Self-harm risk between adolescence and midlife in people who experienced separation from one or both parents during childhood

AbstractBackgroundExperience of child-parent separation predicts adverse outcomes in later life. We conducted a detailed epidemiological examination of this complex relationship by modelling an array of separation scenarios and trajectories and subsequent risk of self-harm.MethodsThis cohort study examined persons born in Denmark during 1971–1997. We measured child-parent separations each year from birth to 15th birthday via complete residential address records in the Civil Registration System. Self-harm episodes between 15th birthday and early middle age were ascertained through linkage to psychiatric and general hospital registers. Incidence rate ratios (IRRs) from Poisson regression models were estimated against a reference category of individuals not separated from their parents.ResultsAll exposure models examined indicated an association with raised self-harm risk. For example, large elevations in risk were observed in relation to separation from both parents at 15th birthday (IRR 5.50, 95% CI 5.25–5.77), experiencing five or more changes in child-parent separation status (IRR 5.24, CI 4.88–5.63), and having a shorter duration of familial cohesion during upbringing. There was no significant evidence for varying strength of association according to child's gender.LimitationsMeasuring child-parent separation according to differential residential addresses took no account of the reason for or circumstances of these separations.ConclusionsThese novel findings suggest that self-harm prevention initiatives should be tailored toward exposed persons who remain psychologically distressed into adulthood. These high-risk subgroups include individuals with little experience of familial cohesion during their upbringing, those with the most complicated trajectories who lived through multiple child-parent separation transitions, and those separated from both parents during early adolescence

Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches

Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an important role in tumour biology by promoting the stabilisation and activity of oncogenic ‘client’ proteins. Inhibition of Hsp90 by small-molecule drugs, acting via its ATP hydrolysis site, has shown promise as a molecularly targeted cancer therapy. Owing to the importance of Hop and other tetratricopeptide repeat (TPR)-containing cochaperones in regulating Hsp90 activity, the Hsp90-TPR domain interface is an alternative site for inhibitors, which could result in effects distinct from ATP site binders. The TPR binding site of Hsp90 cochaperones includes a shallow, positively charged groove that poses a significant challenge for druggability. Herein, we report the apo, solution-state structure of Hop TPR2A which enables this target for NMR-based screening approaches. We have designed prototype TPR ligands that mimic key native ‘carboxylate clamp’ interactions between Hsp90 and its TPR cochaperones and show that they block binding between Hop TPR2A and the Hsp90 C-terminal MEEVD peptide. We confirm direct TPR-binding of these ligands by mapping 1H–15N HSQC chemical shift perturbations to our new NMR structure. Our work provides a novel structure, a thorough assessment of druggability and robust screening approaches that may offer a potential route, albeit difficult, to address the chemically challenging nature of the Hop TPR2A target, with relevance to other TPR domain interactors

Health, employment and relationships: Correlates of personal wellbeing in young adults with and without a history of childhood language impairment

Objective: We examine the potential associations between self-rated health, employment situation, relationship status and personal wellbeing in young adults with and without a history of language impairment (LI). Methods: A total of 172 24-year-olds from the UK participated. Approximately half (N = 84) had a history of LI. Personal wellbeing was measured using ratings from three questions from the Office for National Statistics regarding life satisfaction, happiness and life being worthwhile. Results: There were similarities between individuals with a history of LI and their age-matched peers in self-rated personal wellbeing. However, regression analyses revealed self-rated health was the most consistent predictor of personal wellbeing for individuals with a history of LI in relation to life satisfaction (21% of variance), happiness (11%) and perceptions that things one does in life are worthwhile (32%). None of the regression analyses were significant for their peers. Conclusions: Similarities on ratings of wellbeing by young adults with and without a history of LI can mask heterogeneity and important differences. Young adults with a history of LI are more vulnerable to the effects of health, employment and relationship status on their wellbeing than their peers

Cloning and expression of the uracil-DNA glycosylase inhibitor (UGI) from bacteriophage PBS-1 and crystallization of a uracil-DNA glycosylase-UGI complex

The uracil‐DNA glycosylase inhibitory protein (UGI) from the bacterio‐phage PBS‐l has been cloned and overexpressed. The nucleotide sequence is identical to that for the previously described PBS‐2 inhibitor. The recombinant PBS‐l UGI inhibits the uracil‐DNA glycosylase from herpes simplex virus type‐l (HSV‐l UDGase), and a complex between the HSV‐l UDGase and PBS‐l UGI has been crystallized. The crystals have unit cell dimensions a = 143.21 Å, c = 40.78 Å and are in a polar hexagonal space group. There is a single complex in the asymmetric unit with a solvent content of 62% by volume and the crystals diffract to 2.5Å on a synchrotron radiation source

The problem with Pyrimidines

The chemical properties of cytosine present cells with a serious informational ‘disease’, necessitating enzymes with exquisite specificity for deoxyuridine for its prevention and cure

DNA repair in three dimensions

Crystallographic studies of DNA repair enzymes are revealing a wide range of structural motifs used to recognize specific lesions in DNA, and are helping to unravel the catalytic mechanisms by which these lesions are repaired

Crystallization and preliminary X-ray analysis of the uracil-DNA glycosylase DNA repair enzyme from herpes simplex virus type 1

A 28·5 kDa catalytic fragment of the uracil-DNA glycosylase DNA repair enzyme from Herpes simplex virus type 1 (HSV-1) has been crystallized using protein from a highly expressing Escherichia coli clone of the Herpes simplex virus type 1 UL2 gene. The protein crystallizes at 12 mg/ml from 11% (w/v) polyethylene glycol 8000 at pH values in the range 6·8 to 7·9, in the presence of (NH4)2SO4. Long trigonal rods (0·08 mm × 0·08 mm × >0·5 mm) diffract beyond 3·0 Å using a laboratory source. The enzyme crystallizes in P31 (or P 32) a = 65·3 Å, c = 49·0 Å with a single molecule in the asymmetric unit and an estimated solvent content of 41% by volume

Uracil-DNA glycosylase activities in hyperthermophilic micro-organisms

Hyperthermophiles exist in conditions which present an increased threat to the informational integrity of their DNA, particularly by hydrolytic damage. As in mesophilic organisms, specific activities must exist to restore and protect this template function of DNA. In this study we have demonstrated the presence of thermally stable uracil-DNA glycosylase activities in seven hyperthermophiles; one bacterial: Thermotoga maritima, and six archaeal: Sulfolobus solfataricus, Sulfolobus shibatae, Sulfolobus acidocaldarius, Thermococcus litoralis, Pyrococcus furiosus and Pyrobaculum islandicum. Uracil-DNA glycosylase inhibitor protein of the Bacillus subtilis bacteriophage PBS1 shows activity against all of these, suggesting a highly conserved tertiary structure between hyperthermophilic and mesophilic uracil-DNA glycosylases

Steric hindrance regulation of the Pseudomonas aeruginosa amidase operon

Journal of Biological Chemistry2753930660-30667JBCH

Full spectrum of mental disorders linked with childhood residential mobility

AbstractAlthough links between childhood residential mobility and subsequently increased risks of psychopathology have been well documented, associations across the full spectrum of psychiatric disorders are unknown. We conducted a population-based study of all 1,439,363 persons born in Denmark during 1971–1997 to investigate relationships between childhood cross-municipality residential moves from year of birth to age 14 years and the development of a range of psychiatric disorders from mid-adolescence to early middle age. We examined: (1) Any substance misuse disorders; specifically alcohol misuse, and cannabis misuse; (2) Any personality disorders; specifically antisocial, and borderline personality disorders; (3) Schizophrenia and related disorders; specifically schizophrenia, and schizoaffective disorder; (4) Any mood disorders; specifically bipolar disorder, and depressive disorder; (5) Any anxiety and somatoform disorders; specifically obsessive compulsive disorder; (6) Any eating disorders; specifically anorexia nervosa. Childhood residential mobility was associated with elevated risks of developing most psychiatric disorders, even after controlling for potential confounders. The associations generally rose with increasing age at moving and were stronger for multiple moves in a year compared to a single move. Links were particularly strong for antisocial personality disorder, any substance misuse disorder, and cannabis misuse in particular, for which the highest increases in risks were observed if relocation occurred during adolescence. Childhood residential change was not linked to subsequent risk of developing an eating disorder. Frequent residential mobility could be a marker for familial adversities. Mental health services and schools need to be vigilant of the psychosocial needs of children, particularly adolescents, who have recently moved homes