Whole genome RNAi screens reveal a critical role of REV3 in coping with replication stress

REV3, the catalytic subunit of translesion polymerase zeta (polζ), is commonly associated with DNA damage bypass and repair. Despite sharing accessory subunits with replicative polymerase δ, very little is known about the role of polζ in DNA replication. We previously demonstrated that inhibition of REV3 expression induces persistent DNA damage and growth arrest in cancer cells. To reveal determinants of this sensitivity and obtain insights into the cellular function of REV3, we performed whole human genome RNAi library screens aimed at identification of synthetic lethal interactions with REV3 in A549 lung cancer cells. The top confirmed hit was RRM1, the large subunit of ribonucleotide reductase (RNR), a critical enzyme of de novo nucleotide synthesis. Treatment with the RNR-inhibitor hydroxyurea (HU) synergistically increased the fraction of REV3-deficient cells containing single stranded DNA (ssDNA) as indicated by an increase in replication protein A (RPA). However, this increase was not accompanied by accumulation of the DNA damage marker γH2AX suggesting a role of REV3 in counteracting HU-induced replication stress (RS). Consistent with a role of REV3 in DNA replication, increased RPA staining was confined to HU-treated S-phase cells. Additionally, we found genes related to RS to be significantly enriched among the top hits of the synthetic sickness/lethality (SSL) screen further corroborating the importance of REV3 for DNA replication under conditions of RS.

Making business in the open: coping with economic and institutional risk and insecurity in the Kafue flats, Zambia

This paper deals with the difference between risk and insecurity from an anthropological perspective using a critical New Institutionalist approach. Risk refers to the ability to reduce undesirable outcomes, based on a range of information actors have on possible outcomes; insecurity refers to the lack of this information. With regard to the neo-liberal setting of a resource rich area in Zambia, Central Africa, local actors – men and women – face risk and insecurity in market constellations between rural and urban areas. They attempt to cope with risk using technical means and diversification of livelihood strategies. But as common-pool resources have been transformed from common property institutions to open access, also leading to unpredictability of competitors and partners in “free” markets, actors rely on magic options to reduce insecurity and transform it into risk-assessing strategies as an adaptation to modern times. Keywords: Risk, insecurity, institutional change, neo-liberal market, common pool resources, livelihood strategies, magic, Zambia.

Coping with drought

People in arid and semi-arid regions face difficult living conditions, increasingly aggravated by extended periods of drought and advancing desertification. However, the populations of arid and semi-arid regions can also rely on the great potential for innovation and adaptation that they have developed over centuries of living in these environments. This brochure presents the reality of people living in the world’s arid and semi-arid regions, and shows how SDC supports them in developing innovations and improving their livelihoods.

Management of children with autism spectrum disorder in the dental setting: concerns, behavioural approaches and recommendations

OBJECTIVES This article reviews the present literature on the issues encountered while coping with children with autistic spectrum disorder from the dental perspective. The autistic patient profile and external factors affecting the oral health status of this patient population are discussed upon the existing body of evidence. MATERIAL AND METHODS The MEDLINE database was searched using the terms 'Autistic Disorder', 'Behaviour Control/methods', 'Child', 'Dental care for disabled', 'Education', 'Oral Health', and 'Pediatric Dentistry' to locate related articles published up to January 2013. RESULTS Most of the relevant studies indicate poor oral hygiene whereas they are inconclusive regarding the caries incidence in autistic individuals. Undergraduate dental education appears to determine the competence of dental professionals to treat developmentally disabled children and account partly for compromised access to dental care. Dental management of an autistic child requires in-depth understanding of the background of the autism and available behavioural guidance theories. The dental professional should be flexible to modify the treatment approach according to the individual patient needs.

Anaesthesia with medetomidine, midazolam and ketamine in six gorillas after premedication with oral zuclopenthixol dihydrochloride

OBJECTIVE To evaluate the effects of medetomidine, midazolam and ketamine (MMK) in captive gorillas after premedication with oral zuclopenthixol. STUDY DESIGN Case series. ANIMALS Six gorillas, two males and four females, aged 9-52 years and weighing 63-155 kg. METHODS The gorillas were given zuclopenthixol dihydrochloride 0.2 ± 0.05 mg kg(-1) per os twice daily for 3 days for premedication. On the day of anaesthesia the dose of zuclopenthixol was increased to 0.27 mg kg(-1) and given once early in the morning. Anaesthesia was induced with medetomidine 0.04 ± 0.004 mg kg(-1) , midazolam 0.048 ± 0.003 mg kg(-1) and ketamine 4.9 ± 0.4 mg kg(-1) intramuscularly (IM). Upon recumbency, the trachea was intubated and anaesthesia was maintained on 1-2% isoflurane in oxygen. Physiological parameters were monitored every 10 minutes and arterial blood gas analysis was performed once 30-50 minutes after initial darting. At the end of the procedure, 42-115 minutes after initial darting, immobilisation was antagonized with atipamezole 0.21 ± 0.03 mg kg(-1) and sarmazenil 5 ± 0.4 μg kg(-1) IM. RESULTS Recumbency was reached within 10 minutes in five out of six animals. One animal required two additional darts before intubation was feasible. Heart rate ranged from 60 to 85 beats minute(-1) , respiratory rate from 17 to 46 breaths minute(-1) and temperature from 36.9 to 38.3 °C. No spontaneous recoveries were observed and anaesthetic level was stable. Blood gas analyses revealed mild respiratory acidosis, and mean PaO(2) was 24.87 ± 17.16 kPa (187 ± 129 mmHg) with all values being above 13.4 kPa (101 mmHg). Recovery was smooth and gorillas were sitting within 25 minutes. CONCLUSION AND CLINICAL RELEVANCE The drug combination proved to be effective in anaesthetizing captive gorillas of various ages and both sexes, with minimal cardio-respiratory changes.

Higher emotional distress in female partners of cancer patients: prevalence and patient-partner interdependencies in a 3-year cohort

OBJECTIVE: Assessment and treatment of psychological distress in cancer patients was recognized as a major challenge. The role of spouses, caregivers, and significant others became of salient importance not only because of their supportive functions but also in respect to their own burden. The purpose of this study was to assess the amount of distress in a mixed sample of cancer patients and their partners and to explore the dyadic interdependence. METHODS: An initial sample of 154 dyads was recruited, and distress questionnaires (Hospital Anxiety and Depression Scale, Symptom Checklist 9-Item Short Version and 12-Item Short Form Health Survey) were assessed over four time points. Linear mixed models and actor-partner interdependence models were applied. RESULTS: A significant proportion of patients and their partners (up to 40%) reported high levels of anxiety, depression, psychological distress, and low quality of life over the course of the investigation. Mixed model analyses revealed that higher risks for clinical relevant anxiety and depression in couples exist for female patients and especially for female partners. Although psychological strain decreased over time, the risk for elevated distress in female partners remained. Modeling patient-partner interdependence over time stratified by patients' gender revealed specific effects: a moderate correlation between distress in patients and partners, and a transmission of distress from male patients to their female partners. CONCLUSIONS: Our findings provide empirical support for gender-specific transmission of distress in dyads coping with cancer. This should be considered as an important starting point for planning systemic psycho-oncological interventions and conceptualizing further research.

DNA with Hydrophobic Base Substitutes: A Stable, Zipperlike Recognition Motif Based On Interstrand-Stacking Interactions

No Abstract

Entwicklung und Validierung einer Skala der Bereitschaft zu verzeihen (SBV)

Verzeihen dient der Bewältigung von Kränkungen und zwischenmenschlichen Konflikten. Es werden Definitionen und Operationalisierungen aus dem englischen Sprachraum vorgestellt. Die Entwicklung eines deutschsprachigen szenarienbasierten Instruments zur Erhebung der Bereitschaft zu verzeihen wird beschrieben. Es wird eine Differenzierung des Konstruktes in zwei Komponenten vorgeschlagen: (a) die Bereitschaft, anderen Menschen zu verzeihen, wenn diese ihre Tat bedauern, (b) die Bereitschaft, anderen Menschen zu verzeihen, wenn diese ihre Tat nicht bedauern. Die Messeigenschaften der neu entwickelten Skala wurden in fünf Studien an insgesamt 1824 Probanden untersucht. Die Ergebnisse zeigen, dass das Instrument gute psychometrische Eigenschaften besitzt. Die theoretische Differenzierung des Konstrukts wird empirisch bestätigt. Hinweise auf die Konstruktvalidität der Skala ergeben sich aus Zusammenhängen mit theoretisch einschlägigen Referenzkonstrukten: der habituellen Ärgerneigung, der Wahrnehmung und Klarheit über eigene und fremde Gefühle, positiver und negativer Affektivität, den fünf Persönlichkeitsfaktoren und sozialer Erwünschtheit. Für die Konstruktvalidität der Skala sprechen ferner konvergente Korrelationen mit anderen Maßen der Bereitschaft zu verzeihen.

Association of Trait Resilience With Peritraumatic and Posttraumatic Stress in Patients With Myocardial Infarction.

OBJECTIVE Acute myocardial infarction (MI) is a life-threatening condition, leading to immediate fear and distress in many patients. Approximately 18% of patients develop posttraumatic stress disorder in the aftermath of MI. Trait resilience has shown to be a protective factor for the development of posttraumatic stress disorder. However, whether this buffering effect has already an impact on peritraumatic distress and applies to patients with MI is elusive. METHODS We investigated 98 consecutive patients with acute MI within 48 hours after having reached stable circulatory conditions and 3 months thereafter. Peritraumatic distress was assessed retrospectively with three single-item questions about pain, fear, and helplessness during MI. All patients completed the Posttraumatic Diagnostic Scale (PDS) and the Resilience Scale to self-rate posttraumatic stress and trait resilience. RESULTS Multivariate models adjusting for sociodemographic and medical factors showed that trait resilience was not associated with peritraumatic distress, but significantly so with posttraumatic stress. Patients with greater trait resilience showed lower PDS scores (b = -0.06, p < .001). There was no significant relationship between peritraumatic distress scores and PDS scores; resilience did not emerge as a moderator of this relationship. CONCLUSIONS The findings suggest that trait resilience does not buffer the perception of acute MI as stressful per se but may enhance better coping with the traumatic experience in the longer term, thus preventing the development of MI-associated posttraumatic stress. Trait resilience may play an important role in posttraumatic stress symptoms triggered by medical diseases such as acute MI.

More adaptive versus less maladaptive coping: What is more predictive of symptom severity? Development of a new scale to investigate coping profiles across different psychopathological syndromes

BACKGROUND: Lack of adaptive and enhanced maladaptive coping with stress and negative emotions are implicated in many psychopathological disorders. We describe the development of a new scale to investigate the relative contribution of different coping styles to psychopathology in a large population sample. We hypothesized that the magnitude of the supposed positive correlation between maladaptive coping and psychopathology would be stronger than the supposed negative correlation between adaptive coping and psychopathology. We also examined whether distinct coping style patterns emerge for different psychopathological syndromes. METHODS: A total of 2200 individuals from the general population participated in an online survey. The Patient Health Questionnaire-9 (PHQ-9), the Obsessive-Compulsive Inventory revised (OCI-R) and the Paranoia Checklist were administered along with a novel instrument called Maladaptive and Adaptive Coping Styles (MAX) questionnaire. Participants were reassessed six months later. RESULTS: MAX consists of three dimensions representing adaptive coping, maladaptive coping and avoidance. Across all psychopathological syndromes, similar response patterns emerged. Maladaptive coping was more strongly related to psychopathology than adaptive coping both cross-sectionally and longitudinally. The overall number of coping styles adopted by an individual predicted greater psychopathology. Mediation analysis suggests that a mild positive relationship between adaptive and certain maladaptive styles (emotional suppression) partially accounts for the attenuated relationship between adaptive coping and depressive symptoms. LIMITATIONS: Results should be replicated in a clinical population. CONCLUSIONS: Results suggest that maladaptive and adaptive coping styles are not reciprocal. Reducing maladaptive coping seems to be more important for outcome than enhancing adaptive coping. The study supports transdiagnostic approaches advocating that maladaptive coping is a common factor across different psychopathologies.

Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut

The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA(+) plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-α and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells.

An EEG approach to the neurodevelopmental hypothesis of schizophrenia studying schizophrenics, normal controls and adolescents

Based on an integrative brain model which focuses on memory-driven and EEG state-dependent information processing for the organisation of behaviour, we used the developmental changes of the awake EEG to further investigate the hypothesis that neurodevelopmental abnormalities (deviations in organisation and reorganisation of cortico-cortical connectivity during development) are involved in the pathogenesis of schizophrenia. First-episode, neuroleptic-naive schizophrenics and their matched controls and three age groups of normal adolescents were studied (total: 70 subjects). 19-channel EEG delta-theta, alpha and beta spectral band centroid frequencies during resting (baseline) and after verbal stimuli were used as measure of the level of attained complexity and momentary excitability of the neuronal network (working memory). Schizophrenics compared with all control groups showed lower delta-theta activity centroids and higher alpha and beta activity centroids. Reactivity centroids (centroid after stimulus minus centroid during resting) were used as measure of update of working memory. Schizophrenics showed partial similarities in delta-theta and beta reactivity centroids with the 11-year olds and in alpha reactivity centroids with the 13-year olds. Within the framework of our model, the results suggest multifactorially elicited imbalances in the level of excitability of neuronal networks in schizophrenia, resulting in network activation at dissociated complexity levels, partially regressed and partially prematurely developed. It is hypothesised that activation of age- and/or state-inadequate representations for coping with realities becomes manifest as productive schizophrenic symptoms. Thus, the results support some aspects of the neurodevelopmental hypothesis.