The role of RNF138 in DNA end resection is regulated by ubiquitylation and CDK phosphorylation.

Double-strand breaks (DSBs) are DNA lesions that pose a significant threat to genomic stability. The repair of DSBs by the homologous recombination (HR) pathway is preceded by DNA end resection, the 5' to 3' nucleolytic degradation of DNA away from the DSB. We and others previously identified a role for RNF138, a really interesting new gene finger E3 ubiquitin ligase, in stimulating DNA end resection and HR. Yet, little is known about how RNF138's function is regulated in the context of DSB repair. Here, we show that RNF138 is phosphorylated at residue T27 by cyclin-dependent kinase (CDK) activity during the S and G2 phases of the cell cycle. We also observe that RNF138 is ubiquitylated constitutively, with ubiquitylation occurring in part on residue K158 and rising during the S/G2 phases. Interestingly, RNF138 ubiquitylation decreases upon genotoxic stress. By mutating RNF138 at residues T27, K158, and the previously identified S124 ataxia telangiectasia mutated phosphorylation site (Han et al., 2016, ref. 22), we find that post-translational modifications at all three positions mediate DSB repair. Cells expressing the T27A, K158R, and S124A variants of RNF138 are impaired in DNA end resection, HR activity, and are more sensitive to ionizing radiation compared to those expressing wildtype RNF138. Our findings shed more light on how RNF138 activity is controlled by the cell during HR.

Ileal microbial shifts after Roux-en-Y gastric bypass orchestrate changes in glucose metabolism through modulation of bile acids and L-cell adaptation.

Roux-en-Y gastric bypass (RYGB)-induced glycemic improvement is associated with increases in glucagon-like-peptide-1 (GLP-1) secreted from ileal L-cells. We analyzed changes in ileal bile acids and ileal microbial composition in diet-induced-obesity rats after RYGB or sham surgery to elucidate the early and late effects on L-cells and glucose homeostasis. In early cohorts, there were no significant changes in L-cell density, GLP-1 or glucose tolerance. In late cohorts, RYGB demonstrated less weight regain, improved glucose tolerance, increased L-cell density, and increased villi height. No difference in the expression of GLP-1 genes was observed. There were lower concentrations of ileal bile acids in the late RYGB cohort. Microbial analysis demonstrated decreased alpha diversity in early RYGB cohorts which normalized in the late group. The early RYGB cohorts had higher abundances of Escherichia-Shigella but lower abundances of Lactobacillus, Adlercreutzia, and Proteus while the late cohorts demonstrated higher abundances of Escherichia-Shigella and lower abundances of Lactobacillus. Shifts in Lactobacillus and Escherichia-Shigella correlated with decreases in multiple conjugated bile acids. In conclusion, RYGB caused a late and substantial increase in L-cell quantity with associated changes in bile acids which correlated to shifts in Escherichia-Shigella and Lactobacillus. This proliferation of L-cells contributed to improved glucose homeostasis.

Predicting surgical site infections following laparoscopic bariatric surgery: development of the BariWound tool using the MBSAQIP database.

BACKGROUND: Although bariatric surgery is a safe procedure for severe obesity, incisional surgical site infections (SSI) remain a significant cause of morbidity. Bariatric surgery patients are at high risk due to obesity and diabetes. The objective of this study was to develop a predictive tool for incisional SSI within 30 days of bariatric surgery. METHODS: Data were retrieved from the 2015 and 2016 MBSAQIP databases. This study included patients who underwent primary laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG). The primary outcome of interest was incisional SSI occurring within 30 days. Surgeries performed in 2015 were used in a derivation cohort and the predictive tool was validated against the 2016 cohort. A forward selection algorithm was used to build a logistic regression model predicting probability of SSI. RESULTS: A total of 274,187 patients were included with 71.7% being LSG and 28.3% LRYGB. 0.7% of patients had a SSI in which 71.0% had an incisional SSI, and 29.9% had an organ/space SSI. Of patients who had an incisional SSI, 88.7% were superficial, 10.9% were deep, and 0.4% were both. A prediction model to assess for risk of incisional SSI, BariWound, was derived and validated. BariWound consists of procedure type, chronic steroid or immunosuppressant use, gastroesophageal reflux disease, obstructive sleep apnea, sex, type 2 diabetes, hypertension, operative time, and body mass index. It stratifies individuals into very high (> 10%), high (5-10%), medium (1-5%), and low risk (< 1%) groups. This model accurately predicted events in the validation cohort with an area under the receiver operating characteristic curve of 0.73. CONCLUSIONS: BariWound accurately predicted the risk of 30-day incisional SSI in individuals undergoing bariatric surgery. Stratifying low- and high-risk groups allows for customized SSI prophylactic measures for patients in various risk categories and potentially enables future research targeted at high-risk patients.

Prevalence of malnutrition among HIV-infected children in Central and West-African HIV-care programmes supported by the Growing Up Programme in 2011: a cross-sectional study.

BACKGROUND: The burden of malnutrition among HIV-infected children is not well described in sub-Saharan Africa, even though it is an important problem to take into account to guarantee appropriate healthcare for these children. We assessed the prevalence of malnutrition and its associated factors among HIV-infected children in HIV care programmes in Central and West-Africa. METHODS: A cross-sectional study was conducted from September to December 2011 among the active files of HIV-infected children aged 2-19 years old, enrolled in HIV-care programmes supported by the Sidaction Growing Up Programme in Benin, Burundi, Cameroon, Côte d'Ivoire, Mali, Chad and Togo. Socio-demographics characteristics, anthropometric, clinical data, and nutritional support were collected. Anthropometric indicators, expressed in Z-scores, were used to define malnutrition: Height-for-age (HAZ), Weight-for-Height (WHZ) for children < 5 years and BMI-for-age (BAZ) for children ≥5 years. Three types of malnutrition were defined: acute malnutrition (WHZ/BAZ < -2 SD and HAZ ≥ -2 SD), chronic malnutrition (HAZ < -2 SD and WHZ/BAZ ≥ -2 SD) and mixed malnutrition (WHZ/BAZ < -2 SD and HAZ < -2 SD). A multinomial logistic regression model explored associated factors with each type of malnutrition. RESULTS: Overall, 1350 HIV-infected children were included; their median age was 10 years (interquartile range [IQR]: 7-13 years), 49 % were girls. 80 % were on antiretroviral treatment (ART), for a median time of 36 months. The prevalence of malnutrition was 42 % (95 % confidence interval [95% CI]: 40-44 %) with acute, chronic and mixed malnutrition at 9 % (95% CI: 6-12 %), 26 % (95% CI: 23-28 %), and 7 % (95% CI: 5-10 %), respectively. Among those malnourished, more than half of children didn't receive any nutritional support at the time of the survey. Acute malnutrition was associated with male gender, severe immunodeficiency, and the absence of ART; chronic malnutrition with male gender and age (<5 years); and mixed malnutrition with male gender, age (<5 years), severe immunodeficiency and recent ART initiation (<6 months). Orphanhood and Cotrimoxazole prophylaxis were not associated with any type of malnutrition. CONCLUSIONS: The prevalence of malnutrition in HIV-infected children even on ART remains high in HIV care programmes. Anthropometric measurements and appropriate nutritional care of malnourished HIV-infected children remain insufficient and a priority to improve health care of HIV-infected children in Africa.

Increased gender variance in autism spectrum disorders and attention deficit hyperactivity disorder.

Evidence suggests over-representation of autism spectrum disorders (ASDs) and behavioral difficulties among people referred for gender issues, but rates of the wish to be the other gender (gender variance) among different neurodevelopmental disorders are unknown. This chart review study explored rates of gender variance as reported by parents on the Child Behavior Checklist (CBCL) in children with different neurodevelopmental disorders: ASD (N = 147, 24 females and 123 males), attention deficit hyperactivity disorder (ADHD; N = 126, 38 females and 88 males), or a medical neurodevelopmental disorder (N = 116, 57 females and 59 males), were compared with two non-referred groups [control sample (N = 165, 61 females and 104 males) and non-referred participants in the CBCL standardization sample (N = 1,605, 754 females and 851 males)]. Significantly greater proportions of participants with ASD (5.4%) or ADHD (4.8%) had parent reported gender variance than in the combined medical group (1.7%) or non-referred comparison groups (0-0.7%). As compared to non-referred comparisons, participants with ASD were 7.59 times more likely to express gender variance; participants with ADHD were 6.64 times more likely to express gender variance. The medical neurodevelopmental disorder group did not differ from non-referred samples in likelihood to express gender variance. Gender variance was related to elevated emotional symptoms in ADHD, but not in ASD. After accounting for sex ratio differences between the neurodevelopmental disorder and non-referred comparison groups, gender variance occurred equally in females and males.

Randomized controlled effectiveness trial of executive function intervention for children on the autism spectrum.

BACKGROUND: Unstuck and On Target (UOT) is an executive function (EF) intervention for children with autism spectrum disorders (ASD) targeting insistence on sameness, flexibility, goal-setting, and planning through a cognitive-behavioral program of self-regulatory scripts, guided/faded practice, and visual/verbal cueing. UOT is contextually-based because it is implemented in school and at home, the contexts in which a child uses EF skills. METHODS: To evaluate the effectiveness of UOT compared with a social skills intervention (SS), 3rd-5th graders with ASD (mean IQ = 108; UOT n = 47; SS n = 20) received interventions delivered by school staff in small group sessions. Students were matched for gender, age, race, IQ, ASD symptomotolgy, medication status, and parents' education. Interventions were matched for 'dose' of intervention and training. Measures of pre-post change included classroom observations, parent/teacher report, and direct child measures of problem-solving, EF, and social skills. Schools were randomized and evaluators, but not parents or teachers, were blinded to intervention type. RESULTS: Interventions were administered with high fidelity. Children in both groups improved with intervention, but mean change scores from pre- to postintervention indicated significantly greater improvements for UOT than SS groups in: problem-solving, flexibility, and planning/organizing. Also, classroom observations revealed that participants in UOT made greater improvements than SS participants in their ability to follow rules, make transitions, and be flexible. Children in both groups made equivalent improvements in social skills. CONCLUSIONS: These data support the effectiveness of the first contextually-based EF intervention for children with ASD. UOT improved classroom behavior, flexibility, and problem-solving in children with ASD. Individuals with variable background/training in ASD successfully implemented UOT in mainstream educational settings.