Sleep, anxiety and challenging behaviour in children with intellectual disability and/or autism spectrum disorder

Children with an intellectual disability (ID) and/or autism spectrum disorder (ASD) are known to suffer from significantly more sleep problems, anxiety and challenging behaviour (CB) than typically developing children (TD), yet little is known about the relationship between these factors in the child ID/ASD population. The study aim was to examine these relationships. We hypothesised that there would be significant positive correlations between the three factors and that sleep problems and anxiety would predict a significant amount of the variance in levels of CB. Parental measures of sleep problems, anxiety and CB were completed by 187 parents of children with ID and/or ASD. Significant positive associations were found between the three factors. A hierarchical multiple regression showed that medication, sleep problems and anxiety accounted for 42% of the variance in CB, with a large effect size. These findings suggest that these relationships should be considered during clinical practice, particularly in the case of CB interventions where sleep problems and/or anxiety are also present

Regulation of mature mRNA levels by RNA processing efficiency

Transcription and co-transcriptional processes, including pre-mRNA splicing and mRNA cleavage and polyadenylation, regulate the production of mature mRNAs. The carboxyl terminal domain (CTD) of RNA polymerase (pol) II, which comprises 52 repeats of the Tyr1Ser2Pro3Thr4Ser5Pro6Ser7 peptide, is involved in the coordination of transcription with co-transcriptional processes. The pol II CTD is dynamically modified by protein phosphorylation, which regulates recruitment of transcription and co-transcriptional factors. We have investigated whether mature mRNA levels from intron-containing protein-coding genes are related to pol II CTD phosphorylation, RNA stability, and pre-mRNA splicing and mRNA cleavage and polyadenylation efficiency. We find that genes that produce a low level of mature mRNAs are associated with relatively high phosphorylation of the pol II CTD Thr4 residue, poor RNA processing, increased chromatin association of transcripts, and shorter RNA half-life. While these poorly-processed transcripts are degraded by the nuclear RNA exosome, our results indicate that in addition to RNA half-life, chromatin association due to a low RNA processing efficiency also plays an important role in the regulation of mature mRNA levels

Isoginkgetin and Madrasin are poor splicing inhibitors

The production of eukaryotic mRNAs requires transcription by RNA polymerase (pol) II and co-transcriptional processing, including capping, splicing, and cleavage and polyadenylation. Pol II can positively affect co-transcriptional processing through interaction of factors with its carboxyl terminal domain (CTD), comprising 52 repeats of the heptapeptide Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7, and pol II elongation rate can regulate splicing. Splicing, in turn, can also affect transcriptional activity and transcription elongation defects are caused by some splicing inhibitors. Multiple small molecule inhibitors of splicing are now available, some of which specifically target SF3B1, a U2 snRNP component. SF3B1 inhibition results in a general downregulation of transcription elongation, including premature termination of transcription caused by increased use of intronic poly(A) sites. Here, we have investigated the effect of Madrasin and Isoginkgetin, two non-SF3B1 splicing inhibitors, on splicing and transcription. Surprisingly, we found that both Madrasin and Isoginkgetin affect transcription before any effect on splicing, indicating that their effect on pre-mRNA splicing is likely to be indirect. Both small molecules promote a general downregulation of transcription. Based on these and other published results, we conclude that these two small molecules should not be considered as primarily pre-mRNA splicing inhibitors

Differential effects of pre-mRNA splicing inhibitors on RNA polymerase II transcription

The production of eukaryotic mRNA requires transcription by RNA polymerase (pol) II and co-transcriptional processing, including capping, splicing, and cleavage and polyadenylation (CPA). Pol II can positively affect co-transcriptional processing through interaction of factors with its carboxyl terminal domain (CTD), comprising 52 repeats of the heptapeptide Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. Small molecule inhibitors of the splicing factor SF3B1 cause loss of the transcription elongation factor P-TEFb from protein-coding gene templates and major transcription defects, indicating that splicing can, in turn, positively affect transcription. To understand better the relationship between pre-mRNA splicing and pol II transcription, we have investigated the effect of two other splicing inhibitors, Madrasin and Isoginkgetin, on transcription. We found that Madrasin rapidly inhibits pre-mRNA splicing, whereas Isoginkgetin affects transcription before any detectable effect on pre-mRNA splicing. Interestingly, we found that both of these small molecules promote general downregulation of transcription and global transcriptional readthrough, including on intronless and histone genes. Both small molecules affect the association of the mRNA CPA complex with chromatin, likely explaining the transcription termination defect. However, splicing inhibition is not necessarily associated with transcriptional readthrough as small molecule inhibitors of SF3B1 or knockdown of splicing factors do not cause a global transcription termination defect

Rythmes et structures dans le roman québécois de 1950 à 1965. Thèse de doctorat ès lettres (littérature québécoise), mai 1975, XXIV + 214 p.

Positive transcription elongation factor b (P-TEFb), which comprises cyclin-dependent kinase 9 (CDK9) kinase and cyclin T subunits, is an essential kinase complex in human cells. Phosphorylation of the negative elongation factors by P-TEFb is required for productive elongation of transcription of protein-coding genes by RNA polymerase II (pol II). In addition, P-TEFb-mediated phosphorylation of the carboxyl-terminal domain (CTD) of the largest subunit of pol II mediates the recruitment of transcription and RNA processing factors during the transcription cycle. CDK9 also phosphorylates p53, a tumor suppressor that plays a central role in cellular responses to a range of stress factors. Many viral factors affect transcription by recruiting or modulating the activity of CDK9. In this review, we will focus on how the function of CDK9 is regulated by viral gene products. The central role of CDK9 in viral life cycles suggests that drugs targeting the interaction between viral products and P-TEFb could be effective anti-viral agents

Carbon dioxide assisted blending of biodegradable polyesters

Blends of biodegradable polyesters; poly(ε-caprolactone) (PCL) and poly(lactic acid) (PLA) were produced by a variety of preparation methods; solution casting, melt blending and blending in the presence of carbon dioxide using a single screw extruder. The blends were characterised using scanning electron microscopy (SEM), mechanical testing, differential scanning calorimetry (DSC), Fourier Transform infrared spectroscopy (FTIR), rheology and size exclusion chromatography (SEC). Comparison of the blends produced via the different preparation techniques indicated that carbon dioxide was able to improve the morphology and mechanical properties of the PLA/PCL blends. The influence of carbon dioxide on the reptation time of poly(ε-caprolactone) was investigated using oscillatory rheology. It was shown that by introducing CO2 into the polymer melt, the reptation time was significantly reduced, providing evidence that CO2 was interacting with this polymer. Further analysis of the data showed that the activation energy to flow was reduced, which was consistent with the reduction in the reptation times. Flash DSC, a relatively new thermal analysis technique, was used to explore areas of polymer science that are otherwise unachievable using conventional DSC. It showed the ability to prevent reorganisation and crystallisation in partially crystalline polymers such as poly(ε-caprolactone) and was able to evaluate the activation energy of the glass transition temperature for different amorphous and partially crystalline grades of PLA

APOBEC3B regulates R-loops and promotes transcription-associated mutagenesis in cancer

The single-stranded DNA cytosine-to-uracil deaminase APOBEC3B is an antiviral protein implicated in cancer. However, its substrates in cells are not fully delineated. Here APOBEC3B proteomics reveal interactions with a surprising number of R-loop factors. Biochemical experiments show APOBEC3B binding to R-loops in cells and in vitro. Genetic experiments demonstrate R-loop increases in cells lacking APOBEC3B and decreases in cells overexpressing APOBEC3B. Genome-wide analyses show major changes in the overall landscape of physiological and stimulus-induced R-loops with thousands of differentially altered regions, as well as binding of APOBEC3B to many of these sites. APOBEC3 mutagenesis impacts genes overexpressed in tumors and splice factor mutant tumors preferentially, and APOBEC3-attributed kataegis are enriched in RTCW motifs consistent with APOBEC3B deamination. Taken together with the fact that APOBEC3B binds single-stranded DNA and RNA and preferentially deaminates DNA, these results support a mechanism in which APOBEC3B regulates R-loops and contributes to R-loop mutagenesis in cancer