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The hierarchical modular organization of functional networks in the brain is crucial for supporting diverse cognitive functions. Functional disorders in the brain are associated with an abnormal hierarchical modular organization. The default mode network (DMN) is a complex dynamic network that is linked to specialized cognitive functions and clinically relevant information. In this study, we hypothesize that hierarchical functional segregation and integration of the DMN within attention-deficit/hyperactivity disorder (ADHD) is abnormal. We investigated topological metrics of both segregation and integration in different hierarchical subnetworks of the DMN between patients with ADHD and healthy controls. We found that the hierarchical functional integration and segregation of the DMN decreased and increased, respectively, in ADHD. Our results also indicated that the abnormalities in the DMN are intrinsically caused by changes in functional segregation and integration in its higher-level subnetworks. To better understand the temporally dynamic changes in the hierarchical functional integration and segregation of the DMN within ADHD, we further analyzed the dynamic transitions between functional segregation and integration. We found that the adaptive reorganizational ability of brain network states decreased in ADHD patients, which indicated less adaptive regulation between the DMN subnetworks in ADHD for supporting correspondingly normal cognitive function. From the perspective of hierarchical functional segregation and integration, our results further provide evidence to support dysfunctional brain cognitive functions within ADHD linked to brain network segregation and integration. [ABSTRACT FROM AUTHOR]

Antennal sensory units in nymphs and adults of the spotted Lanternfly, Lycorma delicatula (White) (Hemiptera: Fulgoromorpha: Fulgoridae), an economically important plant pest, are studied with scanning electron microscopy. Sensilla trichodea / chaetica type recognition is based on their external morphology and ratio of their size to diameter. The flagellum Bourgoin’s organ is a complex sensory unit with 2–3 internal sensilla coeloconica. During nymphal stages, the sensory surface available for a chemoreceptive function particularly increases with the number and size of sensilla placodea on the antennal pedicel. From first to fourth instar and to adult males and females, plate organ sensory surface is estimated to increase respectively by 33x, 68x and 125x (= 2.72 mm2 and 5.02 mm2 respectively for males and females). The most important increase (5x) occurs between second and third instar. In parallel, a distinctive pair of plate organs on the flagellum decreases in size from first to third instar, and disappears. Sexual dimorphism occurs in sensilla placodea in adults. Diversity, disparity and evolution of nymphal sensilla, and their sexual dimorphism in adults are discussed in the context of the species and planthopper behaviour. [ABSTRACT FROM AUTHOR]

Many organisms, including the fathead minnow (Pimephales promelas), a toxicological model organism, establish social hierarchies. The social rank of each male in a population is under the control of the hypothalamic-pituitary-gonadal (HPG) axis mainly through regulation of circulating androgen concentrations, which in turn drive the expression of secondary sex characteristics (SSCs). As dominant and subordinate males in an exposure study are initially under different physiological conditions (i.e., differing plasma androgen concentrations), we proposed that they belong to different subpopulations in the context of exposure to compounds that may interact with the HPG axis. Using a meta-analysis of our data from several previously published studies, we corroborated the hypothesis that social status, as indicated by SSCs, results in distinct clusters (eigenvalues >0.8 explaining >80% of variability) with differential expression of plasma vitellogenin, a commonly used biomarker of exposure to contaminants of emerging concern (CEC). Furthermore, we confirmed our predictions that exposure to estrogenic CECs would homogenize plasma vitellogenin response (E1: cluster mean SSC values decreased to 4.33 and 4.86 relative to those of control; E2: decreased to 4.8 and 5.37) across the social hierarchy. In contrast, serotonin-specific reuptake inhibitors expand this response range (cluster mean SSC increased to 5.21 and 6.5 relative to those of control). Our results demonstrated that social hierarchies in male fathead minnows result in heterogeneous responses to chemical exposure. These results represent a cautionary note for the experimental design of single-sex exposure studies. We anticipate our study to be a starting point for the re-evaluation of toxicological data analyses in single sex exposure experiments. [ABSTRACT FROM AUTHOR]

In the current study, we evaluate the equivalent stiffness of peritubular reinforcement effect (PRE) of porous dentine optimized by the thickness of peritubular dentine (PTD). Few studies to date have evaluated or quantitated the effect of PRE on composite dentine. The miscrostructure of porous dentine is captured by scanning electron microscope images, and then finite element modeling is used to quantitate the deformation and stiffness of the porous dentine structure. By optimizing the radius of PTD and dentine tubule (DT), the proposed FE model is able to demonstrate the effect of peritubular reinforcement on porous dentine stiffness. It is concluded that the dentinal equivalent stiffness is reduced and degraded with the increase of the radius of DT (i.e., porosity) in the certain ratio value of Ep/Ei and certain radius of PTD, where Ep is the PTD modulus and Ei is the intertubular dentine modulus. So in order to ensure the whole dentinal equivalent stiffness is not loss, the porosity should get some value while the Ep/Ei is certain. Thus, PTD prevents the stress concentration around DTs and reduces the risk of DTs failure. Mechanically, the overall role of PTD appears to enhance the stiffness of the dentine composite structure. These results provide some new and significant insights into the biological evolution of the optimal design for the porous dentine microstructure. These findings on the biological microstructure design of dentine materials are applicable to other engineering structural designs aimed at increasing the overall structural strength. [ABSTRACT FROM AUTHOR]

Clostridium tetani and Clostridium botulinum produce two of the most potent neurotoxins known, tetanus neurotoxin and botulinum neurotoxin, respectively. Extensive biochemical and genetic investigation has been devoted to identifying and characterizing various C. botulinum strains. Less effort has been focused on studying C. tetani likely because recently sequenced strains of C. tetani show much less genetic diversity than C. botulinum strains and because widespread vaccination efforts have reduced the public health threat from tetanus. Our aim was to acquire genomic data on the U.S. vaccine strain of C. tetani to better understand its genetic relationship to previously published genomic data from European vaccine strains. We performed high throughput genomic sequence analysis on two wild-type and two vaccine C. tetani strains. Comparative genomic analysis was performed using these and previously published genomic data for seven other C. tetani strains. Our analysis focused on single nucleotide polymorphisms (SNP) and four distinct constituents of the mobile genome (mobilome): a hypervariable flagellar glycosylation island region, five conserved bacteriophage insertion regions, variations in three CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) systems, and a single plasmid. Intact type IA and IB CRISPR/Cas systems were within 10 of 11 strains. A type IIIA CRISPR/Cas system was present in two strains. Phage infection histories derived from CRISPR-Cas sequences indicate C. tetani encounters phages common among commensal gut bacteria and soil-borne organisms consistent with C. tetani distribution in nature. All vaccine strains form a clade distinct from currently sequenced wild type strains when considering variations in these mobile elements. SNP, flagellar glycosylation island, prophage content and CRISPR/Cas phylogenic histories provide tentative evidence suggesting vaccine and wild type strains share a common ancestor. [ABSTRACT FROM AUTHOR]

Objective: Ibuprofen is used to prevent high altitude headache (HAH) but its efficacy remains controversial. We conducted a systematic review and meta-analysis of randomized, placebo-controlled trials (RCTs) of ibuprofen for the prevention of HAH. Methods: Studies reporting efficacy of ibuprofen for prevention of HAH were identified by searching electronic databases (until December 2016). The primary outcome was the difference in incidence of HAH between ibuprofen and placebo groups. Risk ratios (RR) were aggregated using a Mantel-Haenszel random effect model. Heterogeneity of included trials was assessed using the I2 statistics. Results: In three randomized-controlled clinical trials involving 407 subjects, HAH occurred in 101 of 239 subjects (42%) who received ibuprofen and 96 of 168 (57%) who received placebo (RR = 0.79, 95% CI 0.66 to 0.96, Z = 2.43, P = 0.02, I2 = 0%). The absolute risk reduction (ARR) was 15%. Number needed to treat (NNT) to prevent HAH was 7. Similarly, The incidence of severe HAH was significant in the two groups (RR = 0.40, 95% CI 0.17 to 0.93, Z = 2.14, P = 0.03, I2 = 0%). Severe HAH occurred in 3% treated with ibuprofen and 10% with placebo. The ARR was 8%. NNT to prevent severe HAH was 13. Headache severity using a visual analogue scale was not different between ibuprofen and placebo. Similarly, the difference between the two groups in the change in SpO2 from baseline to altitude was not different. One included RCT reported one participant with black stools and three participants with stomach pain in the ibuprofen group, while seven participants reported stomach pain in the placebo group. Conclusions: Based on a limited number of studies ibuprofen seems efficacious for the prevention of HAH and may therefore represent an alternative for preventing HAH with acetazolamide or dexamethasone. [ABSTRACT FROM AUTHOR]

The pine aphid Cinara pinitabulaeformis Zhang et Zhang is the main pine pest in China, it causes pine needles to produce dense dew (honeydew) which can lead to sooty mold (black filamentous saprophytic ascomycetes). Although common chemical and physical strategies are used to prevent the disease caused by C. pinitabulaeformis Zhang et Zhang, new strategies based on biological and/or genetic approaches are promising to control and eradicate the disease. However, there is no information about genomics, proteomics or transcriptomics to allow the design of new control strategies for this pine aphid. We used next generation sequencing technology to sequence the transcriptome of C. pinitabulaeformis Zhang et Zhang and built a transcriptome database. We identified 80,259 unigenes assigned for Gene Ontology (GO) terms and information for a total of 11,609 classified unigenes was obtained in the Clusters of Orthologous Groups (COGs). A total of 10,806 annotated unigenes were analyzed to identify the represented biological pathways, among them 8,845 unigenes matched with 228 KEGG pathways. In addition, our data describe propagative viruses, nutrition-related genes, detoxification related molecules, olfactory related receptors, stressed-related protein, putative insecticide resistance genes and possible insecticide targets. Moreover, this study provides valuable information about putative insecticide resistance related genes and for the design of new genetic/biological based strategies to manage and control C. pinitabulaeformis Zhang et Zhang populations. [ABSTRACT FROM AUTHOR]

The susceptibility of a dietary protein to proteolytic degradation by digestive enzymes, such as gastric pepsin, provides information on the likelihood of systemic exposure to a structurally intact and biologically active macromolecule, thus informing on the safety of proteins for human and animal consumption. Therefore, the purpose of standardized in vitro degradation studies that are performed during protein safety assessments is to distinguish whether proteins of interest are susceptible or resistant to pepsin degradation via a study design that enables study-to-study comparison. Attempting to assess pepsin degradation under a wide-range of possible physiological conditions poses a problem because of the lack of robust and consistent data collected under a large-range of sub-optimal conditions, which undermines the needs to harmonize in vitro degradation conditions. This report systematically compares the effects of pH, incubation time, and pepsin-to-substrate protein ratio on the relative degradation of five dietary proteins: three pepsin susceptible proteins [ribulose 1,5-bisphosphate carboxylase-oxygenase (Rubisco), horseradish peroxidase (HRP), hemoglobin (Hb)], and two pepsin resistant proteins [lipid transfer protein (LTP) and soybean trypsin inhibitor (STI)]. The results indicate that proteins susceptible to pepsin degradation are readily distinguishable from pepsin-resistant proteins when the reaction conditions are within the well-characterized optima for pepsin. The current standardized in vitro pepsin resistant assay with low pH and high pepsin-to-substrate ratio fits this purpose. Using non-optimal pH and/or pepsin-to-substrate protein ratios resulted in susceptible proteins no longer being reliably degraded by this stomach enzyme, which compromises the ability of this in vitro assay to distinguish between resistant and susceptible proteins and, therefore, no longer providing useful data to an overall weight-of-evidence approach to assessing safety of proteins. [ABSTRACT FROM AUTHOR]

Caldicellulosiruptor bescii encodes at least six unique multimodular glycoside hydrolases crucial for plant cell wall polysaccharides degradation, with each having two catalytic domains separated by two to three carbohydrate binding modules. Among the six enzymes, three have one N- or C-terminal GH5 domain with identical amino acid sequences. Despite a few reports on some of these multimodular enzymes, little is known about how the conserved GH5 domains behave, which are believed to be important due to the gene duplication. We thus cloned a representative GH5 domain from the C-terminus of a multimodular protein, i.e. the bifunctional cellulase/mannanase CbCel9B/Man5A which has been reported, and expressed it in Escherichia coli. Without any appending CBMs, the recombinant CbMan5A was still able to hydrolyze a variety of mannan substrates with different backbone linkages or side-chain decorations. While CbMan5A displayed the same pH optimum as CbCel9B/Man5A, it had an increased optimal temperature (90°C) and moreover, was activated by heating at 70°C and 80°C, a property not ever reported for the full-length protein. The turnover numbers of CbMan5A on mannan substrates were, however, lower than those of CbCel9B/Man5A. These data suggested that evolution of CbMan5A and the other domains into a single polypeptide is not a simple assembly; rather, the behavior of one module may be affected by the other ones in the full-length enzyme. The differential scanning calorimetry analysis further indicated that heating CbMan5A was not a simple transition state process. To the best knowledge of the authors, CbMan5A is the first glycoside hydrolase with thermal activation property identified from a multimodular bifunctional enzyme. [ABSTRACT FROM AUTHOR]

N-glycans play important roles in various pathophysiological processes and can be used as clinical diagnosis markers. However, plasma N-glycans change and their pathophysiological significance in the setting of hypercholesterolemia, a major risk factor for atherosclerosis, is unknown. Here, we collected plasma from both hypercholesterolemic patients and cholesterol-fed hypercholesterolemic rabbits, and determined the changes in the whole-plasma N-glycan profile by electrospray ionization mass spectrometry. We found that both the hypercholesterolemic patients and rabbits showed a dramatic change in their plasma glycan profile. Compared with healthy subjects, the hypercholesterolemic patients exhibited higher plasma levels of a cluster of high-mannose and complex/hybrid N-glycans (mainly including undecorated or sialylated glycans), whereas only a few fucosylated or fucosylated and sialylated N-glycans were increased. Additionally, cholesterol-fed hypercholesterolemic rabbits also displayed increased plasma levels of high-mannose in addition to high complex/hybrid N-glycan levels. The whole-plasma glycan profiles revealed that the plasma N-glycan levels were correlated with the plasma cholesterol levels, implying that N-glycans may be a target for treatment of hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Environmental health risk assessors are challenged to understand and incorporate new data streams as the field of toxicology continues to adopt new molecular and systems biology technologies. Systematic screening reviews can help risk assessors and assessment teams determine which studies to consider for inclusion in a human health assessment. A tool for systematic reviews should be standardized and transparent in order to consistently determine which studies meet minimum quality criteria prior to performing in-depth analyses of the data. The Systematic Omics Analysis Review (SOAR) tool is focused on assisting risk assessment support teams in performing systematic reviews of transcriptomic studies. SOAR is a spreadsheet tool of 35 objective questions developed by domain experts, focused on transcriptomic microarray studies, and including four main topics: test system, test substance, experimental design, and microarray data. The tool will be used as a guide to identify studies that meet basic published quality criteria, such as those defined by the Minimum Information About a Microarray Experiment standard and the Toxicological Data Reliability Assessment Tool. Seven scientists were recruited to test the tool by using it to independently rate 15 published manuscripts that study chemical exposures with microarrays. Using their feedback, questions were weighted based on importance of the information and a suitability cutoff was set for each of the four topic sections. The final validation resulted in 100% agreement between the users on four separate manuscripts, showing that the SOAR tool may be used to facilitate the standardized and transparent screening of microarray literature for environmental human health risk assessment. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a typical complex multi-factorial disease and many molecules at different levels and pathways were involved in its development. Some studies have investigated the dysregulation in atherosclerosis at mRNA, miRNA or DNA methylation level, respectively. However, to our knowledge, the studies that integrated these data and revealed the abnormal networks of atherosclerosis have not been reported. Using microarray technology, we analyzed the omics data in atherosclerosis at mRNA, miRNA and DNA methylation levels. Our results demonstrated that the global DNA methylation and expression of miRNA/mRNA were significantly decreased in atherosclerotic plaque than in normal vascular tissue. The interaction network constructed using the integrative data revealed many genes, cellular processes and signaling pathways which were widely considered to play crucial roles in atherosclerosis and also revealed some genes, miRNAs or signaling pathways which have not been investigated in atherosclerosis until now (e.g. miR-519d and SNTB2). Moreover, the overall protein ubiquitination in atherosclerotic plaque was significantly increased. The proteasome activity was increased early but decreased in advanced atherosclerosis. Our study revealed many classic and novel genes and miRNAs involved in atherosclerosis and indicated the effects of ubiquitin-proteasome system on atherosclerosis might be closely related to the course of atherosclerosis. However, the efficacy of proteasome inhibitors in the treatment of atherosclerosis still needs more research. [ABSTRACT FROM AUTHOR]

Background: Insulin synthesis and cell proliferation are under tight regulation in pancreatic β-cells to maintain glucose homeostasis. Dysfunction in either aspect leads to development of diabetes. PERK (EIF2AK3) loss of function mutations in humans and mice exhibit permanent neonatal diabetes that is characterized by insufficient β-cell mass and reduced proinsulin trafficking and insulin secretion. Unexpectedly, we found that Perk heterozygous mice displayed lower blood glucose levels. Methodology: Longitudinal studies were conducted to assess serum glucose and insulin, intracellular insulin synthesis and storage, insulin secretion, and β-cell proliferation in Perk heterozygous mice. In addition, modulation of Perk dosage specifically in β-cells showed that the glucose homeostasis phenotype of Perk heterozygous mice is determined by reduced expression of PERK in the β-cells. Principal Findings: We found that Perk heterozygous mice first exhibited enhanced insulin synthesis and secretion during neonatal and juvenile development followed by enhanced β-cell proliferation and a substantial increase in β-cell mass at the adult stage. These differences are not likely to entail the well-known function of PERK to regulate the ER stress response in cultured cells as several markers for ER stress were not differentially expressed in Perk heterozygous mice. Conclusions: In addition to the essential functions of PERK in β-cells as revealed by severely diabetic phenotype in humans and mice completely deficient for PERK, reducing Perk gene expression by half showed that intermediate levels of PERK have a profound impact on β-cell functions and glucose homeostasis. These results suggest that an optimal level of PERK expression is necessary to balance several parameters of β-cell function and growth in order to achieve normoglycemia. [ABSTRACT FROM AUTHOR]

Background & Aims: The cellular immunity has a profound impact on the status of hepatitis C virus (HCV) infection. However, the response of cellular immunity on the virological response in patients with antiviral treatment remains largely unclear. We aimed to clarify the response of peripheral T cells and monocytes in chronic hepatitis C patients with antiviral treatment. Methods: Patients with chronic hepatitis C were treated either with interferon alpha-2b plus ribavirin (n = 37) or with pegylated interferon alpha-2a plus ribavirin (n = 33) for up to 24 weeks. Frequencies of peripheral regulatory T-cells (Tregs), programmed death-1 (PD-1) expressing CD4+ T-cells or CD8+ T-cells and toll-like receptor (TLR) 3 expressing CD14+ monocytes were evaluated by flow cytometry in patients at baseline, 12 and 24 weeks following treatment and in 20 healthy controls. Results: Frequencies of Tregs, PD-1 and TLR3 expressing cells were higher in patients than those in control subjects (P<0.05). Patients with complete early virological response (cEVR) showed lower Tregs, PD-1 expressing CD4+ or CD8+ T-cells than those without cEVR at 12 weeks (P<0.05). Patients with low TLR3 expressing CD14+ monocytes at baseline had a high rate of cEVR (P<0.05). Conclusions: Low peripheral TLR3 expressing CD14+ monocytes at baseline could serve as a predictor for cEVR of antiviral therapy in chronic HCV-infected patients. The cEVR rates were significantly increased in the patients with reduced circulating Tregs, PD-1 expressing CD4+ or CD8+ T-cells. Trial Registration: Chinese Clinical Trial Registry ChiCTR10001090. [ABSTRACT FROM AUTHOR]

With the use of iTRAQ technique, a multifactorial comparative proteomic study can be performed. In this study, to obtain an overview of ethanol, CYP2E1 and gender effects on liver injury and gain more insight into the underlying molecular mechanism, mouse liver proteomes were quantitatively analyzed using iTRAQ under eight conditions including mice of different genders, wild type versus CYP2E1 knockout, and normal versus alcohol diet. A series of statistical and bioinformatic analyses were explored to simplify and clarify multifactorial comparative proteomic data. First, with the Principle Component analysis, six proteins, CYP2E1, FAM25, CA3, BHMT, HIBADH and ECHS1, involved in oxidation reduction, energy and lipid metabolism and amino acid metabolism, were identified as the most differentially expressed gene products across all of the experimental conditions of our chronic alcoholism model. Second, hierarchical clustering analysis showed CYP2E1 knockout played a primary role in the overall differential protein expression compared with ethanol and gender factors. Furthermore, pair-wise multiple comparisons have revealed that the only significant expression difference lied in wild-type and CYP2E1 knockout mice both treated with ethanol. Third, K-mean clustering analysis indicated that the CYP2E1 knockout had the reverse effect on ethanol induced oxidative stress and lipid oxidation. More importantly, IPA analysis of proteomic data inferred that the gene expressions of two upstream regulators, NRF2 and PPARα, regulated by chronic alcohol feeding and CYP2E1 knockout, are involved in ethanol induced oxidative stress and lipid oxidation. The present study provides an effectively comprehensive data analysis strategy to compare multiple biological factors, contributing to biochemical effects of alcohol on the liver. The mass spectrometry proteomics data have been deposited to the ProteomeXchange with data set identifier of PXD000635. [ABSTRACT FROM AUTHOR]