p53FamTaG: a database resource of human p53, p63 and p73 direct target genes combining in silico prediction and microarray data

<p>Abstract</p> <p>Background</p> <p>The p53 gene family consists of the three genes p53, p63 and p73, which have polyhedral non-overlapping functions in pivotal cellular processes such as DNA synthesis and repair, growth arrest, apoptosis, genome stability, angiogenesis, development and differentiation. These genes encode sequence-specific nuclear transcription factors that recognise the same responsive element (RE) in their target genes. Their inactivation or aberrant expression may determine tumour progression or developmental disease. The discovery of several protein isoforms with antagonistic roles, which are produced by the expression of different promoters and alternative splicing, widened the complexity of the scenario of the transcriptional network of the p53 family members. Therefore, the identification of the genes transactivated by p53 family members is crucial to understand the specific role for each gene in cell cycle regulation. We have combined a genome-wide computational search of p53 family REs and microarray analysis to identify new direct target genes. The huge amount of biological data produced has generated a critical need for bioinformatic tools able to manage and integrate such data and facilitate their retrieval and analysis.</p> <p>Description</p> <p>We have developed the p53FamTaG database (p53 FAMily TArget Genes), a modular relational database, which contains p53 family direct target genes selected in the human genome searching for the presence of the REs and the expression profile of these target genes obtained by microarray experiments. p53FamTaG database also contains annotations of publicly available databases and links to other experimental data.</p> <p>The genome-wide computational search of the REs was performed using PatSearch, a pattern-matching program implemented in the DNAfan tool. These data were integrated with the microarray results we produced from the overexpression of different isoforms of p53, p63 and p73 stably transfected in isogenic cell lines, allowing the comparative study of the transcriptional activity of all the proteins in the same cellular background.</p> <p>p53FamTaG database is available free at <url>http://www2.ba.itb.cnr.it/p53FamTaG/</url></p> <p>Conclusion</p> <p>p53FamTaG represents a unique integrated resource of human direct p53 family target genes that is extensively annotated and provides the users with an efficient query/retrieval system which displays the results of our microarray experiments and allows the export of RE sequences. The database was developed for supporting and integrating high-throughput <it>in silico</it> and experimental analyses and represents an important reference source of knowledge for research groups involved in the field of oncogenesis, apoptosis and cell cycle regulation.</p

The association between weekly hours of physical activity and mental health: A three-year follow-up study of 15–16-year-old students in the city of Oslo, Norway

<p>Abstract</p> <p>Background</p> <p>Mental health problems are a worldwide public health burden. The literature concerning the mental health benefits from physical activity among adults has grown. Adolescents are less studied, and especially longitudinal studies are lacking. This paper investigates the associations between weekly hours of physical activity at age 15–16 and mental health three years later.</p> <p>Methods</p> <p>Longitudinal self-reported health survey. The baseline study consisted of participants from the youth section of the Oslo Health Study, carried out in schools in 2000–2001 (<it>n </it>= 3811). The follow-up in 2003–2004 was conducted partly at school and partly through mail. A total of 2489 (1112 boys and 1377 girls) participated in the follow-up. Mental health was measured by the Strengths and Difficulties Questionnaire with an impact supplement. Physical activity was measured by a question on weekly hours of physical activity outside of school, defined as exertion 'to an extent that made you sweat and/or out of breath'. Adjustments were made for well-documented confounders and mental health at baseline.</p> <p>Results</p> <p>In boys, the number of hours spent on physical activity per week at age 15–16 was negatively associated with emotional symptoms [B (95%CI) = -0.09 (-0.15, -0.03)] and peer problems [B (95%CI) = -0.08 (-0.14, -0.03)] at age 18–19 after adjustments. In girls, there were no significant differences in SDQ subscales at age 18–19 according to weekly hours of physical activity at age 15–16 after adjustments. Boys and girls with five to seven hours of physical activity per week at age 15–16 had the lowest mean scores for total difficulties and the lowest percentage with high impact score at age 18–19, but the differences were not statistically significant after adjustments.</p> <p>Conclusion</p> <p>Weekly hours of physical activity at age 15–16 years was weakly associated with mental health at three-year follow-up in boys. Results encourage a search for further knowledge about physical activity as a possible protective factor in relation to mental health problems in adolescence.</p

Preventive interventions in families with parental depression: children’s psychosocial symptoms and prosocial behaviour

The aim is to document the effectiveness of a preventive family intervention (Family Talk Intervention, FTI) and a brief psychoeducational discussion with parents (Let’s Talk about the Children, LT) on children’s psychosocial symptoms and prosocial behaviour in families with parental mood disorder, when the interventions are practiced in psychiatric services for adults in the finnish national health service. Patients with mood disorder were invited to participate with their families. Consenting families were randomized to the two intervention groups. The initial sample comprised 119 families and their children aged 8–16. Of these, 109 completed the interventions and the baseline evaluation. Mothers and fathers filled out questionnaires including standardized rating scales for children’s symptoms and prosocial behaviour at baseline and at 4, 10 and 18 months post-intervention. The final sample consisted of parental reports on 149 children with 83 complete data sets. Both interventions were effective in decreasing children’s emotional symptoms, anxiety, and marginally hyperactivity and in improving children’s prosocial behaviour. The FTI was more effective than the LT on emotional symptoms particularly immediately after the intervention, while the effect of the LT emerged after a longer interval. The study supports the effectiveness of both interventions in families with depressed parents. The FTI is applicable in cultural settings other than the USA. Our findings provide support for including preventive child mental health measures as part of psychiatric services for mentally ill parents

Characterization of Novel and Uncharacterized p53 SNPs in the Chinese Population – Intron 2 SNP Co-Segregates with the Common Codon 72 Polymorphism

Multiple single nucleotide polymorphisms (SNPs) have been identified in the tumor suppressor gene p53, though the relevance of many of them is unclear. Some of them are also differentially distributed in various ethnic populations, suggesting selective functionality. We have therefore sequenced all exons and flanking regions of p53 from the Singaporean Chinese population and report here the characterization of some novel and uncharacterized SNPs - four in intron 1 (nucleotide positions 8759/10361/10506/11130), three in intron 3 (11968/11969/11974) and two in the 3′UTR (19168/19514). Allelic frequencies were determined for all these and some known SNPs, and were compared in a limited scale to leukemia and lung cancer patient samples. Intron 2 (11827) and 7 (14181/14201) SNPs were found to have a high minor allele frequency of between 26–47%, in contrast to the lower frequencies found in the US population, but similar in trend to the codon 72 polymorphism (SNP12139) that shows a distribution pattern correlative with latitude. Several of the SNPs were linked, such as those in introns 1, 3 and 7. Most interestingly, we noticed the co-segregation of the intron 2 and the codon 72 SNPs, the latter which has been shown to be expressed in an allele-specific manner, suggesting possible regulatory cross-talk. Association analysis indicated that the T/G alleles in both the co-segregating intron 7 SNPs and a 4tagSNP haplotype was strongly associated increased susceptibility to lung cancer in non-smoker females [OR: 1.97 (1.32, 3.394)]. These data together demonstrate high SNP diversity in p53 gene between different populations, highlighting ethnicity-based differences, and their association with cancer risk

Comparing three short questionnaires to detect psychosocial dysfunction among primary school children: a randomized method

BACKGROUND: Good questionnaires are essential to support the early identification of children with psychosocial dysfunction in community based settings. Our aim was to assess which of three short questionnaires was most suitable for this identification among school-aged children METHODS: A community-based sample of 2,066 parents of children aged 7-12 years (85% of those eligible) filled out the Child Behavior Checklist (CBCL) and - randomly determined - one of three questionnaires to be compared: the Strengths and Difficulties Questionnaire with Impact Supplement (SDQ), the Pediatric Symptom Checklist (PSC) and the PSYBOBA, a Dutch-origin questionnaire. Preventive Child Healthcare professionals assessed children's psychosocial functioning during routine health examinations. We assessed the scale structure (by means of Structural Equation Modelling), validity (correlation coefficients, sensitivity and specificity) and usability (ratings by parents and professionals) of each questionnaire and the degree to which they could improve the identification based only on clinical assessment (logistic regression). RESULTS: For the three questionnaires, Cronbach's alphas varied between 0.80 and 0.89. Sensitivities for a clinical CBCL at a cut off point with specificity = 0.90 varied between 0.78 and 0.86 for the three questionnaires. Areas under the Receiver Operating Curve, using the CBCL as criterion, varied between 0.93 and 0.96. No differences were statistically significant. All three questionnaires added information to the clinical assessment. Odds ratios (95% confidence intervals) for added information were PSC: 29.3 (14.4-59.8), SDQ: 55.0 (23.1-131.2) and PSYBOBA: 68.5 (28.3-165.6). Parents preferred the SDQ and PSYBOBA. Preventive Child Health Care professionals preferred the SDQ. CONCLUSIONS: This randomized comparison of three questionnaires shows that each of the three questionnaires can improve the detection of psychosocial dysfunction among children substantially

An accurate and efficient identification of children with psychosocial problems by means of computerized adaptive testing

Background: Questionnaires used by health services to identify children with psychosocial problems are often rather short. The psychometric properties of such short questionnaires are mostly less than needed for an accurate distinction between children with and without problems. We aimed to assess whether a short Computerized Adaptive Test (CAT) can overcome the weaknesses of short written questionnaires when identifying children with psychosocial problems. Method: We used a Dutch national data set obtained from parents of children invited for a routine health examination by Preventive Child Healthcare with 205 items on behavioral and emotional problems (n = 2,041, response 84%). In a random subsample we determined which items met the requirements of an Item Response Theory (IRT) model to a sufficient degree. Using those items, item parameters necessary for a CAT were calculated and a cut-off point was defined. In the remaining subsample we determined the validity and efficiency of a Computerized Adaptive Test using simulation techniques, with current treatment status and a clinical score on the Total Problem Scale (TPS) of the Child Behavior Checklist as criteria. Results: Out of 205 items available 190 sufficiently met the criteria of the underlying IRT model. For 90% of the children a score above or below cut-off point could be determined with 95% accuracy. The mean number of items needed to achieve this was 12. Sensitivity and specificity with the TPS as a criterion were 0.89 and 0.91, respectively. Conclusion: An IRT-based CAT is a very promising option for the identification of psychosocial problems in children, as it can lead to an efficient, yet high-quality identification. The results of our simulation study need to be replicated in a real-life administration of this CAT

Fuzzy Tandem Repeats Containing p53 Response Elements May Define Species-Specific p53 Target Genes

Evolutionary forces that shape regulatory networks remain poorly understood. In mammals, the Rb pathway is a classic example of species-specific gene regulation, as a germline mutation in one Rb allele promotes retinoblastoma in humans, but not in mice. Here we show that p53 transactivates the Retinoblastoma-like 2 (Rbl2) gene to produce p130 in murine, but not human, cells. We found intronic fuzzy tandem repeats containing perfect p53 response elements to be important for this regulation. We next identified two other murine genes regulated by p53 via fuzzy tandem repeats: Ncoa1 and Klhl26. The repeats are poorly conserved in evolution, and the p53-dependent regulation of the murine genes is lost in humans. Our results indicate a role for the rapid evolution of tandem repeats in shaping differences in p53 regulatory networks between mammalian species

Dimensions and Latent Classes of Episodic Mania-Like Symptoms in Youth: An Empirical Enquiry

The dramatic increase in diagnostic rates of bipolar disorder in children and adolescents in the USA has led to an intense interest in the phenomenology of the disorder. Here we present data from a newly-developed instrument to assess episodic mania-like symptoms in youth in a large population-based sample (N = 5326) using parent- and self-report. We found that a substantial proportion of children screened positive for having episodes of “going high” and were at an increased risk for morbidity and impairment. Using factor analysis, we identified that episodic mania-like symptoms comprised two dimensions: An under-controlled dimension that was associated with significant impairment, and a low-risk exuberant dimension. Using latent class analysis, we identified a small group of children scoring high on a range of manic symptoms and suffering from severe psychosocial impairment and morbidity. Our results carry implications for the nosology and psychosocial impairment associated with episodic mood changes in young people

Metabolic regulation by p53

We are increasingly aware that cellular metabolism plays a vital role in diseases such as cancer, and that p53 is an important regulator of metabolic pathways. By transcriptional activation and other means, p53 is able to contribute to the regulation of glycolysis, oxidative phosphorylation, glutaminolysis, insulin sensitivity, nucleotide biosynthesis, mitochondrial integrity, fatty acid oxidation, antioxidant response, autophagy and mTOR signalling. The ability to positively and negatively regulate many of these pathways, combined with feedback signalling from these pathways to p53, demonstrates the reciprocal and flexible nature of the regulation, facilitating a diverse range of responses to metabolic stress. Intriguingly, metabolic stress triggers primarily an adaptive (rather than pro-apoptotic) p53 response, and p53 is emerging as an important regulator of metabolic homeostasis. A better understanding of how p53 coordinates metabolic adaptation will facilitate the identification of novel therapeutic targets and will also illuminate the wider role of p53 in human biology

Psychometric Properties of the Parent and Teacher Versions of the Strengths and Difficulties Questionnaire for 4- to 12-Year-Olds: A Review

Since its development, the Strengths and Difficulties Questionnaire (SDQ) has been widely used in both research and practice. The SDQ screens for positive and negative psychological attributes. This review aims to provide an overview of the psychometric properties of the SDQ for 4- to 12-year-olds. Results from 48 studies (N = 131,223) on reliability and validity of the parent and teacher SDQ are summarized quantitatively and descriptively. Internal consistency, test–retest reliability, and inter-rater agreement are satisfactory for the parent and teacher versions. At subscale level, the reliability of the teacher version seemed stronger compared to that of the parent version. Concerning validity, 15 out of 18 studies confirmed the five-factor structure. Correlations with other measures of psychopathology as well as the screening ability of the SDQ are sufficient. This review shows that the psychometric properties of the SDQ are strong, particularly for the teacher version. For practice, this implies that the use of the SDQ as a screening instrument should be continued. Longitudinal research studies should investigate predictive validity. For both practice and research, we emphasize the use of a multi-informant approach