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Diurnal timing of physical activity in relation to obesity and diabetes in the German National Cohort (NAKO)
Physical activity supports weight regulation and metabolic health, but its timing in relation to obesity and diabetes remains unclear. We aimed to assess the diurnal timing of physical activity and its association with obesity and diabetes.
Regulation of mammalian cellular metabolism by endogenous cyanide production
Small, gaseous molecules such as nitric oxide, carbon monoxide and hydrogen sulfide are produced as signalling molecules in mammalian cells. Here, we show that low concentrations of cyanide are generated endogenously in various mammalian tissues and cells. We detect cyanide in several cellular compartments of human cells and in various tissues and the blood of mice. Cyanide production is stimulated by glycine, occurs at the low pH of lysosomes and requires peroxidase activity. When generated at a specific rate, cyanide exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism and cell proliferation, but impairs cellular bioenergetics at high concentrations. Cyanide can modify cysteine residues via protein S-cyanylation, which is detectable basally in cells and mice, and increases in response to glycine. Low-dose cyanide supplementation exhibits cytoprotective effects in hypoxia and reoxygenation models in vitro and in vivo. Conversely, pathologically elevated cyanide production in nonketotic hyperglycinaemia is detrimental to cells. Our findings indicate that cyanide should be considered part of the same group of endogenous mammalian regulatory gasotransmitters as nitric oxide, carbon monoxide and hydrogen sulfide.
Genetically encoded biosensor for fluorescence lifetime imaging of PTEN dynamics in the intact brain
The phosphatase and tensin homolog (PTEN) is a vital protein that maintains an inhibitory brake for cellular proliferation and growth. Accordingly, PTEN loss-of-function mutations are associated with a broad spectrum of human pathologies. Despite its importance, there is currently no method to directly monitor PTEN activity with cellular specificity within intact biological systems. Here we describe the development of a FRET-based biosensor using PTEN conformation as a proxy for the PTEN activity state, for two-photon fluorescence lifetime imaging microscopy. We identify a point mutation that allows the monitoring of PTEN activity with minimal interference to endogenous PTEN signaling. We demonstrate imaging of PTEN activity in cell lines, intact Caenorhabditis elegans and in the mouse brain. Finally, we develop a red-shifted sensor variant that allows us to identify cell-type-specific PTEN activity in excitatory and inhibitory cortical cells. In summary, our approach enables dynamic imaging of PTEN activity in vivo with unprecedented spatial and temporal resolution.
Real-time observation of picosecond-timescale optical quantum entanglement towards ultrafast quantum information processing
Entanglement is a fundamental resource for various optical quantum information processing (QIP) applications. To achieve high-speed QIP systems, entanglement should be encoded in short wavepackets. Here we report the real-time observation of ultrafast optical Einstein–Podolsky–Rosen correlation at a picosecond timescale in a continuous-wave system. Optical phase-sensitive amplification using a 6-THz-bandwidth waveguide-based optical parametric amplifier enhances the effective efficiency of 70-GHz-bandwidth homodyne detectors, mainly used in 5G telecommunication, enabling its use in real-time quantum state measurement. Although power measurement using frequency scanning, such as an optical spectrum analyser, is not performed in real time, our observation is demonstrated through the real-time amplitude measurement and can be directly used in QIP applications. The observed Einstein–Podolsky–Rosen states show quantum correlation of 4.5 dB below the shot-noise level encoded in wavepackets with 40 ps period, equivalent to 25 GHz repetition—103 times faster than previous entanglement observation in continuous-wave systems. The quantum correlation of 4.5 dB is already sufficient for several QIP applications, and our system can be readily extended to large-scale entanglement. Moreover, our scheme has high compatibility with optical communication technology such as wavelength-division multiplexing, and femtosecond-timescale observation is also feasible. Our demonstration is a paradigm shift in accelerating accessible quantum correlation—the foundational resource of all quantum applications—from the nanosecond to picosecond timescales, enabling ultrafast optical QIP.
Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging
Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer’s, retinal degeneration and/or atherosclerosis. However, sex-specific and cell-type-specific differences in CMA with aging remain unexplored. Here, using CMA reporter mice and single-cell transcriptomic data, we report that most organs and cell types show CMA decline with age, with males exhibiting a greater decline with aging. Reduced CMA is often associated with fewer lysosomes competent for CMA. Transcriptional downregulation of CMA genes may further contribute to CMA decline, especially in males. These findings suggest that CMA differences may influence organ vulnerability to age-related degeneration.
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