bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and extensive sequencing of a broadly-consented Genome in a Bottle matched tumor-normal pair
Authors: McDaniel Jennifer H. , Patel Vaidehi , Olson Nathan D. , He Hua-Jun , He Zhiyong , Cole Kenneth D. , Schmitt Anthony , Sikkink Kristin , Sedlazeck Fritz J , Doddapaneni Harsha , Jhangiani Shalini N. , Muzny Donna M. , Gingras Marie-Claude , Mehta Heer , Paulin Luis F , Hastie Alex R , Yu Hung-Chun , Weigman Victor , Rojas Alison , Kennedy Katie , Remington Jamie , Gonzalez Isai , Sudkamp Mitch , Wiseman Kelly , Lajoie Bryan R. , Levy Shawn , Jain Miten , Akeson Stuart , Narzisi Giuseppe , Steinsnyder Zoe , Reeves Catherine , Shelton Jennifer , Kingan Sarah B. , Lambert Christine , Bayabyan Primo , Wenger Aaron M. , McLaughlin Ian J. , Adamson Aaron , Kingsley Christopher , Wescott Melanie , Kim Young , Paten Benedict , Park Jimin , Violich Ivo , Miga Karen H , Gardner Joshua , McNulty Brandy , Rosen Gail , McCoy Rajiv , Brundu Francesco , Sayyari Erfan , Scheffler Konrad , Truong Sean , Catreux Severine , Hannah Lesley Chapman , Lipson Doron , Benjamin Hila , Iremadze Nika , Soifer Ilya , Eacker Stephen , Wood Mary , Cross Erin , Husar Greg , Gross Stephen , Vernich Michael , Kolmogorov Mikhail , Ahmad Tanveer , Keskus Ayse , Bryant Asher , Thibaud-Nissen Francoise , Trow Jonathan , Proszynski Jacqueline , Hirschberg Jeremy W. , Ryon Krista , Mason Christopher E. , Wagner Justin , Xiao Chunlin , Liss Andrew S. , Zook Justin M. 
Published: September 2024

AbstractThe Genome in a Bottle Consortium (GIAB), hosted by the National Institute of Standards and Technology (NIST), is developing new matched tumor-normal samples, the first to be explicitly consented for public dissemination of genomic data and cell lines. Here, we describe a comprehensive genomic dataset from the first individual, HG008, including DNA from an adherent, epithelial-like pancreatic ductal adenocarcinoma (PDAC) tumor cell line and matched normal cells from duodenal and pancreatic tissues. Data for the tumor-normal matched samples comes from thirteen distinct state-of-the-art whole genome measurement technologies, including high depth short and long-read bulk whole genome sequencing (WGS), single cell WGS, and Hi-C, and karyotyping. These data will be used by the GIAB Consortium to develop matched tumor-normal benchmarks for somatic variant detection. We expect these data to facilitate innovation for whole genome measurement technologies,de novoassembly of tumor and normal genomes, and bioinformatic tools to identify small and structural somatic mutations. This first-of-its-kind broadly consented open-access resource will facilitate further understanding of sequencing methods used for cancer biology.
Broadly Reactive Anti-VHH Antibodies for Characterizing, Blocking, or Activating Nanobody-Based CAR-T Cells
Authors: McComb Scott , Dupont Bianca , Shepherd Alex , Bennychen Bigitha , Marcil Anne , Arbabi-Ghahroudi Mehdi , Tamblyn Laura , Raphael Shalini , Sheff Joey , Hussack Greg , Moraitis Anna N. , Wu Cunle , Aubry Annie , Gadoury Christine , Lippens Julie , Pagé Martine , Fortin Annie , Joubert Simon , Lamoureux Linda , Parat Marie , Plante Pierre , Malenfant Félix , Acchione Mauro , Pohankova Petra , Schrag Joe , Acel Andrea , Coutu Mathieu , Smith Emma , Bakkouri Majida El , Hill Jennifer J. , Tremblay Tammy-Lynn , Aziza Manceur , Faulkes Sharlene , Webb John , Zafer Ahmed , Zhu Qin , Nguyen Tina , Pon Robert A. , Weeratna Risini D. 
Published: September 2024

AbstractProduction of chimeric antigen receptor T cell (CAR-T) therapies is dependent on the use of antibody reagents to label, isolate, and/or expand T cell products. We sought to create antibody-based tools that directly target the variable domain of heavy-chain only antibodies (VHH or nanobody) used in some CAR molecules. Two murine antibodies were identified which bind to distinct epitopes in the conserved framework regions of llama-derived VHHs, and not to human VH domains. We produced a high-quality dual-clonal anti-VHH antibody product which reacts with over 98% of VHH proteins, regardless of their antigenic specificity. Anti-VHH binding did not disrupt VHH/antigen interaction, and thus could be used for secondary labeling to assess cellular or tissue reactivity of VHH molecules. Despite not interfering with antigen binding, anti-VHH antibodies potently inhibited VHH-CAR function, blocking CAR-T activation and cytolytic killing of target cells. When immobilized, anti-VHH antibodies could also be applied for activation and expansion of VHH CAR-T cells, inducing 730-fold mean expansion, >94% CAR purity, with retained CD8/CD4 heterogeneity. Functionally, anti-VHH antibody-expanded CAR-T cells maintained strong antigen specific activity without functional exhaustion. Overall, these data identify a useful new tool for understanding and manipulating VHH-based CAR-T cells.Funding SourceThis work was funded by the National Research Council Canada Disruptive Technology Solutions Cell and Gene Therapy challenge program, and BioCanRxDeclaration of interestsThe anti-VHH antibodies reported here are the subject of a provisional patent application by the National Research Council of Canada
Accessible chromatin regions and DNA methylation regulate gene expression leading to changes in agronomic traits inBrassicaallotriploid hybrids
Authors: Quan Chengtao , Zhang Qin , Zhang Xiaoni , Chai Kexin , Cheng Guoting , Ma Chaozhi , Dai Cheng 
Published: September 2024

ABSTRACTIntroductionInterspecific hybridization is a common method in plant breeding to combine traits from different species, resulting in allopolyploidization and significant genetic and epigenetic changes. However, our understanding of genome-wide chromatin and gene expression dynamics during allopolyploidization remains limited.ObjectivesWe aimed to explore the relationship and underlying mechanisms between accessible chromatin regions and DNA methylation and gene transcription in genome-wide reorganization after interspecific hybridization.MethodsThis study generated twoBrassicaallotriploid hybrids via interspecific hybridization, combining transcriptomics, whole-genome bisulfite sequencing (WGBS) and assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq), revealing that accessible chromatin regions (ACRs) and DNA methylation regulate gene expression after interspecific hybridization, ultimately influencing the agronomic traits of the hybrids.ResultsA total of 234,649 ACRs were identified in the parental lines and hybrids, the hybridization process induces changes in the distribution and abundance of there accessible chromatin regions, particularly in gene regions and their proximity. On average, genes associated with Proximal ACRs were more highly expressed than the genes associated with Distal and Genic ACRs. More than half of novel ACRs drove transgressive gene expression in the hybrids, and the transgressive up-regulated genes showed significant enrichment in metal ion binding, especially magnesium ion, calcium ion, and potassium ion binding. We also identified theBna.bZIP11in the single-parent activation ACR (SPA-ACR), which binds toBnaA06.UF3GTto promote anthocyanin accumulation in F1hybrids. Additionally, in F1hybrids, the level of DNA methylation in ACRs was higher compared to gene bodies, and the A-subgenome ACRs were associated with genome dosage rather than DNA methylation.ConclusionsThe interplay among DNA methylation, TEs, and sRNA contributes to the dynamic landscape of ACRs during interspecific hybridization, resulting in distinct gene expression patterns on the genome.HIGHLIGHTSThe study utilized the accessible chromatin regions (ACR) and DNA methylation to elucidate the mechanism behind gene expression changes following interspecific hybridization.Whole-genome recombination after interspecific hybridization leads to the rearrangement of ACR, and novel ACR and single-parent activation ACR regulate the expression of genes.DNA methylation plays a role in repressing gene expression within ACRs, and unmethylated ACRs have more transcriptionally active.A-subgenome ACRs were associated with genome dosage rather than DNA methylation.GRAPHICAL ABSTRACT
Family-Wide Photoproximity Profiling of Integrin Protein Social Networks in Cancer
Authors: Carlos Anthony J. , Yang Dongbo , Thomas Deborah M. , Huang Shuyuan , Harter Keira I. , Moellering Raymond E. 
Published: September 2024

AbstractIntegrin family transmembrane receptors mediate dynamic interactions between cells and their extracellular microenvironment. The heterogeneous interaction partners of integrins directly regulate cell adhesion, motility, proliferation, and intracellular signaling. Despite the recognized importance of protein-protein interactions and the formation of signaling hubs around integrins, the ability to detect and quantify these dynamic binding partners with high spatial and temporal resolution remains challenging. Here, we developed an integrin-family-directed quantitative photoproximity protein interaction (PhotoPPI) profiling method to detect and quantify native integrin-centered protein social networks on live cells and tissues without the need for genetic manipulation, antibodies, or non-physiologic cell culture conditions. We drafted quantitative maps of integrin-centered protein social networks, highlighting conserved and unique binding partners between different cell types and cellular microenvironments. Comparison of integrin social networks in cancer cell lines of diverse tissue of origin and disease state identified specific AND-gate binding partners involved cell migration, microenvironmental interactions and proliferation that serve as markers of tumor cell metastatic state. Finally, we identified unique combinations – or barcodes - of integrin-proximal proteins on the surface of pre- and post-metastatic triple negative breast cancer (TNBC) cells whose expression strongly correlate with both positive and negative disease progression and outcomes in TNBC patients. Taken together, these data provide the first family-wide high-resolution maps of native protein interactors on live cells and identify dynamic integrin-centered social networks as potential AND-gate markers of cell identity, microenvironmental context and disease state.
Peptide-MHC-targeted retroviruses enablein vivoexpansion and gene delivery to tumor-specific T cells
Authors: Xu Ellen J.K. , Smith Blake E. , Conce Alberto Winiffer D. , Walsh Michael J. , Lim Birkley , Hoffman Megan T. , Qiang Li , Dong Jiayi , Garmilla Andrea , Zhao Qingyang Henry , Perez Caleb R. , Gaglione Stephanie A. , Dobson Connor S. , Dougan Michael , Dougan Stephanie K. , Birnbaum Michael E. 
Published: September 2024

AbstractTumor-infiltrating-lymphocyte (TIL) therapy has demonstrated that endogenous T cells can be harnessed to initiate an effective anti-tumor response. Despite clinical promise, current TIL production protocols involve weeks-longex vivoexpansions which can affect treatment efficacy. Therefore, additional tools are needed to engineer endogenous tumor-specific T cells to have increased potency while mitigating challenges of manufacturing. Here, we present a strategy for pseudotyping retroviral vectors with peptide-major histocompatibility complexes (pMHC) for antigen-specific gene delivery to CD8 T cells and examine the efficacy of these transduced cells in immunocompetent mouse models. We demonstrate that pMHC-targeted viruses are able to specifically deliver function-enhancing cargoes while simultaneously activating and expanding anti-tumor T cells. The specificity of these viral vectors enablesin vivoengineering of tumor-specific T cells, circumventingex vivomanufacturing processes and improving overall survival in B16F10-bearing mice. Altogether, we have established that pMHC-targeted viruses are efficient vectors for reprogramming and expanding tumor-specific populations of T cells directlyin vivo, with the potential to substantially streamline engineered cell therapy production for a variety of applications.
Dramatic evolutionary changes of conserved noncoding elements accompanied by extraordinary features ofCaenorhabditis inopinata
Authors: Tamagawa Katsunori , Oomura Shun , Sugimoto Asako , Makino Takashi 
Published: September 2024

AbstractPhenotypic evolution is caused by mutations in noncoding and protein-coding regions. Conserved noncoding elements (CNEs) have—at least partially—gene regulatory functions and contribute to the evolution of organisms by modifying their gene expression. While evolutionary changes of CNEs—such as loss and accelerated evolution—have been intensively studied in vertebrates, only a few studies have focused on invertebrates. The availability of detailed functional genomic information of the model nematodeCaenorhabditis elegansand recent accumulation of genome sequences within the same genus facilitate the use of these nematodes in comparative genomics focusing on CNEs. The recently discovered speciesCaenorhabditis inopinatahas several peculiar traits characterized by a larger body size than that of its close relatives and are regarded as an appropriate species that links phenotypic evolution with genomic changes. Herein, using comparative genomics and transcriptomics inC. inopinata, we analyzed the evolution of CNEs and their functions during phenotypic evolution. We detected substantial evolutionary changes in CNEs inC. inopinatacompared to other relatives—changes frequently associated with body morphology and behavior corresponding to extraordinary body size and unique life cycles. Our study revealed an association between noncoding elements and substantial phenotypic evolution in invertebrates.
Motif distribution in genomes gives insights into gene clustering and co-regulation
Authors: Chakraborty Atreyi , Chopde Sumant , Madhusudhan M.S 
Published: September 2024

ABSTRACTWe read the genome as proteins in the cell would - by studying the distributions of 5-6 base motifs of DNA in the whole genome or smaller stretches such as parts of, or whole chromosomes. This led us to some interesting findings about motif clustering and chromosome organisation. It is quite clear that the motif distribution in genomes is not random at the length scales we examined: 1kbps to entire chromosomes. The observed to expected (OE) ratios of motif distributions show strong correlations in pairs of chromosomes that are susceptible to translocations. With the aid of examples, we suggest that similarity in motif distributions in promoter regions of genes could imply co-regulation. A simple extension of this idea empowers us with the ability to construct gene regulatory networks. Further, we could make inferences about the spatial proximity of genomic fragments using these motif distributions. Spatially proximal regions, as deduced by Hi-C or pcHi-C, were ∼3.5 times more likely to have their motif distributions correlated than non-proximal regions. These correlations had strong contributions from the CTCF protein recognizing motifs which are known markers of TADs. In general, correlating genomic regions by motif distribution comparisons alone is rife with functional information.GRAPHICAL ABSTRACT
Loss of PARP7 increases type I interferon signalling and prevents pancreatic tumour growth by enhancing immune cell infiltration
Authors: Kannen Vinicius , Rasmussen Marit , Das Siddhartha , Giuliana Paolo , Izzati Fauzia N. , Choksi Hani , Erlingsson Linnea A. M. , Olafsen Ninni E. , Cappello Paola , Teino Indrek , Maimets Toivo , Jaudzems Kristaps , Gulbinas Antanas , Dambrauskas Zilvinas , Edgar Landon , Grant Denis M. , Matthews Jason 
Published: September 2024

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and despite low incidence rates, it remains the sixth leading cause of cancer related deaths worldwide. Immunotherapy, which aims to enhance the immune system’s ability to recognize and eliminate cancer cells, has emerged as a promising approach in the battle against PDAC. PARP7, a mono-ADP-ribosyltransferase, is a negative regulator of the type I interferon (IFN-I) pathway and has been reported to reduce anti-tumour immunity. Using murine pancreatic cancer cells, we found that loss ofParp7elevated the levels of interferon stimulated gene factor 3 (ISGF3) and its downstream target genes, even in the absence of STING. Cancer cells deficient inParp7produced smaller tumours when injected into immunocompetent mice. Transcriptomic analyses revealed that tumours knocked out forParp7(Parp7KO) had increased expression of genes involved in immunoregulatory interactions and interferon signalling pathways. Characterization of tumour infiltrating leukocyte (TIL) populations showed that Parp7KOtumours had higher proportions of natural killer cells, CD8 T cells and a lower proportion of anti-inflammatory macrophages (M2). The overall TIL profile of Parp7KOtumours was suggestive of a less suppressive microenvironment. Our data show that loss ofParp7reduces PDAC tumour growth by increasing the infiltration of immune cells and enhancing anti-tumour immunity. These findings provide support to pursue PARP7 as a therapeutic target for PDAC.
BioPAX-Explorer: a Python Object-Oriented framework for overcoming the complexity of querying biological networks
Authors: Moreews François , Bougaud Jean-Baptiste , Becker Emmanuelle , Gondret Florence , Dameron Olivier 
Published: September 2024

AbstractMotivationBiological Pathway Exchange (BioPAX) is a standard language, represented in OWL, that aims to enable the integration, exchange, visualization and analysis of biological pathway data. While public databanks increasingly provide datasets in BioPAX format, their use remains below potential. Users may encounter challenges in harnessing the data due to the BioPAX intricately detailed underlying model. Moreover, extracting data demands specific technical skills, posing a barrier for many potential users.ResultsTo address these obstacles, we developped BioPAX-Explorer. This toolis designed to facilitate the adoption and usage of BioPAX for extracting data or build algorithms and models, within the Python community. BioPAX-Explorer is a Python package that provides an object-oriented data model automatically generated from the BioPAX OWL specification. Moreover, it offers expressive query capabilities that shield users from BioPAX inner complexity. BioPAX-Explorer supports dataset building features, validation facilities and pre-build queries. It simplifies the extraction and processing of data from BioPAX sources by automatically generating SPARQL queries. BioPAX-Explorer also offers a user-friendly interface for Python users, allowing exhaustive exploration of large datasets through features such as memory-efficient query execution, entity-oriented queries without the need for SPARQL knowledge. It also allows to learn and reuse complex SPARQL queries for biological network analysis. Additionally, BioPAX-Explorer can accelerate the development of Python-based network analysis software, since it generates graph data structures from BioPAX queries and facilitates the creation of transparent, reproducible workflows based on the BioPAX OWL standard.Availability and implementationBioPAX-Explorer is freely available. We provide the source code, documentation, installation instructions and a Jupyter notebook with tutorial athttps://fjrmoreews.github.io/biopax-explorer/
Independent derivations of the axis of arrhythmia for predicting drug-induced torsades de pointes
Authors: Heitmann Stewart , Vandenberg Jamie I , Hill Adam P 
Published: September 2024

Torsades de pointes is a potentially lethal ventricular arrhythmia that may be caused by many classes of drugs. The likelihood of arrhythmia depends upon the particular combination of cardiac ion-channels that the drug targets. The risk for a given drug can be measured against the axis of arrhythmia, which is a conceptual line in the parameter space of ventricular cardiomyocyte electrophysiology. The axis describes the most potent combination of ion-channel blocks that is theoretically possible. It thus serves as a convenient yardstick for quantifying the pro-arrhythmic risk of novel drugs from their channel-blocking profiles. To date, the axis of arrhythmia has only been derived from biophysical computer simulations. Here, we derive the axis directly from the response profiles of selected ion-channels to known drugs (n=109). The new method provides an independent line of evidence for estimating the axis of arrhythmia. Using step-wise reduction, the two methods were found to converge to identical estimates of the axis in two ion-currents(ICaLandIKr). The resulting axis predicted the pro-arrhythmic risk of the test drugs with 89.9% to 91.7% accuracy, depending on the dose at which the drug was assessed. The axis of arrhythmia offers a practical method for predicting the pro-arrhythmic risk of novel drugs without the need for drug-specific computer simulations. It is the only metric of pro-arrhythmic risk that has been derived from both a biophysical model and a purely statistical model. It thus combines the benefits of biophysical interpretation and computational efficiency in assessing the torsadogenic risk of new drugs prior to clinical trials.Significance StatementMany classes of drugs can cause lethal cardiac arrhythmias by blocking ion-channels that are needed by heart cells for normal rhythm. International safety guidelines thus require all new drugs be tested in animal hearts or cell cultures prior to undertaking clinical trials in humans. Computer models offer an ethical alternative for drug testing that is gaining acceptance in the safety pharmacology community. However, the current corpus of models are usually too complex to apply outside of specialist computing laboratories. We recently proposed a new approach that eliminates the need for drug-specific computer simulations by using a large one-off computer simulation to identify the most pro-arrhythmic drug that is theoretically possible. Thereafter, that hypothetical drug can be used to assess the pro-arrhythmic risk of real drugs using only pen-and-paper calculations. In that study, the hypothetical drug was described by theaxis of arrhythmiain the cardiac cell model. In the present study, we propose an alternative method for deriving the axis of arrhythmia directly from drug datasets. The two derivations are independent, yet they arrive at the same result. Together, they provide converging lines of evidence in support of this new approach to drug testing in safety pharmacology.