The genetics of alcohol-related liver disease

The presence of cirrhosis is associated with significant morbidity and mortality. The prolonged heavy consumption of alcohol results in the development of cirrhosis in approximately 20% of people. This variance in risk is attributed to both genetic and environmental risk factors. To date there have been no systematic genome-wide association studies to investigate the contribution of common genetic variants to alcohol-related liver disease risk despite the success of these type of analyses in cirrhosis of other aetiologies. The work presented in the first half of this thesis describes the first genome-wide association study of alcohol-related liver disease identifying three highly replicable risk variants in the candidate loci: PNPLA3, TM6SF2 and MBOAT7. Subsequent to this, an extended GWAS was performed including over three-hundred additional cases, resulting in the identification of several novel loci. Of all the identified susceptibility loci, genetic variation in PNPLA3 is by far the most significant contributor to overall risk. The primary genetic variant in this locus is rs738409 and has the largest effect on cirrhosis risk of any genetic variants identified. It encodes a non-synonymous amino acid substitution (Ile148Met) in the PNPLA3 protein and is thought to be functional. This variant was genotyped in a UCL cohort of phenotypically well-characterized patients with cirrhosis and appropriate controls and investigated with regards to disease outcome and prognosis using time-to-event analysis. However, there is considerable debate about the functional significance of the PNPLA3 variant and to date little, if any, information about its structure. This information would provide insight into the pathogenesis of alcohol-related liver injury and identify possible targets for therapy. In the second half of the thesis the work undertaken to obtain the crystal structure of PNPLA3 is described. Initial computational structural modelling of the PNPLA3 protein was undertaken to characterize predicted structural features of the full-length protein to aid understanding of protein and crystallography process. A range of recombinant protein expression vectors were then developed for the purification of the protein in multiple expression systems. This led to the development of a high-yield expression protocol in E. coli obtaining milligram amounts of protein. Work to functionally characterize this protein is on-going

Genetic variants in ALDH1B1 and alcohol dependence risk in a British and Irish population: A bioinformatic and genetic study

Alcohol is metabolized in the liver via the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Polymorphisms in the genes encoding these enzymes, which are common in East Asian populations, can alter enzyme kinetics and hence the risk of alcohol dependence and its sequelae. One of the most important genetic variants, in this regards, is the single nucleotide polymorphism (SNP) rs671 in ALDH2, the gene encoding the primary acetaldehyde metabolizing enzyme ALDH2. However, the protective allele of rs671 is absent in most Europeans although ALDH1B1, which shares significant sequence homology with ALDH2, contains several, potentially functional, missense SNPs that do occur in European populations. The aims of this study were: (i) to use bioinformatic techniques to characterize the possible effects of selected variants in ALDH1B1 on protein structure and function; and, (ii) to genotype three missense and one stop-gain, protein-altering, non-synonymous SNPs in 1478 alcohol dependent cases and 1254 controls of matched British and Irish ancestry. No significant allelic associations were observed between the three missense SNPs and alcohol dependence risk. The minor allele frequency of rs142427338 (Gln378Ter) was higher in alcohol dependent cases than in controls (allelic P = 0.19, OR = 2.98, [0.62-14.37]) but as this SNP is very rare the study was likely underpowered to detect an association with alcohol dependence risk. This potential association will needs to be further evaluated in other large, independent European populations

Hot Streaks in Artistic, Cultural, and Scientific Careers

The hot streak, loosely defined as winning begets more winnings, highlights a specific period during which an individual's performance is substantially higher than her typical performance. While widely debated in sports, gambling, and financial markets over the past several decades, little is known if hot streaks apply to individual careers. Here, building on rich literature on lifecycle of creativity, we collected large-scale career histories of individual artists, movie directors and scientists, tracing the artworks, movies, and scientific publications they produced. We find that, across all three domains, hit works within a career show a high degree of temporal regularity, each career being characterized by bursts of high-impact works occurring in sequence. We demonstrate that these observations can be explained by a simple hot-streak model we developed, allowing us to probe quantitatively the hot streak phenomenon governing individual careers, which we find to be remarkably universal across diverse domains we analyzed: The hot streaks are ubiquitous yet unique across different careers. While the vast majority of individuals have at least one hot streak, hot streaks are most likely to occur only once. The hot streak emerges randomly within an individual's sequence of works, is temporally localized, and is unassociated with any detectable change in productivity. We show that, since works produced during hot streaks garner significantly more impact, the uncovered hot streaks fundamentally drives the collective impact of an individual, ignoring which leads us to systematically over- or under-estimate the future impact of a career. These results not only deepen our quantitative understanding of patterns governing individual ingenuity and success, they may also have implications for decisions and policies involving predicting and nurturing individuals with lasting impact

Genetic variation in GABRβ1 and the risk for developing alcohol dependence

Associations between the [gamma]-aminobutyric acid type-A receptors (GABAA) and alcohol dependence risk have been reported, although the receptor subunit driving the association is unclear. Recent work in mice has highlighted a possible role for variants in the Gabr [beta]1 subunit (Gabr[beta]1) in alcohol dependence risk, although this gene does not contain any common nonsynonymous variants in humans. However, the GABAA receptor is a heteropentamer so multiple potential variants within the gene complex could generate the alcohol dependence phenotype. The association between GABR[beta]1 variants and alcohol dependence risk was explored in a British and Irish population of alcohol-dependent cases (n=450) and ancestrally-matched controls screened to exclude current or historical alcohol misuse (n=555). Twelve common single nucleotide polymorphisms (SNPs) and a rare nonsynonymous variant, rs41311286, were directly genotyped; imputation was then performed across the whole gene. No allelic association was observed between alcohol dependence risk and any of the directly genotyped or imputed SNPs. However, post-hoc testing for genotypic association identified five common intronic SNPs that showed modest evidence for association after correction for multiple testing; two, rs76112682 and rs141719901, were in complete linkage disequilibrium [Pcorrected=0.02, odds ratio (95% confidence interval)=5.9 (1.7-2.06)]. These findings provide limited support for an association between GABR[beta]1 and the risk for developing alcohol dependence; further testing in expanded cohorts may be warranted

Impact of Space Weather on Climate and Habitability of Terrestrial Type Exoplanets

The current progress in the detection of terrestrial type exoplanets has opened a new avenue in the characterization of exoplanetary atmospheres and in the search for biosignatures of life with the upcoming ground-based and space missions. To specify the conditions favorable for the origin, development and sustainment of life as we know it in other worlds, we need to understand the nature of astrospheric, atmospheric and surface environments of exoplanets in habitable zones around G-K-M dwarfs including our young Sun. Global environment is formed by propagated disturbances from the planet-hosting stars in the form of stellar flares, coronal mass ejections, energetic particles, and winds collectively known as astrospheric space weather. Its characterization will help in understanding how an exoplanetary ecosystem interacts with its host star, as well as in the specification of the physical, chemical and biochemical conditions that can create favorable and/or detrimental conditions for planetary climate and habitability along with evolution of planetary internal dynamics over geological timescales. A key linkage of (astro) physical, chemical, and geological processes can only be understood in the framework of interdisciplinary studies with the incorporation of progress in heliophysics, astrophysics, planetary and Earth sciences. The assessment of the impacts of host stars on the climate and habitability of terrestrial (exo)planets will significantly expand the current definition of the habitable zone to the biogenic zone and provide new observational strategies for searching for signatures of life. The major goal of this paper is to describe and discuss the current status and recent progress in this interdisciplinary field and to provide a new roadmap for the future development of the emerging field of exoplanetary science and astrobiology.Comment: 206 pages, 24 figures, 1 table; Review paper. International Journal of Astrobiology (2019

Mineral dust increases the habitability of terrestrial planets but confounds biomarker detection

Identification of habitable planets beyond our solar system is a key goal of current and future space missions. Yet habitability depends not only on the stellar irradiance, but equally on constituent parts of the planetary atmosphere. Here we show, for the first time, that radiatively active mineral dust will have a significant impact on the habitability of Earth-like exoplanets. On tidally-locked planets, dust cools the day-side and warms the night-side, significantly widening the habitable zone. Independent of orbital configuration, we suggest that airborne dust can postpone planetary water loss at the inner edge of the habitable zone, through a feedback involving decreasing ocean coverage and increased dust loading. The inclusion of dust significantly obscures key biomarker gases (e.g. ozone, methane) in simulated transmission spectra, implying an important influence on the interpretation of observations.We demonstrate that future observational and theoretical studies of terrestrial exoplanets must consider the effect of dust

Direct and indirect interactions between ants ( Pheidole megacephala ), scales ( Coccus viridis ) and plants ( Pluchea indica )

This study investigated direct and indirect interactions between the ant, Pheidole megacephala (Fabr.), the green scale, Coccus viridis (Green), and the scale's host plant, Pluchea indica (L.). To examine the influence of ants on scales and host plants, scale population densities, scale mortality rates, and plant performance were studied on control host plants with ants and host plants from which ants had been removed. Plants with ants present had significantly greater scale population densities and scale reproductive rates than did plants without ants. Scale mortality from both parasitism and other causes was increased on plants without ants relative to plants with ants. Predator introduction experiments showed that P. megacephala removes predatory coccinellid larvae, even when they are covered with a protective coating. Host plants from which ants had been removed had significantly higher degrees of honeydew accumulation, which resulted in greater colonization by sooty mold and greater rates of leaf death and abscission. Ants also removed herbivorous lepidopteran larvae from plants. Results are discussed in terms of the potential of P. megacephala to exert direct and indirect positive effects on scale populations and an indirect positive effect on Pluchea indica .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47790/1/442_2004_Article_BF00325261.pd

TRAPPIST-1 Habitable Atmosphere Intercomparison (THAI): Motivations and protocol version 1.0

This is the final version. Available from European Geosciences Union via the DOI in this record. ExoCAM (Wolf and Toon, 2015) is available on GitHub: https://github.com/storyofthewolf/ExoCAM (last access: 8 February 2020). The Met Office Unified Model is available for use under license; see http://www.metoffice.gov.uk/research/modelling-systems/unified-model (Met Office, 2020, last access: 8 February 2020). ROCKE-3D is public domain software and available for download for free from https://simplex.giss.nasa.gov/gcm/ROCKE-3D/ (last access: 8 February 2020, NASA Goddard Institute for Space Studies, 2020a). Annual tutorials for new users take place annually, whose recordings are freely available online at https://www.youtube.com/user/NASAGISStv/playlists?view=50&sort=dd&shelf_id=15 (last access: 8 February 2020b, NASA Goddard Institute for Space Studies, 2020b). LMDG is obtainable upon request from Martin Turbet ([email protected]) and François Forget ([email protected]).Upcoming telescopes such as the James Webb Space Telescope (JWST), the European Extremely Large Telescope (E-ELT), the Thirty Meter Telescope (TMT) or the Giant Magellan Telescope (GMT) may soon be able to characterize, through transmission, emission or reflection spectroscopy, the atmospheres of rocky exoplanets orbiting nearby M dwarfs. One of the most promising candidates is the late M-dwarf system TRAPPIST-1, which has seven known transiting planets for which transit timing variation (TTV) measurements suggest that they are terrestrial in nature, with a possible enrichment in volatiles. Among these seven planets, TRAPPIST-1e seems to be the most promising candidate to have habitable surface conditions, receiving ~ 66 % of the Earth's incident radiation and thus needing only modest greenhouse gas inventories to raise surface temperatures to allow surface liquid water to exist. TRAPPIST-1e is, therefore, one of the prime targets for the JWST atmospheric characterization. In this context, the modeling of its potential atmosphere is an essential step prior to observation. Global climate models (GCMs) offer the most detailed way to simulate planetary atmospheres. However, intrinsic differences exist between GCMs which can lead to different climate prediction and thus observability of gas and/or cloud features in transmission and thermal emission spectra. Such differences should preferably be known prior to observations. In this paper we present a protocol to intercompare planetary GCMs. Four testing cases are considered for TRAPPIST-1e, but the methodology is applicable to other rocky exoplanets in the habitable zone. The four test cases included two land planets composed of modern-Earth and pure-CO2 atmospheres and two aqua planets with the same atmospheric compositions. Currently, there are four participating models (LMDG, ROCKE-3D, ExoCAM, UM); however, this protocol is intended to let other teams participate as well.NASA Planetary Science Division's Internal Scientist Funding ModelEuropean Union’s Horizon 2020NASA Astrobiology Progra

Developing counseling skills through pre-recorded videos and role play: a pre- and post-intervention study in a Pakistani medical school

<p>Abstract</p> <p>Background</p> <p>Interactive methods like role play, recorded video scenarios and objective structured clinical exam (OSCE) are being regularly used to teach and assess communication skills of medical students in the western world. In developing countries however, they are still in the preliminary phases of execution in most institutes. Our study was conducted in a naïve under resourced setup to assess the impact of such teaching methodologies on the counseling skills of medical students.</p> <p>Methods</p> <p>Fifty four 4^thyear MBBS students were identified to be evaluated for communication skills by trained facilitators in a pre-intervention OSCE. The same group of students was given a demonstration of ideal skill level by means of videos and role playing sessions in addition to real life interaction with patients during hospital and community rotations. A post-intervention evaluation was carried out six months later through OSCE and direct observation through structured checklist (DOS) in hospital and community settings. The combined and individual performance levels of these students were analyzed.</p> <p>Results</p> <p>There was a statistically significant difference in the communication skills of students when assessed in the post-intervention OSCE (p = 0.000). Individual post-intervention percentages of study participants displayed improvement as well (n = 45, p = 0.02). No difference was observed between the scores of male and female students when assessed for two specific competencies of antenatal care and breast feeding counseling (p = 0.11). The mean DOS (%) score of 12 randomly selected students was much lower as compared to the post-intervention (%) score but the difference between them was statistically non significant, a result that may have been affected by the small sample size as well as other factors that may come into play in real clinical settings and were not explored in this study (59.41 ± 7.8 against 82.43 ± 22.08, p = 0.88).</p> <p>Conclusions</p> <p>Videos and role play in combination with community and clinical exposure are effective modes of teaching counseling skills to medical students. They can be successfully utilized even in a limited resource setup, as demonstrated by our trial.</p