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Author Correction: Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes

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Nature genetics 2025年第4期57卷 1060页

作者： Alicia Huerta-Chagoya Philip Schroeder Ravi Mandla Jiang Li Lowri Morris Maheak Vora Ahmed Alkanaq Dorka Nagy Lukasz Szczerbinski Jesper G S Madsen Silvia Bonàs-Guarch Fanny Mollandin Joanne B Cole Bianca Porneala Kenneth Westerman Josephine H Li Toni I Pollin Jose C Florez Anna L Gloyn David J Carey Inês Cebola Uyenlinh L Mirshahi Alisa K Manning Aaron Leong Miriam Udler Josep M Mercader Programs in Metabolism and Medical & Population Genetics Broad Institute of Harvard and MIT Cambridge MA USA. Center for Genomic Medicine Massachusetts General Hospital Boston MA USA. Diabetes Unit Massachusetts General Hospital Boston MA USA. Graduate Program in Genomics and Computational Biology University of Pennsylvania Philadelphia PA USA. Department of Genomic Health Geisinger Danville PA USA. Section of Genetics and Genomics Department of Metabolism Digestion and Reproduction Imperial College London London UK. National Heart and Lung Institute Faculty of Medicine London UK. Department of Endocrinology Diabetology and Internal Medicine Medical University of Bialystok Bialystok Poland. Clinical Research Centre Medical University of Bialystok Bialystok Poland. Institute of Mathematics and Computer Science University of Southern Denmark Odense Denmark. The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease Broad Institute of MIT and Harvard Cambridge MA USA. Department of Biochemistry and Molecular Biology University of Southern Denmark Odense Denmark. Centre for Genomic Regulation The Barcelona Institute of Science and Technology Barcelona Spain. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas Madrid Spain. Department of Metabolism Digestion and Reproduction Imperial College London London UK. Department of Medicine Harvard Medical School Boston MA USA. Division of Endocrinology Boston Children's Hospital Boston MA USA. Department of Biomedical Informatics University of Colorado School of Medicine Aurora CO USA. Division of General Internal Medicine Massachusetts General Hospital Boston MA USA. Department of Medicine Massachusetts General Hospital Boston MA USA. University of Maryland School of Medicine Baltimore MD USA. Endocrine Division Massachusetts General Hospital Boston MA USA. Department of Pediatrics Division of Endocrinology Stanford School of Medicine Stanford

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Research highlights

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Lab on a Chip 2013年第4期13卷 599-601页

作者： Francesco Piraino João Ribas Mehmet R. Dokmeci Ali Khademhosseini Bioengineering Department Politecnico di Milano Piazza Leonardo da Vinci 32 20133 Milano Italy Center for Biomedical Engineering Department of Medicine Brigham and Women's Hospital Harvard Medical School Cambridge Massachusetts 02139 USA Harvard-MIT Division of Health Sciences and Technology Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA Biocant-Center of Innovation and Biotechnology 3060-197 Cantanhede Portugal PhD Program in Experimental Biology and Biomedicine CNC-Centre for Neuroscience and Cell Biology 3004-517 Coimbra Portugal Wyss Institute for Biologically Inspired Engineering Harvard University Boston Massachusetts 02115 USA World Premier International – Advanced Institute for Materials Research (WPI-AIMR) Tohoku University Sendai 980-8577 Japan

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Limits on the Ejecta Mass During the Search for Kilonovae Associated with Neutron Star-Black Hole Mergers: A case study of S230518h, GW230529, S230627c and the Low-Significance Candidate S240422ed

arXiv

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arXiv 2025年

作者： Pillas, M. Antier, S. Ackley, K. Ahumada, T. Akl, D. de Almeida, L. Anand, S. Andrade, C. Andreoni, I. Bostroem, K.A. Bulla, M. Burns, E. Cabrera, T. Chang, S. Choi, H. O’Connor, B. Coughlin, M.W. Corradi, W. Gibbs, A.R. Dietrich, T. Dornic, D. Ducoin, J.-G. Duverne, P.-A. Dyer, M. Eggenstein, H.-B. Freeberg, M. Fausnaugh, M. Fong, W. Foucart, F. Frostig, D. Guessoum, N. Gupta, V. Hello, P. Hosseinzadeh, G. Hu, L. Hussenot-Desenonges, T. Im, M. Jayaraman, R. Jeong, M. Karambelkar, V. Karpov, S. Kasliwal, M. Kilpatrick, C.D. Kim, S. Kochiashvili, N. Kunnumkai, K. Lamoureux, M. Lee, C.U. Lourie, N. Lyman, J. Magnani, F. Mašek, M. Mo, G. Molham, M. Navarete, F. O’Neill, D. Nicholl, M. Nitz, A.H. Noysena, K. Paek, G.S.H. Palmese, A. Poggiani, R. Pradier, T. Pyshna, O. Rajabov, Y. Rastinejad, J.C. Sand, D.J. Shawhan, P. Shrestha, M. Simcoe, R. Smartt, S.J. Steeghs, D. Stein, R. Stevance, H.F. Sun, M. Takey, A. Toivonen, A. Turpin, D. Ulaczyk, K. Wold, A. Wouters, T. STAR Institute Liege University Allée du Six Août Liege19C B-4000 Belgium Université de la Côte d’Azur ARTEMIS Nice France IJCLab Univ Paris-Saclay CNRS IN2P3 Orsay France Department of Physics University of Warwick Gibbet Hill Road CoventryCV4 7AL United Kingdom Division of Physics Mathematics and Astronomy California Institute of Technology PasadenaCA91125 United States American University of Sharjah Physics Department PO Box 26666 Sharjah United Arab Emirates Laboratório Nacional de Astrofísica Rua Estado Unidos 154 - MG Itajubá37504-364 Brazil School of Physics and Astronomy University of Minnesota MinneapolisMN55455 United States Department of Physics and Astronomy University of North Carolina at Chapel Hill Chapel HillNC27599-3255 United States Steward Observatory University of Arizona 933 North Cherry Avenue TucsonAZ85721-0065 United States Department of Physics and Earth Science University of Ferrara via Saragat 1 FerraraI-44122 Italy INFN Sezione di Ferrara via Saragat 1 FerraraI-44122 Italy INAF Osservatorio Astronomico d’Abruzzo via Mentore Maggini snc Teramo64100 Italy Department of Physics & Astronomy Louisiana State University Baton RougeLA70803 United States McWilliams Center for Cosmology and Astrophysics Department of Physics Carnegie Mellon University PittsburghPA15213 United States SNU Astronomy Research Center Astronomy Program Department of Physics & Astronomy Seoul National University 1 Gwanak-ro Gwanak-gu Seoul08826 Korea Republic of Lunar and Planetary Laboratory University of Arizona 1629 East University Boulevard TucsonAZ85721-0092 United States Institut für Physik und Astronomie Universität Potsdam Haus 28 Karl-Liebknecht-Str. 24/25 Potsdam14476 Germany Am Mühlenberg 1 Potsdam14476 Germany CPPM Aix Marseille Univ CNRS IN2P3 CPPM Marseille France Université Paris Cité CNRS Astroparticule et Cosmologie ParisF-75013 France Astrophysics Research Cluster School of Mathematical and

Neutron star–black hole (NSBH) mergers, detectable via their gravitational-wave (GW) emission, are expected to produce kilonovae (KNe). Four NSBH candidates have been identified and followed-up by more than fifty instruments since the start of the fourth GW Observing Run (O4), in May 2023, up to July 2024;however, no confirmed associated KN has been detected. This study evaluates ejecta properties from multi-messenger observations to understand the absence of detectable KN: we use GW public information and joint observations taken from 05.2023 to 07.2024 (LVK, ATLAS, DECam, GECKO, GOTO, GRANDMA, SAGUARO, TESS, WINTER, ZTF). First, our analysis on followup observation strategies shows that, on average, more than 50% of the simulated KNe associated with NSBH mergers reach their peak luminosity around one day after merger in the g, r, i- bands, which is not necessarily covered for each NSBH GW candidate. We also analyze the trade-off between observation efficiency and the intrinsic properties of the KN emission, to understand the impact on how these constraints affect our ability to detect the KN, and underlying ejecta properties for each GW candidate. In particular, we can only confirm the kilonova was not missed for 1% of the GW230529 and S230627c sky localization region, given the large sky localization error of GW230529 and the large distance for S230627c and, their respective KN faint luminosities. More constraining, for S230518h, we infer the dynamical ejecta and post-merger disk wind ejecta mdyn, mwind ☉ and the viewing angle θ > 25◦. Similarly, the non-astrophysical origin of S240422ed is likely further confirmed by the fact that we would have detected even a faint KN at the time and presumed distance of the S240422ed event candidate, within a minimum 45% credible region of the sky area, that can be larger depending on the KN scenario. Copyright © 2025, The Authors. All rights reserved.

关键词： Black holes

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Smoking and Risk of Colorectal Cancer Sub-classified by Tumor-infiltrating T Cells (vol 111, pg 42, 2019)

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JNCI-JOURNAL OF THE NATIONAL CANCER institute 2019年第12期111卷 1365-1365页

作者： Hamada, Tsuyoshi Department of Oncologic Pathology Department of Medical Oncology Dana-Farber Cancer Institute and Harvard Medical School Boston MAProgram in Molecular Pathological Epidemiology Department of Pathology Department of Oncologic Pathology Clinical and Translational Epidemiology Unit and Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA Clinical and Translational Epidemiology Unit and Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MADepartment of Nutrition Clinical and Translational Epidemiology Unit and Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MADepartment of NutritionDivision of Public Health Sciences Department of Surgery Washington University School of Medicine St. Louis MO Department of Oncologic Pathology Department of Medical Oncology Dana-Farber Cancer Institute and Harvard Medical School Boston MA Department of Oncologic Pathology Department of Oncologic PathologyDepartment of NutritionDivision of Public Health Sciences Department of Surgery Washington University School of Medicine St. Louis MODepartment of Epidemiology and Biostatistics and the Ministry of Education Key Lab of Environment and Health School of Public Health Huazhong University of Science and Technology Hubei P.R. China Department of Oncologic PathologyDepartment of Medical Oncology Chinese PLA General Hospital Beijing P.R. China Department of Oncologic Pathology Department of Oncologic PathologyCollege of Pharmacy Zhejiang Chinese Medical University Zhejiang P.R. China Department of Oncologic Pathology Department of Gastroenterology Rheumatology and Clinical Immunology Sapporo Medical University School of Medicine Sapporo Japan Department of NutritionDepartment of Food Science and Biotechnology Dongguk University Goyang the Republic of Korea Department of Medical Oncology Dana-Farber Cancer Institute and Harvard Medical School Boston MADepartment of

BackgroundEvidence indicates not only carcinogenic effect of cigarette smoking but also its immunosuppressive effect. We hypothesized that the association of smoking with colorectal cancer risk might be stronger for tumors with lower anti-tumor adaptive immune *** follow-up of 134 981 participants (3 490 851 person-years) in the Nurses’ Health Study and Health Professionals Follow-up Study, we documented 729 rectal and colon cancer cases with available data on T-cell densities in tumor microenvironment. Using the duplication-method Cox regression model, we examined a differential association of smoking status with risk of colorectal carcinoma subclassified by densities of CD3⁺ cells, CD8⁺ cells, CD45RO (PTPRC)⁺ cells, or FOXP3⁺ cells. All statistical tests were *** association of smoking status with colorectal cancer risk differed by CD3⁺ cell density (P_{heterogeneity} = .007). Compared with never smokers, multivariable-adjusted hazard ratios for CD3⁺ cell-low colorectal cancer were 1.38 (95% confidence interval = 1.09 to 1.75) in former smokers and 1.59 (95% confidence interval = 1.14 to 2.23) in current smokers (P_trend = .002, across smoking status categories). In contrast, smoking status was not associated with CD3⁺ cell-high cancer risk (P_trend = .52). This differential association appeared consistent in strata of microsatellite instability, CpG island methylator phenotype, or BRAF mutation status. There was no statistically significant differential association according to densities of CD8⁺ cells, CD45RO⁺ cells, or FOXP3⁺ cells (P_{heterogeneity} > .04, with adjusted α of 0.01).ConclusionsColorectal cancer risk increased by smoking was stronger for tumors with lower T-lymphocyte response, suggesting an interplay of smoking and immunity in colorectal carcinogenesis.

关键词： Association (Psychology) cancer risk Smoking Colorectal Cancer Cancer of Colon Cigarette Smoking Immunosuppression (Physiology) Adaptive Immune Response Tumours T-Lymphocytes cigarette smoke

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Novel Polarimetric Analysis of Near Horizon Flaring Episodes in M87* in Millimeter Wavelength

arXiv

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arXiv 2025年

作者： Emami, Razieh Liska, Matthew Chatterjee, Koushik Bower, Geoffrey C. Benbow, Wystan Finkbeiner, Douglas Wielgus, Maciek Hernquist, Lars Smith, Randall Tremblay, Grant Ricarte, Angelo Steiner, James F. Broderick, Avery E. Saurabh Davelaar, Jordy Grindlay, Josh Vogelsberger, Mark Chan, Chi-Kwan Center for Astrophysics Harvard & Smithsonian 60 Garden Street CambridgeMA02138 United States Center for Relativistic Astrophysics Georgia Institute of Technology Howey Physics Bldg 837 State Street NW AtlantaGA30332 United States Department of Physics University of Maryland College ParkMD United States Academia Sinica Institute of Astronomy and Astrophysics 645 N. A’ohoku Place HiloHI96720 United States Instituto de Astrofísica de Andalucía-CSIC Glorieta de la Astronomía s/n GranadaE-18008 Spain Black Hole Initiative Harvard University 20 Garden Street CambridgeMA02138 United States Perimeter Institute for Theoretical Physics 31 Caroline Street North WaterlooONN2L 2Y5 Canada Department of Physics and Astronomy University of Waterloo 200 University Avenue West WaterlooONN2L 3G1 Canada Max-Planck-Institut für Radioastronomie Auf dem Hügel 69 BonnD-53121 Germany Department of Astrophysical Sciences Peyton Hall Princeton University PrincetonNJ08544 United States NASA Hubble Fellowship Program Department of Physics Kavli Institute for Astrophysics and Space Research Massachusetts Institute of Technology CambridgeMA02139 United States Department of Astronomy and Steward Observatory University of Arizona 933 North Cherry Avenue TucsonAZ85721 United States Data Science Institute University of Arizona 1230 N. Cherry Ave. TucsonAZ85721 United States Program in Applied Mathematics University of Arizona 617 N. Santa Rita TucsonAZ85721 United States

Recent multi-wavelength observations of M87* (Algaba et al. 2024) revealed a high-energy γ-ray flare without a corresponding millimeter counterpart. We present a theoretical polarimetric study to evaluate the presence and nature of a potential millimeter flare in M87*, using a suite of general relativistic magnetohydrodynamical simulations with varying black hole (BH) spins and magnetic field configurations. We find that the emergence of a millimeter flare is strongly influenced by both spin and magnetic structure, with limited sensitivity to the electron distribution (thermal vs. non-thermal). We model the intensity light curve with a damped random walk (DRW) and compare the characteristic timescale (τ) with recent SMA observations, finding that the simulated τ exceeds observed values by over an order of magnitude. In a flaring case with BH spin a=+0.5, we identify a distinct millimeter flare followed by an order-of-magnitude flux drop. All Stokes parameters show variability near the flare, including a sign reversal in the electric vector position angle. While most βm modes remain stable, the EB-correlation phase is highly sensitive to both the flare peak and decay. We examine polarimetric signatures in photon sub-rings, focusing on modes ns=0 and ns=1. The ns=0 signal closely matches the full image, while ns=1 reveals distinct behaviors, highlighting the potential of space VLBI to isolate sub-ring features. Finally, we analyze the magnetic and velocity field evolution during the flare, finding that magnetic reconnection weakens during the flux decay, and the clockwise velocity flow transitions into an outflow-dominated regime. These results suggest that transient radio variability near flares encodes key information about BH spin and magnetic field structure, offering a novel probe into the physics of active galactic nuclei. © 2025, CC BY.

关键词： Magnetohydrodynamics

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Child Opportunity Index at birth and asthma with recurrent exacerbations in the US ECHO program

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Journal of Allergy and Clinical Immunology 2025年

作者： Miller, Rachel L. Schuh, Holly Chandran, Aruna Habre, Rima Angal, Jyoti Aris, Izzuddin M. Aschner, Judy L. Bendixsen, Casper G. Blossom, Jeffrey Bosquet-Enlow, Michelle Breton, Carrie V. Camargo, Carlos A. Carroll, Kecia N. Commodore, Sarah Croen, Lisa A. Dabelea, Dana M. Deoni, Sean C.L. Ferrara, Assiamira Fry, Rebecca C. Ganiban, Jody M. Geiger, Sarah D. Gern, James E. Gilliland, Frank D. Gogcu, Semsa Gold, Diane R. Hare, Marion E. Harte, Robyn N. Hartert, Tina V. Hertz-Picciotto, Irva Hipwell, Alison E. Jackson, Daniel J. Karagas, Margaret K. Khurana Hershey, Gurjit K. Kim, Haejin Litonjua, Augusto A. Marsit, Carmen J. McEvoy, Cynthia T. Mendonça, Eneida A. Moore, Paul E. Nguyen, Anh P. Nkoy, Flory L. Oken, Emily Ownby, Dennis R. Perzanowski, Matthew Rivera-Spoljaric, Katherine Sathyanarayana, Sheela Singh, Anne Marie Stanford, Joseph B. Stroustrup, Annemarie Towe-Goodman, Nissa Wang, Veronica A. Woodruff, Tracey J. Wright, Robert O. Wright, Rosalind J. Zanobetti, Antonella Zoratti, Edward M. Johnson, Christine C. Department of Medicine Icahn School of Medicine at Mount Sinai New York NY United States Columbia University Mailman School of Public Health New York NY United States Northwell Health New York NY United States Johns Hopkins University Bloomberg School of Public Health Baltimore Md United States Keck School of Medicine of University of Southern California Los Angeles Calif United States University of South Dakota Sanford School of Medicine Sioux Falls SD United States Avera Research Institute Sioux Falls SD United States Department of Population Medicine Harvard Medical School Boston Mass United States Department of Psychiatry Harvard Medical School Boston Mass United States Department of Massachusetts General Hospital Harvard Medical School Boston Mass United States Department of Channing Division of Network Medicine Brigham and Women's Hospital Harvard Medical School Boston Mass United States Department of Harvard Pilgrim Health Care Institute Boston Mass United States Department of Psychiatry and Behavioral Sciences Boston Children's Hospital Boston Mass United States Department of Environmental Health Harvard T.H. Chan School of Public Health Boston Mass United States Center for Discovery and Innovation Hackensack Meridian School of Medicine Nutley NJ United States Albert Einstein College of Medicine Bronx NY United States National Farm Medicine Center Marshfield Clinic Research Institute Marshfield Wis United States Harvard University Center for Geographic Analysis Cambridge Mass United States Medical University of South Carolina Charleston SC United States Division of Research Kaiser Permanente Northern California Oakland Calif United States University of Colorado Anschutz Medical Campus Aurora Colo United States Colorado School of Public Health Aurora Colo United States Bill and Melinda Gates Foundation Seattle Wash United States Department of Pediatrics University of Washington Seattle Wash United States Department of Envir

Background: Environmental exposures and social determinants likely influence specific childhood asthma phenotypes. Objective: We hypothesized that the Child Opportunity Index (COI) at birth, measuring multiple neighborhood opportunities, influences incidence rates (IRs) for asthma with recurrent exacerbations (ARE). Methods: We tested for COI associations with ARE IRs in 15,877 children born between 1990 and 2018 in the ECHO (Environmental Influences on Child Health Outcomes) program. Parent-reported race and ethnicity and other demographics were assessed as effect modifiers. Results: The IRs of ARE for children born in very low COI neighborhoods was higher (IR = 10.98;95% CI: 9.71, 12.25) than for other COI categories. Rates for non-Hispanic Black (NHB) children were significantly higher than non-Hispanic White children in every COI category. The ARE IRs for children born in very low COI neighborhoods were several-fold higher for NHB and Hispanic Black children (IR = 15.30;95% CI: 13.10, 17.49;and IR = 18.48;95% CI: 8.80, 28.15, respectively) when compared to White children. Adjusting for individual-level characteristics, children born in very low COI neighborhoods demonstrated an ARE IR ratio of 1.26 (95% CI: 0.99, 1.59) with a higher incidence of cases among children ages 2 to 4 years and with a parental history of asthma. Conclusions: Rates of ARE were higher among children born in under-resourced communities, and this relationship is strongest for young minoritized children with a parental history of asthma. Higher rates for NHB even in the highest COI categories suggest that risk associated with race persists regardless of social disadvantage. © 2025 American Academy of Allergy, Asthma & Immunology

关键词： Asthma child opportunity index environmental and social determinants of asthma incidence rates recurrent asthma exacerbations

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Weakly Supervised AI for Efficient Analysis of 3D Pathology Samples

arXiv

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arXiv 2023年

作者： Song, Andrew H. Williams, Mane Williamson, Drew F.K. Jaume, Guillaume Zhang, Andrew Chen, Bowen Serafin, Robert Liu, Jonathan T.C. Baras, Alex Parwani, Anil V. Mahmood, Faisal Department of Pathology Brigham and Women’s Hospital Harvard Medical School BostonMA United States Department of Pathology Massachusetts General Hospital Harvard Medical School BostonMA United States Cancer Program Broad Institute of Harvard and MIT CambridgeMA United States Data Science Program Dana-Farber Cancer Institute BostonMA United States Department of Biomedical Informatics Harvard Medical School BostonMA United States Harvard-MIT Division of Health Sciences and Technology Massachusetts Institute of Technology CambridgeMA United States Department of Mechanical Engineering Bioengineering Laboratory Medicine & Pathology University of Washington SeattleWA United States Department of Pathology Johns Hopkins Hospital BaltimoreMD United States Department of Biomedical Engineering Johns Hopkins Hospital BaltimoreMD United States Department of Pathology The Ohio State University ColumbusOH United States

Human tissue consists of complex structures that display a diversity of morphologies, forming a tissue microenvironment that is, by nature, three-dimensional (3D). However, the current standard-of-care involves slicing 3D tissue specimens into two-dimensional (2D) sections and selecting a few for microscopic evaluation1,2, with concomitant risks of sampling bias and misdiagnosis3–6. To this end, there have been intense efforts to capture 3D tissue morphology and transition to 3D pathology, with the development of multiple high-resolution 3D imaging modalities7–18. However, these tools have had little translation to clinical practice as manual evaluation of such large data by pathologists is impractical and there is a lack of computational platforms that can efficiently process the 3D images and provide patient-level clinical insights. Here we present Modality-Agnostic Multiple instance learning for volumetric Block Analysis (MAMBA), a deep-learning-based platform for processing 3D tissue images from diverse imaging modalities and predicting patient outcomes. Archived prostate cancer specimens were imaged with open-top light-sheet microscopy12–14 or microcomputed tomography15,16 and the resulting 3D datasets were used to train risk-stratification networks based on 5-year biochemical recurrence outcomes via MAMBA. With the 3D block-based approach, MAMBA achieves an area under the receiver operating characteristic curve (AUC) of 0.86 and 0.74, superior to 2D traditional single-slice-based prognostication (AUC of 0.79 and 0.57), suggesting superior prognostication with 3D morphological features. Further analyses reveal that the incorporation of greater tissue volume improves prognostic performance and mitigates risk prediction variability from sampling bias, suggesting that there is value in capturing larger extents of spatially heterogeneous 3D morphology. With the rapid growth and adoption of 3D spatial biology and pathology techniques by researchers and clinicians, M

关键词： Pathology

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TScan-II:A genome-scale platform for the de novo identification of CD4^(+) T cell epitopes

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四川生理科学杂志 2023年第11期45卷 2164-2164页

作者： Mohammad H Dezfuian Division of Genetics Department of Medicine Howard Hughes Medical Institute Brigham and Women's Hospital Boston MA USA Department of Genetics Harvard Medical School Boston MA USA Adeno-Associated Virus Biology Section National Institute of Dental and Craniofacial Research National Institutes of Health Bethesda MD USA Broad Institute of Harvard and Massachusetts Institute of Technology Cambridge MA USA Department of Biomedical Informatics Harvard Medical School Boston MA USA Department of Medicine Harvard Medical School Boston MA USA Genes and Human Disease Program Oklahoma Medical Research Foundation Oklahoma City OK USA Salivary Disorders Unit National Institute of Dental and Craniofacial Research National Institutes of Health Bethesda MD USA Arthritis and Clinical Immunology Program Oklahoma Medical Research Foundation Oklahoma City OK USA Departmentment of Microbiology and Immunology University of Oklahoma Health Sciences Center Oklahoma City OK USA Department of Pathology University of Oklahoma Health Sciences Center Oklahoma City OK USA Laboratory of Cancer Biology and Genetics Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA

CD4+T cells play fundamental roles in orchestrating immune responses and tissue ***,our inability to associate peptide human leukocyte antigen class-II(HLA-II)complexes with their cognate T cell receptors(TCRs)in an unbiased manner has hampered our understanding of CD4^(+)T cell function and role in ***,we introduce TScan-II,a highly sensitive genome-scale CD4^(+) antigen discovery *** platform seamlessly integrates the endogenous HLA-II antigen-processing machinery in synthetic antigen-presenting cells and TCR signaling in T cells,enabling the simultaneous screening of multiple HLAs and *** genome-scale human,virome,and epitope mutagenesis libraries,TScan-II facilitates de novo antigen discovery and deep exploration of TCR *** demonstrate TScan-II's potential for basic and translational research by identifying a non-canonical antigen for a cancer-reactive CD4^(+)T cell ***,we identified two antigens for clonally expanded CD4^(+)T cells in Sjögren's disease,which bind distinct HLAs and are expressed in HLA-II-positive ductal cells within affected salivary glands.

关键词： endogenous specificity homeostasis

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Male-Biased Spliceosome Mutations in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Impair pDC Activation and Apoptosis

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BLOOD 2020年第Sup1期136卷 13-14页

作者： Togami, Katsuhiro Chung, Sun Sook Madan, Vikas Kenyon, Christopher M. Cabal-Hierro, Lucia Taylor, Justin Kim, Sunhee Griffin, Gabriel K. Ghandi, Mahmoud Li, Jia Li, Yvonne Y. Angelot-Delletre, Fanny Biichle, Sabeha Seiler, Michael Buonamici, Silvia Lovitch, Scott B. Louissaint, Abner, Jr. Morgan, Elizabeth A. Jardin, Fabrice Piccaluga, Pier Paolo Weinstock, David M. Hammerman, Peter S. Yang, Henry Konopleva, Marina Pemmaraju, Naveen Garnache-Ottou, Francine Abdel-Wahab, Omar Koeffler, H. Phillip Lane, Andrew A. Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School Boston MA Cancer Science Institute of Singapore National University of Singapore Singapore Singapore Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center Miami FL Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston MA Broad Institute of Harvard and MIT Cambridge MA Univ. Bourgogne Franche-Comté INSERM EFS Bourgogne Franche-Comté UMR1098 Interactions Hôte-Greffon-Tumeur - Ingénierie Cellulaire et Génique LabEX LipSTIC Besançon France EFS Bourgogne Franche-Comté Laboratoire d’Hématologie Besançon France H3 Biomedicine Cambridge MA Department of Pathology Massachusetts General Hospital Boston MA Inserm U1245 Centre Henri Becquerel Université de Rouen IRIB Rouen France Department of Experimental Diagnostic and Specialty Medicine Bologna University Medical School Bologna Italy Department of Biomolecular Strategies Genetics Avant-Garde Therapies and Neurosciences (SBGN) Euro-Mediterranean Institute of Science and Technology (IEMEST) Palermo Italy School of Health Department of Pathology Jomo Kenyatta University of Agriculture and Technology Nairobi Kenya University of Texas MD Anderson Cancer Center Houston TX Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY Cedars-Sinai Medical Center Division of Hematology/Oncology UCLA School of Medicine Los Angeles CA

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive, male-biased (>3:1 M:F) hematologic malignancy in which some patients have bone marrow involvement at diagnosis (50%) and most have tumor formation in the skin (~90%), often preceding marrow disease. The prognosis is poor (median survival of 12-24 months) and there is unmet need for biological insight. TET2 , ASXL1 , and RNA splicing genes (SRSF2 , SF3B1 , and ZRSR2 ) are recurrently mutated in BPDCN. The X chromosome gene ZRSR2 was the most frequently mutated spliceosome gene reported in a prior BPDCN cohort (7 of 24, 29.2%; Taylor, ASH 2013). Our goal was to define the functional consequences of ZRSR2 mutations in BPDCN. First, we confirmed the frequency of ZRSR2 mutations in a larger cohort from the US and Europe; we found ZRSR2 mutations in 24 of 93 (25.8%). Notably, ZRSR2 mutations were almost exclusively in males (23/73 males vs 1/20 females, P=0.019). Next, we compared the global mutation pattern to 30 predefined signatures from >7000 cancers in COSMIC. Analysis of all somatic single nucleotide variants in 11 tumor-normal pairs using whole exome sequencing (tumor was sorted BPDCN cells from marrow) revealed that BPDCN had an ultraviolet (UV)-induced mutation signature (score >0.25 in 6/11 or 55%; Figure 1A). For comparison, we detected the UV signature in melanoma but not in AML from The Cancer Genome Atlas. These data suggest that mutations acquired in the skin stage of BPDCN evolution are retained in subsequent leukemic disease. Next, we performed RNA-sequencing from sorted BPDCN and normal plasmacytoid dendritic cells (pDCs). Differentially expressed genes between BPDCN and pDCs (BCL2 , MYB , IRF4 , CEP70 , IGLL1 , GZMB ) were similar to those that distinguish BPDCNs from pDCs by bulk and single cell RNA-sequencing. By gene set enrichment analysis (GSEA), BPDCNs were enriched for overexpression of MYC/E2F targets and PI3K/AKT/MTORC1 signaling pathway-associated genes. BPDCNs transcriptom

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Wait, but Tylenol is Acetaminophen… Investigating and Improving Language Models' Ability to Resist Requests for Misinformation

arXiv

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arXiv 2024年

作者： Chen Gao, Mingye Sasse, Kuleen Hartvigsen, Tom Anthony, Brian Fan, Lizhou Aerts, Hugo Gallifant, Jack Bitterman, Danielle Program Mass General Brigham Harvard Medical School BostonMA United States Department of Radiation Oncology Brigham and Women’s Hospital Dana-Farber Cancer Institute BostonMA United States Computational Health Informatics Program Boston Children’s Hospital Harvard Medical School BostonMA United States Massachusetts Institute of Technology CambridgeMA United States Johns Hopkins University BaltimoreMD United States Department of Data Science University of Virginia CharlottesvilleVA United States Radiology and Nuclear Medicine GROW & CARIM Maastricht University Netherlands

Background: Large language models (LLMs) are trained to follow directions, but this introduces a vulnerability to blindly comply with user requests even if they generate wrong information. In medicine, this could accelerate the generation of misinformation that impacts human well-being. Objectives/Methods: We analyzed compliance to requests to generate misleading content about medications in settings where models know the request is illogical. We investigated whether in-context directions and instruction-tuning of LLMs to prioritize logical reasoning over compliance reduced misinformation risk. Results: While all frontier LLMs complied with misinformation requests, both prompt-based and parameter-based approaches can improve the detection of logic flaws in requests and prevent the dissemination of medical misinformation. Conclusion: Shifting LLMs to prioritize logic over compliance could reduce risks of exploitation for medical misinformation. © 2024, CC BY-NC-ND.

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