Cold Spring Harbor perspectives in medicine最新文献

{"title":"Host Cell Death Signaling Pathways Manipulated by <i>Mycobacterium tuberculosis</i>.","authors":"Guanchao Ding, Volker Briken","doi":"10.1101/cshperspect.a041824","DOIUrl":"10.1101/cshperspect.a041824","url":null,"abstract":"<p><p><i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) induces necrotic cell death of infected macrophages, which contributes to tissue necrosis and the progressive loss of lung function during tuberculosis. <i>Mtb</i> can induce multiple forms of programmed necrosis, including necroptosis, pyroptosis and ferroptosis. Concurrently, <i>Mtb</i> also inhibits apoptosis to prevent a host-beneficial cell death response. This paper will first provide an overview of the programmed cell death pathways relevant to <i>Mtb</i> infection. It will then discuss how <i>Mtb</i> activates and manipulates these pathways under different conditions, including a comparison of the findings across mouse, human, and zebrafish-derived macrophages.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13532543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α-Synuclein Biomarkers for Parkinson's Disease.","authors":"Alexandra Lodge, Julian Agin-Liebes","doi":"10.1101/cshperspect.a041944","DOIUrl":"10.1101/cshperspect.a041944","url":null,"abstract":"<p><p>α-Synuclein (α-syn) biomarkers show great promise as diagnostic tools for Parkinson's disease (PD). In recent years, a large body of evidence has validated their efficacy as diagnostic tools for PD and other synucleinopathies and has shown potential for use in patients with isolated prodromal symptoms of PD, such as rapid eye movement (REM) sleep behavior disorder and hyposmia, and further illuminates the pathophysiology of both idiopathic and genetic causes. Various detection methods have been deployed, predominantly immunohistochemistry and α-syn seed amplification assays. α-Syn has been shown to be detectable in many different tissues and biofluids in PD patients, each with benefits and limitations for practical use. α-Syn biomarker studies have shown sensitivities for diagnosis of PD and specificity against healthy controls up to 100%. However, lack of standardization of methods of detection currently limits interlaboratory validation of results. Verification of these assays could lead to more widespread inclusion of these modalities to detect α-syn into biological definitions of PD and provide frameworks for developing disease-modifying therapies. In this review, we discuss the current state of α-syn biomarkers and highlight their potential use in clinical practice and research settings, while identifying further work that is needed in this field.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12863175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental Modeling of Childhood Cancers.","authors":"Kosuke Funato, Viviane Tabar","doi":"10.1101/cshperspect.a041711","DOIUrl":"10.1101/cshperspect.a041711","url":null,"abstract":"<p><p>Growing evidence indicates that childhood cancer is a developmental disease and the oncogenic impact of mutations depends on spatiotemporal developmental contexts. This dependency leads to distinct molecular, genetic, and clinical characteristics across various cancer (sub)types. However, the underlying molecular mechanisms of tumorigenesis are not fully understood, and the development of precision medicine for childhood cancers is still an ongoing effort, partially due to their relative rarity. Therefore, it is crucial to develop and use \"developmental models\" that replicate both mutations and specific developmental contexts that determine their impact. In this review, we summarize recent advances in the growing field of developmental modeling of childhood cancers, which enhance our understanding of the pathogenic mechanisms and pave the way for the development of new therapeutic approaches.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12863174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effector Functions of Conventional and Unconventional <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>)-Specific T Cells.","authors":"Sudhasini Panda, Kendall Kearns, Cecilia S Lindestam Arlehamn","doi":"10.1101/cshperspect.a041829","DOIUrl":"10.1101/cshperspect.a041829","url":null,"abstract":"<p><p>Effector T cells are central to immune defense against <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), exerting complex and multifaceted roles that contribute to both protection and immunopathology. CD4⁺ T cells activate macrophages, maintain granulomas, and coordinate broad immune functions through diverse subsets, including cytokine-producing, cytotoxic, and regulatory cells. CD8⁺ T cells target infected cells through cytolytic activity and cytokine secretion, while unconventional T cells provide rapid, innate-like responses, particularly at mucosal sites. Recent advances in single-cell and spatial transcriptomics have revealed heterogeneity, functional plasticity, and spatial compartmentalization among T-cell subsets. Tissue-resident memory T cells in the lung parenchyma have emerged as key predictors of protective immunity. These insights are reshaping our understanding of T-cell-mediated control of <i>Mtb</i> and highlight the limitations of interferon (IFN)-γ-centric vaccine strategies. Future strategies must aim to elicit a broader range of T-cell responses, promote effective tissue localization, enhance polyfunctionality, and overcome regulatory or exhaustion-associated dysfunctions.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12863182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145437281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Management of Parkinson's Disease: Features, Diagnosis, and Principles of Treatment.","authors":"Bhavana Patel, Ashley Rawls, Tracy Tholanikunnel, Michael S Okun","doi":"10.1101/cshperspect.a041638","DOIUrl":"10.1101/cshperspect.a041638","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive, neurological syndrome that is associated with a plethora of motor and nonmotor symptoms. Recognizing prodromal symptoms and diagnosing PD early and accurately as well as employing timely management strategies targeting motor and nonmotor symptoms across all disease stages will have the potential to improve clinical outcomes. The application of critical advances in the field including the development of biomarkers, pharmacological treatments, exercise, and surgical therapies will be important for clinical practitioners. In this review, we will address differential diagnoses and disease mimics, as well as provide critical updates on clinical diagnosis and management strategies.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12863183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monogenic Type 1 Diabetes: A High Yield Pool in Which to Discover New Mechanisms and Candidate Therapeutics for Type 1 Diabetes.","authors":"Chester E Chamberlain, Michael S German, Louis H Philipson, Mark S Anderson","doi":"10.1101/cshperspect.a041601","DOIUrl":"10.1101/cshperspect.a041601","url":null,"abstract":"<p><p>Rare monogenic forms of disease provide a unique opportunity to understand novel pathways in human biology. With the rapid advances in genomics and next-generation sequencing, we now have the tools to interrogate the genomes of patients on a large scale to identify candidate genes in patients with rare monogenic forms of type 1 diabetes (T1D). These cases are more likely to represent genetic defects in critical pathways of immune tolerance, and the study of these patients provides a high-yield pool in which to discover new mechanisms of disease in T1D. These studies are also expected to have high translational impact for the T1D community by helping to identify at-risk individuals and provide compelling candidate targets for prevention and treatment.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12863179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Security in the Lithotroph of Microbiology-A Commentary.","authors":"James M Welch","doi":"10.1101/cshperspect.a041950","DOIUrl":"10.1101/cshperspect.a041950","url":null,"abstract":"<p><p>This article is a requested personal commentary for this project based on my 20+ years of experience working nationally and globally in the advocacy of safe research and the promotion of biosafety and biosecurity. Although neither a scientist nor a professional practitioner of biosafety or biosecurity, I have probably participated in more training programs and more national and international forums on the topic than the vast majority of those who manage or regulate laboratory safety. The commentary relies on my personal history that includes assisting others to develop national and regional biosafety associations globally as well as the International Federation of Biosafety Associations. I have been an invited participant and speaker in meetings with organizations and agencies such as the U.S. National Academies of Science, American Association for the Advancement of Science, U.S. National Institutes of Health, World Health Organization, U.S. Centers for Disease Control, World Bank, INTERPOL, CBRNE, Prince Mahidol Award Conference, World Organisation for Animal Health, CORDS, World Science Forum, U.S. Department of State, U.S. Department of Agriculture-ARS, and the Asia-Pacific Economic Cooperative. I have served as an elected member of the American Biological Safety Association (ABSA) International Council and served as the first chair of the Global Health Security Agenda Consortium. I am a recipient of the John H. Richardson Award from ABSA International, an honorary member of the Association of Primate Veterinarians and am a member of the International Veterinary Biosafety Working Group. Unlike other contributors to this body of work, I am neither a biosafety/biosecurity professional nor a microbiologist. In fact, I am not even a scientist. What I am-and how I am best known nationally and globally-is a faithful advocate of responsible, safe, and secure research. From the beginning of my 20-year career as the executive director of the Elizabeth R. Griffin Foundation until my retirement from full-time work in 2019, I traveled the United States and every continent except Australia promoting safe science to those within the research world and as an advocate for the importance of that world to those not within it.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12758136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zebrafish Models for Drug Discovery and Therapeutic Validation against Non-Tuberculous Mycobacteria.","authors":"Matt D Johansen, Claire Hamela, Yi Ding, Laurent Kremer","doi":"10.1101/cshperspect.a041832","DOIUrl":"10.1101/cshperspect.a041832","url":null,"abstract":"<p><p>The incidence of non-tuberculous mycobacteria (NTM) is increasing globally, often surpassing the incidence of new tuberculosis (TB) cases in developed countries. Most NTM are environmental organisms; however, there are a number of opportunistic and pathogenic species that can cause severe infections in animals and humans. Many NTM are intrinsically resistant to anti-TB therapies and are incredibly difficult to treat, resulting in poor treatment outcomes for these patients. Recent advances in preclinical animal models such as the zebrafish models have led to the discovery of highly active antimicrobial and host-directed therapies (HDTs) targeting NTM infections that can be applied to treat human infections. Here, we summarize recent progress and technological advancements in the discovery and development of antimicrobial drugs and HDTs that have been applied to NTM zebrafish infection models. We highlight the future directions for this increasingly applicable animal model for the discovery of next-generation therapies to treat NTM diseases.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12758143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Mitochondrial Connection in Parkinson's Disease.","authors":"Eric Schon, Diana Matheoud, Serge Przedborski","doi":"10.1101/cshperspect.a041891","DOIUrl":"10.1101/cshperspect.a041891","url":null,"abstract":"<p><p>Mitochondria are highly dynamic organelles with complex structural features that perform several essential cellular functions, including energy production by oxidative phosphorylation, regulation of calcium and lipid homeostasis, and control of programmed cell death. Given their critical role, alterations in mitochondrial biology can lead to neuronal dysfunction and death. Defects in mitochondrial respiration, especially in oxidative energy production, have long been thought to be implicated in the etiology and pathogenesis of Parkinson's disease. However, given the multifaceted roles of mitochondria in health and diseases, the putative role of mitochondria in Parkinson's disease likely extends well beyond defective respiration. As such, mitochondrial dysfunction represents a promising target for disease-modifying therapies in Parkinson's disease and related conditions.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12758148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Environmental Factors in Type 1 Diabetes.","authors":"Heikki Hyöty, Jutta E Laiho, Suvi M Virtanen","doi":"10.1101/cshperspect.a041590","DOIUrl":"10.1101/cshperspect.a041590","url":null,"abstract":"<p><p>The contribution of environmental factors to the pathogenesis of type 1 diabetes is considered substantial, but their identification has turned out to be challenging. Large prospective studies are crucial for reliable identification of environmental risk and protective factors. However, only few large prospective birth cohort studies have been carried out. Enterovirus infections have shown quite consistent risk association with the initiation of islet autoimmunity (IA) across these studies. Also, certain dietary factors have been consistently associated with IA risk, omega-3 fatty acids inversely, and childhood cow's milk intake directly. However, the mechanisms of these associations are not fully understood, and possible causality has not been confirmed. Clinical trial programs with enterovirus vaccines and antiviral drugs are in progress to evaluate the causality of enterovirus association. The only nutritional primary prevention randomized trial, TRIGR, did not find a difference between weaning to extensively hydrolyzed versus conventional cow's milk-based infant formula.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12758145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}