Design and application of SuRFR: an R package to prioritise candidate functional DNA sequence variants

Genetic analyses such as linkage and genome wide association studies (GWAS) have been extremely successful at identifying genomic regions that harbour genetic variants contributing to complex disorders. Over 90% of disease-associated variants from GWAS fall within non-coding regions (Maurano et al., 2012). However, pinpointing the causal variants has proven a major bottleneck to genetic research. To address this I have developed SuRFR, an R package for the ranked prioritisation of candidate causal variants by predicted function. SuRFR produces rank orderings of variants based upon functional genomic annotations, including DNase hypersensitivity signal, chromatin state, minor allele frequency, and conservation. The ranks for each annotation are combined into a final prioritisation rank using a weighting system that has been parametrised and tested through ten-fold cross-validation. SuRFR has been tested extensively upon a combination of synthetic and real datasets and has been shown to perform with high sensitivity and specificity. These analyses have provided insight into the extent to which different classes of functional annotation are most useful for the identification of known regulatory variants: the most important factor for identifying a true variant across all classes of regulatory variants is position relative to genes. I have also shown that SuRFR performs at least as well as its nearest competitors whilst benefiting from the advantages that come from being part of the R environment. I have applied SuRFR to several genomics projects, particularly the study of psychiatric illness, including genome sequencing of a large Scottish family with bipolar disorder. This has resulted in the prioritisation of such variants for future study

Interprofessional Peer Teaching: Assistive Device Training and Medications Impacting Safe Ambulation

ABSTRACT Purpose: An interprofessional peer teaching activity was designed and implemented to provide students with an opportunity to practice interprofessional education collaborative (IPEC) competencies while improving student knowledge of assistive devices for gait and medications impacting safe ambulation. Method: During the activity, second year physical therapy students instructed third year pharmacy students in the accurate fit and counseling for use of canes, crutches, and walkers. Pharmacy students then demonstrated these skills and were checked off on their ability to accurately fit and instruct consumers on basic gait patterns. The pharmacy students in turn educated the physical therapy students about medications that impact safe ambulation and gait training. The activity was designed to meet the interprofessional competencies of roles and responsibilities, interprofessional communication, teams and teamwork, in addition to specific course objectives. Students completed a 15-item pre- and post-knowledge assessment and a perceptions survey to evaluate the effectiveness of the peer teaching activity. Results: Significant improvements in knowledge and performance were demonstrated following participation in the activity, and students reported positive perceptions of the activity and its impact on their learning about assistive devices and medications reviewed during the session. Our results indicate that physical therapy and pharmacy students can effectively teach each other and learn about assistive devices and medications impacting safe ambulation through an interprofessional peer teaching activity. Conclusion: Peer teaching across disciplines can help prepare students to communicate and collaborate with other healthcare providers

A critical review of life cycle assessment studies of woody biomass conversion to sugars

Funder: Prince of Wales Global Sustainability Fellowship ProgrammeWoody biomass could potentially become a viable raw material for the future sustainable chemical industry. For this, a suitable regulatory framework must exist, that would create favourable economic conditions for wood biorefineries. Such policies must be developed on the basis of scientific evidence—in this case, data supporting the environmental advantages of the bio-based feedstocks to the chemical industry. The most suitable methodology for comprehensive evaluation of environmental performance of technologies is life cycle assessment (LCA). In this review, the available LCA studies of woody biomass fractionation and conversion to bulk chemical feedstocks are critically evaluated. It has been revealed that the majority of the openly available studies do not contain transparent inventory data and, therefore, cannot be verified or re-used; studies containing inventory data are reported in this review. The lack of inventory data also prevents comparison between studies of the same processes performed with different evaluation methods or using different system boundaries. Recommendations are proposed on how to overcome issues of commercial data sensitivity by using black-box modelling when reporting environmental information. From several comparable LCA studies, it has been concluded that today the most environmentally favourable technology for wood biomass fractionation is organosolv. This article is part of the theme issue ‘Bio-derived and bioinspired sustainable advanced materials for emerging technologies (part 1)’

Utility of Visual Counts for Determining Efficacy of Management Tools for California Ground Squirrels

Visual counts are frequently used to assess efficacy of management tools for ground squirrels (Marmotini), but the effectiveness of this approach has not been assessed for many ground squirrel species including California ground squirrels (Otospermophilus spp.). As such, we used visual counts of California ground squirrels to determine the efficacy of diphacinone-treated oat groat applications in rangelands in central California, USA, and compared those results to efficacy values derived from the use of radio-collared ground squirrels in the same plots. We also used location data of radio-collared ground squirrels to explore the size of buffer zone needed around census plots to provide an accurate assessment of efficacy when using visual counts. We did not observe a difference in efficacy associated with the 2 monitoring strategies, indicating that visual counts are an effective monitoring tool for ground squirrels. We observed low efficacy in 2 treatment plots, likely due to low usage of those plots by ground squirrels. Increasing the size of buffer zones would increase the usage of treatment areas by the target population and would help to minimize reinvasion by adjacent ground squirrel populations, which could bias efficacy values low. We suggest a minimum of a 61-m buffer surrounding census plots. Increasing to 66 m or more would further benefit efficacy assessments, but increased size of the buffer zone must be balanced with greater costs and regulatory constraints

Preliminary assessment of pre-morbid DNA methylation in individuals at high genetic risk of mood disorders

OBJECTIVES: Accumulating evidence implicates altered DNA methylation in psychiatric disorders, including bipolar disorder (BD) and major depressive disorder (MDD). It is not clear, however, whether these changes are causative or result from illness progression or treatment. To disentangle these possibilities we profiled genome‐wide DNA methylation in well, unrelated individuals at high familial risk of mood disorder. DNA methylation was compared between individuals who subsequently developed BD or MDD [ill later (IL)] and those who remained well [well later (WL)]. METHODS: DNA methylation profiles were obtained from whole‐blood samples from 22 IL and 23 WL individuals using the Infinium HumanMethylation450 BeadChip. Differential methylation was assessed on a single‐locus and regional basis. Pathway analysis was performed to assess enrichment for particular biological processes amongst nominally significantly differentially methylated loci. RESULTS: Although no locus withstood correction for multiple testing, uncorrected P‐values provided suggestive evidence for altered methylation at sites within genes previously implicated in neuropsychiatric conditions, such as Transcription Factor 4 (TCF4) and Interleukin 1 Receptor Accessory Protein‐Like 1 ([IL1RAPL1]; P≤3.11×10(−5)). Pathway analysis revealed significant enrichment for several neurologically relevant pathways and functions, including Nervous System Development and Function and Behavior; these findings withstood multiple testing correction (q≤0.05). Analysis of differentially methylated regions identified several within the major histocompatibility complex (P≤.000 479), a region previously implicated in schizophrenia and BD. CONCLUSIONS: Our data provide provisional evidence for the involvement of altered whole‐blood DNA methylation in neurologically relevant genes in the aetiology of mood disorders. These findings are convergent with the findings of genome‐wide association studies

The Dairy Industry: Process, Monitoring, Standards, and Quality

Sampling and analysis occur along the milk processing train: from collection at farm level, to intake at the diary plant, the processing steps, and the end products. Milk has a short shelf life; however, products such as milk powders have allowed a global industry to be developed. Quality control tests are vital to support activities for hygiene and food standards to meet regulatory and customer demands. Multiples of chemical and microbiological contamination tests are undertaken. Hazard analysis testing strategies are necessary, but some tests may be redundant; it is therefore vital to identify product optimization quality control strategies. The time taken to undergo testing and turnaround time are rarely measured. The dairy industry is a traditional industry with a low margin commodity. Industry 4.0 vision for dairy manufacturing is to introduce the aspects of operational excellence and implementation of information and communications technologies. The dairy industries’ reply to Industry 4.0 is represented predominantly by proactive maintenance and optimization of production and logistical chains, such as robotic milking machines and processing and packaging line automation reinforced by sensors for rapid chemical and microbial analysis with improved and real-time data management. This chapter reviews the processing trains with suggestions for improved optimization

Regulation of the BRCA1 gene by an SRC3/53BP1 complex

<p>Abstract</p> <p>Background</p> <p>Steroid Receptor coactivator 3(SRC3) is an oncogene and a member of the SRC family of nuclear receptor coactivator proteins that mediate the transcriptional effects of nuclear hormone receptors as well as other transcription factors.</p> <p>Results</p> <p>We have used protein purification and mass spectrometry to identify the 53BP1 tumour suppressor as a novel SRC3-associated protein. Copurification was demonstrated using multiple antibodies, and was not dependent on DNA damage suggesting that SRC3 is not directly involved in the DNA damage response. However using chromatin immunoprecipitation(ChIP) and siRNA knockdown, we have demonstrated that both SRC3 and 53BP1 co-occupy the same region of the BRCA1 promoter and both are required for BRCA1 expression in HeLa cells.</p> <p>Conclusions</p> <p>Our results suggest that both 53BP1 and SRC3 have a common function that converge at the BRCA1 promoter and possibly other genes important for DNA repair and genomic stability.</p

Adolescents' experience with sports-related pain and injury: A systematic review of qualitative research

Objective: The aim of this review is to synthesise qualitative studies examining adolescents’ experience with pain and injury arising from sports participation. Methods: This review was registered on Open Science Framework prior to data extraction. A systematic search of PubMed, Embase, and SPORTDiscus was conducted. Studies were appraised using the CASP (critical appraisal skills programme) checklist. Data was synthesised using a meta aggregation. Study selection criteria: Inclusion criteria included studies related to adolescents aged 14–19yrs with sports related pain/injury, employed a qualitative design, full text publications in English. Results: Sixteen studies of 216 participants were included. Studies investigated severe knee injuries, concussion, or other musculoskeletal injuries. Synthesised findings show that, regardless of injury type, adolescents experience a mix of positive (motivation to rehab and return to sport, optimism) and negative emotions (fear of reinjury, isolation, depressive responses) throughout recovery. Common coping strategies were to ignore symptoms, modify activity levels, or seek support. Conclusion: Sports-related pain and injury has a multifaceted effect on the adolescent athlete. There is a pervasive fear of re-injury and social isolation, but the desire to return to sports is facilitated through motivation and support. Peer motivation effects the willingness of the adolescent to persist with rehabilitation

Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase a oncogene.

BACKGROUND: Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD, indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown. RESULTS: As a molecular mechanism, we demonstrate that PTPRD interacts with aurora kinase A (AURKA), an oncogenic protein that is over-expressed in multiple forms of cancer, including neuroblastoma. Ectopic up-regulation of PTPRD in neuroblastoma dephosphorylates tyrosine residues in AURKA resulting in a destabilization of this protein culminating in interfering with one of AURKA\u27s primary functions in neuroblastoma, the stabilization of MYCN protein, the gene of which is amplified in approximately 25 to 30% of high risk neuroblastoma. CONCLUSIONS: PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing a novel mechanism for the function of PTPRD in neuroblastoma