Generation of Functionalized Azepinone Derivatives via a (4 + 3)-Cycloaddition of Vinyl Ketenes and α-Imino Carbenes Derived from N-Sulfonyl-triazoles.

An intermolecular RhII-catalyzed, formal (4 + 3)-cycloaddition between vinyl ketenes and N-sulfonyl-1,2,3-triazoles for the construction of azepinone products is described. Employing vinyl ketenes as a 1,4-dipolar surrogate, instead of the more commonly used dienyl moieties, allows for the intermolecular and selective formation of azepinone products over a potential (3 + 2)-cycloadduct under mild reaction conditions allows for the generation of azepinone products in up to 98% yield.

Diastereoselective Synthesis of Terminal Bromo-Substituted Propargylamines via Generation of Lithium Bromoacetylide and Addition to Chiral N-tert-Butanesulfinyl Aldimines.

The stereoselective synthesis of terminal bromo-substituted propargylamines via in situ generation of lithium bromoacetylide from 1,2-dibromoethene and addition to Ellman chiral N-tert-butanesulfinyl aldimines is reported. Modest to good yields (43-85%) and diastereoselectivity (dr = 3:1 to >20:1) were achieved for a range of aryl, heteroaryl, alkyl, and α,ß-unsaturated substrates. Terminal bromo-substituted propargylamines prepared via this method can be directly used in the frequently employed Cadiot-Chodkiewicz coupling to produce functionalized diynes. The method reported here increases the structural diversity of chiral terminal bromo-substituted propargylamines that can be readily synthesized as previous methods for the stereoselective synthesis of these compounds rely on amino acid precursors from the chiral pool.

Prospective Physician Awareness of the Associations Between Social Media and Mental Health.

OBJECTIVE: Recently, studies have cited negative, positive, and an absence of impact on mental health with social media use. However, there has been little studied regarding the level of awareness and training of clinicians in screening and identifying for these associations. For this reason, the authors designed a study to assess the awareness of prospective physicians, or current medical students, on the associations between mental health and social media. METHODS: The study was in the form of a 12-question survey. The questions aimed at assessing the awareness through past experiences with social media, education of its use and potential impacts, and self-reported ability to screen, identify, and counsel patients on these associations. The survey was sent to a total of 634 medical students and included all classes from MS1-MS4. A total of 148 students completed this survey (23.3% response rate). RESULTS: The majority of medical students reported first social media use between the ages of 13 and 18, with the most common occurrence of bullying identified in this age group as well. The majority percentage of students believed there could be both positive and negative effects of social media on mental health; however, only a small percentage of students reported being aware of specific patterns of social media use that are associated with mental health. Moreover, only a few students reported feeling adequate in their ability to screen, educate, and counsel patients on these associations. CONCLUSIONS: Findings from this study suggest the need for educational resources to train future physicians in screening, identifying, and counseling patients on associations between social media and mental health. The small numbers in this study are a limiting factor for the validity of result interpretation.

Evaluation of 1,2,3-Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX-770 and VX-809.

The 1,2,3-triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogues derived from VX-809 and VX-770, prominent amide-containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX-809, displayed markedly reduced efficacy in F508del-CFTR correction in cellular TECC assays in comparison to VX-809. Surprisingly, triazole analogues derived from potentiator VX-770 displayed no potentiation of F508del, G551D, or WT-CFTR in cellular Ussing chamber assays. However, patch clamp analysis revealed that triazole 60 potentiates WT-CFTR similarly to VX-770. The efficacy of 60 in the cell-free patch clamp experiment suggests that the loss of activity in the cellular assay could be due to the inability of VX-770 triazole derivatives to reach the CFTR binding site. Moreover, in addition to the negative impact on biological activity, triazoles in both structural classes displayed decreased metabolic stability in human microsomes relative to the analogous amides. In contrast to the many studies that demonstrate the advantages of using the 1,2,3-triazole, these findings highlight the negative impacts that can arise from replacement of the amide with the triazole and suggest that caution is warranted when considering use of the 1,2,3-triazole as an amide bioisostere.

Rational Design and Identification of Harmine-Inspired, N-Heterocyclic DYRK1A Inhibitors Employing a Functional Genomic In Vivo Drosophila Model System.

Deregulation of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays a significant role in developmental brain defects, early-onset neurodegeneration, neuronal cell loss, dementia, and several types of cancer. Herein, we report the discovery of three new classes of N-heterocyclic DYRK1A inhibitors based on the potent, yet toxic kinase inhibitors, harmine and harmol. An initial in vitro evaluation of the small molecule library assembled revealed that the core heterocyclic motifs benzofuranones, oxindoles, and pyrrolones, showed statistically significant DYRK1A inhibition. Further, the utilization of a low cost, high-throughput functional genomic in vivo model system to identify small molecule inhibitors that normalize DYRK1A overexpression phenotypes is described. This in vivo assay substantiated the in vitro results, and the resulting correspondence validates generated classes as architectural motifs that serve as potential DYRK1A inhibitors. Further expansion and analysis of these core compound structures will allow discovery of safe, more effective chemical inhibitors of DYRK1A to ameliorate phenotypes caused by DYRK1A overexpression.

Behavioral addiction and autism spectrum disorder: A systematic review.

BACKGROUND: According to DSM-5 criteria, Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficiencies in social communication and interaction along with the presence of restrictive and repetitive patterns of behavior. Few studies have explored the prevalence of behavioral addiction in individuals with ASD. Since addiction and ASD share common characteristics, individuals with ASD may be more vulnerable to addictive behaviors. Some typical behavioral addictions include internet, gaming, and gambling addiction. While most previous studies on ASD and addiction have looked at chemical addiction, behavioral addiction has not been thoroughly studied to date. AIMS: The objective of this study was to investigate the presence of behavioral addiction among individuals diagnosed with autism spectrum disorder. METHODS AND PROCEDURES: A systematic literature search of five databases was conducted in accordance with the PRISMA guidelines. Search results were reviewed for the predetermined inclusion criteria independently by two authors. OUTCOMES AND RESULTS: The search yielded 539 publications after the removal of duplicates. 61 met the inclusion criteria for title and abstract review. Full texts were reviewed resulting in an additional 31 being removed. The remaining 30 included 4 case reports and 26 original studies. Results included 27 studies that found a positive correlation (15 of significance, 12 of unknown significance) between a behavioral addiction and either ASD or Autistic traits, 1 found a significant negative correlation, 3 did not find a correlation. CONCLUSIONS AND IMPLICATIONS: This review is inconclusive about links between ASD and behavioral addictions. While a vast majority of studies show a positive correlation, many do not provide the statistical analysis to show if the correlations are significant. In addition, a positive correlation between ASD and behavioral addiction is observed in the presence of comorbid mental health conditions in many of the studies. Further research with proper controls and statistical analysis is needed to determine whether the development of behavioral addiction is directly influenced by ASD or if the presence of a comorbid mental health condition is the true cause.

Neurite Orientation Dispersion and Density Imaging (NODDI) and Duration of Untreated Psychosis in Antipsychotic Medication-Naïve First Episode Psychosis Patients.

Background: Diffusion tensor imaging suggests that white matter alterations are already evident in first episode psychosis patients (FEP) and may become more prominent as the duration of untreated psychosis (DUP) increases. But because the tensor model lacks specificity, it remains unclear how to interpret findings on a biological level. Here, we used a biophysical diffusion model, Neurite Orientation Dispersion and Density Imaging (NODDI), to map microarchitecture in FEP, and to investigate associations between DUP and microarchitectural integrity. Methods: We scanned 78 antipsychotic medication-naïve FEP and 64 healthy controls using a multi-shell diffusion weighted sequence and used the NODDI toolbox to compute neurite density (ND), orientation dispersion index (ODI) and extracellular free water (FW) maps. AFNI's 3dttest++ was used to compare diffusion maps between groups and to perform regression analyses with DUP. Results: We found that ND was decreased in commissural and association fibers but increased in projection fibers in FEP. ODI was largely increased regardless of fiber type, and FW showed a mix of increase in decrease across fiber tracts. We also demonstrated associations between DUP and microarchitecture for all NODDI indices. Conclusions: We demonstrated that complex microarchitecture abnormalities are already evident in antipsychotic-naïve FEP. ND alterations are differentially expressed depending on fiber type, while decreased fiber complexity appears to be a uniform marker of white matter deficit in the illness. Importantly, we identified an empirical link between longer DUP and greater white matter pathology across NODDI indices, underscoring the critical importance of early intervention in this devastating illness.

Diverting ß-Hydride Elimination of a π-Allyl PdII Carbene Complex for the Assembly of Disubstituted Indolines via a Highly Diastereoselective (4 + 1)-Cycloaddition.

A Pd0-catalyzed formal (4 + 1)-cycloaddition approach to 2,3-disubstituted dihydroindoles is described. The diastereoselective formation of dihydroindoles that is highlighted by a carbene migratory insertion/reductive elimination sequence proceeding via a π-allyl PdII-species compliments existing methods of indoline assembly.

Mobile device applications and treatment of autism spectrum disorder: a systematic review and meta-analysis of effectiveness.

OBJECTIVE: The current study was performed to assess the evidence for effects of therapeutic intervention with mobile device applications (apps) for individuals with autism spectrum disorder (ASD). DESIGN: The main methodology of the current study was systematic review with meta-analysis. SETTING: Only randomised controlled trials (RCTs) for mobile device apps for individuals with ASD were considered for review in the current study. PATIENTS: The target population was individuals clinically diagnosed with ASD. INTERVENTIONS: Applications that are operable on a smart (mobile) device and interactive with users. MAIN OUTCOME MEASURES: The main outcomes were based on standardised mean differences in pretrial and post-trial scales in each control and intervention group. RESULTS: Out of a total of 1100 studies (after duplicate removal), 7 RCTs were selected for final analysis. Of the seven studies, two RCTs were further analysed for effects based on the visual and fine motor subscales of the Mullen Scales of Early Learning, which favoured the intervention groups (standardised mean difference (SMD)=0.41, 95% CI 0.03 to 0.80; SMD=0.41, 95% CI 0.03 to 0.80), without either having any heterogeneity (p>0.1) or publication bias. CONCLUSIONS: Although it is still early to draw a conclusion, available studies are showing promise for use of mobile device apps for treatment of individuals with ASD. More well-designed and large-scale studies focused on improving behavioural symptoms of ASD are warranted. PROSPERO REGISTRATION NUMBER: CRD42019128362.

l-Methionine anti-biofilm activity against Pseudomonas aeruginosa is enhanced by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor.

BACKGROUND: Biofilms may contribute to refractory chronic rhinosinusitis (CRS), as they lead to antibiotic resistance and failure of effective clinical treatment. l-Methionine is an amino acid with reported biofilm-inhibiting properties. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator with mild antimicrobial activity via inhibition of bacterial DNA gyrase and topoisomerase IV. The objective of this study was to evaluate whether co-treatment with ivacaftor and l-methionine can reduce the formation of Pseudomonas aeruginosa biofilms. METHODS: P aeruginosa (PAO-1 strain) biofilms were studied in the presence of l-methionine and/or ivacaftor. For static biofilm assays, PAO-1 was cultured in a 48-well plate for 72 hours with stepwise combinations of these agents. Relative biofilm inhibitions were measured according to optical density of crystal violet stain at 590 nm. Live/dead assays (BacTiter-Glo™ assay, Promega) were imaged with laser scanning confocal microscopy. An agar diffusion test was used to confirm antibacterial effects of the drugs. RESULTS: l-Methionine (0.5 µM) significantly reduced PAO-1 biofilm mass (32.4 ± 18.0%; n = 4; p < 0.001) compared with controls. Low doses of ivacaftor alone (4, 8, and 12 µg/mL) had no effect on biofilm formation. When combined with ivacaftor (4 µg/mL), a synergistic anti-biofilm effect was noted at 0.05 µM and 0.5 µM of l-methionine (two-way analysis of variane, p = 0.0415) compared with corresponding concentrations of l-methionine alone. CONCLUSION: Ivacaftor enhanced the anti-biofilm activity of l-methionine against the PAO-1 strain of P aeruginosa. Further studies evaluating the efficacy of ivacaftor/l-methionine combinations for P aeruginosa sinusitis are planned.