Methionine Antagonizes para-Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in Mycobacterium tuberculosis

para-Aminosalicylic acid (PAS) is a second-line anti-tubercular drug that is used for the treatment of drug-resistant tuberculosis (TB). PAS efficacy in the treatment of TB is limited by its lower potency against Mycobacterium tuberculosis relative to many other drugs in the TB treatment arsenal. It is known that intrinsic metabolites, such as, para-aminobenzoic acid (PABA) and methionine, antagonize PAS and structurally related anti-folate drugs. While the basis for PABA-mediated antagonism of anti-folates is understood, the mechanism for methionine-based antagonism remains undefined. In the present study, we used both targeted and untargeted approaches to identify factors associated with methionine-mediated antagonism of PAS activity. We found that synthesis of folate precursors as well as a putative amino acid transporter, designated MetM, play crucial roles in this process. Disruption of metM by transposon insertion resulted in a ≥30-fold decrease in uptake of methionine in M. bovis BCG, indicating that metM is the major facilitator of methionine transport. We also discovered that intracellular biotin confers intrinsic PAS resistance in a methionine-independent manner. Collectively, our results demonstrate that methionine-mediated antagonism of anti-folate drugs occurs through sustained production of folate precursors

Age at menarche and current substance use among Canadian adolescent girls: results of a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Substance use is among the key public health threats that find its genesis during adolescence. Timing of puberty has been lately researched as a potential predictor of subsequent substance abuse. The present study, therefore, aims to assess the effect of age at menarche on current practices of smoking, alcohol drinking and drug use among 14-15 year old Canadian girls.</p> <p>Methods</p> <p>The analysis of the study was based on all female respondents aged 14 to 15 years during Cycle 4 (2000/2001) of the National Longitudinal Survey of Children & Youth (NLSCY). The main independent variable was age at menarche assessed as the month and year of the occurrence of the first menstrual cycle. The dependent variables were current smoking, heavy alcohol drinking in the past 12 months and drug use in the past 12 months. Three logistic regression models were performed to investigate the association between age at menarche and each of the substance use outcomes, adjusting for possible confounders. Bootstrapping was performed to account for the complex sampling design.</p> <p>Results</p> <p>The total weighted sample included in the analysis represented 295,042 Canadian girls. The prevalence of current smokers, heavy drinkers (drunk in the past 12 months) and drug users in the past 12 months was approximately 22%, 38% and 26%, respectively. After adjusting of all potential confounders, no association was found between age at menarche and any of the substance use outcomes. School performance and relationship with the father, however, stood out as the main variables to be associated with smoking, heavy drinking and drug use.</p> <p>Conclusions</p> <p>Qualitative studies understanding the social and psychological changes experienced by early maturing Canadian adolescents are warranted to identify other correlates or pathways to substance use in this higher risk population.</p

Smoking onset and the time-varying effects of self-efficacy, environmental smoking, and smoking-specific parenting by using discrete-time survival analysis

This study examined the timing of smoking onset during mid- or late adolescence and the time-varying effects of refusal self-efficacy, parental and sibling smoking behavior, smoking behavior of friends and best friend, and parental smoking-specific communication. We used data from five annual waves of the ‘Family and Health’ project. In total, 428 adolescents and their parents participated at baseline. Only never smokers were included at baseline (n = 272). A life table and Kaplan–Meier survival curve showed that 51% of all adolescents who did not smoke at baseline did not start smoking within 4 years. The risk for smoking onset during mid- or late adolescence is rather stable (hazard ratio between 16 and 19). Discrete-time survival analyses revealed that low refusal self-efficacy, high frequency of communication, and sibling smoking were associated with smoking onset one year later. No interaction effects were found. Conclusively, the findings revealed that refusal self-efficacy is an important predictor of smoking onset during mid- or late adolescence and is independent of smoking-specific communication and smoking behavior of parents, siblings, and (best) friend(s). Findings emphasize the importance of family prevention programs focusing on self-efficacy skills

Outcome After Surgical Stabilization of Rib Fractures Versus Nonoperative Treatment in Patients With Multiple Rib Fractures and Moderate to Severe Traumatic Brain Injury (CWIS-TBI)

BACKGROUND Outcomes after surgical stabilization of rib fractures (SSRF) have not been studied in patients with multiple rib fractures and traumatic brain injury (TBI). We hypothesized that SSRF, as compared with nonoperative management, is associated with favorable outcomes in patients with TBI. METHODS A multicenter, retrospective cohort study was performed in patients with rib fractures and TBI between January 2012 and July 2019. Patients who underwent SSRF were compared to those managed nonoperatively. The primary outcome was mechanical ventilation-free days. Secondary outcomes were intensive care unit length of stay and hospital length of stay, tracheostomy, occurrence of complications, neurologic outcome, and mortality. Patients were further stratified into moderate (GCS score, 9–12) and severe (GCS score, ≤8) TBI. RESULTS The study cohort consisted of 456 patients of which 111 (24.3%) underwent SSRF. The SSRF was performed at a median of 3 days, and SSRF-related complication rate was 3.6%. In multivariable analyses, there was no difference in mechanical ventilation-free days between the SSRF and nonoperative groups. The odds of developing pneumonia (odds ratio [OR], 0.59; 95% confidence interval [95% CI], 0.38–0.98; p = 0.043) and 30-day mortality (OR, 0.32; 95% CI, 0.11–0.91; p = 0.032) were significantly lower in the SSRF group. Patients with moderate TBI had similar outcome in both groups. In patients with severe TBI, the odds of 30-day mortality was significantly lower after SSRF (OR, 0.19; 95% CI, 0.04–0.88; p = 0.034). CONCLUSION In patients with multiple rib fractures and TBI, the mechanical ventilation-free days did not differ between the two treatment groups. In addition, SSRF was associated with a significantly lower risk of pneumonia and 30-day mortality. In patients with moderate TBI, outcome was similar. In patients with severe TBI a lower 30-day mortality was observed. There was a low SSRF-related complication risk. These data suggest a potential role for SSRF in select patients with TBI. LEVEL OF EVIDENCE Therapeutic, level IV

Re-examining the transition into the N=20 island of inversion: structure of 30Mg

Intermediate energy single-neutron removal from $^{31}$Mg has been employed to investigate the transition into the N=20 island of inversion. Levels up to 5~MeV excitation energy in $^{30}$Mg were populated and spin-parity assignments were inferred from the corresponding longitudinal momentum distributions and $\gamma$-ray decay scheme. Comparison with eikonal-model calculations also permitted spectroscopic factors to be deduced. Surprisingly, the 0$^{+}_{2}$ level in $^{30}$Mg was found to have a strength much weaker than expected in the conventional picture of a predominantly $2p - 2h$ intruder configuration having a large overlap with the deformed $^{31}$Mg ground state. In addition, negative parity levels were identified for the first time in $^{30}$Mg, one of which is located at low excitation energy. The results are discussed in the light of shell-model calculations employing two newly developed approaches with markedly different descriptions of the structure of $^{30}$Mg. It is concluded that the cross-shell effects in the region of the island of inversion at Z=12 are considerably more complex than previously thought and that $np - nh$ configurations play a major role in the structure of $^{30}$Mg.Comment: Physics Letters B, Volume 779, 10 April 2018, Pages 124-12

Teasing apart the heterogeneity of autism: Same behavior, different brains in toddlers with fragile X syndrome and autism

To examine brain volumes in substructures associated with the behavioral features of children with FXS compared to children with idiopathic autism and controls. A cross-sectional study of brain substructures was conducted at the first time-point as part of an ongoing longitudinal MRI study of brain development in FXS. The study included 52 boys between 18–42 months of age with FXS and 118 comparison children (boys with autism-non FXS, developmental-delay, and typical development). Children with FXS and autistic disorder had substantially enlarged caudate volume and smaller amygdala volume; whereas those children with autistic disorder without FXS (i.e., idiopathic autism) had only modest enlargement in their caudate nucleus volumes but more robust enlargement of their amygdala volumes. Although we observed this double dissociation among selected brain volumes, no significant differences in severity of autistic behavior between these groups were observed. This study offers a unique examination of early brain development in two disorders, FXS and idiopathic autism, with overlapping behavioral features, but two distinct patterns of brain morphology. We observed that despite almost a third of our FXS sample meeting criteria for autism, the profile of brain volume differences for children with FXS and autism differed from those with idiopathic autism. These findings underscore the importance of addressing heterogeneity in studies of autistic behavior

Comparing early adolescents’ positive bystander responses to cyberbullying and traditional bullying: the impact of severity and gender

Young people are frequently exposed to bullying events in the offline and online domain. Witnesses to these incidents act as bystanders and play a pivotal role in reducing or encouraging bullying behaviour. The present study examined 868 (47.2% female) 11-13-year-old early adolescent pupils’ bystander responses across a series of hypothetical vignettes based on traditional and cyberbullying events. The vignettes experimentally controlled for severity across mild, moderate, and severe scenarios. The findings showed positive bystander responses (PBRs) were higher in cyberbullying than traditional bullying incidents. Bullying severity impacted on PBRs, in that PBRs increased across mild, moderate, and severe incidents, consistent across traditional and cyberbullying. Females exhibited more PBRs across both types of bullying. Findings are discussed in relation to practical applications within the school. Strategies to encourage PBRs to all forms of bullying should be at the forefront of bullying intervention methods