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Regulatory T cells constrain T cells of shared specificity to enforce tolerance during infection

Science (New York, N.Y.) 2025年第6740期387卷 eadk3248页

作者： Klawon, David E J Pagane, Nicole Walker, Matthew T. Ganci, Nicole K. Miller, Christine H. Gai, Eric Rodriguez, Donald M. Ryan-Payseur, Bridgett K. Duncombe, Ryan K. Adams, Erin J. Maienschein-Cline, Mark Freitag, Nancy E. Germain, Ronald N. Wong, Harikesh S. Savage, Peter A. Department of Pathology University of Chicago Chicago IL United States Ragon Institute of Mass General MIT and Harvard Cambridge MA United States Program in Computational and Systems Biology Massachusetts Institute of Technology Cambridge MA United States Interdisciplinary Scientist Training Program University of Chicago Chicago IL United States Department of Microbiology and Immunology University of Illinois Chicago Chicago IL United States Department of Biochemistry and Molecular Biology University of Chicago Chicago IL United States Research Informatics Core Research Resources Center University of Illinois Chicago Chicago IL United States Department of Pharmaceutical Sciences University of Illinois Chicago Chicago IL United States Lymphocyte Biology Section Laboratory of Immune System Biology National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD United States Department of Biology Massachusetts Institute of Technology Cambridge MA United States

During infections, CD4+ Foxp3+ regulatory T (Treg) cells must control autoreactive CD4+ conventional T (Tconv) cell responses against self-peptide antigens while permitting those against pathogen-derived "nonself" peptides. We defined the basis of this selectivity using mice in which Treg cells reactive to a single prostate-specific self-peptide were selectively depleted. We found that self-peptide-specific Treg cells were dispensable for the control of Tconv cells of matched specificity at homeostasis. However, they were required to control such Tconv cells and prevent autoimmunity toward the prostate after exposure to elevated self-peptide during infection. Notably, the Treg cell response to self-peptide did not affect protective Tconv cell responses to a pathogen-derived peptide. Thus, self-peptide-specific Treg cells promoted self-nonself discrimination during infection by selectively controlling Tconv cells of shared self-specificity.

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Lyra: An Efficient and Expressive Subquadratic Architecture for Modeling Biological Sequences

arXiv

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arXiv 2025年

作者： Ramesh, Krithik Siddiqui, Sameed M. Gu, Albert Mitzenmacher, Michael D. Sabeti, Pardis C. Broad Institute of MIT and Harvard CambridgeMA02142 United States Massachusetts Institute of Technology CambridgeMA02139 United States Computational and Systems Biology Program Massachusetts Institute of Technology CambridgeMA02139 United States Machine Learning Department Carnegie Mellon University PittsburgPA15213 United States School of Engineering and Applied Sciences Harvard University CambridgeMA02138 United States Department of Organismic and Evolutionary Biology Harvard University CambridgeMA02138 United States Department of Immunology and Infectious Diseases Harvard T.H. Chan School of Public Health Harvard University BostonMA02115 United States Howard Hughes Medical Institute Chevy ChaseMD20815 United States

Deep learning architectures such as convolutional neural networks and Transformers have revolutionized biological sequence modeling, with recent advances driven by scaling up foundation and task-specific models. The computational resources and large datasets required, however, limit their applicability in biological contexts. We introduce Lyra, a subquadratic architecture for sequence modeling, grounded in the biological framework of epistasis for understanding sequence-to-function relationships. Mathematically, we demonstrate that state space models efficiently capture global epistatic interactions and combine them with projected gated convolutions for modeling local relationships. We demonstrate that Lyra is performant across over 100 wide-ranging biological tasks, achieving state-of-the-art (SOTA) performance in many key areas, including protein fitness landscape prediction, biophysical property prediction (e.g. disordered protein region functions) peptide engineering applications (e.g. antibody binding, cell-penetrating peptide prediction), RNA structure analysis, RNA function prediction, and CRISPR guide design. It achieves this with orders-of-magnitude improvements in inference speed and reduction in parameters (up to 120,000-fold in our tests) compared to recent biology foundation models. Using Lyra, we were able to train and run every task in this study on two or fewer GPUs in under two hours, democratizing access to biological sequence modeling at SOTA performance, with potential applications to many fields. © 2025, CC BY-NC-ND.

关键词： Convolutional neural networks

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A Two-Step GRIN Lens Coating for In Vivo Brain Imaging

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Neuroscience Bulletin 2019年第3期35卷 419-424页

作者： Yupeng Yang Lifeng Zhang Zhenni Wang Bo Liang Giovanni Barbera Casey Moffitt Yun Li Da-Ting Lin Hefei National Laboratory for Physical Sciences at the Microscale School of Life SciencesUniversity of Science and Technology of ChinaHefei 230027China Intramural Research Program National Institute on Drug AbuseNational Institutes of HealthBaltimoreMD 21224USA Department of Zoology and Physiology University of Wyoming College of Arts and SciencesLaramieWY 82071USA

The complex spatial and temporal organization of neural activity in the brain is important for informationprocessing that guides behavior. Hence, revealing the realtime neural dynamics in freely-moving animals is fundamental to elucidating brain function. Miniature fluorescence microscopes have been developed to fulfil this requirement. With the help of GRadient INdex(GRIN)lenses that relay optical images from deep brain regions to the surface, investigators can visualize neural activity during behavioral tasks in freely-moving animals. However, the application of GRIN lenses to deep brain imaging is severely limited by their availability. Here, we describe a protocol for GRIN lens coating that ensures successful long-term intravital imaging with commercially-available GRIN lenses.

关键词： Grin lens Coating Toxic Neurodegeneration

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Top 10 Public health Challenges for 2024: Charting a New Direction for Global health Security

Public Health Challenges

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Public health Challenges 2025年第1期4卷

作者： Lucero-Prisno, Don Eliseo Shomuyiwa, Deborah Oluwaseun Kouwenhoven, M.B.N. Dorji, Thinley Adebisi, Yusuff Adebayo Odey, Goodness Ogeyi George, Nsikakabasi Samuel Ajayi, Oluwatomisin Temidayo Ekerin, Olabode Manirambona, Emery Xu, Lin Obnial, Joseph Christian Viola, Adriana Miranda Ogunkola, Isaac Olushola Ahmed, Mohamed Mustaf Ogaya, Jerico B. Huang, Junjie Sium, Abraham Fessehaye Suntay, Marcus Lester R. Chung, William K. De Paz, Pearl Irish V. Elmi, Hassan Sh Abdirahman Hersi, Omar Osman Gabaake, Kebabonye P. Baricaua, Teresita Dirie, Najib Isse Yepes, Prose Ivy G. Wilson, Donald John Tofaeono-Pifeleti, Rossana Tapia, Ederson Delos Trino Wong, Martin CS Department of Global Health and Development London School of Hygiene and Tropical Medicine London United Kingdom Department of Health Promotion and Behavior College of Public Health University of Georgia Athens GA United States Global Health Focus Lagos Nigeria Department of Physics Xi'an Jiaotong-Liverpool University Suzhou China Department of Internal Medicine Central Regional Referral Hospital Gelephu Bhutan College of Social Sciences University of Glasgow Glasgow United Kingdom Department of Health Policy London School of Economics and Political Science (LSE) London United Kingdom School of Medicine and Population Health University of Sheffield Sheffield United Kingdom Institute of Public Health Jagiellonian University Kraków Poland Department of Public Health State AIDS and STIs Control Program Ministry of Health Kaduna Nigeria School of Public Health University of Port Harcourt Port Harcourt Nigeria College of Medicine and Health Sciences University of Rwanda Kigali Rwanda Department of Thoracic Surgery The First Affiliated Hospital School of Medicine Zhejiang University Zhejiang Hangzhou China National Coalition of Independent Scholars Battleboro VT United States Global Health Focus Asia Bandung Indonesia YouthRise Dublin Ireland Faculty of Medicine and Health Sciences SIMAD University Mogadishu Somalia Department of Medical Technology Institute of Health Sciences and Nursing Far Eastern University Manila Philippines The Jockey Club School of Public Health and Primary Care Faculty of Medicine Chinese University of Hong Kong Hong Kong Department of Obstetrics and Gynecology St. Paul's Hospital Millennium Medical College Addis Ababa Ethiopia Office of the President World Surgical Foundation Manila Philippines Department of Biology Krieger School of Arts and Sciences Johns Hopkins University Baltimore MD United States Research and Development Office Biliran Province State University Naval Biliran Philippines Department of Biology Amo

As we navigate the complex landscape of global public health in 2024, this article provides a comprehensive exploration of challenges, ranging from infectious diseases, mental health, and substance use to environmental sustainability and emerging technologies. The aftermath of the COVID-19 pandemic underscores the critical need to strengthen health systems, increase public financing, and foster effective international collaboration. The intricacies of global geopolitics, diplomacy, and public health highlight the importance of countries that do not address shared challenges through enhanced cooperative mechanisms and joint initiatives. From the imperative of global health security to the persistence of non-communicable diseases and health disparities, this study delves into multifaceted issues, advocating for collective action, targeted interventions, and a commitment to prioritizing public health on a global scale. Focusing on addressing root causes and fostering equity, this study emphasizes the role of sustainable practices, community engagement, and intersectionality of research in building a resilient global health landscape. In this dynamic environment, 2024 calls for a unified global vision that encourages nations to collaborate more effectively to build a healthier and more resilient global community, ultimately paving the way for a future characterized by a shared commitment to public health challenges. © 2024 The Author(s). Public health Challenges published by John Wiley & Sons Ltd.

关键词： artificial intelligence climate fund ethics global health health equity pandemic accord technology

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Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation

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Cancer Cell 2025年第5期43卷 891-904.e10页

作者： Teng, Mona Guo, Jiacheng Xu, Xin Ci, Xinpei Mo, Yulin Kohen, Yakup Ni, Zuyao Chen, Sujun Guo, Wang Yuan Bakht, Martin Ku, Shengyu Sigouros, Michael Luo, Wenqin Macarios, Colette Maya Xia, Ziting Chen, Moliang Ul Haq, Sami Yang, Wen Berlin, Alejandro van der Kwast, Theo Ellis, Leigh Zoubeidi, Amina Zheng, Gang Ming, Jie Wang, Yuzhuo Cui, Haissi Lok, Benjamin H. Raught, Brian Beltran, Himisha Qin, Jun He, Housheng Hansen Department of Medical Biophysics Temerty Faculty of Medicine University of Toronto Toronto ON Canada Princess Margaret Cancer Centre University Health Network Toronto ON Canada Shanghai Institute of Nutrition and Health Chinese Academy of Sciences Shanghai China Institute of Medical Science Temerty Faculty of Medicine University of Toronto Toronto ON Canada Division of Medical Oncology Dana Farber Cancer Institute Boston MA United States Englander Institute for Precision Medicine Weill Cornell Medicine New York NY United States Department of Urology Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou China Department of Chemistry University of Toronto Toronto ON Canada Department of Chemical Engineering and Applied Chemistry University of Toronto Toronto ON Canada Department of Breast and Thyroid Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China Center for Prostate Disease Research Murtha Cancer Center Research Program Department of Surgery Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc. Bethesda MD United States Vancouver Prostate Centre Vancouver BC Canada Department of Urologic Sciences Faculty of Medicine University of British Columbia Vancouver BC Canada Radiation Medicine Program Princess Margaret Cancer Centre Toronto ON Canada

Circular RNA (circRNA) is a class of noncoding RNA with regulatory potentials. Its role in the transdifferentiation of prostate and lung adenocarcinoma into neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC) remains unexplored. Here, we identified circRMST as an exceptionally abundant circRNA predominantly expressed in NEPC and SCLC, with strong conservation between humans and mice. Functional studies using shRNA, siRNA, CRISPR-Cas13, and Cas9 consistently demonstrate that circRMST is essential for tumor growth and the expression of ASCL1, a master regulator of neuroendocrine fate. Genetic knockout of Rmst in NEPC genetic engineered mouse models prevents neuroendocrine transdifferentiation, maintaining tumors in an adenocarcinoma state. Mechanistically, circRMST physically interacts with lineage transcription factors NKX2-1 and SOX2. Loss of circRMST induces NKX2-1 protein degradation through autophagy-lysosomal pathway and alters the genomic binding of SOX2, collectively leading to the loss of ASCL1 transcription. © 2025 The Author(s)

关键词： circular RNA lineage plasticity neuroedocrine prostate cancer noncoding RNA RNA protein interactions small cell lung cancer transcription factors

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Discovery of Z1362873773: a novel fascin inhibitor from a large chemical library for colorectal cancer

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Scientific Reports 2025年第1期15卷 1-15页

作者： Rodríguez-Martínez, Alejandro Giraldo-Ruiz, Lucía Ramos, María C. Luque, Irene Ribeiro, Diogo Postigo-Corrales, Fátima Alburquerque-González, Begoña Montoro-García, Silvia Arroyo-Rodríguez, Ana Belén Conesa-Zamora, Pablo Hurtado, Ana María Luengo-Gil, Ginés Pérez-Sánchez, Horacio Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC) UCAM Universidad Católica de Murcia (UCAM) HiTech Innovation Hub Murcia 30107 Spain Departamento de Química Física Instituto de Biotecnología y Unidad de Excelencia de Química aplicada a Biomedicina y Medioambiente Universidad de Granada Campus Fuentenueva s/n Granada 18071 Spain Fundación MEDINA PTS Health Sciences Technology Park Avenida del Conocimiento 34 Granada 18016 Spain Genetics Molecular Pathology and Rare Diseases Research Group Universidad Católica de Murcia (UCAM) Guadalupe 30107 Spain Molecular Pathology and Pharmacogenetics Research Group Instituto Murciano de Investigación Biosanitaria (IMIB) Hospital General Universitario Santa Lucía Cartagena 30202 Spain Health Sciences PhD Program Universidad Católica de Murcia UCAM Campus de los Jerónimos nº135 Guadalupe Murcia 30107 Spain

Metastasis is one of the leading causes of cancer-related death worldwide. Fascin, a protein that bundles actin filaments to produce protrusions in cancer cells, plays a significant role in the enhancement of cell migration. This protein has been shown that the overexpression of this protein is related to the appearance of different types of cancer, such as colorectal cancer. In this study, we conducted in silico screening of the Enamine library, a compound library with a broad chemical space. Using a ligand-based virtual screening approach based on the pharmacophore model of G2, we identified the predicted inhibitors. First, these compounds were validated by physicochemical analysis. Differential scanning calorimetry (DSF) was used to study the binding between the predicted compounds and fascin protein, followed by an F-actin bundling assay to determine which compounds inhibited the bundling function of fascin. Z1362873773, which exhibited binding to fascin and inhibited F-actin bundling, was further tested in cell cultures to assess its effects on cancer cell viability and migration as well as in organoid models to evaluate potential cytotoxicity. Finally, we established a protocol that can be applied to discover anti-fascin agents from diverse compound libraries. A new molecule has been identified with considerable fascin inhibitory and migration-arresting capacity, which may lead to the development of new therapies to treat cancer. © The Author(s) 2025.

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AI-driven 3D Spatial Transcriptomics

arXiv

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arXiv 2025年

作者： Almagro-Pérez, Cristina Song, Andrew H. Weishaupt, Luca Kim, Ahrong Jaume, Guillaume Williamson, Drew F.K. Hemker, Konstantin Lu, Ming Y. Singh, Kritika Chen, Bowen Le, Long Phi Baras, Alexander S. Jiang, Sizun Bashashati, Ali Liu, Jonathan T.C. Mahmood, Faisal Department of Pathology Mass General Brigham 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 Harvard-MIT Division of Health Sciences and Technology Massachusetts Institute of Technology CambridgeMA United States Department of Pathology Pusan National University Busan Korea Republic of Department of Pathology and Laboratory Medicine Emory University School of Medicine AtlantaGA United States Department of Computer Science & Technology University of Cambridge Cambridge United Kingdom Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology CambridgeMA United States Rutgers Robert Wood Johnson Medical School New BrunswickNJ United States Department of Pathology Johns Hopkins Hospital BaltimoreMD United States Department of Biomedical Engineering Johns Hopkins Hospital BaltimoreMD United States Broad Institute of Harvard and MIT CambridgeMA United States Center for Virology and Vaccine Research Beth Israel Deaconess Medical Center Harvard Medical School BostonMA United States Department of Pathology Dana Farber Cancer Institute BostonMA United States Department of Pathology and Laboratory Medicine University of British Columbia VancouverBC Canada School of Biomedical Engineering University of British Columbia VancouverBC Canada Department of Mechanical Engineering Bioengineering Laboratory Medicine & Pathology University of Washington SeattleWA United States Harvard Data Science Initiative Harvard University CambridgeMA United States

A comprehensive three-dimensional (3D) map of tissue architecture and gene expression is crucial for illuminating the complexity and heterogeneity of tissues across diverse biomedical applications1. However, most spatial transcriptomics (ST) approaches remain limited to two-dimensional (2D) sections of tissue2–4. Although current 3D ST methods hold promise, they typically require extensive tissue sectioning, are complex, are not compatible with non-destructive 3D tissue imaging technologies, and often lack scalability5–8. Here, we present VOlumetrically Resolved Transcriptomics EXpression (VORTEX), an AI framework that leverages 3D tissue morphology and minimal 2D ST to predict volumetric 3D ST. By pretraining on diverse 3D morphology–transcriptomic pairs from heterogeneous tissue samples and then fine-tuning on minimal 2D ST data from a specific volume of interest, VORTEX learns both generic tissue-related and sample-specific morphological correlates of gene expression. This approach enables dense, high-throughput, and fast 3D ST, scaling seamlessly to large tissue volumes far beyond the reach of existing 3D ST techniques. By offering a cost-effective and minimally destructive route to obtaining volumetric molecular insights, we anticipate that VORTEX will accelerate biomarker discovery and our understanding of morphomolecular associations and cell states in complex tissues. Interactive 3D ST volumes can be viewed at https://***/. © 2025, CC BY-NC-ND.

关键词： Vortex flow

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Impact of bilirubin molecular species on mortality in patients with acute on chronic liver failure (ACLF).

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Annals of Hepatology 2025年 30卷 101883-101883页

作者： Castañeda-Castillo, Stephany M. Cordova-Gallardo, Jacqueline Rivera-Espinosa, Liliana Chavez-Pacheco, Juan L. Ramírez-Mejía, Mariana M. Méndez-Sánchez, Nahum Liver Research Unit Medica Sur Clinic & Foundation Mexico City Mexico City Mexico Medical Dental and Health Sciences Master and Doctorate Program National Autonomous University of Mexico Department of Hepatology General Hospital Dr. Manuel Gea González Mexico Faculty of Medicine National Autonomous University of Mexico Pharmacology Department National Institute of Pediatrics Mexico Plan of Combined Studies in Medicine (PECEM-MD/PhD) Faculty of Medicine National Autonomous University of Mexico

Introduction and ObjectivesAcute-on-chronic liver failure (ACLF) represents a serious and potentially life-threatening complication in patients with chronic liver disease. This condition is characterized by a rapid deterioration of liver function in patients with pre-existing chronic liver disease. Among the numerous biomarkers used to assess the severity and prognosis of ACLF, serum bilirubin has emerged as a key indicator of liver dysfunction and clinical deterioration. This study aims to analyze the performance of molecular bilirubin species, such as unconjugated (UCB), monoglucuronide (BMG) and diglucuronide bilirubin (BDG), and their impact on mortality in individuals with ACLF. Materials and PatientsThe study included 45 patients with ACLF of various etiologies. The diagnosis was made using the European Association for the Study of the Liver (EASL-CLIF) consortium definition. Clinical and laboratory data were collected to determine severity and assess mortality during the 90 days following enrollment. Bilirubin was extracted from serum samples to measure UCB, BMG, and BDG by liquid chromatography-mass spectrometry (LC-MS). The quantification of bilirubin was performed by monitoring the mass charge (m/z) ratio. ResultsOf the 45 patients, 40% (n=18) were categorized as ACLF grade 1, 35.5% (n=16) as ACLF grade 2, and 17.7% (n=8) as ACLF grade 3. Regarding the molecular species of bilirubin, it was observed that the values of UCB, BMG, and BDG increased according to the severity of ACLF, specifically those of BMG (p=0.019). Additionally, it was observed that individuals who died had higher levels of BDG (4.49 vs. 1.17), BMG (64.30 vs. 28.57), and UCB (21.92 vs. 16.99) with respect to individuals who remained alive. ConclusionsIn conclusion, our findings reveal an association between BDG, BMG and UCB levels and ACLF severity, suggesting that the suggest that molecular bilirubin species could be useful as prognostic markers in patients with ACLF. However, further st

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Robustness and stability of spin-glass ground states to perturbed interactions

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Physical Review E 2023年第1期107卷 014126-014126页

作者： Vaibhav Mohanty Ard A. Louis Rudolf Peierls Centre for Theoretical Physics University of Oxford Oxford OX1 3NP United Kingdom MD-PhD Program and Program in Health Sciences and Technology Harvard Medical School Boston Massachusetts 02125 USA and Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA

Across many problems in science and engineering, it is important to consider how much the output of a given system changes due to perturbations of the input. Here, we investigate the glassy phase of ±J spin glasses at zero temperature by calculating the robustness of the ground states to flips in the sign of single interactions. For random graphs and the Sherrington-Kirkpatrick model, we find relatively large sets of bond configurations that generate the same ground state. These sets can themselves be analyzed as subgraphs of the interaction domain, and we compute many of their topological properties. In particular, we find that the robustness, equivalent to the average degree, of these subgraphs is much higher than one would expect from a random model. Most notably, it scales in the same logarithmic way with the size of the subgraph as has been found in genotype-phenotype maps for RNA secondary structure folding, protein quaternary structure, gene regulatory networks, as well as for models for genetic programming. The similarity between these disparate systems suggests that this scaling may have a more universal origin.

关键词： Degree correlations Mutation Network structure Scaling laws of complex systems Real world networks Spin glasses

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Reporting quality of systematic review protocols in environmental and occupational toxicology: a meta-epidemiology study protocol

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Evidence-Based Toxicology 2025年第1期3卷

作者： Milica D. Pavlovic Malgorzata Lagisz Natália B. Videira Julia M. L. Menon Gunn E. Vist Elma Omeragic Rebecca L. Morgan Sebastian Hoffmann Evidence-Based Toxicology Collaboration Human Toxicology Program Graduate College University of Iowa Iowa City IA USA Evolution and Ecology Research Centre and School of Biological Earth and Environmental Sciences University of New South Wales Sydney NSW AustraliaTheoretical Sciences Visiting Program Okinawa Institute of Science and Technology Graduate University Onna Japan Affygility Solutions Broomfield CO USA Preclinicaltrials.eu Netherlands Heart Institute Utrecht the Netherlands Division of Health Services Norwegian Institute of Public Health Oslo Norway University of Sarajevo Faculty of Pharmacy University of Sarajevo Sarajevo Bosnia and Herzegovina School of Medicine Case Western Reserve University Cleveland OH USADepartment of Health Research Evidence and Impact McMaster University Hamilton ON Canada Evidence-Based Toxicology Collaboration (EBTC) Johns Hopkins University Bloomberg School of Public Health Baltimore MD USA John Hopkins Bloomberg School of Public Health John Hopkins University Baltimore MD USA

BackgroundSystematic reviews (SR), an evidence-synthesis tool, have been increasingly used in toxicology, for regulatory decision-making and allocation of research funding resources. A critical domain of methodological quality is publicly available in the SR protocol that describes the review methods prior to the review. Earlier work showed that only a small number of published SRs in environmental health had identifiable protocols, but did not evaluate their completeness of reporting. Thus, there is a critical need to assess the number of protocols published in peer-reviewed literature related to environmental/occupational toxicology and how much those SR protocols adhere to current reporting standards such as *** overarching objective of this review is to assess the reporting quality of SR protocols in environmental and occupational toxicology, published in peer-reviewed *** and analysisThis protocol has been reported following PRISMA-P and PRISMA-S checklist and study selection, data extraction, and reporting quality assessment were piloted by independent reviewers. Four electronic databases (PubMed, Scopus, Web of Science, EMBASE) were selected and will be searched for SR protocols using pre-defined strings. Both title/abstract and full-text screening will follow detailed eligibility criteria based on the population concept context (PCC) framework. We will include peer-reviewed, self-identified SR protocols that aim to assess the adverse effects of environmental and occupational exposures. We will perform data extraction using the form that includes general bibliographic information, exposure, adverse effect information, evidence streams, and guidelines/checklists used in protocol reporting or development. A reporting assessment form consisting of 15 PRISMA-P-based items, of which eleven with identical binary responses (reported vs not reported) address critical elements of SR protocol. Assessments of the eleven quality items will

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