Cold Spring Harbor perspectives in medicine最新文献

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.

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.

Tuberculosis (TB) continues to pose a significant global health challenge. An estimated quarter of the world's population has a TB infection (TBI) with an immune response to Mycobacterium tuberculosis (Mtb) without clinical, microbiological, or radiological signs of TB disease. Individuals with TBI have a lifelong risk of reactivation, leading to TB disease in 5%-10% of cases during a lifetime. Current diagnostic tools, including interferon-γ release assays and skin tests, are endorsed by the World Health Organization (WHO) for identifying TBI and guiding preventive therapy. This paper outlines existing diagnostic methods for TBI and explores emerging experimental approaches, focused on detecting circulating bacillary components-such as DNA, mycobacterial proteins, peptides, lipoglycans, and lipoprotein antigens. The development of diagnostic tools that target bacillary elements directly-rather than relying solely on antigen-specific immune responses-could help overcome key limitations of current immunodiagnostic assays, thus offering viable alternatives or complementary solutions. However, these new experimental assays are still under research and not yet validated for clinical use.

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.

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.

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.

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.

The term "basal ganglia" refers to a group of interconnected subcortical nuclei engaged in motor planning and movement initiation, executive functions, behaviors, and emotions. Dopamine released from the substantia nigra is the underlying driving force keeping the basal ganglia network under proper equilibrium and, indeed, reduction of dopamine levels triggers basal ganglia dysfunction, setting the groundwork for several movement disorders. The canonical basal ganglia model has been instrumental for most of our current understanding of the normal and pathological functioning of this subcortical network. This model explains how cortical information flows through the basal ganglia nuclei back to the cortex by going through two pathways with opposing effects that together lead to the proper execution of a given movement. The basal ganglia model has paved the way for the standard clinical management of Parkinson's disease, where pharmacological and neurosurgical treatments in place collectively afford an impressive symptomatic alleviation. Although much of the model has remained, the canonical model has been enriched with new arrivals gathered from evidence provided in the last three decades. Here, we sought to provide a comprehensive review of the basal ganglia network, with emphasis on structure, connectivity patterns, and basic operational principles, both in normal and pathological conditions.

Rapidly proliferating cells, including cancer cells, adapt metabolism to meet the increased energetic and biosynthetic demands of cell growth and division. Many rapidly proliferating cells exhibit increased glucose consumption and fermentation regardless of oxygen availability, a phenotype termed aerobic glycolysis or the Warburg effect in cancer. Several explanations for why cells engage in aerobic glycolysis and how it supports proliferation have been proposed, but none can fully explain all conditions and data where aerobic glycolysis is observed. Nevertheless, there is convincing evidence that the Warburg effect is important for the proliferation of many cancers, and that inhibiting either glucose uptake or fermentation can impair tumor growth. Here, we discuss what is known about metabolism associated with aerobic glycolysis and the evidence supporting various explanations for why aerobic glycolysis may be important in cancer and other contexts.

Over the past thousand years, one can observe a preponderance of evidence demonstrating the emergence and application of safety principles progressing from a crude beginning to the modern era in all human accomplishments. For more than a thousand years, we have seen evidence of the application of safety principles, albeit primitive compared to those of today, for a reasonable approach to accomplish a task. The limited knowledge available in the past, along with a comparative lack of resources, did not deter these early investigators from adapting their thought processes to create solutions to the problems of their day. Notwithstanding their limited knowledge and lack of resources, these early investigators were able to apply their thought processes to reach a goal. Collectively, their practices, experimental results, and findings provided the foundation for the evolution of the disciplines of microbiology, epidemiology, public health, and safety, and eventually biosafety. Many contributions were made in decontamination methodologies and technologies and the use of protective clothing, engineering controls, vaccine development, food preservation, infection control, aseptic practices, and containment. It is wonderful to learn what germs have taught us! This paper provides an overview of historical safety and biosafety events and how they have both influenced and contributed to the development of modern principles and practices.