Prevalence of genetic variants of keratins 8 and 18 in patients with drug-induced liver injury

Abstract Background Keratin 8 and 18 (K8/K18) cytoskeletal proteins protect hepatocytes from undergoing apoptosis and their mutations predispose to adverse outcomes in acute liver failure (ALF). All known K8/K18 variants occur at relatively non-conserved residues and do not cause keratin cytoskeleton reorganization, whereas epidermal keratin-conserved residue mutations disrupt the keratin cytoskeleton and cause severe skin disease. The aim of our study was to identify keratin variants in idiosyncratic drug-induced liver injury (DILI). Methods Genomic DNA was isolated from 800 patients enrolled in an ongoing US multicenter study, with DILI attributed to a wide range of drugs. Specific K8/K18 exonic regions were PCR-amplified and screened by denaturing HPLC followed by DNA sequencing. The functional impact of keratin variants was assessed using cell transfection and immune staining. Results Heterozygous and compound amino acid-altering K8/K18 variants were identified in 86 DILI patients and non-coding variants in 15 subjects. Five novel amino acid-altering (K8 Lys393Arg, K8 Ala351Val, K8 Ala358Val, K8 Ile346Val, K18 Asp89His) and two non-coding variants were observed. Several variants segregated with specific ethnic backgrounds but were found at similar frequencies in DILI subjects and ethnically matched population controls. Notably, variants in highly conserved residues of K8 Lys393Arg (ezetimibe/simvastatin-related) and K18 Asp89His (isoniazid-related) were found in patients with fatal DILI. These novel variants also led to keratin network disruption in transfected cells. Conclusions Novel K8/K18 cytoskeleton-disrupting variants were identified in two patients and segregated with fatal DILI. Other non-cytoskeleton-disrupting keratin variants did not preferentially associate with DILI

Subcellular analysis of starch metabolism in developing barley seeds using a non-aqueous fractionation method

Compartmentation of metabolism in developing seeds is poorly understood due to the lack of data on metabolite distributions at the subcellular level. In this report, a non-aqueous fractionation method is described that allows subcellular concentrations of metabolites in developing barley endosperm to be calculated. (i) Analysis of subcellular volumes in developing endosperm using micrographs shows that plastids and cytosol occupy 50.5% and 49.9% of the total cell volume, respectively, while vacuoles and mitochondria can be neglected. (ii) By using non-aqueous fractionation, subcellular distribution between the cytosol and plastid of the levels of metabolites involved in sucrose degradation, starch synthesis, and respiration were determined. With the exception of ADP and AMP which were mainly located in the plastid, most other metabolites of carbon and energy metabolism were mainly located outside the plastid in the cytosolic compartment. (iii) In developing barley endosperm, the ultimate precursor of starch, ADPglucose (ADPGlc), was mainly located in the cytosol (80–90%), which was opposite to the situation in growing potato tubers where ADPGlc was almost exclusively located in the plastid (98%). This reflects the different subcellular distribution of ADPGlc pyrophosphorylase (AGPase) in these tissues. (iv) Cytosolic concentrations of ADPGlc were found to be close to the published Km values of AGPase and the ADPGlc/ADP transporter at the plastid envelope. Also the concentrations of the reaction partners glucose-1-phosphate, ATP, and inorganic pyrophosphate were close to the respective Km values of AGPase. (v) Knock-out of cytosolic AGPase in Riso16 mutants led to a strong decrease in ADPGlc level, in both the cytosol and plastid, whereas knock-down of the ADPGlc/ADP transporter led to a large shift in the intracellular distribution of ADPGlc. (v) The thermodynamic structure of the pathway of sucrose to starch was determined by calculating the mass–action ratios of all the steps in the pathway. The data show that AGPase is close to equilibrium, in both the cytosol and plastid, whereas the ADPGlc/ADP transporter is strongly displaced from equilibrium in vivo. This is in contrast to most other tissues, including leaves and potato tubers. (vi) Results indicate transport rather than synthesis of ADPGlc to be the major regulatory site of starch synthesis in barley endosperm. The reversibility of AGPase in the plastid has important implications for the regulation of carbon partitioning between different biosynthetic pathways

Increasing crop heterogeneity enhances multitrophic diversity across agricultural regions

International audienceAgricultural landscape homogenization has detrimental effects on biodiversity and key ecosystem services. Increasing agricultural landscape heterogeneity by increasing seminatural cover can help to mitigate biodiversity loss. However, the amount of seminatural cover is generally low and difficult to increase in many intensively managed agricultural landscapes. We hypothesized that increasing the heterogeneity of the crop mosaic itself (hereafter “crop heterogeneity”) can also have positive effects on biodiversity. In 8 contrasting regions of Europe and North America, we selected 435 landscapes along independent gradients of crop diversity and mean field size. Within each landscape, we selected 3 sampling sites in 1, 2, or 3 crop types. We sampled 7 taxa (plants, bees, butterflies, hoverflies, carabids, spiders, and birds) and calculated a synthetic index of multitrophic diversity at the landscape level. Increasing crop heterogeneity was more beneficial for multitrophic diversity than increasing seminatural cover. For instance, the effect of decreasing mean field size from 5 to 2.8 ha was as strong as the effect of increasing seminatural cover from 0.5 to 11%. Decreasing mean field size benefited multitrophic diversity even in the absence of seminatural vegetation between fields. Increasing the number of crop types sampled had a positive effect on landscape-level multitrophic diversity. However, the effect of increasing crop diversity in the landscape surrounding fields sampled depended on the amount of seminatural cover. Our study provides large-scale, multitrophic, cross-regional evidence that increasing crop heterogeneity can be an effective way to increase biodiversity in agricultural landscapes without taking land out of agricultural production

Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers

Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease.info:eu-repo/semantics/publishedVersio

Hidden politics of power and governmentality in transitional justice and peacebuilding:The problem of ‘bringing the local back in’

This paper examines ‘the local’ in peacebuilding by examining how ‘local’ transitional justice projects can become spaces of power inequalities. The paper argues that focusing on how ‘the local’ contests or interacts with ‘the international’ in peacebuilding and post-conflict contexts obscures contestations and power relations amongst different local actors, and how inequalities and power asymmetries can be entrenched and reproduced through internationally funded local projects. The paper argues that externally funded projects aimed at emancipating ‘locals’ entrench inequalities and create local elites that become complicit in governing the conduct and participation of other less empowered ‘locals’. The paper thus proposes that specific local actors—often those in charge of externally funded peacebuilding projects—should also be conceptualised as governing agents: able to discipline and regulate other local actors’ voices and their agency, and thus (re)construct ideas about what ‘the local’ is, or is not

Breakfast habits and factors influencing food choices at breakfast in relation to socio-demographic and family factors among European adolescents. The HELENA Study §

A B S T R A C T Breakfast consumption has been shown to be an important indicator of a healthy lifestyle. Little is known however about factors influencing breakfast consumption and food choices at breakfast in adolescents. The aim of the present study was therefore to describe breakfast habits, and factors influencing food choices at breakfast within the framework of the EU-funded HELENA Study, in 3528 adolescents from ten European cities. Additionally, socio-demographic differences in breakfast habits and in influencing factors were investigated. Half of the adolescents (and fewer girls than boys) indicated being regular breakfast consumers. Girls with mothers with a high level of education, boys from 'traditional' families and boys who perceived low family affluence were positively associated with breakfast consumption. Boys whose parents gave encouragement and girls whose peers ate healthily were more likely to be regular breakfast consumers. 'Hunger', 'taste', 'health concerns' and 'parents or guardian' were the most important influences on the adolescents' food choices at breakfast. Adolescents from southern Europe and girls reported to be more influenced by personal and socio-environmental factors. Sociodemographic differences, in particular regional and gender differences, need to be considered in discussions surrounding the development of nutritional intervention programs intended for adolescents.

Global change effects on plant communities are magnified by time and the number of global change factors imposed

Global change drivers (GCDs) are expected to alter community structure and consequently, the services that ecosystems provide. Yet, few experimental investigations have examined effects of GCDs on plant community structure across multiple ecosystem types, and those that do exist present conflicting patterns. In an unprecedented global synthesis of over 100 experiments that manipulated factors linked to GCDs, we show that herbaceous plant community responses depend on experimental manipulation length and number of factors manipulated. We found that plant communities are fairly resistant to experimentally manipulated GCDs in the short term (<10 y). In contrast, long-term (≥10 y) experiments show increasing community divergence of treatments from control conditions. Surprisingly, these community responses occurred with similar frequency across the GCD types manipulated in our database. However, community responses were more common when 3 or more GCDs were simultaneously manipulated, suggesting the emergence of additive or synergistic effects of multiple drivers, particularly over long time periods. In half of the cases, GCD manipulations caused a difference in community composition without a corresponding species richness difference, indicating that species reordering or replacement is an important mechanism of community responses to GCDs and should be given greater consideration when examining consequences of GCDs for the biodiversity–ecosystem function relationship. Human activities are currently driving unparalleled global changes worldwide. Our analyses provide the most comprehensive evidence to date that these human activities may have widespread impacts on plant community composition globally, which will increase in frequency over time and be greater in areas where communities face multiple GCDs simultaneously

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups