Terkildsenivey0192

3), methanol (16.5), ethanol (20), carbon monoxide (16.3) and methane (12.4), which confirm the high-selectivity towards formaldehyde gas. Finally, a plausible formaldehyde gas sensing mechanism is proposed.The risk of exposure to toxic metals is a known concern to human populations. The overexposure to Mn can lead to a pathological condition, with symptoms similar to Parkinson's disease. Although toxicity of Mn has been reported, studies in neonates are scarce but necessary, as Mn can cross biological barriers. The present study evaluated if chronic perinatal exposure to Mn at low doses lead to neurotoxic effects in mice, after direct and indirect exposure. Couples of mice were exposed to Mn (0.013, 0.13, and 1.3 mg kg-1.day-1) for 60 days prior to mating, as well as during gestation and lactation. The offspring was distributed into two groups animals that were not exposed after weaning - parental exposure only (PE); and animals subject to additional 60-day exposure through gavages after weaning - parental and direct exposure (PDE). Neurological effects were evaluated by Mn quantification, behavior tests and biochemical markers in the brain. PDE animals had alterations in short/long-term memory and increased anxiety-like behavior. Exposure to Mn triggered a decrease of glutathione-s-transferase and increase of cholinesterase activity in different regions of the brain. These findings highlight the risk of exposure to low doses of Mn over a generation and at early stages of development.Several therapeutic options are available for type 1 Gaucher disease (GD1), including enzymatic replacement therapy (ERT) and substrate reduction therapy (SRT). Eliglustat is a selective inhibitor of glucosylceramide synthase that is extensively metabolized by CYP2D6 and, to a lesser extent by CYP3A4; it is also an inhibitor of the P-gp transporter. The aim of this study is to evaluate the metabolizer profile of these cytochrome isoforms in 61 GD1 patients, and to analyze interferences with concomitant therapies. Patients were selected from the Spanish Gaucher Disease Registry considering clinical data, GBA genotype, severity score index, comorbidities, concomitant drugs, type and response to therapy and adverse effects. The polymorphisms of CYP2D6, CYP3A4 and three ABCB1 transporter variants were analyzed by Polymerase Chain Reaction (PCR). The most frequent metabolizer profile was extensive or intermediate for CYP2D6, extensive for CYP3A4*1B and CYP3A4*22 and normal activity for ABCB1. Correlations between metabolizer profile and other variables were analyzed by multiple regression study. Twenty-eight patients received ERT, 17 eliglustat and seven miglustat. Epigenetic activity inhibition Forty-two patients (68.8%) had associated diseases and 54.5% were taking daily concomitant medication. Nine patients under eliglustat therapy received concomitant drugs that interact with the CYPs and/or ABCB1, five of these did not reach therapeutic goals and three presented mild or moderate adverse effects (headache and gastrointestinal disorders). Detailed analysis in four patients with TTT haplotype, corresponding to lack of activity of the transporter, was performed. In order to apply personalized medicine and avoid interferences and adverse effects, the individual CYP metabolizer profile and transporter must be considered when choosing the concomitant medication and/or making dose adjustments.Genotoxicity has been identified as the main cause of infertility and a variety of cancers. The mechanisms affect the structure, quality of the information or the segregation of DNA and are not inherently correlated with mutagenicity. The concept of genotoxicity, the chemical classes that cause genetic damage and the associated mechanisms of action are discussed here. Hazardous effects of pharmaceuticals, cosmetics, agrochemicals, industrial compounds, food additives, natural toxins and nanomaterials are, in large part, identified by genotoxicity and mutagenicity tests. These are critical and early steps in industrial and regulatory health assessment. Though several in vitro experiments are commonly used and approval by regulatory agencies for commercial licensing of drugs, their accuracy in human predictions for genotoxic and mutagenic effects is frequently questioned. Treatment of real and functional genetic toxicity problems depends in detail on the knowledge of mechanisms of DNA damage in the molecular, subcellular, cellular and tissue or organ system levels. Current strategies for risk assessment of human health need revisions to achieve robust and reliable results for optimizing their effectiveness. Additionally, computerized methods, neo-biomarkers leveraging '-omics' approaches, all of which can provide a convincing genotoxicity evaluation to reduce infertility and cancer risk.Metformin, an oral antidiabetic drug, recently demonstrated a reducing effect on bile acids (BA) plasma concentrations in one patient with intrahepatic cholestasis of pregnancy (ICP) by unknown mechanism. Therefore, the aim of the present study was to examine the effect of metformin on BA homeostasis and related molecular pathways in the liver and intestine using a mouse model of ICP. The cholestasis was induced in female C57BL/6 mice by repeated administration of ethinylestradiol (10 mg/kg BW s.c.) and/or metformin (150 mg/kg BW orally) over 5 consecutive days with subsequent bile collection and molecular analysis of samples. We demonstrated that metformin significantly increased the rate of bile secretion in control mice. This increase was BA dependent and was produced both by increased liver BA synthesis via induced cholesterol 7α-hydroxylase (Cyp7a1) and by increased BA reabsorption in the ileum via induction of the apical sodium-dependent BA transporter (Asbt). In contrast, metformin further worsened ethinylestradiol-induced impairment of bile secretion. This reduction was also BA dependent and corresponded with significant downregulation of Bsep, and Ntcp, major excretory and uptake transporters for BA in hepatocytes, respectively. The plasma concentrations of BA were consequently significantly increased in the metformin-treated mice. Altogether, our data indicate positive stimulation of bile secretion by metformin in the intact liver, but this drug also induces serious impairment of BA biliary secretion, with a marked increase in plasma concentrations in estrogen-induced cholestasis. Our results imply that metformin should be used with caution in situations with hormone-dependent cholestasis, such as ICP.In this study, seven new 4-oxothiazolidine derivatives were synthesized and assayed, along 7 known derivatives, for inhibitory properties against deoxyribonuclease I (DNase I) and xanthine oxidase (XO) in vitro. Among tested compounds, (5Z)-Ethyl-2-(2-(cyanomethylene)-4-oxothiazolidin-5-yliden)acetate (6) exhibited inhibitory activity against both enzymes (DNase I IC50 = 67.94 ± 5.99 μM; XO IC50 = 98.98 ± 13.47 μM), therefore being the first reported dual inhibitor of DNase I and XO. Observed DNase I inhibition qualifies compound 6 as the most potent small organic DNase I inhibitor reported so far. Derivatives of 2-alkyliden-4-oxothiazolidinone (1) inhibited DNase I below 200 μM, while the other tested 4-oxothiazolidine derivatives remained inactive against both enzymes. The molecular docking and molecular dynamics simulations into the binding sites of DNase I and XO enzyme allowed us to clarify the binding modes of this 4-oxothiazolidine derivative, which might aid future development of dual DNase I and XO.Language difficulties of children with Developmental Language Disorder (DLD) have been associated with multiple underlying factors and are still poorly understood. One way of investigating the mechanisms of DLD language problems is to compare language-related brain activation patterns of children with DLD to those of a population with similar language difficulties and a uniform etiology. Children with 22q11.2 deletion syndrome (22q11DS) constitute such a population. Here, we conducted an fMRI study, in which children (6-10yo) with DLD and 22q11DS listened to speech alternated with reversed speech. We compared language laterality and language-related brain activation levels with those of typically developing (TD) children who performed the same task. The data revealed no significant differences between groups in language lateralization, but task-related activation levels were lower in children with language impairment than in TD children in several nodes of the language network. We conclude that language impairment in children with DLD and in children with 22q11DS may involve (partially) overlapping cortical areas.Emotional conflict adaptation involving ventral anterior cingulate cortex (ACC) suppression of the amygdala is thought to be important in emotion regulation, with evidence of impaired implicit emotion regulation in emotional distress disorders. However, it is unclear how this impairment is associated with daily-life emotion dysregulation in emotional distress disorders. In the current study, female participants with an emotional distress disorder (N = 27) were scanned with MRI while completing an implicit emotion conflict regulation task that involved identifying the facial expression of an image while ignoring an overlaid congruent or incongruent affect label. Participants then completed two weeks of ambulatory assessment of daily-life emotion dysregulation. Consistent with previous research on comorbid emotional distress disorders (Etkin and Schatzberg, 2011), there was no behavioral effect of emotional conflict adaptation (p = .701) but a significant effect of congruent adaptation (p = .006), suggesting impairment is specific to implicit emotional conflict regulation. Additionally, there was no neural evidence of emotional conflict adaptation in the ventral ACC and amygdala (ps > .766). Further, in our primary psychophysiological interactions analyses, we examined ventral ACC-amygdala functional connectivity. As hypothesized, increased ventral ACC-amygdala functional connectivity for emotional conflict adaptation was associated with increased daily-life affective instability (p = .022), but not mean daily-life negative affect (p = .372). Overall, results provide behavioral and neural evidence of impaired implicit emotional conflict adaptation in individuals with emotional distress disorders and suggests that this impairment is related to daily-life affective instability in these disorders.This study cross-validates reported changes in behavioural and event-related potential (ERP) correlates of prospective memory (PM) inhibitory control performance applying different PM response selection demands (Bisiacchi et al., 2009). Participants were randomly assigned to a control group condition with no PM requirement, or to either inhibit ongoing task processing to respond to PM task cues (task-switch; TS) or provide an ongoing task response prior to providing a PM button press (dual-task; DT). The behavioural data indicated that ongoing task reaction time (RT) performance was similar in the DT, TS, and control group conditions. PM cue detection mechanisms reflected by the N300 did not differ between PM tasks. However, early occurring (400-700 ms) PM late parietal complex (LPC) amplitudes recorded over anterior electrode sites were larger in the TS compared to the DT-PM condition, and this difference persisted during the 700-1000 ms epoch. Thus, ERP correlates of PM task-set remapping were significantly altered via the induction of different PM response production rules retrieved from retrospective memory (RM).