Recursion (United States)

Neuroinflammation has emerged as a dynamic and multifactorial process that is central to both normal brain aging and the progression of A systems-level framework, combining longitudinal profiling, network biology, and hormonal analysis, will be crucial to unravel how sex, glial cell dynamics, and environmental inputs interact to shape complex neuroinflammatory outcomes. Such mechanistic understanding will guide the design of targeted interventions and preventative strategies tailored to the distinct neurobiological needs of aging men and women.

Low testosterone in males (hypogonadism) is associated with limb muscle mass loss, yet the underlying mechanisms of muscle mass loss remain largely unknown. We previously showed androgen deprivation disrupted limb muscle molecular clock function, and the disruption coincided with elevated levels of the primary molecular clock suppressor, Period 2 (Per2). The purposes herein were to determine if PER2 overexpression leads to muscle atrophy and if preventing PER2 accumulation blunts limb muscle mass loss in response to androgen deprivation. Here, we identify Per2 as a negative regulator of muscle size. Overexpression of Per2 in differentiated C2C12 myotubes reduced myotube diameter, while deletion of Per2 in male mice partially preserved tibialis anterior (TA) mass following castration. The muscle-sparing effect of Per2 deletion in vivo was specific to the TA despite evidence of molecular clock disruption and mass loss in other muscles. Subsequently, we show overexpression of the other primary clock suppressor, Period 1 (Per1) also reduced myotube diameter in differentiated C2C12 myotubes. Mechanistically, both Per1 and Per2 overexpression in vitro induced muscle atrophy in part by an autocrine-mediated mechanism likely involving inflammation as their overexpression induced an inflammatory gene expression signature and increased cytokine/chemokine secretion. Moreover, incubation of C2C12 myotubes in the media conditioned from Per1 or Per2 overexpressing myotubes reduced myotube diameter. Several inflammatory genes identified in vitro were also altered in the limb muscles in response to androgen deprivation. These findings identify a previously unrecognized role for Per1/2 in regulating skeletal muscle mass with implications for muscle loss during hypogonadism.

Clinical and biological information in large datasets of gene expression across cancers could be tapped with unsupervised deep learning. However, difficulties associated with biological interpretability and methodological robustness have made this impractical. Here we describe an unsupervised deep-learning framework for the generation of low-dimensional latent spaces for gene-expression data from 50,211 transcriptomes across 18 human cancers. The framework, which we named DeepProfile, outperformed dimensionality-reduction methods with respect to biological interpretability and allowed us to unveil that genes that are universally important in defining latent spaces across cancer types control immune cell activation, whereas cancer-type-specific genes and pathways define molecular disease subtypes. By linking latent variables in DeepProfile to secondary characteristics of tumours, we discovered that mutation burden is closely associated with the expression of cell-cycle-related genes, and that the activity of biological pathways for DNA-mismatch repair and MHC class II antigen presentation are consistently associated with patient survival. We also found that tumour-associated macrophages are a source of survival-correlated MHC class II transcripts. Unsupervised learning can facilitate the discovery of biological insight from gene-expression data.

Parkinson's disease (PD) is a chronic, neurodegenerative condition characterized by motor symptoms such as bradykinesia, rigidity, and tremor, alongside multiple nonmotor symptoms. The appearance of motor symptoms is linked to progressive dopaminergic neuron loss within the substantia nigra. PD incidence increases sharply with age, suggesting a strong association between mechanisms driving biological aging and the development and progression of PD. However, the role of aging in the pathogenesis of PD remains understudied. Numerous models of PD, including cell models, toxin-induced models, and genetic models in rodents and nonhuman primates (NHPs), reproduce different aspects of PD, but preclinical studies of PD rarely incorporate age as a factor. Studies using patient neurons derived from stem cells via reprogramming methods retain some aging features, but their characterization, particularly of aging markers and reproducibility of neuron type, is suboptimal. Investigation of age-related changes in PD using animal models indicates an association, but this is likely in conjunction with other disease drivers. The biggest barrier to drawing firm conclusions is that each model lacks full characterization and appropriate time-course assessments. There is a need to systematically investigate whether aging increases the susceptibility of mouse, rat, and NHP models to develop PD and understand the role of cell models. We propose that a significant investment in time and resources, together with the coordination and sharing of resources, knowledge, and data, is required to accelerate progress in understanding the role of biological aging in PD development and improve the reliability of models to test interventions.

Approximately 20 TP53 retrogenes exist in the African and Asian elephant genomes (Loxodonta Africana, Elephas Maximus) in addition to a conserved TP53 gene that encodes a full-length protein. Elephant TP53-RETROGENE 9 (TP53-R9) encodes a p53 protein (p53-R9) that is truncated in the middle of the canonical DNA binding domain. This C-terminally truncated p53 retrogene protein lacks the nuclear localization signals and oligomerization domain of its full-length counterpart. When expressed in human osteosarcoma cells (U2OS), p53-R9 binds to Tid1, the chaperone protein responsible for mitochondrial translocation of human p53 in response to cellular stress. Tid1 expression is required for p53-R9-induced apoptosis. At the mitochondria, p53-R9 binds to the pro-apoptotic BCL-2 family member Bax, which leads to caspase activation, cytochrome c release, and cell death. Our data show, for the first time, that expression of this truncated elephant p53 retrogene protein induces apoptosis in human cancer cells. Understanding the molecular mechanism by which the additional elephant TP53 retrogenes function may provide evolutionary insight that can be utilized for the development of therapeutics to treat human cancers.

Abstract Vitiligo is an autoimmune disease that results in destruction of skin melanocytes and patches of white skin and hair. Family studies of vitiligo demonstrated that a strong, but complex genetic component underlies disease risk and that vitiligo often occurs with other autoimmune diseases, suggesting shared autoimmune susceptibility. Genome‐wide linkage and association studies have identified over 50 vitiligo susceptibility loci, with most loci harbouring genes involved in immune regulation, apoptosis or melanocyte function. The identified loci fit together in a model of melanocyte‐directed autoimmunity, and many loci are shared with other autoimmune diseases. Surprisingly, some genetic vitiligo susceptibility alleles are inversely associated with melanoma, suggesting that vitiligo may represent enhanced immune surveillance against melanoma. Genetic studies of vitiligo have greatly advanced understanding of vitiligo pathobiology and may additionally provide insights into melanoma and other autoimmune disease.Key ConceptsVitiligo is an autoimmune disease in which destruction of skin melanocytes results in patches of white skin and hair.Vitiligo heritability is approximately 80% in Caucasians, about two‐thirds attributable to common genetic variants and one‐third to rarer variation.Vitiligo risk in both familial and sporadic cases follows a polygenic additive model, principally involving common risk alleles as well as unknown environmental triggers.Over 50 loci have been genetically associated with vitiligo, principally in Caucasian populations, though several exhibit trans‐ethnic association with vitiligo in other populations.Most vitiligo‐associated loci encode components of the immune system or proteins involved in melanogenesis; some of the latter comprise vitiligo autoantigens. Together, these provide a possible framework for vitiligo pathogenesis.Vitiligo is epidemiologically associated with several other autoimmune diseases, and nearly half of vitiligo‐associated loci are also associated with these other diseases. Though themajor histocompatibility complex(MHC) is associated with most of these diseases, in vitiligo principal MHC association appears to be regulatory rather than protein coding.Some loci that encode melanocyte proteins exhibit inverse association between vitiligo and melanoma and other skin cancers, suggesting that vitiligo may represent dysregulated immune surveillance against melanoma.