Poly(ADP-ribosyl)ation of TIMELESS limits DNA replication stress and promotes stalled fork protection.

Poly(ADP-ribosyl)ation (PARylation), catalyzed mainly by poly(ADP-ribose) polymerase (PARP)1, is a key posttranslational modification involved in DNA replication and repair. Here, we report that TIMELESS (TIM), an essential scaffold of the replisome, is PARylated, which is linked to its proteolysis. TIM PARylation requires recognition of auto-modified PARP1 via two poly(ADP-ribose)-binding motifs, which primes TIM for proteasome-dependent degradation. Cells expressing the PARylation-refractory TIM mutant or under PARP inhibition accumulate TIM at DNA replication forks, causing replication stress and hyper-resection of stalled forks. Mechanistically, aberrant engagement of TIM with the replicative helicase impedes RAD51 loading and protection of reversed forks. Accordingly, defective TIM degradation hypersensitizes BRCA2-deficient cells to replication damage. Our study defines TIM as a substrate of PARP1 and elucidates how the control of replisome remodeling by PARylation is linked to stalled fork protection. Therefore, we propose a mechanism of PARP inhibition that impinges on the DNA replication fork instability caused by defective TIM turnover.

The Practice and Feasibility of Screening, Treatment, and Referral for Gaming Problems in Gambling, Alcohol and Other Drugs, and Youth Services.

Screening, brief intervention, and referral to treatment (SBIRT) is a comprehensive approach to identifying people at risk of addiction, but its feasibility for gaming disorder is unknown. This study surveyed 88 clinicians from gambling, alcohol and other drugs, and youth services in New Zealand. Results indicated that the most frequent GD screening method was an unstructured interview (61%), but 74% stated they would use a standardized tool if available. Responsivity to the detection of GD was an immediate intervention (84%), and rates of referral were low (28%). Around 50% of clinicians indicated high confidence in administering motivational approaches and relapse prevention. There was strong support for screening training (85%), treatment guidelines (88%), self-help materials (92%), and access to internet-delivered CBT that could be used in conjunction with other treatment (84%). Clinicians appear motivated and willing to implement SBIRT for GD but report lacking necessary training and resources, including access to screening tools and treatment guidelines.

Content and Effectiveness of Web-Based Treatments for Online Behavioral Addictions: Systematic Review.

BACKGROUND: Very few people seek in-person treatment for online behavioral addictions including gaming and gambling or problems associated with shopping, pornography use, or social media use. Web-based treatments have the potential to address low rates of help seeking due to their convenience, accessibility, and capacity to address barriers to health care access (eg, shame, stigma, cost, and access to expert care). However, web-based treatments for online behavioral addictions have not been systematically evaluated. OBJECTIVE: This review aimed to systematically describe the content of web-based treatments for online behavioral addictions and describe their therapeutic effectiveness on symptom severity and consumption behavior. METHODS: A database search of MEDLINE, Embase, PsycInfo, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar was conducted in June 2022. Studies were eligible if the study design was a randomized controlled trial or a pre-post study with at least 1 web-based intervention arm for an online behavioral addiction and if the study included the use of a validated measure of problem severity, frequency, or duration of online behavior. Data on change techniques were collected to analyze intervention content, using the Gambling Intervention System of CharacTerization. Quality assessment was conducted using the Effective Public Health Practice Project Quality Assessment Tool. RESULTS: The review included 12 studies with 15 intervention arms, comprising 7 randomized controlled trials and 5 pre-post studies. The primary focus of interventions was gaming (n=4), followed by internet use inclusive of screen time and smartphone use (n=3), gambling (n=3), and pornography (n=2). A range of different technologies were used to deliver content, including websites (n=6), email (n=2), computer software (n=2), social media messaging (n=1), smartphone app (n=1), virtual reality (n=1), and videoconferencing (n=1). Interventions contained 15 different change techniques with an average of 4 per study. The techniques most frequently administered (>30% of intervention arms) were cognitive restructuring, relapse prevention, motivational enhancement, goal setting, and social support. Assessment of study quality indicated that 7 studies met the criteria for moderate or strong global ratings, but only 8 out of 12 studies evaluated change immediately following the treatment. Across included studies, two-thirds of participants completed after-treatment evaluation, and one-quarter completed follow-up evaluation. After-intervention evaluation indicated reduced severity (5/9, 56%), frequency (2/3, 67%), and duration (3/7, 43%). Follow-up evaluation indicated that 3 pre-post studies for gaming, gambling, and internet use demonstrated reduced severity, frequency, and duration of consumption. At 3-month evaluation, just 1 pre-post study indicated significant change to mental health symptoms. CONCLUSIONS: Web-based treatments for online behavioral addictions use an array of mechanisms to deliver cognitive and behavioral change techniques. Web-based treatments demonstrate promise for short-term reduction in symptoms, duration, or frequency of online addictive behaviors. However, there is limited evidence on the effectiveness of web-based treatments over the longer term due to the absence of controlled trials.

The impact of COVID-19 on addiction treatment in New Zealand.

COVID-19 public health measures, including lockdowns, have disrupted psychological service delivery for substance use and behavioural addictions. This study aimed to examine how addictions treatment had been affected by COVID-19 related factors from the perspective of addiction and mental health service providers. Participants (n = 93) were experienced service managers and clinicians in New Zealand who completed an online survey. Clinicians reported increased presentations for problems related to internet gambling (n = 57, 61%), gaming (n = 53, 57%), social media use (n = 52, 56%), and pornography (n = 28, 30%). A qualitative analysis of responses generated six themes. Themes included service management and increased administrative burden, and service delivery reconfiguration. Access improved for some clients because of convenience and reduced structural barriers. However, online service delivery was problematic for those with unstable or no internet access and devices that could not support video conferencing and/or lack of safe, confidential or private spaces at home. Increased client complexity and restricted in-person care prompted changes to focus, and content of clinical interventions, and some respondents offered more frequent but shorter appointments. Clinicians who provided services by phone or email, rather than video conferencing, reported treatment was less effective, with reduced rapport and engagement a contributing factor. The New Zealand addictions sector has responded to COVID-19 by increasing treatment access through distance-based options. Maintaining multifaceted models of care that are agile to rapidly changing environments presents unique challenges but is critical to addressing the needs of people impacted by addiction.

Person-centred interventions for problem gaming: a stepped care approach.

BACKGROUND: Problem gaming is reported by approximately 1-3% of the population and is associated with decreased health and wellbeing. Research on optimal health responses to problem gaming remains limited. This study aimed to identify and describe the key components of a person-centred approach to interventions for problem gaming for individuals who voluntary seek assistance. METHODS: Online interviews were conducted with 20 adults (90% male; Mage = 23y) currently seeking help for problem gaming. The interview protocol was guided by a health care access framework which investigated participants' experiences and needs related to accessing professional support. Transcripts were analysed in NVivo using qualitative content analysis to systematically classify participant data into the themes informed by this framework. RESULTS: Participants had mixed views on how the negative consequences of problem gaming could be best addressed. Some indicated problems could be addressed through self-help resources whereas others suggested in-person treatment with a health professional who had expertise in gaming. Participants described the essential components of an effective health service for problem gaming as including: valid and reliable screening tools; practitioners with specialist knowledge of gaming; and access to a multimodal system of intervention, including self-help, internet and in-person options that allow gamers to easily transition between types and intensity of support. CONCLUSION: A comprehensive health care approach for interventions for problem gaming is in its infancy, with numerous service access and delivery issues still to be resolved. This study highlights the importance of involving individuals with gaming-related problems in developing solutions that are fit for purpose and address the spectrum of individual preferences and needs. These findings recommend a stepped healthcare system that adheres to evidence-based practice tailored to each individual and the implementation of standard assessment and routine outcome monitoring.

SDE2 integrates into the TIMELESS-TIPIN complex to protect stalled replication forks.

Protecting replication fork integrity during DNA replication is essential for maintaining genome stability. Here, we report that SDE2, a PCNA-associated protein, plays a key role in maintaining active replication and counteracting replication stress by regulating the replication fork protection complex (FPC). SDE2 directly interacts with the FPC component TIMELESS (TIM) and enhances its stability, thereby aiding TIM localization to replication forks and the coordination of replisome progression. Like TIM deficiency, knockdown of SDE2 leads to impaired fork progression and stalled fork recovery, along with a failure to activate CHK1 phosphorylation. Moreover, loss of SDE2 or TIM results in an excessive MRE11-dependent degradation of reversed forks. Together, our study uncovers an essential role for SDE2 in maintaining genomic integrity by stabilizing the FPC and describes a new role for TIM in protecting stalled replication forks. We propose that TIM-mediated fork protection may represent a way to cooperate with BRCA-dependent fork stabilization.

Estimated Dietary Bisphenol-A Exposure and Adiposity in Samoan Mothers and Children.

The Pacific Island nation of Samoa is marked by prevalent obesity and an increasing dependence on packaged foods likely to contain the endocrine disruptor bisphenol-A (BPA). We evaluated participant- and household-level characteristics associated with estimated dietary BPA exposure in Samoan mothers and their children and examined associations between dietary BPA exposure and body mass index (BMI) and abdominal circumference (AC). Dietary BPA exposure indices were estimated for 399 mother-child pairs by combining information from dietary questionnaires and relative concentrations of BPA measured in foods/beverages. We observed moderate to strong correlation between mother-child daily BPA indices (Spearman's rho = 0.7, p < 0.0001). In mothers, we observed lower daily BPA indices in those who were less physically active (p = 0.0004) and living in homes with higher income (p = 0.00001). In children, we observed lower daily BPA indices in those living in homes with higher income (p = 0.0003) and following a less modern dietary pattern (p = 0.002), and higher daily BPA indices in those who were less physically active (p = 0.02). No significant associations were observed between daily BPA indices and BMI or AC. Despite this, the application of the daily BPA index identified factors associated with dietary BPA exposure and warrants further examination in Samoa and other understudied populations.

Proteolytic control of genome integrity at the replication fork.

Faithful duplication of the genome is critical for the survival of an organism and prevention of malignant transformation. Accurate replication of a large amount of genetic information in a timely manner is one of the most challenging cellular processes and is often perturbed by intrinsic and extrinsic barriers to DNA replication fork progression, a phenomenon referred to as DNA replication stress. Elevated DNA replication stress is a primary source of genomic instability and one of the key hallmarks of cancer. Therefore, targeting DNA replication stress is an emerging concept for cancer therapy. The replication machinery associated with PCNA and other regulatory factors coordinates the synthesis and repair of DNA strands at the replication fork. The dynamic interaction of replication protein complexes with DNA is essential for sensing and responding to various signaling events relevant to DNA replication and damage. Thus, the disruption of the spatiotemporal regulation of protein homeostasis at the replication fork impairs genome integrity, which often involves the deregulation of ubiquitin-mediated proteolytic signaling. Notably, emerging evidence has highlighted the role of the AAA+ATPase VCP/p97 in extracting ubiquitinated protein substrates from the chromatin and facilitating the turnover of genome surveillance factors during DNA replication and repair. Here, we review recent advances in our understanding of chromatin-associated degradation pathways at the replication fork and the implication of these findings for cancer therapy.

Conditional degradation of SDE2 by the Arg/N-End rule pathway regulates stress response at replication forks.

Multiple pathways counteract DNA replication stress to prevent genomic instability and tumorigenesis. The recently identified human SDE2 is a genome surveillance protein regulated by PCNA, a DNA clamp and processivity factor at replication forks. Here, we show that SDE2 cleavage after its ubiquitin-like domain generates Lys-SDE2Ct, the C-terminal SDE2 fragment bearing an N-terminal Lys residue. Lys-SDE2Ct constitutes a short-lived physiological substrate of the Arg/N-end rule proteolytic pathway, in which UBR1 and UBR2 ubiquitin ligases mediate the degradation. The Arg/N-end rule and VCP/p97UFD1-NPL4 segregase cooperate to promote phosphorylation-dependent, chromatin-associated Lys-SDE2Ct degradation upon UVC damage. Conversely, cells expressing the degradation-refractory K78V mutant, Val-SDE2Ct, fail to induce RPA phosphorylation and single-stranded DNA formation, leading to defects in PCNA-dependent DNA damage bypass and stalled fork recovery. Together, our study elucidates a previously unappreciated axis connecting the Arg/N-end rule and the p97-mediated proteolysis with the replication stress response, working together to preserve replication fork integrity.

Child, maternal and household-level correlates of nutritional status: a cross-sectional study among young Samoan children.

OBJECTIVE: Young children are particularly vulnerable to malnutrition as nutrition transition progresses. The present study aimed to document the prevalence, coexistence and correlates of nutritional status (stunting, overweight/obesity and anaemia) in Samoan children aged 24-59 months. DESIGN: A cross-sectional community-based survey. Height and weight were used to determine prevalence of stunting (height-for-age Z-score +2) based on WHO growth standards. Anaemia was determined using an AimStrip Hemoglobin test system (Hb <110 g/l). SETTING: Ten villages on the Samoan island of Upolu. SUBJECTS: Mother-child pairs (n 305) recruited using convenience sampling. RESULTS: Moderate or severe stunting was apparent in 20·3 % of children, 16·1 % were overweight/obese and 34·1 % were anaemic. Among the overweight/obese children, 28·6 % were also stunted and 42·9 % anaemic, indicating dual burden of malnutrition. Stunting was significantly less likely among girls (OR=0·41; 95 % CI 0·21, 0·79, P<0·01) than boys. Overweight/obesity was associated with higher family socio-economic status and decreased sugar intake (OR per 10 g/d=0·89, 95 % CI 0·80, 0·99, P=0·032). The odds of anaemia decreased with age and anaemia was more likely in children with an anaemic mother (OR=2·20; 95 % CI 1·22, 3·98, P=0·007). No child, maternal or household characteristic was associated with more than one of the nutritional status outcomes, highlighting the need for condition-specific interventions in this age group. CONCLUSIONS: The observed prevalences of stunting, overweight/obesity and anaemia suggest that it is critical to invest in nutrition and develop health programmes targeting early childhood growth and development in Samoa.

Neurodevelopmental management strategies for children with cerebral palsy: optimizing function, promoting participation, and supporting families.

There is a spectrum of outcomes in health, functional skills, and participation among children with one of the cerebral palsy syndromes. Medical advances have allowed us to better understand the importance of goal-oriented management and attention to nutrition, safe feeding, seizures, deformity, and spasticity. However, ensuring long-term successful outcomes require coordination between medicine, social services, education, and rehabilitation and continually examining how to promote functioning and participation. Until multicentered population registries and networks for clinical trials are established, our knowledge of evidence-based outcomes will remain partial and incomplete.

The spectrum of behavioral outcomes after extreme prematurity: regulatory, attention, social, and adaptive dimensions.

Advances in obstetrics and neonatology have increased the survival rates of premature infants with very preterm (<32 weeks) and extremely preterm (<28 weeks) gestations. However, survivors have a high frequency of challenges in academic and social skills. There has been an increased emphasis on examination of outcomes beyond survival rates and rates of neurosensory disabilities at ages 18 to 24 months (eg, cerebral palsy, blindness, deafness, global development delay). One of the key strategies for understanding pathways of risk and resilience is to examine behavioral, social-emotional, and adaptive competencies. The purpose of this paper is to apply the International Classification of Functioning framework to a spectrum of behavioral outcomes after extreme prematurity, describe useful tools for measuring behavioral, social, and adaptive competencies, as well as review model outcome studies before middle childhood. Thus, we can use current information to begin to understand pathways underlying behavioral health, well-being, and social competence.