tbuckley/cabot-search huggingface dataset:
A metagenome-assembled genome inventory for children reveals early-life gut bacteriome and virome dynamics
Authors: Ye Peng, Jie Zhu, Shilan Wang, Yingzhi Liu, Xin Liu, Orlando DeLeon, Wenyi Zhu, Zhilu Xu, Xi Zhang, Shilin Zhao, Suisha Liang, Hang Li, Brian Ho, Jessica Yuet-Ling Ching, Chun Pan Cheung, Ting Fan Leung, Wing Hung Tam, Tak Yeung Leung, Eugene B Chang, Francis Ka Leung Chan, Lin Zhang, Siew Chien Ng, Hein Min Tun
Journal: Cell Host & Microbe (2024)
Length of Hospital Stay for Endocarditis Before and After the Partial Oral Treatment of Endocarditis Trial
Authors: Lauge Østergaard, Mia Marie Pries-Heje, Marianne Voldstedlund, Niels Eske Bruun, Jonas Agerlund Povlsen, Nana Køber, Nikolaj Ihlemann, Christian Tuxen, Rasmus Hasselbalch, Peter Godsk Jørgensen, Anna Stahl, Eva Havers-Borgersen, Jeppe Kofoed Petersen, Claus Moser, Lars Køber, Kasper Iversen, Henning Bundgaard, Emil Loldrup Fosbøl
Journal: Journal of the American College of Cardiology (2024)
Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer
Authors: Camila Robles-Oteíza, Katherine Hastings, Jungmin Choi, Isabelle Sirois, Arvind Ravi, Francisco Expósito, Fernando de Miguel, James R. Knight, Francesc López-Giráldez, Hyejin Choi, Nicholas D. Socci, Taha Merghoub, Mark Awad, Gad Getz, Justin Gainor, Matthew D. Hellmann, Étienne Caron, Susan M. Kaech, Katerina Politi
Journal: The Journal of Experimental Medicine (2024)

Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and ∼50% of patients whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers of AR, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed AR to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNγ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia-activated pro-drug delayed AR to ICIs in murine Msh2 KO tumors. Thus, this work provides a rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition.
Loss of the Endothelial Glycocalyx Component EMCN Leads to Glomerular Impairment
Authors: Zhengping Hu, Issahy Cano, Fengyang Lei, Jie Liu, Ramon Bossardi Ramos, Harper Gordon, Eleftherios I. Paschalis, Magali Saint-Geniez, Yin Shan Eric Ng, Patricia A. D’Amore
Journal: Circulation Research (2024)

BACKGROUND: EMCN (endomucin), an endothelial-specific glycocalyx component, was found to be highly expressed by the endothelium of the renal glomerulus. We reported an anti-inflammatory role of EMCN and its involvement in the regulation of VEGF (vascular endothelial growth factor) activity through modulating VEGFR2 (VEGF receptor 2) endocytosis. The goal of this study is to investigate the phenotypic and functional effects of EMCN deficiency using the first global EMCN knockout mouse model. METHODS: Global EMCN knockout mice were generated by crossing EMCN-floxed mice with ROSA26-Cre mice. Flow cytometry was used to analyze infiltrating myeloid cells in the kidneys. The ultrastructure of the glomerular filtration barrier was examined by transmission electron microscopy, whereas urinary albumin, creatinine, and total protein levels were analyzed from freshly collected urine samples. Expression and localization of EMCN, EGFP, CD45, CD31, CD34, podocin, and albumin were examined by immunohistochemistry. Mice were weighed regularly, and their systemic blood pressure was measured using a noninvasive tail-cuff system. Glomerular endothelial cells and podocytes were isolated by fluorescence-activated cell sorting for RNA sequencing. Transcriptional profiles were analyzed to identify differentially expressed genes in both endothelium and podocytes, followed by gene ontology analysis. Protein levels of EMCN, albumin, and podocin were quantified by Western blot. RESULTS: The EMCN −/− mice exhibited increased infiltration of CD45 + cells, with an increased proportion of Ly6G high Ly6C high myeloid cells and higher VCAM-1 (vascular cell adhesion molecule 1) expression. EMCN −/− mice displayed albuminuria with increased albumin in the Bowman’s space compared with the EMCN +/+ littermates. Glomeruli in EMCN −/− mice revealed fused and effaced podocyte foot processes and disorganized endothelial fenestrations. We found no significant difference in blood pressure between EMCN knockout mice and their wild-type littermates. RNA sequencing of glomerular endothelial cells revealed downregulation of cell-cell adhesion and MAPK (mitogen-activated protein kinase)/ERK (extracellular signal–regulated kinase) pathways, along with glycocalyx and extracellular matrix remodeling. In podocytes, we observed reduced VEGF signaling and alterations in cytoskeletal organization. Notably, there was a significant decrease in both mRNA and protein levels of podocin, a key component of the slit diaphragm. CONCLUSION: Our study demonstrates a critical role of the endothelial marker EMCN in supporting normal glomerular filtration barrier structure and function by maintaining glomerular endothelial tight junction and homeostasis and podocyte function through endothelial-podocyte crosstalk.
IOC consensus statement: interpersonal violence and safeguarding in sport
Authors: Yetsa A Tuakli-Wosornu, Kirsty Burrows, Kari Fasting, Mike Hartill, Ken Hodge, Keith Kaufman, Emma Kavanagh, Sandra L Kirby, Jelena G MacLeod, Margo Mountjoy, Sylvie Parent, Minhyeok Tak, Tine Vertommen, Daniel J A Rhind
Journal: British Journal of Sports Medicine (2024)

Interpersonal violence (IV) in sport is challenging to define, prevent and remedy due to its subjectivity and complexity. The 2024 International Olympic Committee Consensus on Interpersonal Violence and Safeguarding aimed to synthesise evidence on IV and safeguarding in sport, introduce a new conceptual model of IV in sport and offer more accessible safeguarding guidance to all within the sports ecosystem by merging evidence with insights from Olympic athletes.
Artificial Intelligence awarded two Nobel Prizes for innovations that will shape the future of medicine
Authors: Ben Li, Stephen Gilbert
Journal: npj Digital Medicine (2024)

John J. Hopfield and Geoffrey E. Hinton were awarded the 2024 Nobel Prize in Physics for developing machine learning technology using artificial neural networks. In Chemistry it was awarded to Demis Hassabis and John M. Jumper for developing an AI algorithm that solved the 50-year protein structure prediction challenge. This highlights AI's impact on science, medicine and society; however, the winners acknowledge ethical aspects of AI that must be considered.
Transcriptional profiling of zebrafish intestines identifies macrophages as host cells for human norovirus infection
Authors: Emma Roux, Reegan J. Willms, Jana Van Dycke, Álvaro Cortes Calabuig, Lore Van Espen, Geert Schoofs, Jelle Matthijnssens, Johan Neyts, Peter de Witte, Edan Foley, Joana Rocha-Pereira
Journal: Gut Microbes (2024)

Human noroviruses (HuNoVs) are a major cause of diarrheal disease, yet critical aspects of their biology, including cellular tropism, remain unclear. Although research has traditionally focused on the intestinal epithelium, the hypothesis that HuNoV infects macrophages has been recurrently discussed and is investigated here using a zebrafish larval model. Through single-cell RNA sequencing of dissected zebrafish intestines, we unbiasedly identified macrophages as host cells for HuNoV replication, with all three open reading frames mapped to individual macrophages. Notably, HuNoV preferentially infects actively phagocytosing inflammatory macrophages. HuNoV capsid proteins and double-stranded RNA colocalized within intestinal macrophages of infected zebrafish larvae, and the negative-strand RNA intermediate was detected within FACS-sorted macrophages. Flow cytometry confirmed viral replication within these macrophages, constituting approximately 23% of HuNoV's host cells. Identifying macrophages as host cells prompts a reevaluation of their role in HuNoV pathogenesis, offering new directions for understanding and controlling this infection.
Microviridae bacteriophages influence behavioural hallmarks of food addiction via tryptophan and tyrosine signalling pathways
Authors: Anna Castells-Nobau, Irene Puig, Anna Motger-Albertí, Lisset de la Vega-Correa, Marisel Rosell-Díaz, María Arnoriaga-Rodríguez, Anira Escrichs, Josep Garre-Olmo, Josep Puig, Rafael Ramos, Lluís Ramió-Torrentà, Vicente Pérez-Brocal, Andrés Moya, Reinald Pamplona, Mariona Jové, Joaquim Sol, Elena Martin-Garcia, Manuel Martinez-Garcia, Gustavo Deco, Rafael Maldonado, José Manuel Fernández-Real, Jordi Mayneris-Perxachs
Journal: Nature Metabolism (2024)
Infraslow noradrenergic locus coeruleus activity fluctuations are gatekeepers of the NREM–REM sleep cycle
Authors: Alejandro Osorio-Forero, Georgios Foustoukos, Romain Cardis, Najma Cherrad, Christiane Devenoges, Laura M. J. Fernandez, Anita Lüthi
Journal: Nature Neuroscience (2024)
Inceptor binds to and directs insulin towards lysosomal degradation in β cells
Authors: Johanna Siehler, Sara Bilekova, Prisca Chapouton, Alessandro Dema, Pascal Albanese, Sem Tamara, Chirag Jain, Michael Sterr, Stephen J. Enos, Chunguang Chen, Chetna Malhotra, Adrian Villalba, Leopold Schomann, Sreya Bhattacharya, Jin Feng, Melis Akgün Canan, Federico Ribaudo, None Ansarullah, Ingo Burtscher, Christin Ahlbrecht, Oliver Plettenburg, Thomas Kurth, Raphael Scharfmann, Stephan Speier, Richard A. Scheltema, Heiko Lickert
Journal: Nature Metabolism (2024)

Abstract Blunted first-phase insulin secretion and insulin deficiency are indicators of β cell dysfunction and diabetes manifestation. Therefore, insights into molecular mechanisms that regulate insulin homeostasis might provide entry sites to replenish insulin content and restore β cell function. Here, we identify the insulin inhibitory receptor (inceptor; encoded by the gene IIR/ELAPOR1 ) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (SC)-derived islets, we show that IIR knockout (KO) results in enhanced SC β cell differentiation and survival. Strikingly, extended in vitro culture of IIR KO SC β cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS). We find that inceptor localizes to clathrin-coated vesicles close to the plasma membrane and in the trans -Golgi network as well as in secretory granules, where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody increases proinsulin and insulin content and improves SC β cell GSIS. Altogether, our findings reveal the basic mechanisms of β cell insulin turnover and identify inceptor as an insulin degradation receptor.
A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia
Authors: Jason Xu, Changya Chen, Jonathan H. Sussman, Satoshi Yoshimura, Tiffaney Vincent, Petri Pölönen, Jianzhong Hu, Shovik Bandyopadhyay, Omar Elghawy, Wenbao Yu, Joseph Tumulty, Chia-hui Chen, Elizabeth Y. Li, Caroline Diorio, Rawan Shraim, Haley Newman, Lahari Uppuluri, Alexander Li, Gregory M. Chen, David W. Wu, Yang-yang Ding, Jessica A. Xu, Damjan Karanfilovski, Tristan Lim, Miles Hsu, Anusha Thadi, Kyung Jin Ahn, Chi-Yun Wu, Jacqueline Peng, Yusha Sun, Alice Wang, Rushabh Mehta, David Frank, Lauren Meyer, Mignon L. Loh, Elizabeth A. Raetz, Zhiguo Chen, Brent L. Wood, Meenakshi Devidas, Kimberly P. Dunsmore, Stuart S. Winter, Ti-Cheng Chang, Gang Wu, Stanley B. Pounds, Nancy R. Zhang, William Carroll, Stephen P. Hunger, Kathrin Bernt, Jun J. Yang, Charles G. Mullighan, Kai Tan, David T. Teachey
Journal: Nature Cancer (2024)

Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to curing T cell acute lymphoblastic leukemia (T-ALL). While tumor heterogeneity has been implicated in treatment failure, the cellular and genetic factors contributing to resistance and relapse remain unknown. Here we linked tumor subpopulations with clinical outcome, created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic analysis to a diverse cohort of 40 T-ALL cases. We identified a bone marrow progenitor (BMP)-like leukemia subpopulation associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL and revealed that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. Through in silico and in vitro drug screenings, we identified a therapeutic vulnerability of BMP-like blasts to apoptosis-inducing agents including venetoclax. Collectively, our study establishes multiomic signatures for rapid risk stratification and targeted treatment of high-risk T-ALL.
Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer
Authors: Brittany L. Angarola, Siddhartha Sharma, Neerja Katiyar, Hyeon Gu Kang, Djamel Nehar-Belaid, SungHee Park, Rachel Gott, Giray N. Eryilmaz, Mark A. LaBarge, Karolina Palucka, Jeffrey H. Chuang, Ron Korstanje, Duygu Ucar, Olga Anczukόw
Journal: Nature Aging (2024)

Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. In this study, we investigated how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory and cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk
Single-cell multiomics analysis reveals dynamic clonal evolution and targetable phenotypes in acute myeloid leukemia with complex karyotype
Authors: Aino-Maija Leppä, Karen Grimes, Hyobin Jeong, Frank Y. Huang, Alvaro Andrades, Alexander Waclawiczek, Tobias Boch, Anna Jauch, Simon Renders, Patrick Stelmach, Carsten Müller-Tidow, Darja Karpova, Markus Sohn, Florian Grünschläger, Patrick Hasenfeld, Eva Benito Garagorri, Vera Thiel, Anna Dolnik, Bernardo Rodriguez-Martin, Lars Bullinger, Krzysztof Mrózek, Ann-Kathrin Eisfeld, Alwin Krämer, Ashley D. Sanders, Jan O. Korbel, Andreas Trumpp
Journal: Nature Genetics (2024)

Abstract Chromosomal instability is a major driver of intratumoral heterogeneity (ITH), promoting tumor progression. In the present study, we combined structural variant discovery and nucleosome occupancy profiling with transcriptomic and immunophenotypic changes in single cells to study ITH in complex karyotype acute myeloid leukemia (CK-AML). We observed complex structural variant landscapes within individual cells of patients with CK-AML characterized by linear and circular breakage–fusion–bridge cycles and chromothripsis. We identified three clonal evolution patterns in diagnosis or salvage CK-AML (monoclonal, linear and branched polyclonal), with 75% harboring multiple subclones that frequently displayed ongoing karyotype remodeling. Using patient-derived xenografts, we demonstrated varied clonal evolution of leukemic stem cells (LSCs) and further dissected subclone-specific drug–response profiles to identify LSC-targeting therapies, including BCL-xL inhibition. In paired longitudinal patient samples, we further revealed genetic evolution and cell-type plasticity as mechanisms of disease progression. By dissecting dynamic genomic, phenotypic and functional complexity of CK-AML, our findings offer clinically relevant avenues for characterizing and targeting disease-driving LSCs.
Canonical Amplifications and <i>CDKN2A/B</i> Loss Refine <i>IDH1/2</i>-mutant Astrocytoma Prognosis
Authors: Hia S Ghosh, Ruchit V Patel, Elizabeth B Claus, Luis Nicolas Gonzalez Castro, Patrick Y Wen, Keith L Ligon, David M Meredith, Wenya Linda Bi
Journal: Neuro-Oncology (2024)

Abstract Background Molecular features have been incorporated alongside histologic criteria to improve glioma diagnostics and prognostication. CDKN2A/B homozygous-loss associates with worse survival in IDH1/2-mutant astrocytomas (IDHmut-astrocytomas), the presence of which denotes a grade 4 tumor independent of histologic features. However, no molecular features distinguish survival amongst histologically defined grade 2 and 3 IDHmut-astrocytomas. Methods We assembled a cohort of patients ≥19 years old diagnosed with an IDHmut-astrocytoma between 1989 and 2020 from public datasets and several academic medical centers. Multivariate modeling and unbiased clustering were used to stratify risk. Results We identified 998 IDHmut-astrocytoma patients (41.5% female; 85.6% white). Tumor grade, CDKN2A/B loss, and/or ≥1 focal amplification were associated with reduced survival. Grade 2/3 patients with intact CDKN2A/B and no focal amplifications survived the longest (OS 205.7 months). Survival for grade 2/3 cases with either CDKN2A/B hemizygous-loss or focal amplifications (80.4, 88.7 months respectively) did not differ significantly from grade 4 cases with intact CDKN2A/B and no amplifications (91.5 months, P = .93). Grade 4 patients with either hemizygous or homozygous loss of CDKN2A/B had the shortest survival (OS 31.9, 32.5 months respectively), followed by grade 4 cases with intact CDKN2A/B and focal gene amplifications (OS 55.9 months). Integrating CDKN2A/B status and amplifications alongside histopathologic grade refined overall survival prediction. Unbiased clustering revealed 9 distinct molecular profiles, with differential survival. IDHmut-astrocytomas with any CDKN2A/B loss clustered together, regardless of grade, and exhibited the poorest outcomes. Conclusions Combining CDKN2A/B hemizygous-loss and focal gene amplifications reveals a group of IDHmut-astrocytoma patients with an intermediate prognosis, refining IDHmut-astrocytoma classification.
Hierarchical annotation of eQTLs by H-eQTL enables identification of genes with cell type-divergent regulation
Authors: Pawel F. Przytycki, Katherine S. Pollard
Journal: Genome biology (2024)

While context-type-specific regulation of genes is largely determined by cis-regulatory regions, attempts to identify cell type-specific eQTLs are complicated by the nested nature of cell types. We present hierarchical eQTL (H-eQTL), a network-based model for hierarchical annotation of bulk-derived eQTLs to levels of a cell type tree using single-cell chromatin accessibility data and no clustering of cells into discrete cell types. Using our model, we annotate bulk-derived eQTLs from the developing brain with high specificity to levels of a cell type hierarchy, which allows sensitive detection of genes with multiple distinct non-coding elements regulating their expression in different cell types.
Genomic surveillance of multidrug-resistant organisms based on long-read sequencing
Authors: Fabian Landman, Casper Jamin, Angela de Haan, Sandra Witteveen, Jeroen Bos, Han G. J. van der Heide, Leo M. Schouls, Antoni P. A. Hendrickx, A. L. E. van Arkel, M. A. Leversteijn-van Hall, W. van den den Bijllaardt, R. van Mansfeld, K. van Dijk, B. Zwart, B. M. W. Diederen, H. Berkhout, D. W. Notermans, A. Ott, K. Waar, W. Ang, J. da Silva, A. L. M. Vlek, A. G. M. Buiting, L. G. M. Bode, A. Jansz, S. Paltansing, A. J. van Griethuysen, J. R. Lo Ten Foe, M. J. C. A. van Trijp, M. Wong, A. E. Muller, M. P. M. van der Linden, M. van Rijn, S. B. Debast, E Kolwijck, N. Al Naiemi, T. Schulin, S. Dinant, S. P. van Mens, D. C. Melles, J. W. T. Cohen Stuart, P. Gruteke, A. P. van Dam, I. Maat, B. Maraha, J. C. Sinnige, E. van der Vorm, M. P. A. van Meer, M. de Graaf, E. de Jong, S. J. Vainio, E. Heikens, M. den Reijer, J. W. Dorigo-Zetsma, A. Troelstra, E. Bathoorn, J. de Vries, D. W. van Dam, E. I. G. B. de Brauwer, R. Steingrover
Journal: Genome Medicine (2024)

Multidrug-resistant organisms (MDRO) pose a significant threat to public health worldwide. The ability to identify antimicrobial resistance determinants, to assess changes in molecular types, and to detect transmission are essential for surveillance and infection prevention of MDRO. Molecular characterization based on long-read sequencing has emerged as a promising alternative to short-read sequencing. The aim of this study was to characterize MDRO for surveillance and transmission studies based on long-read sequencing only.
Publisher Correction: Tagging large CNV blocks in wheat boosts digitalization of germplasm resources by ultra-low-coverage sequencing
Authors: Jianxia Niu, Wenxi Wang, Zihao Wang, Zhe Chen, Xiaoyu Zhang, Zhen Qin, Lingfeng Miao, Zhengzhao Yang, Chaojie Xie, Mingming Xin, Huiru Peng, Yingyin Yao, Jie Liu, Zhongfu Ni, Qixin Sun, Weilong Guo
Journal: Genome biology (2024)
Extensive Macular Atrophy with Pseudodrusen-like appearance (EMAP) Clinical characteristics, diagnostic criteria, and insights from allied Inherited Retinal Diseases and Age-related Macular Degeneration
Authors: Alessio Antropoli, Lorenzo Bianco, Francesco Romano, Andrea Trinco, Alessandro Arrigo, Amine Benadji, Raphaël Atia, Oana Palacci, Dorothée Dagostinoz, Céline Devisme, Christel Condroyer, Aline Antonio, Francesca Bosello, Stefano Casati, Anna Paola Salvetti, Chiara Zaffalon, Alain Gaudric, José-Alain Sahel, Giovanni Staurenghi, Francesco Bandello, Florian Sennlaub, Christina Zeitz, Isabelle Meunier, Maurizio Battaglia Parodi, Isabelle Audo
Journal: Progress in Retinal and Eye Research (2024)
Multidimensional Directionality-Enhanced Segmentation via large vision model
Authors: Xingru Huang, Changpeng Yue, Yihao Guo, Jian Huang, Zhengyao Jiang, Mingkuan Wang, Zhaoyang Xu, Guangyuan Zhang, Jin Liu, Tianyun Zhang, Zhiwen Zheng, Xiaoshuai Zhang, Hong He, Shaowei Jiang, Yaoqi Sun
Journal: Medical Image Analysis (2024)
Size-transformable nanotherapeutics for cancer therapy
Authors: Teng Ma, Tuyen Ba Tran, Ethan Lin, Stephanie Hunt, Riley Haveman, Kylie Castro, Jianqin Lu
Journal: Acta Pharmaceutica Sinica B (2024)

The size of nanodrugs plays a crucial role in shaping their chemical and physical characteristics, consequently influencing their therapeutic and diagnostic interactions within biological systems. The optimal size of nanomedicines, whether small or large, offers distinct advantages in disease treatment, creating a dilemma in the selection process. Addressing this challenge, size-transformable nanodrugs have surfaced as a promising solution, as they can be tailored to entail the benefits associated with both small and large nanoparticles. In this review, various strategies are summarized for constructing size-transformable nanosystems with a focus on nanotherapeutic applications in the field of biomedicine. Particularly we highlight recent research developments in cancer therapy. This review aims to inspire researchers to further develop various toolboxes for fabricating size-transformable nanomedicines for improved intervention against diverse human diseases.