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Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism utilized by a subset of cancers to promote replicative immortality. The ALT mechanism is driven by increased replication stress and persistent DNA damage response signaling that leads to a homology-directed repair mechanism called break-induced telomere synthesis (BITS). In particular, ALT cells are hypersensitive to inhibition of ataxia telangiectasia Rad3-related (ATR), a DNA damage response kinase implicated in telomere mobility and recruitment of repair proteins for telomere elongation in ALT. However, little is known about what regulates ATR activity at ALT telomeres. Given the importance of ATR in the ALT mechanism, we hypothesized that known ATR activators, ETAA1 and TopBP1, regulate ALT activity and telomere synthesis. Here, we show that ETAA1 and TopBP1 localize to ALT telomeres at sites of ALT activity and telomeric damage. Furthermore, depletion of ETAA1 and TopBP1 leads to defects in ATR signaling, a decrease in BITS and compensatory engagement of telomeric MiDAS (spontaneous mitotic telomere synthesis) for replication stress resolution. Taken together, our findings show that both ETAA1 and TopBP1 are important for mediating BITS at ALT telomeres and may better inform our efforts in targeting the ATR signaling pathway in ALT-positive cancers.

Abstract: Biological antifreeze substances are widely found in the tissues of cold-blooded organisms indigenous to polar environments. Prior to 2009, all these compounds were associated with protein, leading to the widespread assumption that all biological antifreeze substances must possess a protein or peptide core. This perception was dispelled by Duman and co-workers in 2009, whose discovery of a protein-free xylomannan-based antifreeze glycolipid from the Alaskan Beetle Upis ceramboides heralded a new class of biological antifreeze. Though the structure of the xylomannan has been known for over a decade, no one has yet to address several questions regarding the identity of lipid component, the size of the xylomannan portion and the influence of these two factors in the overall antifreeze activity. To undertake such investigations, a library of structurally well-defined glycolipid mimetics will be required, and these are typically achieved through total chemical synthesis. Each compound will differ in both the number of disaccharide repeating units (between one to five units), and three different hydrophobic aglycones selected in lieu of the unidentified lipid component. Consequently, a total of fifteen compounds will be synthesized. A major challenge in this project is the synthesis of each beta-mannosidic linkage in the xylomannan portion. Moreover, beta-mannosylation as a means of glycan chain assembly remains relatively less explored. Therefore the ulosyl bromide approach was selected to investigate such a possibility. This was successfully demonstrated in the synthesis of xylomannan disaccharides; however, issues inherent to this approach led to the search for another alternative. In the second approach, a simultaneous multiple C-2 inversion strategy was developed as a convenient way to assemble all the oligosaccharides. The strategy developed involves the use of beta-glucosylation in assembling the glycan chain, followed by simultaneous C-2 inversion to convert all the glucose residues into the beta-mannosides. This was successfully demonstrated in the synthesis of all the target fifteen compounds, which will then be delivered to lab of Prof. Hubbard (Department of Chemistry, University of Alberta) for assessment of antifreeze activity.

The study was to analyze how senior high school students used their time (in-school and after-school time), and also connected their use of time to socio-cultural factors (i.e., social class, gender) as well as academic performance. To this end, the study utilized mixed methods, including both quantitative and qualitative approaches, to collect the required data. The research findings indicated that the Taiwanese three-year senior high school students' use of time was influenced by their cultural capital (parents' disciplinary styles, use of time, the amount of subjects acquired in cram schools). In particular, the middle-class students had more cultural capital, showed more active learning attitudes, and achieved higher in school, when compared with their working-class counterparts. In addition, female students also achieved higher than their male counterparts. However, there was no observed gender difference in the disciplinary styles of the parents with difference social classes. The findings also showed that students created a "double-context learning situation" in an ongoing class, which included teacher's context and student's context. There were five types of use of in-class time derived from the interactions between the two contexts: Regular Learning (RL), Hop-on-and-Hop-off Learning (HHL) (on-subject or off-subject), Self Learning (SL) (on-subject or off-subject), Fragmented Learning (FL), and Not Learning (NL). The middle-class students were found to use RL, HHL, and SL by using the "Time-Stealing" strategy to steal time from an ongoing class to read something on their own. By contrast, the working-class students appeared to use RL, FL, and NL, letting the learning time pass. One of the purposes of this study was to figure out some possible explanations for working-class students with high academic performance and middle-class students with low academic performance, which cannot be accounted for by Bourdieu's cultural reproduction and Willis's cultural production. The working-class students obtained high scores because of the operation of "anti-reproduction" attitude from their parents, while middle-class students failed in school due to the process of "mutual cultural adaption." In the end, some implications for future research, practitioners, and policy makers are provided.