Intermolecular oxidative phenol coupling is the main process in nature for the formation of atroposelective biaryl compounds. Although well defined in plants and fungi, this type of dimerization ...reaction in bacteria is poorly understood. Therefore, the biosynthesis of julichromes, spectomycins, and setomimycin was investigated. The monomeric subunits of these biarylic pre-anthraquinones are derived from a common polyketidic precursor, yet the coupling reaction proceeds in a regioselective manner, with the position of attachment of the two subunits depending on the specific streptomycete strain. By using genome analysis and deletion experiments, the biosynthetic gene clusters were identified. Furthermore, it was established that cytochrome P450 enzymes are fundamentally involved during dimerization of the polyketide monomers.
Aims
Sacubitril/valsartan is a neprilysin‐inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post‐hoc analysis of a 3‐year randomized controlled trial ...showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase‐4 inhibitor increases active glucagon‐like peptide‐1 (GLP‐1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase‐4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP‐1.
Methods
We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.
Results
Postprandial plasma glucose increased by 57% (incremental area under the curve 0‐240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6‐2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP‐1 and C‐peptide concentrations increased after sacubitril/valsartan, but insulin and glucose‐dependent insulinotropic polypeptide did not change.
Conclusions
The glucose‐lowering effects of long‐term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero‐pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study.
ClinicalTrials.gov (NCT03893526).
Scientific interest in debris-covered glaciers (DCGs) significantly increased during the last two decades, primarily from an abiotic perspective, but also regarding their distinctive ecology. An ...increasing body of evidence shows that, given a minimum of debris thickness and sufficient substrate stability, DCGs host surprisingly diverse plant assemblages, both floristically and structurally, despite being obviously cold and in parts also highly mobile habitats. As a function of site conditions, floristic composition and vegetation structure, DCGs represent a mosaic of environments, including subnival pioneer communities, glacier foreland early- to late-successional stages, morainal locations, and locally, even forest sites. On shallow supraglacial debris layers, cryophilous alpine/subnival taxa can grow considerably below their common elevational niche due to the cooler temperatures within the root horizon caused by the underlying ice. In contrast, a greater debris thickness allows even thermophilous plant species of lower elevations to grow on glacier surfaces. Employing the principle of uniformitarianism, DCGs are assumed to have been important and previously undocumented refugia for plants during repeated Quaternary cold and warm cycles. This review and recent study summarize the current knowledge on the vegetation ecology of DCGs and evaluates their potential function as plant habitat under ongoing climate warming.
Thioalkalivibrio is a genus of obligate chemolithoautotrophic haloalkaliphilic sulfur-oxidizing bacteria. Their habitat are soda lakes which are dual extreme environments with a pH range from 9.5 to ...11 and salt concentrations up to saturation. More than 100 strains of this genus have been isolated from various soda lakes all over the world, but only ten species have been effectively described yet. Therefore, the assignment of the remaining strains to either existing or novel species is important and will further elucidate their genomic diversity as well as give a better general understanding of this genus. Recently, the genomes of 76 Thioalkalivibrio strains were sequenced. On these, we applied different methods including (i) 16S rRNA gene sequence analysis, (ii) Multilocus Sequence Analysis (MLSA) based on eight housekeeping genes, (iii) Average Nucleotide Identity based on BLAST (ANIb) and MUMmer (ANIm), (iv) Tetranucleotide frequency correlation coefficients (TETRA), (v) digital DNA:DNA hybridization (dDDH) as well as (vi) nucleotide- and amino acid-based Genome BLAST Distance Phylogeny (GBDP) analyses. We detected a high genomic diversity by revealing 15 new "genomic" species and 16 new "genomic" subspecies in addition to the ten already described species. Phylogenetic and phylogenomic analyses showed that the genus is not monophyletic, because four strains were clearly separated from the other Thioalkalivibrio by type strains from other genera. Therefore, it is recommended to classify the latter group as a novel genus. The biogeographic distribution of Thioalkalivibrio suggested that the different "genomic" species can be classified as candidate disjunct or candidate endemic species. This study is a detailed genome-based classification and identification of members within the genus Thioalkalivibrio. However, future phenotypical and chemotaxonomical studies will be needed for a full species description of this genus.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The objective of this paper is to assess the volume, accuracy, and timeliness of radiology resident preliminary reports as part of an independent call system. This study seeks to understand the ...relationship between resident year in training, study modality, and discrepancy rate.
Resident preliminary interpretations on radiographs, ultrasound, CT, and MRI from October 2009 through December 2013 were prospectively scored by faculty on a modified RADPEER scoring system. Discrepancy rates were evaluated based on postgraduate year of the resident and the study modality. Turnaround times for reports were also reviewed. Differences between groups were compared with a chi-square test with a significance level of 0.05. Institutional review board approval was waived as only deidentified data were used in the study.
A total of 416,413 studies were reported by 93 residents, yielding 135,902 resident scores. The rate of major resident-faculty assessment discrepancies was 1.7%. Discrepancy rates improved with increasing experience, both overall (PGY-3: 1.8%, PGY-4: 1.7%, PGY-5: 1.5%) and for each individual modality. Discrepancy rates were highest for MR (3.7%), followed by CT (2.4%), radiographs (1.4%), and ultrasound (0.6%). Emergency department report turnaround time averaged 31.7 min. The average graduating resident has been scored on 2,746 ± 267 reports during residency.
Resident preliminary reports have a low rate of major discrepancies, which improves over 3 years of call-taking experience. Although more complex cross-sectional studies have slightly higher discrepancy rates, discrepancies were still within the range of faculty report variation.
It is current practice that researchers testing specific, theory-driven predictions do not only use a planned contrast to model and test their hypotheses, but also test the residual variance (the C+R ...approach). This analysis strategy relies on work by Abelson and Prentice (1997), who suggested that the result of a planned contrast needs to be interpreted in light of the variance that is left after the variance explained by the contrast has been subtracted from the variance explained by the factors of the statistical model. Unfortunately, the C + R approach leads to 6 fundamental problems. In particular, the C + R approach (a) relies on the interpretation of a nonsignificant result as evidence for no effect, (b) neglects the impact of sample size, (c) creates problems for a priori power analyses, (d) may lead to significant effects that lack a meaningful interpretation, (e) may give rise to misinterpretations, and (f) is inconsistent with the interpretation of other statistical analyses. Given these flaws, researchers should refrain from testing the residual variance when conducting planned contrasts. Single contrasts, Bayes factors, and likelihood ratios provide reasonable alternatives that are less problematic.
Symbioses between bacteria and eukaryotes are ubiquitous, yet our understanding of the interactions driving these associations is hampered by our inability to cultivate most host-associated microbes. ...Here we use a metagenomic approach to describe four co-occurring symbionts from the marine oligochaete Olavius algarvensis, a worm lacking a mouth, gut and nephridia. Shotgun sequencing and metabolic pathway reconstruction revealed that the symbionts are sulphur-oxidizing and sulphate-reducing bacteria, all of which are capable of carbon fixation, thus providing the host with multiple sources of nutrition. Molecular evidence for the uptake and recycling of worm waste products by the symbionts suggests how the worm could eliminate its excretory system, an adaptation unique among annelid worms. We propose a model that describes how the versatile metabolism within this symbiotic consortium provides the host with an optimal energy supply as it shuttles between the upper oxic and lower anoxic coastal sediments that it inhabits.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Plasma concentrations of glucagon, GLP-1 and GIP are reported in numerous clinical trials as outcome measures but preanalytical guidelines are lacking. We addressed the impact of commonly used blood ...containers in metabolic research on measurements of glucagon, GLP-1 and GIP in humans.
Seventeen overweight individuals were subjected to an overnight fast followed by an intravenous infusion of amino acids to stimulate hormonal secretion. Blood was sampled into five containers: EDTA-coated tubes supplemented with DMSO (control), a neprilysin inhibitor, aprotinin (a kallikrein inhibitor) or a DPP-4 inhibitor, and P800 tubes. Plasma was kept on ice before and after centrifugation and stored at -80 Celsius until batch analysis using validated sandwich ELISAs or radioimmunoassays (RIA).
Measures of fasting plasma glucagon did not depend on sampling containers, whether measured by ELISA or RIA. Amino acid-induced hyperglucagonemia was numerically higher when blood was collected into P800 tubes or tubes with aprotinin. The use of p800 tubes resulted in higher concentrations of GLP-1 by RIA compared to control tubes but not for measurements with sandwich ELISA. Plasma concentrations of GIP measured by ELISA were higher in control tubes and negatively affected by P800 and the addition of aprotinin.
The choice of blood containers impacts on measurements of plasma concentrations of glucagon, GLP-1 and GIP, and based on this study, we recommend using EDTA-coated tubes without protease inhibitors or P800 tubes for measurements of glucagon, GLP-1 and GIP in clinical trials.
Summary
Members of the Bacteroidetes, formerly known as the Cytophaga‐Flavobacteria‐Bacteroides (CFB) phylum, are among the major taxa of marine heterotrophic bacterioplankton frequently found on ...macroscopic organic matter particles (marine snow). In addition, they have been shown to also represent a significant part of free‐living microbial assemblages in nutrient‐rich microenvironments. Their abundance and distribution pattern in combination with enzymatic activity studies has led to the notion that organisms of this group are specialists for degradation of high molecular weight compounds in both the dissolved and particulate fraction of the marine organic matter pool, implying a major role of Bacteroidetes in the marine carbon cycle. Despite their ecological importance, comprehensive molecular data on organisms of this group have been scarce so far. Here we report on the first whole genome analysis of a marine Bacteroidetes representative, ‘Gramella forsetii’ KT0803. Functional analysis of the predicted proteome disclosed several traits which in joint consideration suggest a clear adaptation of this marine Bacteroidetes representative to the degradation of high molecular weight organic matter, such as a substantial suite of genes encoding hydrolytic enzymes, a predicted preference for polymeric carbon sources and a distinct capability for surface adhesion.
A physiological feedback system exists between hepatocytes and the alpha cells, termed the liver-alpha cell axis and refers to the relationship between amino acid-stimulated glucagon secretion and ...glucagon-stimulated amino acid catabolism. Several reports indicate that non-alcoholic fatty liver disease (NAFLD) disrupts the liver-alpha cell axis, because of impaired glucagon receptor signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans. The objective was to develop an experimental test to determine glucagon sensitivity with respect to amino acid and glucose metabolism in humans. The proposed glucagon sensitivity test (comprising two elements: 1) i.v. injection of 0.2 mg glucagon and 2) infusion of mixed amino acids 331 mg/hour/kg) is based on nine pilot studies which are presented. Calculation of a proposed glucagon sensitivity index with respect to amino acid catabolism is also described. Secondly, we describe a complete study protocol (GLUSENTIC) according to which the glucagon sensitivity test will be applied in a cross-sectional study currently taking place. 65 participants including 20 individuals with a BMI 18.6–25 kg/m2, 30 individuals with a BMI ≥ 25–40 kg/m2, and 15 individuals with type 1 diabetes with a BMI between 18.6 and 40 kg/m2 will be included. Participants will be grouped according to their degree of hepatic steatosis measured by whole-liver magnetic resonance imaging (MRI). The primary outcome measure will be differences in the glucagon sensitivity index between individuals with and without hepatic steatosis. Developing a glucagon sensitivity test and index may provide insight into the physiological and pathophysiological mechanism of glucagon action and glucagon-based therapies.
•A glucagon sensitivity test towards hepatic amino acid catabolism was developed.•Pilot studies leading to the final glucagon test are presented.•A novel glucagon sensitivity index is presented.•The test may be an important tool to investigate glucagon resistance.
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