AimsGenetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce.Methods and resultsRespirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration.ConclusionMitochondrial dysfunction is explained by cardiomyocyte architecture disruption and is linked to septal hypertrophy in genotype-negative HCM. Despite severe myocardial remodelling mitochondria were responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in HCM. Mitochondria-targeting therapy may particularly benefit genotype-negative patients with HCM, given the tight link between mitochondrial impairment and septal thickening in this subpopulation.
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Eight new primer sets were designed for PCR detection of (i) mono-oxygenase and dioxygenase gene sequences involved in initial attack of bacterial aerobic BTEX degradation and of (ii) catechol 2,3-dioxygenase gene sequences responsible for meta-cleavage of the aromatic ring. The new primer sets allowed detection of the corresponding genotypes in soil with a detection limit of 10(3)-10(4) or 10(5)-10(6) gene copies g(-1) soil, assuming one copy of the gene per cell. The primer sets were used in PCR to assess the distribution of the catabolic genes in BTEX degrading bacterial strains and DNA extracts isolated from soils sampled from different locations and depths (vadose, capillary fringe and saturated zone) within a BTEX contaminated site. In both soil DNA and the isolates, tmoA-, xylM- and xylE1-like genes were the most frequently recovered BTEX catabolic genes. xylM and xylE1 were only recovered from material from the contaminated samples while tmoA was detected in material from both the contaminated and non-contaminated samples. The isolates, mainly obtained from the contaminated locations, belonged to the Actinobacteria or Proteobacteria (mainly Pseudomonas). The ability to degrade benzene was the most common BTEX degradation phenotype among them and its distribution was largely congruent with the distribution of the tmoA-like genotype. The presence of tmoA and xylM genes in phylogenetically distant strains indicated the occurrence of horizontal transfer of BTEX catabolic genes in the aquifer. Overall, these results show spatial variation in the composition of the BTEX degradation genes and hence in the type of BTEX degradation activity and pathway, at the examined site. They indicate that bacteria carrying specific pathways and primarily carrying tmoA/xylM/xylE1 genotypes, are being selected upon BTEX contamination.
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Phytophthora infestans, the causal agent of late blight, remains the main threat to potato production worldwide. Screening of 19 accessions of Solanum dulcamara with P. infestans isolate Ipo82001 in detached leaf assays revealed strong resistance in an individual belonging to accession A54750069-1. This plant was crossed with a susceptible genotype, and an F(1) population consisting of 63 individuals was obtained. This population segregated for resistance in 1:1 ratio, both in detached leaf assays and in an open-field experiment. Presence of the formerly mapped Rpi-dlc1 gene as the cause of the observed segregating resistance could be excluded. Subsequently, AFLP analyses using 128 primer combinations enabled identification of five markers linked to a novel resistance gene named Rpi-dlc2. AFLP markers did not show sequence similarity to the tomato and potato genomes, hampering comparative genetic positioning of the gene. For this reason we used next-generation mapping (NGM), an approach that exploits direct sequencing of DNA (in our case: cDNA) pools from bulked segregants to calculate the genetic distance between SNPs and the locus of interest. Plotting of these genetic distances on the tomato and potato genetic map and subsequent PCR-based marker analysis positioned the gene on chromosome 10, in a region overlapping with the Rpi-ber/ber1 and -ber2 loci from S. berthaultii. Pyramiding of Rpi-dlc2 and Rpi-dlc1 significantly increased resistance to P. infestans, compared with individuals containing only one of the genes, showing the usefulness of this strategy to enhance resistance against Phytophthora.
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Probiotic bacteria harbor effector molecules that confer health benefits, but also adaptation factors that enable them to persist in the gastrointestinal tract of the consumer. To study these adaptation factors, an antibiotic-resistant derivative of the probiotic model organism Lactobacillus plantarum WCFS1 was repeatedly exposed to the mouse digestive tract by three consecutive rounds of (re)feeding of the longest persisting colonies. This exposure to the murine intestine allowed the isolation of intestine-adapted derivatives of the original strain that displayed prolonged digestive tract residence time. Re-sequencing of the genomes of these adapted derivatives revealed single nucleotide polymorphisms as well as a single nucleotide insertion in comparison with the genome of the original WCFS1 strain. Detailed in silico analysis of the identified genomic modifications pinpointed that alterations in the coding regions of genes encoding cell envelope associated functions and energy metabolism appeared to be beneficial for the gastrointestinal tract survival of L. plantarum WCFS1. This work demonstrates the feasibility of experimental evolution for the enhancement of the gastrointestinal residence time of probiotic strains, while full-genome resequencing of the adapted isolates provided clues towards the bacterial functions involved. Enhanced gastrointestinal residence is industrially relevant because it enhances the efficacy of the delivery of viable probiotics in situ.
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Background. One of the stakeholders in tackling the rise and health consequences of overweight and obesity is the general practice physician (GP). GPs are in a good position to inform and give nutrition guidance to overweight patients. Objective. Assessment of working mechanism of determinants of the nutrition guidance practice: noticing patients’ overweight and guidance of treatment by GPs [linear analysis of structural relations (LISREL) path model] in a longitudinal study. Methods. This longitudinal study measured data in 1992, 1997 and 2007. The 1992 LISREL path model (Hiddink GJ, Hautvast J, vanWoerkumCMJ, Fieren CJ, vantHofMA. Nutrition guidance by primary-care physicians: LISREL analysis improves understanding. Prev Med 1997; 26: 29–36.) demonstrated that ‘noticing patients’ overweight and guidance of treatment’ was directly and indirectly influenced by predisposing factors, driving forces and perceived barriers. This article defines and discusses the path analysis of the 2007 data (compared with 1997). Results. This analysis shows both similarity and differences inworking mechanism of determinants of noticing patients’ overweight and guidance of treatment between 1997 and 2007. The backbone of themechanism with four predisposing factors is the similarity. The number of driving forces and of paths through intermediary factors to the dependent variable constitutes the difference. Conclusions. The backbone of the working mechanism of determinants of the nutrition guidance practice: noticing patients’ overweight and guidance of treatment by GPs was similar in 2007 and 1997. The influence of GPs task perception on noticing patients’ overweight and guidance of treatment considerably increased in 2007 compared to 1997. The longitudinal character of this article gives a strong practice-based evidence for weight management by GPs.
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Het overvoeren van zeer jonge kinderen (0 - 3 jaar) leidt ertoe dat zij later als volwassene een enorm hongergevoel hebben en daardoor in onze maatschappij van automatisering en overvloed overgewicht ontwikkelen. Daarnaast slapen mensen met overgewicht significant korter. In dit artikel wordt uiteengezet wat de evolutionaire verklaring hiervoor zou kunnen zijn. Tevens wordt een toetsbare hypothese opgesteld waarin de voorspelling wordt gedaan dat overvoeren op jonge leeftijd leidt tot overgewicht en korter slapen op latere leeftijd.
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Plant photosynthesis and biomass production are associated with the amount of intercepted light, especially the light distribution inside the canopy. Three virtual canopies (n = 80, 3.25 plants/m2) were constructed based on average leaf size of the digitized plant structures: ‘small leaf’ (98.1 cm2), ‘medium leaf’ (163.0 cm2) and ‘big leaf’ (241.6 cm2). The ratios of diffuse light were set in three gradients (27.8%, 48.7%, 89.6%). The simulations of light interception were conducted under different ratios of diffuse light, before and after the normalization of incident radiation. With 226.1% more diffuse light, the result of light interception could increase by 34.4%. However, the 56.8% of reduced radiation caused by the increased proportion of diffuse light inhibited the advantage of diffuse light in terms of a 26.8% reduction in light interception. The big-leaf canopy had more mutual shading effects, but its larger leaf area intercepted 56.2% more light than the small-leaf canopy under the same light conditions. The small-leaf canopy showed higher efficiency in light penetration and higher light interception per unit of leaf area. The study implied the 3D structural model, an effective tool for quantitative analysis of the interaction between light and plant canopy structure.
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Er lijkt een duidelijke mate van evidentie te bestaan betreffende de relatie fysieke activiteit, respectievelijk fitheid en gezondheid in de algemene populatie en bij bepaalde pathologieën. Er is evenwel nog behoefte aan verder wetenschappelijk onderzoek naar mogelijke determinanten en onderliggende mechanismen, als ook naar evidentie bij bepaalde, specifieke aandoeningen. Tevens mag duidelijk zijn dat ondanks de bestaande evidentie fysieke activiteit/oefening te weinig toegepast wordt in de gezondheidszorg. Het onderzoek naar de effectiviteit van gezondheidskundige interventies is dan ook uitermate belangrijk. Dit lectoraat hoopt dan ook een bescheiden bijdrage hieraan te kunnen leveren. Hiervoor heeft zij reeds afspraken tot samenwerking met de academische en medische wereld (in Utrecht, Amsterdam, Maastricht en Leuven), met de gezondheidszorg (RIVM Bilthoven en GG&GD Utrecht) en met de beroepen- of bedrijfswereld (Politie regio Utrecht; Enraf Nonius, Delft). De beoogde doelstellingen zullen echter naar alle waarschijnlijkheid beduidend meer tijd in beslag nemen dan de periode van 4 jaar die de Stichting Kennis Ontwikkeling voorzien heeft met betrekking tot het oprichten en financieren van de lectoraten.
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