Sequestration of Highly Expressed mRNAs in Cytoplasmic Granules, P-Bodies, and Stress Granules Enhances Cell Viability

Transcriptome analyses indicate that a core 10%–15% of the yeast genome is modulated by a variety of different stresses. However, not all the induced genes undergo translation, and null mutants of many induced genes do not show elevated sensitivity to the particular stress. Elucidation of the RNA lifecycle reveals accumulation of non-translating mRNAs in cytoplasmic granules, P-bodies, and stress granules for future regulation. P-bodies contain enzymes for mRNA degradation; under stress conditions mRNAs may be transferred to stress granules for storage and return to translation. Protein degradation by the ubiquitin-proteasome system is elevated by stress; and here we analyzed the steady state levels, decay, and subcellular localization of the mRNA of the gene encoding the F-box protein, UFO1, that is induced by stress. Using the MS2L mRNA reporter system UFO1 mRNA was observed in granules that colocalized with P-bodies and stress granules. These P-bodies stored diverse mRNAs. Granules of two mRNAs transported prior to translation, ASH1-MS2L and OXA1-MS2L, docked with P-bodies. HSP12 mRNA that gave rise to highly elevated protein levels was not observed in granules under these stress conditions. ecd3, pat1 double mutants that are defective in P-body formation were sensitive to mRNAs expressed ectopically from strong promoters. These highly expressed mRNAs showed elevated translation compared with wild-type cells, and the viability of the mutants was strongly reduced. ecd3, pat1 mutants also exhibited increased sensitivity to different stresses. Our interpretation is that sequestration of highly expressed mRNAs in P-bodies is essential for viability. Storage of mRNAs for future regulation may contribute to the discrepancy between the steady state levels of many stress-induced mRNAs and their proteins. Sorting of mRNAs for future translation or decay by individual cells could generate potentially different phenotypes in a genetically identical population and enhance its ability to withstand stress

Personal values and involvement in problem behaviors among Bahamian early adolescents: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Few studies, particularly in developing countries, have explored the relationship between adolescents and parental values with adolescent problem behaviors. The objectives of the study are to (1) describe adolescents' personal values, their problem behaviors, and the relationships thereof according to gender and (2) examine the relationship between parental values, adolescent values, and adolescents' problem behaviors among sixth-grade students and one of their parents.</p> <p>Methods</p> <p>The data used in these analyses were from the baseline assessment of a school-based HIV risk reduction intervention being conducted and evaluated among sixth grade students and one of their parents across 9 elementary schools in The Bahamas. Personal values were measured by the Portrait Values Questionnaire (PVQ). Seven reported problem behaviors were queried from the students, which included physical fight with a friend, drank alcohol, beer, or wine, smoked a cigarette, pushed or carried any drugs, carried a gun, knife, screwdriver or cutlass to use as a weapon, had sex and used marijuana or other illicit drugs over the past 6 months. Multilevel modeling for binary data was performed to estimate the associations between adolescent and parental values and adolescent problem behaviors.</p> <p>Results</p> <p>Among 785 students, 47% of the students reported at least one problem behavior. More boys (54%) reported having one or more problem behaviors than girls (41%, p < 0.01). Boys compared to girls expressed a higher level of self-enhancement (means score: 36.5 vs. 35.1; p = 0.03), while girls expressed a higher level of self-transcendence (42.3 vs. 40.7; p = 0.03). The results of multilevel modeling indicates that boys with a higher level of self-enhancement and girls with a higher level of openness to change and a lower level of conservation were more likely to report engagement in problem behaviors. Only two parental values (self-transcendence and conservation) were low or modestly correlated with youth' values (openness to change and self-enhancement). Parental-reported values documented limited association on adolescents' reported values and behaviors.</p> <p>Conclusion</p> <p>In designing interventions for reducing adolescents' problem behaviors, it may be important to understand the values associated with specific problem behaviors. Further exploration regarding lack of association between adolescent and parental values and problem behaviors is needed.</p

Dynamic changes in eIF4F-mRNA interactions revealed by global analyses of environmental stress responses

BACKGROUND: Translation factors eIF4E and eIF4G form eIF4F, which interacts with the messenger RNA (mRNA) 5' cap to promote ribosome recruitment and translation initiation. Variations in the association of eIF4F with individual mRNAs likely contribute to differences in translation initiation frequencies between mRNAs. As translation initiation is globally reprogrammed by environmental stresses, we were interested in determining whether eIF4F interactions with individual mRNAs are reprogrammed and how this may contribute to global environmental stress responses. RESULTS: Using a tagged-factor protein capture and RNA-sequencing (RNA-seq) approach, we have assessed how mRNA associations with eIF4E, eIF4G1 and eIF4G2 change globally in response to three defined stresses that each cause a rapid attenuation of protein synthesis: oxidative stress induced by hydrogen peroxide and nutrient stresses caused by amino acid or glucose withdrawal. We find that acute stress leads to dynamic and unexpected changes in eIF4F-mRNA interactions that are shared among each factor and across the stresses imposed. eIF4F-mRNA interactions stabilised by stress are predominantly associated with translational repression, while more actively initiating mRNAs become relatively depleted for eIF4F. Simultaneously, other mRNAs are insulated from these stress-induced changes in eIF4F association. CONCLUSION: Dynamic eIF4F-mRNA interaction changes are part of a coordinated early translational control response shared across environmental stresses. Our data are compatible with a model where multiple mRNA closed-loop complexes form with differing stability. Hence, unexpectedly, in the absence of other stabilising factors, rapid translation initiation on mRNAs correlates with less stable eIF4F interactions

Youth in the Netherlands Study (JOiN): study design

Background: Adolescence is a critical developmental period regarding exposure to substances. Therefore, it is important to be able to identify those adolescents who are most vulnerable to substance abuse in the (near) future. The JOiN study was specifically designed to examine two endophenotypes of adolescent substance use in a normal risk (NR) and high risk (HR) sample of adolescents: (1) behavioural disinhibition, and (2) individual differences in stress sensitivity. Methods: The NR adolescents were part of a longitudinal general population study at the Erasmus Medical Center in Rotterdam, the Netherlands of children and adolescents initially aged 6 to 18 years old. Three assessment waves have been nearly completed, and data are available of N = 711 participants for stress sensitivity measures, and of a subsample of N = 110 for electroencephalography (EEG) measures. Added to this study, HR adolescents who had at least one parent with a substance use disorder and who were treated by an outpatient clinic of a primary addiction care provider were approached via their parent(s). In total, N = 83 adolescents formed this HR sample. NR and HR adolescents participated in standardized stress procedure and EEG procedures in our laboratory. Questionnaires were filled out on background variables, behavioural and emotional problems, and substance use, and a diagnostic interview was conducted with adolescents and parents to assess psychopathology symptoms. DNA was collected through saliva or blood samples. Discussion: The design of the JOiN study is optimal for examining the predictive role of endophenotypes of adolescent substance use. The combination of different methods, i.e. stress physiology, electrophysiology, genetics, and questionnaire data from several informants on a range of behaviours and environmental factors enables the investigation of the multifactorial nature of adolescent substance use

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe