The endoplasmic reticulum(ER) is a multifunctional organelle within which protein folding, lipid biosynthesis, and calcium storage occurs. Perturbations such as energy or nutrient depletion, disturbances in calcium or redox status that disrupt ER homeostasis lead to the misfolding of proteins, ER stress and up-regulation of several signaling pathways coordinately called the unfolded protein response (UPR). The UPR is characterized by the induction of chaperones, degradation of misfolded proteins and attenuation of protein translation. The UPR plays a fundamental role in the maintenance of cellular homeostasis and thus is central to normal physiology. However, sustained unresolved ER stress leads to apoptosis. Aging linked declines in expression and activity of key ER molecular chaperones and folding enzymes compromise proper protein folding and the adaptive response of the UPR. One mechanism to explain age associated declines in cellular functions and age-related diseases is a progressive failure of chaperoning systems. In many of these diseases, proteins or fragments of proteins convert from their normally soluble forms to insoluble fibrils or plaques that accumulate in a variety of organs including the liver, brain or spleen. This group of diseases, which typically occur late in life includes Alzheimer's, Parkinson's, type II diabetes and a host of less well known but often equally serious conditions such as fatal familial insomnia. The UPR is implicated in many of these neurodegenerative and familial protein folding diseases as well as several cancers and a host of inflammatory diseases including diabetes, atherosclerosis, inflammatory bowel disease and arthritis. This review will discuss age-related changes in the ER stress response and the role of the UPR in age-related diseases.

The human body at cellular resolution: the NIH Human Biomolecular Atlas Program HuBMAP consortium* Transformative technologies are enabling the construction of three-dimensional maps of tissues with unprecedented spatial and molecular resolution. Over the next seven years, the NIH Common Fund Human Biomolecular Atlas Program (HuBMAP) intends to develop a widely accessible framework for comprehensively mapping the human body at singlecell resolution by supporting technology development, data acquisition, and detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies, programs, consortia, and the biomedical research community at large towards the shared vision of a comprehensive, accessible three-dimensional molecular and cellular atlas of the human body, in health and under various disease conditions. t he human body is an incredible machine. Trillions of cells, organized across an array of spatial scales and a multitude of functional states, contribute to a symphony of physiology. While we broadly know how cells are organized in most tissues, a comprehensive understanding of the cellular and molecular states and interactive networks resident in the tissues and organs, from organizational and functional perspectives, is lacking. The specific three-dimensional organization of different cell types, together with the effects of cell-cell and cell-matrix interactions in their natural milieu, have a profound impact on normal function, natural ageing, tissue remodelling, and disease progression in different tissues and organs. Recently, new technologies have enabled the molecular characterization of a multitude of cell types 1-4 and mapping of their spatial relationships in complex tissues at unprecedented scale and single-cell resolution. These advances create the opportunity to build a high-resolution atlas of three-dimensional maps of human tissues and organs. HuBMAP (https://commonfund.nih.gov/hubmap) is an NIHsponsored program with the goals of developing an open framework and technologies for mapping the human body at cellular resolution as well as generating foundational maps for several tissues obtained from normal individuals across a wide range of ages. A previous NIH-sponsored project, GTEx 5 , examined DNA variants and bulk tissue expression patterns across approximately a thousand individuals, but HuBMAP is a distinct project focused on generating molecular maps that are spatially resolved at the single-cell level but using samples from a more limited number of people. To achieve these goals, HuBMAP has been designed as a cohesive and collaborative organization, with a culture of openness and sharing using team science-based approaches 6. The HuBMAP Consortium (https://hubmapconsortium.org/) will actively work with other ongoing initiatives including the Human Cell Atlas 7 , Human Protein Atlas 8 , LIfeTime (https://lifetime-fetflagship.eu/), and related NIH-funded consortia that are mapping specific organs (including the brain 9 , lungs (https://www.lungmap.net/), kidney (https...

Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses-ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation-are mediated in a time of day-dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, "Sleep Insufficiency, Circadian Misalignment, and the Immune Response," to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential. This Review summarizes topics discussed and highlights immediate opportunities for delineating clinically relevant connections among biological rhythms, sleep, and immune regulation. Circadian rhythms are daily variations in behavior and biological activity that stem from an intrinsic ability of organisms to align themselves with the environmental 24-hour light/dark cycle. These rhythms originate from an internal biological clock that drives many aspects of human physiology, including the sleepwake cycle and daily variations in blood pressure, body temperature, and cortisol (1). A growing body of epidemiological evidence demonstrates an association between altering circadian timing through shift work or frequent time zone travel and increased rates of cardiovascular disorders, metabolic syndrome, and cancer (2-4). Clinical aspects of disease such as pain perception, asthma exacerbations, and myocardial infarctions are more common at certain times of day or night (5, 6). The discovery of the genetic basis for the circadian clock in the 1980s and 1990s has ushered in a new era in which long-appreciated circadian rhythms in physiology and clinical medicine are being reframed in terms of gene expression, metabolism, signal transduction, and cellular physiology (7). The translation of circadian discovery into strategies to improve the prevention and management of disease promises to be transformative, but at present, fundamental research is outpacing clinical application (Figure 1A). Much will depend on research identifying the critical mechanisms and targets to which circadian rhythm-based therapeutic strategies can be applied. An emerging example of exciting circadian discovery with potential clinical relevance is the intersection between circadian function and immune regulation (Figure 1B). The NIH recently sponsored a workshop entitled "Sleep Insufficiency, Circadian Misalignment, and the Immune Response" (May 16-17, 2019, Rockville, Maryland, USA). Its aim was to highlight basic and clinical advances linking sleep and circadian biology to immune dysfunction, thereby stimulating the application of circadian biology to translational medicine. The Workshop was cosponsored by four NIH institutes-the National Heart, Lung, and Blood Institute (NHLBI), National Institute on Aging (NIA), National Institute of Allergy and Infectious Diseases (NIAID), and National Institute on Alcohol Abuse and Alcoholism (NIAAA)-reflecting a...

No abstract