A novel homozygous variant of the thrombomodulin gene causes a hereditary bleeding disorder

ArticleBlood Advances. 5(19): 3830-3838 (2021)journal articl

NAD(+)-Dependent Deacetylase Hst1p Controls Biosynthesis and Cellular NAD(+) Levels in Saccharomyces cerevisiae

Nicotine adenine dinucleotide (NAD(+)) performs key roles in electron transport reactions, as a substrate for poly(ADP-ribose) polymerase and NAD(+)-dependent protein deacetylases. In the latter two processes, NAD(+) is consumed and converted to ADP-ribose and nicotinamide. NAD(+) levels can be maintained by regeneration of NAD(+) from nicotinamide via a salvage pathway or by de novo synthesis of NAD(+) from tryptophan. Both pathways are conserved from yeast to humans. We describe a critical role of the NAD(+)-dependent deacetylase Hst1p as a sensor of NAD(+) levels and regulator of NAD(+) biosynthesis. Using transcript arrays, we show that low NAD(+) states specifically induce the de novo NAD(+) biosynthesis genes while the genes in the salvage pathway remain unaffected. The NAD(+)-dependent deacetylase activity of Hst1p represses de novo NAD(+) biosynthesis genes in the absence of new protein synthesis, suggesting a direct effect. The known Hst1p binding partner, Sum1p, is present at promoters of highly inducible NAD(+) biosynthesis genes. The removal of HST1-mediated repression of the NAD(+) de novo biosynthesis pathway leads to increased cellular NAD(+) levels. Transcript array analysis shows that reduction in cellular NAD(+) levels preferentially affects Hst1p-regulated genes in comparison to genes regulated with other NAD(+)-dependent deacetylases (Sir2p, Hst2p, Hst3p, and Hst4p). In vitro experiments demonstrate that Hst1p has relatively low affinity toward NAD(+) in comparison to other NAD(+)-dependent enzymes. These findings suggest that Hst1p serves as a cellular NAD(+) sensor that monitors and regulates cellular NAD(+) levels

Synchrotron Mössbauer spectroscopic and X-ray diffraction study of ferropericlase at high pressures of lower mantle region

Systematic change of structural transition and high-spin (HS) to low-spin (LS) transition of Fe2+ in synthetic (Mg0.6Fe0.4 )O ferropericlase for pressures up to that of the lower mantle region were investigated using synchrotron XRD and synchrotron Mössbauer spectroscopic methods. The XRD patterns and the Mössbauer spectra were measured up to 160 GPa at room temperature. The results of the synchrotron XRD analysis indicate that the cubic structure of (Mg0.6Fe0.4)O ferropericlase is maintained up to 160 GPa. The Mössbauer spectra at 19.8 and 24.0 GPa consist of three doublets assigned to HS Fe2+ at the octahedral site. At pressures from 61 to 136 GPa, a singlet assigned to LS Fe2+ is added to the three HS Fe2+ doublets, and its area ratio with respect to the HS Fe2+ doublets gradually increase with increasing pressure. At pressures above 136 GPa, the Mössbauer spectra consist of only an LS Fe2+ singlet, implying that all Fe at these pressures is in a LS state. The resulting spin crossover pressure interval from 61 to 136 GPa indicates the coexistence of both HS and LS Fe2+ at pressure conditions from the upper part to the bottom of the lower mantle

Electronic properties and compressional behavior of Fe–Si alloys at high pressure

Planetary cores are composed mainly of Fe with minor elements such as Ni, Si, O, and S. The physical properties of Fe alloys depend on their composition. Changes in c/a ratio, center shifts, and elastic properties of Fe and Fe–Ni alloys were reported previously. However, such properties of Fe light-element alloys have not yet been extensively studied. Si is a plausible candidate as a light element in planetary cores. Therefore, we studied the electronic properties and compressional behavior of Fe-Si alloys with a hexagonal-close-packed (hcp) structure under high pressure using synchrotron Mössbauer spectroscopy (SMS) and X-ray diffraction (XRD). Center shifts (CS) were observed at pressures of 21.4–45.3 GPa for Fe-2.8wt%Si and of 30.9–62.2 GPa for Fe-6.1wt%Si. Some of SMS and XRD measurements were performed under the same conditions using a newly developed system at the BL10XU beamline

Prediction Model of Extubation Outcomes in Critically Ill Patients: A Multicenter Prospective Cohort Study

Liberation from mechanical ventilation is of great importance owing to related complications from extended ventilation time. In this prospective multicenter study, we aimed to construct a versatile model for predicting extubation outcomes in critical care settings using obtainable physiological predictors. The study included patients who had been extubated after a successful 30 min spontaneous breathing trial (SBT). A multivariable logistic regression model was constructed to predict extubation outcomes (successful extubation without reintubation and uneventful extubation without reintubation or noninvasive respiratory support) using eight parameters: age, heart failure, respiratory disease, rapid shallow breathing index (RSBI), PaO2/FIO2, Glasgow Coma Scale score, fluid balance, and endotracheal suctioning episodes. Of 499 patients, 453 (90.8%) and 328 (65.7%) achieved successful and uneventful extubation, respectively. The areas under the curve for successful and uneventful extubation in the novel prediction model were 0.69 (95% confidence interval (CI), 0.62–0.77) and 0.70 (95% CI, 0.65–0.74), respectively, which were significantly higher than those in the conventional model solely using RSBI (0.58 (95% CI, 0.50–0.66) and 0.54 (95% CI, 0.49–0.60), p = 0.004 and <0.001, respectively). The model was validated using a bootstrap method, and an online application was developed for automatic calculation. Our model, which is based on a combination of generally obtainable parameters, established an accessible method for predicting extubation outcomes after a successful SBT