Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Impact of growth matrix on pharmacodynamics of antimicrobial drugs for pig pneumonia pathogens

Abstract Background The most widely used measure of potency of antimicrobial drugs is Minimum Inhibitory Concentration (MIC). MIC is usually determined under standardised conditions in broths formulated to optimise bacterial growth on a species-by-species basis. This ensures comparability of data between laboratories. However, differences in values of MIC may arise between broths of differing chemical composition and for some drug classes major differences occur between broths and biological fluids such as serum and inflammatory exudate. Such differences must be taken into account, when breakpoint PK/PD indices are derived and used to predict dosages for clinical use. There is therefore interest in comparing MIC values in several broths and, in particular, in comparing broth values with those generated in serum. For the pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida, MICs were determined for three drugs, florfenicol, oxytetracycline and marbofloxacin, in five broths [Mueller Hinton Broth (MHB), cation-adjusted Mueller Hinton Broth (CAMHB), Columbia Broth supplemented with NAD (CB), Brain Heart Infusion Broth (BHI) and Tryptic Soy Broth (TSB)] and in pig serum. Results For each drug, similar MIC values were obtained in all broths, with one exception, marbofloxacin having similar MICs for three broths and 4–5-fold higher MICs for two broths. In contrast, for both organisms, quantitative differences between broth and pig serum MICs were obtained after correction of MICs for drug binding to serum protein (fu serum MIC). Potency was greater (fu serum MIC lower) in serum than in broths for marbofloxacin and florfenicol for both organisms. For oxytetracycline fu serum:broth MIC ratios were 6.30:1 (P. multocida) and 0.35:1 (A. pleuropneumoniae), so that potency of this drug was reduced for the former species and increased for the latter species. The chemical composition of pig serum and broths was compared; major matrix differences in 14 constituents did not account for MIC differences. Bacterial growth rates were compared in broths and pig serum in the absence of drugs; it was concluded that broth/serum MIC differences might be due to differing growth rates in some but not all instances. Conclusions For all organisms and all drugs investigated in this study, it is suggested that broth MICs should be adjusted by an appropriate scaling factor when used to determine pharmacokinetic/pharmacodynamic breakpoints for dosage prediction

Treatment of an Intramammary Bacterial Infection with 25-Hydroxyvitamin D3

Deficiency of serum levels of 25-hydroxyvitamin D3 has been correlated with increased risk of infectious diseases such as tuberculosis and influenza. A plausible reason for this association is that expression of genes encoding important antimicrobial proteins depends on concentrations of 1,25-dihydroxyvitamin D3 produced by activated immune cells at sites of infection, and that synthesis of 1,25-dihydroxyvitamin D3 is dependent on the availability of 25-hydroxyvitamin D3. Thus, increasing the availability of 25(OH)D3 for immune cell synthesis of 1,25-dihydroxyvitamin D3 at sites of infection has been hypothesized to aid in clearance of the infection. This report details the treatment of an acute intramammary infection with infusion of 25-hydroxyvitamin D3 to the site of infection. Ten lactating cows were infected with in one quarter of their mammary glands. Half of the animals were treated intramammary with 25-hydroxyvitamin D3. The 25-hydroxyvitamin D3 treated animal showed significantly lower bacterial counts in milk and showed reduced symptomatic affects of the mastitis. It is significant that treatment with 25-hydroxyvitamin D3 reduced the severity of an acute bacterial infection. This finding suggested a significant non-antibiotic complimentary role for 25-hydroxyvitamin D3 in the treatment of infections in compartments naturally low in 25-hydroxyvitamin D3 such as the mammary gland and by extension, possibly upper respiratory tract infections

Assessment of α-Synuclein Secretion in Mouse and Human Brain Parenchyma

Genetic, biochemical, and animal model studies strongly suggest a central role for α-synuclein in the pathogenesis of Parkinson's disease. α-synuclein lacks a signal peptide sequence and has thus been considered a cytosolic protein. Recent data has suggested that the protein may be released from cells via a non-classical secretory pathway and may therefore exert paracrine effects in the extracellular environment. However, proof that α-synuclein is actually secreted into the brain extracellular space in vivo has not been obtained. We developed a novel highly sensitive ELISA in conjugation with an in vivo microdialysis technique to measure α-synuclein in brain interstitial fluid. We show for the first time that α-synuclein is readily detected in the interstitial fluid of both α-synuclein transgenic mice and human patients with traumatic brain injury. Our data suggest that α-synuclein is physiologically secreted by neurons in vivo. This interstitial fluid pool of the protein may have a role in the propagation of synuclein pathology and progression of Parkinson's disease

Tikhonov adaptively regularized gamma variate fitting to assess plasma clearance of inert renal markers

The Tk-GV model fits Gamma Variates (GV) to data by Tikhonov regularization (Tk) with shrinkage constant, λ, chosen to minimize the relative error in plasma clearance, CL (ml/min). Using 169Yb-DTPA and 99mTc-DTPA (n = 46, 8–9 samples, 5–240 min) bolus-dilution curves, results were obtained for fit methods: (1) Ordinary Least Squares (OLS) one and two exponential term (E1 and E2), (2) OLS-GV and (3) Tk-GV. Four tests examined the fit results for: (1) physicality of ranges of model parameters, (2) effects on parameter values when different data subsets are fit, (3) characterization of residuals, and (4) extrapolative error and agreement with published correction factors. Test 1 showed physical Tk-GV results, where OLS-GV fits sometimes-produced nonphysical CL. Test 2 showed the Tk-GV model produced good results with 4 or more samples drawn between 10 and 240 min. Test 3 showed that E1 and E2 failed goodness-of-fit testing whereas GV fits for t > 20 min were acceptably good. Test 4 showed CLTk-GV clearance values agreed with published CL corrections with the general result that CLE1 > CLE2 > CLTk-GV and finally that CLTk-GV were considerably more robust, precise and accurate than CLE2, and should replace the use of CLE2 for these renal markers

Visualizing the Distribution of Synapses from Individual Neurons in the Mouse Brain

BACKGROUND:Proper function of the mammalian brain relies on the establishment of highly specific synaptic connections among billions of neurons. To understand how complex neural circuits function, it is crucial to precisely describe neuronal connectivity and the distributions of synapses to and from individual neurons. METHODS AND FINDINGS:In this study, we present a new genetic synaptic labeling method that relies on expression of a presynaptic marker, synaptophysin-GFP (Syp-GFP) in individual neurons in vivo. We assess the reliability of this method and use it to analyze the spatial patterning of synapses in developing and mature cerebellar granule cells (GCs). In immature GCs, Syp-GFP is distributed in both axonal and dendritic regions. Upon maturation, it becomes strongly enriched in axons. In mature GCs, we analyzed synapses along their ascending segments and parallel fibers. We observe no differences in presynaptic distribution between GCs born at different developmental time points and thus having varied depths of projections in the molecular layer. We found that the mean densities of synapses along the parallel fiber and the ascending segment above the Purkinje cell (PC) layer are statistically indistinguishable, and higher than previous estimates. Interestingly, presynaptic terminals were also found in the ascending segments of GCs below and within the PC layer, with the mean densities two-fold lower than that above the PC layer. The difference in the density of synapses in these parts of the ascending segment likely reflects the regional differences in postsynaptic target cells of GCs. CONCLUSIONS:The ability to visualize synapses of single neurons in vivo is valuable for studying synaptogenesis and synaptic plasticity within individual neurons as well as information flow in neural circuits

Seasonality in Human Zoonotic Enteric Diseases: A Systematic Review

BACKGROUND: Although seasonality is a defining characteristic of many infectious diseases, few studies have described and compared seasonal patterns across diseases globally, impeding our understanding of putative mechanisms. Here, we review seasonal patterns across five enteric zoonotic diseases: campylobacteriosis, salmonellosis, vero-cytotoxigenic Escherichia coli (VTEC), cryptosporidiosis and giardiasis in the context of two primary drivers of seasonality: (i) environmental effects on pathogen occurrence and pathogen-host associations and (ii) population characteristics/behaviour. METHODOLOGY/PRINCIPAL FINDINGS: We systematically reviewed published literature from 1960-2010, resulting in the review of 86 studies across the five diseases. The Gini coefficient compared temporal variations in incidence across diseases and the monthly seasonality index characterised timing of seasonal peaks. Consistent seasonal patterns across transnational boundaries, albeit with regional variations was observed. The bacterial diseases all had a distinct summer peak, with identical Gini values for campylobacteriosis and salmonellosis (0.22) and a higher index for VTEC (Gini  0.36). Cryptosporidiosis displayed a bi-modal peak with spring and summer highs and the most marked temporal variation (Gini = 0.39). Giardiasis showed a relatively small summer increase and was the least variable (Gini = 0.18). CONCLUSIONS/SIGNIFICANCE: Seasonal variation in enteric zoonotic diseases is ubiquitous, with regional variations highlighting complex environment-pathogen-host interactions. Results suggest that proximal environmental influences and host population dynamics, together with distal, longer-term climatic variability could have important direct and indirect consequences for future enteric disease risk. Additional understanding of the concerted influence of these factors on disease patterns may improve assessment and prediction of enteric disease burden in temperate, developed countries

Effect of Sodium Trimetaphosphate on Hydroxyapatite Solubility: An In Vitro Study

This study evaluated the effect of different concentrations of sodium trimetaphosphate (TMP) with and without fluoride (F) on the concentration of calcium (Ca), phosphorus (P) and F in hydroxyapatite (HA). Synthetic HA powder (0.15 g) was suspended (n=6) in solutions (75 mL) of TMP at 0%, 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 2.0%, 4.0%, 6.0%, 8.0% and 10% concentrations in the presence and absence of 100 ppm F and subjected to a pH-cycling process. The precipitates were filtrated, dried at 70° C for 24 h and ground onto a fine powder. The concentrations of F (KOH (CaF2) and HCl (FA) soluble), Ca (Arsenazo III), and P (molybdate method) in HA were determined. The Ca P, and Ca/P ratio data were subjected to Tukey's test and the F data were subjected to Student-Newman-Keuls test (p<0.05). The addition of TMP to the samples reduced F deposition to 98% (p<0.001). The groups containing 100 ppm F and 0.4% or 0.6% TMP exhibited a higher Ca concentration than the group containing only 100 ppm F (p<0.05). Furthermore, the HA treated with 0.2% and 0.4% TMP and 100 ppm F showed a higher Ca/P ratio than the other groups (p<0.001). In conclusion, TMP at 0.2%, 0.4% and 0.6% concentrations combined with F seemed to be able to precipitate HA with low solubility. However, especially at high concentrations, TMP interferes with F deposition on HA.Department of Pediatric Dentistry and Public Health Dental School UNESP - Universidade Estadual Paulista, Araçatuba, SPDepartment of Pediatric Dentistry and Public Health Dental School UNESP - Universidade Estadual Paulista, Araçatuba, S

Trace elements in hemodialysis patients: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Hemodialysis patients are at risk for deficiency of essential trace elements and excess of toxic trace elements, both of which can affect health. We conducted a systematic review to summarize existing literature on trace element status in hemodialysis patients.</p> <p>Methods</p> <p>All studies which reported relevant data for chronic hemodialysis patients and a healthy control population were eligible, regardless of language or publication status. We included studies which measured at least one of the following elements in whole blood, serum, or plasma: antimony, arsenic, boron, cadmium, chromium, cobalt, copper, fluorine, iodine, lead, manganese, mercury, molybdenum, nickel, selenium, tellurium, thallium, vanadium, and zinc. We calculated differences between hemodialysis patients and controls using the differences in mean trace element level, divided by the pooled standard deviation.</p> <p>Results</p> <p>We identified 128 eligible studies. Available data suggested that levels of cadmium, chromium, copper, lead, and vanadium were higher and that levels of selenium, zinc and manganese were lower in hemodialysis patients, compared with controls. Pooled standard mean differences exceeded 0.8 standard deviation units (a large difference) higher than controls for cadmium, chromium, vanadium, and lower than controls for selenium, zinc, and manganese. No studies reported data on antimony, iodine, tellurium, and thallium concentrations.</p> <p>Conclusion</p> <p>Average blood levels of biologically important trace elements were substantially different in hemodialysis patients, compared with healthy controls. Since both deficiency and excess of trace elements are potentially harmful yet amenable to therapy, the hypothesis that trace element status influences the risk of adverse clinical outcomes is worthy of investigation.</p

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe