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Microbial pathogens are exposed to damaging reactive oxygen species (ROS) produced from a variety of sources including chemical reactions due to exposure to stress (UV, heat) or by hosts as a defense response. Here we demonstrate that a bifunctional catalase-peroxidase, MakatG1, in the locust-specific fungal pathogen, Metarhizium acridum, functions as a ROS detoxification mechanism during host cuticle penetration. MakatG1 expression was highly induced during on-cuticle appressoria development as compared to vegetative (mycelia) growth or during in vivo growth in the insect hemocoel. A MakatG1 deletion mutant strain (ΔMakatG1) showed decreased catalase and peroxidase activities and significantly increased susceptibility to oxidative (H2 O2 and menadione) and UV stress as compared to wild type and complemented strains. Insect bioassays revealed significantly reduced virulence of the ΔMakatG1 mutant when topically inoculated, but no impairment when the insect cuticle was bypassed. Germination and appressoria formation rates for the ΔMakatG1 mutant were decreased on locust wings and quinone/phenolic compounds derived from locust wings, but were not affected on plastic surfaces compared with the wild type strain. These data indicate that MakatG1 plays a pivotal role in penetration, reacting to and detoxifying specific cuticular compounds present on the host cuticle during the early stages of fungal infection. This article is protected by copyright. All rights reserved.

Concepts: Oxygen, Microbiology, Bacteria, Oxidative stress, Arthropod, Oxidative phosphorylation, Reactive oxygen species, Hydrogen peroxide


It is challenging to hierarchically pattern high-aspect-ratio nanostructures on microstructures using conventional lithographic techniques, where photoresist film is not able to uniformly cover on the microstructures as the aspect ratio increases. Such non-uniformity causes poor definition of nanopatterns over the microstructures. Nanostencil lithography can provide an alternative means to hierarchically construct nanostructures on microstructures via direct deposition or plasma etching through a free-standing nanoporous membrane. In this work, we demonstrate the hierarchical fabrication of high-aspect-ratio nanostructures on microstructures of silicon using a free-standing nanostencil, which is a nanoporous membrane consisting of metal (Cr), photoresist (PR), and anti-reflective coating (ARC). The nanostencil membrane is used as a deposition mask to define Cr nanodot patterns on the predefined silicon microstructures. Then, deep reactive ion etching (DRIE) is used to hierarchically create nanostructures on the microstructures using the Cr nanodots as an etch mask. With simple modification of the main fabrication processes, high-aspect-ratio nanopillars are selectively defined only on top of the microstructures, on bottom, or on both top and bottom.

Concepts: Etching, Deep reactive-ion etching, Lithography, Printmaking, Pattern, Definition, Semiconductor device fabrication, Reactive-ion etching


PurposeWe sought to determine the analytical sensitivity of several extended exome variation analysis approaches in terms of their contribution to diagnostic yield and their clinical feasibility.MethodsWe retrospectively analyzed the results of genetic testing in 1,059 distinct cases referred for exome sequencing to our institution. In these, we routinely employed extended exome analysis approaches in addition to basic variant analysis, including (i) copy-number variation (CNV) detection, (ii) nonconsensus splice defect detection, (ii) genomic breakpoint detection, (iv) homozygosity mapping, and (v) mitochondrial variant analysis.ResultsExtended exome analysis approaches assisted in identification of causative genetic variant in 44 cases, which represented a 4.2% increase in diagnostic yield. The greatest contribution was associated with CNV analysis (1.8%) and splice variant prediction (1.2%), and the remaining approaches contributed an additional 1.2%. Analysis of workload has shown that on average nine additional variants per case had to be interpreted in the extended analysis.ConclusionWe show that extended exome analysis approaches improve the diagnostic yield of heterogeneous genetic disorders and result in considerable increase of diagnostic yield of exome sequencing with a minor increase of interpretative workload.GENETICS in MEDICINE advance online publication, 14 September 2017; doi:10.1038/gim.2017.142.

Concepts: Gene, DNA, Copy number variation, Human genome, Genetic disorder, Cancer, Mutation, Genetics


Objectives To examine the risk of relapse and time to relapse after discontinuation of antidepressants in patients with anxiety disorder who responded to antidepressants, and to explore whether relapse risk is related to type of anxiety disorder, type of antidepressant, mode of discontinuation, duration of treatment and follow-up, comorbidity, and allowance of psychotherapy.Design Systematic review and meta-analyses of relapse prevention trials.Data sources PubMed, Cochrane, Embase, and clinical trial registers (from inception to July 2016).Study selection Eligible studies included patients with anxiety disorder who responded to antidepressants, randomised patients double blind to either continuing antidepressants or switching to placebo, and compared relapse rates or time to relapse.Data extraction Two independent raters selected studies and extracted data. Random effect models were used to estimate odds ratios for relapse, hazard ratios for time to relapse, and relapse prevalence per group. The effect of various categorical and continuous variables was explored with subgroup analyses and meta-regression analyses respectively. Bias was assessed using the Cochrane tool.Results The meta-analysis included 28 studies (n=5233) examining relapse with a maximum follow-up of one year. Across studies, risk of bias was considered low. Discontinuation increased the odds of relapse compared with continuing antidepressants (summary odds ratio 3.11, 95% confidence interval 2.48 to 3.89). Subgroup analyses and meta-regression analyses showed no statistical significance. Time to relapse (n=3002) was shorter when antidepressants were discontinued (summary hazard ratio 3.63, 2.58 to 5.10; n=11 studies). Summary relapse prevalences were 36.4% (30.8% to 42.1%; n=28 studies) for the placebo group and 16.4% (12.6% to 20.1%; n=28 studies) for the antidepressant group, but prevalence varied considerably across studies, most likely owing to differences in the length of follow-up. Dropout was higher in the placebo group (summary odds ratio 1.31, 1.06 to 1.63; n=27 studies).Conclusions Up to one year of follow-up, discontinuation of antidepressant treatment results in higher relapse rates among responders compared with treatment continuation. The lack of evidence after a one year period should not be interpreted as explicit advice to discontinue antidepressants after one year. Given the chronicity of anxiety disorders, treatment should be directed by long term considerations, including relapse prevalence, side effects, and patients' preferences.

Concepts: Posttraumatic stress disorder, Epidemiology, Anxiety disorders, Medical statistics, Effect size, Odds ratio, Anxiety disorder, Selective serotonin reuptake inhibitor


The brinjal eggplant (Solanum melongena L.) is an important vegetable species worldwide, while African eggplants (S. aethiopicum L., S. macrocarpon L.) are indigenous vegetable species of local significance. Taxonomy of eggplants and their wild relatives is complicated and still unclear. Hence, the objective of the study was to clarify taxonomic position of cultivars and landraces of brinjal, its wild relatives and African eggplant species and their wild ancestors using chemotaxonomic markers and multivariate analysis techniques for data processing, with special attention paid to the recognition of markers characteristic for each group of the plants. The total of 34 accessions belonging to 9 species from genus Solanum L. were used in the study. Chemotaxonomic analysis was based on the profiles of cuticular n-alkanes and methylalkanes, obtained using gas chromatography-mass spectrometry and gas chromatography with flame ionization detector. Standard hierarchical cluster analysis (HCA) and principal component analysis (PCA) were used for the classification, while the latter and two-way HCA allowed to identify markers responsible for the clustering of the species. Cultivars, landraces and wild forms of S. melongena were practically identical in terms of their taxonomic position. The results confirmed high and statistically significant distinctiveness of all African eggplant species from the brinjal eggplant. The latter was characterized mostly by abundant long chain hydrocarbons in the range of 34-37 carbon atoms. The differences between both African eggplant species were, however, also statistically significant; S. aethiopicum displayed the highest contribution of 2-methylalkanes to the total cuticular hydrocarbons, while S. macrocarpon was characterized by elevated n-alkanes in the range of 25-32 carbon atoms. Wild ancestors of both African eggplant species were identical with their cultivated relatives. Concluding, high usefulness of the chemotaxonomic approach in classification of this important group of plants was confirmed.

Concepts: Turkish cuisine, Greek cuisine, Vegetable, Solanaceae, Fruit, Tomato, Eggplant, Solanum


Lilium lancifolium Thunb. is a Chinese traditional plant with various health benefits. In this study, we purified and characterized the water-soluble polysaccharide fraction (LLP-1A) of L. lancifolium. We also investigated the in vitro immune-enhancing activity of LLP-1A in macrophages and the underlying molecular mechanism. Results showed that LLP-1A was mainly composed of mannose and glucose at a molar ratio of 1.77:1, and its molecular weight was approximately 78.61kDa. The Fourier transform-infrared spectra of LLP-1A also revealed typical polysaccharide characteristics: the presence of uronic acid, pyranose rings and β-glycosidic bonds. With regard to its effects on macrophages, LLP-1A enhanced phagocytic activity and induced the NO production in a dose-dependent manner. Further, it induced expression of the cytokines interleukin-6, monocyte chemotactic protein 1, tumor necrosis factor-α and interleukin-1β. With regard to the molecular mechanism, LLP-1A increased protein expression of Toll-like receptor 4 and phosphorylation of the inhibitor of nuclear factor kappa-B kinase, inhibitor of NF-κB, and nuclear factor-kappa B in RAW 264.7 cells. Therefore, the data suggest that LLP-1A significantly upregulated the expression of immune reactive cytokines in RAW 264.7 macrophages through the TLR4-mediated NF-κB signal pathway. Thus, LLP-1A may have immunomodulatory functions that may prove beneficial for the treatment of immune-related diseases.

Concepts: Bacteria, DNA, Glucose, Cell biology, Polysaccharide, Protein, Immune system, Signal transduction


For an organism to develop and maintain homeostasis, cell types with distinct functions must often be separated by physical boundaries. The formation and maintenance of such boundaries are commonly attributed to mechanisms restricted to the cells lining the boundary. Here we show that, besides these local subcellular mechanisms, the formation and maintenance of tissue boundaries involves long-lived, long-ranged mechanical events. Following contact between two epithelial monolayers expressing, respectively, EphB2 and its ligand ephrinB1, both monolayers exhibit oscillatory patterns of traction forces and intercellular stresses that tend to pull cell-matrix adhesions away from the boundary. With time, monolayers jam, accompanied by the emergence of deformation waves that propagate away from the boundary. This phenomenon is not specific to EphB2/ephrinB1 repulsion but is also present during the formation of boundaries with an inert interface and during fusion of homotypic epithelial layers. Our findings thus unveil a global physical mechanism that sustains tissue separation independently of the biochemical and mechanical features of the local tissue boundary.

Concepts: Systems theory, DNA, Homeostasis, Metabolism, Continuum mechanics, Organism, Cell, Force


Long-range enhancer interactions critically regulate gene expression, yet little is known about how their coordinated activities contribute to CNS development or how this may, in turn, relate to disease states. By examining the regulation of the transcription factor NFIA in the developing spinal cord, we identified long-range enhancers that recapitulate NFIA expression across glial and neuronal lineages in vivo. Complementary genetic studies found that Sox9-Brn2 and Isl1-Lhx3 regulate enhancer activity and NFIA expression in glial and neuronal populations. Chromatin conformation analysis revealed that these enhancers and transcription factors form distinct architectures within these lineages in the spinal cord. In glioma models, the glia-specific architecture is present in tumors, and these enhancers are required for NFIA expression and contribute to glioma formation. By delineating three-dimensional mechanisms of gene expression regulation, our studies identify lineage-specific chromatin architectures and associated enhancers that regulate cell fate and tumorigenesis in the CNS.

Concepts: Promoter, Transcription, Transcription factor, Gene, Cell nucleus, Genetics, Gene expression, DNA


A major challenge in inflammatory bowel disease (IBD) is the integration of diverse IBD data sets to construct predictive models of IBD. We present a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through genome-wide association studies (GWAS) using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD. Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. We performed key driver analysis to identify genes predicted to modulate network regulatory states associated with IBD, prioritizing and prospectively validating 12 of the top key drivers experimentally. This validated key driver set not only introduces new regulators of processes central to IBD but also provides the integrated circuits of genetic, molecular, and clinical traits that can be directly queried to interrogate and refine the regulatory framework defining IBD.

Concepts: Genome-wide association study, Gastroenterology, Genomics, Inflammation, Genetics, Ulcerative colitis, Immune system, Inflammatory bowel disease


It has been hypothesized that depression and obesity are bi-directionally associated, and when overweight people appear to show a lower risk of depression, this supports the “Jolly Fat” hypothesis. The aim of this study was to examine the “Jolly Fat” hypothesis in middle-aged women in Korea, by different perceived stress levels.

Concepts: Dieting, Adipose tissue, Hangul, Nutrition, Obesity