Previously, we reported that Candidatus Liberibacter asiaticus (Las)‐infected Diaphorina citri are characterized by lower levels of cytochrome P450 monooxygenases than uninfected counterparts. In the ...present study, we investigated expression levels of family 4 cytochrome P450 (CYP4) genes in Las‐infected and uninfected D. citri adults. Five novel CYP4 genes (CYP4C67, CYP4DA1, CYP4C68, CYP4DB1 and CYP4G70) were identified. Four of the five CYP4 genes were expressed at significantly higher levels in uninfected than Las‐infected males, whereas only one was expressed at significantly higher levels in uninfected than Las‐infected females. These results suggest that levels of cytochrome P450 monooxygenases in D. citri may be linked to expression levels of these CYP4 genes. Expression of all five CYP4 genes was induced by exposure of D. citri to imidacloprid, suggesting their possible involvement in metabolism of this toxin. Higher expression of the five CYP4 genes was found in nymphs than adults, which is congruent with previous results indicating higher levels of cytochrome P450 monooxygenases in nymphs than adults. These five CYP4 genes may be promising candidates for RNA‐interference to silence overexpression of genes associated with insecticide resistance in D. citri. These newly identified genes may also serve as DNA‐based screening markers for cytochrome P450‐mediated insecticide resistance in field populations of D. citri.
Autism Spectrum Symptoms in a Tourette's Disorder Sample Darrow, Sabrina M; Grados, Marco; Sandor, Paul ...
Journal of the American Academy of Child and Adolescent Psychiatry,
07/2017, Letnik:
56, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Tourette's disorder (TD) and autism spectrum disorder (ASD) share clinical features and possibly an overlapping etiology. The aims of this study were to examine ASD symptom rates in participants with ...TD, and to characterize the relationships between ASD symptom patterns and TD, obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD).
Participants with TD (n = 535) and their family members (n =234) recruited for genetic studies reported TD, OCD, and ADHD symptoms and completed the Social Responsiveness Scale Second Edition (SRS), which was used to characterize ASD symptoms.
SRS scores in participants with TD were similar to those observed in other clinical samples but lower than in ASD samples (mean SRS total raw score = 51; SD = 32.4). More children with TD met cut-off criteria for ASD (22.8%) than adults with TD (8.7%). The elevated rate in children was primarily due to high scores on the SRS Repetitive and Restricted Behaviors (RRB) subscale. Total SRS scores were correlated with TD (r = 0.27), OCD (r = 0.37), and ADHD (r = 0.44) and were higher among individuals with OCD symptom-based phenotypes than for those with tics alone.
Higher observed rates of ASD among children affected by TD may in part be due to difficulty in discriminating complex tics and OCD symptoms from ASD symptoms. Careful examination of ASD-specific symptom patterns (social communication vs. repetitive behaviors) is essential. Independent of ASD, the SRS may be a useful tool for identifying patients with TD with impairments in social communication that potentially place them at risk for bullying and other negative sequelae.
Tourette syndrome and chronic tic disorder are heritable but aetiologically complex. Although environment plays a role in their development, existing studies of non-genetic risk factors are ...inconsistent.
To examine the association between pre- and perinatal exposures and Tourette syndrome/chronic tic disorder in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective longitudinal pre-birth cohort.
Relationships between exposures and Tourette syndrome/chronic tic disorder were examined in 6090 children using logistic regression.
Maternal alcohol and cannabis use, inadequate maternal weight gain and parity were associated with Tourette syndrome or Tourette syndrome/chronic tic disorder. Other previously reported exposures, including birth weight and prenatal maternal smoking, were not associated with Tourette syndrome/chronic tic disorder.
This study supports previously reported relationships between Tourette syndrome/chronic tic disorder and prenatal alcohol exposure, and identifies additional previously unexplored potential prenatal risk factors.
To determine the associations between maternal and paternal psychiatric diagnoses and Tourette syndrome (TS)/chronic tic disorder (CT) in a nationwide study.
This nested case-control study linked ...data derived from three national registers. All singletons born and diagnosed with TS/CT in Finland between January 1991 and December 2010 were identified (n = 1,120) and matched to four controls (n = 4,299). Conditional logistic regression was used to examine the associations between parental psychopathology and TS/CT.
Altogether, 24.9% of patients with TS/CT and 12.0% of controls had a mother with a psychiatric diagnosis. Similarly, 17.9% and 12.9% had a father with a psychiatric diagnosis. Any maternal and any paternal psychiatric diagnosis was associated with offspring TS/CT (odds ratio OR 2.3; 95% CI 1.9-2.7 and OR 1.2; 95% CI 1.01-1.5, respectively). The association between maternal psychiatric diagnosis and TS/CT was stronger than that between paternal psychiatric diagnosis and TS/CT (p < .001). Maternal personality disorders (OR 3.1, 95% CI 1.9-5.1), anxiety disorders (OR 2.6, 95% CI 1.9-3.5), affective disorders (OR 2.3, 95% CI 1.8-2.9), psychotic disorders (OR 2.0, 95% CI 1.2-3.3), and addiction disorders (OR 1.8, 95% CI 1.1-2.8) were associated with TS/CT. Paternal OCD (OR 6.5, 95% CI 1.1-39.5) and anxiety disorders (OR 1.5, 95% CI 1.1-2.3) were associated with TS/CT.
Parental psychiatric diagnoses (especially in the mother) are associated with diagnosed offspring TS/CT. Further studies are required before the results can be generalized to all children with TS/CT. The associations between maternal psychiatric disorders and TS may reflect both maternal specific environmental and/or genetic influences.
Background:
Limited data exist concerning the unique pain characteristics of patients with non-cancer terminal diseases referred for inpatient hospice care.
Aims:
To define the unique pain ...characteristics of patients admitted to an acute inpatient hospice setting with end-stage dementia or chronic obstructive lung disease (or chronic obstructive pulmonary disease) and to compare them to patients with end-stage cancer.
Design:
Retrospective patient chart review. Demographic, physiological, pain parameters, and medication utilization data were extracted. Associations between pain characteristics, medication utilization, and admission diagnoses were assessed. Analyses included descriptive statistics.
Setting/participants:
In total, 146 patients admitted to an acute inpatient hospice between 1 April 2011 and 31 March 2012 with an underlying primary diagnosis of chronic obstructive pulmonary disease (n = 51), dementia (n = 48), or cancer (n = 47).
Results:
Pain was highly prevalent in all diagnostic groups, with cancer patients experiencing more severe pain on admission. Cancer patients received a significantly higher cumulative opioid dose compared with dementia and chronic obstructive pulmonary disease patients. Pain control within 24 h of pain onset was achieved in less than half of all patient groups with chronic obstructive pulmonary disease patients the least likely to achieve pain control.
Conclusions:
Despite the fact that pain is the most common complaint at the end of life, pain management may be suboptimal for some primary diagnoses. Admission diagnosis is the strongest predictor of pain control. Patient with cancer achieve the best pain control, and chronic obstructive pulmonary disease patients are the least likely to have their pain adequately treated.
The peritrophic matrix (PM) is a noncellular structure that lines the gut of most insects. Because of its close involvement in digestive processes and its role as a barrier against pathogens and ...toxins, the PM is an attractive target for pest management strategies. The objectives of this study were to (1) reduce the expression of a chitin synthase gene (Reticulitermes flavipes chitin synthase B, RfCHSB), a putative peritrophin R. flavipes Protein with Peritrophin‐A domain 1, (RfPPAD1) and a confirmed peritrophin R. flavipes Protein with Peritrophin‐A domain 2 (RfPPAD2) in R. flavipes by means of RNA interference, and (2) to evaluate the susceptibility of R. flavipes to termiticides and a bacterial pathogen, after silencing the target genes. Force feeding termites with 55 and 100 ng of long double‐stranded RNAs (dsRNAs), targeting RfCHSB and RfPPAD2, respectively, resulted in the highest levels of transcript suppression. RfCHSB expression was reduced by 70%, whereas the transcript level of RfPPAD2 was decreased by 90%. Force feeding 100 ng/termite of a long RfPPAD1 dsRNA reduced the expression of the transcript by 30%. Challenging termites with imidacloprid, chlorantraniliprole and noviflumuron, after silencing RfCHSB, significantly increased termite mortality. Force feeding termites a dsRNA cocktail, targeting RfCHSB, RfPPAD1 and RfPPAD2, caused the highest significant increase in termite mortality after challenging the insects with imidacloprid. These results demonstrate the viability of the R. flavipes PM as a target in termite pest management.
Genome-wide microarray analysis (Affymetrix array) was used (i) to determine whether only one gene, the cytochrome P450 enzyme Cyp6g1, is differentially transcribed in dichlorodiphenyltrichloroethane ...(DDT)-resistant vs. -susceptible Drosophila; and (ii) to profile common genes differentially transcribed across a DDT-resistant field isolate Rst(2)DDTWisconsin and a laboratory DDT-selected population Rst(2)DDT91-R. Statistical analysis (ANOVA model) identified 158 probe sets that were differentially transcribed among Rst(2)DDT91-R, Rst(2)DDTWisconsin, and the DDT-susceptible genotype Canton-S (P < 0.01). The cytochrome P450 Cyp6a2 and the diazepam-binding inhibitor gene (Dbi) were over transcribed in the two DDT-resistant geno-types when compared to the wild-type Drosophila, and this difference was significant at the most stringent statistical level, a Bonferroni correction. The list of potential candidates differentially transcribed also includes 63 probe sets for which molecular function ontology annotation of the probe sets did not exist. A total of four genes (Cyp6a2, Dbi, Uhg1, and CG11176) were significantly different $(P<5.6\ {\rm e}^{-06})$ between Rst(2)DDT91-R and Canton-S. Additionally, two probe sets encoding Cyp12d1 and Dbi were significantly different between Rst(2)DDTWisconsin and Canton-S after a Bonferroni correction. Fifty-two probe sets, including those associated with pesticide detoxification, ion transport, signal transduction, RNA transcription, and lipid metabolism, were commonly expressed in both resistant lines but were differentially transcribed in Canton-S. Our results suggest that more than Cyp6g1 is overtranscribed in field and laboratory DDT-resistant genotypes, and the number of commonalities suggests that similar resistance mechanisms may exist between laboratory- and field-selected DDT-resistant fly lines.
The unique phenotypic and genetic aspects of obsessive-compulsive (OCD) and attention-deficit/hyperactivity disorder (ADHD) among individuals with Tourette syndrome (TS) are not well characterized. ...Here, we examine symptom patterns and heritability of OCD and ADHD in TS families.
OCD and ADHD symptom patterns were examined in TS patients and their family members (N = 3494) using exploratory factor analyses (EFA) for OCD and ADHD symptoms separately, followed by latent class analyses (LCA) of the resulting OCD and ADHD factor sum scores jointly; heritability and clinical relevance of the resulting factors and classes were assessed.
EFA yielded a 2-factor model for ADHD and an 8-factor model for OCD. Both ADHD factors (inattentive and hyperactive/impulsive symptoms) were genetically related to TS, ADHD, and OCD. The doubts, contamination, need for sameness, and superstitions factors were genetically related to OCD, but not ADHD or TS; symmetry/exactness and fear-of-harm were associated with TS and OCD while hoarding was associated with ADHD and OCD. In contrast, aggressive urges were genetically associated with TS, OCD, and ADHD. LCA revealed a three-class solution: few OCD/ADHD symptoms (LC1), OCD & ADHD symptoms (LC2), and symmetry/exactness, hoarding, and ADHD symptoms (LC3). LC2 had the highest psychiatric comorbidity rates (⩾50% for all disorders).
Symmetry/exactness, aggressive urges, fear-of-harm, and hoarding show complex genetic relationships with TS, OCD, and ADHD, and, rather than being specific subtypes of OCD, transcend traditional diagnostic boundaries, perhaps representing an underlying vulnerability (e.g. failure of top-down cognitive control) common to all three disorders.
While selective inhibition is one of the key assets for a small molecule drug, many diseases can only be tackled by simultaneous inhibition of several proteins. An example where achieving selectivity ...is especially challenging are ligands targeting human kinases. This difficulty arises from the high structural conservation of the kinase ATP binding sites, the area targeted by most inhibitors. We investigated the possibility to identify novel small molecule ligands with pre-defined binding profiles for a series of kinase targets and anti-targets by in silico docking. The candidate ligands originating from these calculations were assayed to determine their experimental binding profiles. Compared to previous studies, the acquired hit rates were low in this specific setup, which aimed at not only selecting multi-target kinase ligands, but also designing out binding to anti-targets. Specifically, only a single profiled substance could be verified as a sub-micromolar, dual-specific EGFR/ErbB2 ligand that indeed avoided its selected anti-target BRAF. We subsequently re-analyzed our target choice and in silico strategy based on these findings, with a particular emphasis on the hit rates that can be expected from a given target combination. To that end, we supplemented the structure-based docking calculations with bioinformatic considerations of binding pocket sequence and structure similarity as well as ligand-centric comparisons of kinases. Taken together, our results provide a multi-faceted picture of how pocket space can determine the success of docking in multi-target drug discovery efforts.
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