tbuckley/cabot-search huggingface dataset:
Metabolic targeting of regulatory T cells in oral squamous cell carcinoma: new horizons in immunotherapy
Authors: Menglai Gan, Nanshu Liu, Wenting Li, Mingwei Chen, Zhongyu Bai, Dongjuan Liu, Sai Liu
Journal: Molecular Cancer (2024)

Oral squamous cell carcinoma (OSCC) is a prevalent oral malignancy, which poses significant health risks with a high mortality rate. Regulatory T cells (Tregs), characterized by their immunosuppressive capabilities, are intricately linked to OSCC progression and patient outcomes. The metabolic reprogramming of Tregs within the OSCC tumor microenvironment (TME) underpins their function, with key pathways such as the tryptophan-kynurenine-aryl hydrocarbon receptor, PI3K-Akt-mTOR and nucleotide metabolism significantly contributing to their suppressive activities. Targeting these metabolic pathways offers a novel therapeutic approach to reduce Treg-mediated immunosuppression and enhance anti-tumor responses. This review explores the metabolic dependencies and pathways that sustain Treg function in OSCC, highlighting key metabolic adaptations such as glycolysis, fatty acid oxidation, amino acid metabolism and PI3K-Akt-mTOR signaling pathway that enable Tregs to thrive in the challenging conditions of the TME. Additionally, the review discusses the influence of the oral microbiome on Treg metabolism and evaluates potential therapeutic strategies targeting these metabolic pathways. Despite the promising potential of these interventions, challenges such as selectivity, toxicity, tumor heterogeneity, and resistance mechanisms remain. The review concludes with perspectives on personalized medicine and integrative approaches, emphasizing the need for continued research to translate these findings into effective clinical applications for OSCC treatment.
Decoding Spatial Complexity of Diverse RNA Species in Archival Tissues
Authors: Junjie Zhu, Fangqing Zhao
Journal: Genomics Proteomics & Bioinformatics (2024)

Spatial transcriptomics has recently emerged as a powerful tool for deciphering the spatial organization of gene expression in situ, providing critical insights into tissue architecture, disease progression, and cellular interactions [1][2][3].Notably, microfluidicbased spatial transcriptomics technologies provide distinguished cost-effectiveness, flexible designs, and widespread accessibility within the community [4,5].Formalinfixed paraffin-embedded (FFPE) tissues, routinely used in histopathology for clinical diagnosis, are a valuable resource for human biology research, with extensive repositories accumulated over decades [6,7].However, RNA in FFPE tissues frequently undergoes fragmentation, degradation or chemical modifications during embedding process and storage [8], which has historically hindered their utility in conventional poly(A)-based spatial transcriptomic studies.Moreover, most spatial transcriptomics technologies primarily focus on mRNA, with limited capacity to map the full landscape of diverse RNA species and their functional dynamics [9,10].To address these limitations, Bai, Zhang [11] developed Patho-DBiT, a cuttingedge spatial transcriptomics platform specifically tailored to unravel the complex RNA biology in clinically archived FFPE tissues (Figure 1A).This innovative method integrates in situ polyadenylation, microfluidic tissue barcoding, and advanced computational approaches.By appending poly(A) tails, Patho-DBiT enables genomewide spatial co-profiling of mRNA, large and small non-coding RNAs, alternative splicing, and sequence variants, providing exceptional coverage and sensitivity.The authors further demonstrated the platform's ability to dissect the spatiotemporal complexity of clinical samples.
From plague to planetary crisis: climate fiction before cli-fi
Authors: Lakshmi Krishnan
Journal: BMJ (2024)

Our oldest stories begin in the soil or by the sea, myth being the original ecological narrative.The Mandé and Sumerians tell of people growing from seeds or moulded from earth; Rigveda, the ancient Hindu sacred text, and the Kojiki, the earliest written Japanese chronicle, speak of births from primordial oceans; and Abrahamic traditions place us in Eden's lushness.With industrialisation came a new imperative: writers began exploring not just our connection to nature but also our power to destroy it.Climate fiction is a recent literary genre confronting environmental and societal breakdown.But literature has grappled with the interplay of people and environment long before "cli-fi" exploded in the 2010s.These works offer more than historical perspective.They reveal how story and imagination might help us grasp what climate data alone cannot-the full scope of our crisis-while helping us to envision paths beyond catastrophe.
Guideline‐directed medical therapy for heart failure in arrhythmia‐induced cardiomyopathy with improved left ventricular ejection fraction
Authors: Luis Manuel Domínguez‐Rodríguez, David Dobarro, Carla Iglesias‐Otero, María G. Crespo‐Leiro, Sergio Raposeiras‐Roubín, Jesús Álvarez‐García, Manuel Barreiro‐Pérez, Isabel Muñoz‐Pousa, Angel Sánchez‐Recalde, Ándrés Íñiguez‐Romo, José Luis Zamorano
Journal: European Journal of Heart Failure (2024)

No study has analyzed the impact of guideline-directed medical therapy in preventing heart failure (HF) relapse in patients with arrhythmia-induced cardiomyopathy (AiCM) following left ventricular ejection fraction (LVEF) improvement.
HIPSD&amp;R-seq enables scalable genomic copy number and transcriptome profiling
Authors: Jan Otoničar, Olga Lazareva, Jan-Philipp Mallm, Milena Simovic-Lorenz, George Philippos, Pooja Sant, Urja Parekh, Linda Hammann, Albert Li, Umut Yildiz, Mikael Marttinen, Judith Zaugg, Kyung Min Noh, Oliver Stegle, Aurélie Ernst
Journal: Genome biology (2024)

Abstract Single-cell DNA sequencing (scDNA-seq) enables decoding somatic cancer variation. Existing methods are hampered by low throughput or cannot be combined with transcriptome sequencing in the same cell. We propose HIPSD&amp;R-seq (HIgh-throughPut Single-cell Dna and Rna-seq), a scalable yet simple and accessible assay to profile low-coverage DNA and RNA in thousands of cells in parallel. Our approach builds on a modification of the 10X Genomics platform for scATAC and multiome profiling. In applications to human cell models and primary tissue, we demonstrate the feasibility to detect rare clones and we combine the assay with combinatorial indexing to profile over 17,000 cells.
EpiGePT: a pretrained transformer-based language model for context-specific human epigenomics
Authors: Zijing Gao, Qiao Liu, Wanwen Zeng, Rui Jiang, Wing Hung Wong
Journal: Genome biology (2024)

Abstract The inherent similarities between natural language and biological sequences have inspired the use of large language models in genomics, but current models struggle to incorporate chromatin interactions or predict in unseen cellular contexts. To address this, we propose EpiGePT, a transformer-based model designed for predicting context-specific human epigenomic signals. By incorporating transcription factor activities and 3D genome interactions, EpiGePT outperforms existing methods in epigenomic signal prediction tasks, especially in cell-type-specific long-range interaction predictions and genetic variant impacts, advancing our understanding of gene regulation. A free online prediction service is available at http://health.tsinghua.edu.cn/epigept .
Spatial transcriptome profiling identifies DTX3L and BST2 as key biomarkers in esophageal squamous cell carcinoma tumorigenesis
Authors: Rutao Li, Na Li, Qianqian Yang, Xing Tong, Wei Wang, Chang Li, Jun Zhao, Dong Jiang, Haitao Huang, Chen Fang, Kai Xie, Jiamin Yuan, Shaomu Chen, Guangbin Li, Haitao Luo, Zhibo Gao, Dongfang Wu, Xiaoli Cui, Wei Jiang, Lingchuan Guo, Haitao Ma, Yu Feng
Journal: Genome Medicine (2024)

Understanding the stepwise progression of esophageal squamous cell carcinoma (ESCC) is crucial for developing customized strategies for early detection and optimal clinical management. Herein, we aimed to unravel the transcriptional and immunologic alterations occurring during malignant transformation and identify clinically significant biomarkers of ESCC. Digital spatial profiling (DSP) was performed on 11 patients with early-stage ESCC (pT1) to explore the transcriptional alterations in epithelial, immune cell, and non-immune cell stromal compartments across regions of distinct histology, including normal tissues, low- and high-grade dysplasia, and cancerous tissues. Furthermore, single-cell spatial transcriptomics was performed using the CosMx Spatial Molecular Imaging (SMI) system on 4 additional patients with pT1 ESCC. Immunohistochemical (IHC) analysis was performed on consecutive histological sections of 20 pT1 ESCCs. Additionally, public bulk and single-cell RNA-sequencing (scRNA-seq) datasets were analyzed, and in vitro and in vivo functional studies were conducted. Spatial transcriptional reprogramming and dynamic cell signaling pathways that determined ESCC progression were delineated. Increased infiltration of macrophages from normal tissues through dysplasia to cancerous tissues occurred. Macrophage subtypes were characterized using the scRNA-seq dataset. Cell–cell communication analysis of scRNA-seq and SMI data indicated that the migration inhibitory factor (MIF)-CD74 axis may exhibit pro-tumor interactions between macrophages and epithelial cells. DSP, SMI, and IHC data demonstrated that DTX3L expression in epithelial cells and BST2 expression in stromal cells increased gradually with ESCC progression. Functional studies demonstrated that DTX3L or BST2 knockdown inhibited ESCC proliferation and migration and decreased M2 polarization of tumor-associated macrophages. Spatial profiling comprehensively characterized the molecular and immunological hallmarks from normal tissue to ESCC, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease and contributing to the prevention of ESCC. Within this exploration, we uncovered biomarkers that exhibit a robust correlation with ESCC progression, offering potential new avenues for insightful therapeutic approaches.
SQUiD: ultra-secure storage and analysis of genetic data for the advancement of precision medicine
Authors: Jacob Blindenbach, Jiayi Kang, Seungwan Hong, Caline Karam, Thomas Lehner, Gamze Gürsoy
Journal: Genome biology (2024)

Cloud computing allows storing the ever-growing genotype-phenotype datasets crucial for precision medicine. Due to the sensitive nature of this data and varied laws and regulations, additional security measures are needed to ensure data privacy. We develop SQUiD, a secure queryable database for storing and analyzing genotype-phenotype data. SQUiD allows storage and secure querying of data in a low-security, low-cost public cloud using homomorphic encryption in a multi-client setting. We demonstrate SQUiD's practical usability and scalability using synthetic and UK Biobank data.
Evaluating data requirements for high-quality haplotype-resolved genomes for creating robust pangenome references
Authors: Prasad Sarashetti, Josipa Lipovac, Filip Tomas, Mile Šikić, Jianjun Liu
Journal: Genome biology (2024)

Long-read technologies from Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT) have transformed genomics research by providing diverse data types like HiFi, Duplex, and ultra-long ONT. Despite recent strides in achieving haplotype-phased gapless genome assemblies using long-read technologies, concerns persist regarding the representation of genetic diversity, prompting the development of pangenome references. However, pangenome studies face challenges related to data types, volumes, and cost considerations for each assembled genome, while striving to maintain sensitivity. The absence of comprehensive guidance on optimal data selection exacerbates these challenges.
Transcriptional regulatory network reveals key transcription factors for regulating agronomic traits in soybean
Authors: Wu Jiao, Mangmang Wang, Yijian Guan, Wei Guo, Chang Zhang, Yuanchun Wei, Zhenwei Zhao, Hongyu Ma, Longfei Wang, Xinyu Jiang, Wenxue Ye, Dong Cao, Qingxin Song
Journal: Genome biology (2024)

Transcription factors (TFs) bind regulatory genomic regions to orchestrate spatio-temporal expression of target genes. Global dissection of the cistrome is critical for elucidating transcriptional networks underlying complex agronomic traits in crops. Here, we generate a comprehensive genome-wide binding map for 148 TFs using DNA affinity purification sequencing in soybean. We find TF binding sites (TFBSs) exhibit elevated chromatin accessibility and contain more rare alleles than other genomic regions. Intriguingly, the methylation variations at TFBSs partially contribute to expression bias among whole genome duplication paralogs. Furthermore, we construct a soybean gene regulatory network (SoyGRN) by integrating TF-target interactions with diverse datasets encompassing gene expression, TFBS motifs, chromatin accessibility, and evolutionarily conserved regulation. SoyGRN comprises 2.44 million genome-wide interactions among 3188 TFs and 51,665 target genes. We successfully identify key TFs governing seed coat color and oil content and prioritize candidate genes within quantitative trait loci associated with various agronomic traits using SoyGRN. To accelerate utilization of SoyGRN, we develop an interactive webserver ( www.soytfbase.cn ) for soybean community to explore functional TFs involved in trait regulation. Overall, our study unravels intricate landscape of TF-target interactions in soybean and provides a valuable resource for dissecting key regulators for control of agronomic traits to accelerate soybean improvement.
SyntheVAEiser: augmenting traditional machine learning methods with VAE-based gene expression sample generation for improved cancer subtype predictions
Authors: Brian Karlberg, Raphael Kirchgaessner, Jordan Lee, Matthew Peterkort, Liam Beckman, Jeremy Goecks, Kyle Ellrott
Journal: Genome biology (2024)

The accuracy of machine learning methods is often limited by the amount of training data that is available. We proposed to improve machine learning training regimes by augmenting datasets with synthetically generated samples. We present a method for synthesizing gene expression samples and test the system's capabilities for improving the accuracy of categorical prediction of cancer subtypes. We developed SyntheVAEiser, a variational autoencoder based tool that was trained and tested on over 8000 cancer samples. We have shown that this technique can be used to augment machine learning tasks and increase performance of recognition of underrepresented cohorts.
Cas12f1 gene drives propagate efficiently in herpesviruses and induce minimal resistance
Authors: Zhuangjie Lin, Qiaorui Yao, Keyuan Lai, Kehua Jiao, Xianying Zeng, Guanxiong Lei, Tongwen Zhang, Hongsheng Dai
Journal: Genome biology (2024)

Synthetic CRISPR-Cas9 gene drive has been developed to control harmful species. However, resistance to Cas9 gene drive can be acquired easily when DNA repair mechanisms patch up the genetic insults introduced by Cas9 and incorporate mutations to the sgRNA target. Although many strategies to reduce the occurrence of resistance have been developed so far, they are difficult to implement and not always effective. Here, Cas12f1, a recently developed CRISPR-Cas system with minimal potential for causing mutations within target sequences, has been explored as a potential platform for yielding low-resistance in gene drives. We construct Cas9 and Cas12f1 gene drives in a fast-replicating DNA virus, HSV1. Cas9 and Cas12f1 gene drives are able to spread among the HSV1 population with specificity towards their target sites, and their transmission among HSV1 viruses is not significantly affected by the reduced fitness incurred by the viral carriers. Cas12f1 gene drives spread similarly as Cas9 gene drives at high introduction frequency but transmit more slowly than Cas9 gene drives at low introduction frequency. However, Cas12f1 gene drives outperform Cas9 gene drives because they reach higher penetration and induce lower resistance than Cas9 gene drives in all cases. Due to lower resistance and higher penetration, Cas12f1 gene drives could potentially supplant Cas9 gene drives for population control.
GenomeDelta: detecting recent transposable element invasions without repeat library
Authors: Riccardo Pianezza, Anna Haider, Robert Kofler
Journal: Genome biology (2024)

We present GenomeDelta, a novel tool for identifying sample-specific sequences, such as recent transposable element (TE) invasions, without requiring a repeat library. GenomeDelta compares high-quality assemblies with short-read data to detect sequences absent from the short reads. It is applicable to both model and non-model organisms and can identify recent TE invasions, spatially heterogeneous sequences, viral insertions, and hotizontal gene transfers. GenomeDelta was validated with simulated and real data and used to discover three recent TE invasions in Drosophila melanogaster and a novel TE with geographic variation in Zymoseptoria tritici.
Correction: The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons
Authors: Jace Jones-Tabah, Kathy He, Nathan Karpilovsky, Konstantin Senkevich, Ghislaine Deyab, Isabella Pietrantonio, Thomas Goiran, Yuting Cousineau, Daria Nikanorova, Taylor Goldsmith, Esther del Cid Pellitero, Carol X.-Q. Chen, Wen Luo, Zhipeng You, Narges Abdian, Jamil Ahmad, Jennifer A. Ruskey, Farnaz Asayesh, Dan Spiegelman, Stanley Fahn, Cheryl Waters, Oury Monchi, Yves Dauvilliers, Nicolas Dupré, Irina Miliukhina, Alla Timofeeva, Anton Emelyanov, Sofya Pchelina, Lior Greenbaum, Sharon Hassin-Baer, Roy N. Alcalay, Austen Milnerwood, Thomas M. Durcan, Ziv Gan-Or, Edward A. Fon
Journal: Molecular Neurodegeneration (2024)
CD2AP deficiency aggravates Alzheimer’s disease phenotypes and pathology through p38 MAPK activation
Authors: Yan-Yan Xue, Zhe-Sheng Zhang, Rong-Rong Lin, Hui-Fen Huang, Ke-Qing Zhu, Dian-Fu Chen, Zhi-Ying Wu, Qing-Qing Tao
Journal: Translational Neurodegeneration (2024)

Abstract Background Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder, which is characterized by a decline in cognitive abilities. Genome-wide association and clinicopathological studies have demonstrated that the CD2-associated protein ( CD2AP ) gene is one of the most important genetic risk factors for AD. However, the precise mechanisms by which CD2AP is linked to AD pathogenesis remain unclear. Methods The spatiotemporal expression pattern of CD2AP was determined. Then, we generated and characterized an APP/PS1 mouse model with neuron-specific Cd2ap deletion, using immunoblotting, immunofluorescence, enzyme-linked immunosorbent assay, electrophysiology and behavioral tests. Additionally, we established a stable CD2AP -knockdown SH-SY5Y cell line to further elucidate the specific molecular mechanisms by which CD2AP contributes to AD pathogenesis. Finally, the APP/PS1 mice with neuron-specific Cd2ap deletion were treated with an inhibitor targeting the pathway identified above to further validate our findings. Results CD2AP is widely expressed in various regions of the mouse brain, with predominant expression in neurons and vascular endothelial cells. In APP/PS1 mice, neuronal knockout of Cd2ap significantly aggravated tau pathology, synaptic impairments and cognitive deficits. Mechanistically, the knockout of Cd2ap activated p38 mitogen-activated protein kinase (MAPK) signaling, which contributed to increased tau phosphorylation, synaptic injury, neuronal apoptosis and cognitive impairment. Furthermore, the phenotypes of neuronal Cd2ap knockout were ameliorated by a p38 MAPK inhibitor. Conclusion Our study presents the first in vivo evidence that CD2AP deficiency exacerbates the phenotypes and pathology of AD through the p38 MAPK pathway, identifying CD2AP/p38 MAPK as promising therapeutic targets for AD.
Prediction of new‐onset atrial fibrillation in patients with hypertrophic cardiomyopathy using machine learning
Authors: Ree Lu, Heidi S. Lumish, Kohei Hasegawa, Mathew S. Maurer, Muredach P. Reilly, Shepard D. Weiner, Albree Tower‐Rader, Michael A. Fifer, Yuichi J. Shimada
Journal: European Journal of Heart Failure (2024)
How to transport a polar bear, and other idiosyncrasies in providing emergency medical services in the Arctic
Authors: Astrid K V Harring, Siri Idland, Mari Mowe Martinsen, Ingelin Skjørland-Bolkesjø, Trine M Jørgensen
Journal: BMJ (2024)

Daniel Auguin1,2,*, Julien Robert-Paganin1,*, Stéphane Réty3, Carlos Kikuti1, Amandine David1, Gabriele Theumer4, Arndt W. Schmidt4, Hans-Joachim Knölker4 and Anne Houdusse1,#Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University, 26 rue d'Ulm, 75258 Paris cedex 05, FranceLaboratoire de Biologie des Ligneux et des Grandes Cultures, Université d'Orléans, UPRES EA 1207, INRAE-USC1328, F-45067 Orléans, FranceLaboratoire de Biologie et Modélisation de la Cellule, ENS de Lyon, University Claude Bernard, CNRS UMR 5239, INSERM U1210, 46 Allée d'Italie Site Jacques Monod, F-69007 Lyon, FranceFaculty of Chemistry, TU Dresden, Bergstraße 66, 01069 Dresden, Germany↵Correspondence: anne.houdusse{at}curie.fr.↵* Contributed equally.
The carbonyl nucleobase adduct M3Ade is a potent antigen for adaptive polyclonal MR1-restricted T cells
Authors: Andrew Chancellor, Daniel Constantin, None Giuliano Berloffa, Qinmei Yang, Vladimir Nosi, José Pedro Loureiro, Rodrigo Colombo, Roman P Jakob, Daniel Joss, Michael Pfeffer, Giulia De Simone, Aurelia Morabito, Verena Schaefer, Alessandro Vacchini, Laura Brunelli, Daniela Montagna, Markus Heim, Alfred Zippelius, Enrico Davoli, Daniel Häussinger, Timm Maier, Lucia Mori, Gennaro De Libero
Journal: Immunity (2024)

The major histocompatibility complex (MHC) class I-related molecule MHC-class-I-related protein 1 (MR1) presents metabolites to distinct MR1-restricted T cell subsets, including mucosal-associated invariant T (MAIT) and MR1T cells. However, self-reactive MR1T cells and the nature of recognized antigens remain underexplored. Here, we report a cell endogenous carbonyl adduct of adenine (8-(9H-purin-6-yl)-2-oxa-8-azabicyclo[3.3.1]nona-3,6-diene-4,6-dicarbaldehyde [M