Evaluating aryl esters as bench-stable C(1)-ammonium enolate precursors in catalytic, enantioselective Michael addition-lactonisations

We thank the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC Grant Agreement no. 279850 (CMY, JET). ADS thanks the Royal Society for a Wolfson Merit Award. We also thank the EPSRC UK National Mass Spectrometry Facility at Swansea University. The data underpinning this research can be found at DOI: https://doi.org/10.17630/cb133261-b58e-4d72-b380-c877c993dc5dAn evaluation of a range of aryl, alkyl and vinyl esters as prospective C(1)-ammonium enolate precursors in enantioselective Michael addition-lactonisation processes with (E)-trifluoromethylenones using isothiourea catalysis is reported. Electron deficient aryl esters are required for reactivity, with 2,4,6-trichlorophenyl esters providing optimal product yields. Catalyst screening showed that tetramisole was the most effective isothiourea catalyst, giving the desired dihydropyranone product in excellent yield and stereoselectivity (up to 90:10 dr and 98:2 er). The scope and limitations of this process have been evaluated, with a range of diester products being generated after ring-opening with MeOH to give stereodefined dihydropyranones with excellent stereocontrol (10 examples, typically ~90:10 dr and >95:5 er).PostprintPeer reviewe

Isothiourea-catalyzed formal enantioselective conjugate addition of benzophenone imines to ß-fluorinated a,ß-unsaturated esters

The DOST-SEI and DOST-Foreign Graduate Scholarship Program of the Philippines are thanked for a PhD scholarship (J. E. L) and the Royal Society for a Newton Fellowship (C. S.).The isothiourea-catalyzed formal enantioselective conjugate addition of 2-hydroxybenzophenone imine derivatives to α,β-unsaturated para-nitrophenyl esters has been developed. Investigations of the scope and limitations of this procedure showed that β-electron withdrawing substituents within the α,β-unsaturated ester component was necessary for good product yield, giving rise to a range of β-imino ester and amide derivatives in moderate to good isolated yields with excellent enantioselectivity (20 examples, up to 81% yield and 97:3 er).Publisher PDFPeer reviewe

Incremental Medians via Online Bidding

In the k-median problem we are given sets of facilities and customers, and distances between them. For a given set F of facilities, the cost of serving a customer u is the minimum distance between u and a facility in F. The goal is to find a set F of k facilities that minimizes the sum, over all customers, of their service costs. Following Mettu and Plaxton, we study the incremental medians problem, where k is not known in advance, and the algorithm produces a nested sequence of facility sets where the kth set has size k. The algorithm is c-cost-competitive if the cost of each set is at most c times the cost of the optimum set of size k. We give improved incremental algorithms for the metric version: an 8-cost-competitive deterministic algorithm, a 2e ~ 5.44-cost-competitive randomized algorithm, a (24+epsilon)-cost-competitive, poly-time deterministic algorithm, and a (6e+epsilon ~ .31)-cost-competitive, poly-time randomized algorithm. The algorithm is s-size-competitive if the cost of the kth set is at most the minimum cost of any set of size k, and has size at most s k. The optimal size-competitive ratios for this problem are 4 (deterministic) and e (randomized). We present the first poly-time O(log m)-size-approximation algorithm for the offline problem and first poly-time O(log m)-size-competitive algorithm for the incremental problem. Our proofs reduce incremental medians to the following online bidding problem: faced with an unknown threshold T, an algorithm submits "bids" until it submits a bid that is at least the threshold. It pays the sum of all its bids. We prove that folklore algorithms for online bidding are optimally competitive.Comment: conference version appeared in LATIN 2006 as "Oblivious Medians via Online Bidding

Will HIV Vaccination Reshape HIV Risk Behavior Networks? A Social Network Analysis of Drug Users\u27 Anticipated Risk Compensation

Background An HIV vaccine could substantially impact the epidemic. However, risk compensation (RC), or post-vaccination increase in risk behavior, could present a major challenge. The methodology used in previous studies of risk compensation has been almost exclusively individual-level in focus, and has not explored how increased risk behavior could affect the connectivity of risk networks. This study examined the impact of anticipated HIV vaccine-related RC on the structure of high-risk drug users\u27 sexual and injection risk network. Methods A sample of 433 rural drug users in the US provided data on their risk relationships (i.e., those involving recent unprotected sex and/or injection equipment sharing). Dyad-specific data were collected on likelihood of increasing/initiating risk behavior if they, their partner, or they and their partner received an HIV vaccine. Using these data and social network analysis, a post-vaccination network was constructed and compared to the current network on measures relevant to HIV transmission, including network size, cohesiveness (e.g., diameter, component structure, density), and centrality. Results Participants reported 488 risk relationships. Few reported an intention to decrease condom use or increase equipment sharing (4% and 1%, respectively). RC intent was reported in 30 existing risk relationships and vaccination was anticipated to elicit the formation of five new relationships. RC resulted in a 5% increase in risk network size (n = 142 to n = 149) and a significant increase in network density. The initiation of risk relationships resulted in the connection of otherwise disconnected network components, with the largest doubling in size from five to ten. Conclusions This study demonstrates a new methodological approach to studying RC and reveals that behavior change following HIV vaccination could potentially impact risk network connectivity. These data will be valuable in parameterizing future network models that can determine if network-level change precipitated by RC would appreciably impact the vaccine\u27s population-level effectiveness

Rate and equilibrium constants for the addition of triazolium salt derived N-heterocyclic carbenes to heteroaromatic aldehydes

Heteroaromatic aldehydes are often used preferentially or exclusively in a range of NHC-catalysed processes that proceed through the generation of a reactive diaminoenol or Breslow Intermediate (BI), with the reason for their unique reactivity currently underexplored. This manuscript reports measurement of rate and equilibrium constants for the reaction between N-aryl triazolium NHCs and heteroaromatic aldehydes, providing insight into the effect of the NHC and heteroaromatic aldehyde structure up to formation of the BI. Variation in NHC catalyst and heteroaromatic aldehyde structure markedly affect the observed kinetic parameters of adduct formation, decay to starting materials and onward reaction to BI. In particular, large effects are observed with both 3-halogen (Br, F) and 3-methyl substituted pyridine-2-carboxaldehyde derivatives which substantially favour formation of the tetrahedral intermediate relative to benzaldehyde derivatives. Key observations indicate that increased steric hindrance leads to a reduction in both k2 and k−1 for large (2,6-disubstituted)-N-Ar groups within the triazolium scaffold, and sterically demanding aldehyde substituents in the 3-position, but not in the 6-position of the pyridine-2-carboxaldehyde derivatives. As part of this study, the isolation and characterisation of twenty tetrahedral adducts formed upon addition of N-aryl triazolium derived NHCs into heteroaromatic aldehydes are described. These adducts are key intermediates in NHC-catalysed umpolung addition of heteroaromatic aldehydes and are BI precursors

Regional differences in nutrient-induced secretion of gut serotonin

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Enterochromaffin (EC) cells located in the gastrointestinal (GI) tract provide the vast majority of serotonin (5‐HT) in the body and constitute half of all enteroendocrine cells. EC cells respond to an array of stimuli, including various ingested nutrients. Ensuing 5‐HT release from these cells plays a diverse role in regulating gut motility as well as other important responses to nutrient ingestion such as glucose absorption and fluid balance. Recent data also highlight the role of peripheral 5‐HT in various pathways related to metabolic control. Details related to the manner by which EC cells respond to ingested nutrients are scarce and as that the nutrient environment changes along the length of the gut, it is unknown whether the response of EC cells to nutrients is dependent on their GI location. The aim of the present study was to identify whether regional differences in nutrient sensing capability exist in mouse EC cells. We isolated mouse EC cells from duodenum and colon to demonstrate differential responses to sugars depending on location. Measurements of intracellular calcium concentration and 5‐HT secretion demonstrated that colonic EC cells are more sensitive to glucose, while duodenal EC cells are more sensitive to fructose and sucrose. Short‐chain fatty acids (SCFAs), which are predominantly synthesized by intestinal bacteria, have been previously associated with an increase in circulating 5‐HT; however, we find that SCFAs do not acutely stimulate EC cell 5‐HT release. Thus, we highlight that EC cell physiology is dictated by regional location within the GI tract, and identify differences in the regional responsiveness of EC cells to dietary sugars

Removal of a below knee plaster cast worn for 28 months: a case report

<p>Abstract</p> <p>Introduction</p> <p>An unusual situation in which a below knee cast was removed after 28 months is reported. To the best of our knowledge no similar cases have been reported in the literature.</p> <p>Case presentation</p> <p>The cast was removed from the leg of a 45-year-old Caucasian woman. Significant muscle atrophy and dense skin scales were present but the underlying skin surface was relatively healthy with only small pitted 1-2 mm ulcers. No pathogenic organisms were cultured from this environment.</p> <p>Conclusion</p> <p>It seems likely that skin can tolerate cast immobilization for prolonged duration.</p

The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male Mice

Female mice lacking ATRX in the pancreas have increased sensitivity to pancreatic cancer, whereas male mice without ATRX are protected. This study identifies such susceptibility in pancreatic cancer and highlights the need for sex-specific approaches in cancer treatment. BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in North America, accounting for \u3e30,000 deaths annually. Although somatic activating mutations in KRAS appear in 97% of PDAC patients, additional factors are required to initiate PDAC. Because mutations in genes encoding chromatin remodelling proteins have been implicated in KRAS-mediated PDAC, we investigated whether loss of chromatin remodeler.-thalassemia, mental-retardation, X-linked (ATRX) affects oncogenic KRAS\u27s ability to promote PDAC. ATRX affects DNA replication, repair, and gene expression and is implicated in other cancers including glioblastomas and pancreatic neuroendocrine tumors. The hypothesis was that deletion of Atrx in pancreatic acinar cells will increase susceptibility to injury and oncogenic METHODS: Mice allowing conditional loss of Atrx within pancreatic acinar cells were examined after induction of recurrent cerulein-induced pancreatitis or oncogenic KRAS (KRASG12D). Histologic, biochemical, and molecular analysis examined pancreatic pathologies up to 2 months after induction of Atrx deletion. RESULTS: Mice lacking Atrx showed more progressive damage, inflammation, and acinar-to-duct cell metaplasia in response to injury relative to wild-type mice. In combination with KRASG12D, Atrx-deficient acinar cells showed increased fibrosis, inflammation, progression to acinar-to-duct cell metaplasia, and pre-cancerous lesions relative to mice expressing only KRASG12D. This sensitivity appears only in female mice, mimicking a significant prevalence of ATRX mutations in human female PDAC patients. CONCLUSIONS: Our results indicate the absence of ATRX increases sensitivity to injury and oncogenic KRAS only in female mice. This is an instance of a sex-specific mutation that enhances oncogenic KRAS\u27s ability to promote pancreatic intraepithelial lesion formation