Nicotinamide riboside (NR) is an NAD+ precursor that boosts cellular NAD+ concentrations. Preclinical studies have shown profound metabolic health effects after NR supplementation.
We aimed to ...investigate the effects of 6 wk NR supplementation on insulin sensitivity, mitochondrial function, and other metabolic health parameters in overweight and obese volunteers.
A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received 6 wk NR (1000 mg/d) and placebo supplementation, followed by broad metabolic phenotyping, including hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy, muscle biopsies, and assessment of ex vivo mitochondrial function and in vivo energy metabolism.
Markers of increased NAD+ synthesis—nicotinic acid adenine dinucleotide and methyl nicotinamide—were elevated in skeletal muscle after NR compared with placebo. NR increased body fat-free mass (62.65% ± 2.49% compared with 61.32% ± 2.58% in NR and placebo, respectively; change: 1.34% ± 0.50%, P = 0.02) and increased sleeping metabolic rate. Interestingly, acetylcarnitine concentrations in skeletal muscle were increased upon NR (4558 ± 749 compared with 3025 ± 316 pmol/mg dry weight in NR and placebo, respectively; change: 1533 ± 683 pmol/mg dry weight, P = 0.04) and the capacity to form acetylcarnitine upon exercise was higher in NR than in placebo (2.99 ± 0.30 compared with 2.40 ± 0.33 mmol/kg wet weight; change: 0.53 ± 0.21 mmol/kg wet weight, P = 0.01). However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism.
NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed. This trial was registered at clinicaltrials.gov as NCT02835664
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The neutron-rich nucleus Ba-144 (t(1/2) = 11.5 s) is expected to exhibit some of the strongest octupole correlations among nuclei with mass numbers A less than 200. Until now, indirect evidence for ...such strong correlations has been inferred from observations such as enhanced E1 transitions and interleaving positive- and negative-parity levels in the ground-state band. In this experiment, the octupole strength was measured directly by sub-barrier, multistep Coulomb excitation of a post-accelerated 650-MeV Ba-144 beam on a 1.0-mg/cm(2) Pb-208 target. The measured value of the matrix element, < 3(1)(-)parallel to M(E3)parallel to 0(1)(+)> = 0.65((+17)(-23)) eb(3/2,) corresponds to a reduced Bd(E3) transition probability of 48((+25)(-34)) W.u. This result represents an unambiguous determination of the octupole collectivity, is larger than any available theoretical prediction, and is consistent with octupole deformation.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
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BACKGROUND:Intraoperative lung-protective ventilation has been recommended to reduce postoperative pulmonary complications ...after abdominal surgery. Although the protective role of a more physiologic tidal volume has been established, the added protection afforded by positive end-expiratory pressure (PEEP) remains uncertain. The authors hypothesized that a low fixed PEEP might not fit all patients and that an individually titrated PEEP during anesthesia might improve lung function during and after surgery.
METHODS:Forty patients were studied in the operating room (20 laparoscopic and 20 open-abdominal). They underwent elective abdominal surgery and were randomized to institutional PEEP (4 cm H2O) or electrical impedance tomography–guided PEEP (applied after recruitment maneuvers and targeted at minimizing lung collapse and hyperdistension, simultaneously). Patients were extubated without changing selected PEEP or fractional inspired oxygen tension while under anesthesia and submitted to chest computed tomography after extubation. Our primary goal was to individually identify the electrical impedance tomography–guided PEEP value producing the best compromise of lung collapse and hyperdistention.
RESULTS:Electrical impedance tomography–guided PEEP varied markedly across individuals (median, 12 cm H2O; range, 6 to 16 cm H2O; 95% CI, 10–14). Compared with PEEP of 4 cm H2O, patients randomized to the electrical impedance tomography–guided strategy had less postoperative atelectasis (6.2 ± 4.1 vs. 10.8 ± 7.1% of lung tissue mass; P = 0.017) and lower intraoperative driving pressures (mean values during surgery of 8.0 ± 1.7 vs. 11.6 ± 3.8 cm H2O; P < 0.001). The electrical impedance tomography–guided PEEP arm had higher intraoperative oxygenation (435 ± 62 vs. 266 ± 76 mmHg for laparoscopic group; P < 0.001), while presenting equivalent hemodynamics (mean arterial pressure during surgery of 80 ± 14 vs. 78 ± 15 mmHg; P = 0.821).
CONCLUSIONS:PEEP requirements vary widely among patients receiving protective tidal volumes during anesthesia for abdominal surgery. Individualized PEEP settings could reduce postoperative atelectasis (measured by computed tomography) while improving intraoperative oxygenation and driving pressures, causing minimum side effects.
Cross sections for proton knockout observed in (e,e'p) reactions are apparently quenched by a factor of ∼0.5, an effect attributed to short-range correlations between nucleons. Here we demonstrate ...that such quenching is not restricted to proton knockout, but a more general phenomenon associated with any nucleon transfer. Measurements of absolute cross sections on a number of targets between 16O and 208Pb were analyzed in a consistent way, with the cross sections reduced to spectroscopic factors through the distorted-wave Born approximation with global optical potentials. Across the 124 cases analyzed here, induced by various proton- and neutron-transfer reactions and with angular momentum transfer ℓ=0-7, the results are consistent with a quenching factor of 0.55. This is an apparently uniform quenching of single-particle motion in the nuclear medium. The effect is seen not only in (d,p) reactions but also in reactions with A=3 and 4 projectiles, when realistic wave functions are used for the projectiles.
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Here, absolute cross sections for the addition of s- and d-wave neutrons to 14C and 14N have been determined simultaneously via the (d,p) reaction at 10 MeV/u. The difference between the neutron and ...proton separation energies, ΔS, is around -20 MeV for the 14C+n system and +8 MeV for 14N+n. The population of the 1s1/2 and 0d5/2 orbitals for both systems is reduced by a factor of approximately 0.5 compared with the independent single-particle model, or about 0.6 when compared with the shell model. This finding strongly contrasts with results deduced from intermediate-energy knockout reactions between similar nuclei on targets of 9Be and 12C. The simultaneous technique used removes many systematic uncertainties.
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Increased understanding of intrinsically disordered proteins (IDPs) and protein regions has revolutionized our view of the relationship between protein structure and function. Data now support that ...IDPs can be functional in the absence of a single, fixed, three-dimensional structure. Due to their dynamic morphology, IDPs have the ability to display a range of kinetics and affinity depending on what the system requires, as well as the potential for large-scale association. Although several studies have shed light on the functional properties of IDPs, the class of intrinsically disordered transcription factors (TFs) is still poorly characterized biophysically due to their combination of ordered and disordered sequences. In addition, TF modulation by small molecules has long been considered a difficult or even impossible task, limiting functional probe development. However, with evolving technology, it is becoming possible to characterize TF structure–function relationships in unprecedented detail and explore avenues not available or not considered in the past. Here we provide an introduction to the biophysical properties of intrinsically disordered TFs and we discuss recent computational and experimental efforts toward understanding the role of intrinsically disordered TFs in biology and disease. We describe a series of successful TF targeting strategies that have overcome the perception of the “undruggability” of TFs, providing new leads on drug development methodologies. Lastly, we discuss future challenges and opportunities to enhance our understanding of the structure–function relationship of intrinsically disordered TFs.
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•Proteins that contain intrinsically disordered regions have emerged as key players in numerous crucial cell functions.•Disorder offers transcription factors increased conformational flexibility and binding promiscuity.•Transcription factors that contain intrinsically disordered regions are highly abundant among disease-related proteins and present attractive therapeutic targets.•Major approaches targeting transcription factors with disordered regions include targeting aberrant pathogenic aggregates, protein–protein interactions, or targeting the DNA-binding domains.•Methodological advances in biophysical methods and their combination with molecular dynamics simulations have led the successful targeting of pathogenic disordered transcription factors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The nuclei below lead but with more than 126 neutrons are crucial to an understanding of the astrophysical r process in producing nuclei heavier than A∼190. Despite their importance, the structure ...and properties of these nuclei remain experimentally untested as they are difficult to produce in nuclear reactions with stable beams. In a first exploration of the shell structure of this region, neutron excitations in ^{207}Hg have been probed using the neutron-adding (d,p) reaction in inverse kinematics. The radioactive beam of ^{206}Hg was delivered to the new ISOLDE Solenoidal Spectrometer at an energy above the Coulomb barrier. The spectroscopy of ^{207}Hg marks a first step in improving our understanding of the relevant structural properties of nuclei involved in a key part of the path of the r process.
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The apparent splitting between orbitals that are spin-orbit partners can be substantially influenced by the effects of weak binding. In particular, such effects can account for the observed decrease ...in separation of the neutron 1p_{3/2} and 1p_{1/2} orbitals between the ^{41}Ca and ^{35}Si isotopes. This behavior has been the subject of recent experimental and theoretical works and cited as evidence for a proton "bubble" in ^{34}Si causing an explicit weakening of the spin-orbit interaction. The results reported here suggest that the change in the separation between the 1p_{3/2} and 1p_{1/2} partners occurs dominantly because of the behavior of the energies of these 1p neutron states near zero binding.
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Mild cold acclimation for 10 days has been previously shown to markedly improve insulin sensitivity in patients with type 2 diabetes. Here we show in a single-arm intervention study (Trialregister.nl ...ID: NL4469/NTR5711) in nine patients with type 2 diabetes that ten days of mild cold acclimation (16-17 °C) in which observable, overt shivering was prevented, does not result in improved insulin sensitivity, postprandial glucose and lipid metabolism or intrahepatic lipid content and only results in mild effects on overnight fasted fat oxidation, postprandial energy expenditure and aortic augmentation index. The lack of marked metabolic effects in this study is associated with a lack of self-reported shivering and a lack of upregulation of gene expression of muscle activation or muscle contraction pathways in skeletal muscle and suggests that some form of muscle contraction is needed for beneficial effects of mild cold acclimation.
We demonstrate a new technique for obtaining fission data for nuclei away from β stability. These types of data are pertinent to the astrophysical r process, crucial to a complete understanding of ...the origin of the heavy elements, and for developing a predictive model of fission. These data are also important considerations for terrestrial applications related to power generation and safeguarding. Experimentally, such data are scarce due to the difficulties in producing the actinide targets of interest. The solenoidal-spectrometer technique, commonly used to study nucleon-transfer reactions in inverse kinematics, has been applied to the case of transfer-induced fission as a means to deduce the fission-barrier height, among other variables. The fission-barrier height of ^{239}U has been determined via the ^{238}U(d,pf) reaction in inverse kinematics, the results of which are consistent with existing neutron-induced fission data indicating the validity of the technique.
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