Cold Spring Harbor perspectives in medicine最新文献

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.

Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells destroying insulin-producing β cells. Identifying the antigenic epitopes targeted by autoreactive T cells is crucial for understanding pathogenesis, detecting biomarkers, and developing immunotherapies. This paper covers T-cell epitopes in T1D, focusing on pre-proinsulin and hybrid insulin peptides (HIPs) as major autoantigens. Substantial evidence highlights epitopes in the insulin B-chain and C-peptide as dominant targets for pathogenic CD4 and CD8 T cells infiltrating the islets. HIPs, formed by proinsulin fragments ligated to other peptides, constitute a novel class of epitopes detected in human and mouse islets. In addition, the paper also examines neoepitopes arising from posttranslational modifications, splice variants, and defective ribosomal products. A key challenge is differentiating genuinely pathogenic epitopes driving disease from nonpathogenic mimotopes. Identifying any essential, indispensable epitopes among this array could enable the development of antigen-specific immunotherapies targeting the root causative factors underlying T1D.

Tuberculosis (TB) is a major cause of disease and death in young children from TB-endemic countries, especially in areas affected by poverty, social disruption, and human immunodeficiency virus (HIV) infection. This article reviews the disease burden and the natural history of disease in children with TB. It also provides guidance regarding the diagnosis, treatment, and prevention of TB in children.

High-grade serous ovarian carcinoma (HGSC) remains an incompletely understood, highly lethal disease. Historically, a lack of fidelitous in vitro and in vivo models representing HGSC biology and therapy response has been a major barrier to progress. As we discuss below, multiple (if not most) early studies used-and some investigators continue to use-human "ovarian cancer cell lines" that lack key genomic/genetic features of HGSC, rendering their conclusions questionable. The frequently deployed ID8 syngeneic mouse model is similarly suspect, as it derives from ovarian surface epithelium (OSE) and is Trp53 wild-type. In contrast, most, if not all, HGSC arises in fallopian tube epithelium (FTE), and bona fide HGSC is universally TP53 mutant or silenced. Over the past 10 years, attempts have been made to rectify these historical deficiencies, including careful assessment of the genetic composition of standard ovarian cancer cell lines and the development of mouse and human organoids, genetically engineered mouse models (GEMMs), and patient-derived xenografts (PDXs). In this review, we discuss these advances, exploring their differences, strengths, and weaknesses. We also describe "next-generation" approaches to more faithfully model HGSC cells in the context of a more realistic tumor microenvironment.

Hematologic malignancies (HMs) have been increasingly recognized in association with an underlying genetic predisposition syndrome (GPS) in individuals of all ages. It is critical for hematology and oncology providers to be aware of the diagnostic findings, physical examination findings, and aspects of family history that raise suspicion for an underlying GPS. Moreover, recognition of how somatic gene panel testing, frequently done at the time of HM diagnosis, may raise suspicion for an underlying germline condition based on the mutation profile reported, is prudent. With knowledge of an underlying germline condition, the chemotherapy used for a given HM may be impacted and the role of hematopoietic stem cell transplant more critically considered. Off-therapy monitoring after HM treatment is completed will also likely be impacted. In this work, we review key features of several GPSs associated with increased risks for HM while also outlining the diagnostic workup to identify GPSs and treatment considerations for affected patients. Armed with this knowledge, treating providers may evaluate the possibility of a GPS in patients with leukemia/lymphoma and modify their treatment plan accordingly.