Extragenic suppressor mutations in ΔripA disrupt stability and function of LpxA

Abstract Background Francisella tularensis is a Gram-negative bacterium that infects hundreds of species including humans, and has evolved to grow efficiently within a plethora of cell types. RipA is a conserved membrane protein of F. tularensis, which is required for growth inside host cells. As a means to determine RipA function we isolated and mapped independent extragenic suppressor mutants in ∆ripA that restored growth in host cells. Each suppressor mutation mapped to one of two essential genes, lpxA or glmU, which are involved in lipid A synthesis. We repaired the suppressor mutation in lpxA (S102, LpxA T36N) and the mutation in glmU (S103, GlmU E57D), and demonstrated that each mutation was responsible for the suppressor phenotype in their respective strains. We hypothesize that the mutation in S102 altered the stability of LpxA, which can provide a clue to RipA function. LpxA is an UDP-N-acetylglucosamine acyltransferase that catalyzes the transfer of an acyl chain from acyl carrier protein (ACP) to UDP-N-acetylglucosamine (UDP-GlcNAc) to begin lipid A synthesis. Results LpxA was more abundant in the presence of RipA. Induced expression of lpxA in the ΔripA strain stopped bacterial division. The LpxA T36N S102 protein was less stable and therefore less abundant than wild type LpxA protein. Conclusion These data suggest RipA functions to modulate lipid A synthesis in F. tularensis as a way to adapt to the host cell environment by interacting with LpxA.http://deepblue.lib.umich.edu/bitstream/2027.42/110509/1/12866_2014_Article_336.pd

Perceived discrimination amongst the indigenous Mapuche people in Chile : some comparisons with Australia

With similar settler-colonial histories having left them occupying the position of marginalized minority groups, indigenous people in Chile and Australia are struggling to assert their rights and retain their cultures. Research in each location suggests that there is widespread prejudice and discrimination against them, even though the mainstream society sees itself as tolerant and harmonious. This paper reports on a study in which thirty Mapuche people in Chile were interviewed about their perceptions of discrimination against them. Their responses were systematically analysed using a taxonomy of racist experiences established in a study of Aborigines in Australia. Like indigenous Australians, the Mapuche people of Chile reported that they experience extensive discrimination in all areas of life. These findings are discussed with respect to the issues related to relationships between settlers and colonized communities.<br /

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Attitudes and social conditions : essays

For his study of Western Australian attitudes towards Aborigines Dr Taft chose three samples: in Perth, where there arc few Aborigines; in a large country town with a reputation for bad relations between Europeans and Aborigines; and in a small country town where relations were good. He analyses these attitudes with respect to several variables and finds that the most important influences on the relationships are the effects of community norms. Some interesting aspects of European attitudes to one another also emerge. Dr Dawson's study is part of a larger research program concerned with the effects of rapid biological and social change. He examines in detail the attitudes of two groups of Aborigines, one living in metropolitan Sydney and one in a rural settlement on the South Coast of New South Wales. The effects of the different environments arc clearly shown in the attitudes of the two groups towards education and integration. After a preliminary survey of the Redfern-Chippendale area, Mrs Beasley extended her research over the whole of Sydney, as she moved around the city getting to know Aboriginal families in their own homes. She examines in detail the nature of these households - where the members come from, what their living conditions are like, what kind of schooling they have had, and what jobs they hold. The three studies will be of interest to all those concerned with European-Aboriginal relations