Enhancing the early student experience

This paper is concerned with identifying how the early student experience can be enhanced in order to improve levels of student retention and achievement. The early student experience is the focus of this project as the literature has consistently declared the first year to be the most critical in shaping persistence decisions. Programme managers of courses with high and low retention rates have been interviewed to identify activities that appear to be associated with good retention rates. The results show that there are similarities in the way programmes with high retention are run, with these features not being prevalent on programmes with low retention. Recommendations of activities that appear likely to enhance the early student experience are provided

Classification of protein domain movements using Dynamic Contact Graphs

A new method for the classification of domain movements in proteins is described and applied to 1822 pairs of structures from the Protein Data Bank that represent a domain movement in two-domain proteins. The method is based on changes in contacts between residues from the two domains in moving from one conformation to the other. We argue that there are five types of elemental contact changes and that these relate to five model domain movements called: ‘‘free’’, ‘‘openclosed’’, ‘‘anchored’’, ‘‘sliding-twist’’, and ‘‘see-saw.’’ A directed graph is introduced called the ‘‘Dynamic Contact Graph’’ which represents the contact changes in a domain movement. In many cases a graph, or part of a graph, provides a clear visual metaphor for the movement it represents and is a motif that can be easily recognised. The Dynamic Contact Graphs are often comprised of disconnected subgraphs indicating independent regions which may play different roles in the domain movement. The Dynamic Contact Graph for each domain movement is decomposed into elemental Dynamic Contact Graphs, those that represent elemental contact changes, allowing us to count the number of instances of each type of elemental contact change in the domain movement. This naturally leads to sixteen classes into which the 1822 domain movements are classified

Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

Background: Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches. Methods: We describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour. Results: We found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA, KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA, KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after. Conclusion: This case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision medicine success

Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

In a glioblastoma tumour with multi-region sequencing before and after recurrence, we find an IDH1 mutation that is clonal in the primary but lost at recurrence. We also describe the evolution of a double-minute chromosome encoding regulators of the PI3K signalling axis that dominates at recurrence, emphasizing the challenges of an evolving and dynamic oncogenic landscape for precision medicin

Transcriptomic and Epigenetic Regulation of Disuse Atrophy and the Return to Activity in Skeletal Muscle

Physical inactivity and disuse are major contributors to age-related muscle loss. Denervation of skeletal muscle has been previously used as a model with which to investigate muscle atrophy following disuse. Although gene regulatory networks that control skeletal muscle atrophy after denervation have been established, the transcriptome in response to the recovery of muscle after disuse and the associated epigenetic mechanisms that may function to modulate gene expression during skeletal muscle atrophy or recovery have yet to be investigated. We report that silencing the tibialis anterior muscle in rats with tetrodotoxin (TTX)—administered to the common peroneal nerve—resulted in reductions in muscle mass of 7, 29, and 51% with corresponding reductions in muscle fiber cross-sectional area of 18, 42, and 69% after 3, 7, and 14 d of TTX, respectively. Of importance, 7 d of recovery, during which rodents resumed habitual physical activity, restored muscle mass from a reduction of 51% after 14 d TTX to a reduction of only 24% compared with sham control. Returning muscle mass to levels observed at 7 d TTX administration (29% reduction). Transcriptome-wide analysis demonstrated that 3714 genes were differentially expressed across all conditions at a significance of P ≤ 0.001 after disuse-induced atrophy. Of interest, after 7 d of recovery, the expression of genes that were most changed during TTX had returned to that of the sham control. The 20 most differentially expressed genes after microarray analysis were identified across all conditions and were cross-referenced with the most frequently occurring differentially expressed genes between conditions. This gene subset included myogenin (MyoG), Hdac4, Ampd3, Trim63 (MuRF1), and acetylcholine receptor subunit α1 (Chrna1). Transcript expression of these genes and Fboxo32 (MAFbx), because of its previously identified role in disuse atrophy together with Trim63 (MuRF1), were confirmed by real-time quantitative RT-PCR, and DNA methylation of their promoter regions was analyzed by PCR and pyrosequencing. MyoG, Trim63 (MuRF1), Fbxo32 (MAFbx), and Chrna1 demonstrated significantly decreased DNA methylation at key time points after disuse-induced atrophy that corresponded with significantly increased gene expression. Of importance, after TTX cessation and 7 d of recovery, there was a marked increase in the DNA methylation profiles of Trim63 (MuRF1) and Chrna1 back to control levels. This also corresponded with the return of gene expression in the recovery group back to baseline expression observed in sham-operated controls. To our knowledge, this is the first study to demonstrate that skeletal muscle atrophy in response to disuse is accompanied by dynamic epigenetic modifications that are associated with alterations in gene expression, and that these epigenetic modifications and gene expression profiles are reversible after skeletal muscle returns to normal activity

Assessment of motor functioning in the preschool period

The assessment of motor functioning in young children has become increasingly important in recent years with the acknowledgement that motor impairment is linked with cognitive, language, social and emotional difficulties. However, there is no one gold standard assessment tool to investigate motor ability in children. The aim of the current paper was to discuss the issues related to the assessment of motor ability in young pre-school children and to provide guidelines on the best approach for motor assessment. The paper discusses the maturational changes in brain development at the preschool level in relation to motor ability. Other issues include sex differences in motor ability at this young age, and evidence for this in relation to sociological versus biological influences. From the previous literature it is unclear what needs to be assessed in relation to motor functioning. Should the focus be underlying motor processes or movement skill assessment? Several key assessment tools are discussed that produce a general measure of motor performance followed by a description of tools that assess specific skills, such as fine and gross motor, ball and graphomotor skills. The paper concludes with recommendations on the best approach in assessing motor function in pre-school children

HumBugDB: a large-scale acoustic mosquito dataset

This paper presents the first large-scale multi-species dataset of acoustic recordings of mosquitoes tracked continuously in free flight. We present 20 hours of audio recordings that we have expertly labelled and tagged precisely in time. Significantly, 18 hours of recordings contain annotations from 36 different species. Mosquitoes are well-known carriers of diseases such as malaria, dengue and yellow fever. Collecting this dataset is motivated by the need to assist applications which utilise mosquito acoustics to conduct surveys to help predict outbreaks and inform intervention policy. The task of detecting mosquitoes from the sound of their wingbeats is challenging due to the difficulty in collecting recordings from realistic scenarios. To address this, as part of the HumBug project, we conducted global experiments to record mosquitoes ranging from those bred in culture cages to mosquitoes captured in the wild. Consequently, the audio recordings vary in signal-to-noise ratio and contain a broad range of indoor and outdoor background environments from Tanzania, Thailand, Kenya, the USA and the UK. In this paper we describe in detail how we collected, labelled and curated the data. The data is provided from a PostgreSQL database, which contains important metadata such as the capture method, age, feeding status and gender of the mosquitoes. Additionally, we provide code to extract features and train Bayesian convolutional neural networks for two key tasks: the identification of mosquitoes from their corresponding background environments, and the classification of detected mosquitoes into species. Our extensive dataset is both challenging to machine learning researchers focusing on acoustic identification, and critical to entomologists, geo-spatial modellers and other domain experts to understand mosquito behaviour, model their distribution, and manage the threat they pose to humans

Novel Feature for Catalytic Protein Residues Reflecting Interactions with Other Residues

Owing to their potential for systematic analysis, complex networks have been widely used in proteomics. Representing a protein structure as a topology network provides novel insight into understanding protein folding mechanisms, stability and function. Here, we develop a new feature to reveal correlations between residues using a protein structure network. In an original attempt to quantify the effects of several key residues on catalytic residues, a power function was used to model interactions between residues. The results indicate that focusing on a few residues is a feasible approach to identifying catalytic residues. The spatial environment surrounding a catalytic residue was analyzed in a layered manner. We present evidence that correlation between residues is related to their distance apart most environmental parameters of the outer layer make a smaller contribution to prediction and ii catalytic residues tend to be located near key positions in enzyme folds. Feature analysis revealed satisfactory performance for our features, which were combined with several conventional features in a prediction model for catalytic residues using a comprehensive data set from the Catalytic Site Atlas. Values of 88.6 for sensitivity and 88.4 for specificity were obtained by 10fold crossvalidation. These results suggest that these features reveal the mutual dependence of residues and are promising for further study of structurefunction relationship

Recruitment of rare 3-grams at functional sites: Is this a mechanism for increasing enzyme specificity?

<p>Abstract</p> <p>Background</p> <p>A wealth of unannotated and functionally unknown protein sequences has accumulated in recent years with rapid progresses in sequence genomics, giving rise to ever increasing demands for developing methods to efficiently assess functional sites. Sequence and structure conservations have traditionally been the major criteria adopted in various algorithms to identify functional sites. Here, we focus on the distributions of the 20³different types of <it>3</it>-grams (or triplets of sequentially contiguous amino acid) in the entire space of sequences accumulated to date in the UniProt database, and focus in particular on the rare <it>3</it>-grams distinguished by their high entropy-based information content.</p> <p>Results</p> <p>Comparison of the UniProt distributions with those observed near/at the active sites on a non-redundant dataset of 59 enzyme/ligand complexes shows that the active sites preferentially recruit <it>3</it>-grams distinguished by their low frequency in the UniProt. Three cases, Src kinase, hemoglobin, and tyrosyl-tRNA synthetase, are discussed in details to illustrate the biological significance of the results.</p> <p>Conclusion</p> <p>The results suggest that recruitment of rare <it>3</it>-grams may be an efficient mechanism for increasing specificity at functional sites. Rareness/scarcity emerges as a feature that may assist in identifying key sites for proteins function, providing information complementary to that derived from sequence alignments. In addition it provides us (for the first time) with a means of identifying potentially functional sites from sequence information alone, when sequence conservation properties are not available.</p