Cold Spring Harbor perspectives in medicine最新文献

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.

Parkinson's disease (PD) is a complex genetic disorder that is associated with environmental risk factors and aging. Vertebrate genetic models, especially in mice, has aided the study of autosomal-dominant and autosomal-recessive PD. Mice are capable of exhibiting a broad range of phenotypes and coupled with their conserved genetic and anatomical structures provides unparalleled molecular and pathological tool to model human disease. These models used in combination with aging and PD-associated toxins have expanded our understanding of PD pathogenesis. Attempts to refine PD animal models using conditional approaches have yielded in vivo nigrostriatal degeneration that is instructive in ordering pathogenic signaling and in developing therapeutic strategies to cure or halt the disease. α-Synuclein preformed fibril (PFF) injections, which induce the aggregation of endogenous α-synuclein, remarkably recapitulate pathological processes observed in human PD. Here, we provide an overview of the generation and characterization of transgenic and knockout mice and the α-synuclein PFF models used to study PD followed by molecular insights that have been gleamed these PD mouse models.

Cancer cells undergo changes in metabolism that distinguish them from non-malignant tissue. These may provide a growth advantage by promoting oncogenic signaling and redirecting intermediates to anabolic pathways that provide building blocks for new cellular components. Cancer metabolism is far from uniform, however, and recent work has shed light on its heterogenity within and between tumors. This work is also revealing how cancer metabolism adapts to the tumor microenvironment, as well as ways in which we may capitalize on metabolic changes in cancer cells to create new therapies.

Mycobacterium tuberculosis thrives inside macrophages by modulating intracellular pathways and adapting to various lung environments. Here, we first describe how the bacillus alters phagosome maturation, endures intracellular pressure, and obtains essential nutrients. These mechanisms have been primarily defined in cell lines and macrophage models derived from monocytes. However, recent findings regarding macrophage biology suggest that such intracellular processes might differ depending on the origin and surrounding local environment. For this reason, we then examine how different cell origins and lung niches affect infection dynamics, focusing on alveolar and interstitial macrophages, which exhibit unique metabolic and immunological characteristics. Finally, we emphasize newly identified interstitial macrophage subsets related to nerves and blood vessels, whose functions in tuberculosis are mostly unexplored but could signify potential new research opportunities. Altogether, this review highlights that a better understanding of the ontogeny and location of a macrophage is as important as comprehending its microbicidal programs in the fight against tuberculosis, by merging intracellular cellular processes with cell origin and spatial context.

The fungal kingdom includes a large set of species with pathogenic potential for humans, plants, and wildlife. Whereas threats from the fungal kingdom to agriculture are appreciated, the potential of fungi to threaten humans, animals, ecosystems, and infrastructure is often unappreciated. Fungal disease and mold damage often follow natural disasters. The threats from the fungal kingdom are amplified by the relative paucity of countermeasures, which includes few antifungal drugs and fungicides and an increasing prevalence of resistance to both. Anthropomorphic climate change resulting in global warming is expected to increase the likelihood and potential number of threats from the fungal kingdom. Preparation against fungal threats requires continued investments in basic research to understand the unique aspects of fungal metabolism, development of vaccines, investment in new drugs and fungicides, and a careful mapping of the natural world to identify the existing taxonomic diversity and their potential for harm.

Research in the last few decades has brought us closer to an understanding of the brain circuit abnormalities that underlie parkinsonian motor signs. This article summarizes the current knowledge in this rapidly emerging field. Traditional observations of activity changes of basal ganglia neurons that accompany akinesia and bradykinesia have been supplemented with new knowledge regarding specific pathophysiologic changes that are associated with other parkinsonian signs, such as tremor and gait impairments. New research also emphasizes the role of non-basal ganglia structures in parkinsonism, including the pedunculopontine nucleus, the cerebellum, and the cerebral cortex, and the role of structural and functional neuroplasticity. A more detailed understanding of the brain network abnormalities that result from Parkinson's disease is necessary to arrive at more effective and specific treatments for these symptoms in parkinsonian patients through circuit interventions reaching from deep brain stimulation to genetic and chemogenetic treatments.

Since the publication of our article "Dopamine Cell-Based Replacement Therapies" (Kayhanian and Barker. 2025. Cold Spring Harb Perspect Med doi:10.1101/cshperspect.a041611), three significant studies have published results that are important to the progress of the field of dopamine cell-based replacement therapies. In this addendum, we provide an update and short commentary on these results.