Part I: Asymmetric Synthesis of α-Allyl-α-Aryl α-Amino Acids Part II: Asymmetric Spirocyclization of Allenyl Ketones Part III: Chemoselective Activation of C(sp3)−h Bond Over C(sp2)−h Bond With Pd(II)

Part I. The first asymmetric synthesis of a-allyl-a-aryl a-amino acids by means of a three component coupling of a-iminoesters, Grignard reagents, and cinnamyl acetate is reported. Notably, the enolate from the tandem process provides a much higher level of reactivity and selectivity than the same enolate generated via direct deprotonation, presumably due to differences in the solvation/aggregation state. A novel method for removal of a homoallylic amine protecting group delivers the free amine congeners. The a-allyl moiety offers a means to generate further valuable a-amino acid structures. Cross-metathesis of the tandem product provided allylic diversity not afforded in the parent reaction. Cyclic a-amino acid derivatives could be accessed by ring closing metathesis presenting a viable strategy to higher ring homologues of enantioenriched a-substituted proline. The 8-member proline analog was successfully converted to the pyrrolizidine natural product backbone. Part II. The asymmetric spirocyclization of allenyl ketones is reported. High-throughput experimentation by means of a chiral Lewis acid library enabled the determination of a suitable catalyst system. Protecting group manipulation provides an orthogonal route to enantioenriched para-quinone and ortho-quinone spirocycles. This novel technology provides access to the spirocyclic core that is prevalent in many natural products. Part III. Palladium has been identified as a suitable catalyst for the chemoselective activation of C(sp3)-H bond over C(sp2)-H bond of toluene and tolyl analogs. This technology has been combined with the C(sp3)-H activation of acidic C-H bonds to form new C-C bonds. High-throughput experimentation was used for identifying conditions that reduced toluene loading and engendered catalyst turnover via a suitable oxidant. The parent reaction has been extended to include the Pd catalyzed alkylation of phenylglycine azlactones with ethylbenzene, 2-ethylnaphthalene, propylbenzene and butylbenzene. Mechanistic studies were initiated to determine whether the process occurs via free radicals or via Pd mediated C(sp3)-H activation. Our studies support a Pd mediated process in which the C(sp3)-H activation of the tolyl analog is the rate determining step. This finding represents a paradigm shift in our understanding of Pd and its selectivity for arene activation vs benzylic activation

Probe-dependent negative allosteric modulators of the long-chain free fatty acid receptor FFA4

High-affinity and selective antagonists that are able to block the actions of both endogenous and synthetic agonists of G protein–coupled receptors are integral to analysis of receptor function and to support suggestions of therapeutic potential. Although there is great interest in the potential of free fatty acid receptor 4 (FFA4) as a novel therapeutic target for the treatment of type II diabetes, the broad distribution pattern of this receptor suggests it may play a range of roles beyond glucose homeostasis in different cells and tissues. To date, a single molecule, 4-methyl-N-9H-xanthen-9-yl-benzenesulfonamide (AH-7614), has been described as an FFA4 antagonist; however, its mechanism of antagonism remains unknown. We synthesized AH-7614 and a chemical derivative and demonstrated these to be negative allosteric modulators (NAMs) of FFA4. Although these NAMs did inhibit FFA4 signaling induced by a range of endogenous and synthetic agonists, clear agonist probe dependence in the nature of allosteric modulation was apparent. Although AH-7614 did not antagonize the second long-chain free fatty acid receptor, free fatty acid receptor 1, the simple chemical structure of AH-7614 containing features found in many anticancer drugs suggests that a novel close chemical analog of AH-7614 devoid of FFA4 activity, 4-methyl-N-(9H-xanthen-9-yl)benzamide (TUG-1387), will also provide a useful control compound for future studies assessing FFA4 function. Using TUG-1387 alongside AH-7614, we show that endogenous activation of FFA4 expressed by murine C3H10T1/2 mesenchymal stem cells is required for induced differentiation of these cells toward a more mature, adipocyte-like phenotype

An expanded phylogeny of social amoebas (Dictyostelia) shows increasing diversity and new morphological patterns

<p>Abstract</p> <p>Background</p> <p>Social Amoebae or Dictyostelia are eukaryotic microbes with a unique life cycle consisting of both uni- and multicellular stages. They have long fascinated molecular, developmental and evolutionary biologists, and <it>Dictyostelium discoideum </it>is now one of the most widely studied eukaryotic microbial models. The first molecular phylogeny of Dictyostelia included most of the species known at the time and suggested an extremely deep taxon with a molecular depth roughly equivalent to Metazoa. The group was also shown to consist of four major clades, none of which correspond to traditional genera. Potential morphological justification was identified for three of the four major groups, on the basis of which tentative names were assigned.</p> <p>Results</p> <p>Over the past four years, the Mycetozoan Global Biodiversity Survey has identified many new isolates that appear to be new species of Dictyostelia, along with numerous isolates of previously described species. We have determined 18S ribosomal RNA gene sequences for all of these new isolates. Phylogenetic analyses of these data show at least 50 new species, and these arise from throughout the dictyostelid tree breaking up many previously isolated long branches. The resulting tree now shows eight well-supported major groups instead of the original four. The new species also expand the known morphological diversity of the previously established four major groups, violating nearly all previously suggested deep morphological patterns.</p> <p>Conclusions</p> <p>A greatly expanded phylogeny of Dictyostelia now shows even greater morphological plasticity at deep taxonomic levels. In fact, there now seem to be no obvious deep evolutionary trends across the group. However at a finer level, patterns in morphological character evolution are beginning to emerge. These results also suggest that there is a far greater diversity of Dictyostelia yet to be discovered, including novel morphologies.</p

HCV genome-wide genetic analyses in context of disease progression and hepatocellular carcinoma

<div><p>Hepatitis C virus (HCV) is a major cause of hepatitis and hepatocellular carcinoma (HCC) world-wide. Most HCV patients have relatively stable disease, but approximately 25% have progressive disease that often terminates in liver failure or HCC. HCV is highly variable genetically, with seven genotypes and multiple subtypes per genotype. This variation affects HCV’s sensitivity to antiviral therapy and has been implicated to contribute to differences in disease. We sequenced the complete viral coding capacity for 107 HCV genotype 1 isolates to determine whether genetic variation between independent HCV isolates is associated with the rate of disease progression or development of HCC. Consensus sequences were determined by sequencing RT-PCR products from serum or plasma. Positions of amino acid conservation, amino acid diversity patterns, selection pressures, and genome-wide patterns of amino acid covariance were assessed in context of the clinical phenotypes. A few positions were found where the amino acid distributions or degree of positive selection differed between in the HCC and cirrhotic sequences. All other assessments of viral genetic variation and HCC failed to yield significant associations. Sequences from patients with slow disease progression were under a greater degree of positive selection than sequences from rapid progressors, but all other analyses comparing HCV from rapid and slow disease progressors were statistically insignificant. The failure to observe distinct sequence differences associated with disease progression or HCC employing methods that previously revealed strong associations with the outcome of interferon α-based therapy implies that variable ability of HCV to modulate interferon responses is not a dominant cause for differential pathology among HCV patients. This lack of significant associations also implies that host and/or environmental factors are the major causes of differential disease presentation in HCV patients.</p></div

Planck 2013 results. XXVI. Background geometry and topology of the Universe

Peer reviewe

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration: NCT02010073. Registered on 12 December 2013

Epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in ICUs across 50 countries

Background: To better understand the epidemiology and patterns of tracheostomy practice for patients with acute respiratory distress syndrome (ARDS), we investigated the current usage of tracheostomy in patients with ARDS recruited into the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) study. Methods: This is a secondary analysis of LUNG-SAFE, an international, multicenter, prospective cohort study of patients receiving invasive or noninvasive ventilation in 50 countries spanning 5 continents. The study was carried out over 4 weeks consecutively in the winter of 2014, and 459 ICUs participated. We evaluated the clinical characteristics, management and outcomes of patients that received tracheostomy, in the cohort of patients that developed ARDS on day 1-2 of acute hypoxemic respiratory failure, and in a subsequent propensity-matched cohort. Results: Of the 2377 patients with ARDS that fulfilled the inclusion criteria, 309 (13.0%) underwent tracheostomy during their ICU stay. Patients from high-income European countries (n = 198/1263) more frequently underwent tracheostomy compared to patients from non-European high-income countries (n = 63/649) or patients from middle-income countries (n = 48/465). Only 86/309 (27.8%) underwent tracheostomy on or before day 7, while the median timing of tracheostomy was 14 (Q1-Q3, 7-21) days after onset of ARDS. In the subsample matched by propensity score, ICU and hospital stay were longer in patients with tracheostomy. While patients with tracheostomy had the highest survival probability, there was no difference in 60-day or 90-day mortality in either the patient subgroup that survived for at least 5 days in ICU, or in the propensity-matched subsample. Conclusions: Most patients that receive tracheostomy do so after the first week of critical illness. Tracheostomy may prolong patient survival but does not reduce 60-day or 90-day mortality. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013