Evolution of Burkholderia pseudomallei in Recurrent Melioidosis

Burkholderia pseudomallei, the etiologic agent of human melioidosis, is capable of causing severe acute infection with overwhelming septicemia leading to death. A high rate of recurrent disease occurs in adult patients, most often due to recrudescence of the initial infecting strain. Pathogen persistence and evolution during such relapsing infections are not well understood. Bacterial cells present in the primary inoculum and in late infections may differ greatly, as has been observed in chronic disease, or they may be genetically similar. To test these alternative models, we conducted whole-genome comparisons of clonal primary and relapse B. pseudomallei isolates recovered six months to six years apart from four adult Thai patients. We found differences within each of the four pairs, and some, including a 330 Kb deletion, affected substantial portions of the genome. Many of the changes were associated with increased antibiotic resistance. We also found evidence of positive selection for deleterious mutations in a TetR family transcriptional regulator from a set of 107 additional B. pseudomallei strains. As part of the study, we sequenced to base-pair accuracy the genome of B. pseudomallei strain 1026b, the model used for genetic studies of B. pseudomallei pathogenesis and antibiotic resistance. Our findings provide new insights into pathogen evolution during long-term infections and have important implications for the development of intervention strategies to combat recurrent melioidosis

Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity

AIMS/HYPOTHESIS: Insulin controls glucose metabolism via multiple signalling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway in muscle and adipose tissue. The protein/lipid phosphatase Pten (phosphatase and tensin homologue deleted on chromosome 10) attenuates PI3K signalling by dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate generated by PI3K. The current study was aimed at investigating the effect of haploinsufficiency for Pten on insulin-stimulated glucose uptake. MATERIALS AND METHODS: Insulin sensitivity in Pten heterozygous (Pten(+/−)) mice was investigated in i.p. insulin challenge and glucose tolerance tests. Glucose uptake was monitored in vitro in primary cultures of myocytes from Pten(+/−) mice, and in vivo by positron emission tomography. The phosphorylation status of protein kinase B (PKB/Akt), a downstream signalling protein in the PI3K pathway, and glycogen synthase kinase 3β (GSK3β), a substrate of PKB/Akt, was determined by western immunoblotting. RESULTS: Following i.p. insulin challenge, blood glucose levels in Pten(+/−) mice remained depressed for up to 120 min, whereas glucose levels in wild-type mice began to recover after approximately 30 min. After glucose challenge, blood glucose returned to normal about twice as rapidly in Pten(+/−) mice. Enhanced glucose uptake was observed both in Pten(+/−) myocytes and in skeletal muscle of Pten(+/−) mice by PET. PKB and GSK3β phosphorylation was enhanced and prolonged in Pten(+/−) myocytes. CONCLUSIONS/INTERPRETATION: Pten is a key negative regulator of insulin-stimulated glucose uptake in vitro and in vivo. The partial reduction of Pten due to Pten haploinsufficiency is enough to elicit enhanced insulin sensitivity and glucose tolerance in Pten(+/−) mice

Overview and future challenges of nearly zero energy buildings (nZEB) design in Southern Europe

In times of great transition of the European construction sector to energy efficient and nearly zero energy buildings (nZEB), a market observation containing qualitative and quantitative indications should help to fill out some of the current gaps concerning the EU 2020 carbon targets. Next to the economic challenges, there are equally important factors that hinder renovating the existing residential building stock and adding newly constructed high performance buildings. Under these circumstances this paper summarises the findings of a cross-comparative study of the societal and technical barriers of nZEB implementation in 7 Southern European countries. The study analyses the present situation and provides an overview on future prospects for nZEB in Southern Europe. The result presents an overview of challenges and provides recommendations based on available empirical evidence to further lower those barriers in the European construction sector. The paper finds that the most Southern European countries are poorly prepared for nZEB implementation and especially to the challenge opportunity of retrofitting existing buildings. Creating a common approach to further develop nZEB targets, concepts and definitions in synergy with the climatic, societal and technical state of progress in Southern Europe is essential. The paper provides recommendations for actions to shift the identified gaps into opportunities for future development of climate adaptive high performance buildings. (C) 2017 Elsevier B.V. All rights reserved.info:eu-repo/semantics/publishedVersio

Current clinical applications of spectral tissue Doppler echocardiography (E/E' ratio) as a noninvasive surrogate for left ventricular diastolic pressures in the diagnosis of heart failure with preserved left ventricular systolic function

Congestive heart failure with preserved left ventricular systolic function has emerged as a growing epidemic medical syndrome in developed countries, which is characterized by high morbidity and mortality rates. Rapid and accurate diagnosis of this condition is essential for optimizing the therapeutic management. The diagnosis of congestive heart failure is challenging in patients presenting without obvious left ventricular systolic dysfunction and additional diagnostic information is most commonly required in this setting. Comprehensive Doppler echocardiography is the single most useful diagnostic test recommended by the ESC and ACC/AHA guidelines for assessing left ventricular ejection fraction and cardiac abnormalities in patients with suspected congestive heart failure, and non-invasively determined basal or exercise-induced pulmonary capillary hypertension is likely to become a hallmark of congestive heart failure in symptomatic patients with preserved left ventricular systolic function. The present review will focus on the current clinical applications of spectral tissue Doppler echocardiography used as a reliable noninvasive surrogate for left ventricular diastolic pressures at rest as well as during exercise in the diagnosis of heart failure with preserved left ventricular systolic function. Chronic congestive heart failure, a disease of exercise, and acute heart failure syndromes are characterized by specific pathophysiologic and diagnostic issues, and these two clinical presentations will be discussed separately

Observations of Lyα\alpha Emitters at High Redshift

In this series of lectures, I review our observational understanding of high-$z$ Ly$\alpha$ emitters (LAEs) and relevant scientific topics. Since the discovery of LAEs in the late 1990s, more than ten (one) thousand(s) of LAEs have been identified photometrically (spectroscopically) at $z\sim 0$ to $z\sim 10$. These large samples of LAEs are useful to address two major astrophysical issues, galaxy formation and cosmic reionization. Statistical studies have revealed the general picture of LAEs' physical properties: young stellar populations, remarkable luminosity function evolutions, compact morphologies, highly ionized inter-stellar media (ISM) with low metal/dust contents, low masses of dark-matter halos. Typical LAEs represent low-mass high-$z$ galaxies, high-$z$ analogs of dwarf galaxies, some of which are thought to be candidates of population III galaxies. These observational studies have also pinpointed rare bright Ly$\alpha$ sources extended over $\sim 10-100$ kpc, dubbed Ly$\alpha$ blobs, whose physical origins are under debate. LAEs are used as probes of cosmic reionization history through the Ly$\alpha$ damping wing absorption given by the neutral hydrogen of the inter-galactic medium (IGM), which complement the cosmic microwave background radiation and 21cm observations. The low-mass and highly-ionized population of LAEs can be major sources of cosmic reionization. The budget of ionizing photons for cosmic reionization has been constrained, although there remain large observational uncertainties in the parameters. Beyond galaxy formation and cosmic reionization, several new usages of LAEs for science frontiers have been suggested such as the distribution of {\sc Hi} gas in the circum-galactic medium and filaments of large-scale structures. On-going programs and future telescope projects, such as JWST, ELTs, and SKA, will push the horizons of the science frontiers.Comment: Lecture notes for `Lyman-alpha as an Astrophysical and Cosmological Tool', Saas-Fee Advanced Course 46. Verhamme, A., North, P., Cantalupo, S., & Atek, H. (eds.) --- 147 pages, 103 figures. Abstract abridged. Link to the lecture program including the video recording and ppt files : https://obswww.unige.ch/Courses/saas-fee-2016/program.cg

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

ICAR: endoscopic skull‐base surgery

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The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC

Galaxy And Mass Assembly (GAMA): Data Release 4 and the z < 0.1 total and z < 0.08 morphological galaxy stellar mass functions

In Galaxy And Mass Assembly Data Release 4 (GAMA DR4), we make available our full spectroscopic redshift sample. This includes 248 682 galaxy spectra, and, in combination with earlier surveys, results in 330 542 redshifts across five sky regions covering similar to 250 deg(2). The redshift density, is the highest available over such a sustained area, has exceptionally high completeness (95 per cent to r(KiDS) = 19.65 mag), and is well-suited for the study of galaxy mergers, galaxy groups, and the low redshift (z < 0.25) galaxy population. DR4 includes 32 value-added tables or Data Management Units (DMUs) that provide a number of measured and derived data products including GALEX, ESO KiDS, ESO VIKING, WISE, and HerschelSpace Observatory imaging. Within this release, we provide visual morphologies for 15 330 galaxies to z < 0.08, photometric redshift estimates for all 18 million objects to r(KiDS) similar to 25 mag, and stellar velocity dispersions for 111 830 galaxies. We conclude by deriving the total galaxy stellar mass function (GSMF) and its sub-division by morphological class (elliptical, compact-bulge and disc, diffuse-bulge and disc, and disc only). This extends our previous measurement of the total GSMF down to 10(6.75) M-circle dot h(70)(-2) and we find a total stellar mass density of rho(*) = (2.97 +/- 0.04) x 10(8) M-circle dot h(70) Mpc(-3) or Omega(*)=(2.17 +/- 0.03) x 10(-3) h(70)(-1). We conclude that at z < 0.1, the Universe has converted 4.9 +/- 0.1 per cent of the baryonic mass implied by big bang Nucleosynthesis into stars that are gravitationally bound within the galaxy population