Genetic modifiers of repeat expansion disorders

Repeat expansion disorders (REDs) are monogenic diseases caused by a sequence of repetitive DNA expanding above a pathogenic threshold. A common feature of the REDs is a strong genotype-phenotype correlation in which a major determinant of age at onset (AAO) and disease progression is the length of the inherited repeat tract. Over a disease-gene carrier's life, the length of the repeat can expand in somatic cells, through the process of somatic expansion which is hypothesised to drive disease progression. Despite being monogenic, individual REDs are phenotypically variable, and exploring what genetic modifying factors drive this phenotypic variability has illuminated key pathogenic mechanisms that are common to this group of diseases. Disease phenotypes are affected by the cognate gene in which the expansion is found, the location of the repeat sequence in coding or non-coding regions and by the presence of repeat sequence interruptions. Human genetic data, mouse models and in vitro models have implicated the disease-modifying effect of DNA repair pathways via the mechanisms of somatic mutation of the repeat tract. As such, developing an understanding of these pathways in the context of expanded repeats could lead to future disease-modifying therapies for REDs

Measurement of physical activity in urban and rural South African adults: a comparison of two self-report methods

Abstract Background Due to the large mortality from inactivity-related non-communicable diseases in low- and middle- income countries, accurate assessment of physical activity is important for surveillance, monitoring and understanding of physical (in)activity epidemiology in many of these countries. Research on relative performance of self-report physical activity instruments commonly used for epidemiological research in Africa have rarely been reported. The present study compared estimates of physical activity measured with the International Physical Activity Questionnaire – Short Form (IPAQ-SF) and the Baecke Physical Activity Questionnaire (BPAQ) among urban and rural black South African adults. Methods Self-reported physical activity data using the IPAQ-SF and BPAQ were collected from a representative sample of 910 urban and rural black South African adults (age = 59.2 ± 9.5 years, 69.7 % women) participating in the 2015 wave of the Prospective Urban and Rural Epidemiological (PURE) study in the North West Province of South Africa. Between-method relationships (pearson correlations [r] and intraclass correlation coefficients [ICCs]) and agreements (Bland-Altman mean difference with 95 % limits of agreement and Kappa coefficient [k]) of IPAQ-SF and BPAQ variables were estimated. Sensitivity and specificity of the BPAQ relative to the IPAQ-SF to classify individuals according to the international guidelines for sufficient physical activity were calculated using chi-square statistics. Results Correlations between IPAQ-SF scores and BPAQ indices were small (r = 0.08–0.18; ICCs = 0.09–0.18) for BPAQ leisure and sport indices, moderate-to-large for work index (r = 0.42–0.59; ICCs = 0.40–0.62) and total physical activity index (r = 0.52–0.60; ICCs = 0.36–0.51). Between methods mean difference for total physical activity was large (1.85 unit), and agreement in physical activity classifications was poor to moderate (k = 0.16–0.44). The sensitivity of the BPAQ to identify sufficiently active people from the IPAQ-SF was very good (98 %), but its specificity to correctly classify insufficiently active people was weak (23 %). Conclusion Notable disparities in physical activity estimates between methods suggest that utilization of IPAQ-SF and BPAQ for surveillance and epidemiology studies in Africa should depend on research questions and population to be studied. Future studies with objective measures are needed to confirm the relative validity between the two instruments

Exercise testing and intervention: translation into a low resource community

Ikageng is a low-resource community on the outskirts of Potchefstroom in the North West Province of South Africa. South Africa experiences a burden of disease that includes both diseases of lifestyle due to obesity and sedentary behaviour, and diseases of poverty due to poor sanitation and insufficient public health measures. Exercise interventions are powerful tools to modify diseases of lifestyle, and the effects of these interventions can be readily measured using structured fitness tests, clinical examination procedures, and pencil and paper tests of health and wellbeing. In Ikageng we explored the possible translation of exercise intervention and testing into a low-resource community. We undertook a series of linked studies, commending with the translation of the SF-8 into Tswana, and the test-retest reliability, internal consistency, and face validity testing of this questionnaire in the community. We bench-marked the Tswana SF-8 against the South African English version of the same. We then compared several variations of a graduated step test for the prediction of VO2 peak, comparing the individual test when completed stepping in time to a metronome against a test completed using music to hold time, and the preferred of these individual tests against the step test completed in pairs. Once we had identified the most acceptable forms of these field tests, we conducted pilot testing of these tools during a community based exercise intervention (dancing). We have been able to demonstrate that the Tswana version of the SF-8, and modified step tests, are similarly robust, valid, and as practically useful as their traditional English and laboratory based forms respectively

Community and home-based exercise for the prevention and treatment

Using Evidence. Improving live

Validity and reliability of the Setswana translation of the Short Form-8 health-related quality of life health survey in adults

Background: The absence of culturally relevant measures in indigenous languages could pose a challenge to epidemiological studies on health-related quality of life (HRQoL) in developing nations. Aim: To explore the feasibility and determine the validity and reliability of the Setswana translation of the HRQoL Short Form-8 (SF-8) among Setswana-speaking adults. Setting: Potchefstroom in the North West province. Methods: Sixty healthy men (n = 26) and women (n = 34), aged 45.5 ± 9.3 years, completed a Setswana translation of the SF-8 questionnaire and the original English version twice, with a 4-week interval between completions. Results: The Setswana SF-8 presented good concurrent validity with the Spearman’s correlation coefficients (ρ) of 0.72 for role physical to 0.91 for social functioning. The Cronbach’s alpha coefficients for the first and second measurements were 0.87 and 0.87, respectively, for the Setswana-translated SF-8 and 0.86 and 0.89 for the original English SF-8. The reliability coefficients were moderate for the mental health (ρ = 0.60), social functioning (ρ = 0.56) and role emotional (ρ = 0.50) domains, as well as the mental component summary (ρ = 0.50) and physical component summary (ρ = 0.45), but fair for the role physical (ρ = 0.43), body pain (ρ = 0.43), general health (ρ = 0.42), physical functioning (ρ = 0.41) and vitality (ρ = 0.38) domains on the translated Setswana version of the SF-8. Conclusion: The Setswana SF-8 version was feasible, acceptable and had acceptable concurrent validity and fair to moderate evidence of test–retest reliability for assessing HRQoL among adult Setswana-speaking community dwellers

Excavating Awareness and Power in Data Science: A Manifesto for Trustworthy Pervasive Data Research

Frequent public uproar over forms of data science that rely on information about people demonstrates the challenges of defining and demonstrating trustworthy digital data research practices. This paper reviews problems of trustworthiness in what we term pervasive data research: scholarship that relies on the rich information generated about people through digital interaction. We highlight the entwined problems of participant unawareness of such research and the relationship of pervasive data research to corporate datafication and surveillance. We suggest a way forward by drawing from the history of a different methodological approach in which researchers have struggled with trustworthy practice: ethnography. To grapple with the colonial legacy of their methods, ethnographers have developed analytic lenses and researcher practices that foreground relations of awareness and power. These lenses are inspiring but also challenging for pervasive data research, given the flattening of contexts inherent in digital data collection. We propose ways that pervasive data researchers can incorporate reflection on awareness and power within their research to support the development of trustworthy data science

Origin and implications of early diagenetic quartz in the Mississippian Bowland Shale formation, Craven Basin, UK

Silica cementation exerts a key control on the compaction and geotechnical properties of mudstones, and by extension, the style of hydrocarbon and/or mineral systems present in a given sedimentary basin. Integrated microscopic and bulk geochemical observations demonstrate that siliceous mudstones in the Bowland Shale Formation, a target for UK shale gas extraction, exhibit abundant dispersed, discrete, μm-scale quartz cements, and exhibit silica enrichment (‘excess’) above a local detrital Si/Al threshold of 2.5. Dissolution of siliceous radiolarian tests during early diagenesis is identified as the main source of silica (opal A) required for quartz precipitation, either via opal CT or directly to quartz, and potentially generated as a product of anoxic marine ‘weathering’ (dissolution) of reactive silicates during early diagenesis. Excess silica correlates with free hydrocarbons (S1) normalised to total organic carbon (oil saturation index; OSI); we propose early diagenetic quartz precipitation suppressed pore collapse (‘buttress effect’), retaining the pore space capacity to host oil. Quartz precipitation was likely catalysed, for example via low porewater pH, elevated Al and/or Fe oxide content, and/or abundant labile organic matter. Juxtaposition of siliceous mudstones and mudstones lacking quartz cement indicates silica was immobile beyond the bed scale. Thus metre-scale siliceous packages likely represent more prospective units within the Bowland Shale (in terms of unconventional hydrocarbons), on the basis of early diagenetic biogenic-derived quartz cementation leading to improved hydrocarbon storage capacity coupled to enhanced brittleness. These findings are relevant for shale oil and shale gas systems, specifically where oil retained in pores subsequently cracks to generate gas. These findings also suggest the Bowland Shale is a sub-class of black shale, defined by the potential to host a relatively large volume of early diagenetic fluids, derived from anoxic bottom waters, which were potentially S- and/or metal-bearing. This is potentially relevant for understanding the genesis of adjacent and related Pb-Zn mineral deposits

RNA-Seq of Huntington's disease patient myeloid cells reveals innate transcriptional dysregulation associated with proinflammatory pathway activation

Innate immune activation beyond the central nervous system is emerging as a vital component of the pathogenesis of neurodegeneration. Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The systemic innate immune system is thought to act as a modifier of disease progression; however, the molecular mechanisms remain only partially understood. Here we use RNA-sequencing to perform whole transcriptome analysis of primary monocytes from thirty manifest HD patients and thirty-three control subjects, cultured with and without a proinflammatory stimulus. In contrast with previous studies that have required stimulation to elicit phenotypic abnormalities, we demonstrate significant transcriptional differences in HD monocytes in their basal, unstimulated state. This includes previously undetected increased resting expression of genes encoding numerous proinflammatory cytokines, such as IL6. Further pathway analysis revealed widespread resting enrichment of proinflammatory functional gene sets, while upstream regulator analysis coupled with Western blotting suggests that abnormal basal activation of the NFOEB pathway plays a key role in mediating these transcriptional changes. That HD myeloid cells have a proinflammatory phenotype in the absence of stimulation is consistent with a priming effect of mutant huntingtin, whereby basal dysfunction leads to an exaggerated inflammatory response once a stimulus is encountered. These data advance our understanding of mutant huntingtin pathogenesis, establish resting myeloid cells as a key source of HD immune dysfunction, and further demonstrate the importance of systemic immunity in the potential treatment of HD and the wider study of neurodegeneration

Intellectual enrichment and genetic modifiers of cognition and brain volume in Huntington’s disease

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington’s disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle, and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington’s disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington’s disease gene-carriers, and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared to non-carriers, in agreement with its role in somatic instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, ie. those who were better educated, had higher verbal intelligence and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington’s disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non-carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than non-carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington’s disease and their effect on brain structure

Back-carrying in children is related to lower limb development

Back-carrying of children is a culturally accepted method of transport and safekeeping of babies in many cultures. Developmental consequences related to back-carrying practices have not been directly investigated. This study determined the relationship between frontal and transverse plane lower limb (LL) development, and back-carrying practices, in black Setswana-speaking children. In 691 2- to 9-year-old Setswana-speaking children, the tibiofemoral angle, intermalleolar distance, femoral anteversion angle (AVA) and tibial torsion angle (TTA), were measured to determine LL development. Back-carrying practices were recorded with a questionnaire and Classification and Regression Tree (CART) was used for the analyses. Significant (p < 0.001) relationships, between back-carrying practices and LL development, were discovered. Statistically significant greater genu valgum (F(5, 690) = 7.2, p < 0.001), greater internal TTAs (F(9, 684) = 17.8, p < 0.001), and smaller AVAs (F(13, 685) = 5.1, p < 0.001) were observed in children back-carried more frequently than children back-carried less frequently. There are relationships between back-carrying practices and LL development in both the frontal and transverse plane. However, the genu valgum, internal TTA and smaller AVA noted in more frequently back-carried children is still within normal limits, thus no educational intervention in back-carrying methods or durations is required. Further research should determine the exact back-carrying practice factors (age until which the child is back-carried) impacting lower limb development the greatest.This is a part of the Ph.D. thesis of Mariaan van Aswegen at North-West University, Potchefstroom 2520, South Africa.https://www.mdpi.com/journal/childrendm2022Consumer ScienceFood Scienc