Synthesis and crystal structure of (+)-(2R,3R)-N, N '-bis-trityl-2,3-bis-aziridine

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Prevalence, predictors, and outcomes of clonal hematopoiesis in individuals aged ≥80 years

Clonal hematopoiesis (CH), characterized by a fraction of peripheral blood cells carrying an acquired genetic variant, emerges with age. Although in general CH is associated with increased mortality and morbidity, no higher risk of death was observed for individuals ≥80 years. Here, we investigated CH in 621 individuals aged ≥80 years from the population-based LifeLines cohort. Sensitive error-corrected sequencing of 27 driver genes at a variant allele frequency ≥1% revealed CH in the majority (62%) of individuals, independent of gender. The observed mutational spectrum was dominated by DNMT3A and TET2 variants, which frequently (29%) displayed multiple mutations per gene. In line with previous results in individuals ≥80 years, the overall presence of CH did not associate with a higher risk of death (hazard ratio, 0.91; 95% confidence interval, 0.70-1.18; P = .48). Being able to assess the causes of death, we observed no difference between individuals with or without CH, except for deaths related to hematological malignancies. Interestingly, comparison of mutational spectra confined to DNMT3A and TET2 vs spectra containing other mutated genes, showed a higher risk of death when mutations other than DNMT3A or TET2 were present (hazard ratio, 1.48; 95% confidence interval, 1.06-2.08; P = .025). Surprisingly, no association of CH with cardiovascular morbidity was found, irrespective of clone size. Further, CH associated with chronic obstructive pulmonary disease. Data on estimated exposure to DNA damaging toxicities (ie, smoking, a history of cancer [as a proxy for previous genotoxic therapy], and job-related pesticide exposure) showed an association with spliceosome and ASXL1 variants, but not with DNMT3A and TET2 variants

Novel antibacterial agents SAAP-148 and halicin combat Gram-negative bacteria colonizing catheters

The antibiotic management of catheter-related infections (CRIs) often fails owing to the emergence of antimicrobial-resistant strains and/or biofilm/persister apparitions. Thus, we investigated the efficacy of two novel antimicrobial agents, i.e., the synthetic peptide SAAP-148 and the novel antibiotic halicin, against Gram-negative bacteria (GNB) colonizing catheters. The antibacterial, anti-biofilm, and anti-persister activities of both agents were evaluated against Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae strains. The enrolled strains were isolated from catheters and selected based on their resistance to at least three antibiotic classes and biofilm formation potential. Furthermore, the hemolysis and endotoxin neutralization abilities of these agents were explored. The bactericidal activity of both agents was reduced in urine and plasma as compared to buffered saline. In a dose-dependent manner, SAAP-148 and halicin reduced bacterial counts in 24 h preformed biofilms on silicone elastomer discs and eliminated persisters originating from antibiotic-exposed mature 7-day biofilms, with halicin being less effective than SAAP-148. Importantly, SAAP-148 and halicin acted synergistically on E. coli and K. pneumoniae biofilms but not on A. baumannii biofilms. The peptide, but not halicin, decreased the production of IL-12p40 upon exposure to UV-killed bacteria. This preliminary study showed that SAAP-148 and halicin alone/in combination are promising candidates to fight GNB colonizing catheters.Transplantation and autoimmunit

Copeptin as an Indicator of Hemodynamic Derangement and Prognosis in Liver Cirrhosis

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Copeptin in acute decompensation of liver cirrhosis: relationship with acute-on-chronic liver failure and short-term survival

BACKGROUND: Acute-on-chronic liver failure (ACLF) is characterized by the presence of acute decompensation (AD) of cirrhosis, organ failure, and high short-term mortality rates. Hemodynamic dysfunction and activation of endogenous vasoconstrictor systems are thought to contribute to the pathogenesis of ACLF. We explored whether copeptin, a surrogate marker of arginine vasopressin, is a potential marker of outcome in patients admitted for AD or ACLF and whether it might be of additional value to conventional prognostic scoring systems in these patients. METHODS: All 779 patients hospitalized for AD of cirrhosis from the CANONIC database with at least one serum sample available for copeptin measurement were included. Presence of ACLF was defined according to the CLIF-consortium organ failure (CLIF-C OF) score. Serum copeptin was measured in samples collected at days 0-2, 3-7, 8-14, 15-21, and 22-28 when available. Competing-risk regression analysis was applied to evaluate the impact of serum copeptin and laboratory and clinical data on short-term survival. RESULTS: Serum copeptin concentration was found to be significantly higher in patients with ACLF compared with those without ACLF at days 0-2 (33 (14-64) vs. 11 (4-26) pmol/L; p < 0.001). Serum copeptin at admission was shown to be a predictor of mortality independently of MELD and CLIF-C OF scores. Moreover, baseline serum copeptin was found to be predictive of ACLF development within 28 days of follow-up. CONCLUSIONS: ACLF is associated with significantly higher serum copeptin concentrations at hospital admission compared with those with traditional AD. Copeptin is independently associated with short-term survival and ACLF development in patients admitted for AD or ACLF

Plasma copeptin as biomarker of disease progression and prognosis in cirrhosis

Lay summary: Copeptin is a fragment of the vasopressin precursor, a hormone that is known to be increased in patients with cirrhosis and that plays a role in the development of complications of the disease. Vasopressin is difficult to measure, but copeptin is a more stable molecule and is easier to measure in blood. Sola and Kerbert and colleagues have shown in a series of 361 patients that copeptin is markedly increased in patients with cirrhosis who develop complications during the following 3 months, compared to those patients who do not develop complications. Moreover, copeptin correlates with prognosis. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Following Ariadne's thread: a new perspective on RBR ubiquitin ligases

Ubiquitin signaling pathways rely on E3 ligases for effecting the final transfer of ubiquitin from E2 ubiquitin conjugating enzymes to a protein target. Here we re-evaluate the hybrid RING/HECT mechanism used by the E3 family RING-between-RINGs (RBRs) to transfer ubiquitin to substrates. We place RBRs into the context of current knowledge of HECT and RING E3s. Although not as abundant as the other types of E3s (there are only slightly more than a dozen RBR E3s in the human genome), RBRs are conserved in all eukaryotes and play important roles in biology. Re-evaluation of RBR ligases as RING/HECT E3s provokes new questions and challenges the field

Identification of the Pangenome and Its Components in 14 Distinct Aggregatibacter actinomycetemcomitans Strains by Comparative Genomic Analysis

Aggregatibacter actinomycetemcomitans is genetically heterogeneous and comprises distinct clonal lineages that may have different virulence potentials. However, limited information of the strain-to-strain genomic variations is available.The genome sequences of 11 A. actinomycetemcomitans strains (serotypes a-f) were generated de novo, annotated and combined with three previously sequenced genomes (serotypes a-c) for comparative genomic analysis. Two major groups were identified; serotypes a, d, e, and f, and serotypes b and c. A serotype e strain was found to be distinct from both groups. The size of the pangenome was 3,301 genes, which included 2,034 core genes and 1,267 flexible genes. The number of core genes is estimated to stabilize at 2,060, while the size of the pangenome is estimated to increase by 16 genes with every additional strain sequenced in the future. Within each strain 16.7-29.4% of the genome belonged to the flexible gene pool. Between any two strains 0.4-19.5% of the genomes were different. The genomic differences were occasionally greater for strains of the same serotypes than strains of different serotypes. Furthermore, 171 genomic islands were identified. Cumulatively, 777 strain-specific genes were found on these islands and represented 61% of the flexible gene pool.Substantial genomic differences were detected among A. actinomycetemcomitans strains. Genomic islands account for more than half of the flexible genes. The phenotype and virulence of A. actinomycetemcomitans may not be defined by any single strain. Moreover, the genomic variation within each clonal lineage of A. actinomycetemcomitans (as defined by serotype grouping) may be greater than between clonal lineages. The large genomic data set in this study will be useful to further examine the molecular basis of variable virulence among A. actinomycetemcomitans strains