Multidrug-resistant Gram-negative bacteria (MDR-GNB) are an emerging public health threat. Accurate estimates of their clinical impact are vital for justifying interventions directed towards ...preventing or managing infections caused by these pathogens. A retrospective observational cohort study was conducted between 1 January 2007 and 31 July 2009, involving subjects with healthcare-associated and nosocomial Gram-negative bacteraemia at two large Singaporean hospitals. Outcomes studied were mortality and length of stay post-onset of bacteraemia in survivors (LOS). There were 675 subjects (301 with MDR-GNB) matching study inclusion criteria. On multivariate analysis, multidrug resistance was not associated with 30-day mortality, but it was independently associated with longer LOS in survivors (coefficient, 0.34; 95% CI, 0.21–0.48; p < 0.001). The excess LOS attributable to multidrug resistance after adjustment for confounders was 6.1 days. Other independent risk factors for higher mortality included male gender, higher APACHE II score, higher Charlson comorbidity index, intensive care unit stay and presence of concomitant pneumonia. Concomitant urinary tract infection and admission to a surgical discipline were associated with lower risk of mortality. Appropriate empirical antibiotic therapy was neither associated with 30-day mortality nor LOS, although the study was not powered to assess this covariate adequately. Our study adds to existing evidence that multidrug resistance per se is not associated with higher mortality when effective antibiotics are used for definitive therapy. However, its association with longer hospitalization justifies the use of control efforts.
Transient receptor potential melastatin member 8 (TRPM8) is a calcium ion (Ca
)-permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling ...compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP
), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo-electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP
, and Ca
, as well as in complex with the menthol analog WS-12 and PIP
Our structures reveal the binding sites for cooling agonists and PIP
in TRPM8. Notably, PIP
binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP
and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.
► We conducted two laboratory experiments over 3years on three porous pavement types. ► Continual wetting with no drying, and variable inflow with drying were simulated. ► Variable inflow and drying ...periods approximately doubled the lifespan of all systems. ► A simple regression model to predict hydraulic resistance (clogging) was developed. ► Hydraulic resistance is an exponential function of cumulative volume and flow rate.
Porous pavements are easily retrofitted, and effective in improving water quality and hydrology, but prone to clogging. Despite being a major determinant in the lifespan of porous pavements, there is limited information on the physical clogging processes through these systems. The aim of this study was to understand the main physical processes that govern physical clogging and develop a simple black-box model that predicts physical clogging. The key variables that were hypothesised to influence clogging were pavement design and climate characteristics. Two compressed time scale laboratory experiments were conducted over 3years on three common porous pavement types; monolithic porous asphalt, modular Hydrapave and monolithic Permapave. Pavement design was found to be an important role in clogging. Permapave did not clog even after 26years of operation in simulated sub-tropical Brisbane (Australia) climate while porous asphalt and Hydrapave clogged after just 12years, from surface clogging and geotextile clogging, respectively. Each system was tested using two different dosing patterns: (1) continual wetting with no dry periods and (2) variable inflow rates with drying periods (i.e. representing more natural conditions). The latter dosing method approximately doubled the lifespan of all systems suggesting the influence of climate conditions on clogging. Clogging was found to be highly correlated with cumulative volume and flow rate. A simple black-box regression model that predicts physical clogging was developed as a function of cumulative volume and Brisbane climatic conditions. However it is very likely that the shape of this regression is general, and that it could be calibrated for different climates in the future.
The transfer of spin angular momentum from a spin-polarized current to a ferromagnet can generate sufficient torque to reorient the magnet's moment. This torque could enable the development of ...efficient electrically actuated magnetic memories and nanoscale microwave oscillators. Yet difficulties in making quantitative measurements of the spin-torque vector have hampered understanding. Here we present direct measurements of both the magnitude and direction of the spin torque in magnetic tunnel junctions, the type of device of primary interest for applications. At low bias V, the differential torque dtau/dV lies in the plane defined by the electrode magnetizations, and its magnitude is in excellent agreement with recent predictions for near-perfect spin-polarized tunnelling. We find that the strength of the in-plane differential torque remains almost constant with increasing bias, despite a substantial decrease in the device magnetoresistance, and that with bias the torque vector also rotates out of the plane. PUBLICATION ABSTRACT
Epidermal growth factor receptor (EGFR) gene amplification and mutations are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive tumor growth ...are not well understood. Here, through integrated epigenome and transcriptome analyses of cell lines, genotyped clinical samples, and TCGA data, we show that EGFR mutations remodel the activated enhancer landscape of GBM, promoting tumorigenesis through a SOX9 and FOXG1-dependent transcriptional regulatory network in vitro and in vivo. The most common EGFR mutation, EGFRvIII, sensitizes GBM cells to the BET-bromodomain inhibitor JQ1 in a SOX9, FOXG1-dependent manner. These results identify the role of transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy.
Display omitted
•Oncogenic EGFRvIII mutation remodels the enhancer landscape in GBM•EGFRvIII induces SOX9 and FOXG1 transcription in GBM•SOX9 and FOXG1 collaborate to activate an oncogenic gene regulatory program•EGFRvIII-dependent transcription sensitizes GBM cells to JQ1
Epidermal growth factor receptor (EGFR) gene amplification and mutations are the most common oncogenic events in glioblastoma (GBM). Through an integrative genomics analysis, Liu et al., identify a role for transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy.
Most patients with Alzheimer's disease present with amnestic problems; however, a substantial proportion, over-represented in young-onset cases, have atypical phenotypes including predominant visual, ...language, executive, behavioural, or motor dysfunction. In the past, these individuals often received a late diagnosis; however, availability of CSF and PET biomarkers of Alzheimer's disease pathologies and incorporation of atypical forms of Alzheimer's disease into new diagnostic criteria increasingly allows them to be more confidently diagnosed early in their illness. This early diagnosis in turn allows patients to be offered tailored information, appropriate care and support, and individualised treatment plans. These advances will provide improved access to clinical trials, which often exclude atypical phenotypes. Research into atypical Alzheimer's disease has revealed previously unrecognised neuropathological heterogeneity across the Alzheimer's disease spectrum. Neuroimaging, genetic, biomarker, and basic science studies are providing key insights into the factors that might drive selective vulnerability of differing brain networks, with potential mechanistic implications for understanding typical late-onset Alzheimer's disease.
Abstract
Chemical modification of transcripts with 5′ caps occurs in all organisms. Here, we report a systems-level mass spectrometry-based technique, CapQuant, for quantitative analysis of an ...organism's cap epitranscriptome. The method was piloted with 21 canonical caps—m7GpppN, m7GpppNm, GpppN, GpppNm, and m2,2,7GpppG—and 5 ‘metabolite’ caps—NAD, FAD, UDP-Glc, UDP-GlcNAc, and dpCoA. Applying CapQuant to RNA from purified dengue virus, Escherichia coli, yeast, mouse tissues, and human cells, we discovered new cap structures in humans and mice (FAD, UDP-Glc, UDP-GlcNAc, and m7Gpppm6A), cell- and tissue-specific variations in cap methylation, and high proportions of caps lacking 2′-O-methylation (m7Gpppm6A in mammals, m7GpppA in dengue virus). While substantial Dimroth-induced loss of m1A and m1Am arose with specific RNA processing conditions, human lymphoblast cells showed no detectable m1A or m1Am in caps. CapQuant accurately captured the preference for purine nucleotides at eukaryotic transcription start sites and the correlation between metabolite levels and metabolite caps.
Nonalcoholic fatty liver disease (NAFLD) occurs due to the accumulation of fat in the liver, leading to fatal liver diseases such as nonalcoholic steatohepatitis (NASH) and cirrhosis. Elucidation of ...the molecular mechanisms underlying NAFLD is critical for its prevention and therapy. Here, we observed that deubiquitinase USP15 expression was upregulated in the livers of mice fed a high-fat diet (HFD) and liver biopsies of patients with NAFLD or NASH. USP15 interacts with lipid-accumulating proteins such as FABPs and perilipins to reduce ubiquitination and increase their protein stability. Furthermore, the severity of NAFLD induced by an HFD and NASH induced by a fructose/palmitate/cholesterol/trans-fat (FPC) diet was significantly ameliorated in hepatocyte-specific USP15 knockout mice. Thus, our findings reveal an unrecognized function of USP15 in the lipid accumulation of livers, which exacerbates NAFLD to NASH by overriding nutrients and inducing inflammation. Therefore, targeting USP15 can be used in the prevention and treatment of NAFLD and NASH.
Aim
To describe the methods of the 2016 International Tobacco Control (ITC) Four Country Smoking and Vaping (4CV) Survey, conducted in 2016 in Australia (AU), Canada (CA), England (EN) and the United ...States (US).
Methods
The respondents were cigarette smokers, former smokers (quit within the previous 2 years), and at‐least‐weekly vapers, aged 18 years and older. Eligible cohort members from the ITC Four Country Survey (4C) were retained. New respondents were sampled by commercial firms from their panels. Where possible, ages 18–24 and vapers were oversampled. Data were collected online, and respondents were remunerated. Survey weights were calibrated to benchmarks from nationally representative surveys.
Results
Response rates by country for new recruits once invited ranged from 15.2 to 49.6%. Sample sizes for smokers/former smokers were 1504 in AU, 3006 in CA, 3773 in EN and 2239 in the US. Sample sizes for additional vapers were 727 in CA, 551 in EN and 494 in the US.
Conclusion
The International Tobacco Control Four Country Smoking and Vaping Survey design and data collection methods allow analyses to examine prospectively the use of cigarettes and nicotine vaping products in jurisdictions with different regulatory policies. The effects on the sampling designs and response quality of recruiting the respondents from commercial panels are mitigated by the use of demographic and geographic quotas in sampling; by quality control measures; and by the construction of survey weights taking into account smoking/vaping status, sex, age, education and geography.
Although gas breakdown phenomena have been intensively studied over 100 years, the breakdown mechanism in a strongly magnetized system, such as tokamak, has been still obscured due to complex ...electromagnetic topologies. There has been a widespread misconception that the conventional breakdown model of the unmagnetized system can be directly applied to the strongly magnetized system. However, we found clear evidence that existing theories cannot explain the experimental results. Here, we demonstrate the underlying mechanism of gas breakdown in tokamaks, a turbulent ExB mixing avalanche, which systematically considers multi-dimensional plasma dynamics in the complex electromagnetic topology. This mechanism clearly elucidates the experiments by identifying crucial roles of self-electric fields produced by space-charge that decrease the plasma density growth rate and cause a dominant transport via ExB drifts. A comprehensive understanding of plasma dynamics in complex electromagnetic topology provides general design strategy for robust breakdown scenarios in a tokamak fusion reactor.
PDF
