bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploration of Mechanisms of Drug Resistance in a Microfluidic Device and Patient Tissues
Authors: Lim Wanyoung , Hwang Inwoo , Zhang Jiande , Chen Zhenzhong , Han Jeonghun , Jeon Jaehyung , Koo Bon-Kyoung , Kim Sangmin , Lee Jeong Eon , Kim Youngkwan , Pienta Kenneth J. , Amend Sarah R. , Austin Robert H. , Ahn Jee-Yin , Park Sungsu 
Published: November 2022

AbstractChemoresistance is a major cause of treatment failure in many cancers. However, the life cycle of cancer cells as they respond to and survive environmental and therapeutic stress is understudied. In this study, we utilized a microfluidic device to induce the development of doxorubicin-resistant (DOXR) cells from triple negative breast cancer (TNBC) cells within 11 days by generating gradients of DOX and medium.In vivochemoresistant xenograft models, an unbiased genome-wide transcriptome analysis, and a patient data/tissue analysis all showed that chemoresistance arose from failed epigenetic control of the nuclear protein-1 (NUPR1)/histone deacetylase 11 (HDAC11) axis, and highNupr1expression correlated with poor clinical outcomes. These results suggest that the chip can rapidly induce resistant cells that increase tumor heterogeneity and chemoresistance, highlighting the need for further studies on the epigenetic control of the NUPR1/HDAC11 axis in TNBC.
A pan-cancer interrogation of intronic polyadenylation and its association with cancer characteristics
Authors: Liu Liang , Sun Peiqing , Zhang Wei 
Published: November 2022

ABSTRACTmRNA cleavage and polyadenylation is an integral 2-step process in the generation of protein-encoding mRNA or noncoding transcripts. More than 60% of human genes have multiple polyadenylation sites either in the 3’ untranslated region (3’UTR-APA) or in the intronic/exonic region, resulting in expression of isoforms with alternative polyadenylation (APA) under different physiologic conditions. The 3’UTR-APAs have been extensively studied, but the biology of intronic polyadenylations (IPA) remain largely unexplored. Here we characterized the IPA profiles of 9,679 patient samples across 32 cancer types from the Cancer Genome Atlas (TCGA) cohort. Overall, we identified 22,260 detectable IPA sites; 9,014 (40.5%) occurred in all 32 cancer types and 11,676 (52.5%) occurred in 2 to 31 cancer types. By comparing tumors and their paired normal tissues, we identified 180 to 4,645 dysregulated IPAs in 132 to 2,249 genes in each of 690 patient tumors from 22 cancer types that showed consistent patterns within individual cancer types. Furthermore, across all cancer types, IPA isoforms and their gene regulation showed consistent pan-cancer patterns, and cancer types with similar histologic features were clustered at higher levels of hierarchy. We selected 2,741 genes that were consistently regulated by IPAs across cancer types, including 1,834 pan-cancer tumor-enriched and 907 tumor-depleted IPA genes. Pan-cancer tumor-enriched IPA genes were amply represented in the functional pathways such as cilium assembly and DNA damage repair. Expression of IPA isoforms in DNA damage repair genes was associated with tumor mutation burdens. Expression of IPA isoforms of tumor-enriched IPA genes was also associated with patient characteristics (e.g., sex, race, cancer stages, and subtypes) in cancer-specific and feature-specific manners. Importantly, IPA isoform expression for some genes could be a more accurate prognostic marker than gene expression (summary of all possible isoforms). In summary, our study reveals the roles and the clinical relevance of tumor-associated IPAs in cancer.
CREPE: A Shiny App for Transcription Factor Cataloguing
Authors: Rosado-Tristani Diego A. , Rodríguez-Martínez José A. 
Published: November 2022

AbstractTranscription factors (TFs) are proteins that directly interpret the genome to regulate gene expression and determine cellular phenotypes. TF identification is a common first step in unravelling gene regulatory networks. We present CREPE, an R Shiny app to catalogue and annotate TFs. CREPE was benchmarked against curated human transcription factor datasets. Next, we use CREPE to explore the TF repertoires ofHeliconius erato and Heliconius melpomenebutterflies. CREPE is available as a Shiny app package available at GitHub (github.com/dirostri/CREPE).
A transcriptional response to replication stress selectively expands a subset ofBRCA2-mutant mammary epithelial cells
Authors: Najafabadi Maryam Ghaderi , Gray G. Kenneth , Kong Li Ren , Gupta Komal , Perera David , Brugge Joan , Venkitaraman Ashok , Shehata Mona 
Published: November 2022

AbstractBRCA2 mutation carriers preferentially develop luminal-like breast cancers, but it remains unclear how BRCA2 mutations affect mammary epithelial subpopulations. Here, we report that Brca2mut/WTmammary organoids subjected to replication stress activated a transcriptional response that selectively expands Brca2mut/WTluminal cells lacking hormone receptor expression (HR-). While CyTOF analyses revealed comparable epithelial compositions among wildtype and Brca2mut/WTmammary glands, Brca2mut/WTHR- luminal cells exhibited greater organoid formation and preferentially survived and expanded under replication stress. ScRNA-seq analysis corroborated the expansion of HR- luminal cells which express elevated levels of Tetraspanin-8 (Tspan8) andThrspmRNA, and pathways implicated in replication stress survival including Type I interferon responses. Notably, CRISPR/Cas9-mediated deletion ofTspan8orThrspprevented Brca2mut/WTHR- luminal cell expansion. Our findings indicate that Brca2mut/WTcells have an activate a transcriptional response after replication stress that preferentially favours outgrowth of HR- luminal cells through the expression of interferon-responsive and mammary alveolar genes.
A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing drugs in RB1-deficient ovarian and breast cancer cells
Authors: Bulanova Daria , Akimov Yevhen , Senkowski Wojciech , Oikkonen Jaana , Gall-Mas Laura , Timonen Sanna , Elmadani Manar , Hynninen Johanna , Hautaniemi Sampsa , Aittokallio Tero , Wennerberg Krister 
Published: November 2022

AbstractTreatment of patients with high-grade serous ovarian carcinoma (HGSOC) and triple-negative breast cancer (TNBC) includes platinum-based drugs, gemcitabine, and PARP inhibitors. However, resistance to these therapies develops in most cases, highlighting the need for novel therapeutic approaches and biomarkers to guide the optimal treatment choice. Using a CRISPR loss-of-function screen for carboplatin sensitizers in the HGSOC cell line OVCAR8, we identifiedCSNK2A2, the gene encoding for the alpha’ (α’) catalytic subunit of casein kinase 2 (CK2). Expanding on this finding, we confirmed that the CK2 inhibitors silmitasertib and SGC-CK2-1 sensitized many, but not all, TNBC and HGSOC cell lines to the drugs that perturb DNA replication, including platinum drugs, gemcitabine, and PARP inhibitors. We identified RB1 tumor suppressor deficiency as a prerequisite context for the CK2 inhibition-mediated sensitization to these therapeutics. In RB1-deficient cells, CK2 inhibition resulted in accumulation of cells in S phase of the cell cycle, associated with micronuclei formation, and accelerated PARP inhibitor-induced aneuploidy and mitotic cell death. Patient HGSOC organoids that lacked RB1 expression displayed an enhanced long-term response to carboplatin and PARP inhibitor niraparib when combined with silmitasertib, suggesting RB1-stratified efficacy in patients. As RB1 deficiency affects up to 25% of HGSOC and 40% of TNBC cases, CK2 inhibition, proven safe from previous clinical exploration with silmitasertib, is a promising approach to overcome resistance to standard therapeutics in large strata of patients.
Rational strain design with minimal phenotype perturbation
Authors: Narayanan Bharath , Weilandt Daniel , Masid Maria , Miskovic Ljubisa , Hatzimanikatis Vassily 
Published: November 2022

AbstractIncreased availability of multi-omics data has facilitated the characterization of metabolic phenotypes of cellular organisms. However, devising genetic interventions that drive cellular organisms toward the desired phenotype remains challenging in terms of time, cost, and resources. Kinetic models, in particular, hold great potential for accelerating this task since they can simulate the metabolic responses to environmental and genetic perturbations. Although the challenges in building kinetic models have been well-documented, there exists no consensus on how to use these models for strain design in a computationally tractable manner. A straightforward approach that exhaustively simulates and evaluates putative designs would be impractical, considering the intensive computational requirements when targeting multiple enzymes. We address this issue by introducing a framework to efficiently scout the space of designs while respecting the physiological requirements of the cell. The framework employs mixed-integer linear programming and nonlinear simulations with large-scale nonlinear kinetic models to devise genetic interventions in a scalable manner while accounting for the network effects of these perturbations. More importantly, the framework ensures the engineered strain’s robustness by maintaining its phenotype close to that of the reference strain. We use the framework to improve the production of anthranilate, a precursor for pharmaceutical drugs, inE. coli. The devised strategies include eight previously experimentally validated targets and also novel designs suitable for experimental implementation. As an essential part of the future design-build-test-learn cycles, we anticipate that this novel framework will enable high throughput designs and accelerated turnover in biotechnological processes.
Evolution of tissue-specific expression of ancestral genes across vertebrates and insects
Authors: Mantica Federica , Iñiguez Luis P. , Marquez Yamile , Permanyer Jon , Torres-Mendez Antonio , Cruz Josefa , Franch-Marro Xavi , Tulenko Frank , Burguera Demian , Bertrand Stephanie , Doyle Toby , Nouzova Marcela , Currie Peter , Noriega Fernando G. , Escriva Hector , Arnone Maria Ina , Albertin Caroline B , Wotton Karl R , Almudi Isabel , Martin David , Irimia Manuel 
Published: November 2022

AbstractRegulation of gene expression is arguably the main mechanism contributing to tissue phenotypic diversity within and between species. Here, we assembled an extensive transcriptomic dataset covering twenty bilaterian species and eight tissues, selecting a specular phylogeny that allowed both the combined and parallel investigation of gene expression evolution between vertebrates and insects. We specifically focused on widely conserved ancestral genes, identifying strong cores of pan-bilaterian tissue-specific genes and even larger groups that diverged to define vertebrate and insect tissues. Systematic inferences of tissue-specificity gains and losses show that nearly half of all ancestral genes have been recruited into tissue-specific transcriptomes. This occurred during both ancient and, especially, recent bilaterian evolution, with several gains being associated with the emergence of unique phenotypes. Such pervasive evolution of tissue-specificity was linked to gene duplication coupled with specialization, including an unappreciated prolonged effect of whole genome duplications during recent vertebrate evolution.
Highly accurate genome assembly of an improved high-yielding silkworm strain, Nichi01
Authors: Waizumi Ryusei , Tsubota Takuya , Jouraku Akiya , Kuwazaki Seigo , Yokoi Kakeru , Iizuka Tetsuya , Yamamoto Kimiko , Sezutsu Hideki 
Published: November 2022

AbstractThe silkworm (Bombyx mori) is an important lepidopteran model insect, and an industrial domestic animal traditionally used for silk production. Here, we report the genome assembly of an improved Japanese strain Nichi01, in which the cocoon yield is comparable to that of commercial silkworm strains. The integration of PacBio Sequel II long-read and ddRAD-seq-based high-density genetic linkage map achieved the highest quality genome assembly of silkworms to date; 22 of the 28 pseudomolecules contained telomeric repeats at both ends, and only four gaps were present in the assembly. A total of 452 Mbp of the assembly with an N50 of 16.614 Mbp covered 99.3% of the complete orthologs of the Arthropod core genes. Although the genome sequence of Nichi01 and that of the previously reported low-yielding tropical strain p50T assured their accuracy in most regions, we corrected several regions, misassembled in p50T, in our assembly. A total of 18,397 proteins were predicted using over 95 Gb of mRNA-seq derived from 10 different organs, covering 96.9% of the complete orthologs of the Arthropod core genes. The final assembly and annotation files are available in KAIKObase (https://kaikobase.dna.affrc.go.jp/index.html) along with a genome browser and BLAST searching service, which would facilitate further studies and the breeding of silkworms and other insects.
Tau polarizes an aging transcriptional signature to excitatory neurons and glia
Authors: Wu Timothy , Deger Jennifer M. , Ye Hui , Guo Caiwei , Dhindsa Justin , Pekarek Brandon T. , Al-Ouran Rami , Liu Zhandong , Al-Ramahi Ismael , Botas Juan , Shulman Joshua M. 
Published: November 2022

SummaryAging is a major risk factor for Alzheimer’s disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing inDrosophilawith pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell type-specific manner. Integration of cellular abundance and gene expression pinpoints Nuclear Factor Kappa B signaling as a potential marker for neuronal vulnerability. We also highlight the conservation of cell type-specific transcriptional patterns betweenDrosophilaand human postmortem brain tissue. Overall, our results create a resource for dissection of dynamic, age-dependent gene expression changes at cellular resolution in a genetically tractable model of tauopathy.
Analysis of Larval Fish Feeding Behavior under Naturalistic Conditions
Authors: Bar Shir , Levy Liraz , Avidan Shai , Holzman Roi 
Published: November 2022

AbstractModern research efforts concerned with animal behavior rely heavily on image and video analysis. While such data are now quick to obtain, extracting and analyzing complex behaviors under naturalistic conditions is still a major challenge, specifically when the behavior of interest is sporadic and rare. In this study, we present an end-to-end system for capturing, detecting and analyzing larval fish feeding behavior in unconstrained naturalistic environments. We first constructed a specialized system for imaging these tiny, fast-moving creatures and deployed it in large aquaculture rearing pools. We then designed an analysis pipeline using several action classification backbones, and compare their performance. A natural feature of the data was the extremely low prevalence of feeding events, leading to low sample sizes and highly imbalanced datasets despite extensive annotation efforts. Nevertheless, our pipeline successfully detected and classified the sparsely-occurring feeding behavior of fish larvae in a curated experimental setting from videos featuring multiple animals. We introduce three new annotated datasets of underwater videography, in a curated and an uncurated setting. As challenges related to data imbalance and expert’s annotation are common to the analysis of animal behavior under naturalistic conditions, we believe our findings can contribute to the growing field of computer vision for the study and understanding of animal behavior.
Dynamic involvement of premotor and supplementary motor areas in bimanual pinch force control
Authors: Karabanov Anke Ninija , Chillemi Gaetana , Madsen Kristoffer Hougaard , Siebner Hartwig Roman 
Published: November 2022

AbstractMany bimanual activities of daily living require quick shifts between symmetric and asymmetric motor output generated by the right and left hand. Bimanual motor control has been mostly studied during continuous repetitive tasks, while little research has been carried out in experimental settings requiring dynamic changes in motor output generated by both hands. Here, we performed functional magnetic resonance imaging (MRI) while healthy volunteers performed a visually guided, bimanual pinch force task. This enabled us to map functional activity and connectivity of premotor and motor areas during bimanual pinch force control in different task contexts, requiring mirror-symmetric or inverse-asymmetric changes in discrete pinch force exerted with the right and left hand. The bilateral dorsal premotor cortex showed increased activity and effective coupling to the ipsilateral supplementary motor area (SMA) in the inverse-asymmetric context compared to the mirror-symmetric context of bimanual pitch force control. Compared to unilateral pinches, all bimanual pinch force conditions were characterized by an increased level of activation in the bilateral primary motor hand area (M1-HAND) and stronger coupling from SMA to the ipsilateral M1-HAND. Task-related activity of a cluster in the left caudal SMA scaled positively with the degree of synchronous initiation of bilateral pinch force adjustments, irrespectively of the task context. The results suggest that the dorsal premotor cortex mediates increasing complexity of bimanual coordination by increasing coupling to the SMA-M1 network.
Somatic Loss of the Y Chromosome and Alzheimer’s Disease Risk
Authors: Palmer Ellen , Benchek Penelope , Wheeler Nicholas , Smeiszek Sandra , Naj Adam C. , Haines Jonathan L. , Pericak-Vance Margaret A. , Forsberg Lars A. , Cukier Holly N. , Song Yeunjoo , Bush William S. 
Published: November 2022

AbstractMosaic loss of the Y chromosome (LOY) is a somatic, age-related event that has been previously associated with a variety of diseases of aging. A prior study of European cohorts demonstrated an association between LOY and Alzheimer’s Disease and more recent molecular studies have shown that LOY can also occur within microglia, suggesting a potential functional role in AD pathogenesis. In this study, we further validate the association between LOY and AD via prospective analyses of 1,447 males, and perform Mendelian Randomization analysis on 10,013 males across 26 US cohorts. Significant results from these analyses provide further evidence for a role of LOY in the development of Alzheimer’s Disease.
scAbsolute: measuring single-cell ploidy and replication status
Authors: Schneider Michael P. , Cullen Amy , Pangonyte Justina , Skelton Jason , Major Harvey , Van Oudenhove Elke , Garcia Maria J. , Chaves-Urbano Blas , Piskorz Anna M. , Brenton James D. , Macintyre Geoff , Markowetz Florian 
Published: November 2022

AbstractCancer cells often exhibit DNA copy number aberrations and can vary widely in their ploidy. Correct estimation of the ploidy of single cell genomes is paramount for downstream analysis. Based only on single-cell DNA sequencing information,scAbsoluteachieves accurate and unbiased measurement of single-cell ploidy and replication status, including whole-genome duplications. We demonstratescAbsolute’scapabilities using experimental cell multiplets, a FUCCI cell cycle expression system, and a benchmark against state-of-the-art methods.scAbsoluteprovides a robust foundation for single-cell DNA sequencing analysis across different technologies and has the potential to enable improvements in a number of downstream analyses.
MOT: a Multi-Omics Transformer for multiclass classification tumour types predictions
Authors: Osseni Mazid Abiodoun , Tossou Prudencio , Laviolette Francois , Corbeil Jacques 
Published: November 2022

MotivationBreakthroughs in high-throughput technologies and machine learning methods have enabled the shift towards multi-omics modelling as the preferred means to understand the mechanisms underlying biological processes. Machine learning enables and improves complex disease prognosis in clinical settings. However, most multi-omic studies primarily use transcriptomics and epigenomics due to their over-representation in databases and their early technical maturity compared to others omics. For complex phenotypes and mechanisms, not leveraging all the omics despite their varying degree of availability can lead to a failure to understand the underlying biological mechanisms and leads to less robust classifications and predictions.ResultsWe proposed MOT (Multi-Omic Transformer), a deep learning based model using the transformer architecture, that discriminates complex phenotypes (herein cancer types) based on five omics data types: transcriptomics (mRNA and miRNA), epigenomics (DNA methylation), copy number variations (CNVs), and proteomics. This model achieves an F1-score of 98.37% among 33 tumour types on a test set without missing omics views and an F1-score of 96.74% on a test set with missing omics views. It also identifies the required omic type for the best prediction for each phenotype and therefore could guide clinical decisionmaking when acquiring data to confirm a diagnostic. The newly introduced model can integrate and analyze five or more omics data types even with missing omics views and can also identify the essential omics data for the tumour multiclass classification tasks. It confirms the importance of each omic view. Combined, omics views allow a better differentiation rate between most cancer diseases. Our study emphasized the importance of multi-omic data to obtain a better multiclass cancer classification.Availability and implementationMOT source code is available athttps://github.com/dizam92/multiomic_predictions.
Age and Sex-Dependent Differences in Human Cardiac Matrix-Bound Exosomes Modulate Fibrosis through Synergistic miRNA Effects
Authors: Ronan George , Bahcecioglu Gokhan , Yang Jun , Zorlutuna Pinar 
Published: November 2022

ABSTRACTAging is a risk factor for cardiovascular disease, the leading cause of death worldwide. Cardiac fibrosis is a harmful result of repeated myocardial infarction that increases risk of morbidity and future injury. Interestingly, rates of cardiac fibrosis are different between young and aged individuals, as well as men and women. Here, for the first time, we identify and isolate matrix-bound extracellular vesicles from the left ventricles (LVs) of young or aged men and women. These LV vesicles (LVVs) show differences in morphology and content between these four cohorts. LVVs effects on fibrosis were also investigatedin vitro, and it was shown that aged male LVVs were pro-fibrotic, while other LVVs were anti-fibrotic. miRNAs identified from these LVVs could partially recapitulate these effects together, but not individually, and confer other benefits. These data suggest that synergistic effects of matrix-resident exosomal miRNAs may influence the differential clinical response to MI.