Comprehensive genomic screens identify a role for PLZF-RAR alpha as a positive regulator of cell proliferation via direct regulation of c-MYC

The t(11; 17)(q23;q21) translocation is associated with a retinoic acid (RA)-insensitive form of acute promyelocytic leukemia (APL), involving the production of reciprocal fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor alpha (PLZF-RAR alpha) and RAR alpha-PLZF. Using a combination of chromatin immuno-precipitation promotor arrays (ChIP-chip) and gene expression profiling, we identify novel, direct target genes of PLZF-RAR alpha that tend to be repressed in APL compared with other myeloid leukemias, supporting the role of PLZF-RAR alpha as an aberrant repressor in APL. In primary murine hematopoietic progenitors, PLZF-RAR alpha promotes cell growth, and represses Dusp6 and Cdkn2d, while inducing c-Myc expression, consistent with its role in leukemogenesis. PLZF-RAR alpha binds to a region of the c-MYC promoter overlapping a functional PLZF site and antagonizes PLZF-mediated repression, suggesting that PLZF-RAR alpha may act as a dominant-negative version of PLZF by affecting the regulation of shared targets. RA induced the differentiation of PLZF-RAR alpha-transformed murine hematopoietic cells and reduced the frequency of clonogenic progenitors, concomitant with c-Myc down-regulation. Surviving RA-treated cells retained the ability to be replated and this was associated with sustained c-Myc expression and repression of Dusp6, suggesting a role for these genes in maintaining a self-renewal pathway triggered by PLZF-RAR alpha. (Blood. 2009; 114: 5499-5511)

Synthesis and SAR of centrally active mGlu(5) positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu(5) receptor. 'Molecular switches' were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical model that shows similar positive effects with known antipsychotic agents. Published by Elsevier Ltd.

Realising political equality: the European Court of Human Rights and positive obligations in a democracy'

The European Convention on Human Rights (ECHR) speaks of the importance of an “effective political democracy” in its Preamble, though it is only in Article 3 of Protocol 1 (P1-3) that we find a right to free elections. This paper discusses the role of “positive obligations” under P1-3. This paper outlines the positive obligations in P1-3 focusing on obligations where the state is required to do more than just change the law. This may mean providing resources or facilities, adopting regulatory frameworks or creating new institutions. The paper highlights specific positive obligations that need to be further developed in the jurisprudence of the European Court of Human Rights (ECtHR). Sometimes these can be developed by analogy with positive obligations recognised in other areas of ECtHR jurisprudence. However, beyond these cases, states should ensure that members of vulnerable and disadvantaged minorities are able to participate in the electoral process and should ensure that dominant political groups cannot abuse their political power to exclude other parties unfairly. This is necessary to realise equal political rights. The second section of this paper sketches some preliminary points about the Strasbourg institutions’ approach to P1-3. After that, the third section identifies circumstances where the ECtHR should apply a more intense scrutiny in P1-3 cases. The fourth, fifth and sixth sections look at positive obligations relating to the right to vote, the right to run for election and the regulation of political parties.

Parenting stress and children with cerebral palsy: A European cross-sectional survey

Aim
The aim of this study was to describe stress in the parents of children with cerebral palsy and investigate associations with very high stress.

Method
A cross-sectional survey was conducted of parents of 818 children aged 8 to 12 years from nine regions in Europe. Families were eligible to participate if they were living in one of the specified geographic areas. Parental stress was captured using the Parenting Stress Index Short Form, which has 36 items and takes 10 minutes to complete. Parents rate items on a 5-point Likert scale, with higher scores indicating higher stress. The Short Form yields scores on three subscales and a Total Stress score. A trained research associate administered the questionnaire in the child’s home and visits lasted 90 to 120 minutes. All data collected were reported by parents unless otherwise stated.

Results
The Total Stress score on the Parenting Stress Index was dichotomized into scores of less than 99 or 99 or more, the latter indicating ‘very high’ stress. Most respondents were mothers (94%), and 26% reported very high stress levels. The parents of children with communication impairment had higher odds for very high stress (odds ratio [OR] 1.9; 95% confidence interval [CI] 1.2–3.0) than those whose child had no such impairment; the parents of children with moderate or severe pain had higher odds for very high stress (OR 1.7 [95% CI 1.1–2.4] and 2.5 [95% CI 1.5–4.3] respectively) than those whose child had no pain; and the parents of children with an intellectual impairment had higher odds for very high stress (OR 1.8; 95% CI 1.2–2.9) than those whose child had none. There was no association between very high stress and motor impairment. The subscales ‘parent–child dysfunctional interaction’ and ‘difficult child’ contributed most to the Total Stress score.

Interpretation
Parents of children with communication difficulties, intellectual impairment, or pain are at very high risk of stress. The final model explained 12% of the observed variation in very high stress.

Large acoustic solitons and double layers in plasmas with two positive ion species

Large nonlinear acoustic waves are discussed in a plasma made up of cold supersonic and adiabatic subsonic positive ions, in the presence of hot isothermal electrons, with the help of Sagdeev pseudopotential theory. In this model, no solitons are found at the acoustic speed, and no compositional parameter ranges exist where solutions of opposite polarities can coexist. All nonlinear modes are thus super-acoustic, but polarity changes are possible. The upper limits on admissible structure velocities come from different physical arguments, in a strict order when the fractional cool ion density is increased: infinite cold ion compression, warm ion sonic point, positive double layers, negative double layers, and finally, positive double layers again. However, not all ranges exist for all mass and temperature ratios. Whereas the cold and warm ion sonic point limitations are always present over a wide range of mass and temperature ratios, and thus positive polarity solutions can easily be obtained, double layers have a more restricted existence range, specially if polarity changes are sought. (C) 2011 American Institute of Physics. [doi:10.1063/1.3579397]

School-related predictors of smoking, drinking and drug use: Evidence from the Belfast Youth Development Study

Objective

To examine whether students’ school engagement, relationships with teachers, educational aspirations and involvement in fights at school are associated with various measures of subsequent substance use.
Methods

Data were drawn from the Belfast Youth Development Study (n = 2968). Multivariate logistic models examined associations between school-related factors (age 13/14) and substance use (age 15/16).
Results

The two factors which were consistently and independently associated with regular substance use among both males and females were student–teacher relationships and fighting at school: positive teacher-relationships reduced the risk of daily smoking by 48%, weekly drunkenness by 25%, and weekly cannabis use by 52%; being in a fight increased the risk of daily smoking by 54%, weekly drunkenness by 31%, and weekly cannabis use by 43%. School disengagement increased the likelihood of smoking and cannabis use among females only.
Conclusion

Further research should focus on public health interventions promoting positive relationships and safety at school.

Parenting Control in Contexts of Political Violence: Testing Bidirectional Relations Between Violence Exposure and Control in Post-Accord Belfast

Objective. The authors examined bidirectional relations between youth exposure to sectarian and nonsectarian antisocial behavior and mothers' efforts to control youths' exposure to community violence in Belfast, Northern Ireland. Design. Mother-child dyads (N = 773) were interviewed in their homes twice over 2 years regarding youths' exposure to sectarian and nonsectarian community antisocial behavior and mothers' use of control strategies, including behavioral and psychological control. Results. Youths' exposure to nonsectarian antisocial behavior was related to increases in mothers' use of behavioral and psychological control strategies over time, controlling for earlier levels of these constructs. Reflecting bidirectional relations, mothers' behavioral control strategies were associated with youths' reduced exposure to nonsectarian and sectarian antisocial behavior over time, whereas psychological control was not related to reduced exposure. Conclusion. Only nonsectarian community violence was associated longitudinally with mothers' increased use of control strategies, and only behavioral control strategies were effective in reducing youths' exposure to community antisocial behavior, including sectarian and nonsectarian antisocial behavior.

Cross-Cultural Patterns in Dynamic Ratings of Positive and Negative Natural Emotional Behaviour

Background: Studies of cross-cultural variations in the perception of emotion have typically compared rates of recognition of static posed stimulus photographs. That research has provided evidence for universality in the recognition of a range of emotions but also for some systematic cross-cultural variation in the interpretation of emotional expression. However, questions remain about how widely such findings can be generalised to real life emotional situations. The present study provides the first evidence that the previously reported interplay between universal and cultural influences extends to ratings of natural, dynamic emotional stimuli.

Methodology/Principal Findings: Participants from Northern Ireland, Serbia, Guatemala and Peru used a computer based tool to continuously rate the strength of positive and negative emotion being displayed in twelve short video sequences by people from the United Kingdom engaged in emotional conversations. Generalized additive mixed models were developed to assess the differences in perception of emotion between countries and sexes. Our results indicate that the temporal pattern of ratings is similar across cultures for a range of emotions and social contexts. However, there are systematic differences in intensity ratings between the countries, with participants from Northern Ireland making the most extreme ratings in the majority of the clips.

Conclusions/Significance: The results indicate that there is strong agreement across cultures in the valence and patterns of ratings of natural emotional situations but that participants from different cultures show systematic variation in the intensity with which they rate emotion. Results are discussed in terms of both ‘in-group advantage’ and ‘display rules’ approaches. This study indicates that examples of natural spontaneous emotional behaviour can be used to study cross-cultural variations in the perception of emotion.

Regarding “Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor-positive early breast cancer patients”

We read the interesting research article published by van Nes et al. [1], which described the use of Snail and TWIST together in the prognosis of breast cancer, and in particular in estrogen receptor (ER)-positive breast cancer patients.

The Association of Ownership Type With Job Insecurity and Worry About Job Stability The Moderating Effects of Fair Management, Positive Leadership, and Employment Type

This study examined whether the ownership type is associated with job insecurity and worry about job stability and whether the type of employment contract, positive leadership, and fair management moderated these associations. Survey data from 1249 Finnish female elderly care staff aged 18 to 69 years were used. Job insecurity and worry about job stability were highest in not-for-profit sheltered homes. However, positive leadership and fair management were able to mitigate this insecurity and worry. Job insecurity was highest among fixed-term employees in public sheltered homes or not-for-profit nursing homes. Thus, promoting good leadership and fair management would be of importance.