A Non-Canonical Role for Choline Acetyltransferase in Chromatin Organization and the Response to Beta-Amyloid

The three-dimensional structure of chromatin is essential for context-dependent regulation of gene expression in post-mitotic neurons. Chromosomal rearrangements have been observed in the aging brain, and proteins involved in chromatin organization have altered expression and/or localization in Alzheimer’s disease (AD). A human- and primate-specific transcript of choline acetyltransferase produces an 82-kDa protein (82-kDa ChAT) that is localized to the nucleus of cholinergic neurons, but is found in the cytoplasm in individuals with mild cognitive impairment (MCI) and AD. The function of the 82-kDa ChAT protein is unknown, though recent evidence suggests it has a role in gene expression changes in response to cellular perturbations. In the present study, we explore whether 82-kDa ChAT is involved in global chromatin organization and an epigenetic response to cytotoxic amyloid-β(Aβ) exposure. We show that 82-kDa ChAT associates with chromatin in human SH-SY5Y neural cells using chromatin immunoprecipitation with next-generation sequencing (ChIP-seq), finding that acute exposure of cells to oligomeric Aβ1–42 increases 82-kDa ChAT associations with gene promoters and introns. Following Aβ1–42-exposure, 82-kDa ChAT co-localizes in nuclear aggregates with special AT-rich binding protein 1 (SATB1), which anchors DNA to scaffolding/matrix attachment regions (S/MARs). SATB1 has similar increases in genic associations following Aβ1–42-exposure, and both SATB1 and 82-kDa ChAT associate with synapse-related genes. The 82-kDa ChAT and SATB1 proteins have patterned genomic associations at regions enriched with S/MAR binding motifs, preventing an Aβ1–42-induced increase in an isoform-specific APP mRNA transcript. Finally, we show that 82-kDa ChAT expression during cholinergic differentiation of SH-SY5Y cells increases the steady-state levels of proteins related to synapse formation, resulting in increased neurite complexity. These results demonstrate that 82-kDa ChAT and SATB1 regulate chromatin organization at S/MARs, resulting in context-dependent gene expression changes in cholinergic cells and increased expression of synapse formation-related proteins during cholinergic differentiation. Cholinergic synapse dysfunction and degeneration is observed early in AD progression and 82-kDa ChAT is mislocalized in AD, therefore the loss of both the epigenetic response to Aβ and gene expression changes related to synapse formation and maintenance may have implications for the etiology or progression of MCI and AD

Discipline-based educational development: examples from four Canadian universities

Discipline-based educational development , integrating the principles of teaching and learning with specific content knowledge of a discipline, is emerging as a complement to more traditional, centralized models of teaching support, bringing with it its own advantages and challenges. Partly, it is a question of belonging: it helps to be part of a team of people - possibly with a variety of specialties in areas like curriculum, pedagogy, educational technology - and operating from a centre offers this important support, but coming from a single unit across campus may make it harder to connect with those teaching in departments. Conversely, working in a department creates many opportunities to connect with faculty and students, but can be isolating as there is unlikely to be a team of any size at the department level doing similar work. This panel discussion will explore four examples of discipline-based educational development at Canadian universities, highlighting successful initiatives and challenges faced by educators in implementing this approach. In one case, teaching is transforming via graduate student projects within specific courses, and the others have variations on teaching centre models with different levels of connections to departments - in one case with staff members embedded in departments. We will also be interested to learn of other models from those who attend the discussion. Overall, this panel discussion aims to raise awareness of the value of discipline-based education development in STEM education and to provide a platform for dialogue and collaboration among educators and educational developers in Canadian post-secondary institutions

Hypertension genomics and cardiovascular prevention.

Hypertension continues to be a major risk factor for global mortality, and recent genome-wide association studies (GWAS) have expanded in size, leading to the identification of further genetic loci influencing blood pressure. In light of the new knowledge from the largest cardiovascular GWAS to date, we review the potential impact of genomics on discovering potential drug targets, risk stratification with genetic risk scores, drug selection with pharmacogenetics, and exploring insights provided by gene-environment interactions

Contingent negative variation and its relation to time estimation: a theoretical evaluation

The relation between the contingent negative variation (CNV) and time estimation is evaluated in terms of temporal accumulation and preparation processes. The conclusion is that the CNV as measured from the electroencephalogram (EEG) recorded at fronto-central and parietal-central areas is not a direct reflection of the underlying interval timing mechanism(s), but more likely represents a time-based response preparation/decision-making process

Pulmonary effects of inhalation of spark-generated silver nanoparticles in Brown-Norway and Sprague-Dawley rats

The increasing use of silver nanoparticles (AgNPs) in consumer products is concerning. We examined the potential toxic effects when inhaled in Brown-Norway (BN) rats with a pre-inflammatory state compared to Sprague-Dawley (SD) rats.We determined the effect of AgNPs generated from a spark generator (mass concentration: 600-800 μg/mm(3); mean diameter: 13-16 nm; total lung doses: 8 [Low] and 26-28 [High] μg) inhaled by the nasal route in both rat strains. Rats were sacrificed at day 1 and day 7 after exposure and measurement of lung function.In both strains, there was an increase in neutrophils in bronchoalveolar lavage (BAL) fluid at 24 h at the high dose, with concomitant eosinophilia in BN rats. While BAL inflammatory cells were mostly normalised by Day 7, lung inflammation scores remained increased although not the tissue eosinophil scores. Total protein levels were elevated at both lung doses in both strains. There was an increase in BAL IL-1β, KC, IL-17, CCL2 and CCL3 levels in both strains at Day 1, mostly at high dose. Phospholipid levels were increased at the high dose in SD rats at Day 1 and 7, while in BN rats, this was only seen at Day 1; surfactant protein D levels decreased at day 7 at the high dose in SD rats, but was increased at Day 1 at the low dose in BN rats. There was a transient increase in central airway resistance and in tissue elastance in BN rats at Day 1 but not in SD rats. Positive silver-staining was seen particularly in lung tissue macrophages in a dose and time-dependent response in both strains, maximal by day 7. Lung silver levels were relatively higher in BN rat and present at day 7 in both strains.Presence of cellular inflammation and increasing silver-positive macrophages in lungs at day 7, associated with significant levels of lung silver indicate that lung toxicity is persistent even with the absence of airway luminal inflammation at that time-point. The higher levels and persistence of lung silver in BN rats may be due to the pre-existing inflammatory state of the lungs

Teaching Linux based Operating System

The teaching of operating system internals at UCT does not take a practical view of the operating system. Students are not given the opportunity to gain any experience with source code, and the inner functions. To decrease the impact of testing, a minimized version of the operating system would be ideal. The Linux operating system presents opportunities to alter source code, but the amount of information available to prospective users is limited. Also there is a means to implement a minimalist version of the kernel. Sections of interest are the scheduler, the file system, and the virtual memory manager. The goal was to provide detailed information about each section, as well as some means of altering it

QSRA – a quality-value guided de novo short read assembler

<p>Abstract</p> <p>Background</p> <p>New rapid high-throughput sequencing technologies have sparked the creation of a new class of assembler. Since all high-throughput sequencing platforms incorporate errors in their output, short-read assemblers must be designed to account for this error while utilizing all available data.</p> <p>Results</p> <p>We have designed and implemented an assembler, Quality-value guided Short Read Assembler, created to take advantage of quality-value scores as a further method of dealing with error. Compared to previous published algorithms, our assembler shows significant improvements not only in speed but also in output quality.</p> <p>Conclusion</p> <p>QSRA generally produced the highest genomic coverage, while being faster than VCAKE. QSRA is extremely competitive in its longest contig and N50/N80 contig lengths, producing results of similar quality to those of EDENA and VELVET. QSRA provides a step closer to the goal of de novo assembly of complex genomes, improving upon the original VCAKE algorithm by not only drastically reducing runtimes but also increasing the viability of the assembly algorithm through further error handling capabilities.</p

Interpersonal interactions for haptic guidance during maximum forward reaching

Caregiver-patient interactions rely on interpersonal coordination (IPC) involving the haptic and visual modalities. We investigated in healthy individuals spontaneous IPC during joint maximum forward reaching. A 'contact-provider' (CP; n=2) kept light interpersonal touch (IPT) laterally with the wrist of the extended arm of a forward reaching, blind-folded 'contact-receiver' (CR; n=22). Due to the stance configuration, CP was intrinsically more stable. CR received haptic feedback during forward reaching in two ways: (1) presence of a light object (OBT) at the fingertips, (2) provision of IPT. CP delivered IPT with or without vision or tracked manually with vision but without IPT. CR's variabilities of Centre-of-Pressure velocity (CoP) and wrist velocity, interpersonal cross-correlations and time lags served as outcome variables. OBT presence increased CR's reaching amplitude and reduced postural variability in the reach end-state. CR's variability was lowest when CP applied IPT without vision. OBT decreased the strength of IPC. Correlation time lags indicated that CP retained a predominantly reactive mode with CR taking the lead. When CP had no vision, presumably preventing an effect of visual dominance, OBT presence made a qualitative difference: with OBT absent, CP was leading CR. This observation might indicate a switch in CR's coordinative strategy by attending mainly to CP's haptic 'anchor'. Our paradigm implies that in clinical settings the sensorimotor states of both interacting partners need to be considered. We speculate that haptic guidance by a caregiver is more effective when IPT resembles the only link between both partners

Randomized controlled trial of a good practice approach to treatment of childhood obesity in Malaysia: Malaysian childhood obesity treatment trial (MASCOT)

Context. Few randomized controlled trials (RCTs) of interventions for the treatment of childhood obesity have taken place outside the Western world. Aim. To test whether a good practice intervention for the treatment of childhood obesity would have a greater impact on weight status and other outcomes than a control condition in Kuala Lumpur, Malaysia. Methods. Assessor-blinded RCT of a treatment intervention in 107 obese 7- to 11-year olds. The intervention was relatively low intensity (8 hours contact over 26 weeks, group based), aiming to change child sedentary behavior, physical activity, and diet using behavior change counselling. Outcomes were measured at baseline and six months after the start of the intervention. Primary outcome was BMI z-score, other outcomes were weight change, health-related quality of life (Peds QL), objectively measured physical activity and sedentary behavior (Actigraph accelerometry over 5 days). Results. The intervention had no significant effect on BMI z score relative to control. Weight gain was reduced significantly in the intervention group compared to the control group (+1.5 kg vs. +3.5 kg, respectively, t-test p &lt; 0.01). Changes in health-related quality of life and objectively measured physical activity and sedentary behavior favored the intervention group. Conclusions. Treatment was associated with reduced rate of weight gain, and improvements in physical activity and quality of life. More substantial benefits may require longer term and more intensive interventions which aim for more substantive lifestyle changes