tbuckley/cabot-search huggingface dataset:
HO-1 impairs the efficacy of radiotherapy by redistributing cGAS and STING in tumors
Authors: Chuqing Zhang, Zhenji Deng, Jiawei Wu, Cong Ding, Zhe Li, Zhimin Xu, Weipeng Chen, Kaibin Yang, Hanmiao Wei, Tingxiang He, Liufen Long, Jun Ma, Cheng Xu, Xiaoyu Liang
Journal: Journal of Clinical Investigation (2024)

Type I IFNs (IFN-Is) induced by radiotherapy (RT) are critical for its efficacy, while the mechanism by which tumor cells inhibit IFN-I production remains largely unsolved. By an unbiased CRISPR screen, we identified hemeoxygenase 1 (HO-1) as an RT-related regulator of IFN-I production. Mechanistically, the ER-anchored, full-length HO-1 disrupted stimulator of IFN genes (STING) polymerization and subsequent coat protein complex II-mediated (COPII-mediated) ER-Golgi transportation, leading to hampered activation of downstream signaling. This process was exacerbated by the upregulation of HO-1 expression under RT. Importantly, RT also induced HO-1 cleavage. Cleaved HO-1 underwent nuclear translocation, interacted with cyclic GMP-AMP synthase (cGAS), and inhibited its nuclear export upon irradiation, leading to suppressed 2'3'-cyclic GMP-AMP (cGAMP) production. Furthermore, we revealed that HO-1 inhibitors could enhance local and distant tumor control of RT in vivo. Clinically, higher HO-1 expression was associated with a poorer prognosis and earlier tumor relapse after RT in multiple types of patient tumors. Collectively, through comprehensive inhibition of the cGAS/STING pathway, HO-1 strongly inhibited RT-induced IFN-I production, and targeting HO-1 was shown to be a promising RT-sensitizing therapeutic strategy.
Supportive care or exhausted neglect: the role of microglia at the end stage of prion disease
Authors: Victoria A. Lawson
Journal: Journal of Clinical Investigation (2024)

The transmissible nature of prion diseases enables reproduction of neurodegeneration in small animal models that faithfully follows the disease process observed in the natural disease of animals and humans. This allows the temporal development of disease to be investigated and correlated with pathology in a complex brain environment. In this issue of the JCI, Makarava et al. describe a shift in microglia morphology from an active phagocytic phenotype to a passive association with neuronal cell bodies. Whether this morphological change reflects a supportive action of microglia in response to neuronal impairment or exhaustion of PrPSc-laden microglia remains to be determined. However, if microglial populations effectively contain PrPSc propagation early in the infection process, as the current study suggests, identifying ways to maintain or enhance the function of this cell population could be the key to prolonging patient survival.
Dysregulated Treg repair responses lead to chronic rejection after heart transplantation
Authors: Jordan Jp Warunek, Lu Fan, Xue Zhang, Sihua Wang, Steven M Sanders, Tengfang Li, Lisa R Mathews, Gaelen K Dwyer, Michelle A Wood-Trageser, Stephanie Traczek, Andrew Lesniak, Kassandra Baron, Hailey Spencer, Johnny Bou Saba, Emmanuel León Colón, Tracy Tabib, Robert Lafyatis, Mark A Ross, Anthony J Demetris, Simon C Watkins, Steven A Webber, Khodor I Abou-Daya, Hēth R Turnquist
Journal: Journal of Clinical Investigation (2024)

Chronic rejection (CR) after organ transplantation is alloimmune injury manifested by graft vascular remodeling and fibrosis that is resistant to immunosuppression. Single-cell RNA-Seq analysis of MHC class II-mismatched (MHCII-mismatched) heart transplants developing chronic rejection identified graft IL-33 as a stimulator of tissue repair pathways in infiltrating macrophages and Tregs. Using IL-33-deficient donor mice, we show that graft fibroblast-derived IL-33 potently induced amphiregulin (Areg) expression by recipient Tregs. The assessment of clinical samples also confirmed increased expression of Areg by intragraft Tregs also during rejection. Areg is an EGF secreted by multiple immune cells to shape immunomodulation and tissue repair. In particular, Areg is proposed to play a major role in Treg-mediated muscle, epithelium, and nerve repair. Assessment of recipient mice with Treg-specific deletion of Areg surprisingly uncovered that Treg secretion of Areg contributed to CR. Specifically, heart transplants from recipients with Areg-deficient Tregs showed less fibrosis, vasculopathy, and vessel-associated fibrotic niches populated by recipient T cells. Mechanistically, we show that Treg-secreted Areg functioned to increase fibroblast proliferation. In total, these studies identify how a dysregulated repair response involving interactions between IL-33+ fibroblasts in the allograft and recipient Tregs contributed to the progression of CR.
Sex, cells, and metabolism: Androgens temper Th17-mediated immunity
Authors: Nikita L Mani, Samuel E Weinberg
Journal: Journal of Clinical Investigation (2024)

Sex-based differences in autoimmune disease susceptibility have long been recognized, prompting investigations into how sex hormones influence immunity. Recent advances suggest that hormones may shape immune responses by altering cellular metabolism. In this issue of the JCI, Chowdhury et al. authenticates this model, showing that androgen receptor signaling modulates T helper 17 (Th17) cell metabolism, specifically glutaminolysis, reducing airway inflammation in males. This work provides insight into sex-specific regulation of immunity, highlighting the interplay between hormones, metabolism, and immune function. The findings raise intriguing questions about how hormonal fluctuations affect immunity and how sex-specific metabolic pathways might be leveraged for targeted therapies in autoimmune diseases.
Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1
Authors: Teresa Mezza, Nicolai J Wewer Albrechtsen, Gianfranco Di Giuseppe, Pietro Manuel Ferraro, Laura Soldovieri, Gea Ciccarelli, Michela Brunetti, Giuseppe Quero, Sergio Alfieri, Enrico Celestino Nista, Antonio Gasbarrini, Vincenzo Tondolo, Andrea Mari, Alfredo Pontecorvi, Andrea Giaccari, Jens J Holst
Journal: Metabolism (2024)
HTAD: a human-in-the-loop framework for supervised chromatin domain detection
Authors: Wei Shen, Ping Zhang, Yiwei Jiang, Hailin Tao, Zhike Zi, Li Li
Journal: Genome biology (2024)

Topologically associating domains (TADs) are essential units of genome architecture, influencing transcriptional regulation and diseases. Despite numerous methods proposed for TAD identification, it remains challenging due to complex background and nested TAD structures. We introduce HTAD, a human-in-the-loop TAD caller that combines machine learning with human supervision to achieve high accuracy. HTAD begins with feature extraction for potential TAD border pairs, followed by an interactive labeling process through active learning. Performance assessments using public curation and synthetic datasets demonstrate HTAD's superiority over other state-of-the-art methods and reveal highly hierarchical TAD structures, offering a human-in-the-loop solution for detecting complex genomic patterns.
Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors
Authors: Daniel J. Merk, Foteini Tsiami, Sophie Hirsch, Bianca Walter, Lara A. Haeusser, Jens D. Maile, Aaron Stahl, Mohamed A. Jarboui, Anna Lechado-Terradas, Franziska Klose, Sepideh Babaei, Jakob Admard, Nicolas Casadei, Cristiana Roggia, Michael Spohn, Jens Schittenhelm, Stephan Singer, Ulrich Schüller, Federica Piccioni, Nicole S. Persky, Manfred Claassen, Marcos Tatagiba, Philipp J. Kahle, David E. Root, Markus Templin, Ghazaleh Tabatabai
Journal: Genome biology (2024)

Abstract Background Atypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Despite intensive research efforts, the prognosis for ATRT patients under currently established treatment protocols is poor. While novel therapeutic strategies are urgently needed, the generation of molecular-driven treatment concepts is a challenge mainly due to the absence of actionable genetic alterations. Results We here use a functional genomics approach to identify genetic dependencies in ATRT, validate selected hits using a functionally instructed small molecule drug library, and observe preferential activity in ATRT cells without subgroup-specific selectivity. CDK4/6 inhibitors are among the most potent drugs and display anti-tumor efficacy due to mutual exclusive dependency on CDK4 or CDK6 . Chemogenetic interactor screens reveal a broad spectrum of G1 phase cell cycle regulators that differentially enable cell cycle progression and modulate response to CDK4/6 inhibition in ATRT cells. In this regard, we find that the ubiquitin ligase substrate receptor AMBRA1 acts as a context-specific inhibitor of cell cycle progression by regulating key components of mitosis including aurora kinases. Conclusions Our data provide a comprehensive resource of genetic and chemical dependencies in ATRTs, which will inform further preclinical evaluation of novel targeted therapies for this tumor entity. Furthermore, this study reveals a unique mechanism of cell cycle inhibition as the basis for tumor suppressive functions of AMBRA1.
Comprehensive pathogen identification and antimicrobial resistance prediction from positive blood cultures using nanopore sequencing technology
Authors: Po-Yu Liu, Han-Chieh Wu, Ying-Lan Li, Hung-Wei Cheng, Ci-Hong Liou, Feng-Jui Chen, Yu-Chieh Liao
Journal: Genome Medicine (2024)

Abstract Background Blood cultures are essential for diagnosing bloodstream infections, but current phenotypic tests for antimicrobial resistance (AMR) provide limited information. Oxford Nanopore Technologies introduces nanopore sequencing with adaptive sampling, capable of real-time host genome depletion, yet its application directly from blood cultures remains unexplored. This study aimed to identify pathogens and predict AMR using nanopore sequencing. Methods In this cross-sectional genomic study, 458 positive blood cultures from bloodstream infection patients in central Taiwan were analyzed. Parallel experiments involved routine microbiologic tests and nanopore sequencing with a 15-h run. A bioinformatic pipeline was proposed to analyze the real-time sequencing reads. Subsequently, a comparative analysis was performed to evaluate the performance of species identification and AMR prediction. Results The pipeline identified 76 species, with 88 Escherichia coli , 74 Klebsiella pneumoniae , 43 Staphylococcus aureus , and 9 Candida samples. Novel species were also discovered. Notably, precise species identification was achieved not only for monomicrobial infections but also for polymicrobial infections, which was detected in 23 samples and further confirmed by full-length 16S rRNA amplicon sequencing. Using a modified ResFinder database, AMR predictions showed a categorical agreement rate exceeding 90% (3799/4195) for monomicrobial infections, with minimal very major errors observed for K. pneumoniae (2/186, 1.1%) and S. aureus (1/90, 1.1%). Conclusions Nanopore sequencing with adaptive sampling can directly analyze positive blood cultures, facilitating pathogen detection, AMR prediction, and outbreak investigation. Integrating nanopore sequencing into clinical practices signifies a revolutionary advancement in managing bloodstream infections, offering an effective antimicrobial stewardship strategy, and improving patient outcomes.
MoCHI: neural networks to fit interpretable models and quantify energies, energetic couplings, epistasis, and allostery from deep mutational scanning data
Authors: Andre J. Faure, Ben Lehner
Journal: Genome biology (2024)

Abstract We present MoCHI, a tool to fit interpretable models using deep mutational scanning data. MoCHI infers free energy changes, as well as interaction terms (energetic couplings) for specified biophysical models, including from multimodal phenotypic data. When a user-specified model is unavailable, global nonlinearities (epistasis) can be estimated from the data. MoCHI also leverages ensemble, background-averaged epistasis to learn sparse models that can incorporate higher-order epistatic terms. MoCHI is freely available as a Python package ( https://github.com/lehner-lab/MoCHI ) relying on the PyTorch machine learning framework and allows biophysical measurements at scale, including the construction of allosteric maps of proteins.
Gas Empowered Dual‐Cascade Strategy for Augmented Single‐Atom Nanotherapies
Authors: Yong Liu, Xiao‐Qiong Li, Qiao Yu, Bin Kang, Xueli Zhao, Jing‐Juan Xu
Journal: Advanced Healthcare Materials (2024)

Abstract Single‐atom nanotherapies have received numerous attention in malignant oncotherapy. However, the insufficient enzyme substrate and the upregulation of heat shock proteins during therapeutic interventions are seldom concurrently noticed. Herein, a novel gas empowered dual‐cascade synergistic treatment strategy is demonstrated with domino effect, which can sequentially reinforce single‐atom nanozyme (SAzyme)‐based enzymatic therapeutics and mild photothermal therapy (PTT) (&lt; 45 °C). In the proof‐of‐concept study, Fe single atom nanozyme (Fe/SAzyme) loaded with hydrogen sulfide (H 2 S) donor NaHS is developed for HSPs‐silencing mediated mild PTT. The generated H 2 S suppresses the catalase activity to achieve “intracellular H 2 O 2 conservation”, thereby furnishing the enzyme substrate to Fe/SAzyme to produce abundant cytotoxic hydroxyl radicals (·OH) for augmented enzymatic therapeutics. Then, excess ·OH induced mitochondrial dysfunction blocks adenosine triphosphate (ATP) energy supply to realize cellular energy remodeling, which hinders overexpression of HSPs and enhances mild PTT of Fe/SAzyme both in vitro and vivo. Consequently, the gas‐triggered dual‐cascade strategy achieves domino H 2 S/·OH/mitochondrial dysfunction synergistic effect, endowing SAzymes with maximum antitumor efficacy via enzymatic therapeutics combined with mild PTT. This dual‐cascaded gas/enzymatic/mild PTT synergistic oncotherapy not only exhibits a new pathway for gas‐facilitated mild PTT, but also offers a valuable paradigm for the application of “1 + 1 + 1 &gt; 3” multimodal synergistic tumor therapy.
Engineered Nanoparticles for Theranostic Applications in Kidney Repair
Authors: Can Jin, Lingling Xue, Leilei Zhang, Lixia Yu, Peipei Wu, Hui Qian
Journal: Advanced Healthcare Materials (2024)

Kidney diseases are characterized by their intricate nature and complexity, posing significant challenges in their treatment and diagnosis. Nanoparticles (NPs), which can be further classified as synthetic and biomimetic NPs, have emerged as promising candidates for treating various diseases. In recent years, the development of engineered nanotherapeutics has focused on targeting damaged tissues and serving as drug delivery vehicles. Additionally, these NPs have shown superior sensitivity and specificity in diagnosis and imaging, thus providing valuable insights for the early detection of diseases. This review aims to focus on the application of engineered synthetic and biomimetic NPs in kidney diseases in the aspects of treatment, diagnosis, and imaging. Notably, the current perspectives and challenges are evaluated, which provide inspiration for future research directions, and encourage the clinical application of NPs in this field.
Self‐Assembled Nanoparticles with Well‐Defined Oligosaccharide Promote Osteogenesis by Regulating Golgi Stress Response
Authors: Pingping Niu, Liman Zhao, Jing Yang, Yanan Ding, Xiaoqiao Xu, Sijin Li, Lige Song, Guosong Chen, Yao Sun
Journal: Advanced Healthcare Materials (2024)

Abstract Osteoporosis, a prevalent disease characterized by low bone density and increased fracture risk, poses significant health challenges for the elderly. Current treatments offer short‐term benefits but are limited by long‐term efficacy and adverse effects, highlighting the need for new strategies. Chondroitin sulfate polysaccharides (CS), a major component of the bone matrix, are crucial for bone and cartilage health. However, their role in osteoporosis is understudied due to the heterogeneity of natural CS. we found reduced CS levels in osteoporosis patients and developed CS4‐NP, a self‐assembled tetrasaccharide nanoparticle that mimics CS's structure. CS4‐NP, which efficiently delivers the active CS4, significantly improves bone mass in ovariectomized osteoporosis models. It activates the Activating Transcription Factor 4‐Cystathionine gamma‐Lyase signaling axis in pre‐osteoblasts, enhancing osteogenesis. our findings suggest that CS4‐NP, an oligosaccharide‐based nanomaterial, could address the limitations of current treatments and provide a viable strategy for osteoporosis.
SMART: spatial transcriptomics deconvolution using marker-gene-assisted topic model
Authors: Chen Xi Yang, Don D. Sin, Raymond T. Ng
Journal: Genome biology (2024)

Abstract While spatial transcriptomics offer valuable insights into gene expression patterns within the spatial context of tissue, many technologies do not have a single-cell resolution. Here, we present SMART, a marker gene-assisted deconvolution method that simultaneously infers the cell type-specific gene expression profile and the cellular composition at each spot. Using multiple datasets, we show that SMART outperforms the existing methods in realistic settings. It also provides a two-stage approach to enhance its performance on cell subtypes. The covariate model of SMART enables the identification of cell type-specific differentially expressed genes across conditions, elucidating biological changes at a single-cell-type resolution.
Interferon gamma‐mediated prevention of tumor progression in a mouse model of multiple myeloma
Authors: Zoltán Kellermayer, Sabrin Tahri, Madelon M. E. de Jong, Natalie Papazian, Cathelijne Fokkema, Elodie C. G. Stoetman, Remco Hoogenboezem, Gregory van Beek, Mathijs A. Sanders, Louis Boon, Chelsea Den Hollander, Annemiek Broijl, Pieter Sonneveld, Tom Cupedo
Journal: HemaSphere (2024)

Abstract Malignant plasma cells in multiple myeloma patients reside in the bone marrow and continuously interact with local immune cells. Progression and therapy response are influenced by this immune environment, highlighting the need for a detailed understanding of endogenous immune responses to malignant plasma cells. Here we used the 5TGM1 murine transfer model of multiple myeloma to dissect early immune responses to myeloma cells. We modeled stable and progressive disease by transferring 5TGM1 murine myeloma cells into C57Bl/6 mice and KaLwRij mice, respectively. We used flow cytometry and single‐cell and bulk transcriptomic analyses to characterize differential immune responses in stable and progressive disease. Transfer of 5TGM1 cells in C57Bl/6 mice led to stable disease with low tumor burden in a subset of animals. Stable disease was associated with sustained activation and expansion of NK cells, ILC1, and CD8 + T cells, a response that was lost upon disease progression. Single‐cell RNA‐sequencing of immune cells and bulk RNA sequencing of immune and mesenchymal stromal cells implicated the activation of interferon responses as a central immune pathway during stable disease. Experimentally, neutralization of IFNγ significantly increased myeloma development and progression in C57Bl/6 mice, testifying to the importance of this pathway in early disease control. In conclusion, we provide a framework for studying immune responses to multiple myeloma progression in immunocompetent and genetically modifiable mice and highlight the importance of bone marrow immunity in tumor control.
A chimeric peptide promotes immune surveillance of senescent cells in injury, fibrosis, tumorigenesis and aging
Authors: Xinliang Ming, Ze Yang, Yuqiao Huang, Zhiguo Wang, Qingyan Zhang, Changchang Lu, Yandi Sun, Yuanhao Chen, Liang Zhang, Jicheng Wu, Hao Shou, Zhimin Lu, Ben Wang
Journal: Nature Aging (2024)
Integrating binding affinity and tonic signaling enables a rational CAR design for augmented T cell function
Authors: Markus Barden, Patrick Ronan Elsenbroich, Vivian Haas, Moritz Ertelt, Philip Pervan, Lukas Velas, Bence Gergely, Árpád Szöőr, Dennis Christoph Harrer, Valerie Bezler, Astrid Holzinger, Rasmus Ulslev Wegener Friis, Gyorgy Vereb, Gerhard J Schütz, Clara T Schoeder, Andreas A Hombach, Hinrich Abken
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies has not yet translated into long-term elimination of solid tumors indicating the need for adequately tuning CAR T cell functionality. Methods We leveraged a translational pipeline including biophysical characterization and structural prediction of the CAR binding moiety, evaluation of cellular avidity, synapse formation, T cell motility, and functional capacities under repetitive target challenge and in sustained tumor control. Results As an example of clinical relevance, we derived a panel of anti-Her2 CARs covering a 4-log affinity range, all expected to target the same Her2 epitope. The same scFv mutations increased both antigen-specific affinity, cellular avidity, and antigen-independent “tonic” signaling; above a minimum threshold, raise in affinity translated into functional avidity in a non-linear fashion. In this case, replacement by amino acids of higher hydrophobicity within the scFv coincidentally augmented affinity, non-specific binding, spontaneous CAR clustering, and tonic signaling, all together relating to T cell functionality in an integrated fashion. Conclusions Data emphasize that tonic signaling is not always due to the positive charge but can be driven by hydrophobic interactions of the scFv. CAR binding affinity above the threshold and tonic signaling are required for sustained T cell functionality in antigen rechallenge and long-term tumor control.
Antiviral target compound profile for pandemic preparedness
Authors: James F. Demarest, Ruxandra Draghia-Akli, Tomas Cihlar, Kenneth Bradley, John A. T. Young, Richa Chandra, Sujata Vaidyanathan, Margaret Chu-Moyer, Christopher L. Lynch, Andrew Campbell, Kumar Singh Saikatendu, John P. Bilello, Yoshihiko Murata, Marnix van Loock, Aeron C. Hurt, Timothy Tellinghuisen, Lee Ruggiero, Richard Mackman, Nina M. Hill, John C. Pottage, Marnix van Loock
Journal: Nature Reviews Drug Discovery (2024)
Author Correction: Cutaneous T cell lymphoma atlas reveals malignant TH2 cells supported by a B cell-rich tumor microenvironment
Authors: Ruoyan Li, Johanna Strobl, Elizabeth F. M. Poyner, Aya Balbaa, Fereshteh Torabi, Pavel V. Mazin, Nana-Jane Chipampe, Emily Stephenson, Ciro Ramírez-Suástegi, Vijaya Baskar Mahalingam Shanmugiah, Louis Gardner, Bayanne Olabi, Rowen Coulthard, Rachel A. Botting, Nina Zila, Elena Prigmore, Nusayhah H. Gopee, Marta A. Chroscik, Efpraxia Kritikaki, Justin Engelbert, Issac Goh, Hon Man Chan, Harriet F. Johnson, Jasmine Ellis, Victoria Rowe, Win Tun, Gary Reynolds, Dexin Yang, April Rose Foster, Laure Gambardella, Elena Winheim, Chloe Admane, Benjamin Rumney, Lloyd Steele, Laura Jardine, Julia Nenonen, Keir Pickard, Jennifer Lumley, Philip Hampton, Simeng Hu, Fengjie Liu, Xiangjun Liu, David Horsfall, Daniela Basurto-Lozada, Louise Grimble, Chris M. Bacon, Sophie C. Weatherhead, Hanna Brauner, Yang Wang, Fan Bai, Nick J. Reynolds, Judith E. Allen, Constanze Jonak, Patrick M. Brunner, Sarah A. Teichmann, Muzlifah Haniffa
Journal: Nature Immunology (2024)
Publisher Correction: Disease-associated B cells and immune endotypes shape adaptive immune responses to SARS-CoV-2 mRNA vaccination in human SLE
Authors: Caterina E. Faliti, Trinh T. P. Van, Fabliha A. Anam, Narayanaiah Cheedarla, M. Elliott Williams, Ashish Kumar Mishra, Sabeena Y. Usman, Matthew C. Woodruff, Geoff Kraker, Martin C. Runnstrom, Shuya Kyu, Daniel Sanz, Hasan Ahmed, Midushi Ghimire, Andrea Morrison-Porter, Hannah Quehl, Natalie S. Haddad, Weirong Chen, Suneethamma Cheedarla, Andrew S. Neish, John D. Roback, Rustom Antia, Jennifer Hom, Christopher M. Tipton, John M. Lindner, Eliver Ghosn, Surender Khurana, Christopher D. Scharer, Arezou Khosroshahi, F. Eun-Hyung Lee, Ignacio Sanz
Journal: Nature Immunology (2024)