in previously characterized planthoppers, these symbionts share nutritional responsibilities, withVidaniaproviding seven out of ten essential amino acids.Sulcialineages across the Auchenorrhyncha have a highly conserved genome but with multiple independent rearrangements occurring in an early ancestor of Cicadomorpha or Fulgoromorpha and in a few succeeding lineages. Genomic synteny was also observed within each of the betaproteobacterial symbiont generaNasuia,Zinderia, andVidania, but not across them, which challenges the expectation of a shared ancestry for these symbionts. The further comparison of other biological traits strongly suggests an independent origin ofVidaniaearly in the planthopper evolution and possibly ofNasuiaandZinderiain their respective host lineages.Originality-Significance StatementWe sequenced and characterized the genomes of two ancient nutritional symbionts,SulciaandVidania, in three species from the genusPyropsin the species- and symbiont-rich but understudied insect clade, Fulgoromorpha (planthoppers). We describe—for the first time—several independent genome rearrangements inSulcia, which is often cited as a premier example of extreme genome stability spanning hundreds of millions of years. We also show a global lack of synteny across the genomes of the Auchenorrhynchan betaproteobacterial symbionts (Vidania,Nasuia, andZinderia). This result is unexpected given previous hypotheses of a common origin for these symbionts >250 million years ago alongsideSulcia. Taken together, we suggest an independent origin ofVidaniaand possibly ofNasuiaandZinderiasymbiont lineages as well. This hypothesis further links the potential acquisition of novel nutritional endosymbiont lineages with the emergence of auchenorrhyncham superfamilies.
TranceptEVE: Combining Family-specific and Family-agnostic Models of Protein Sequences for Improved Fitness Prediction
Authors: Notin Pascal , Van Niekerk Lood , Kollasch Aaron W , Ritter Daniel , Gal Yarin , Marks Debora S. 
Published: December 2022

AbstractModeling the fitness landscape of protein sequences has historically relied on training models on family-specific sets of homologous sequences called Multiple Sequence Alignments. Many proteins are however difficult to align or have shallow alignments which limits the potential scope of alignment-based methods. Not subject to these limitations, large protein language models trained on non-aligned sequences across protein families have achieved increasingly high predictive performance – but have not yet fully bridged the gap with their alignment-based counterparts. In this work, we introduce TranceptEVE – a hybrid method between family-specific and family-agnostic models that seeks to build on the relative strengths from each approach. Our method gracefully adapts to the depth of the alignment, fully relying on its autoregressive transformer when dealing with shallow alignments and leaning more heavily on the family-specific models for proteins with deeper alignments. Besides its broader application scope, it achieves state-of-the-art performance for mutation effects prediction, both in terms of correlation with experimental assays and with clinical annotations from ClinVar.
A Scoping Review of Mathematical Models Covering Alzheimer’s Disease Progression
Authors: Moravveji Seyedadel , Doyon Nicolas , Mashreghi Javad , Duchesne Simon 
Published: December 2022

AbstractAlzheimer’s disease is a complex, multi-factorial and multi-parametric neurodegenerative etiology. Mathematical models can help understand such a complex problem by providing a way to explore and conceptualize principles, merging biological knowledge with experimental data into a model amenable to simulation and external validation, all without the need for extensive clinical trials.We performed a scoping review of mathematical models of AD with a search strategy applied to the PubMed database which yielded 846 entries. After applying our exclusion criteria, only 17 studies remained from which we extracted data, focusing on three aspects of mathematical modeling: how authors addressed continuous time, how models were solved, and how the high dimensionality and non-linearity of models were managed. Most articles modeled AD at the cellular range of the disease process, operating on a short time scale (e.g., minutes; hours), i.e., the micro view (12/17); the rest considered regional or brain-level processes, with longer timescales (e.g., years, decades) (the macro view). Most papers were concerned primarily withAβ(n= 8), few modeled with bothAβand tau proteins (n= 3), and some considered more than these two factors in the model (n= 6). Models used partial differential equations (PDEs;n= 3), ordinary differential equations (ODEs;n= 7), both PDEs and ODEs (n= 3). Some didn’t specify the mathematical formalism (n= 4). Sensitivity analyses were performed in only a small number of papers (4/17).Overall, we found that only two studies could be considered valid in terms of parameters and conclusions, and two more were partially valid. The majority (n= 13) either was invalid or there was insufficient information to ascertain their status. While mathematical models are powerful and useful tools for the study of AD, closer attention to reporting is necessary to gauge the quality of published studies to replicate or continue with their contributions.
Conserved Biophysical Compatibility Among the Highly Variable Germline-Encoded Regions Shapes TCR-MHC Interactions
Authors: Boughter Christopher T. , Meier-Schellersheim Martin 
Published: December 2022

AbstractT cells are critically important components of the adaptive immune system primarily responsible for identifying and responding to pathogenic challenges. This recognition of pathogens is driven by the interaction between membrane-bound T cell receptors (TCRs) and antigenic peptides presented on major histocompatibility complex (MHC) molecules. The formation of the TCR-peptide-MHC complex (TCR-pMHC) involves interactions among germline-encoded and hypervariable amino acids. Germline-encoded and hypervariable regions can form contacts critical for complex formation, but only interactions between germline-encoded contacts are likely to be shared across many of all the possible productive TCR-pMHC complexes. Despite this, experimental investigation of these interactions have focused on only a small fraction of the possible interaction space. To address this, we analyzed every possible germline-encoded TCR-MHC contact in humans, thereby generating the first comprehensive characterization of these largely antigen-independent interactions. Our analysis shows that germline-encoded TCR-MHC interactions that are conserved at the sequence level are rare due to the high amino acid diversity of the TCR CDR1 and CDR2 loops, and that such conservation is unlikely to dominate the dynamic protein-protein binding interface. Instead, we find that binding properties such as the docking orientation are defined by regions of biophysical compatibility between these loops and the MHC surface.
Heterotrophic bacteria drive sulfide oxidation in coastal sediments
Authors: Cao Qun , Yang Yunyun , Lu Chuanjuan , Wang Qingda , Xia Yongzhen , Qin Qilong , Xun Luying , Liu Huaiwei 
Published: December 2022

ABSTRACTSulfate reduction and sulfur oxidation are very active in coastal sediments. They shape the biogeochemistry and microbial ecology at hot places of organic matter metabolism. Different from the well-studied sulfate reduction, sulfur oxidation in coastal sediments is still full of questions. Herein, we investigated the distribution of reduced sulfur compounds in differently layers of coastal sediments at the Yellow sea and found that sulfide (H2S), sulfane sulfur (S0), and thiosulfate mainly accumulated in anaerobic sediments and were mostly oxidized in anoxic and oxic interface in the sediments and the sea water. Bacterial community analysis indicated that heterotrophic bacteria are dominating species in surface sediments and sea water. Metagenome analysis showed that two sulfur-oxidizing genes encoding sulfide:quinone oxidoreductases (SQR) and persufide dioxygenases (PDO), were sharply more abundant than other sulfur-oxidizing genes in the coastal sediments. Since members of the marine Roseobacter clade were dominant in coastal waters and sediments, we studied the sulfur oxidation pathway in the RoseobacterRuegeria pomeroyiDSS-3 and found that sulfide:quinone oxidoreductase, persulfide dioxygenase, and sulfite-oxidizing enzyme were the main enzymes for the oxidation of H2S, zerovalent sulfur, and sulfite/thiosulfate. This study, for the first time, clarified the dominating function of heterotrophic bacteria in sulfur oxidation in the coastal sediments and sea water.IMPORTANCECoastal sediments are the most productive ecosystems. We performed the microbial community diversity and metagenomic analysis of seawater and coastal sediments of the Yellow Sea and explored the sulfur oxidation process in them. We found that heterotrophic bacteria are dominating species in surface sediments and sea water, sulfide and sulfane sulfur were mostly oxidized in surface sediments, and the genes encoding SQR, PDO, and SOE are abundant. UsingRuegeria pomeroyiDSS-3 as the model strain, we studied how these enzymes cooperate to oxidize H2S to sulfate. Thus, this research revealed the critical role of heterotrophic bacteria in sulfur oxidation in coastal sediments and sea water.
Species-specific LUBAC-mediated M1 ubiquitination regulates necroptosis by segregating the cellular distribution and fate of activated MLKL
Authors: Weinelt Nadine , Wächtershäuser Kaja Nicole , Smith Sonja , Andrieux Geoffroy , Das Tonmoy , Jeiler Birte , Roedig Jens , Feist Leonard , Rotter Björn , Boerries Melanie , Pampaloni Francesco , van Wijk Sjoerd J. L. 
Published: December 2022

SummaryPlasma membrane accumulation of phosphorylated mixed lineage kinase domain-like (MLKL) is a hallmark of necroptosis, leading to membrane rupture and inflammatory cell death. Pro-death functions of MLKL are tightly controlled by several checkpoints, including phosphorylation. Endocytosis and exocytosis limit MLKL membrane accumulation and counteract necroptosis, but the exact mechanisms remain poorly understood. Here, we identify linear ubiquitin chain assembly complex (LUBAC)-mediated M1 poly-ubiquitination (poly-Ub) as novel checkpoint for necroptosis regulation downstream of activated MLKL in human cells. Loss of LUBAC activity inhibits necroptosis, without affecting necroptotic signaling, but by preventing membrane accumulation of activated MLKL. Flotillin-1/2 act as putative necroptotic M1 poly-Ub targets that inhibit necroptosis suppression induced by LUBAC inhibition. Finally, we confirm LUBAC-dependent activation of necroptosis in primary human pancreatic organoids. Our findings identify LUBAC as species-specific regulator of necroptosis which promotes MLKL membrane accumulation and pioneer primary human organoids to model necroptosis in near-physiological settings.
Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol
Authors: Spildrejorde Mari , Samara Athina , Sharma Ankush , Leithaug Magnus , Falck Martin , Modafferi Stefania , Sundaram Arvind Y. M. , Acharya Ganesh , Nordeng Hedvig , Eskeland Ragnhild , Gervin Kristina , Lyle Robert 
Published: December 2022

SummaryPrenatal paracetamol exposure has been associated with neurodevelopmental outcomes in childhood. Pharmacoepigenetic studies show differences in cord blood DNA methylation between paracetamol exposed and unexposed neonates. However, causal implications and impact of long-term prenatal long-term paracetamol exposure on brain development remain unclear. Using a multi-omics approach, we investigated the effects of paracetamol on a model of early human brain development. We exposed human embryonic stem cells undergoing in vitro neuronal differentiation to daily media changes with paracetamol concentrations corresponding to maternal therapeutic doses. Single-cell RNA-seq and ATAC-seq integration identified paracetamol-induced chromatin-opening changes linked to gene expression. Differentially methylated and/or expressed genes were involved in signalling, neurotransmission, and cell fate-determination trajectories. Some genes involved in neuronal injury and development-specific pathways, such asKCNE3, overlapped with differentially methylated genes previously identified in cord blood associated with prenatal paracetamol exposure. Our data suggest that paracetamol may play a causal role in impaired neurodevelopment.Graphical Abstract
Evidence implicating sequential commitment of the founder lineages in the human blastocyst by order of hypoblast gene activation
Authors: Corujo-Simon Elena , Radley Arthur H. , Nichols Jennifer 
Published: December 2022

AbstractSuccessful human pregnancy depends upon rapid establishment of three founder lineages: trophectoderm, epiblast and hypoblast, which together form the blastocyst. Each plays an essential role in preparing the embryo for implantation and subsequent development. Several models are proposed to define the lineage segregation. The first suggests that all specify simultaneously; the second favours differentiation of trophectoderm before separation of epiblast and hypoblast, either via differentiation of hypoblast from established epiblast, or production of both tissues from the inner cell mass precursor. To begin to resolve this discrepancy and thereby understand the sequential process for production of viable human embryos, we investigated the expression order of genes associated with emergence of hypoblast. Based upon published data and immunofluorescence analysis for candidate genes, we present a basic blueprint for human hypoblast differentiation, lending support to the proposed model of sequential segregation of the founder lineages of the human blastocyst. The first characterised marker, specific initially to the early inner cell mass, and subsequently identifying presumptive hypoblast is PDGFRA, followed by SOX17, FOXA2 and GATA4 in sequence as the hypoblast becomes committed.Summary StatementOptimal segregation of human blastocyst founder lineages is essential to establish healthy human pregnancies. Mapping activation of hypoblast marker genes over time helps understand how the yolk sac is regulated.
NewAequoreafluorescent proteins for cell-free bioengineering
Authors: Deich Christopher , Gaut Nathaniel J. , Sato Wakana , Engelhart Aaron E. , Adamala Katarzyna P. 
Published: December 2022

AbstractRecently, a new subset of fluorescent proteins has been identified from the Aequorea species of jellyfish. These fluorescent proteins were characterizedin vivo; however, there has not been validation of these proteins within cell-free systems. Cell-free systems and technology development is a rapidly expanding field, encompassing foundational research, synthetic cells, bioengineering, biomanufacturing and drug development. Cell-free systems rely heavily on fluorescent proteins as reporters. Here we characterize and validate this new set of Aequorea proteins for use in a variety of cell-free and synthetic cell expression platforms.Abstract Figure