bluuebunny/crossref_metadata_2025_split huggingface dataset:
The senescent mesothelial matrix accentuates colonization by ovarian cancer cells
Authors: Thapa Bharat Vivan , Glimm Tilmann , Saini Deepak K , Bhat Ramray 
Published: June 2023

ABSTRACTOvarian cancer is amongst the most morbid of gynecological malignancies due to its diagnosis at an advanced stage, a transcoelomic mode of metastasis, and rapid transition to chemotherapeutic resistance. Like all other malignancies, the progression of ovarian cancer may be interpreted as an emergent outcome of the conflict between metastasizing cancer cells and the natural defense mounted by microenvironmental barriers to such migration. Here, we asked whether senescence in coelom-lining mesothelia, brought about by drug exposure, affects their interaction with disseminated ovarian cancer cells. We observed that cancer cells adhered faster on, senescent human and murine mesothelial monolayers than non-senescent controls. Time-lapse epifluorescent microscopy showed that mesothelial cells were cleared by a host of cancer cells that surrounded the former, even under sub-confluent conditions. A multiscale computational model predicted that such colocalized mesothelial clearance under sub-confluence requires greater adhesion between cancer cells and senescent mesothelia. Consistent with the prediction, we observed that senescent mesothelia expressed extracellular matrix with higher levels of fibronectin, laminins and hyaluronan than non-senescent controls. On senescent matrix, cancer cells adhered more efficiently, spread better, and moved faster and persistently, aiding the spread of cancer. Inhibition assays using RGD cyclopeptides suggested the adhesion was predominantly contributed by fibronectin and laminin. These findings led us to propose that the senescence-associated matrisomal phenotype of peritoneal barriers enhances the colonization of invading ovarian cancer cells and their clearance contributing to the metastatic burden associated with the disease.
Global changes in open reading frame dominance of RNAs during cancer initiation and progression
Authors: Suenaga Yusuke , Kogashi Hiroyuki , Nakatani Kazuma , Lin Jason , Hasegawa Yoshinori , Kugou Kazuto , Kawashima Yusuke , Furukawa Eisaku , Okumura Kazuhiro , Kita Emiri , Wakabayashi Yuichi , Kato Mamoru , Kawazu Masahito , Hippo Yoshitaka 
Published: June 2023

AbstractCancer cells express unique RNA transcripts; however, the factors determining their translation have remained unclear. We recently developed open reading frame (ORF) dominance as a measure that correlates with coding potential of RNAs. Upon calculating the ORF dominance of cancer-specific transcripts across 24 human tumor types, 14 exhibited significantly higher ORF dominance in cancer than in normal tissues. In organoid-based mouse genetic models, ORF dominance increased with carcinogenesis. Gene ontology analysis revealed that gene sets with increased ORF dominance were associated with cell proliferation, while those with decreased ORF dominance were linked to DNA damage response. Translatome analyses demonstrated that elevated ORF dominance during carcinogenesis resulted in higher translation frequencies of ribosome-bound RNAs. As cancer progressed, ORF dominance showed that the boundary between coding and noncoding transcripts became blurred prior to distant metastasis, indicating decreased proliferative cell populations and increased generation of RNA isoforms that potentially translate neoantigens before the development of metastatic tumors. These findings suggest that cancer evolution leads to dynamic changes in ORF dominance, resulting in global translational alterations in transcriptomes.
Necessary Role of Acute Ceramide Formation in The Human Microvascular Endothelium During Health and Disease
Authors: SenthilKumar Gopika , Katunaric Boran , Zirgibel Zachary , Lindemer Brian , Jaramillo-Torres Maria J. , Bordas-Murphy Henry , Schulz Mary E. , Pearson Paul J. , Freed Julie K. 
Published: June 2023

ABSTRACTBackgroundElevated plasma ceramides independently predict adverse cardiac events and we have previously shown that exposure to exogenous ceramide induces microvascular endothelial dysfunction in arterioles from otherwise healthy adults (0-1 risk factors for heart disease). However, evidence also suggests that activation of the shear-sensitive, ceramide forming enzyme neutral sphingomyelinase (NSmase) enhances vasoprotective nitric oxide (NO) production. Here we explore a novel hypothesis that acute ceramide formation through NSmase is necessary for maintaining NO signaling within the human microvascular endothelium. We further define the mechanism through which ceramide exerts beneficial effects and discern key mechanistic differences between arterioles from otherwise healthy adults and patients with coronary artery disease (CAD).MethodsHuman arterioles were dissected from otherwise discarded surgical adipose tissue (n=123), and vascular reactivity to flow and C2-ceramide was assessed. Shear-induced NO production was measured in arterioles using fluorescence microscopy. Hydrogen peroxide (H2O2) fluorescence was assessed in isolated human umbilical vein endothelial cells.ResultsInhibition of NSmase in arterioles from otherwise healthy adults induced a switch from NO to H2O2-mediated flow-induced dilation within 30 minutes. In endothelial cells, NSmase inhibition acutely increased H2O2production. Endothelial dysfunction in both models was prevented by treatment with C2-ceramide, S1P, and an agonist of S1P-receptor 1 (S1PR1), while the inhibition of S1P/S1PR1 signaling axis induced endothelial dysfunction. Ceramide increased NO production in arterioles from healthy adults, an effect that was diminished with inhibition of S1P/S1PR1/S1PR3 signaling. In arterioles from patients with CAD, inhibition of NSmase impaired dilation to flow. This effect was not restored with exogenous S1P. Although, inhibition of S1P/S1PR3 signaling impaired normal dilation to flow. Acute ceramide administration to arterioles from patients with CAD also promoted H2O2as opposed to NO production, an effect dependent on S1PR3 signaling.ConclusionThese data suggest that despite key differences in downstream signaling between health and disease, acute NSmase-mediated ceramide formation and its subsequent conversion to S1P is necessary for proper functioning of the human microvascular endothelium. As such, therapeutic strategies that aim to significantly lower ceramide formation may prove detrimental to the microvasculature.
VitTCR: A deep learning method for peptide recognition prediction
Authors: Jiang Mengnan , Yu Zilan , Lan Xun 
Published: June 2023

AbstractThe identification of the interaction between T-cell receptors (TCRs) and immunogenic peptides is important for the development of novel cancer immunotherapies and vaccines. However, experimentally determining whether a TCR recognizes a peptide is still time– and labour-consuming. In this study, we introduced VitTCR, a predictive model based on the architecture of the vision transformer (ViT), designed to forecast TCR-peptide interactions. Prior to prediction, VitTCR converts the TCR-peptide interactions into a numerical tensor named AtchleyMaps using Atchley factors. Subsequently, VitTCR takes AtchleyMaps as inputs and predicts whether an interaction between a TCR and a peptide exists. Through comprehensive evaluations, we demonstrate that VitTCR surpasses other published methods in classifying TCR-peptide pairs, exhibiting superior performance in terms of the area under the receiver operating characteristic (AUROC) and the area under the precision-recall curve (AUPR). To determine the focal contact point between TCRs and peptides, we obtained a positional bias weight matrix (PBWM) from the empirical amino acid (AA) contact probabilities derived from 83 structurally resolved pMHC-TCR complexes. The comparison of VitTCR with and without the integration of the PBWM revealed significant enhancements in the performance of the model. Moreover, the predicted probabilities generated by VitTCR exhibit significant correlations with immunological factors such as the clonal expansion and activation percentages of T cells. This further supports the efficacy of VitTCR in capturing biologically meaningful TCR-peptide interactions. In conclusion, VitTCR provides a useful computational tool for the prediction of TCR-peptide interactions, thereby contributing to our understanding in this field.
Cysteine enrichment mediates co-option of uricase in reptilian skin and transition to uricotelism
Authors: Mori Giulia , Liuzzi Anastasia , Ronda Luca , Palma Michele Di , Chegkazi Magda S. , Bui Soi , Garcia-Maya Mitla , Ragazzini Jasmine , Malatesta Marco , Monica Emanuele Della , Rivetti Claudio , Antin Parker , Bettati Stefano , Steiner Roberto A. , Percudani Riccardo 
Published: June 2023

AbstractUric acid is the main means of nitrogen excretion in uricotelic vertebrates (birds and reptiles) and the end product of purine catabolism in humans and a few other mammals. While uricase is inactivated in mammals unable to degrade urate, the presence of orthologous genes without inactivating mutations in avian and reptilian genomes is unexplained. Here we show that theGallus gallusgene we name cysteine-rich urate oxidase (CRUOX) encodes a functional protein representing a unique case of cysteine enrichment in the evolution of vertebrate orthologous genes. CRUOX retains the ability to catalyze urate oxidation to hydrogen peroxide and 5-hydroxyisourate (HIU), albeit with a 100-fold reduced efficiency. However, differently from all uricases hitherto characterized, it can also facilitate urate regeneration from HIU, a catalytic property which we propose depends on its enrichment in cysteine residues. X-ray structural analysis highlights differences in the active site compared to known orthologs and suggests a mechanism for cysteine-mediated self-aggregation under H2O2-oxidative conditions. Cysteine enrichment was concurrent with transition to uricotelism and a shift in gene expression from the liver to the skin where CRUOX is co-expressed with β-keratins. Therefore, the loss of urate degradation in amniotes has followed opposite evolutionary trajectories: while uricase has been eliminated by pseudogenization in some mammals, it has been repurposed as a redox-sensitive enzyme in the reptilian skin.
Lamivudine (3TC), a nucleoside reverse transcriptase inhibitor, prevents the neuropathological alterations present in mutant tau transgenic mice
Authors: Vallés-Saiz Laura , Ávila Jesús , Hernández Félix 
Published: June 2023

AbstractThe dysregulation of transposable elements contributes to neurodegenerative disorders. Previous studies have reported an increase in retrotransposon transcription inDrosophilamodels, as well as in human tauopathies. In this context, here we tested the possible protective effects of a reverse transcriptase inhibitor, namely lamivudine (also known as 3TC), in P301S mice, an animal model of Alzheimeŕs disease based on FTDP-17-tau overexpression. Transgenic P301S mice administered lamivudine through drinking water showed a decrease in the following histopathological marks typical of tauopathies: tau phosphorylation; inflammation; neuronal death; and hippocampal atrophy. Lamivudine treatment attenuated motor deficits (Rotarod test) and improved short-term memory (Y-maze test). To evaluate the role of tau in retrotransposition, we cotransfected HeLa cells with a plasmid containing a complete LINE-1 sequence and a neomycin reporter cassette designed for retrotransposition assays, and a plasmid with the tau sequence. LINE-1 insertion increased considerably in the cotransfection compared to the transfection without tau. In addition, lamivudine inhibited the insertion of LINE-1. Our data suggest that the progression of the tauopathy can be attenuated by the administration of lamivudine upon the first symptoms of neuropathology.HighlightsLamivudine treatment in drinking water inhibited a tau-associated pathology in a mouse model of tauopathy.Tau promotes the insertion of transposable elements LINE-1in vitro. LINE-1 insertionin vitrois inhibited by lamivudine.Lamivudine attenuates memory and motor deficits in tau transgenic mice.
Electrochemical biosensor based on NAD(P)H-dependent Quinone Reductase for rapid and efficient detection of vitamin K3
Authors: Khalife Majd , Stankovic Dalibor , Stankovic Vesna , Danicka Julia , Rizzotto Francesco , Costache Vlad , Slama Schwok Anny , Gaudu Philippe , Vidic Jasmina 
Published: June 2023

AbstractVitamin K refers to a group of vitamins that play an important role in blood coagulation and regulation of bone and vascular metabolism. However, vitamin K3 may give severe side effects in animal and humans when improperly added to food and feed due to its toxicity. Here, an electrochemical biosensor, based on the YaiB NADPH-dependent quinone reductase fromLactococcus lactis(YaiB), was developed to achieve rapid and redox probe-free detection of vitamin K3. First, we demonstrated the ability of the carbon electrode to distinguish between 1,4-benzoquinone and hydroquinone. Then, we engineered YaiB to work as a bioreceptor immobilized at the electrode and we demonstrated its sensitivity and specificity to reduce vitamin K3. Finally, to demonstrate the practical potential of the biosensor, we tested it directly in spiked milk samples, achieving 15-minute quantification of the vitamin K3. The limit of detection was 0.18μM and 0.86 μM in buffer and milk, respectively.
Near chromosome-level genome assembly of the microsporidiumHamiltosporidium tvaerminnensis
Authors: Angst Pascal , Pombert Jean-François , Ebert Dieter , Fields Peter D. 
Published: June 2023

AbstractMicrosporidia are intracellular parasitic fungi whose genomes rank among the smallest of all known eukaryotes. A number of outstanding questions remain concerning the evolution of their large-scale variation in genome architecture, responsible for genome size variation of more than an order of magnitude. This genome report presents a first near-chromosomal assembly of a large-genome microsporidium,Hamiltosporidium tvaerminnensis. Combined Oxford Nanopore, Pacific Biosciences, and Illumina sequencing led to a genome assembly of 17 contigs, 11 of which represent complete chromosomes. Our assembly is 21.64 Mb in length, has an N50 of 1.44 Mb, and consists of 39.56 % interspersed repeats. We introduce a novel approach in microsporidia, PacBio Iso-Seq, as part of a larger annotation pipeline for obtaining high-quality annotations of 3,573 protein-coding genes. Based on direct evidence from the full-length Iso-Seq transcripts, we present evidence for alternative polyadenylation and variation in splicing efficiency, which are potential regulation mechanisms for gene expression in microsporidia. The generated high-quality genome assembly is a necessary resource for comparative genomics that will help elucidate the evolution of genome architecture in response to intracellular parasitism.SignificanceMicrosporidia are a model for genome evolution in response to intracellular parasitism, but we lack high-quality resources from species with large genomes. We present a near complete assembly of a large-genome microsporidium,Hamiltosporidium tvaerminnensis, and obtain high-quality gene annotations through full-length transcripts using Iso-Seq, a novel approach in microsporidia. Our study provides insights into gene regulation and paves the way for comparative genomic analyses aiming to understand the evolution of genome reduction and expansion in these intracellular parasites.
Differential dynamics specify MeCP2 function at methylated DNA and nucleosomes
Authors: Chua Gabriella N. L. , Watters John W. , Olinares Paul Dominic B. , Luo Joshua A. , Chait Brian T. , Liu Shixin 
Published: June 2023

AbstractMethyl-CpG-binding protein 2 (MeCP2) is an essential chromatin-binding protein whose mutations cause Rett syndrome (RTT), a leading cause of monogenic intellectual disabilities in females. Despite its significant biomedical relevance, the mechanism by which MeCP2 navigates the chromatin epigenetic landscape to regulate chromatin structure and gene expression remains unclear. Here, we used correlative single-molecule fluorescence and force microscopy to directly visualize the distribution and dynamics of MeCP2 on a variety of DNA and chromatin substrates. We found that MeCP2 exhibits differential diffusion dynamics when bound to unmethylated and methylated bare DNA. Moreover, we discovered that MeCP2 preferentially binds nucleosomes within the context of chromatinized DNA and stabilizes them from mechanical perturbation. The distinct behaviors of MeCP2 at bare DNA and nucleosomes also specify its ability to recruit TBLR1, a core component of the NCoR1/2 co-repressor complex. We further examined several RTT mutations and found that they disrupt different aspects of the MeCP2-chromatin interaction, rationalizing the heterogeneous nature of the disease. Our work reveals the biophysical basis for MeCP2’s methylation-dependent activities and suggests a nucleosome-centric model for its genomic distribution and gene repressive functions. These insights provide a framework for delineating the multifaceted functions of MeCP2 and aid in our understanding of the molecular mechanisms of RTT.
Interleukin-21 Drives a Hypermetabolic State and CD4+T Cell-associated Pathogenicity in Chronic Intestinal Inflammation
Authors: Bamidele Adebowale O. , Mishra Shravan K. , Hirsova Petra , Fehrenbach Patrick J. , Valenzuela-Pérez Lucia , Kim Lee Hyun Se 
Published: June 2023

BACKGROUND & AIMSIncapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease (IBD); however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis.METHODSUsing human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing Seahorse XF analyzer. We utilized Crohn’s disease single-cell RNA sequencing dataset to infer therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically-modified Tregs in CD4+T cell-induced murine colitis models.RESULTSMitochondria-endoplasmic reticulum (ER) appositions, known to mediate pyruvate entry into mitochondria via VDAC1, are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate (MePyr) supplementation. Notably, IL-21 diminished mitochondria-ER appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 β (GSK3β), a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. MePyr and GSK3β pharmacologic inhibitor (LY2090314) reversed IL-21-induced metabolic rewiring and inflammatory state. Moreover, IL-21-induced metabolic genes in Tregsin vitrowere enriched in human Crohn’s disease intestinal Tregs. Adoptively transferredIl21r-/-Tregs efficiently rescued murine colitis in contrast to wild-type Tregs.CONCLUSIONSIL-21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL-21-induced metabolism in Tregs may mitigate CD4+T cell-driven chronic intestinal inflammation.
A flexible and high-throughput genotyping workflow tracked the emergence of SARS-CoV-2 variants in the UK in 2022
Authors: Lee Suki , Grujic Stefan , Modern Sam , Wann Angela , Fraser Donald , Percival Benita 
Published: June 2023

AbstractIn late 2021, the Omicron SARS-CoV-2 variant spread rapidly worldwide. To track its emergence, and the continued evolution of SARS-CoV-2 while giving actionable epidemiological data that informs public health policy, we developed a high-throughput, automated, genotyping workflow that pairs flexible liquid handling with a re-configurable LIMS system. This workflow facilitated the real-time monitoring of the spread of BA.4 and BA.5, and by the time of its retirement, the system was responsible for typingc. 400,000 SARS-CoV-2 samples. When combined with a population-scale testing program, genotyping assays, can offer a rapid and cost-effective method of determining variants and horizon-scanning for changes in the pool of circulating mutations. Strategies to prepare diagnostics infrastructure for Pathogen X should consider the development of flexible systems with interchangeable components that can be rapidly re-configured to meet uncertain and changing requirements.
A Boltzmann model predicts glycan structures from lectin binding
Authors: Yom Aria , Chiang Austin , Lewis Nathan E. 
Published: June 2023

AbstractGlycans are complex oligosaccharides involved in many diseases and biological processes. Unfortunately, current methods for determining glycan composition and structure (glycan sequencing) are laborious and require a high level of expertise. Here, we assess the feasibility of sequencing glycans based on their lectin binding fingerprints. By training a Boltzmann model on lectin binding data, we predict the approximate structures of 88±7% of N-glycans and 87±13% of O-glycans in our test set. We show that our model generalizes well to the pharmaceutically relevant case of Chinese Hamster Ovary (CHO) cell glycans. We also analyze the motif specificity of a wide array of lectins and identify the most and least predictive lectins and glycan features. These results could help streamline glycoprotein research and be of use to anyone using lectins for glycobiology.
Cancer drug sensitivity prediction from routine histology images
Authors: Dawood Muhammad , Vu Quoc Dang , Young Lawrence S. , Branson Kim , Jones Louise , Rajpoot Nasir , Minhas Fayyaz ul Amir Afsar 
Published: June 2023

SummaryDrug sensitivity prediction models can aid in personalising cancer therapy, biomarker discovery, and drug design. Such models require survival data from randomized controlled trials which can be time consuming and expensive. In this proof-of-concept study, we demonstrate for the first time that deep learning can link histological patterns in whole slide images (WSIs) of Haematoxylin & Eosin (H&E) stained breast cancer sections with drug sensitivities inferred from cell lines. We employ patient-wise drug sensitivities imputed from gene expression based mapping of drug effects on cancer cell lines to train a deep learning model that predicts sensitivity to multiple drugs from WSIs. We show that it is possible to use routine WSIs to predict the drug sensitivity profile of a cancer patient for a number of approved and experimental drugs. We also show that the proposed approach can identify cellular and histological patterns associated with drug sensitivity profiles of cancer patients.HighlightsPredicting drug sensitivity from routine histology images and cell linesDiscovery of histology image patterns linked to drug sensitivityA novel deep learning pipeline for analysing drug sensitivity profiles