Stable isotope-assisted untargeted metabolomics identifies ALDH1A1-driven erythronate accumulation in lung cancer cells

Using an untargeted stable isotope-assisted metabolomics approach, we identify erythronate as a metabolite that accumulates in several human cancer cell lines. Erythronate has been reported to be a detoxification product derived from off-target glycolytic metabolism. We use chemical inhibitors and genetic silencing to define the pentose phosphate pathway intermediate erythrose 4-phosphate (E4P) as the starting substrate for erythronate production. However, following enzyme assay-coupled protein fractionation and subsequent proteomics analysis, we identify aldehyde dehydrogenase 1A1 (ALDH1A1) as the predominant contributor to erythrose oxidation to erythronate in cell extracts. Through modulating ALDH1A1 expression in cancer cell lines, we provide additional support. We hence describe a possible alternative route to erythronate production involving the dephosphorylation of E4P to form erythrose, followed by its oxidation by ALDH1A1. Finally, we measure increased erythronate concentrations in tumors relative to adjacent normal tissues from lung cancer patients. These findings suggest the accumulation of erythronate to be an example of metabolic reprogramming in cancer cells, raising the possibility that elevated levels of erythronate may serve as a biomarker of certain types of cancer

Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state

Idiopathic Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, but the exact disease etiology remains largely unknown. To date, Parkinson's disease research has mainly focused on nigral dopaminergic neurons, although recent studies suggest disease-related changes also in non-neuronal cells and in midbrain regions beyond the substantia nigra. While there is some evidence for glial involvement in Parkinson's disease, the molecular mechanisms remain poorly understood. The aim of this study was to characterize the contribution of all cell types of the midbrain to Parkinson's disease pathology by single-nuclei RNA sequencing and to assess the cell type-specific risk for Parkinson's disease employing the latest genome-wide association study. We profiled >41 000 single-nuclei transcriptomes of postmortem midbrain from six idiopathic Parkinson's disease patients and five age-/sex-matched controls. To validate our findings in a spatial context, we utilized immunolabeling of the same tissues. Moreover, we analyzed Parkinson's disease-associated risk enrichment in genes with cell type-specific expression patterns. We discovered a neuronal cell cluster characterized by CADPS2 overexpression and low TH levels, which was exclusively present in IPD midbrains. Validation analyses in laser-microdissected neurons suggest that this cluster represents dysfunctional dopaminergic neurons. With regard to glial cells, we observed an increase in nigral microglia in Parkinson's disease patients. Moreover, nigral idiopathic Parkinson's disease microglia were more amoeboid, indicating an activated state. We also discovered a reduction in idiopathic Parkinson's disease oligodendrocyte numbers with the remaining cells being characterized by a stress-induced upregulation of S100B. Parkinson's disease risk variants were associated with glia- and neuron-specific gene expression patterns in idiopathic Parkinson's disease cases. Furthermore, astrocytes and microglia presented idiopathic Parkinson's disease-specific cell proliferation and dysregulation of genes related to unfolded protein response and cytokine signaling. While reactive patient astrocytes showed CD44 overexpression, idiopathic Parkinson's disease-microglia revealed a pro-inflammatory trajectory characterized by elevated levels of IL1B, GPNMB, and HSP90AA1. Taken together, we generated the first single-nuclei RNA sequencing dataset from the idiopathic Parkinson's disease midbrain, which highlights a disease-specific neuronal cell cluster as well as 'pan-glial' activation as a central mechanism in the pathology of the movement disorder. This finding warrants further research into inflammatory signaling and immunomodulatory treatments in Parkinson's disease

Multipurpose silicon photonics signal processor core

[EN] Integrated photonics changes the scaling laws of information and communication systems offering architectural choices that combine photonics with electronics to optimize performance, power, footprint, and cost. Application-specific photonic integrated circuits, where particular circuits/chips are designed to optimally perform particular functionalities, require a considerable number of design and fabrication iterations leading to long development times. A different approach inspired by electronic Field Programmable Gate Arrays is the programmable photonic processor, where a common hardware implemented by a two-dimensional photonic waveguide mesh realizes different functionalities through programming. Here, we report the demonstration of such reconfigurable waveguide mesh in silicon. We demonstrate over 20 different functionalities with a simple seven hexagonal cell structure, which can be applied to different fields including communications, chemical and biomedical sensing, signal processing, multiprocessor networks, and quantum information systems. Our work is an important step toward this paradigm.J.C. acknowledges funding from the ERC Advanced Grant ERC-ADG-2016-741415 UMWP-Chip, I.G. acknowledges the funding through the Spanish MINECO Ramon y Cajal program. D.P. acknowledges financial support from the UPV through the FPI predoctoral funding scheme. D.J.T. acknowledges funding from the Royal Society for his University Research Fellowship.Pérez-López, D.; Gasulla Mestre, I.; Crudgington, L.; Thomson, DJ.; Khokhar, AZ.; Li, K.; Cao, W.... (2017). Multipurpose silicon photonics signal processor core. Nature Communications. 8(1925):1-9. https://doi.org/10.1038/s41467-017-00714-1S1981925Doerr, C. R. & Okamoto, K. Advances in silica planar lightwave circuits. J. 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Reexamining the effect of gustatory disgust on moral judgment: A multi-lab direct replication of Eskine, Kacinik, and Prinz (2011)

Tufts University Faculty Research Awar

Acute effects of fine particulate air pollution on ST segment height: A longitudinal study

Background The mechanisms for the relationship between particulate air pollution and cardiac disease are not fully understood. Air pollution-induced myocardial ischemia is one of the potentially important mechanisms. Methods We investigate the acute effects and the time course of fine particulate pollution (PM2.5) on myocardium ischemic injury as assessed by ST-segment height in a community-based sample of 106 healthy non-smokers. Twenty-four hour beat-to-beat electrocardiogram (ECG) data were obtained using a high resolution 12-lead Holter ECG system. After visually identifying and removing all the artifacts and arrhythmic beats, we calculated beat-to-beat ST-height from ten leads (inferior leads II, III, and aVF; anterior leads V3 and V4; septal leads V1 and V2; lateral leads I, V5, and V6,). Individual-level 24-hour real-time PM2.5 concentration was obtained by a continuous personal PM2.5 monitor. We then calculated, on a 30-minute basis, the corresponding time-of-the-day specific average exposure to PM2.5 for each participant. Distributed lag models under a linear mixed-effects models framework were used to assess the regression coefficients between 30-minute PM2.5 and ST-height measures from each lead; i.e., one lag indicates a 30-minute separation between the exposure and outcome. Results The mean (SD) age was 56 (7.6) years, with 41% male and 74% white. The mean (SD) PM2.5 exposure was 14 (22) μg/m3. All inferior leads (II, III, and aVF) and two out of three lateral leads (I and V6), showed a significant association between higher PM2.5 levels and higher ST-height. Most of the adverse effects occurred within two hours after PM2.5 exposure. The multivariable adjusted regression coefficients β (95% CI) of the cumulative effect due to a 10 μg/m3 increase in Lag 0-4 PM2.5 on ST-I, II, III, aVF and ST-V6 were 0.29 (0.01-0.56) μV, 0.79 (0.20-1.39) μV, 0.52 (0.01-1.05) μV, 0.65 (0.11-1.19) μV, and 0.58 (0.07-1.09) μV, respectively, with all p < 0.05. Conclusions Increased PM2.5 concentration is associated with immediate increase in ST-segment height in inferior and lateral leads, generally within two hours. Such an acute effect of PM2.5 may contribute to increased potential for regional myocardial ischemic injury among healthy individuals

Precision Measurement of the Boron to Carbon Flux Ratio in Cosmic Rays from 1.9 GV to 2.6 TV with the Alpha Magnetic Spectrometer on the International Space Station

Knowledge of the rigidity dependence of the boron to carbon flux ratio (B/C) is important in understanding the propagation of cosmic rays. The precise measurement of the B/C ratio from 1.9 GV to 2.6 TV, based on 2.3 million boron and 8.3 million carbon nuclei collected by AMS during the first 5 years of operation, is presented. The detailed variation with rigidity of the B/C spectral index is reported for the first time. The B/C ratio does not show any significant structures in contrast to many cosmic ray models that require such structures at high rigidities. Remarkably, above 65 GV, the B/C ratio is well described by a single power law R[superscript Δ] with index Δ=-0.333±0.014(fit)±0.005(syst), in good agreement with the Kolmogorov theory of turbulence which predicts Δ=-1/3 asymptotically.National Science Foundation (U.S.) (Grants 1455202 and 1551980)Wyle Research (Firm) (Grant 2014/T72497)United States. National Aeronautics and Space Administration (NASA Earth and Space Science Fellowship Grant HELIO15F-0005

Antiproton Flux, Antiproton-to-Proton Flux Ratio, and Properties of Elementary Particle Fluxes in Primary Cosmic Rays Measured with the Alpha Magnetic Spectrometer on the International Space Station

International audienceA precision measurement by AMS of the antiproton flux and the antiproton-to-proton flux ratio inprimary cosmic rays in the absolute rigidity range from 1 to 450 GV is presented based on 3.49 × 105antiproton events and 2.42 × 109 proton events. The fluxes and flux ratios of charged elementary particlesin cosmic rays are also presented. In the absolute rigidity range ∼60 to ∼500 GV, the antiproton ¯p, protonp, and positron eþ fluxes are found to have nearly identical rigidity dependence and the electron e− fluxexhibits a different rigidity dependence. Below 60 GV, the ( ¯ p=p), ( ¯ p=eþ), and (p=eþ) flux ratios eachreaches a maximum. From ∼60 to ∼500 GV, the ( ¯ p=p), ( ¯ p=eþ), and (p=eþ) flux ratios show no rigiditydependence. These are new observations of the properties of elementary particles in the cosmos

Electron and positron fluxes in primary cosmic rays measured with the alpha magnetic spectrometer on the international space station

Precision measurements by the Alpha Magnetic Spectrometer on the International Space Station of the primary cosmic-ray electron flux in the range 0.5 to 700 GeV and the positron flux in the range 0.5 to 500 GeV are presented. The electron flux and the positron flux each require a description beyond a single power-law spectrum. Both the electron flux and the positron flux change their behavior at &sim;30GeV but the fluxes are significantly different in their magnitude and energy dependence. Between 20 and 200 GeV the positron spectral index is significantly harder than the electron spectral index. The determination of the differing behavior of the spectral indices versus energy is a new observation and provides important information on the origins of cosmic-ray electrons and positrons.</p