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Background: The aim of the study was to assess underlying genetic cause(s), clinical features, and response to therapy in catecholaminergic polymorphic ventricular tachycardia (CPVT) probands. Methods and results: We identified 13 missense mutations in the cardiac ryanodine receptor (RYR2) in 12 probands with CPVT. Twelve were new, of which two are de novo mutations. A further 11 patients were silent gene carriers, suggesting that some mutations are associated with low penetrance. A marked resting sinus bradycardia off drugs was observed in all carriers. On β blocker treatment, 98% of the RYR2 mutation carriers remained symptom free with a median follow up of 2 (range: 2–37) years. Conclusion: CPVT patients with RYR2 mutation have bradycardia regardless of the site of the mutation, which could direct molecular diagnosis in (young) patients without structural heart disease presenting with syncopal events and a slow heart rate but with normal QTc at resting ECG. Treatment with β blockers has been very effective in our CPVT patients during initial or short term follow up. Given the risk of sudden death and the efficacy of β blocker therapy, the identification of large numbers of RYR2 mutations thus calls for genetic screening, early diagnosis, and subsequent preventive strategies.

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes.

Background In the Netherlands, more than one million patients have type 2 diabetes (T2D), and approximately 36% of these patients have chronic kidney disease (CKD). Yearly medical costs related to T2D and CKD account for approximately €1.3 billion and €805 million, respectively. The FIDELIO-DKD trial showed that the addition of finerenone to the standard of care (SoC) lowers the risk of CKD progression and cardiovascular (CV) events in patients with CKD stages 2–4 associated with T2D. This study investigates the cost-effectiveness of adding finerenone to the SoC of patients with advanced CKD and T2D compared to SoC monotherapy. Methods The validated FINE-CKD model is a Markov cohort model which simulates the disease pathway of patients over a lifetime time horizon. The model was adapted to reflect the Dutch societal perspective. The model estimated the incremental costs, utilities, and incremental cost-effectiveness ratio (ICER). Sensitivity and scenario analyses were performed to assess the effect of parameter uncertainty on model robustness. Results When used in conjunction with SoC, finerenone extended time free of CV events and renal replacement therapy by respectively 0.30 and 0.31 life years compared to SoC alone, resulting in an extension of 0.20 quality-adjusted life years (QALYs). The reduction in renal and CV events led to a €6136 decrease in total lifetime costs per patient compared to SoC alone, establishing finerenone as a dominant treatment option. Finerenone in addition to SoC had a 83% probability of being dominant and a 93% probability of being cost-effective at a willingness-to-pay threshold of €20,000. Conclusion By reducing the risk of CKD progression and CV events, finerenone saves costs to society while gaining QALYs in patients with T2D and advanced CKD in the Netherlands.

Stephanie London, Martin Tobin and colleagues report meta-analyses of genome-wide association studies for forced vital capacity (FVC), a spirometric measure of pulmonary function that reflects lung volume. They identify six regions newly associated with FVC and demonstrate that candidate genes at these loci are expressed in lung tissue and primary lung cells. Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance ( P < 5 × 10 −8 ) with FVC in or near EFEMP1 , BMP6 , MIR129-2 – HSD17B12 , PRDM11 , WWOX and KCNJ2 . Two loci previously associated with spirometric measures ( GSTCD and PTCH1 ) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

Genome-wide association studies (GWAS) have identified loci reproducibly associated with pulmonary diseases; however, the molecular mechanism underlying these associations are largely unknown. The objectives of this study were to discover genetic variants affecting gene expression in human lung tissue, to refine susceptibility loci for asthma identified in GWAS studies, and to use the genetics of gene expression and network analyses to find key molecular drivers of asthma. We performed a genome-wide search for expression quantitative trait loci (eQTL) in 1,111 human lung samples. The lung eQTL dataset was then used to inform asthma genetic studies reported in the literature. The top ranked lung eQTLs were integrated with the GWAS on asthma reported by the GABRIEL consortium to generate a Bayesian gene expression network for discovery of novel molecular pathways underpinning asthma. We detected 17,178 cis- and 593 trans- lung eQTLs, which can be used to explore the functional consequences of loci associated with lung diseases and traits. Some strong eQTLs are also asthma susceptibility loci. For example, rs3859192 on chr17q21 is robustly associated with the mRNA levels of GSDMA (P = 3.55 × 10(-151)). The genetic-gene expression network identified the SOCS3 pathway as one of the key drivers of asthma. The eQTLs and gene networks identified in this study are powerful tools for elucidating the causal mechanisms underlying pulmonary disease. This data resource offers much-needed support to pinpoint the causal genes and characterize the molecular function of gene variants associated with lung diseases.

Aquatic risk assessments for fungicides are carried out without information on their toxicity to non-target aquatic fungi. This might cause an underestimation of the toxic effects to the aquatic fungal community. This study focuses on the question whether recently derived concentrations limits for fungicides considered to protect populations of primary producers and (in)vertebrates also do protect the aquatic fungi. A panel of fungal species and Oomycetes was isolated and identified from unpolluted surface waters in the Netherlands. Toxicity tests were used to determine effects of seven fungicides with different modes of actions. For the triazoles epoxiconazole and tebuconazole, the chronic lowest observable effect concentration was lower than the regulatory acceptable concentration based on acute HC5 values.

During multicellular development, specification of distinct cell fates is often regulated by the same transcription factors operating differently in distinct cis-regulatory modules(1-3), either through different protein complexes, conformational modification of protein complexes, or combinations of both. Direct visualization of different transcription factor complex states guiding specific gene expression programs has been challenging. Here we use in vivo FRET-FLIM (Forster resonance energy transfer measured by fluorescence lifetime microscopy) to reveal spatial partitioning of protein interactions in relation to specification of cell fate. We show that, in Arabidopsis roots, three fully functional fluorescently tagged cell fate regulators establish cell-type-specific interactions at endogenous expression levels and can form higher order complexes. We reveal that cell-type-specific in vivo FRET-FLIM distributions reflect conformational changes of these complexes to differentially regulate target genes and specify distinct cell fates.

Water flow on mers Understanding how surface water flow could have produced the observed deltas and alluvial fans on the surface of Mars is fundamental to understanding the history of water on the planet. Flow duration in particular is an important factor, but to date, estimates for the longevity of martian hydrologic events have varied erratically, from decades to millions of years. Now, in a series of experiments here on Earth, in the Eurotank facility at Utrecht University, the characteristic morphology of martian stepped or terraced deltas has been recreated. The findings suggest that the stepped fans were formed by sudden release of water from subsurface storage, rather than by surface precipitation. In the conditions prevailing on Mars, this morphology is consistent with a single basin-filling event taking tens of years, and may have required an amount of water comparable to that discharged by a large terrestrial river about the size of the Mississippi. The cover image is a photo composite of a 4 mm-per-pixel digital terrain model of an experimentally formed crater from the Eurotank. Sand flume studies show that the distinct morphology of martian stepped deltas could only have originated from a single basin-filling event on a timescale of tens of years and may have required an amount of water comparable to that discharged by large terrestrial rivers. Deltas and alluvial fans preserved on the surface of Mars provide an important record of surface water flow 1 , 2 , 3 . Understanding how surface water flow could have produced the observed morphology is fundamental to understanding the history of water on Mars. To date, morphological studies have provided only minimum time estimates for the longevity of martian hydrologic events, which range from decades to millions of years 4 , 5 , 6 , 7 . Here we use sand flume studies to show that the distinct morphology of martian stepped (terraced) deltas 8 , 9 , 10 , 11 could only have originated from a single basin-filling event on a timescale of tens of years. Stepped deltas therefore provide a minimum and maximum constraint on the duration and magnitude of some surface flows on Mars. We estimate that the amount of water required to fill the basin and deposit the delta is comparable to the amount of water discharged by large terrestrial rivers, such as the Mississippi. The massive discharge, short timescale, and the associated short canyon lengths favour the hypothesis that stepped fans are terraced delta deposits draped over an alluvial fan and formed by water released suddenly from subsurface storage.