bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concerted transformation of a hyper-paused transcription complex and its reinforcing protein
Authors: Zuber Philipp K. , Said Nelly , Hilal Tarek , Wang Bing , Loll Bernhard , González-Higueras Jorge , Ramírez-Sarmiento César A. , Belogurov Georgiy A. , Artsimovitch Irina , Wahl Markus C. , Knauer Stefan 
Published: June 2023

SUMMARYRfaH, a paralog of the universally conserved NusG, binds to RNA polymerases (RNAP) and ribosomes to activate expression of virulence genes. In free, autoinhibited RfaH, an α-helical KOW domain sequesters the RNAP-binding site. Upon recruitment to RNAP paused at anopssite, KOW is released and refolds into a β-barrel, which binds the ribosome. Our structures ofops-paused transcription elongation complexes alone and bound to the autoinhibited and activated RfaH reveal swiveled, pre-translocated pause states stabilized by anopshairpin in the non-template DNA. Autoinhibited RfaH binds and twists theopshairpin, expanding the RNA:DNA hybrid to 11 base pairs and triggering the KOW release. Once activated, RfaH hyper-stabilizes the pause, which thus requires anti-backtracking factors for escape. Our results suggest that the entire RfaH cycle is solely determined by theopsand RfaH sequences and provide insights into mechanisms of recruitment and metamorphosis of NusG homologs across all life.HIGHLIGHTS-The nontemplate DNA strand of anops-paused transcription complex forms a hairpin-Autoinhibited RfaH binds and twists theopshairpin to expand the RNA:DNA hybrid-RfaH-hairpin contacts are solely responsible for triggering RfaH activation-Upon recruitment, RfaH hyper-stabilizes the pause and promotes RNAP backtracking
Dendrimeric DNA Coordinate Barcoding Design for Spatial RNA Sequencing
Authors: Cao Jiao , Zheng Zhong , Sun Di , Chen Xin , Cheng Rui , Lv Tianpeng , An Yu , Zheng Junhua , Song Jia , Wu Lingling , Yang Chaoyong 
Published: June 2023

AbstractSpatially resolved transcriptomic technologies show promise in revealing complex pathophysiological processes, but developing sensitive, high-resolution, and cost-effective methodology is challenging. Here, we report adendrimeric DNAcoordinate barcodingdesign for spatialRNAsequencing (Decoder-seq). This technology combined dendrimeric nano-substrates with microfluidic coordinate barcoding to generate high-density spatial DNA arrays with deterministically combinatorial barcodes in a resolution-flexible and cost-effective manner (∼$0.5/mm2). Decoder-seq achieved high RNA capture efficiency, ∼68.9% that ofin situsequencing, and enhanced the detection of lowly expressed genes by ∼five-fold compared to 10× Visium. Decoder-seq visualized a spatial single-cell atlas of mouse hippocampus at near-cellular resolution (15 μm) and revealed dendrite-enriched mRNAs. Application to renal cancers dissected the heterogeneous tumor microenvironment of two subtypes, and identified spatial gradient expressed genes with the potential in predicting tumor prognosis and progression. Decoder-seq is compatible with sensitivity, resolution, and cost, making spatial transcriptomic analysis accessible to wider biomedical applications and researchers.
Inserting a Neuropixels probe into awake monkey cortex: two probes, two methods
Authors: Namima Tomoyuki , Kempkes Erin , Smith Bob , Pasupathy Anitha 
Published: June 2023

AbstractNeuropixels probes have revolutionized neurophysiological studies in the rodent, but inserting these probes through the much thicker primate dura remains a challenge. Here we describe two methods we have developed for the insertion of two types of Neuropixels probes acutely into the awake monkey cortex. For the fine rodent probe, which is unable to pierce native primate dura, we developed a duraleyelet method to insert the probe repeatedly without breakage. For the thicker NHP probe, we developed an artificial dura system to insert the probe. We have now conducted successful experiments in 3 animals across 7 recording chambers with the procedures described here and have achieved stable recordings over several months in each case. Here we describe our hardware, surgical preparation, methods for insertion and methods for removal of broken probe parts. We hope that our methods are of value to primate physiologists everywhere.
Covering Hierarchical Dirichlet Mixture Models on binary data to enhance genomic stratifications in Onco-Hematology
Authors: Dall’Olio Daniele , Sträng Eric , Turki Amin T , Tettero Jesse M , Barbus Martje , Schulze-Rath Renate , Elicegui Javier Martinez , Matteuzzi Tommaso , Merlotti Alessandra , Carota Luciana , Sala Claudia , Della Porta Matteo G , Giampieri Enrico , Hernández-Rivas Jesús María , Bullinger Lars , Castellani Gastone ,   HARMONY Healthcare Alliance Consortium
Published: June 2023

AbstractOnco-hematological studies are increasingly adopting statistical mixture models to support the advancement of the genetically-driven classification systems for blood cancer. Targeting enhanced patients stratification based on the sole role of molecular biology attracted much interest and contributes to bring personalized medicine closer to reality. In particular, Dirichlet processes have become the preferred method to approach the fit of mixture models. Usually, the multinomial distribution is at the core of such models. However, despite their advanced statistical formalism, these processes are not to be considered black box techniques and a better understanding of their working mechanisms enables to improve their employment and explainability. Focused on genomic data in Acute Myeloid Leukemia, this work unfolds the driving factors and rationale of the Hierarchical Dirichlet Mixture Models of multinomials on binary data. In addition, we introduce a novel approach to perform accurate patients clustering via multinomials based on statistical considerations. The newly reported adoption of the Multivariate Fisher’s Non-Central Hypergeometric distributions reveals promising results and outperformed the multinomials in clustering both on simulated and real onco-hematological data.Author summaryExplainable models are particularly attractive nowadays since they have the advantage to convince clinicians and patients. In this work we show that a deeper understanding of the Hierarchical Dirichlet Mixture Model, a non-black box method, can lead to better data modelling. In onco-hematology Hierarchical Dirichlet Mixture Models typically help to cluster molecular alterations rather than patients. Here, an intuitive statistical approach is presented to tackle patient classification based on the Hierarchical Dirichlet Mixture Models outcome. Additionally, molecular alterations are usually modelled by Hierarchical Dirichlet Mixture Models as a mixture of multinomial distributions. This work highlights that the alternative Fisher’s Non-Central Hypergeometric distribution can provide even better results and can give a higher priority to rare molecular alterations for patient classification.
Effect of using Diffusion-Weightage Imaging on Diagnostic Accuracy of MRI in catching Parotid carcinoma: A meta-analysis
Authors: Desai Dev , Todorovski Marko , Malafi Maria Eleni , Shah Abhijay B. , Andharia Dev 
Published: June 2023

AbstractBackgroundA wide variety of benign and malignant tumors can develop in the salivary gland, which makes up roughly 3-5% of all head and neck tumors. Making a precise pre-operative distinction between benign and malignant salivary gland tumors, or identifying the precise histologic subtype, is crucial since this knowledge has a significant impact on the treatment strategy. The results of fine-needle aspiration cytology can occasionally be inaccurate since it is an intrusive procedure for diagnosing parotid tumors before surgery. Because of the tiny sample size or the deep placement of the tumor, it is sometimes impossible to gather adequate samples therefore Salivary gland tumors are increasingly being evaluated before surgery using MRI since it can pinpoint their precise location, size, and surrounding tissues.MethodsMedical literature was comprehensively searched and reviewed without restrictions to particular study designs, or publication dates using PubMed, Cochrane Library, and Google Scholar databases for all relevant literature. The extraction of necessary data proceeded after specific inclusion and exclusion criteria were applied. The inclusion criteria were as follows:; (1) Literature that provided information about the accurate diagnosis with MRI(DWI) and only MRI ; (2) papers published in English; (3) papers with appropriate patient criteria. The exclusion criteria were: (1) articles that were not full text, (2) unpublished articles, and (3) non-English articles. In this Meta-Analysis, a total of 8 RCTs with a total of 944 patients were selected, out of which 3 RCTs with a total of 356 patients were selected for MRI and 5 RCTs with a total of 588 patients were selected for MRI+DWI study. wherein two writers independently assessed the caliber of each study as well as the use of the Cochrane tool for bias risk apprehension. The statistical software packages RevMan (Review Manager, version 5.3), SPSS (Statistical Package for the Social Sciences, version 20), and Excel in Stata 14 were used to perform the statistical analyses.ResultsWe calculated the sensitivity and specificity of MRI in diagnosing parotid gland lesions in the different papers, For the MRI, The sensitivity is 0.81 with a CI of 95% in a range of 0.77 to 0.86, the mean being 0.049. The Sensitivity of the MRI is 0.790 with a CI of 95% in a range of (0.772 to 0.809) the mean being (0.0183). The Specificity of the MRI is 0.794 with a CI of 95% in a range of (0.613 to 0.975) the mean being (0.181). For the MRI+DWI study, The Sensitivity of the MRI+DWI is 0.618 with a CI of 95% in a range of (0.498 to 0.737); the mean being (0.119). The Specificity of the MRI+DWI is 0.892 with a CI of 95% in a range of (0.813 to 0.97) the mean being (0.079).ConclusionIn addition to simple MRI or Single DWI MRI, A combination of both would detect higher lesions and it should be helpful for staging and early diagnosis purposes only.
Prediction of tumor-specific splicing from somatic mutations as a source of neoantigen candidates
Authors: Lang Franziska , Sorn Patrick , Suchan Martin , Henrich Alina , Albrecht Christian , Koehl Nina , Beicht Aline , Riesgo-Ferreiro Pablo , Holtsträter Christoph , Schrörs Barbara , Weber David , Löwer Martin , Sahin Ugur , Ibn-Salem Jonas 
Published: June 2023

AbstractSplicing is dysregulated in many tumors and may result in tumor-specific transcripts that can encode neoantigens, which are promising targets for cancer immunotherapy. Detecting tumor-specific splicing is challenging because many non-canonical splice junctions identified in tumor transcriptomes also appear in healthy tissues.Here, we developed splice2neo to integrate the predicted splice effects from somatic mutations with splice junctions detected in tumor RNA-seq for individual cancer patients. Splice2neo excludes splice junctions from healthy tissue samples, annotates resulting transcript and peptide sequences, and provides targeted re-quantification of supporting RNA-seq reads. We developed a stringent detection rule to predict splice junctions as mutation-derived targets and identified 1.7 target splice junctions per tumor with a false discovery rate below 5% in a melanoma cohort. We confirmed tumor-specificity using independent, healthy tissue samples. Furthermore, using tumor-derived RNA, we confirmed individual exon skipping events experimentally. Most target splice junctions encoded neoepitope candidates with predicted MHC-I or MHC-II binding. Compared to neoepitope candidates derived from non-synonymous point mutations, the splicing-derived MHC-I neoepitope candidates had a lower self-similarity to corresponding wild-type peptides.In conclusion, we demonstrate that identifying mutation-derived and tumor-specific splice junctions can lead to additional neoantigen candidates to expand the target repertoire for cancer immunotherapies.Key Pointssplice2neo is a versatile tool for identifying and analyzing of splice junctions as a source of neoantigen candidatesWe identified mutation-retrieved splice junctions supported by RNA-seq in melanoma samplesThe predicted target splice junctions exhibited a strong tumor-specificity as they were absent in healthy tissues.Target splice junctions often lead to frame-shift peptides and encode promising neoantigen candidates
Polygenic risk score prediction accuracy convergence
Authors: Henches Léo , Kim Jihye , Yang Zhiyu , Rubinacci Simone , Pires Gabriel , Albiñana Clara , Boetto Christophe , Julienne Hanna , Frouin Arthur , Auvergne Antoine , Suzuki Yuka , Djebali Sarah , Delaneau Olivier , Ganna Andrea , Vilhjálmsson Bjarni , Privé Florian , Aschard Hugues 
Published: June 2023

AbstractPolygenic risk scores (PRS) trained from genome-wide association study (GWAS) results are set to play a pivotal role in biomedical research addressing multifactorial human diseases. The prospect of using these risk scores in clinical care and public health is generating both enthusiasm and controversy, with varying opinions about strengths and limitations across experts1. The performances of existing polygenic scores are still limited, and although it is expected to improve with increasing sample size of GWAS and the development of new powerful methods, it remains unclear how much prediction can be ultimately achieved. Here, we conducted a retrospective analysis to assess the progress in PRS prediction accuracy since the publication of the first large-scale GWASs using six common human diseases with sufficient GWAS data. We show that while PRS accuracy has grown rapidly for years, the improvement pace from recent GWAS has decreased substantially, suggesting that further increasing GWAS sample size may translate into very modest risk discrimination improvement. We next investigated the factors influencing the maximum achievable prediction using recently released whole genome-sequencing data from 125K UK Biobank participants, and state-of-the-art modeling of polygenic outcomes. Our analyses point toward increasing the variant coverage of PRS, using either more imputed variants or sequencing data, as a key component for future improvement in prediction accuracy.
Engineering Human Pluripotent Stem Cell Lines to Evade Xenogeneic Transplantation Barriers
Authors: Pizzato Hannah A. , Alonso-Guallart Paula , Woods James , Johannesson Bjarki , Connelly Jon P. , Fehniger Todd A. , Atkinson John P. , Pruett-Miller Shondra M. , Monsma Frederick J. , Bhattacharya Deepta 
Published: June 2023

SummaryAllogeneic human pluripotent stem cell (hPSC)-derived cells and tissues for therapeutic transplantation must necessarily overcome immunological rejection by the recipient. To define these barriers and to create cells capable of evading rejection for preclinical testing in immunocompetent mouse models, we genetically ablatedβ2m,Tap1,Ciita,Cd74,Mica, andMicbto limit expression of HLA-I, HLA-II, and natural killer cell activating ligands in hPSCs. Though these and even unedited hPSCs readily formed teratomas in cord blood-humanized immunodeficient mice, grafts were rapidly rejected by immunocompetent wild-type mice. Transplantation of these cells that also expressed covalent single chain trimers of Qa1 and H2-Kbto inhibit natural killer cells and CD55, Crry, and CD59 to inhibit complement deposition led to persistent teratomas in wild-type mice. Expression of additional inhibitory factors such as CD24, CD47, and/or PD-L1 had no discernible impact on teratoma growth or persistence. Transplantation of HLA-deficient hPSCs into mice genetically deficient in complement and depleted of natural killer cells also led to persistent teratomas. Thus, T cell, NK cell, and complement evasion are necessary to prevent immunological rejection of hPSCs and their progeny. These cells and versions expressing human orthologs of immune evasion factors can be used to refine tissue- and cell type-specific immune barriers, and to conduct preclinical testing in immunocompetent mouse models.
Unveiling targeted cell-free DNA methylation regions through paired methylome analysis of tumor and normal tissues
Authors: Li Tingyi , Patel Krupal B , Yu Xiaoqing , Yao Sijie , Wang Liang , Chung Christine H , Wang Xuefeng 
Published: June 2023

ABSTRACTLiquid biopsy analysis of cell-free DNA (cfDNA) has revolutionized cancer research by enabling non-invasive assessment of tumor-derived genetic and epigenetic changes. In this study, we conducted a comprehensive paired-sample differential methylation analysis (psDMR) on reprocessed methylation data from two large datasets, CPTAC and TCGA, to identify and validate differentially methylated regions (DMRs) as potential cfDNA biomarkers for head and neck squamous cell carcinoma (HNSC). Our hypothesis is that the paired sample test provides a more suitable and powerful approach for the analysis of heterogeneous cancers like HNSC. The psDMR analysis revealed a significant number of overlapped hypermethylated DMRs between two datasets, indicating the reliability and relevance of these regions for cfDNA methylation biomarker discovery. We identified several candidate genes, includingCALCA, ALX4, andHOXD9, which have been previously established as liquid biopsy methylation biomarkers in various cancer types. Furthermore, we demonstrated the efficacy of targeted region analysis using cfDNA methylation data from oral cavity squamous cell carcinoma and nasopharyngeal carcinoma patients, further validating the utility of psDMR analysis in prioritizing cfDNA methylation biomarkers. Overall, our study contributes to the development of cfDNA-based approaches for early cancer detection and monitoring, expanding our understanding of the epigenetic landscape of HNSC, and providing valuable insights for liquid biopsy biomarker discovery not only in HNSC and other cancer types.
Genetic similarity between relatives provides evidence on the presence and history of assortative mating
Authors: Sunde Hans Fredrik , Eftedal Nikolai Haahjem , Cheesman Rosa , Corfield Elizabeth C. , Kleppesto Thomas H. , Seierstad Anne Caroline , Ystrom Eivind , Eilertsen Espen Moen , Torvik Fartein Ask 
Published: June 2023

AbstractAssortative mating – the non-random mating of individuals with similar traits – is known to increase trait-specific genetic variance and genetic similarity between relatives. However, empirical evidence is limited for many traits, and the implications hinge on whether assortative mating has started recently or many generations ago. Here we show theoretically and empirically that genetic similarity between relatives can provide evidence on the presence and history of assortative mating. First, we employed path analysis to understand how assortative mating affects genetic similarity between family members across generations, finding that similarity between distant relatives is more affected than close relatives. Next, we correlated polygenic indices of 47,135 co-parents from the Norwegian Mother, Father, and Child Cohort Study (MoBa) and found genetic evidence of assortative mating in nine out of sixteen examined traits. The same traits showed elevated similarity between relatives, especially distant relatives. Six of the nine traits, including educational attainment, showed greater genetic variance among offspring, which is inconsistent with stable assortative mating over many generations. These results suggest an ongoing increase in familial similarity for these traits. The implications of this research extend to genetic methodology and the understanding of social and economic disparities.
The ChickenGTEx pilot analysis: a reference of regulatory variants across 28 chicken tissues
Authors: Guan Dailu , Bai Zhonghao , Zhu Xiaoning , Zhong Conghao , Hou Yali ,   The ChickenGTEx Consortium, Lan Fangren , Diao Shuqi , Yao Yuelin , Zhao Bingru , Zhu Di , Li Xiaochang , Pan Zhangyuan , Gao Yahui , Wang Yuzhe , Zou Dong , Wang Ruizhen , Xu Tianyi , Sun Congjiao , Yin Hongwei , Teng Jinyan , Xu Zhiting , Lin Qing , Shi Shourong , Shao Dan , Degalez Fabien , Lagarrigue Sandrine , Wang Ying , Wang Mingshan , Peng Minsheng , Rocha Dominique , Charles Mathieu , Smith Jacqueline , Watson Kellie , Buitenhuis Albert Johannes , Sahana Goutam , Lund Mogens Sandø , Warren Wesley , Frantz Laurent , Larson Greger , Lamont Susan J. , Si Wei , Zhao Xin , Li Bingjie , Zhang Haihan , Luo Chenglong , Shu Dingming , Qu Hao , Luo Wei , Li Zhenhui , Nie Qinghua , Zhang Xiquan , Zhang Zhe , Zhang Zhang , Liu George E. , Cheng Hans , Yang Ning , Hu Xiaoxiang , Zhou Huaijun , Fang Lingzhao 
Published: June 2023

AbstractChicken is a valuable model for understanding fundamental biology, vertebrate evolution and diseases, as well as a major source of nutrient-dense and lean-protein-enriched food globally. Although it is the first non-mammalian amniote genome to be sequenced, the chicken genome still lacks a systematic characterization of functional impacts of genetic variants. Here, through integrating 7,015 RNA-Seq and 2,869 whole-genome sequence data, the Chicken Genotype- Tissue Expression (ChickenGTEx) project presents the pilot reference of regulatory variants in 28 chicken tissue transcriptomes, including millions of regulatory effects on primary expression (including protein-coding genes, lncRNA and exon) and post-transcriptional modifications (alternative splicing and 3’ untranslated region alternative polyadenylation). We explored the tissue-sharing and context-specificity of these regulatory variants, their underlying molecular mechanisms of action, and their utility in interpreting adaptation and genome-wide associations of 108 chicken complex traits. Finally, we illustrated shared and lineage-specific features of gene regulation between chickens and mammals, and demonstrated how the ChickenGTEx resource can further assist with translating genetic findings across species.One-Sentence SummaryThe ChickenGTEx provides a multi-tissue reference of regulatory variants for chicken genetics and genomics, functional genomics, precision breeding, veterinary medicine, vertebrate evolution and even human biomedicine.
Attenuation of colitis-induced visceral hypersensitivity and pain by silencing TRPV1-expressing fibers in rat colon
Authors: Mazor Yoav , Engelmayer Nurit , Nashashibi Halla , Rottenfußer Lisa , Lev Shaya , Binshtok Alexander M 
Published: June 2023

AbstractBackground and AimsAbdominal pain in patients with inflammatory bowel disease (IBD) is common and debilitating. In our study, we aim to utilize transient receptor potential vanilloid 1 (TRPV1) channels, large-pore cation channels expressed on nociceptors, as a drug delivery system to selectively inhibit visceral nociceptors and thus visceral pain in a rodent model of IBD.MethodsWe induced colitis in rats using intrarectal dinitrobenzene sulfonic acid. Visceral hypersensitivity, spontaneous pain, and responsiveness of the hind paws to noxious heat stimuli were examined before and after the intrarectal application of sodium channel blocker QX-314 alone or together with TRPV1 channel activators or blockers.ResultsIntrarectal co-application of QX-314 with TRPV1 channel activator capsaicin significantly inhibited colitis-induced gut hypersensitivity. Furthermore, in the model of colitis, but not in naïve rats, QX-314 alone was sufficient to reverse gut hypersensitivity. The blockade of TRPV1 channels prevented this effect of QX-314. Finally, applying QX-314 alone to the inflamed gut inhibited colitis-induced ongoing pain.ConclusionsSelective silencing of nociceptors by QX-314 entering via exogenously or endogenously activated TRPV1 channels diminish IBD-induced gut hypersensitivity. These results yet again confirm the central role of TRPV1-expressing nociceptive neurons in IBD pain. The lack of QX-314 effect on naïve rats suggests its selective analgesic effect in IBD pain. Moreover, our results demonstrating the effect of QX-314 alone imply the role of a tonically active TRPV1 channel in the pathophysiology of IBD pain. This approach provides proof-of-concept for using charged activity blockers for selective and effective blockade of visceral pain.