Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of Brca2 and Stable Rad51 Nucleofilaments.

Brca2 deficiency causes Mre11-dependent degradation of nascent DNA at stalled forks, leading to cell lethality. To understand the molecular mechanisms underlying this process, we isolated Xenopus laevis Brca2. We demonstrated that Brca2 protein prevents single-stranded DNA gap accumulation at replication fork junctions and behind them by promoting Rad51 binding to replicating DNA. Without Brca2, forks with persistent gaps are converted by Smarcal1 into reversed forks, triggering extensive Mre11-dependent nascent DNA degradation. Stable Rad51 nucleofilaments, but not RPA or Rad51T131P mutant proteins, directly prevent Mre11-dependent DNA degradation. Mre11 inhibition instead promotes reversed fork accumulation in the absence of Brca2. Rad51 directly interacts with the Pol α N-terminal domain, promoting Pol α and δ binding to stalled replication forks. This interaction likely promotes replication fork restart and gap avoidance. These results indicate that Brca2 and Rad51 prevent formation of abnormal DNA replication intermediates, whose processing by Smarcal1 and Mre11 predisposes to genome instability.

Timeless couples G-quadruplex detection with processing by DDX11 helicase during DNA replication.

Regions of the genome with the potential to form secondary DNA structures pose a frequent and significant impediment to DNA replication and must be actively managed in order to preserve genetic and epigenetic integrity. How the replisome detects and responds to secondary structures is poorly understood. Here, we show that a core component of the fork protection complex in the eukaryotic replisome, Timeless, harbours in its C-terminal region a previously unappreciated DNA-binding domain that exhibits specific binding to G-quadruplex (G4) DNA structures. We show that this domain contributes to maintaining processive replication through G4-forming sequences, and exhibits partial redundancy with an adjacent PARP-binding domain. Further, this function of Timeless requires interaction with and activity of the helicase DDX11. Loss of both Timeless and DDX11 causes epigenetic instability at G4-forming sequences and DNA damage. Our findings indicate that Timeless contributes to the ability of the replisome to sense replication-hindering G4 formation and ensures the prompt resolution of these structures by DDX11 to maintain processive DNA synthesis.

A three-organelle complex made by wrappER contacts with peroxisomes and mitochondria responds to liver lipid flux changes.

Hepatic lipid homeostasis depends on intracellular pathways that respire fatty acid in peroxisomes and mitochondria, and on systemic pathways that secrete fatty acid into the bloodstream, either free or condensed in very-low-density lipoprotein (VLDL) triglycerides. These systemic and intracellular pathways are interdependent, but it is unclear whether and how they integrate into a single cellular circuit. Here, we report that mouse liver wrappER, a distinct endoplasmic reticulum (ER) compartment with apparent fatty acid- and VLDL-secretion functions, connects peroxisomes and mitochondria. Correlative light electron microscopy, quantitative serial section electron tomography and three-dimensional organelle reconstruction analysis show that the number of peroxisome-wrappER-mitochondria complexes changes throughout fasting-to-feeding transitions and doubles when VLDL synthesis stops following acute genetic ablation of Mttp in the liver. Quantitative proteomic analysis of peroxisome-wrappER-mitochondria complex-enriched fractions indicates that the loss of Mttp upregulates global fatty acid ß-oxidation, thereby integrating the dynamics of this three-organelle association into hepatic fatty acid flux responses. Therefore, liver lipid homeostasis occurs through the convergence of systemic and intracellular fatty acid-elimination pathways in the peroxisome-wrappER-mitochondria complex.

Ctf4 Is a Hub in the Eukaryotic Replisome that Links Multiple CIP-Box Proteins to the CMG Helicase.

Replisome assembly at eukaryotic replication forks connects the DNA helicase to DNA polymerases and many other factors. The helicase binds the leading-strand polymerase directly, but is connected to the Pol α lagging-strand polymerase by the trimeric adaptor Ctf4. Here, we identify new Ctf4 partners in addition to Pol α and helicase, all of which contain a "Ctf4-interacting-peptide" or CIP-box. Crystallographic analysis classifies CIP-boxes into two related groups that target different sites on Ctf4. Mutations in the CIP-box motifs of the Dna2 nuclease or the rDNA-associated protein Tof2 do not perturb DNA synthesis genome-wide, but instead lead to a dramatic shortening of chromosome 12 that contains the large array of rDNA repeats. Our data reveal unexpected complexity of Ctf4 function, as a hub that connects multiple accessory factors to the replisome. Most strikingly, Ctf4-dependent recruitment of CIP-box proteins couples other processes to DNA synthesis, including rDNA copy-number regulation.

The relationship between cognitive phenotypes of compulsivity and impulsivity and clinical variables in obsessive-compulsive disorder: A systematic review and Meta-analysis.

BACKGROUND: This systematic review and meta-analysis explored the relationship between cognitive phenotypes of compulsivity and impulsivity and clinical variables in obsessive-compulsive disorder (OCD). METHODS: We searched Pubmed, Scopus, Cochrane Library and PsychINFO databases until February 2023 for studies comparing patients with OCD and healthy controls on cognitive tests of compulsivity and impulsivity. The study followed PRISMA guidelines and was pre-registered on PROSPERO (CRD42021299017). RESULTS: Meta-analyses of 112 studies involving 8313 participants (4289 patients with OCD and 4024 healthy controls) identified significant impairments in compulsivity (g = -0.58, [95%CI -0.68, -0.47]; k = 76) and impulsivity (g = -0.48, [95%CI -0.57, -0.38]; k = 63); no significant difference between impairments. Medication use and comorbid psychiatric disorders were not significantly related to impairments. No associations were revealed with OCD severity, depression/anxiety, or illness duration. CONCLUSION: Cognitive phenotypes of compulsivity and impulsivity in patients with OCD appear to be orthogonal to clinical variables, including severity of OCD symptomatology. Their clinical impact is poorly understood and may require different clinical assessment tools and interventions.

Feasibility, acceptability and practicality of transcranial stimulation in obsessive compulsive symptoms (FEATSOCS): A randomised controlled crossover trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive form of neurostimulation with potential for development as a self-administered intervention. It has shown promise as a safe and effective treatment for obsessive compulsive disorder (OCD) in a small number of studies. The two most favourable stimulation targets appear to be the left orbitofrontal cortex (L-OFC) and the supplementary motor area (SMA). We report the first study to test these targets head-to-head within a randomised sham-controlled trial. Our aim was to inform the design of future clinical research studies, by focussing on the acceptability and safety of the intervention, feasibility of recruitment, adherence to and tolerability of tDCS, and the size of any treatment-effect. METHODS: FEATSOCS was a randomised, double-blind, sham-controlled, cross-over, multicentre study. Twenty adults with DSM-5-defined OCD were randomised to treatment, comprising three courses of clinic-based tDCS (SMA, L-OFC, Sham), randomly allocated and delivered in counterbalanced order. Each course comprised four 20-min 2 mA stimulations, delivered over two consecutive days, separated by a 'washout' period of at least four weeks. Assessments were carried out by raters who were blind to stimulation-type. Clinical outcomes were assessed before, during, and up to four weeks after stimulation. Patient representatives with lived experience of OCD were actively involved at all stages. RESULTS: Clinicians showed willingness to recruit participants and recruitment to target was achieved. Adherence to treatment and study interventions was generally good, with only two dropouts. There were no serious adverse events, and adverse effects which did occur were transient and mostly mild in intensity. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores were numerically improved from baseline to 24 h after the final stimulation across all intervention groups but tended to worsen thereafter. The greatest effect size was seen in the L-OFC arm, (Cohen's d = -0.5 [95% CI -1.2 to 0.2] versus Sham), suggesting this stimulation site should be pursued in further studies. Additional significant sham referenced improvements in secondary outcomes occurred in the L-OFC arm, and to a lesser extent with SMA stimulation. CONCLUSIONS: tDCS was acceptable, practicable to apply, well-tolerated and appears a promising potential treatment for OCD. The L-OFC represents the most promising target based on clinical changes, though the effects on OCD symptoms were not statistically significant compared to sham. SMA stimulation showed lesser signs of promise. Further investigation of tDCS in OCD is warranted, to determine the optimal stimulation protocol (current, frequency, duration), longer-term effectiveness and brain-based mechanisms of effect. If efficacy is substantiated, consideration of home-based approaches represents a rational next step. TRIAL REGISTRATION: ISRCTN17937049. https://doi.org/10.1186/ISRCTN17937049.

Episodic obsessive-compulsive disorder and bipolar spectrum disorder: new evidence from a large Italian OCD sample.

OBJECTIVES: Obsessive-Compulsive Disorder (OCD) has been considered to be a chronic illness; however, some authors described a subtype of OCD characterised by symptom-free periods of time: Episodic-OCD (E-OCD). Only few studies focussed on this subtype of the disorder. The objectives of this research were to study the association between the episodic course of the disorder and lifetime psychiatric comorbidities and to investigate socio-demographic and other clinical features correlated to the episodic course. METHODS: The sample is composed of adult OCD patients. The course was defined episodic when at least one circumscribed symptom-free interval of at least 6 months was present. The sample was divided into two subgroups: Episodic-OCD and Chronic-OCD. Differences between groups were analysed with Student's t-test, χ2 tests, Fisher test and multivariate logistic regression. RESULTS: Data regarding 585 individuals were collected. 14.2% (N = 83) of our sample had an episodic course. Bipolar I comorbid disorder, abrupt onset, lower severity of illness and lower rates of repeating compulsions were associated with the likelihood of having an E-OCD. CONCLUSIONS: Our findings confirm that a significant proportion of OCD patients have an episodic course and that E-OCD could represent a specific endophenotype.

A significant proportion of OCD patients has an episodic course;Episodic OCD was related to comorbid Bipolar I Disorder;Episodic course was associated with an abrupt onset of OCD;Lower rates of repeating compulsions were associated with Episodic OCD.

Effects of exercise on obsessive-compulsive disorder symptoms: a systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis assessed the efficacy of exercise in reducing OCD symptoms. METHODS: We searched PubMed, Cochrane Central Register of Controlled Trials, MEDLINE, Scopus and grey literature until March 2022. The study was preregistered at Prospero (CRD42021283931). We included randomised controlled and pre-post trials assessing physical activity as an intervention for OCD. Risk of bias was assessed using the Cochrane ROBINS-I tool and the RoB2 tool. RESULTS: The analysis included 6 trials (N = 92); 2 were RCTS and 4 were pre-post design studies. A random-effects meta-analysis of pre-post data identified a large reduction of OCD symptoms following exercise (g = 1.33 [95%CI 1.06-1.61]; k = 6). Exercise was also associated with significant pre-post reductions in anxiety (g = 0.71 [95%CI 0.37-1.05; k = 4) and depression (g = 0.57 [95%CI 0.26-0.89]; k = 2). Risk of bias was moderate-high in uncontrolled trials on the ROBINS-I and RCTs showed 'some concerns' on the RoB2. CONCLUSION: Exercise was associated with a large pre-post reduction of OCD symptoms; however, few trials were of robust quality and all were at risk of bias. Further well-powered and better quality RCTs are required to assess the role of exercise as an intervention for OCD.KEY POINTSStudies exploring exercise as an adjunct therapy for OCD have small participant numbers, therefore a systematic review and meta-analysis is needed to estimate potential efficacy.Pre-post analysis shows that exercise was associated with a large reduction of OCD symptomsThe current systematic review and meta-analysis points to the potential for exercise to be beneficial for the treatment for OCD symptoms. However, more well-powered and better controlled RCTs are required to fully assess the benefit of exercise for the treatment of OCD symptoms.

Problematic internet use during the COVID-19 pandemic: A systematic review and meta-analysis of prevalence data.

AIMS: This study sought to synthesize prevalence rates of problematic internet use (PIU) during the COVID-19 pandemic in the general adult (age over 18 years old) population and to investigate its possible moderators. METHODS: A preregistered systematic literature review using the PubMed/MEDLINE, EBSCOhost/PsycINFO, Web of Science, Cochrane Library, GSK Clinical Study Register, and ClinicalTrials.gov databases was conducted. Research was completed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 checklist. RESULTS: A total of 22 publications were identified, fulfilling inclusion criteria from a total of 595 studies. The analysis revealed that the prevalence of PIU during the COVID-19 pandemic period was 25%, however applying a stringent threshold for the PIU, resulted in a much lower prevalence of 7.9%. CONCLUSION: The PIU prevalence rate during the COVID-19 pandemic in the general population was 7.9%. Measuring the prevalence of PIU remains complicated due to the large methodological and cultural diversity that exists, so global prevalence estimates of PIU vary substantially. More methodologically sound research on psychodiagnostic assessment and cultural variances is required. (Neuropsychopharmacol Hung 2023; 25(3): 131-141) Keywords: COVID-19; internet addiction; problematic usage of the internet; prevalence; systematic review, meta-analysis Systematic review registration: PROSPERO registration number: CRD42021284619.

Histone H2A-H2B binding by Pol α in the eukaryotic replisome contributes to the maintenance of repressive chromatin.

The eukaryotic replisome disassembles parental chromatin at DNA replication forks, but then plays a poorly understood role in the re-deposition of the displaced histone complexes onto nascent DNA. Here, we show that yeast DNA polymerase α contains a histone-binding motif that is conserved in human Pol α and is specific for histones H2A and H2B. Mutation of this motif in budding yeast cells does not affect DNA synthesis, but instead abrogates gene silencing at telomeres and mating-type loci. Similar phenotypes are produced not only by mutations that displace Pol α from the replisome, but also by mutation of the previously identified histone-binding motif in the CMG helicase subunit Mcm2, the human orthologue of which was shown to bind to histones H3 and H4. We show that chromatin-derived histone complexes can be bound simultaneously by Mcm2, Pol α and the histone chaperone FACT that is also a replisome component. These findings indicate that replisome assembly unites multiple histone-binding activities, which jointly process parental histones to help preserve silent chromatin during the process of chromosome duplication.

Two distinct conformational states define the interaction of human RAD51-ATP with single-stranded DNA.

An essential mechanism for repairing DNA double-strand breaks is homologous recombination (HR). One of its core catalysts is human RAD51 (hRAD51), which assembles as a helical nucleoprotein filament on single-stranded DNA, promoting DNA-strand exchange. Here, we study the interaction of hRAD51 with single-stranded DNA using a single-molecule approach. We show that ATP-bound hRAD51 filaments can exist in two different states with different contour lengths and with a free-energy difference of ~4 kBT per hRAD51 monomer. Upon ATP hydrolysis, the filaments convert into a disassembly-competent ADP-bound configuration. In agreement with the single-molecule analysis, we demonstrate the presence of two distinct protomer interfaces in the crystal structure of a hRAD51-ATP filament, providing a structural basis for the two conformational states of the filament. Together, our findings provide evidence that hRAD51-ATP filaments can exist in two interconvertible conformational states, which might be functionally relevant for DNA homology recognition and strand exchange.

Meta-analysis of cognitive behaviour therapy and selective serotonin reuptake inhibitors for the treatment of hypochondriasis: Implications for trial design.

BACKGROUND: Classification of hypochondriasis as an obsessive-compulsive and related disorder in the International Classification of Diseases 11th Revision (ICD-11) has generated new heuristics for treatment of this common, chronic and disabling disorder. Standard treatment involves cognitive behaviour therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs), but no meta-analysis has so far considered hypochondriasis as a structured diagnosis or assessed the role of medication. A clearer understanding of the relative effectiveness of these interventions and identification of clinically relevant factors moderating the treatment response is needed for clinical guideline development. METHODS: The current systematic review and meta-analysis of interventions for hypochondriasis was preregistered on PROSPERO (CRD42020185768) and follows PRISMA guidelines. We searched MEDLINE, PsycINFO, and Cochrane Library databases until July 2021 for randomized controlled trials (RCTs) of interventions for patients diagnosed with hypochondriasis (or historical diagnostic equivalents). We assessed aspects of study quality using: the CONSORT Checklist for evaluation of RCTs, the Cochrane Risk of Bias 2 tool, researcher allegiance and treatment fidelity. The primary outcome was improvement in hypochondriasis symptoms, comparing intervention and control groups at trial endpoint. Moderator variables were assessed using subgroup and meta-regression analyses. RESULTS: Searches identified 13 randomised controlled trials (RCTs) (N = 1405); 12 included CBT (N = 1212) and three included SSRI (N = 193) arms as the experimental intervention. Random effects meta-analysis yielded a moderate-to-large effect size for CBT versus all controls (g = -0.70 [95% CI -0.99 to -0.41], k = 18, I2 = 81.1%). Funnel plot asymmetry indicated possible publication bias and two potentially missing trials, reducing the effect size (g = -0.60 [95% CI -0.88 to -0.32]). Subgroup analysis showed that choice of control significantly moderated effect size, with those in CBT vs. wait-list (g = -1.32 [95% CI -1.75 to -0.90], k = 7, I2 = 0%) being double those of CBT vs. psychological or pharmacological placebo controls (g = -0.58 [95% CI -0.95 to -0.22], k = 7, I2 = 82%). Analysis of studies directly comparing CBT and SSRIs found a numerical, but not statistical advantage for SSRIs (g = 0.21 [95% CI -0.46 to 0.87], k = 2, I2 = 58.34%) and a modest effect size emerged for SSRIs vs. pill placebo (g = -0.29 [95% CI -0.57 to -0.01], k = 3, I2 = 0%). Most studies (11/13) were rated as high on potential researcher allegiance bias in favour of CBT. Meta-regressions revealed that effect sizes were larger in younger participants, and smaller in better quality and more recent RCTs and those with greater CBT fidelity. CONCLUSION: CBT and SSRIs are effective in the acute treatment of hypochondriasis, with some indication that intervention at a younger age produces better outcomes for CBT. In the case of CBT, effect sizes appear to have been significantly inflated by the use of wait list controls, and researcher allegiance bias. We recommend that a definitive, adequately controlled trial, designed with respect to the methodological issues raised in this meta-analysis, is needed to determine the magnitude effects for CBT and SSRIs with confidence and the long-term effect of treatments, to inform mental health service provision for this overlooked patient group.

Repetitive transcranial magnetic stimulation (r-TMS) and selective serotonin reuptake inhibitor-resistance in obsessive-compulsive disorder: A meta-analysis and clinical implications.

INTRODUCTION: Despite promising results from several randomized controlled trials (RCTs) and meta-analyses, the efficacy of r-TMS as a treatment for OCD remains controversial, at least in part owing to inconsistency in the trial methodologies and heterogeneity in the trial outcomes. This meta-analysis attempts to explain some of this heterogeneity by comparing the efficacy of r-TMS in patients with or without resistance to treatment with selective serotonin reuptake inhibitors (SSRI), defined using standardized criteria. METHODS: We conducted a pre-registered (PROSPERO ID: 241381) systematic review and meta-analysis. English language articles reporting blinded RCTs were retrieved from searches using MEDLINE, PsycINFO, and Cochrane Library databases. Studies were subjected to subgroup analysis based on four stages of treatment resistance, defined using an adaptation of published criteria (1 = not treatment resistant, 2 = one SSRI trial failed, 3 = two SSRI trials failed, 4 = two SSRI trials failed plus one or more CBT trial failed). Meta-regression analyses investigated patient and methodological factors (age, duration of OCD, illness severity, stage of treatment-resistance, or researcher allegiance) as possible moderators of effect size. RESULTS: Twenty-five independent comparisons (23 studies) were included. Overall, r-TMS showed a medium-sized reduction of Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores (Hedge's g: -0.47; 95%CI: - 0.67 to -0.27) with moderate heterogeneity (I2 = 39.8%). Assessment of publication bias using Trim and Fill analysis suggested a reduced effect size that remained significant (g: -0.29; 95%CI: -0.51 to -0.07). Subgroup analysis found that those studies including patients non-resistant to SSRI (stage 1) (g: -0.65; 95%CI: -1.05 to -0.25, k = 7) or with low SSRI-resistance (stage 2) (g:-0.47; 95%CI: -0.86 to -0.09, k = 6) produced statistically significant results with low heterogeneity, while studies including more highly resistant patients at stage 3 (g: -0.39; 95%CI: -0.90 to 0.11, k = 4) and stage 4 (g: -0.36; 95%CI: -0.75 to 0.03, k = 8) did not. Intriguingly, the only significant moderator of the effect size found by meta-regression was the severity of baseline depressive symptoms. All trials showed evidence of researcher allegiance in favour of the intervention and therefore caution is required in interpreting the reported effect sizes. CONCLUSION: This meta-analysis shows that r-TMS is an effective treatment for OCD, but largely for those not resistant to SSRI or failing to respond to only one SSRI trial. As a consequence, r-TMS may be best implemented earlier in the care pathway. These findings would have major implications for clinical service development, but further well-powered RCTs, which eliminate bias from researcher allegiance, are needed before definitive conclusions can be drawn.

Advances in problematic usage of the internet research - A narrative review by experts from the European network for problematic usage of the internet.

Global concern about problematic usage of the internet (PUI), and its public health and societal costs, continues to grow, sharpened in focus under the privations of the COVID-19 pandemic. This narrative review reports the expert opinions of members of the largest international network of researchers on PUI in the framework of the European Cooperation in Science and Technology (COST) Action (CA 16207), on the scientific progress made and the critical knowledge gaps remaining to be filled as the term of the Action reaches its conclusion. A key advance has been achieving consensus on the clinical definition of various forms of PUI. Based on the overarching public health principles of protecting individuals and the public from harm and promoting the highest attainable standard of health, the World Health Organisation has introduced several new structured diagnoses into the ICD-11, including gambling disorder, gaming disorder, compulsive sexual behaviour disorder, and other unspecified or specified disorders due to addictive behaviours, alongside naming online activity as a diagnostic specifier. These definitions provide for the first time a sound platform for developing systematic networked research into various forms of PUI at global scale. Progress has also been made in areas such as refining and simplifying some of the available assessment instruments, clarifying the underpinning brain-based and social determinants, and building more empirically based etiological models, as a basis for therapeutic intervention, alongside public engagement initiatives. However, important gaps in our knowledge remain to be tackled. Principal among these include a better understanding of the course and evolution of the PUI-related problems, across different age groups, genders and other specific vulnerable groups, reliable methods for early identification of individuals at risk (before PUI becomes disordered), efficacious preventative and therapeutic interventions and ethical health and social policy changes that adequately safeguard human digital rights. The paper concludes with recommendations for achievable research goals, based on longitudinal analysis of a large multinational cohort co-designed with public stakeholders.

CryoEM structures of human CMG-ATPγS-DNA and CMG-AND-1 complexes.

DNA unwinding in eukaryotic replication is performed by the Cdc45-MCM-GINS (CMG) helicase. Although the CMG architecture has been elucidated, its mechanism of DNA unwinding and replisome interactions remain poorly understood. Here we report the cryoEM structure at 3.3 Å of human CMG bound to fork DNA and the ATP-analogue ATPγS. Eleven nucleotides of single-stranded (ss) DNA are bound within the C-tier of MCM2-7 AAA+ ATPase domains. All MCM subunits contact DNA, from MCM2 at the 5'-end to MCM5 at the 3'-end of the DNA spiral, but only MCM6, 4, 7 and 3 make a full set of interactions. DNA binding correlates with nucleotide occupancy: five MCM subunits are bound to either ATPγS or ADP, whereas the apo MCM2-5 interface remains open. We further report the cryoEM structure of human CMG bound to the replisome hub AND-1 (CMGA). The AND-1 trimer uses one ß-propeller domain of its trimerisation region to dock onto the side of the helicase assembly formed by Cdc45 and GINS. In the resulting CMGA architecture, the AND-1 trimer is closely positioned to the fork DNA while its CIP (Ctf4-interacting peptide)-binding helical domains remain available to recruit partner proteins.

Functional interventions as augmentation strategies for obsessive-compulsive disorder (OCD): scoping review and expert survey from the international college of obsessive-compulsive spectrum disorders (ICOCS).

BACKGROUND: Patients with obsessive-compulsive disorder (OCD) commonly exhibit a range of functional difficulties, presumed linked to neurocognitive changes. Evidence-based first-line treatments have limited effect on improving these cognitive-functional problems. Candidate interventions could be used to augment evidence-based treatments by the multi-professional mental health team. METHODS: A scoping review was performed to identify any intervention with at least one peer-reviewed report of clinical improvement in any of the 13 functional domains of the Cognitive Assessment Instrument of Obsessions and Compulsions (CAIOC-13). Next, an online survey of experts of the International College of Obsessive-Compulsive Spectrum Disorders was conducted. RESULTS: Forty-four studies were identified reporting a positive outcome for 27 different kinds of intervention. Twenty-six experts from 12 different countries, including at least one expert from each continent, completed the opinion survey. Five interventions were identified as 'highly promising', none of which was moderated by rater-related factors, suggesting global applicability. CONCLUSION: Patients with OCD may benefit from a detailed functional assessment, to identify areas of unmet need. A variety of interventions show theoretical promise for treating the complex functional difficulties in OCD as adjuncts to first-line treatments, but the published evidence is weak. Randomised controlled trials are needed to determine the clinical effectiveness of these interventions.HighlightsFunctional-cognitive problems are common in patients with OCD.First-line evidence-based treatments have limited effect on these functionalcognitive difficulties.In our scoping review we found 44 studies reporting of improved clinical outcomes in any of the 13 functional domains of the Cognitive Assessment Instrument of Obsessions and Compulsions (CAIOC-13).An online survey of experts of the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS) was conducted and identified five interventions as "highly promising" candidate treatments for functional-cognitive problems in OCD.Randomised controlled trials are needed to determine the clinical effectiveness of these interventions.

A preliminary investigation of Cyberchondria and its correlates in a clinical sample of patients with obsessive-compulsive disorder, anxiety and depressive disorders attending a tertiary psychiatric clinic.

Objectives. This cross-sectional study aimed to investigate the frequency and presentation of cyberchondria (CYB) in patients with obsessive-compulsive disorder (OCD), anxiety disorders (ADs), and major depression disorder (MDD).Methods. Seventy-seven patients (OCD:25, ADs:26, MDD:26) referred to a tertiary psychiatry outpatient clinic and 27 healthy controls (HCs) were included. A 'working' definition of CYB was used to measure CYB frequency. CYB severity was measured with the Cyberchondria Severity Scale (CSS).Results. CYB as currently defined was present in just 1.3% of the combined patients' sample. Using a broader definition (omitting the disability criterion), we found a higher distribution (OCD:12%, ADs:19.2%, MDD:15.4%, HCs:3.7%) and greater CYB symptom severity. Patients with OCD (63.3 ± 18.9) and ADs (63.3 ± 25.9) showed a higher CYB severity, compared with HCs (48.4 ± 9.9, p<.05). In the combined patients' sample, a positive correlation was found between the CSS scores and measures of health anxiety or hypochondriasis. Higher CYB symptom severity emerged in patients with a positive family history of psychiatric disorders and in those prescribed benzodiazepines or mood-stabilisers.Conclusion. CYB represents a common transdiagnostic syndrome in patients with OCD, ADs, and MDD with a spectrum of severity and indicates a variable burden of illness, supporting the need for specific clinical considerations and interventions.Key pointsCyberchondria (CYB) represents a common transdiagnostic syndrome in patients with obsessive-compulsive disorder, anxiety, and depressive disorders.CYB's frequency as a syndrome of compulsive online health searches associated with an increased anxiety and distress was reported in 10-20% patients.Health anxiety/hypochondriasis showed a strong correlation with CYB.Patients with a positive family history of psychiatric disorders and those prescribed benzodiazepines or mood-stabilisers showed higher CYB symptom severity.Considering the spread of Internet use for health-related information, additional studies investigating CYB in clinical samples are encouraged.

Suicidality in patients with obsessive-compulsive and related disorders (OCRDs): A meta-analysis.

INTRODUCTION: Previous meta-analyses showed that OCD is associated with a substantial risk of suicidal behaviours. Conclusive rates of suicidal ideation (current and lifetime) and suicide attempts based on pooled prevalence rates have not so far been calculated using meta-analysis for the other DSM-5 Obsessive-Compulsive and Related Disorders (OCRDs). OBJECTIVES: This meta-analysis aims to separately calculate the pooled prevalence rates of lifetime suicide attempts and current or lifetime suicidal ideation in BDD, Hoarding Disorder (HD), Skin Picking Disorder (SPD) and Trichotillomania (TTM) and to identify factors associated with increased suicide rates. METHODS: Our protocol was pre-registered with PROSPERO (CRD42020164395). A systematic review and meta-analysis following PRISMA reporting guidelines was performed by searching in PubMed/Medline, PsycINFO, Web of Science and CINAHL databases from the date of the first available article to April 20th, 2020. Stata version 15 was used for the statistical analysis. Given the small number of studies in TTM and SPD, the two grooming disorders were grouped together. Meta-analyses of proportions based on random effects (Der-Simonian and Laird method) were used to derive the pooled estimates. RESULTS: Thirty-eigth studies (N = 4559 participants) were included: 23 for BDD, 8 for HD, 7 for Grooming Disorders. For BDD, the pooled prevalence of lifetime suicide attempts, current and lifetime suicidal ideation was, respectively 35.2% (CI:23.4-47.8), 37.2% (CI:23.8-51.6) and 66.1% (CI:53.5-77.7). For HD, the pooled prevalence of lifetime suicide attempts, current and lifetime suicidal ideation was 24.1% (CI:12.8-37.6), 18.4% (CI:10.2-28.3) and 38.3% (CI:35.0-41.6), respectively. For Grooming Disorders, the pooled prevalence of lifetime suicide attempts and current suicidal ideation were 13.3% (CI:5.9-22.8) and 40.4% (CI:35.7-45.3), respectively (no data available for lifetime suicidal ideation). CONCLUSIONS: The OCRDs as a group are associated with relatively high rates of suicidal behaviour. Through indirect comparisons, we infer that BDD has the greatest risk. Comorbid substance abuse, possibly reflecting poor underlying impulse control, is associated with higher rates of suicidal behaviour in BDD. Our data emphasize the need for clinicians to consider the risk of suicidal behaviour in the management of patients presenting with all forms of OCRDs.

An archaeal primase functions as a nanoscale caliper to define primer length.

The cellular replicative DNA polymerases cannot initiate DNA synthesis without a priming 3' OH. During DNA replication, this is supplied in the context of a short RNA primer molecule synthesized by DNA primase. The primase of archaea and eukaryotes, despite having varying subunit compositions, share sequence and structural homology. Intriguingly, archaeal primase has been demonstrated to possess the ability to synthesize DNA de novo, a property shared with the eukaryotic PrimPol enzymes. The dual RNA and DNA synthetic capabilities of the archaeal DNA primase have led to the proposal that there may be a sequential hand-off between these synthetic modes of primase. In the current work, we dissect the functional interplay between DNA and RNA synthetic modes of primase. In addition, we determine the key determinants that govern primer length definition by the archaeal primase. Our results indicate a primer measuring system that functions akin to a caliper.

Phosphatases control PKA-dependent functional microdomains at the outer mitochondrial membrane.

Evidence supporting the heterogeneity in cAMP and PKA signaling is rapidly accumulating and has been largely attributed to the localization or activity of adenylate cyclases, phosphodiesterases, and A-kinase-anchoring proteins in different cellular subcompartments. However, little attention has been paid to the possibility that, despite homogeneous cAMP levels, a major heterogeneity in cAMP/PKA signaling could be generated by the spatial distribution of the final terminators of this cascade, i.e., the phosphatases. Using FRET-based sensors to monitor cAMP and PKA-dependent phosphorylation in the cytosol and outer mitochondrial membrane (OMM) of primary rat cardiomyocytes, we demonstrate that comparable cAMP increases in these two compartments evoke higher levels of PKA-dependent phosphorylation in the OMM. This difference is most evident for small, physiological increases of cAMP levels and with both OMM-located probes and endogenous OMM proteins. We demonstrate that this disparity depends on differences in the rates of phosphatase-dependent dephosphorylation of PKA targets in the two compartments. Furthermore, we show that the activity of soluble phosphatases attenuates PKA-driven activation of the cAMP response element-binding protein while concurrently enhancing PKA-dependent mitochondrial elongation. We conclude that phosphatases can sculpt functionally distinct cAMP/PKA domains even in the absence of gradients or microdomains of this messenger. We present a model that accounts for these unexpected results in which the degree of PKA-dependent phosphorylation is dictated by both the subcellular distribution of the phosphatases and the different accessibility of membrane-bound and soluble phosphorylated substrates to the cytosolic enzymes.