Triaminocyclopentadienyl Ruthenium Complexes - New Catalysts for Cascade Conversions of Propargyl Alcohols.

Various triaminocyclopentadienyl ruthenium complexes have been synthesized from Ru3 (CO)12 . The new complexes were tested for their ability to catalyze cascade conversions of propargyl alcohols. Their associated catalytic activities complement the activities of known diaminocyclopentadienone ruthenium complexes. In particular, the substrate scope of catalytic cycloadditions with 3-ketolactones or phloroglucinol derivatives is extended to terpenoid-derived propargyl alcohols containing an internal alkyne moiety. A wide range of cyclic terpenoid and phloroglucinol adducts are obtained by complementary application of both types of catalysts.

The vicious circle of social exclusion and psychopathology: a systematic review of experimental ostracism research in psychiatric disorders.

Social exclusion (ostracism) is a major psychosocial factor contributing to the development and persistence of psychiatric disorders and is also related to their social stigma. However, its specific role in different disorders is not evident, and comprehensive social psychology research on ostracism has rather focused on healthy individuals and less on psychiatric patients. Here, we systematically review experimental studies investigating psychological and physiological reactions to ostracism in different responses of psychiatric disorders. Moreover, we propose a theoretical model of the interplay between psychiatric symptoms and ostracism. A systematic MEDLINE and PsycINFO search was conducted including 52 relevant studies in various disorders (some of which evaluated more than one disorder): borderline personality disorder (21 studies); major depressive disorder (11 studies); anxiety (7 studies); autism spectrum disorder (6 studies); schizophrenia (6 studies); substance use disorders (4 studies); and eating disorders (2 studies). Psychological and physiological effects of ostracism were assessed with various experimental paradigms: e.g., virtual real-time interactions (Cyberball), social feedback and imagined scenarios. We critically review the main results of these studies and propose the overall concept of a vicious cycle where psychiatric symptoms increase the chance of being ostracized, and ostracism consolidates or even aggravates psychopathology. However, the specificity and stability of reactions to ostracism, their neurobiological underpinnings, determinants, and moderators (e.g., attachment style, childhood trauma, and rejection sensitivity) remain elusive.

The Role of Self-Esteem in Depression: A Longitudinal Study.

BACKGROUND: Based on the vulnerability model, several studies indicate that low self-esteem seems to contribute to depressive symptoms. AIMS: The aim of this study was to treat depressive symptoms in a cognitive behavioural group therapy, focusing on the enhancement of self-esteem, and to explore co-variation in depressive symptoms and the level of self-esteem. METHOD: The Multidimensional Self-esteem Scale (MSWS) and the Beck Depression Inventory (BDI) were administered to 147 psychiatric in-patients with current depressive symptoms due to an affective disorder (major depression, bipolar I, dysthymia). Self-esteem was measured pre-treatment (t0) and post-treatment (t4, after 5 weeks of eight group sessions); the BDI was applied weekly. A linear mixed growth analysis was conducted to estimate the change in depressive symptoms including interactions with self-esteem. RESULTS: Within the 5 weeks of group therapy, depressive symptoms showed a linear decline, which was stronger for patients with higher gains in self-esteem between t0 and t4. Self-esteem at t0 was unrelated to the change in depression but predicted self-esteem at t4. CONCLUSIONS: Treating depressive symptoms in a cognitive behavioural group therapy in a naturalistic setting might have a positive effect on the process of recovery. Moreover, depressive symptoms and level of self-esteem seemed to co-vary.

Chronic sleep reduction in adolescents-clinical cut-off scores for the Chronic Sleep Reduction Questionnaire (CSRQ).

The Chronic Sleep Reduction Questionnaire is a validated questionnaire that measures symptoms of prolonged insufficient and/or poor sleep and therefore accounts for individuals' sleep need and sleep debt. This study extends its psychometric properties by providing cut-off scores, using a matched sample of 298 healthy adolescents (15.38 ± 1.63 years, 37.9% male, mean Chronic Sleep Reduction Questionnaire score: 32.98 ± 6.51) and 298 adolescents with insomnia/delayed sleep-wake phase disorder (15.48 ± 1.62 years; 37.9% male, mean Chronic Sleep Reduction Questionnaire score: 42.59 ± 7.06). We found an area under the curve of 0.84 (95% confidence interval: 0.81-0.87). Cut-off scores for optimal sensitivity, optimal specificity and based on Youden's criterion are provided. These cut-off scores are highly relevant for use of the Chronic Sleep Reduction Questionnaire in future studies and clinical practice.

Ruthenium-Catalyzed Cascade Annulation of Indole with Propargyl Alcohols.

Cascade transformations forming multiple bonds and one-pot procedures provide rapid access to natural-product-like scaffolds from simple precursors. These atom-economic processes are valuable tools in organic synthesis and drug discovery. Herein, we report on ruthenium-catalyzed cascade annulations of indole with readily available propargyl alcohols. These provide rapid access to diverse carbazoles, cyclohepta[b]indoles, and further fused polycycles with high selectivity. A bifunctional ruthenium complex featuring a redox-coupled cyclopentadienone ligand acts as a common catalyst for the different cascade processes.

In vitro model for DNA double-strand break repair analysis in breast cancer reveals cell type-specific associations with age and prognosis.

Dysfunction of homologous recombination is a common denominator of changes associated with breast cancer-predisposing mutations. In our previous work, we identified a functional signature in peripheral blood lymphocytes from women who were predisposed that indicated a shift from homologous recombination to alternative, error-prone DNA double-strand break (DSB) repair pathways. To capture both hereditary and nonhereditary factors, we newly established a protocol for isolation and ex vivo analysis of epithelial cells, epithelial-mesenchymal transition cells (EMTs), and fibroblasts from breast cancer specimens (147 patients). By applying a fluorescence-based test system, we analyzed the error-prone DSB repair pathway microhomology-mediated end joining in these tumor-derived cell types and peripheral blood lymphocytes. In parallel, we investigated DNA lesion processing by quantitative immunofluorescence microscopy of histone H2AX phosphorylated on Ser139 focus after radiomimetic treatment. Our study reveals elevated histone H2AX phosphorylated on Ser139 damage removal in epithelial cells, not EMTs, and poly(ADP-ribose)polymerase inhibitor sensitivities, which suggested a DSB repair pathway shift with increasing patient age. Of interest, we found elevated microhomology-mediated end joining in EMTs, not epithelial cells, from patients who received a treatment recommendation of adjuvant chemotherapy, that is, those with high-risk tumors. Our discoveries of altered DSB repair activities in cells may serve as a method to further classify breast cancer to predict responsiveness to adjuvant chemotherapy and/or therapeutics that target DSB repair-dysfunctional tumors.-Deniz, M., Kaufmann, J., Stahl, A., Gundelach, T., Janni, W., Hoffmann, I., Keimling, M., Hampp, S., Ihle, M., Wiesmüller, L. In vitro model for DNA double-strand break repair analysis in breast cancer reveals cell type-specific associations with age and prognosis.

Adolescents' electronic media use at night, sleep disturbance, and depressive symptoms in the smartphone age.

Adolescence is a time of increasing vulnerability for poor mental health, including depression. Sleep disturbance is an important risk factor for the development of depression during adolescence. Excessive electronic media use at night is a risk factor for both adolescents' sleep disturbance and depression. To better understand the interplay between sleep, depressive symptoms, and electronic media use at night, this study examined changes in adolescents' electronic media use at night and sleep associated with smartphone ownership. Also examined was whether sleep disturbance mediated the relationship between electronic media use at night and depressive symptoms. 362 adolescents (12-17 year olds, M = 14.8, SD = 1.3; 44.8% female) were included and completed questionnaires assessing sleep disturbance (short sleep duration and sleep difficulties) and depressive symptoms. Further, participants reported on their electronic media use in bed before sleep such as frequency of watching TV or movies, playing video games, talking or text messaging on the mobile phone, and spending time online. Smartphone ownership was related to more electronic media use in bed before sleep, particularly calling/sending messages and spending time online compared to adolescents with a conventional mobile phone. Smartphone ownership was also related to later bedtimes while it was unrelated to sleep disturbance and symptoms of depression. Sleep disturbance partially mediated the relationship between electronic media use in bed before sleep and symptoms of depression. Electronic media use was negatively related with sleep duration and positively with sleep difficulties, which in turn were related to depressive symptoms. Sleep difficulties were the more important mediator than sleep duration. The results of this study suggest that adolescents might benefit from education regarding sleep hygiene and the risks of electronic media use at night.

BRCA1-mediated repression of mutagenic end-joining of DNA double-strand breaks requires complex formation with BACH1.

BACH1 (BRCA1-associated C-terminal helicase 1), the product of the BRIP1 {BRCA1 [breast cancer 1, early onset]-interacting protein C-terminal helicase 1; also known as FANCJ [FA-J (Fanconi anaemia group J) protein]} gene mutated in Fanconi anaemia patients from complementation group J, has been implicated in DNA repair and damage signalling. BACH1 exerts DNA helicase activities and physically interacts with BRCA1 and MLH1 (mutL homologue 1), which differentially control DNA DSB (double-strand break) repair processes. The present study shows that BACH1 plays a role in both HR (homologous recombination) and MMEJ (microhomology-mediated non-homologous end-joining) and reveals discrete mechanisms underlying modulation of these pathways. Our results indicate that BACH1 stimulates HR, which depends on the integrity of the helicase domain. Disruption of the BRCA1-BACH1 complex through mutation of BACH1 compromised errorfree NHEJ (non-homologous end-joining) and accelerated error-prone MMEJ. Conversely, molecular changes in BACH1 abrogating MLH1 binding interfered neither with HR nor with MMEJ. Importantly, MMEJ is a mutagenic DSB repair pathway, which is derepressed in hereditary breast and ovarian carcinomas. Since BRCA1 and BACH1 mutations targeting the BRCA1-BACH1 interaction have been associated with breast cancer susceptibility, the results of the present study thus provide evidence for a novel role of BACH1 in tumour suppression.

Seeking Care for Long COVID: A Narrative Analysis of Canadian Experiences.

The goal of this study was to explore the experiences of individuals seeking care for long COVID-19 in the Canadian healthcare system. Recorded virtual interviews were carried out with 8 participants and narrative analysis was used to examine the stories produced and identify the central narratives that defined participants' experiences. Care-seeking experiences were characterized by (1) often debilitating multi-system symptoms for which little information about prognosis was available and no effective treatments were provided, (2) compounded by the frustration of trying to convince family, friends, and health care practitioners of the legitimacy of their illness, (3) access to medical care was severely limited by the global pandemic and associated higher thresholds for care, (4) like others suffering from complex, multi-system conditions, people with long COVID are often struggling with a health-care system ill-suited for dealing with long-term and possibly chronic conditions. To make system-level improvements to better serve those with chronic conditions, it is critical that we understand the care-seeking experiences of chronic illness patients, including the unique experiences of those with long COVID.

Possible strategies to reduce altitude-related excessive polycythemia.

We sought to determine the effects of three treatments on hemoglobin (Hb) levels in patients with chronic mountain sickness (CMS): 1) descent to lower altitude, 2) nocturnal O2 supply, 3) administration of acetazolamide. Nineteen patients with CMS living at an altitude of 3,940 ± 130 m participated in the study, which consisted of a 3-wk intervention phase and a 4-wk postintervention phase. Six patients spent 3 wk at an altitude of 1,050 m (low altitude group, LAG), six received supplemental oxygen for 12 h overnight (oxygen group, OXG), and seven received 250 mg of acetazolamide daily (acetazolamide group, ACZG). Hemoglobin mass (Hbmass) was determined using an adapted carbon monoxide (CO) rebreathing method before, weekly during, and 4 wk postintervention. Hbmass decreased by 245 ± 116 g (P < 0.01) in the LAG and by 100 ± 38 g in OXG, and 99 ± 64 g in ACZG (P < 0.05, each), respectively. In LAG, hemoglobin concentration ([Hb]) decreased by 2.1 ± 0.8 g/dL and hematocrit by 7.4 ± 2.9% (both P < 0.01), whereas OXG and ACZG only trended toward lower values. Erythropoietin concentration ([EPO]) decreased between 81 ± 12% and 73 ± 21% in LAG at low altitude (P < 0.01) and increased by 161 ± 118% 5 days after return (P < 0.01). In OXG and ACZG, the [EPO] decrease was ∼75% and ∼50%, respectively, during the intervention (P < 0.01). Descent to low altitude (from 3,940 m to 1,050 m) is a fast-acting measure for the treatment of excessive erythrocytosis in patients with CMS, reducing Hbmass by 16% within 3 wk. Nighttime oxygen supplementation and daily acetazolamide administration are also effective, but reduce Hbmass by only 6%.NEW & NOTEWORTHY To our knowledge, this is the first study examining the effect of three different treatments [descending to lower altitude (from 3,900 m to 1,050 m), nocturnal oxygen supply, and administration of acetazolamide] on changes in hemoglobin mass in patients experiencing chronic mountain sickness (CMS). We report that descent to low altitude is a fast-acting measure for the treatment of excessive erythrocytosis in patients with CMS, reducing Hbmass by 16% within 3 wk. Nighttime oxygen supplementation and daily acetazolamide administration are also effective, but reduce Hbmass by only 6%. In all three treatments, the underlying mechanism is a reduction in plasma erythropoietin concentration due to higher oxygen availability.

Association between the behavioral response during social exclusion and recalled childhood maltreatment.

Social exclusion is a critical event for mental health. Patients with interpersonal dysfunction, e.g., with borderline personality disorder (BPD) or persistent depressive disorder (PDD), are particularly vulnerable, often based on their experiences of early adversity in life. The etiological pathways from childhood maltreatment (CM) to current behavior during social exclusion are still underexplored. This cross-diagnostic study investigated the relationship between self-reported CM and behavioral reaction to social exclusion in an experimental paradigm (Cyberball). Data from 140 subjects including patients with BPD and PDD as well as healthy controls were analyzed. The effect of CM (Childhood Trauma Questionnaire, CTQ) on behavior to social exclusion during Cyberball (ball tossing behavior) was analyzed including rejection sensitivity (RS) as a mediator. In the whole sample, the CTQ score (B = -.004, p < .05) as well as the emotional neglect subscore (B = -.016, p < .01) were associated with a reduced ball tossing behavior towards the excluder. There were no significant indirect effects involving RS. These current findings support the relationship between CM and an altered interpersonal response in critical interpersonal situations. Larger cohorts with multidimensional data in social domains are warranted to further investigate the link between CM and current interpersonal dysfunction.

Effects of resilience and timing of adverse and adaptive experiences on interpersonal behavior: a transdiagnostic study in a clinical sample.

Adverse childhood experiences (ACE) have been linked to less prosocial behavior during social exclusion in vulnerable groups. However, little is known about the impact of the timing of ACE and the roles of protective factors. Therefore, this study investigated the association of the behavioral response to experimental partial social exclusion with adverse and adaptive experiences across age groups and resilience in clinical groups with persistent depressive disorder and borderline personality disorder, i.e., groups with high ACE, and in healthy controls (HC) (N = 140). Adverse and adaptive experiences during childhood, youth, and adulthood were assessed with the Traumatic Antecedents Questionnaire, and resilience was measured with the Connor Davidson Resilience Scale. A modified version of the Cyberball paradigm was used to assess the direct behavioral response to partial social exclusion. In patients, adverse events during youth (B = - 0.12, p = 0.016) and adulthood (B = - 0.14, p = 0.013) were negatively associated with prosocial behavior, whereas in the HC sample, adaptive experiences during youth were positively associated with prosocial behavior (B = 0.25, p = 0.041). Resilience did not mediate these effects. The findings indicate that critical events during youth may be particularly relevant for interpersonal dysfunction in adulthood.

Cognitive Behavioral Therapy for Insomnia in School-Aged Children and Adolescents.

One of the most prevalent sleep disorders in children and adolescents is "insomnia," which can be briefly described as problems with initiating and/or maintaining sleep with associated daytime consequences. These are typical insomnia symptoms, and when experienced for long enough and when they interfere with an important area of the young person's life (eg, schooling), then a diagnosis of an insomnia disorder may be warranted. The authors strongly urge the scientific community to conduct further controlled trials, including dismantling trials that evaluate the relative effectiveness of individual cognitive behavioral therapy for insomnia components.

Sequential Social Exclusion in a Novel Cyberball Paradigm Leads to Reduced Behavioral Repair and Plasma Oxytocin in Borderline Personality Disorder.

Patients with borderline personality disorder (BPD) show interpersonal deficits, and altered emotional and oxytocin (OT) responses to social exclusion (Cyberball). In order to extend previous findings, this study applies a novel Cyberball variant. Nineteen BPD patients and 56 healthy controls (HC) played Cyberball for 2 minutes of inclusion, 5 minutes of partial exclusion by one of two co-players, and 2 minutes total exclusion by both. Plasma OT levels at baseline and after 7, 9, 15, and 40 minutes were measured with radioimmunoassay. BPD patients showed a greater aversive reaction and a trend for greater OT reduction after social exclusion than HC. BPD patients also tended to play less frequently with the excluder. Though limited by our sample size, we partially replicate previous findings. Our preliminary behavioral data support the notion of an altered OT regulation and reduced capacity for social cooperation in BPD.

Association of loneliness and social network size in adulthood with childhood maltreatment: Analyses of a population-based and a clinical sample.

BACKGROUND: Perceived loneliness and objective social network size are related but distinct factors, which negatively affect mental health and are prevalent in patients who have experienced childhood maltreatment (CM), for example, patients with persistent depressive disorder (PDD) and borderline personality disorder (BPD). This cross-diagnostic study investigated whether loneliness, social network size, or both are associated with self-reported CM. METHODS: Loneliness and social network size were assessed in a population-based sample at two time points (Study 1, N = 509), and a clinical group of patients with PDD or BPD (Study 2, N = 190) using the UCLA Loneliness Scale and the Social Network Index. Further measures were the Childhood Trauma Questionnaire, and standard depression rating scales. Linear regression analyses were applied to compare associations of loneliness or social network size with CM. Multiple mediation analyses were used to test the relative importance of loneliness and social network size in the relationship between CM and depressive symptoms. RESULTS: In both studies, loneliness showed a stronger association than social network size with CM. This was particularly marked for emotional neglect and emotional abuse. Loneliness but not social network size mediated the relationship between CM and depressive symptoms. CONCLUSIONS: Loneliness is particularly associated with self-reported CM, and in this respect distinct from the social network size. Our results underline the importance of differentiating both psychosocial constructs and suggest focusing on perceived loneliness and its etiological underpinnings by mechanism-based psychosocial interventions.

Altered immediate behavioral response to partial social exclusion: A cross-diagnostic study in patients with borderline personality disorder and persistent depressive disorder.

Borderline personality disorder (BPD) and persistent depressive disorder (PDD) are related to interpersonal dysfunction which might become particularly apparent in situations of social exclusion (SE). While emotional responses to SE have been widely explored, behavioral data in clinical samples are lacking. In this cross-diagnostic study, we applied a variant of the Cyberball paradigm to investigate the dynamic behavioral response to partial SE in BPD and PDD. BPD patients (n = 36), PDD patients (n = 34) and age and gender matched healthy controls (HC) (total n = 70) played experimental (i.e. partial SE Cyberball) and control (i.e. inclusion only) conditions in randomized order. While all groups tended to increase ball tosses towards the excluder in response to SE, this behavioral turn was significantly lower in PDD (p = .03, d = -.30) and trendwise in BPD patients (p = .06, d = -.28). Thus, an altered immediate response to partial SE was observed in BPD and PDD, in addition to the emotional reactions. This study supports the hypothesis of a behavioral coping with SE in BPD and PDD that might be problematic in the long run and provides an experimental paradigm for future research on interpersonal dysfunction.

Sleep characteristics across the lifespan in 1.1 million people from the Netherlands, United Kingdom and United States: a systematic review and meta-analysis.

We aimed to obtain reliable reference charts for sleep duration, estimate the prevalence of sleep complaints across the lifespan and identify risk indicators of poor sleep. Studies were identified through systematic literature search in Embase, Medline and Web of Science (9 August 2019) and through personal contacts. Eligible studies had to be published between 2000 and 2017 with data on sleep assessed with questionnaires including ≥100 participants from the general population. We assembled individual participant data from 200,358 people (aged 1-100 years, 55% female) from 36 studies from the Netherlands, 471,759 people (40-69 years, 55.5% female) from the United Kingdom and 409,617 people (≥18 years, 55.8% female) from the United States. One in four people slept less than age-specific recommendations, but only 5.8% slept outside of the 'acceptable' sleep duration. Among teenagers, 51.5% reported total sleep times (TST) of less than the recommended 8-10 h and 18% report daytime sleepiness. In adults (≥18 years), poor sleep quality (13.3%) and insomnia symptoms (9.6-19.4%) were more prevalent than short sleep duration (6.5% with TST < 6 h). Insomnia symptoms were most frequent in people spending ≥9 h in bed, whereas poor sleep quality was more frequent in those spending <6 h in bed. TST was similar across countries, but insomnia symptoms were 1.5-2.9 times higher in the United States. Women (≥41 years) reported sleeping shorter times or slightly less efficiently than men, whereas with actigraphy they were estimated to sleep longer and more efficiently than man. This study provides age- and sex-specific population reference charts for sleep duration and efficiency which can help guide personalized advice on sleep length and preventive practices.