Vorhersagbarkeit konvektiver Niederschläge: Hochauflösende Ensemblesimulationen für Westafrika

Während der Monsunsaison erzeugen konvektive Systeme in Westafrika den größten Teil des Jahresniederschlags. Hier wird ihre Vorhersagbarkeit mit Hilfe von Ensemblesimulationen mit dem COSMO-Modell untersucht. Dabei ist speziell der Einfluss der Landoberfläche von Interesse. Sind Wechselwirkungen zwischen Landoberfläche und Atmosphäre in Westafrika genauso wichtig für die Niederschlagsvorhersage wie die synoptischen Gegebenheiten? Welche physikalischen Prozesse sind dabei von Bedeutung

The face-specific N170 component is modulated by emotional facial expression

BACKGROUND: According to the traditional two-stage model of face processing, the face-specific N170 event-related potential (ERP) is linked to structural encoding of face stimuli, whereas later ERP components are thought to reflect processing of facial affect. This view has recently been challenged by reports of N170 modulations by emotional facial expression. This study examines the time-course and topography of the influence of emotional expression on the N170 response to faces. METHODS: Dense-array ERPs were recorded in response to a set (n = 16) of fear and neutral faces. Stimuli were normalized on dimensions of shape, size and luminance contrast distribution. To minimize task effects related to facial or emotional processing, facial stimuli were irrelevant to a primary task of learning associative pairings between a subsequently presented visual character and a spoken word. RESULTS: N170 to faces showed a strong modulation by emotional facial expression. A split half analysis demonstrates that this effect was significant both early and late in the experiment and was therefore not associated with only the initial exposures of these stimuli, demonstrating a form of robustness against habituation. The effect of emotional modulation of the N170 to faces did not show significant interaction with the gender of the face stimulus, or hemisphere of recording sites. Subtracting the fear versus neutral topography provided a topography that itself was highly similar to the face N170. CONCLUSION: The face N170 response can be influenced by emotional expressions contained within facial stimuli. The topography of this effect is consistent with the notion that fear stimuli exaggerates the N170 response itself. This finding stands in contrast to previous models suggesting that N170 processes linked to structural analysis of faces precede analysis of emotional expression, and instead may reflect early top-down modulation from neural systems involved in rapid emotional processing

Acquisition of clarithromycin resistance mutations in the 23S rRNA gene of Mycobacterium abscessus in the presence of inducible erm(41)

Objectives Antibiotic therapy of pulmonary Mycobacterium abscessus infection is based on a combination treatment including clarithromycin. Recent data demonstrated that M. abscessus may carry a chromosomal, inducible erm gene coding for the ribosomal methylase Erm(41). The purpose of this study was to investigate whether in patients with chronic M. abscessus infection undergoing clarithromycin therapy, M. abscessus acquires clarithromycin resistance mutations in the rrl gene in addition to the presence of an inducible Erm(41) methylase. Methods We determined clarithromycin MICs, erm(41) and rrl sequences for 29 clinical M. abscessus subsp. abscessus isolates of five different patients. The isolates were obtained between 2007 and 2011 covering a longitudinal observation period of 2-4 years for the individual patients. Results In three out of five patients with an initial rrl wild-type isolate, follow-up isolates demonstrated acquisition of resistance mutations in the rrl gene in addition to the presence of an inducible Erm methylase. Conclusions Our results show that in M. abscessus, clarithromycin resistance mutations in the 23S rRNA peptidyltransferase region provide an additional selective advantage independent of a functional erm(41) gen

Predictability of convective precipitation for West Africa: verification of convection-permitting and global ensemble simulations

Within the framework of this investigation, convection-permitting (CP) ensemble forecasts were generated for West Africa by combining different initial and lateral boundary conditions (IBCs) with perturbations that address the uncertainty of land-surface atmosphere interactions (land-surface perturbations). For a multi-analysis setup, IBCs were taken from model analyses of different global models; for a single-model setup, they were selected from the ensemble system of the European Centre for Medium-range Weather Forecasts (ECMWF). The different ensemble setups were assessed using common probabilistic scores as well as by spatial forecast verification of precipitation generated mainly by convective systems during the West African monsoon season. Additionally, it was investigated whether the CP ensemble forecasts were superior to the ECMWF ensemble forecasts.Probabilistic scores were higher for the single-model ensemble than for the multi-analysis setup, but the latter displayed a larger dispersion and more extreme scenarios. From this, it is concluded that the different model analyses can differ strongly from each other. The land-surface perturbations were able to generate sufficient complementary spread. While the CP simulations showed a stronger negative precipitation bias in the southernmost region near the Guinean coast, the ECMWF simulations exhibited a negative bias further north in the Sahel region, where larger convective systems occur less frequently. Not in all cases did the CP ensemble versions produce better probabilistic scores than the global ensemble forecasts, but they yielded larger spread and less underdispersion. Rank histograms, though, were also influenced by the different structure of the precipitation patterns of the global and CP forecasts. Scores improved when using a later version of the CP model as well as with the skill of the global ensemble forecasts used as IBCs. Altogether, the proposed realization of CP ensemble forecasts is found to be suited for the prediction of convective precipitation in West Africa

Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study

There is an increasing interest for monitoring circulating myeloid-derived suppressor cells (MDSCs) in cancer patients, but there are also divergences in their phenotypic definition. To overcome this obstacle, the Cancer Immunoguiding Program under the umbrella of the Association of Cancer Immunotherapy is coordinating a proficiency panel program that aims at harmonizing MDSC phenotyping. After a consultation period, a two-stage approach was designed to harmonize MDSC phenotype. In the first step, an international consortium of 23 laboratories immunophenotyped 10 putative MDSC subsets on pretested, peripheral blood mononuclear cells of healthy donors to assess the level of concordance and define robust marker combinations for the identification of circulating MDSCs. At this stage, no mandatory requirements to standardize reagents or protocols were introduced. Data analysis revealed a small intra-laboratory, but very high inter-laboratory variance for all MDSC subsets, especially for the granulocytic subsets. In particular, the use of a dead-cell marker altered significantly the reported percentage of granulocytic MDSCs, confirming that these cells are especially sensitive to cryopreservation and/or thawing. Importantly, the gating strategy was heterogeneous and associated with high inter-center variance. Overall, our results document the high variability in MDSC phenotyping in the multicenter setting if no harmonization/standardization measures are applied. Although the observed variability depended on a number of identified parameters, the main parameter associated with variation was the gating strategy. Based on these findings, we propose further efforts to harmonize marker combinations and gating parameters to identify strategies for a robust enumeration of MDSC subsets

Aminoglycoside-modifying enzymes determine the innate susceptibility to aminoglycoside antibiotics in rapidly growing mycobacteria

Objectives Infections caused by the rapidly growing mycobacterium (RGM) Mycobacterium abscessus are notoriously difficult to treat due to the innate resistance of M. abscessus to most clinically available antimicrobials. Aminoglycoside antibiotics (AGA) are a cornerstone of antimicrobial chemotherapy against M. abscessus infections, although little is known about intrinsic drug resistance mechanisms. We investigated the role of chromosomally encoded putative aminoglycoside-modifying enzymes (AME) in AGA susceptibility in M. abscessus. Methods Clinical isolates of M. abscessus were tested for susceptibility to a series of AGA with different substituents at positions 2′, 3′ and 4′ of ring 1 in MIC assays. Cell-free extracts of M. abscessus type strain ATCC 19977 and Mycobacterium smegmatis strains SZ380 [aac(2′)-Id+], EP10 [aac(2′)-Id−] and SZ461 [aac(2′)-Id+, rrs A1408G] were investigated for AGA acetylation activity using thin-layer chromatography (TLC). Cell-free ribosome translation assays were performed to directly study drug-target interaction. Results Cell-free translation assays demonstrated that ribosomes of M. abscessus and M. smegmatis show comparable susceptibility to all tested AGA. MIC assays for M. abscessus and M. smegmatis, however, consistently showed the lowest MIC values for 2′-hydroxy-AGA as compared with 2′-amino-AGA, indicating that an aminoglycoside-2′-acetyltransferase, Aac(2′), contributes to innate AGA susceptibility. TLC experiments confirmed enzymatic activity consistent with Aac(2′). Using M. smegmatis as a model for RGM, acetyltransferase activity was shown to be up-regulated in response to AGA-induced inhibition of protein synthesis. Conclusions Our findings point to AME as important determinants of AGA susceptibility in M. abscessu

PLANT EXTRACTS USED FOR THE CONTROL OF ENDO AND ECTOPARASITES OF LIVESTOCK: A REVIEW OF THE LAST 13 YEARS OF SCIENCE

A variety of endo and ectoparasites can affect livestock, causing poor animal performance and low welfare conditions. Haemonchus contortus (Trichostrongyloidae), Rhipicephalus microplus (Ixodidae), Cochliomyia sp. and Lucilia sp. (Calliphoridae) are some of the most important parasites to livestock in Brazil and in many other tropical and subtropical countries, where farmers need to be vigilant. Although a constant parasite control uses large-spectrum anthelmintics or synthetic insecticides, giving a timely potent reduction of the infections, they also represent a threat to the lifespan of these compounds due to drug-selected parasites. Thus, the development of plant-based therapies is a solid alternative for standard, agroecological, and holistic farming systems, as well as it is an important ally to combat drug resistant parasite populations. In this article, we discussed the scientific literature on plant extracts, notably hydroalcoholic extract or essential oils, used for the control of the above livestock parasites published in the last 13 years. Our objective was to pinpoint the most important issues for this promising area of research, exploring the potential and the challenges that are facing us by examining more than 150 in vitro and in vivo studies. Almost all the authors reported positive data from plants or isolates, the most important challenges that were faced during our search were the lack of a proper experimental study design, and the deficiency in the characterization of the plants used. It is our opinion that plant-based products may be a solid choice for parasite control in livestock animals achieving high welfare standards and mitigate farming input (i.e. use of chemicals and their waste into the environment)

Cabozantinib and Tivantinib, but Not INC280, Induce Antiproliferative and Antimigratory Effects in Human Neuroendocrine Tumor Cells in vitro: Evidence for 'Off-Target' Effects Not Mediated by c-Met Inhibition

Background/Aims: The hepatocyte growth factor/transmembrane tyrosine kinase receptor c-Met has been defined as a potential target in antitumoral treatment of various carcinomas. We aimed to investigate the direct effect of c-Met inhibition on neuroendocrine tumor cells in vitro. Methods: The effects of the multi-tyrosine kinase inhibitors cabozantinib and tivantinib and of the highly specific c-Met inhibitor INC280 were investigated in human pancreatic neuroendocrine BON1, bronchopulmonary NCI-H727 and midgut GOT1 cells in vitro. Results: INC280, cabozantinib and tivantinib inhibited c-Met phosphorylation, respectively. However, while equimolar concentrations (10 mu M) of cabozantinib and tivantinib inhibited cell viability and cell migration, INC280 had no inhibitory effect. Knockdown experiments with c-Met siRNA also did not demonstrate effects on cell viability. Cabozantinib and tivantinib caused a G2 arrest in neuroendocrine tumor cells. Conclusions: Our in vitro data suggest that c-Met inhibition alone is not sufficient to exert direct antitumoral or antimigratory effects in neuroendocrine tumor cells. The multi-tyrosine kinase inhibitors cabozantinib and tivantinib show promising antitumoral and antimigratory effects in neuroendocrine tumor cells, which are most probably 'off-target' effects, not mediated by c-Met. (C) 2015 S. Karger AG, Base

Topical inflammasome inhibition with disulfiram prevents irritant contact dermatitis

Background: The pathogenesis of contact dermatitis, a common inflammatory skin disease with limited treatment options, is held to be driven by inflammasome activation induced by allergens and irritants. We here aim to identify inflammasome-targeting treatment strategies for irritant contact dermatitis. Methods: A high content screen with 41,184 small molecules was performed using fluorescent Apoptosis associated speck-like protein containing a CARD (ASC) speck formation as a readout for inflammasome activation. Hit compounds were validated for inhibition of interleukin (IL)-1β secretion. Of these, the approved thiuramdisulfide derivative disulfiram was selected and tested in a patch test model of irritant contact dermatitis in 25 healthy volunteers. Topical application of disulfiram, mometasone or vehicle was followed by application of sodiumdodecylsulfate (SDS) for 24 h each. Eczema induction was quantified by mexameter and laser speckle imaging. Corneocyte sampling of lesional skin was performed to assess inflammasome-mediated cytokines IL-1β and IL-18. Results: Disulfiram induced a dose-dependent inhibition of ASC speck formation and IL-1β release in cellular assays in vitro. In vivo, treatment with disulfiram, but not with vehicle and less mometasone, inhibited SDS-induced eczema. This was demonstrated by significantly lower erythema and total perfusion values assessed by mexameter and laser speckle imaging for disulfiram compared to vehicle (p < 0.001) and/or mometasone (p < 0.001). Also, corneocyte IL-18 levels were significantly reduced after application of disulfiram compared to vehicle (p < 0.001). Conclusion: We show that disulfiram is a dose-dependent inhibitor of inflammasome pathway activation in vitro and inhibitor of SDS-induced eczema in vivo. Topical application of disulfiram represents a potential treatment option for irritant contact dermatitis

Impaired sweating in patients with cholinergic urticaria is linked to low expression of acetylcholine receptor CHRM3 and acetylcholine esterase in sweat glands

BackgroundCholinergic urticaria (CholU), a frequent form of chronic inducible urticaria, is characterized by itchy wheals and angioedema in response to sweating. As of now, the rate and pathophysiological relevance of impaired sweating in patients with CholU are ill-defined.AimTo assess in CholU patients the rate and extent of impaired sweating and its links to clinical and pathophysiological features of CholU.Patients and methodsWe assessed sweating in patients with CholU (n = 13) subjected to pulse-controlled ergometry (PCE) provocation testing. Pre- and post-PCE biopsies of lesional (L) and non-lesional (NL) skin were analyzed for the expression of acetylcholine receptor M3 (CHRM3) and acetylcholine esterase (ACh-E) by quantitative histomorphometry and compared to those of healthy control subjects (HCs). CholU patients were assessed for disease duration and severity as well as other clinical features.ResultsOf the 13 patients with CholU, 10 showed reduced sweating in response to PCE provocation, and 3 had severely reduced sweating. Reduced sweating was linked to long disease duration and high disease severity. CholU patients with impaired sweating responses showed reduced sweat gland epithelial expression of CHRM3 and ACh-E.ConclusionReduced sweating is common in CholU patients, especially in those with long-standing and severe disease, and it can be severe. Reduced expression of CHRM3 and ACh-E may be the cause or consequence of CholU in patients with impaired sweating, and this should be explored by further studies