SLX4IP Antagonizes Promiscuous BLM Activity during ALT Maintenance.

Cancer cells acquire unlimited proliferative capacity by either re-expressing telomerase or inducing alternative lengthening of telomeres (ALT), which relies on telomere recombination. Here, we show that ALT recombination requires coordinate regulation of the SMX and BTR complexes to ensure the appropriate balance of resolution and dissolution activities at recombining telomeres. Critical to this control is SLX4IP, which accumulates at ALT telomeres and interacts with SLX4, XPF, and BLM. Loss of SLX4IP increases ALT-related phenotypes, which is incompatible with cell growth following concomitant loss of SLX4. Inactivation of BLM is sufficient to rescue telomere aggregation and the synthetic growth defect in this context, suggesting that SLX4IP favors SMX-dependent resolution by antagonizing promiscuous BLM activity during ALT recombination. Finally, we show that SLX4IP is inactivated in a subset of ALT-positive osteosarcomas. Collectively, our findings uncover an SLX4IP-dependent regulatory mechanism critical for telomere maintenance in ALT cancer cells.

Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN.

Classical non-homologous end joining (cNHEJ) and homologous recombination compete for the repair of double-stranded DNA breaks during the cell cycle. Homologous recombination is inhibited during the G1 phase of the cell cycle, but both pathways are active in the S and G2 phases. However, it is unclear why cNHEJ does not always outcompete homologous recombination during the S and G2 phases. Here we show that CYREN (cell cycle regulator of NHEJ) is a cell-cycle-specific inhibitor of cNHEJ. Suppression of CYREN allows cNHEJ to occur at telomeres and intrachromosomal breaks during the S and G2 phases, and cells lacking CYREN accumulate chromosomal aberrations upon damage induction, specifically outside the G1 phase. CYREN acts by binding to the Ku70/80 heterodimer and preferentially inhibits cNHEJ at breaks with overhangs by protecting them. We therefore propose that CYREN is a direct cell-cycle-dependent inhibitor of cNHEJ that promotes error-free repair by homologous recombination during cell cycle phases when sister chromatids are present.

The Replisome-Coupled E3 Ubiquitin Ligase Rtt101Mms22 Counteracts Mrc1 Function to Tolerate Genotoxic Stress.

Faithful DNA replication and repair requires the activity of cullin 4-based E3 ubiquitin ligases (CRL4), but the underlying mechanisms remain poorly understood. The budding yeast Cul4 homologue, Rtt101, in complex with the linker Mms1 and the putative substrate adaptor Mms22 promotes progression of replication forks through damaged DNA. Here we characterized the interactome of Mms22 and found that the Rtt101(Mms22) ligase associates with the replisome progression complex during S-phase via the amino-terminal WD40 domain of Ctf4. Moreover, genetic screening for suppressors of the genotoxic sensitivity of rtt101Δ cells identified a cluster of replication proteins, among them a component of the fork protection complex, Mrc1. In contrast to rtt101Δ and mms22Δ cells, mrc1Δ rtt101Δ and mrc1Δ mms22Δ double mutants complete DNA replication upon replication stress by facilitating the repair/restart of stalled replication forks using a Rad52-dependent mechanism. Our results suggest that the Rtt101(Mms22) E3 ligase does not induce Mrc1 degradation, but specifically counteracts Mrc1's replicative function, possibly by modulating its interaction with the CMG (Cdc45-MCM-GINS) complex at stalled forks.

Testing Mediators of Youth Intervention Outcomes Using Single-Case Experimental Designs.

The major aim of this manuscript is to bring together two important topics that have recently received much attention in child and adolescent research, albeit separately from each other: single-case experimental designs and statistical mediation analysis. Single-case experimental designs (SCEDs) are increasingly recognized as a valuable alternative for Randomized Controlled Trials (RCTs) to test intervention effects in youth populations. Statistical mediation analysis helps provide understanding about the most potent mechanisms of change underlying youth intervention outcomes. In this manuscript we: (i) describe the conceptual framework and outline desiderata for methods for mediation analysis in SCEDs; (ii) describe the main aspects of several data-analytic techniques potentially useful to test mediation in SCEDs; (iii) apply these methods to a single-case treatment data set from one clinically anxious client; and (iv) discuss pros and cons of these methods for testing mediation in SCEDs, and provide future directions.

What are the odds of anxiety disorders running in families? A family study of anxiety disorders in mothers, fathers, and siblings of children with anxiety disorders.

This family study investigated (1) the prevalence of anxiety disorders (ADs) in parents and siblings of children (n = 144) aged 8-18 years with ADs compared to control children (n = 49), and (2) the specificity of relationships between child-mother, child-father, and child-sibling ADs. Clinical interviews were used to assess current DSM-IV-TR ADs in children and siblings, and lifetime and current ADs in parents. Results showed that children with ADs were two to three times more likely to have at least one parent with current and lifetime ADs than the control children (odds ratio (OR) = 2.04 and 3.14). Children with ADs were more likely to have mothers with current ADs (OR = 2.51), fathers with lifetime ADs (OR = 2.84), but not siblings with ADs (OR = 0.75). Specific relationships between mother-child ADs were found for Social Anxiety Disorder (SAD, OR = 3.69) and Generalized Anxiety Disorder (OR = 3.47). Interestingly, all fathers and siblings with SAD came from families of children with SAD. Fathers of children with SAD were more likely to have lifetime ADs themselves (OR = 2.86). Findings indicate that children with ADs more often have parents with ADs, and specifically SAD is more prevalent in families of children with SAD. Influence of parent's (social) ADs should be considered when treating children with ADs.

Executive function as a mediator in the link between single or complex trauma and posttraumatic stress in children and adolescents.

PURPOSE: In this study, we examined whether there is a mediating role of executive function (EF) in the relationship between trauma exposure and posttraumatic stress in youth. METHODS: Children and adolescents exposed to trauma were recruited at an academic center for child psychiatry in The Netherlands. The total sample consisted of 119 children from 9 to 17 years old (M = 13.65, SD = 2.45). Based on retrospective life event information, the sample was divided into three groups: a single trauma group (n = 41), a complex trauma group (n = 38), and a control group that was not exposed to traumatic events (n = 40). RESULTS: Our findings revealed that youth exposed to complex trauma had more deficits in EF compared to youth in the single trauma and control groups. EF was found to partly mediate posttraumatic stress symptoms for youth exposed to complex trauma, but not for youth exposed to single trauma. Youth exposed to complex trauma showed more deficits in EF, which was in turn associated with higher levels of posttraumatic stress symptoms. CONCLUSIONS: Our findings provide partial support for the role of EF in mediating posttraumatic stress outcomes for youth exposed to complex trauma. This points to the important role of EF in the etiology and treatment of complexly traumatized youth.

Are Anxiety Disorders in Children and Adolescents Less Impairing Than ADHD and Autism Spectrum Disorders? Associations with Child Quality of Life and Parental Stress and Psychopathology.

We compared clinically referred children with anxiety disorders (AD; n = 63) to children with autism spectrum disorder (ASD; n = 39), ADHD Combined (ADHD-C; n = 62), ADHD Predominantly Inattentive (ADHD-I; n = 64), and typically developing children (n = 42) on child quality of life (QOL), paternal and maternal psychopathology and parental stress. Diagnoses were based on DSM-IV-TR criteria. Multilevel analyses showed that QOL in AD was higher on school and social functioning, compared to respectively ADHD and ASD, and lower compared to normal controls on all five domains. Fathers reported their AD children higher QOL than mothers. Also, AD appeared to be associated with less parental stress and parental psychopathology than other child psychopathology. Therefore, parental factors may need to be considered more in treatment of children with ADHD/ASD than AD.

Negative Cognitive Errors in Youth: Specificity to Anxious and Depressive Symptoms and Age Differences.

BACKGROUND: Negative cognitive errors are important in the etiology and treatment of youth internalizing problems, but less is known about their unique relations with anxiety and depression. AIMS: The major purpose of this study was to examine associations between distinct negative cognitive errors and anxiety and depression in youth. METHOD: In a community sample of children and adolescents (aged 9-17; N = 278) negative cognitive errors were assessed using the revised version of the Children's Negative Cognitive Error Questionnaire (CNCEQ-R). Anxiety and depression were assessed with the Multidimensional Anxiety Scale for Children and Children's Depression Inventory, respectively. RESULTS: The strongest predictors of anxiety were the negative cognitive errors "underestimation of the ability to cope" and "mind reading". The strongest predictors of depression were the errors "selective abstraction" and "overgeneralizing", with the first error explaining most variance. Analyses of age effects showed that, in comparison to adolescents, children reported higher scores on the total CNCEQ-R score, and on the errors "overgeneralizing", "personalizing", and "mind reading". CONCLUSIONS: The findings underscore the importance of researching the role of distinct cognitive processing in youth with anxiety and depression and further development of the CNCEQ-R. Implications for clinical practice are discussed.

Cognitive mediation of cognitive-behavioural therapy outcomes for anxiety-based school refusal.

BACKGROUND: Cognitive-behavioural therapy (CBT) has proven to be effective for anxiety-based school refusal, but it is still unknown how CBT for school refusal works, or through which mechanisms. AIMS: Innovative statistical approaches for analyzing small uncontrolled samples were used to investigate the role of self-efficacy in mediating CBT outcomes for anxiety-based school refusal. METHOD: Participants were 19 adolescents (12 to 17 years) who completed a manual-based cognitive-behavioural treatment. Primary outcomes (school attendance; school-related fear; anxiety) and secondary outcomes (depression; internalizing problems) were assessed at post-treatment and 2-month follow-up. RESULTS: Post-treatment increases in school attendance and decreases in fear about attending school the next day were found to be mediated by self-efficacy. Mediating effects were not observed at 2-month follow-up. CONCLUSIONS: These findings provide partial support for the role of self-efficacy in mediating the outcome of CBT for school refusal. They contribute to a small body of literature suggesting that cognitive change enhances CBT outcomes for young people with internalizing problems. Regarding methodology, the product of coefficient test appears to be a valuable way to study mediation in outcome studies involving small samples.

How did the Treatment Work for Robin? And for Dylan? Studying Individual Youth Treatment Mediators Using Single-Case Experimental Designs.

Study of individual treatment mechanisms in youth interventions facilitates evidence-based development, selection and implementation of treatment components that are most effective for each individual child. This position paper aims to bring together two important topics from the area of youth intervention research: mediators of treatment outcomes and single-case experimental design methodology. We start by outlining the benefits of studying within-person mechanisms and propose how statistical mediation analysis and single-case methods can be integrated to enable this type of research. Further, we review existing methodology for the study of individual youth treatment mechanisms and provide recommendations for the clinical practice research.

A Multilevel Meta-analysis of Single-Case Research on Interventions for Internalizing Disorders in Children and Adolescents.

The effectiveness of interventions for internalizing disorders in children and adolescents was studied using a review and meta-analysis of published single-case research. Databases and other resources were searched for quantitative single-case studies in youth with anxiety, depressive, and posttraumatic stress disorders. Raw data from individual cases were aggregated and analyzed by means of multilevel meta-analytic models. Outcome variables were symptom severity assessed across baseline and treatment phases of the studies, and diagnostic status at post- and follow-up treatment. Single-case studies were rated for quality. We identified 71 studies including 321 cases (Mage = 10.66 years; 55% female). The mean quality of the studies was rated as below average, although there were considerable differences between the studies. Overall, positive within-person changes during the treatment phase in comparison to the baseline phase were found. In addition, positive changes in the diagnostic status were observed at post- and follow-up treatment. Yet high variability in treatment effects was found between cases and studies. This meta-analysis harvests the knowledge from published single-case research in youth-internalizing disorders and illustrates how within-person information from single-case studies can be summarized to explore the generalizability of the results from this type of research. The results emphasize the importance of keeping account of individual variability in providing and investigating youth interventions.

Idiopathic premature ventricular complexes treatment: Comparison of flecainide, propafenone, and sotalol.

BACKGROUND: Beta-blockers (BB) or dihydropyridine calcium channel blockers (CCBs) are still the first choices in the treatment of idiopathic premature ventricular complexes (PVCs), with low-modest efficacy. Antiarrhythmic drugs (AADs) of Ic class are moderate to highly efficient but the evidence on their benefits is still limited. AIM: To compare effectiveness and safety of flecainide, propafenone, and sotalol in the treatment of symptomatic idiopathic PVCs. METHODS: Our single-center retrospective study analyzed 104 consecutive patients with 130 medication episodes of frequent idiopathic PVCs treated with AADs flecainide, propafenone (Ic class) or sotalol (III class). The primary outcome was complete/near complete reduction of PVCs after medication episode (PVCs burden reduction >99%), and the secondary outcome was significant PVC burden reduction (≥80%). RESULTS: The complete/near complete PVCs burden reduction occurred in 31% and was significant in 43% of treated patients. A reduction of PVC burden for >99% was achieved in 56% of patients on flecainide, in 11% of patients on propafenone (p = .002), and in 21% of patients receiving sotalol (p = .031). There was no difference between propafenone and sotalol (p = .174). A reduction of PVC burden for ≥80% was achieved in 64% of patients on flecainide, in 30% of patients on propafenone (p = .009), and 33% of patients on sotalol (p = .020). There was no difference between propafenone and sotalol (p = .661). CONCLUSIONS: The efficacy of AADs class Ic and III in the treatment of idiopathic PVCs was modest. Flecainide was the most effective AAD in the achievement of complete/near complete or significant PVC burden reduction, compared to propafenone and sotalol.

The role of cognition in school refusal: an investigation of automatic thoughts and cognitive errors.

AIMS: The purpose of this study was to investigate the cognitions of anxious school refusers. The cognitive constructs under investigation included negative cognition commonly linked to youth anxiety (i.e. negative automatic thoughts and cognitive errors) and positive automatic thoughts. METHOD: The cognition of school refusers (n = 50) and youth from a community sample (n = 181) was assessed with the Children's Automatic Thoughts Scale-Negative/Positive and the Children's Negative Cognitive Error Questionnaire-Revised. RESULTS: When controlling for anxiety, school refusers were found to report more negative automatic thoughts concerning personal failure, fewer negative automatic thoughts concerning hostility, and fewer positive automatic thoughts. Negative automatic thoughts concerning personal failure and hostility, and the negative cognitive error of overgeneralizing were found to independently predict school refusal. CONCLUSIONS: The findings underscore the importance of further researching the role of cognition in the development, maintenance, and treatment of anxiety-based school refusal.

Seismic Assessment and Retrofitting of Existing Road Bridges: State of the Art Review.

The load-carrying capacity assessment of existing road bridges, is a growing challenge for civil engineers worldwide due to the age and condition of these critical parts of the infrastructure network. The critical loading event for road bridges is the live load; however, in earthquake-prone areas bridges generally require an additional seismic evaluation and often retrofitting in order to meet more stringent design codes. This paper provides a review of state-of-the-art methods for the seismic assessment and retrofitting of existing road bridges which are not covered by current design codes (Eurocode). The implementation of these methods is presented through two case studies in Croatia. The first case study is an example of how seismic assessment and retrofitting proposals should be conducted during a regular inspection. On the other hand, the second case study bridge is an example of an urgent assessment and temporary retrofit after a catastrophic earthquake. Both bridges were built in the 1960s and are located on state highways; the first one is a reinforced concrete bridge constructed monolithically on V-shaped piers, while the second is an older composite girder bridge located in Sisak-Moslavina County. The bridge was severely damaged during recent earthquakes in the county, requiring urgent assessment and subsequent strengthening of the substructure to prevent its collapse.

Differences in changes in health-related anxiety between Western and non-Western participants in a trauma-focused study.

Disaster victims from ethnic minorities manifest more health complaints and concerns than others following a medical investigation. The authors aimed at analyzing ethnicity as a proxy for risk factors predictive of changes in health-related anxiety, and mediators that explain ethnic group differences after participating in a medical investigation. Western (n = 406) and non-Western participants (n = 379) were assessed at baseline and 12-week follow-up. Education, unemployment, years of residence, and posttraumatic stress disorder symptoms were independent predictors of changes in health-related anxiety, excluding ethnicity. The predictive value of ethnicity was mediated mainly by changes in psychopathology, fatigue, and quality of life. Stronger responses to a trauma-related investigation by more vulnerable ethnic minority groups may explain their enhanced health-related anxiety.

Does executive function capacity moderate the outcome of executive function training in children with ADHD?

Executive functioning (EF) training interventions aimed at ADHD-symptom reduction have limited results. However, EF training might only be effective for children with relatively poor EF capacity. This randomized double-blind placebo-controlled study examined whether pre-training EF capacity moderates the outcome of an EF-training intervention on measures of near transfer (EF performance) and far transfer (ADHD symptoms and parent-rated EF behavior) immediately after treatment and at 3-month follow-up. Sixty-one children with ADHD (aged 8-12) were randomized either to an EF-training condition where working memory, inhibition and cognitive flexibility were trained, or to a placebo condition. Single moderation models were used. All significant moderation outcomes had small effect sizes. After Bonferroni correction, there were no significant moderators of treatment outcome. Children with poor EF capacity do not benefit more from EF training than from placebo training. Training only EF-impaired children will probably not improve outcomes of EF training studies.

Correction to: Does executive function capacity moderate the outcome of executive function training in children with ADHD?

The original version of this article unfortunately contained a mistake. The captions of Figures 1 and 2 were swapped.

Is Clinical Anxiety a Risk or a Protective Factor for Executive Functioning in Youth with ADHD? A Meta-regression Analysis.

Comorbidity rates between ADHD and anxiety disorders (AD) are high, but little is known about the nature of this co-occurrence. A dominant idea is that AD may intensify some (i.e., attention and working memory) and attenuate other (i.e., inhibition) ADHD symptoms. Results are mixed, potentially because of between-study differences. To investigate this further we performed a meta-regression analysis on 11 studies (n 'ADHD-only' = 695; n 'ADHD + AD' = 608), containing 35 effect sizes on attention, inhibition and working memory. Main results were: (1) no evidence of a negative effect of AD on attention and working memory; (2) better response inhibition in children with ADHD with AD than those with only ADHD (medium ES g = - .40); (3) medication moderated this association: the effect seemed limited to studies that included medication-naïve participants; (4) the difference between the two groups increased with age for attention and with proportion of boys for working memory ability. There was no effect of comorbid disruptive behavior disorder. In conclusion, AD seems to be a protective factor for inhibition problems as assessed with laboratory tasks in ADHD, especially in children who are medication naïve. Further, AD may have a protective function for attention in older children, and for working memory in boys with ADHD. It is therefore important to screen for AD when diagnosing ADHD, and to educate those with comorbid AD about the possible positive function of feeling anxious. Potential negative effects of ADHD medication on inhibition in children with comorbid AD should be considered.

Parental Involvement in CBT for Anxiety-Disordered Youth Revisited: Family CBT Outperforms Child CBT in the Long Term for Children With Comorbid ADHD Symptoms.

OBJECTIVE: The objective of this study was to examine the efficacy of child cognitive-behavioral therapy (CCBT) versus family CBT (FCBT) in anxiety-disordered youth with high and low comorbid ADHD symptoms. METHOD: Youth with anxiety disorders ( n = 123, aged 8-18) were classified in four groups according to (a) the type of CBT received (child vs. family) and (b) their comorbid ADHD symptoms, measured with the Child Behavior Checklist (CBCL) Attention Problems syndrome scale level (normal vs. [sub]clinical). Severity of anxiety disorders was assessed with Anxiety Disorders Interview Schedule-Child and Parent (ADIS-C/P) version and anxiety symptoms via a 71-item anxiety symptom questionnaire, the Screen for Child Anxiety and Related Emotional Disorders (SCARED-71), before and after CBT, and at 3 months and 1-year follow-ups. RESULTS: Based on the severity of anxiety disorders, children with high ADHD symptoms profit more from FCBT than CCBT in the long term. For children low on ADHD symptoms, and for anxiety symptoms and attention problems, no differences between CCBT and FCBT occurred. CONCLUSION: Family involvement seems a valuable addition to CBT for children with comorbid anxiety and ADHD symptoms.

Ufd1-Npl4 Recruit Cdc48 for Disassembly of Ubiquitylated CMG Helicase at the End of Chromosome Replication.

Disassembly of the Cdc45-MCM-GINS (CMG) DNA helicase is the key regulated step during DNA replication termination in eukaryotes, involving ubiquitylation of the Mcm7 helicase subunit, leading to a disassembly process that requires the Cdc48 "segregase". Here, we employ a screen to identify partners of budding yeast Cdc48 that are important for disassembly of ubiquitylated CMG helicase at the end of chromosome replication. We demonstrate that the ubiquitin-binding Ufd1-Npl4 complex recruits Cdc48 to ubiquitylated CMG. Ubiquitylation of CMG in yeast cell extracts is dependent upon lysine 29 of Mcm7, which is the only detectable site of ubiquitylation both in vitro and in vivo (though in vivo other sites can be modified when K29 is mutated). Mutation of K29 abrogates in vitro recruitment of Ufd1-Npl4-Cdc48 to the CMG helicase, supporting a model whereby Ufd1-Npl4 recruits Cdc48 to ubiquitylated CMG at the end of chromosome replication, thereby driving the disassembly reaction.