Unexpected cell type-dependent effects of autophagy on polyglutamine aggregation revealed by natural genetic variation in C. elegans.

BACKGROUND: Monogenic protein aggregation diseases, in addition to cell selectivity, exhibit clinical variation in the age of onset and progression, driven in part by inter-individual genetic variation. While natural genetic variants may pinpoint plastic networks amenable to intervention, the mechanisms by which they impact individual susceptibility to proteotoxicity are still largely unknown. RESULTS: We have previously shown that natural variation modifies polyglutamine (polyQ) aggregation phenotypes in C. elegans muscle cells. Here, we find that a genomic locus from C. elegans wild isolate DR1350 causes two genetically separable aggregation phenotypes, without changing the basal activity of muscle proteostasis pathways known to affect polyQ aggregation. We find that the increased aggregation phenotype was due to regulatory variants in the gene encoding a conserved autophagy protein ATG-5. The atg-5 gene itself conferred dosage-dependent enhancement of aggregation, with the DR1350-derived allele behaving as hypermorph. Surprisingly, increased aggregation in animals carrying the modifier locus was accompanied by enhanced autophagy activation in response to activating treatment. Because autophagy is expected to clear, not increase, protein aggregates, we activated autophagy in three different polyQ models and found a striking tissue-dependent effect: activation of autophagy decreased polyQ aggregation in neurons and intestine, but increased it in the muscle cells. CONCLUSIONS: Our data show that cryptic natural variants in genes encoding proteostasis components, although not causing detectable phenotypes in wild-type individuals, can have profound effects on aggregation-prone proteins. Clinical applications of autophagy activators for aggregation diseases may need to consider the unexpected divergent effects of autophagy in different cell types

Cross-lagged associations between depressive symptoms and response style in adolescents

Depressive disorders are highly prevalent during adolescence and they are a major concern for individuals and society. The Response Style Theory and the Scar Theory both suggest a relationship between response styles and depressive symptoms, but the theories differ in the order of the development of depressive symptoms. Longitudinal reciprocal prospective relationships between depressive symptoms and response styles were examined in a community sample of 1343 adolescents. Additionally, response style was constructed with the traditional approach, which involves examining three response styles separately without considering the possible relations between them, and with the ratio approach, which accounts for all three response styles simultaneously. No reciprocal relationships between depressive symptoms and response style were found over time. Only longitudinal relationships between response style and depressive symptoms were significant. This study found that only depressive symptoms predicted response style, whereas the response style did not emerge as an important underlying mechanism responsible for developing and maintaining depressive symptoms in adolescents. These findings imply that prevention and intervention programs for adolescents with low depressive symptoms should not focus on adaptive and maladaptive response style strategies to decrease depressive symptoms, but should focus more on behavioral interventions

Народное образование крымских татар в конце XIX - начале XX вв.: история и опыт в свете модернизации высшего образования Украины

Процесс модернизации высшего образования Украины проходит параллельно с процессом интеграции крымскотатарского населения в гражданское общество Украины.Процес модернізації вищого утворення України проходить паралельно з процесом інтеграції кримськотатарського населення в цивільне суспільство України

Self-control and early adolescent antisocial behavior: A longitudinal analysis

Contains fulltext : 73179.pdf (publisher's version ) (Closed access)The article discusses a three-wave longitudinal study that investigates the relationship between self-control and aggressive and delinquent behavior of early adolescent boys and girls. The sample consists of 1,012 Dutch adolescents (mean age = 12.3) in their first year of secondary education. Structural equation modeling analyses reveal that high levels of self-control consistently decrease aggressive and delinquent behavior in the subsequent 6 months follow-up intervals. Results for the total sample do not support the hypothesis that self-control is influenced by previous levels of aggression or delinquency. For boys, the partial evidence found indicates reciprocal effects of self-control and delinquency.21 p

Decreased Mitochondrial DNA Mutagenesis in Human Colorectal Cancer

Genome instability is regarded as a hallmark of cancer. Human tumors frequently carry clonally expanded mutations in their mitochondrial DNA (mtDNA), some of which may drive cancer progression and metastasis. The high prevalence of clonal mutations in tumor mtDNA has commonly led to the assumption that the mitochondrial genome in cancer is genetically unstable, yet this hypothesis has not been experimentally tested. In this study, we directly measured the frequency of non-clonal (random) de novo single base substitutions in the mtDNA of human colorectal cancers. Remarkably, tumor tissue exhibited a decreased prevalence of these mutations relative to adjacent non-tumor tissue. The difference in mutation burden was attributable to a reduction in C∶G to T∶A transitions, which are associated with oxidative damage. We demonstrate that the lower random mutation frequency in tumor tissue was also coupled with a shift in glucose metabolism from oxidative phosphorylation to anaerobic glycolysis, as compared to non-neoplastic colon. Together these findings raise the intriguing possibility that fidelity of mitochondrial genome is, in fact, increased in cancer as a result of a decrease in reactive oxygen species-mediated mtDNA damage

Replication Pauses of the Wild-Type and Mutant Mitochondrial DNA Polymerase Gamma: A Simulation Study

The activity of polymerase γ is complicated, involving both correct and incorrect DNA polymerization events, exonuclease activity, and the disassociation of the polymerase:DNA complex. Pausing of pol-γ might increase the chance of deletion and depletion of mitochondrial DNA. We have developed a stochastic simulation of pol-γ that models its activities on the level of individual nucleotides for the replication of mtDNA. This method gives us insights into the pausing of two pol-γ variants: the A467T substitution that causes PEO and Alpers syndrome, and the exonuclease deficient pol-γ (exo−) in premature aging mouse models. To measure the pausing, we analyzed simulation results for the longest time for the polymerase to move forward one nucleotide along the DNA strand. Our model of the exo− polymerase had extremely long pauses, with a 30 to 300-fold increase in the time required for the longest single forward step compared to the wild-type, while the naturally occurring A467T variant showed at most a doubling in the length of the pauses compared to the wild-type. We identified the cause of these differences in the polymerase pausing time to be the number of disassociations occurring in each forward step of the polymerase

Stochastic Drift in Mitochondrial DNA Point Mutations: A Novel Perspective Ex Silico

The mitochondrial free radical theory of aging (mFRTA) implicates Reactive Oxygen Species (ROS)-induced mutations of mitochondrial DNA (mtDNA) as a major cause of aging. However, fifty years after its inception, several of its premises are intensely debated. Much of this uncertainty is due to the large range of values in the reported experimental data, for example on oxidative damage and mutational burden in mtDNA. This is in part due to limitations with available measurement technologies. Here we show that sample preparations in some assays necessitating high dilution of DNA (single molecule level) may introduce significant statistical variability. Adding to this complexity is the intrinsically stochastic nature of cellular processes, which manifests in cells from the same tissue harboring varying mutation load. In conjunction, these random elements make the determination of the underlying mutation dynamics extremely challenging. Our in silico stochastic study reveals the effect of coupling the experimental variability and the intrinsic stochasticity of aging process in some of the reported experimental data. We also show that the stochastic nature of a de novo point mutation generated during embryonic development is a major contributor of different mutation burdens in the individuals of mouse population. Analysis of simulation results leads to several new insights on the relevance of mutation stochasticity in the context of dividing tissues and the plausibility of ROS ”vicious cycle” hypothesis

Randomized control trial testing the effectiveness of implemented depression prevention in high-risk adolescents

BACKGROUND: Adolescent depression is a global mental health concern. Identification and effective prevention in an early stage are necessary. The present randomized, controlled trial aimed to examine the effectiveness of Cognitive Behavioral Therapy (CBT)-based depression prevention in adolescents with elevated depressive symptoms. This prevention approach is implemented in school communities, which allows to examine effects under real-life circumstances. METHODS: A total of 5222 adolescents were screened for elevated depressive symptoms in the second grade of secondary schools; 130 adolescents aged between 12 and 16 years old (M = 13.59; SD = 0.68; 63.8% girls) were randomly assigned to the experimental (OVK 2.0) or control condition (psycho-education). Self- and parent-reported depressive symptoms were assessed at pretest and post intervention, as well as 6- and 12-months follow-up. Clinical assessment of depression was assessed at pretest and 6-months follow-up. RESULTS: Intent-to-treat analyses revealed that the decrease in adolescent-rated depressive symptoms was significantly larger in the intervention condition than in the control condition. There was no significant difference in decrease of parent-rated depressive symptoms between both conditions. CONCLUSIONS: Based on the findings, we recommend the implementation of screening and prevention in schools, according the basics of this study design. Since this is a new step forward, we discuss the clinical impact and challenges, as well possibilities for future research. TRIAL REGISTRATION: The s