Therapeutic methods to modulate skin pigmentation has important implications for skin cancer prevention and for treating meta-inflammatory-triggered cutaneous conditions. Modulators of cAMP signalling of melanocyte have met with minimal clinical efficacy. Towards defining new potential targets, we followed temporal dynamics orchestrating melanocyte differentiation by using a cell-autonomous pigmentation model. Our study elucidates three dominant phases of synchronized metabolic and transcriptional reprogramming. The induction phase is concomitant with a paradoxical decrease in MITF levels, reduced proliferation, and increased anabolic metabolism mediated by AKT phosphorylation. The melanogenic phase shows rapid uptake of glucose and fatty acid, transiently forming lipid droplets through SREBF1-mediated regulation of fatty acid metabolism. This heightened bioenergetic activity impairs mitochondria and the recovery phase is marked by a shift to aerobic glycolysis and activation of the NRF2 detoxication pathway. Finally, we show that inhibitors of lipid metabolism indeed resolve hyper-pigmentary conditions in a guinea pig UV-tanning model. Our studies reveal metabolic control mechanisms of melanocytes that could govern the balance between differentiation and proliferation in a variety of cutaneous diseases.
Breakthrough infections with SARS-CoV-2 Delta variant have been reported in vaccine recipients and in individuals infected with previous variants. Studies of viral spread within hospital settings have highlighted the potential for transmission between patients and health care workers, and highlighted the benefits of high-grade respiratory protection for health care workers. However the extent to which vaccination is preventative of viral spread in health care settings is less well studies. We here analyse data from health care workers in two hospitals in India, constructing probable transmission networks from epidemiological and virus genome sequence data using a suite of computational approaches. A maximum likelihood reconstruction of transmission involving known cases of infection suggests a high probability that doubly vaccinated health care workers transmitted SARS-CoV-2 between each other, and highlights potential cases of virus transmission between individuals who had received two doses of vaccine. Our findings support the need for ongoing infection control measures even in highly vaccinated populations.
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