Longitudinal self-concept development in adolescence

This longitudinal behavioral neuroimaging study tested two hypotheses concerning self-concept development in adolescence: domain-specific self-concept and similarity between own (direct) and perceived peers’ (reflected) opinions of the self. Participants (N = 189; 10–24 years) evaluated their traits in academic, physical appearance and prosocial domains from direct and reflected perspectives in an functional magnetic resonance imaging session across three time points (TP1: n = 160; TP2: n = 151; TP3: n = 144). Behaviorally, we observed a mid-adolescent dip in self-concept positivity, which was strongest for the academic domain, showing domain differentiation in mid-adolescence. Self-evaluations were associated with activity in, e.g. medial prefrontal cortex (mPFC) and temporal–parietal junction (TPJ). mPFC showed an adolescent-emerging peak in activation, pronounced more for direct than reflected self-evaluations. TPJ activation was generally stronger for reflected self-evaluations, and activation linearly increased with age for both reflected and direct self-evaluations. Longitudinal prediction analyses showed that positivity of self-evaluations predicted increases in self-concept clarity and less fear of negative evaluation 1 and 2 years later, highlighting the developmental benefits of acquiring a positive self-concept. Together, we show that adolescent self-development is characterized by dissociable neural patterns underlying self-evaluations in different domains, and from reflected and direct perspectives, confirming adolescence as a formative phase for developing a coherent and positive self-concept.</p

Longitudinal associations between structural prefrontal cortex and nucleus accumbens development and daily identity formation processes across adolescence

We tested whether adolescents with daily high identity uncertainty showed differential structural brain development across adolescence and young adulthood. Participants (N = 150, MageT1 15.92 years) were followed across three waves, covering 4 years. Self-reported daily educational identity and structural brain data of lateral prefrontal cortex (lPFC)/anterior cingulate cortex (ACC), medial PFC, and nucleus accumbens (NAcc) was collected across three waves. All hypotheses were pre-registered. Latent class growth analyses confirmed 2 identity subgroups: an identity synthesis class (characterized by strong commitments, and low uncertainty), and an identity moratorium class (high daily identity uncertainty). Latent growth curve models revealed, on average, delayed maturation of the lateral PFC/ACC and medial PFC and stable NAcc. Yet, adolescents in identity moratorium showed lower levels and less decline in NAcc gray matter volume. Lateral PFC/ACC and medial PFC trajectories did not differ between identity subgroups. Exploratory analyses revealed that adolescents with higher baseline levels and delayed maturation of lateral PFC/ACC and medial PFC gray matter volume, surface area, and cortical thickness reported higher baseline levels and stronger increases of in-depth exploration. These results provide insight into how individual differences in brain develop

hTERT promoter activity and CpG methylation in HPV-induced carcinogenesis

<p>Abstract</p> <p>Background</p> <p>Activation of telomerase resulting from deregulated hTERT expression is a key event during high-risk human papillomavirus (hrHPV)-induced cervical carcinogenesis. In the present study we examined hTERT promoter activity and its relation to DNA methylation as one of the potential mechanisms underlying deregulated hTERT transcription in hrHPV-transformed cells.</p> <p>Methods</p> <p>Using luciferase reporter assays we analyzed hTERT promoter activity in primary keratinocytes, HPV16- and HPV18-immortalized keratinocyte cell lines and cervical cancer cell lines. In the same cells as well as cervical specimens we determined hTERT methylation by bisulfite sequencing analysis of the region spanning -442 to +566 (relative to the ATG) and quantitative methylation specific PCR (qMSP) analysis of two regions flanking the hTERT core promoter.</p> <p>Results</p> <p>We found that in most telomerase positive cells increased hTERT core promoter activity coincided with increased hTERT mRNA expression. On the other hand basal hTERT promoter activity was also detected in telomerase negative cells with no or strongly reduced hTERT mRNA expression levels. In both telomerase positive and negative cells regulatory sequences flanking both ends of the core promoter markedly repressed exogenous promoter activity.</p> <p>By extensive bisulfite sequencing a strong increase in CpG methylation was detected in hTERT positive cells compared to cells with no or strongly reduced hTERT expression. Subsequent qMSP analysis of a larger set of cervical tissue specimens revealed methylation of both regions analyzed in 100% of cervical carcinomas and 38% of the high-grade precursor lesions, compared to 9% of low grade precursor lesions and 5% of normal controls.</p> <p>Conclusions</p> <p>Methylation of transcriptionally repressive sequences in the hTERT promoter and proximal exonic sequences is correlated to deregulated hTERT transcription in HPV-immortalized cells and cervical cancer cells. The detection of DNA methylation at these repressive regions may provide an attractive biomarker for early detection of cervical cancer.</p

Polo-Like Kinase-1 Controls Aurora A Destruction by Activating APC/C-Cdh1

Polo-like kinase-1 (Plk1) is activated before mitosis by Aurora A and its cofactor Bora. In mitosis, Bora is degraded in a manner dependent on Plk1 kinase activity and the E3 ubiquitin ligase SCF-βTrCP. Here, we show that Plk1 is also required for the timely destruction of its activator Aurora A in late anaphase. It has been shown that Aurora A destruction is controlled by the auxiliary subunit Cdh1 of the Anaphase-Promoting Complex/Cyclosome (APC/C). Remarkably, we found that Plk1-depletion prevented the efficient dephosphorylation of Cdh1 during mitotic exit. Plk1 mediated its effect on Cdh1, at least in part, through direct phosphorylation of the human phosphatase Cdc14A, controlling the phosphorylation state of Cdh1. We conclude that Plk1 facilitates efficient Aurora A degradation through APC/C-Cdh1 activation after mitosis, with a potential role for hCdc14A

Re-emerging antimetabolites with novel mechanism of action with respect to epigenetic regulation: Basic aspects

Azacitidine (AzaC) and decitabine (DAC) are epigenetic modulators, which are used for treatment of several hematological malignancies. The epigenetic mode of action of these compounds comprises reduction of DNA methylation by inhibition of DNA methyltransferases (DNMTs), which include the maintenance DNA methyltransferase 1 and de novo methyltransferase DNMT3A and DNMT3B. This property leads to a decrease in CpG island methylation and a reactivation of tumor suppressor genes that are silenced by promoter hypermeth- ylation, thereby contributing to the anti-tumor effect. Insight in the mechanisms of action of these drugs is essential for our understanding how synthetic epigenetic modulators can affect cellular processes. In this review the intracellular metabolism of these cytidine analogs and some novel cytidine analogs are summarized. In addition, the mechanism of DNMT downregulation is discussed, which besides the incorporation of modified nucleotides into the DNA, more recently was also shown to involve proteasomal degradation