Vacuolin-1 potently and reversibly inhibits autophagosome-lysosome fusion by activating RAB5A

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Potential benefits of vitamin D for sepsis prophylaxis in critical ill patients

BackgroundVitamin D deficiency is common in critically ill patients with suspected infection and is strongly associated with the predisposition of sepsis and a poor prognosis. The effectiveness of vitamin D supplementation for preventing sepsis remains unclear. This retrospective cohort study investigated the effect of vitamin D supplementation on sepsis prophylaxis in critically ill patients with suspected infection.MethodsThis retrospective cohort study included 19,816 adult patients with suspected infection in intensive care units (ICU) from 2008 to 2019 at the Beth Israel Deaconess Medical Center, Boston, USA. The included patients were divided into the vitamin D cohort or non-vitamin D cohort according to vitamin D administration status. The primary outcomes were the incidence of sepsis in ICU. The secondary outcomes included 28-day all-cause mortality, length of ICU and hospital stay and the requirements of vasopressors or mechanical ventilation. A propensity score matching cohort was used to test the differences in primary and secondary outcomes between groups.ResultsThe results showed that vitamin D supplementation demonstrated a lower risk of sepsis (odd ratio 0.46; 95% CI 0.35–0.60; P < 0.001) and a lower risk of new mechanical ventilation requirement (odd ratio 0.70; 95% CI 0.53-0.92; P = 0.01), but no significant difference in the risk of 28-day mortality was observed (hazard ratio 1.02; 95% CI 0.77–1.35; P = 0.89). In the sensitive analysis, among the patients who suspected infection within 24 h before or after ICU admission, a lower risk of sepsis and a lower percentage of new mechanical ventilation also were detected in the vitamin D cohort.ConclusionVitamin D supplementation may have a positively prophylactic effect on sepsis in critically ill patients with suspected infection

Quantitative Trait Locus Mapping of Soybean Maturity Gene E6

Soybean [ Glycine max (L.) Merr.] sensitivity to photoperiod determines adaptation to a specific range of latitudes for soybean cultivars. When temperate-adapted soybean cultivars are grown in low latitude under short day conditions, they flower early, resulting in low grain yield, and consequently limiting their utility in tropical areas. Most cultivars adapted to low-latitude environments have the trait of delayed flowering under short day conditions, and this trait is commonly called long juvenile (LJ). In this study, the E6 locus, the classical locus conditioning the LJ trait, was molecularly mapped on Gm04 near single-nucleotide polymorphism marker HRM101. Testcross, genetic mapping, and sequencing suggest that the E6 and J loci might be tightly linked. Genetic interaction evaluation between E6 and E1 suggests that E6 has a suppressive effect on E1 and that the function of E6 is dependent on E1. The tagging markers for E6 are very useful for molecular breeding for wide adaptation and stable productivity of soybean under lowlatitude environments. Molecular identification and functional characterization of the E6 gene will greatly facilitate the understanding of the genetic and molecular mechanisms underlying the LJ trait

Adjunctive granisetron therapy in patients with sepsis or septic shock (GRANTISS): A single-center, single-blinded, randomized, controlled clinical trial

Background: In preclinical experiments, we demonstrated that the 5-HT3 receptor antagonist granisetron results in reduced inflammation and improved survival in septic mice. This randomized controlled trial was designed to assess the efficacy and safety of granisetron in patients with sepsis.Methods: Adult patients with sepsis and procalcitonin ≥ 2 ng/ml were randomized in a 1:1 ratio to receive intravenous granisetron (3 mg every 8 h) or normal saline at the same volume and frequency for 4 days or until intensive care unit discharge. The primary outcome was 28-day all-cause mortality. Secondary outcomes included the duration of supportive therapies for organ function, changes in sequential organ failure assessment scores over 96 h, procalcitonin reduction rate over 96 h, the incidence of new organ dysfunction, and changes in laboratory variable over 96 h. Adverse events were monitored as the safety outcome.Results: The modified intention-to-treat analysis included 150 septic patients. The 28-day all-cause mortalities in the granisetron and placebo groups were 34.7% and 35.6%, respectively (odds ratio, 0.96; 95% CI, 0.49–1.89). No differences were observed in secondary outcomes. In the subgroup analysis of patients without abdominal or digestive tract infections, the 28-day mortality in the granisetron group was 10.9% lower than mortality in the placebo group. Adverse events were not statistically different between the groups.Conclusion: Granisetron did not improve 28-day mortality in patients with sepsis. However, a further clinical trial targeted to septic patients without abdominal/digestive tract infections perhaps is worthy of consideration

Molecular Dynamics Analysis Reveals Structural Insights into Mechanism of Nicotine N-Demethylation Catalyzed by Tobacco Cytochrome P450 Mono-Oxygenase

CYP82E4, a cytochrome P450 monooxygenase, has nicotine N-demethylase (NND) activity, which mediates the bioconversion of nicotine into nornicotine in senescing tobacco leaves. Nornicotine is a precursor of the carcinogen, tobacco-specific nitrosamine. CYP82E3 is an ortholog of CYP82E4 with 95% sequence identity, but it lacks NND activity. A recent site-directed mutagenesis study revealed that a single amino acid substitution, i.e., cysteine to tryptophan at the 330 position in the middle of protein, restores the NND activity of CYP82E3 entirely. However, the same amino acid change caused the loss of the NND activity of CYP82E4. To determine the mechanism of the functional turnover of the two molecules, four 3D structures, i.e., the two molecules and their corresponding cys–trp mutants were modeled. The resulting structures exhibited that the mutation site is far from the active site, which suggests that no direct interaction occurs between the two sites. Simulation studies in different biological scenarios revealed that the mutation introduces a conformation drift with the largest change at the F-G loop. The dynamics trajectories analysis using principal component analysis and covariance analysis suggests that the single amino acid change causes the opening and closing of the transfer channels of the substrates, products, and water by altering the motion of the F-G and B-C loops. The motion of helix I is also correlated with the motion of both the F-G loop and the B-C loop and; the single amino acid mutation resulted in the curvature of helix I. These results suggest that the single amino acid mutation outside the active site region may have indirectly mediated the flexibility of the F-G and B-C loops through helix I, causing a functional turnover of the P450 monooxygenase