Theory of Spin Relaxation in Two-Electron Lateral Coupled Quantum Dots

A global quantitative picture of the phonon-induced two-electron spin relaxation in GaAs double quantum dots is presented using highly accurate numerical calculations. Wide regimes of interdot coupling, magnetic field magnitude and orientation, and detuning are explored in the presence of a nuclear bath. Most important, the unusually strong magnetic anisotropy of the singlet-triplet relaxation can be controlled by detuning switching the principal anisotropy axes: a protected state becomes unprotected upon detuning, and vice versa. It is also established that nuclear spins can dominate spin relaxation for unpolarized triplets even at high magnetic fields, contrary to common belief. These findings are central to designing quantum dots geometries for spin-based quantum information processing with minimal environmental impact.Comment: 8 pages, 8 figure

SLC25A51 is a mammalian mitochondrial NAD+ transporter

Mitochondria require nicotinamide adenine dinucleotide (NAD+) to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction. Mitochondrial NAD+ transporters have been identified in yeast and plants1,2, but their existence in mammals remains controversial3,4,5. Here we demonstrate that mammalian mitochondria can take up intact NAD+, and identify SLC25A51 (also known as MCART1)—an essential6,7 mitochondrial protein of previously unknown function—as a mammalian mitochondrial NAD+ transporter. Loss of SLC25A51 decreases mitochondrial—but not whole-cell—NAD+ content, impairs mitochondrial respiration, and blocks the uptake of NAD+ into isolated mitochondria. Conversely, overexpression of SLC25A51 or SLC25A52 (a nearly identical paralogue of SLC25A51) increases mitochondrial NAD+ levels and restores NAD+ uptake into yeast mitochondria lacking endogenous NAD+ transporters. Together, these findings identify SLC25A51 as a mammalian transporter capable of importing NAD+ into mitochondria.acceptedVersio

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Development of fluorogenic substrates for NAD(P)‑Snifits enables the investigation of nicotinamide adenine dinucleotide metabolism in primary neurons

The members of the cofactor family of nicotinamide adenine dinucleotides are involved in many biological processes. New insights about their role in health and disease have highlighted the need to measure these metabolites in live cells. Fluorescent biosensors have been proven to be valuable tools for metabolite measurements with subcellular resolution. Among them, the NAD(P)‑Snifits have been developed to measure free NAD⁺ levels and NADPH/NADP⁺ ratios, respectively. The applicability of these FRET‑based biosensors in physiological relevant model systems is limited by the permeability of the tetramethylrhodamine (TMR)‑based FRET donor substrate and its SNAP‑tag labelling. In this work, fluorogenic FRET donor substrates were developed by manipulating the spirocyclization equilibrium of TMR. Their permeability and cellular SNAP‑tag labelling outperformed early versions of these substrates, especially when they were derivatized with an optimized SPR inhibitor. Systematic characterization selected two FRET donor substrates that could also label the NAD(P)‑Snifits in cultured primary neurons. Consequently, free subcellular NAD⁺ levels and NADPH/NADP⁺ ratios could be measured for the first time in primary neurons. These improvements allowed the comparison of free subcellular NAD⁺ levels and NADPH/NADP⁺ ratios between U2OS cells and primary neurons by FLIM‑FRET measurements. Significant differences were revealed in free mitochondrial NAD⁺ levels and NADPH/NADP⁺ ratios, which could be the result of differences in oxidative phosphorylation activity and have not been described before. In short, this work provides new tools for the quantification of NAD(P) metabolites in physiological relevant model system and thus help to gain new insights into their metabolism

Das Buch vom Teufel : Geschichte, Kult, Erscheinungsformen / Anna Maria Crispino ; Fabio Giovannini ; Marco Zatterin. Aus dem Italien. übers. von Werner Raith

DAS BUCH VOM TEUFEL : GESCHICHTE, KULT, ERSCHEINUNGSFORMEN / ANNA MARIA CRISPINO ; FABIO GIOVANNINI ; MARCO ZATTERIN. AUS DEM ITALIEN. ÜBERS. VON WERNER RAITH Das Buch vom Teufel : Geschichte, Kult, Erscheinungsformen / Anna Maria Crispino ; Fabio Giovannini ; Marco Zatterin. Aus dem Italien. übers. von Werner Raith (1) Einband (1) Vortitelblatt (10) Titelblatt (12) Inhaltsverzeichnis (14) Vorwort (16) I. Die Geographie des Teufels (18) II. Der heilige Teufel (42) III. Der Aufgeklärte Teufel (60) IV. Besessene und Dämonisierte (76) V. Der Gebildete Teufel (92) VI. Der Teufel als Musikant (114) VII. Der Abgebildete Teufel (138) VIII. Der Teufel auf der Bühne (158) IX. Der Teufel auf der Leinwand (178) Bibliographie (194

Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment

The reduction in androgen synthesis and the blockade of the androgen receptor (AR) function by chemical castration and AR signaling inhibitors represent the main treatment lines for the initial stages of prostate cancer. Unfortunately, resistance mechanisms ultimately develop due to alterations in the AR pathway, such as gene amplification or mutations, and also the emergence of alternative pathways that render the tumor less or, more rarely, completely independent of androgen activation. An essential oncogenic axis activated in prostate cancer is the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, as evidenced by the frequent alterations of the negative regulator phosphatase and tensin homolog (PTEN) and by the activating mutations in PI3K subunits. Additionally, crosstalk and reciprocal feedback loops between androgen signaling and the PI3K/AKT/mTOR signaling cascade that activate pro-survival signals and play an essential role in disease recurrence and progression have been evidenced. Inhibitors addressing different players of the PI3K/AKT/mTOR pathway have been evaluated in the clinic. Only a limited benefit has been reported in prostate cancer up to now due to the associated side effects, so novel combination approaches and biomarkers predictive of patient response are urgently needed. Here, we reviewed recent data on the crosstalk between AR signaling and the PI3K/AKT/mTOR pathway, the selective inhibitors identified, and the most advanced clinical studies, with a focus on combination treatments. A deeper understanding of the complex molecular mechanisms involved in disease progression and treatment resistance is essential to further guide therapeutic approaches with improved outcomes

Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment

The reduction in androgen synthesis and the blockade of the androgen receptor (AR) function by chemical castration and AR signaling inhibitors represent the main treatment lines for the initial stages of prostate cancer. Unfortunately, resistance mechanisms ultimately develop due to alterations in the AR pathway, such as gene amplification or mutations, and also the emergence of alternative pathways that render the tumor less or, more rarely, completely independent of androgen activation. An essential oncogenic axis activated in prostate cancer is the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, as evidenced by the frequent alterations of the negative regulator phosphatase and tensin homolog (PTEN) and by the activating mutations in PI3K subunits. Additionally, crosstalk and reciprocal feedback loops between androgen signaling and the PI3K/AKT/mTOR signaling cascade that activate pro-survival signals and play an essential role in disease recurrence and progression have been evidenced. Inhibitors addressing different players of the PI3K/AKT/mTOR pathway have been evaluated in the clinic. Only a limited benefit has been reported in prostate cancer up to now due to the associated side effects, so novel combination approaches and biomarkers predictive of patient response are urgently needed. Here, we reviewed recent data on the crosstalk between AR signaling and the PI3K/AKT/mTOR pathway, the selective inhibitors identified, and the most advanced clinical studies, with a focus on combination treatments. A deeper understanding of the complex molecular mechanisms involved in disease progression and treatment resistance is essential to further guide therapeutic approaches with improved outcomes

Mitochondrial NAD+ Controls Nuclear ARTD1-Induced ADP-Ribosylation

In addition to its role as an electron transporter, mitochondrial nicotinamide adenine dinucleotide (NAD+) is an important co-factor for enzymatic reactions, including ADP-ribosylation. Although mitochondria harbor the most intra-cellular NAD+, mitochondrial ADP-ribosylation remains poorly understood. Here we provide evidence for mitochondrial ADP-ribosylation, which was identified using various methodologies including immunofluorescence, western blot, and mass spectrometry. We show that mitochondrial ADP-ribosylation reversibly increases in response to respiratory chain inhibition. Conversely, H2O2-induced oxidative stress reciprocally induces nuclear and reduces mitochondrial ADP-ribosylation. Elevated mitochondrial ADP-ribosylation, in turn, dampens H2O2-triggered nuclear ADP-ribosylation and increases MMS-induced ARTD1 chromatin retention. Interestingly, co-treatment of cells with the mitochondrial uncoupler FCCP decreases PARP inhibitor efficacy. Together, our results suggest that mitochondrial ADP-ribosylation is a dynamic cellular process that impacts nuclear ADP-ribosylation and provide evidence for a NAD+-mediated mitochondrial-nuclear crosstalk

Mitochondrial NAD+ Controls Nuclear ARTD1-Induced ADP-Ribosylation

In addition to its role as an electron transporter, mitochondrial nicotinamide adenine dinucleotide (NAD+) is an important co-factor for enzymatic reactions, including ADP-ribosylation. Although mitochondria harbor the most intra-cellular NAD+, mitochondrial ADP-ribosylation remains poorly understood. Here we provide evidence for mitochondrial ADP-ribosylation, which was identified using various methodologies including immunofluorescence, western blot, and mass spectrometry. We show that mitochondrial ADP-ribosylation reversibly increases in response to respiratory chain inhibition. Conversely, H2O2-induced oxidative stress reciprocally induces nuclear and reduces mitochondrial ADP-ribosylation. Elevated mitochondrial ADP-ribosylation, in turn, dampens H2O2-triggered nuclear ADP-ribosylation and increases MMS-induced ARTD1 chromatin retention. Interestingly, co-treatment of cells with the mitochondrial uncoupler FCCP decreases PARP inhibitor efficacy. Together, our results suggest that mitochondrial ADP-ribosylation is a dynamic cellular process that impacts nuclear ADP-ribosylation and provide evidence for a NAD+-mediated mitochondrial-nuclear crosstalk.ISSN:1097-2765ISSN:1097-416

SLC25A51 is a mammalian mitochondrial NAD+ transporter

Mitochondria require nicotinamide adenine dinucleotide (NAD+) to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction. Mitochondrial NAD+ transporters have been identified in yeast and plants1,2, but their existence in mammals remains controversial3,4,5. Here we demonstrate that mammalian mitochondria can take up intact NAD+, and identify SLC25A51 (also known as MCART1)—an essential6,7 mitochondrial protein of previously unknown function—as a mammalian mitochondrial NAD+ transporter. Loss of SLC25A51 decreases mitochondrial—but not whole-cell—NAD+ content, impairs mitochondrial respiration, and blocks the uptake of NAD+ into isolated mitochondria. Conversely, overexpression of SLC25A51 or SLC25A52 (a nearly identical paralogue of SLC25A51) increases mitochondrial NAD+ levels and restores NAD+ uptake into yeast mitochondria lacking endogenous NAD+ transporters. Together, these findings identify SLC25A51 as a mammalian transporter capable of importing NAD+ into mitochondria