Ca2+ signaling is vital for various cellular processes including synaptic vesicle exocytosis, muscle contraction, regulation of secretion, gene transcription, and cellular proliferation. The ...endoplasmic reticulum (ER) is the largest intracellular Ca2+ store, and dysregulation of ER Ca2+ signaling and homeostasis contributes to the pathogenesis of various complex disorders and Mendelian disease traits. We describe four unrelated individuals with a complex multisystem disorder characterized by woolly hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and global developmental delay. Through whole-exome sequencing and family-based genomics, we identified bi-allelic variants in CCDC47 that encodes the Ca2+-binding ER transmembrane protein CCDC47. CCDC47, also known as calumin, has been shown to bind Ca2+ with low affinity and high capacity. In mice, loss of Ccdc47 leads to embryonic lethality, suggesting that Ccdc47 is essential for early development. Characterization of cells from individuals with predicted likely damaging alleles showed decreased CCDC47 mRNA expression and protein levels. In vitro cellular experiments showed decreased total ER Ca2+ storage, impaired Ca2+ signaling mediated by the IP3R Ca2+ release channel, and reduced ER Ca2+ refilling via store-operated Ca2+ entry. These results, together with the previously described role of CCDC47 in Ca2+ signaling and development, suggest that bi-allelic loss-of-function variants in CCDC47 underlie the pathogenesis of this multisystem disorder.
In the 2000s a new aid regime evolved. This promised to move beyond the former neoliberal approach in a number of ways. It would involve greater consultation between donors and recipients, shift the ...focus from economic growth to broader factors, including poverty, and hand back the responsibility for this to the nation-state. This approach bears strong resemblance to the rise of neostructuralism, a development paradigm that has become highly influential in Latin America. In this article we trace the shifts in the aid regime and ask to what extent the contemporary regime can be defined a postneoliberal paradigm.
Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets.
We used exome sequence data and electronic health records from 46,544 participants in the ...DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples.
A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10
) and AST (P=6.2×10
). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% 95% confidence interval {CI}, 20 to 58 among heterozygotes and by 53% 95% CI, 3 to 77 among homozygotes), nonalcoholic liver disease (by 17% 95% CI, 8 to 25 among heterozygotes and by 30% 95% CI, 13 to 43 among homozygotes), alcoholic cirrhosis (by 42% 95% CI, 14 to 61 among heterozygotes and by 73% 95% CI, 15 to 91 among homozygotes), and nonalcoholic cirrhosis (by 26% 95% CI, 7 to 40 among heterozygotes and by 49% 95% CI, 15 to 69 among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity.
A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.).
In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart ...failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target.
Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis.
We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)-a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide.
Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.
To estimate the prevalence of
sequence variants associated with DYT1 dystonia.
We determined the frequency of the common trinucleotide deletion that causes DYT1 in the Genome Aggregation Database and ...the Penn Medicine Biobank, totaling exomes from over 135,000 individuals. We also evaluated the prevalence of other possible pathogenic variants in this gene and asked whether the D216H polymorphism is linked to a higher diagnostic rate for dystonia independent of the DYT1-causing mutation.
The estimated range of prevalence of the most common pathogenic variant that causes DYT1 is ∼17.6-26.1 carriers per 100,000 individuals. Based on the different data sets used, we predict that there are between 54,366 and 80,891 mutation carriers in the United States, which, due to the reduced penetrance of this variant, would translate into 16,475-24,513 DYT1 patients.
Our data provide a prevalence estimate of the most common DYT1 mutation in the general population. This information is specifically important for those with interest in the development of precision therapeutics for dystonia.
Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, ...providing a strategy for the discovery of new therapeutic targets.
We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations.
The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in
,
,
, and
were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in
, which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in
(combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 U per liter; 95% confidence interval CI, -1.66 to -0.83; P = 4.8×10
) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P = 9.9×10
). Rare coding variants in
were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in
were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 scores range from 0 to 8, with higher scores indicating more severe disease). In human hepatoma cell lines challenged with oleate,
small interfering RNA knockdown prevented the buildup of large lipid droplets.
Rare germline mutations in
conferred substantial protection from liver disease. (Funded by Regeneron Pharmaceuticals.).
AbstractThe design of pier foundations in expansive soils is an important and challenging aspect of geotechnical engineering. Established methods for pier analysis include rigid and elastic methods. ...These methods have certain limitations that restrict their applicability to evaluate certain complex aspects of pier heave, including variable soil profiles, complex wetting profiles, large length-to-diameter ratios, and complex pier configurations and materials. To address those limitations, a method of analysis was developed providing a versatile and robust tool to predict both pier heave and axial forces developed by expansive soils. This method utilizes a standard finite-element code to solve for pier heave and force in the pier for the given boundary conditions. This paper contains both a discussion of the general design procedure and the finite-element formulation. This design procedure, including the finite-element code, accurately determines pier heave and force in a pier compared with field-measured data. The design procedure and the finite-element code in particular, address the limitations of the established rigid and elastic pier analysis methods with the flexibility to evaluate complex design situations. A comparison with field-measured pier heave and tensile force in the pier demonstrates that the design procedure accurately models both the magnitude of pier heave and force in the pier. The results obtained using this design procedure have been compared with those obtained using the established pier analysis methods for simplified drilled pier examples. The comparison of the various methods of analysis demonstrates that the finite-element design procedure predicts pier heave values that are generally less than the existing elastic and rigid pier analysis methods. It is believed that the proposed design method is more realistic and provides a design tool with improved accuracy compared with existing methods.
Electronic health records (EHR) provide a comprehensive resource for discovery, allowing unprecedented exploration of the impact of genetic architecture on health and disease. The data of EHRs also ...allow for exploration of the complex interactions between health measures across health and disease. The discoveries arising from EHR based research provide important information for the identification of genetic variation for clinical decision-making. Due to the breadth of information collected within the EHR, a challenge for discovery using EHR based data is the development of high-throughput tools that expose important areas of further research, from genetic variants to phenotypes. Phenome-Wide Association studies (PheWAS) provide a way to explore the association between genetic variants and comprehensive phenotypic measurements, generating new hypotheses and also exposing the complex relationships between genetic architecture and outcomes, including pleiotropy. EHR based PheWAS have mainly evaluated associations with case/control status from International Classification of Disease, Ninth Edition (ICD-9) codes. While these studies have highlighted discovery through PheWAS, the rich resource of clinical lab measures collected within the EHR can be better utilized for high-throughput PheWAS analyses and discovery. To better use these resources and enrich PheWAS association results we have developed a sound methodology for extracting a wide range of clinical lab measures from EHR data. We have extracted a first set of 21 clinical lab measures from the de-identified EHR of participants of the Geisinger MyCodeTM biorepository, and calculated the median of these lab measures for 12,039 subjects. Next we evaluated the association between these 21 clinical lab median values and 635,525 genetic variants, performing a genome-wide association study (GWAS) for each of 21 clinical lab measures. We then calculated the association between SNPs from these GWAS passing our Bonferroni defined p-value cutoff and 165 ICD-9 codes. Through the GWAS we found a series of results replicating known associations, and also some potentially novel associations with less studied clinical lab measures. We found the majority of the PheWAS ICD-9 diagnoses highly related to the clinical lab measures associated with same SNPs. Moving forward, we will be evaluating further phenotypes and expanding the methodology for successful extraction of clinical lab measurements for research and PheWAS use. These developments are important for expanding the PheWAS approach for improved EHR based discovery.
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