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The pathogenic mechanisms of many diseases are well understood at the molecular level, but there are prevalent syndromes associated with pathogenic signaling, such as diabetes and chronic inflammation, where our understanding is more limited. Here, we report that pathogenic signaling suppresses the mobility of a spectrum of proteins that play essential roles in cellular functions known to be dysregulated in these chronic diseases. The reduced protein mobility, which we call proteolethargy, was linked to cysteine residues in the affected proteins and signaling-related increases in excess reactive oxygen species. Diverse pathogenic stimuli, including hyperglycemia, dyslipidemia, and inflammation, produce similar reduced protein mobility phenotypes. We propose that proteolethargy is an overlooked cellular mechanism that may account for various pathogenic features of diverse chronic diseases. 

Abstract Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin’s role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches. 

Abstract The Maritime Continent (MC) is a low-latitude chokepoint of the world oceans with the Indonesian throughflow (ITF) linking the Indo-Pacific oceans, influencing global ocean circulation, climate, and biogeochemistry. While previous studies suggested that South-China-Sea freshwaters north of the MC intruding the Indonesian Seas weaken the ITF during boreal winter, the impact of the MC water cycle on the ITF has not been investigated. Here we use ocean-atmosphere-land satellite observations to reveal the dominant contribution of the MC monsoonal water cycle to boreal winter−spring freshening in the Java Sea through local precipitation and runoff from Kalimantan, Indonesia. We further demonstrate that the freshening corresponds to a reduced southward pressure gradient that would weaken the ITF. Therefore, the MC water cycle plays a critical role regulating ITF seasonality. The findings have strong implications to longer-term variations of the ITF associated with the variability and change of Indo-Pacific climate and MC water cycle. 

Recent results using wind and sea surface temperature data from satellites and high-resolution coupled models suggest that mesoscale ocean–atmosphere interactions affect the locations and evolution of storms and seasonal precipitation over continental regions such as the western US and Europe. The processes responsible for this coupling are difficult to verify due to the paucity of accurate air–sea turbulent heat and moisture flux data. These fluxes are currently derived by combining satellite measurements that are not coincident and have differing and relatively low spatial resolutions, introducing sampling errors that are largest in regions with high spatial and temporal variability. Observational errors related to sensor design also contribute to increased uncertainty. Leveraging recent advances in sensor technology, we here describe a satellite mission concept, FluxSat, that aims to simultaneously measure all variables necessary for accurate estimation of ocean–atmosphere turbulent heat and moisture fluxes and capture the effect of oceanic mesoscale forcing. Sensor design is expected to reduce observational errors of the latent and sensible heat fluxes by almost 50%. FluxSat will improve the accuracy of the fluxes at spatial scales critical to understanding the coupled ocean–atmosphere boundary layer system, providing measurements needed to improve weather forecasts and climate model simulations.