Investigating the Role of the Gut Microbiome in Huntington Disease

Huntington disease (HD) is an inherited neurodegenerative disease caused by a trinucleotide repeat expansion in the huntingtin (HTT) gene. Metabolic dysfunction is a feature of HD that is recapitulated in HD mouse models. Our lab has shown that circadian feeding rhythms are disrupted in humanized HD mice and restored by suppression of brain HTT. Furthermore, when circadian feeding rhythm is artificially restored, in addition to normalization of metabolic function, liver and striatal HTT is temporarily reduced, demonstrating that HTT is involved in gut-brain feedback. The gut microbiome, which can regulate gut-brain feedback, has been implicated in the pathogenesis of other central nervous system disorders and we hypothesize it also plays a role in HD. The objective of this study is to investigate alterations in relative abundance of HD gut microbiota using existing plasma metabolomics data to identify candidate bacteria. If distinct microbiota profiles are demonstrated, this would provide the basis for future unbiased studies to investigate the complete HD microbiome

Caterpillars on a Phytochemical Landscape: The Case of Alfalfa and the Melissa Blue Butterfly

Modern metabolomic approaches that generate more comprehensive phytochemical profiles than were previously available are providing new opportunities for understanding plant‐animal interactions. Specifically, we can characterize the phytochemical landscape by asking how a larger number of individual compounds affect herbivores and how compounds covary among plants. Here we use the recent colonization of alfalfa (Medicago sativa) by the Melissa blue butterfly (Lycaeides melissa) to investigate the effects of indivdiual compounds and suites of covarying phytochemicals on caterpillar performance. We find that survival, development time, and adult weight are all associated with variation in nutrition and toxicity, including biomolecules associated with plant cell function as well as putative anti‐herbivore action. The plant‐insect interface is complex, with clusters of covarying compounds in many cases encompassing divergent effects on different aspects of caterpillar performance. Individual compounds with the strongest associations are largely specialized metabolites, including alkaloids, phenolic glycosides, and saponins. The saponins are represented in our data by more than 25 individual compounds with beneficial and detrimental effects on L. melissa caterpillars, which highlights the value of metabolomic data as opposed to approaches that rely on total concentrations within broad defensive classes

Smart Contracts in Insurance: A Law and Futurology Perspective

Smart contracts are innovative contracts that differ from traditional ones in that they are self-executing, as they entail the possibility of representing contract terms in programming code that gets automatically executed on a blockchain or other distributed ledgers. Following the latest developments in blockchain technology, smart contracts have been the focus of growing attention and are currently among the major innovations that are taking place in financial services. This paper investigates the scope for their application in insurance both in the near and longer term, exploring the legal challenges that they pose. The analysis shows that in the near term smart contracts will be mainly exploited to automate underwriting, claims handling and payouts. It considers how the automation of these processes will operate at law and emphasises the impact that smart contracts can have especially on the reduction of transaction costs and on the very essence of the insurance contract—the insurer's promise to pay. Building on current technological developments, the paper then turns to role that smart contracts can play in insurance in the longer term, advancing the prospect of the automation of the entire insurance contract. In particular, it argues that the interaction between smart contracts and artificial intelligence and machine learning can challenge traditional frameworks of thought such as incomplete contracting and, in the farther-distant future, will culminate in contracts that will both self-interpret and self-enforce their terms—what can be called the true smart contracts. The analysis identifies and addresses the main legal issues that can arise in this context, exploring how to strike a balance between the goal of fostering innovation and the need to ensure policyholder and investor protection

Heterogeneity in drinking practices in England and Wales and its association with violent behaviour: a latent class analysis

Background: Crude single-item consumption metrics, such as ‘binge drinking’ measures, mask the complexity and heterogeneity in young people’s drinking; thus limiting our understanding of young people’s drinking patterns as well as how alcohol drinking is associated with violent outcomes. Objectives: The current study employed a range of consumption and contextual indicators to explore heterogeneity in young people’s (16-29 years) drinking practices, giving due consideration to their social nature. It also assessed to what extent heterogeneity in drinking practices was associated with violent outcomes. Methods: Employing data from the 2006 Offending Crime and Justice Survey, three measures of alcohol consumption and nine drinking context indicators were utilised within latent class analysis to create typologies of drinking practices amongst current drinkers in England and Wales (n=2,711) and examine their association with violent outcomes. The validity of the typologies was also assessed on age, sex and socio-economic status. Results: Three discernible drinking profiles were identified: ‘regular social drinkers’ (48%), ‘regular pub binge drinkers’ (32%), and ‘moderate drinkers’ (20%). The ‘regular pub binge drinkers’ were found to be more than twice as likely to commit an assault offence (odds ratio = 2.8 95% CI [1.3, 6.2]) when compared to ‘moderate drinkers’. Interaction analyses demonstrated a stronger risk of violence among ‘regular social drinkers’ of low socio-economic status. Conclusions: Interventions aimed at reducing alcohol-related violence ought to give due consideration to the social context of drinking, the levels of consumption, as well as the socio-economic characteristics of the drinker

Using formative research to develop CHANGE! : a curriculum-based physical activity promoting intervention

Background : Low childhood physical activity levels are currently one of the most pressing public health concerns. Numerous school-based physical activity interventions have been conducted with varied success. Identifying effective child-based physical activity interventions are warranted. The purpose of this formative study was to elicit subjective views of children, their parents, and teachers about physical activity to inform the design of the CHANGE! (Children\u27s Health, Activity, and Nutrition: Get Educated!) intervention programme. Methods : Semi-structured mixed-gender interviews (group and individual) were conducted in 11 primary schools, stratified by socioeconomic status, with 60 children aged 9-10 years (24 boys, 36 girls), 33 parents (4 male, 29 female) and 10 teachers (4 male, 6 female). Questions for interviews were structured around the PRECEDE stage of the PRECEDE-PROCEDE model and addressed knowledge, attitudes and beliefs towards physical activity, as well as views on barriers to participation. All data were transcribed verbatim. Pen profiles were constructed from the transcripts in a deductive manner using the Youth Physical Activity Promotion Model framework. The profiles represented analysis outcomes via a diagram of key emergent themes. Results : Analyses revealed an understanding of the relationship between physical activity and health, although some children had limited understanding of what constitutes physical activity. Views elicited by children and parents were generally consistent. Fun, enjoyment and social support were important predictors of physical activity participation, though several barriers such as lack of parental support were identified across all group interviews. The perception of family invested time was positively linked to physical activity engagement. Conclusions : Families have a powerful and important role in promoting health-enhancing behaviours. Involvement of parents and the whole family is a strategy that could be significant to increase children\u27s physical activity levels. Addressing various perceived barriers to such behaviours therefore, remains imperative. <br /

Brachyury and Related Tbx Proteins Interact with the Mixl1 Homeodomain Protein and Negatively Regulate Mixl1 Transcriptional Activity

Mixl1 is a homeodomain transcription factor required for mesoderm and endoderm patterning during mammalian embryogenesis. Despite its crucial function in development, co-factors that modulate the activity of Mixl1 remain poorly defined. Here we report that Mixl1 interacts physically and functionally with the T-box protein Brachyury and related members of the T-box family of transcription factors. Transcriptional and protein analyses demonstrated overlapping expression of Mixl1 and Brachyury during embryonic stem cell differentiation. In vitro protein interaction studies showed that the Mixl1 with Brachyury associated via their DNA-binding domains and gel shift assays revealed that the Brachyury T-box domain bound to Mixl1-DNA complexes. Furthermore, luciferase reporter experiments indicated that association of Mixl1 with Brachyury and related T-box factors inhibited the transactivating potential of Mixl1 on the Gsc and Pdgfrα promoters. Our results indicate that the activity of Mixl1 can be modulated by protein-protein interactions and that T-box factors can function as negative regulators of Mixl1 activity

Influences of club connectedness among young adults in Western Australian community-based sports clubs

Background: Along with physical benefits, community-based sport provides opportunities to enhance connectedness, an important protective factor of social and emotional health. However, young Australians participating in sport have been found to drink alcohol at higher levels than their non-sporting peers, and many clubs serve unhealthy food and beverages. This study explored the association between the dependent variable, level of alcohol consumption (AUDIT-C) and connectedness to club and other health behaviours among young people aged 18-30 years who play club sport in Western Australia. Methods: An online cross sectional survey measured levels of alcohol consumption (AUDIT-C), alcohol-related harm, connectedness (including volunteering and team cohesion), mental wellbeing, healthy food options and club sponsorship among young adults aged 18-30 years involved in sports clubs in Western Australia (n = 242). Relationships and association between the dependent variable (AUDIT-C) and independent variables were assessed. Results: Male sportspeople were more likely to drink alcohol at high-risk levels than females (p <.001), and respondents belonging to a club that received alcohol-related sponsorship were more likely to drink at high-risk levels (p =.019). Females were significantly more likely to want healthy food and beverage options provided at their clubs (p = 0.011). When all factors were considered team cohesion (p = 0.02), alcohol expectations (p = <.001), occurrences of experienced alcohol-related harm (p = <.001) and length of club membership (p = 0.18) were significant predictors of high-risk AUDIT-C (R 2 =.34, adjusted R 2 =.33, F (4, 156) = 20.43, p = <.001). High-risk AUDIT-C and club connectedness predicted strong team cohesion (R 2 =.39, adjusted R 2 =.39, F (2, 166) = 53.74, p = <.001). Conclusions: Findings from this study may inform policy and practice to enhance healthy behaviours among young adults participating in community sports clubs in Australia and other countries

What’s retinoic acid got to do with it? Retinoic acid regulation of the neural crest in craniofacial and ocular development

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151310/1/dvg23308.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151310/2/dvg23308_am.pd

The Physics of the B Factories

This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C

Obesity is Associated With Increased Risk of Crohn's disease, but not Ulcerative Colitis: A Pooled Analysis of Five Prospective Cohort Studies

Background and Aims: It is unclear whether obesity is associated with the development of inflammatory bowel disease despite compelling data from basic science studies. We therefore examined the association between obesity and risk of Crohn's disease (CD) and ulcerative colitis (UC). Methods: We conducted pooled analyses of 5 prospective cohorts with validated anthropometric measurements for body mass index (BMI) and waist-hip ratio and other lifestyle factors. Diagnoses of CD and UC were confirmed through medical records or ascertained using validated definitions. We used Cox proportional hazards modeling to calculate pooled multivariable-adjusted HRs (aHRs) and 95% confidence intervals (CIs). Results: Among 601,009 participants (age range, 18-98 years) with 10,110,018 person-years of follow-up, we confirmed 563 incident cases of CD and 1047 incident cases of UC. Obesity (baseline BMI ≥30 kg/m2) was associated with an increased risk of CD (pooled aHR, 1.34; 95% CI, 1.05-1.71, I2 = 0%) compared with normal BMI (18.5 to <25 kg/m2). Each 5 kg/m2 increment in baseline BMI was associated with a 16% increase in risk of CD (pooled aHR, 1.16; 95% CI, 1.05-1.22; I2 = 0%). Similarly, with each 5 kg/m2 increment in early adulthood BMI (age, 18-20 years), there was a 22% increase in risk of CD (pooled aHR, 1.22; 95% CI, 1.05-1.40; I2 = 13.6%). An increase in waist-hip ratio was associated with an increased risk of CD that did not reach statistical significance (pooled aHR across quartiles, 1.08; 95% CI, 0.97-1.19; I2 = 0%). No associations were observed between measures of obesity and risk of UC. Conclusions: In an adult population, obesity as measured by BMI was associated with an increased risk of older-onset CD but not UC