Caenorhabditis elegans as a model system for studying drug induced mitochondrial toxicity

Today HIV-1 infection is recognized as a chronic disease with obligatory lifelong treatment to keep viral titers below detectable levels. The continuous intake of antiretroviral drugs however, leads to severe and even life-threatening side effects, supposedly by the deleterious impact of nucleoside-analogue type compounds on the functioning of the mitochondrial DNA polymerase. For detailed investigation of the yet partially understood underlying mechanisms, the availability of a versatile model system is crucial. We therefore set out to develop the use of Caenorhabditis elegansto study drug induced mitochondrial toxicity. Using a combination of molecular-biological and functional assays, combined with a quantitative analysis of mitochondrial network morphology, we conclude that anti-retroviral drugs with similar working mechanisms can be classified into distinct groups based on their effects on mitochondrial morphology and biochemistry. Additionally we show that mitochondrial toxicity of antiretroviral drugs cannot be exclusively attributed to interference with the mitochondrial DNA polymerase

Psychosocial sequelae in 29 children with giant congenital melanocytic naevi

Giant congenital melanocytic naevus (GCMN) may be expected to affect psychosocial functioning of children and their parents due to deviant appearance and painful treatment. To obtain insight into clinical aspects and psychosocial functioning of those suffering from GCMN, 29 children diagnosed with GCMN syndrome or single GCMN received a dermatological examination, were interviewed, and their mothers and teachers completed standardized questionnaires on the child's competence and behavioural/emotional problems and their own adjustment. Social problems were reported for 30% of the patients and behavioural/emotional problems for 25.9%. There was no correlation between visibility of the naevus, treatment or child age and psychological problems. Mothers reported considerable psychosocial burden. It is concluded that children with GCMN are at increased risk of social and behavioural/emotional problems, and mothers suffer considerable psychological impact of their child's condition

The human homologue of the yeast mitochondrial AAA metalloprotease Yme1p complements a yeast yme1 disruptant

AbstractIn yeast, three AAA superfamily metalloproteases (Yme1p, Afg3p and Rca1p) are localized to the mitochondrial inner membrane where they perform roles in the assembly and turnover of the respiratory chain complexes. We have investigated the function of the proposed human orthologue of yeast Yme1p, encoded by the YME1L gene on chromosome 10p. Transfection of both HEK-293EBNA and yeast cells with a green fluorescent protein-tagged YME1L cDNA confirmed mitochondrial targeting. When expressed in a yme1 disruptant yeast strain, YME1L restored growth on glycerol at 37°C. We propose that YME1L plays a phylogenetically conserved role in mitochondrial protein metabolism and could be involved in mitochondrial pathologies

Relationships between renal cytoplasmic and nuclear aldosterone-receptors

Relationships between renal cytoplasmic and nuclear aldosteronereceptors.Three 3H-aldosterone receptor complexes have been recovered from rat kidneys: 1) cytosol (high speed supernatants), 2) Tris-soluble nuclear (obtained by an osmotic shock procedure), and 3) chromatin-bound (prepared by extracting post-shock nuclei with 0.4 M KCl).Glycerol density gradient analyses of cytosol labelled in vivo or in vitro with 3H-aldosterone yielded two specific peaks -4.5S and 8.5S.These peaks were sensitive to salt concentration; 0.4 M KCl shifted the 8.5S to 4.5S and the addition of Ca++ (6 mM) resulted in a further shift to 3.5S.The Tris-soluble nuclear species sedimented at 3S and the chromatin-bound species at 4S.The time-course of generation of the 3H-aldosterone-labelled cytosol and nuclear receptor species was studied in vivo and in vitro by tissue slice and reconstitution methods.The results obtained are consistent with a three-step mechanism: cytosol (8.5S or 4.5S)→ Tris-soluble nuclear (3S)→ chromatin-bound (4S).Alternatively, the 3S and 4S complexes may be attached to independent nuclear sites.The formation of the chromatin-bound species was temperature sensitive and failed to form at 0°C.Pre-treatment with DNase but not RNase impaired the generation of both the Tris-soluble nuclear and chromatin-bound species.These results imply a close association between nuclear aldosterone-receptor complexes and intact DNA

Een nieuwe en handzame lysimeter: eerste stap naar een nationaal netwerk voor de werkelijke verdamping?

Vrijwel overal op aarde verdampt meer dan de helft van het neerslagwater, ook in Nederland. Toch wordt deze grote verliespost in ons land slechts sporadisch gemeten. Door inspanningen van kennisinstituten, bedrijven en overheid is daarom een lysimeter ontwikkeld. Metingen in 2014 en 2015 op twee locaties vertonen opvallende verschillen, maar ook grote overeenkomsten, met eddy-correlatiemetingen. Schattingen van de verdamping via satellietdata zijn hoger dan de metingen. Tijd daarom, om metingen in het veld te combineren met modellen en waarnemingen vanuit de ruimt

Circulating metabolites modulated by diet are associated with depression

Metabolome reflects the interplay of genome and exposome at molecular level and thus can provide deep insights into the pathogenesis of a complex disease like major depression. To identify metabolites associated with depression we performed a metabolome-wide association analysis in 13,596 participants from five European population-based cohorts characterized for depression, and circulating metabolites using ultra high-performance liquid chromatography/tandem accurate mass spectrometry (UHPLC/MS/MS) based Metabolon platform. We tested 806 metabolites covering a wide range of biochemical processes including those involved in lipid, amino-acid, energy, carbohydrate, xenobiotic and vitamin metabolism for their association with depression. In a conservative model adjusting for life style factors and cardiovascular and antidepressant medication use we identified 8 metabolites, including 6 novel, significantly associated with depression. In individuals with depression, increased levels of retinol (vitamin A), 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1) (lecithin) and mannitol/sorbitol and lower levels of hippurate, 4-hydroxycoumarin, 2-aminooctanoate (alpha-aminocaprylic acid), 10-undecenoate (11:1n1) (undecylenic acid), 1-linoleoyl-GPA (18:2) (lysophosphatidic acid; LPA 18:2) are observed. These metabolites are either directly food derived or are products of host and gut microbial metabolism of food-derived products. Our Mendelian randomization analysis suggests that low hippurate levels may be in the causal pathway leading towards depression. Our findings highlight putative actionable targets for depression prevention that are easily modifiable through diet interventions.</p

Prevention of depression and anxiety in adolescents: A randomized controlled trial testing the efficacy and mechanisms of Internet-based self-help problem-solving therapy

<p>Abstract</p> <p>Background</p> <p>Even though depression and anxiety are highly prevalent in adolescence, youngsters are not inclined to seek help in regular healthcare. Therapy through the Internet, however, has been found to appeal strongly to young people. The main aim of the present study is to examine the efficacy of preventive Internet-based guided self-help problem-solving therapy with adolescents reporting depressive and anxiety symptoms. A secondary objective is to test potential mediating and moderating variables in order to gain insight into how the intervention works and for whom it works best.</p> <p>Methods/design</p> <p>This study is a randomized controlled trial with an intervention condition group and a wait-list control group. The intervention condition group receives Internet-based self-help problem-solving therapy. Support is provided by a professional and delivered through email. Participants in the wait-list control group receive the intervention four months later. The study population consists of adolescents (12-18-year-olds) from the general population who report mild to moderate depressive and/or anxiety symptoms and are willing to complete a self-help course. Primary outcomes are symptoms of depression and anxiety. Secondary outcomes are quality of life, social anxiety, and cost-effectiveness. The following variables are examined for their moderating role: demographics, motivation, treatment credibility and expectancy, externalizing behaviour, perceived social support from parents and friends, substance use, the experience of important life events, physical activity, the quality of the therapeutic alliance, and satisfaction. Mediator variables include problem-solving skills, worrying, mastery, and self-esteem. Data are collected at baseline and at 3 weeks, 5 weeks, 4 months, 8 months, and 12 months after baseline. Both intention-to-treat and completer analyses will be conducted.</p> <p>Discussion</p> <p>This study evaluates the efficacy and mechanisms of Internet-based problem-solving therapy for adolescents. If Internet-based problem-solving therapy is shown to reduce depressive and anxiety symptoms in adolescents, the implication is to implement the intervention in clinical practice. Strengths and limitations of the study are discussed.</p> <p>Trial registration</p> <p>Netherlands Trial Register NTR1322</p

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been