HAND2 is an ancestral regulator of heart development and one of four transcription factors that control the reprogramming of fibroblasts into cardiomyocytes. Deletion of Hand2 in mice results in ...right ventricle hypoplasia and embryonic lethality. Hand2 expression is tightly regulated by upstream enhancers that reside within a super-enhancer delineated by histone H3 acetyl Lys27 (H3K27ac) modifications. Here we show that transcription of a Hand2-associated long non-coding RNA, which we named upperhand (Uph), is required to maintain the super-enhancer signature and elongation of RNA polymerase II through the Hand2 enhancer locus. Blockade of Uph transcription, but not knockdown of the mature transcript, abolished Hand2 expression, causing right ventricular hypoplasia and embryonic lethality in mice. Given the substantial number of uncharacterized promoter-associated long non-coding RNAs encoded by the mammalian genome, the Uph-Hand2 regulatory partnership offers a mechanism by which divergent non-coding transcription can establish a permissive chromatin environment.
Micropeptides function as master regulators of calcium-dependent signaling in muscle. Sarco/endoplasmic reticulum Ca
ATPase (SERCA), the membrane pump that promotes muscle relaxation by taking up Ca
...into the sarcoplasmic reticulum, is directly inhibited by three muscle-specific micropeptides: myoregulin (MLN), phospholamban (PLN), and sarcolipin (SLN). The widespread and essential function of SERCA across diverse cell types has raised questions as to how SERCA is regulated in cells that lack MLN, PLN, and SLN. We identified two transmembrane micropeptides, endoregulin (ELN) and another-regulin (ALN), that share key amino acids with their muscle-specific counterparts and function as direct inhibitors of SERCA pump activity. The distribution of transcripts encoding ELN and ALN mirrored that of SERCA isoform-encoding transcripts in nonmuscle cell types. Our findings identify additional members of the SERCA-inhibitory micropeptide family, revealing a conserved mechanism for the control of intracellular Ca
dynamics in both muscle and nonmuscle cell types.
The tricarboxylic acid （TCA） cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance require- ments. Despite early dogma that ...cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for thera- peutic interventions in various cancer types.
Diet as a whole, encompassing food composition, calorie intake, and the length and frequency of fasting periods, affects the time span in which health and functional capacity are maintained. Here, we ...analyze aging and nutrition studies in simple organisms, rodents, monkeys, and humans to link longevity to conserved growth and metabolic pathways and outline their role in aging and age-related disease. We focus on feasible nutritional strategies shown to delay aging and/or prevent diseases through epidemiological, model organism, clinical, and centenarian studies and underline the need to avoid malnourishment and frailty. These findings are integrated to define a longevity diet based on a multi-pillar approach adjusted for age and health status to optimize lifespan and healthspan in humans.
Longo and Anderson synthesize and weigh the literature, from molecular mechanisms to epidemiology and spanning yeast to people, about what you should eat, how much you should eat, and when should you eat it to live a long and healthy life.
Astrocyte dysfunction in Alzheimer disease Acosta, Crystal; Anderson, Hope D.; Anderson, Christopher M.
Journal of neuroscience research,
December 2017, Letnik:
95, Številka:
12
Journal Article
For the 2009 influenza A H1N1 pandemic, in most infected people these epidemiological quantities were short with a day or so to infectiousness and a few days of peak infectiousness to others.3 By ...contrast, for COVID-19, the serial interval is estimated at 4·4–7·5 days, which is more similar to SARS.4 First among the important unknowns about COVID-19 is the case fatality rate (CFR), which requires information on the denominator that defines the number infected. ...the effect of seasons on transmission of COVID-19 is unknown;11 however, with an R0 of 2–3, the warm months of summer in the northern hemisphere might not necessarily reduce transmission below the value of unity as they do for influenza A, which typically has an R0 of around 1·1–1·5.12 Closely linked to these factors and their epidemiological determinants is the impact of different mitigation policies on the course of the COVID-19 epidemic. A key issue for epidemiologists is helping policy makers decide the main objectives of mitigation—eg, minimising morbidity and associated mortality, avoiding an epidemic peak that overwhelms health-care services, keeping the effects on the economy within manageable levels, and flattening the epidemic curve to wait for vaccine development and manufacture on scale and antiviral drug therapies. Avoiding large gatherings of people will reduce the number of super-spreading events; however, if prolonged contact is required for transmission, this measure might only reduce a small proportion of transmissions. ...broader-scale social distancing is likely to be needed, as was put in place in China.
Summary
Autoimmune diabetes mellitus is a rare but significant side effect of treatment with immune checkpoint inhibitors. Immune checkpoint inhibitor‐induced diabetes mellitus (CPI‐DM) is ...characterized by acute onset of dramatic hyperglycemia with severe insulin deficiency and occurrence following exposure to programmed cell death‐1/programmed cell death ligand‐1 (PD‐1/PD‐L1) inhibitors rather than cytotoxic T lymphocyte‐associated antigen 4 (CTLA‐4) inhibitors. As a growing number of patients undergo immunotherapy, further understanding of the characteristics of CPI‐DM patients is needed for improved prognostic and diagnostic application in order to reduce overall morbidity for this already at‐risk population. Additionally, understanding of the features and mechanisms of CPI‐DM may contribute to understanding mechanisms of spontaneous type I diabetes mellitus (T1DM). Here, we summarize the clinical features of CPI‐DM and interrogate the genetic and cellular mechanisms that may contribute to the disease, as well as the clinical challenges for predicting and treating these patients as increasing cancer immunotherapies reach clinical utility.
Immune checkpoint inhibitor‐induced diabetes mellitus (CPI‐DM) is characterized by acute onset of dramatic hyperglycemia with severe insulin deficiency and occurrence following exposure to PD‐1/PD‐L1 inhibitors rather than CTLA‐4 inhibitors. Genetic predisposition is likely to play a role, as is a second trigger. Improved understanding of CPI‐DM is needed clinically to reduce overall morbidity and may also contribute to understanding mechanisms of spontaneous T1DM.
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