Fluxes and fluences of SEP events derived from SOLPENCO

International audienceWe have developed aran04 a tool for rapid predictions of proton flux and fluence profiles observed during gradual solar energetic particle (SEP) events and upstream of the associated traveling interplanetary shocks. This code, named SOLPENCO (for SOLar Particle ENgineering COde), contains a data base with a large set of interplanetary scenarios under which SEP events develop. These scenarios are basically defined by the solar longitude of the parent solar activity, ranging from E75 to W90, and by the position of the observer, located at 0.4 AU or at 1.0 AU, from the Sun. We are now analyzing the performance and reliability of SOLPENCO. We address here two features of SEP events especially relevant to space weather purposes: the peak flux and the fluence. We analyze how the peak flux and the fluence of the synthetic profiles generated by SOLPENCO vary as a function of the strength of the CME-driven shock, the heliolongitude of the solar parent activity and the particle energy considered. In particular, we comment on the dependence of the fluence on the radial distance of the observer (which does not follow an inverse square law), and we draw conclusions about the influence of the shock as a particle accelerator in terms of its evolving strength and the heliolongitude of the solar site where the SEP event originated

Comprehensive transcriptomic analysis of cell lines as models of primary tumors across 22 tumor types.

Cancer cell lines are a cornerstone of cancer research but previous studies have shown that not all cell lines are equal in their ability to model primary tumors. Here we present a comprehensive pan-cancer analysis utilizing transcriptomic profiles from The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia to evaluate cell lines as models of primary tumors across 22 tumor types. We perform correlation analysis and gene set enrichment analysis to understand the differences between cell lines and primary tumors. Additionally, we classify cell lines into tumor subtypes in 9 tumor types. We present our pancreatic cancer results as a case study and find that the commonly used cell line MIA PaCa-2 is transcriptionally unrepresentative of primary pancreatic adenocarcinomas. Lastly, we propose a new cell line panel, the TCGA-110-CL, for pan-cancer studies. This study provides a resource to help researchers select more representative cell line models

Evaluation of severity score-guided approaches to macrolide use in community-acquired pneumonia

International guidelines including those in the UK, Japan, Australia and South Africa recommend the avoidance of macrolides in patients with low-severity community-acquired pneumonia (CAP). We hypothesised that severity scores are poor predictors of atypical pneumonia and response to macrolide therapy, and thus, inadequate tools for guiding antibiotic prescriptions. Secondary analysis of four independent prospective CAP datasets was conducted. The predictive values of the CURB-65 and pneumonia severity index (PSI) for clinically important groups of causative pathogens were evaluated. The effect of macrolide use according to risk class was assessed by multivariable analysis. Patients (3297) were evaluated, and the predictive values of CURB-65 and PSI for atypical pathogens were poor (AUC values of 0.37 and 0.42, respectively). No significant differences were noted among the effects of macrolide use on mortality in patients with mild, moderate and severe CAP, according to either CURB-65 (interaction testing severe versus mild disease OR=0.74 (0.29–1.89)) or PSI (severe versus mild disease OR=3.4 (0.055–2.10)), indicating that severity scores were not significant modifiers of response to macrolide therapy. Severity scores did not accurately predict response to macrolide therapy in CAP, suggesting that current guidance to use these tools for empirical antibiotic choices might not be justified

Microstructural, Densitometric and Metabolic Variations in Bones from Rats with Normal or Altered Skeletal States

Background: High resolution μCT, and combined μPET/CT have emerged as non-invasive techniques to enhance or even replace dual energy X-ray absorptiometry (DXA) as the current preferred approach for fragility fracture risk assessment. The aim of this study was to assess the ability of µPET/CT imaging to differentiate changes in rat bone tissue density and microstructure induced by metabolic bone diseases more accurately than current available methods. Methods: Thirty three rats were divided into three groups of control, ovariectomy and vitamin-D deficiency. At the conclusion of the study, animals were subjected to glucose (18FDG) and sodium fluoride (Na18F) PET/CT scanning. Then, specimens were subjected to µCT imaging and tensile mechanical testing. Results: Compared to control, those allocated to ovariectomy and vitamin D deficiency groups showed 4% and 22% (significant) increase in 18FDG uptake values, respectively. DXA-based bone mineral density was higher in the vitamin D deficiency group when compared to the other groups (cortical bone), yet μCT-based apparent and mineral density results were not different between groups. DXA-based bone mineral density was lower in the ovariectomy group when compared to the other groups (cancellous bone); yet μCT-based mineral density results were not different between groups, and the μCT-based apparent density results were lower in the ovariectomy group compared to the other groups. Conclusion: PET and micro-CT provide an accurate three-dimensional measurement of the changes in bone tissue mineral density, as well as microstructure for cortical and cancellous bone and metabolic activity. As osteomalacia is characterized by impaired bone mineralization, the use of densitometric analyses may lead to misinterpretation of the condition as osteoporosis. In contrast, µCT alone and in combination with the PET component certainly provides an accurate three-dimensional measurement of the changes in both bone tissue mineral density, as well as microstructure for cortical and cancellous bone and metabolic activity

Intragenic DNA methylation: implications of this epigenetic mechanism for cancer research

Epigenetics is the study of all mechanisms that regulate gene transcription and genome stability that are maintained throughout the cell division, but do not include the DNA sequence itself. The best-studied epigenetic mechanism to date is DNA methylation, where methyl groups are added to the cytosine base within cytosine–guanine dinucleotides (CpG sites). CpGs are frequently clustered in high density (CpG islands (CGIs)) at the promoter of over half of all genes. Current knowledge of transcriptional regulation by DNA methylation centres on its role at the promoter where unmethylated CGIs are present at most actively transcribed genes, whereas hypermethylation of the promoter results in gene repression. Over the last 5 years, research has gradually incorporated a broader understanding that methylation patterns across the gene (so-called intragenic or gene body methylation) may have a role in transcriptional regulation and efficiency. Numerous genome-wide DNA methylation profiling studies now support this notion, although whether DNA methylation patterns are a cause or consequence of other regulatory mechanisms is not yet clear. This review will examine the evidence for the function of intragenic methylation in gene transcription, and discuss the significance of this in carcinogenesis and for the future use of therapies targeted against DNA methylation

Predicting temporary threshold shifts in a bottlenose dolphin (Tursiops truncatus) : the effects of noise level and duration

Author Posting. © Acoustical Society of America, 2009. This article is posted here by permission of Acoustical Society of America for personal use, not for redistribution. The definitive version was published in Journal of the Acoustical Society of America 125 (2009): 1816-1826, doi:10.1121/1.3068456.Noise levels in the ocean are increasing and are expected to affect marine mammals. To examine the auditory effects of noise on odontocetes, a bottlenose dolphin (Tursiops truncatus) was exposed to octave-band noise (4–8 kHz) of varying durations (<2–30 min) and sound pressures (130–178 dB re 1 µPa). Temporary threshold shift (TTS) occurrence was quantified in an effort to (i) determine the sound exposure levels (SELs) (dB re 1 µPa2 s) that induce TTS and (ii) develop a model to predict TTS onset. Hearing thresholds were measured using auditory evoked potentials. If SEL was kept constant, significant shifts were induced by longer duration exposures but not for shorter exposures. Higher SELs were required to induce shifts in shorter duration exposures. The results did not support an equal-energy model to predict TTS onset. Rather, a logarithmic algorithm, which increased in sound energy as exposure duration decreased, was a better predictor of TTS. Recovery to baseline hearing thresholds was also logarithmic (approximately −1.8 dB/doubling of time) but indicated variability including faster recovery rates after greater shifts and longer recoveries necessary after longer duration exposures. The data reflected the complexity of TTS in mammals that should be taken into account when predicting odontocete TTS.This work was funded by the Office of Naval Research Grant No. 00014-098-1-687 to P.E.N. and the support of Bob Gisiner and Mardi Hasting is noted. Additional support came from SeaSpace to T.A.M

Negative regulation of syntaxin4/SNAP-23/VAMP2-mediated membrane fusion by Munc18c <i>In Vitro</i>

Background: Translocation of the facilitative glucose transporter GLUT4 from an intracellular store to the plasma membrane is responsible for the increased rate of glucose transport into fat and muscle cells in response to insulin. This represents a specialised form of regulated membrane trafficking. Intracellular membrane traffic is subject to multiple levels of regulation by conserved families of proteins in all eukaryotic cells. Notably, all intracellular fusion events require SNARE proteins and Sec1p/Munc18 family members. Fusion of GLUT4-containing vesicles with the plasma membrane of insulin-sensitive cells involves the SM protein Munc18c, and is regulated by the formation of syntaxin 4/SNAP23/VAMP2 SNARE complexes. Methodology/Principal Findings Here we have used biochemical approaches to characterise the interaction(s) of Munc18c with its cognate SNARE proteins and to examine the role of Munc18c in regulating liposome fusion catalysed by syntaxin 4/SNAP23/VAMP2 SNARE complex formation. We demonstrate that Munc18c makes contacts with both t- and v-SNARE proteins of this complex, and directly inhibits bilayer fusion mediated by the syntaxin 4/SNAP23/VAMP2 SNARE complex. Conclusion/Significance Our reductionist approach has enabled us to ascertain a direct inhibitory role for Munc18c in regulating membrane fusion mediated by syntaxin 4/SNAP23/VAMP2 SNARE complex formation. It is important to note that two different SM proteins have recently been shown to stimulate liposome fusion mediated by their cognate SNARE complexes. Given the structural similarities between SM proteins, it seems unlikely that different members of this family perform opposing regulatory functions. Hence, our findings indicate that Munc18c requires a further level of regulation in order to stimulate SNARE-mediated membrane fusion

Environmental Inequality Dataset

The Disaggreated RSEI model data (also known as RSEI-GM, or Geographic Microdata) version 2.3.4 was downloaded from the Amazon Web Service created by EPA. The RSEI-GM provides detailed air model results from EPA’s Risk-Screening Environmental Indicators (RSEI) model. The results include chemical concentration, toxicity-weighted concentration and score, calculated for each 810 meter square grid cell in a 49-km circle around the emitting facility, for every year from 1988 through 2014. The data can be used to examine trends in air pollution from industrial facilities over time and across geographies. In order to allow for evaluation of toxic-weighted concentration over time, we used only the core chemicals and industries that have been consistently required to report since 1988. Thus we filtered the RSEI-GM disaggregated dataset to exclude additional chemicals and industries added after 1988. Crosswalks to translate data from the RSEI grid cell system to U.S. census block geographies, provided by EPA, were used to combine RSEI results with census data and aggregate the results to the census tract level. We used the Longitudinal Tract Database created by Brown University, which adjusts data from previous years to 2010 census tract boundaries, to combine census demographic information for years 1989 through 2004. We used the 2006-2010 American Community Survey (ACS) for years 2005 through 2009 and the 2010-2014 ACS for years 2010 through 2014. This data were then used to calculate measures of environmental inequality. The ZIP file with the dataset is available below under additional files

Genome-wide methylation analysis identifies genes silenced in non-seminoma cell lines

Silencing of genes by DNA methylation is a common phenomenon in many types of cancer. However, the genome wide effect of DNA methylation on gene expression has been analysed in relatively few cancers. Germ cell tumours (GCTs) are a complex group of malignancies. They are unique in developing from a pluripotent progenitor cell. Previous analyses have suggested that non-seminomas exhibit much higher levels of DNA methylation than seminomas. The genomic targets that are methylated, the extent to which this results in gene silencing and the identity of the silenced genes most likely to play a role in the tumours’ biology have not yet been established. In this study, genome-wide methylation and expression analysis of GCT cell lines was combined with gene expression data from primary tumours to address this question. Genome methylation was analysed using the Illumina infinium HumanMethylome450 bead chip system and gene expression was analysed using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Regulation by methylation was confirmed by demethylation using 5-aza-2-deoxycytidine and reverse transcription–quantitative PCR. Large differences in the level of methylation of the CpG islands of individual genes between tumour cell lines correlated well with differential gene expression. Treatment of non-seminoma cells with 5-aza-2-deoxycytidine verified that methylation of all genes tested played a role in their silencing in yolk sac tumour cells and many of these genes were also differentially expressed in primary tumours. Genes silenced by methylation in the various GCT cell lines were identified. Several pluripotency-associated genes were identified as a major functional group of silenced genes