The continuously increasing association of Alzheimer's disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for ...therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer's disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application.
: We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain.
: This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals.
: Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD.
Recent selective mutism (SM) treatment approaches focusing on the delivery of interventions using intensive doses of cognitive behavioral therapy (CBT) and Parent-Child Interaction Therapy (PCIT-SM). ...In the current study, we sought to examine the effectiveness of an eight-session weekly outpatient group program for youth ages 3 to 14 diagnosed with SM. Group interventions included caregiver coaching and support for CBT skills, particularly graded speaking exposures for youth using the PCIT-SM framework. A total of 112 youth (M
age
= 7.26; 57.1% white; 63.4% girls) were referred for treatment; 100 youth completed the weekly program with at least one caregiver. Initial evaluations assessed SM symptomology, communication behavior, anxiety, and impairment due to symptoms at pre-treatment and post-treatment. Parents and clinicians tracked communication behaviors during all treatment sessions. Results suggested a significant reduction in SM symptoms in various settings (e.g., school, social) and impairment associated with anxiety from pre- to post-treatment. Youth demonstrated a significant increase in speaking behaviors across treatment session, with a corresponding decrease in use of nonverbal communication behaviors. Caregivers did not report a significant change in family impairment, though this was not unexpected due to the demands placed on caregivers as part of treatment. Overall, the results of this study support the efficacy of a brief, weekly intervention for SM, even when symptoms are significantly impairing. Weekly outpatient treatment should be considered a viable option when intensive options are not feasible.
The purpose of this study was to examine the confluence of genetic and familial risk factors in children with Autism Spectrum Disorder (ASD) with distinct de novo genetic events. We hypothesized that ...gene-disrupting mutations would be associated with reduced rates of familial psychiatric disorders relative to structural mutations. Participants included families of children with ASD in four groups: de novo duplication copy number variations (DUP, n=62), de novo deletion copy number variations (DEL, n=74), de novo likely gene-disrupting mutations (LGDM, n=267), and children without a known genetic etiology (NON, n=2111). Familial rates of psychiatric disorders were calculated from semistructured interviews. Results indicated overall increased rates of psychiatric disorders in DUP families compared to DEL and LGDM families, specific to paternal psychiatric histories, and particularly evident for depressive disorders. Higher rates of depressive disorders in maternal psychiatric histories were observed overall compared to paternal histories and higher rates of anxiety disorders were observed in paternal histories for LGDM families compared to DUP families. These findings support the notion of an additive contribution of genetic etiology and familial factors are associated with ASD risk and highlight critical need for continued work targeting these relationships.
Maxiban and Monteban are 2 products marketed by Elanco Animal Health. They contain narasin and are used for the prevention of coccidiosis in chickens. Products used in the European market must be ...regularly re-registered with new data to support label claims. This study was undertaken as part of such a re-registration effort. A method for the determination of narasin in poultry tissue was previously registered with the authorities; however, a method with more environmentally friendly solvents was desired. The Canadian Food Inspection Agency accomplished this goal and published an improved method. In order to register the method with European authorities as the official Elanco method for determination of narasin, Elanco scientists were required to provide validation data for all edible poultry tissues. This paper shows the validation of the method to detect residues of narasin using solid-phase extraction followed by liquid chromatographic analysis utilizing post-column derivatization.
Epidemiological data have suggested maternal infection and fever to be associated with increased risk of autism spectrum disorder (ASD). Animal studies show that gestational infections perturb fetal ...brain development and result in offspring with the core features of autism and have demonstrated that behavioral effects of maternal immune activation are dependent on genetic susceptibility. The goal of this study was to explore the impact of ASD-associated copy number variants (CNVs) and prenatal maternal infection on clinical severity of ASD within a dataset of prenatal history and complete genetic and phenotypic findings.
We analyzed data from the Simons Simplex Collection sample including 1971 children with a diagnosis of ASD aged 4 to 18 years who underwent array comparative genomic hybridization screening. Information on infection and febrile episodes during pregnancy was collected through parent interview. ASD severity was clinically measured through parent-reported interview and questionnaires.
We found significant interactive effects between the presence of CNVs and maternal infection during pregnancy on autistic symptomatology, such that individuals with CNVs and history of maternal infection demonstrated increased rates of social communicative impairments and repetitive/restricted behaviors. In contrast, no significant interactions were found between presence of CNVs and prenatal infections on cognitive and adaptive functioning of individuals with ASD.
Our findings support a gene-environment interaction model of autism impairment, in that individuals with ASD-associated CNVs are more susceptible to the effects of maternal infection and febrile episodes in pregnancy on behavioral outcomes and suggest that these effects are specific to ASD rather than to global neurodevelopment.
The synthesis of symmetric and asymmetric piperazinyl-linked dimers of the fluoroquinolone class of antibiotics is described. Specific dimers are shown to possess potent antibacterial activity ...against drug-resistant strains of
Staphylococcus aureus, including strains possessing resistance due to the NorA multidrug efflux pump and a mutation in the quinolone resistance-determining region of topoisomerase IV.
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The induction of polyamine catabolism has been directly associated with the cytotoxic response of various tumor types to the antitumor polyamine analogues. Initially, human polyamine catabolism was ...assumed to be under the control of a rate-limiting spermidine/spermine N1-acetyltransferase (SSAT) that provides substrate for an acetylpolyamine oxidase (PAO). We have recently cloned a new polyamine analogue-inducible human polyamine oxidase (PAOh1/SMO) that efficiently uses spermine as a substrate. The induction of PAOh1/SMO in response to multiple polyamine analogues was examined in representative lung tumor cell lines.
Representatives of three different classes of antitumor polyamine analogues were examined for their ability to induce PAOh1/SMO.
The human adenocarcinoma line, NCI A549 was found to be the most responsive line with respect to induction of PAOh1/SMO in response to analogue exposure. Similar to previous observations with SSAT expression, PAOh1/SMO induction was found to occur primarily in non-small-cell lung cancers cell lines. Using a series of polyamine analogues, it was found that the most potent inducers of PAOh1/SMO possessed multiple three-carbon linkers between nitrogens, as typified by N1,N11-bis(ethyl)norspermine.
Since PAOh1/SMO is an analogue-inducible enzyme that produces H2O2 as a metabolic product, it may play a significant role in determining the sensitivity of various human tumors to specific polyamine analogues.
This dissertation in practice aimed to introduce the design thinking framework to educators at a K-12 school in a large metropolitan area of Ohio and explore how the design thinking framework ...influences their instructional practices, especially as some educators faced moving to an online or remote environment with the onset of a global pandemic of Covid-19. The study focused on the pedagogical shifts of instruction using the design thinking model (Brown & Katz, 2009) and the instructional strategies that the teachers continued to use as a recent world health event caused them to have to shift pedagogies abruptly from their real classrooms into virtual ones. This study examined nine teachers’ utilization of the design thinking framework within K-12 schools and how it impacted their instructional practices; each one volunteered to be interviewed about their instructional practices and experiences prior to and during a global pandemic.The study also looked at the teachers’ practice using the design thinking framework and how they modeled the use of deeper learning and opportunities for inquiry (Fullan, 2015) while promoting communication, creativity, collaboration, and critical thinking. Educators shared about their use of design thinking as a pedagogical strategy to support student-centered learning, real-world problem solving, and classroom instruction.
The objective of this research is to assess the feasibility of an interdisciplinary team diagnostic assessment model for autism spectrum disorder (ASD).
Medical records from 366 patients evaluated ...for ASD at the Seattle Children's Autism Center (SCAC) were reviewed. ASD diagnostic outcomes, provider satisfaction, engagement in follow-up care, billed time, and reimbursement amounts were compared in patients evaluated through an interdisciplinary team approach (n = 91) with those seen in multidisciplinary evaluations led by either a psychologist (n = 165) or a physician (n = 110).
Diagnostic determination was made in 90% of patients evaluated through the interdisciplinary team model in a single day. Rates of ASD diagnosis were similar across the 3 tracks, ranging from 61% to 72%. Demographic characteristics did not impact the likelihood of ASD diagnosis. Rates of patient follow-up care and provider satisfaction were significantly higher in interdisciplinary versus multidisciplinary teams. Interdisciplinary team evaluations billed 1.8 fewer hours yet generated more net hourly clinic income compared with psychology-led multidisciplinary evaluations.
An interdisciplinary team approach, focusing on ruling-in or ruling-out ASD, was sufficient to determine ASD diagnosis in most patients seen at the SCAC Interdisciplinary teams generated more clinic income and decreased the time spent in evaluation compared with a psychology-led approach. They did so while maintaining consistency in diagnostic rates, demonstrating increased provider satisfaction and an increased likelihood of engagement in follow-up care.
The current study explored depression symptoms, parental stress and dispositional mindfulness in mothers of children with and without autism spectrum disorder (ASD). This study sought to clarify ...whether parental stress was a risk factor for maternal depression symptomology and if dispositional mindfulness explained the variation in parental stress and depressive symptoms in this population. Participants included 32 mothers of children with typical development (n = 21; TD) and ASD (n = 11) between the ages of 3:0 and 6:11. Groups differed significantly by child sex (ASD = 81.1% male; TD = 42.9% male). No additional group differences were present for children or mothers in terms of age, verbal abilities, ethnicity, income, relationship status, and education. Self-report measures of maternal depressive symptoms, parental stress, and dispositional mindfulness were collected from both groups. Results indicated that diagnostic status significantly predicted parent reported depression symptoms and stress, such that there was a significant, positive association between mothers of children with ASD, depression; F(1,30) = 8.63 p = .006, R2 = .22 ) and maternal stress b = 14.15, t(30) = 6.37, p < .001, R2 = .58. Parental stress fully mediated the relation between status and depression symptoms, significantly explaining the variance between status and depression and indicating the presence of a full mediation, B = 4.20, CI95 = 1.27 to 7.08. The conditional indirect effect of mindfulness moderating indirect effects of diagnostic status via stress on depression was not significant. Post hoc analyses revealed 73% mothers of children with ASD reported clinically significant depression symptoms, compared to 23% of mothers within the TD group. Correlations displayed lower mindfulness abilities in mothers with higher depression and stress when both groups were combined. The results of this study underscore the significant mental health burden that mothers of children with ASD experience. In particular, mothers of children with ASD are considerably more affected by depression symptoms and have greater stress than mothers of children without ASD. While the results in this study did not support mindfulness as a protective trait for mothers, post hoc analyses imply the possibility that mindfulness may continue to be an important area of intervention.
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