Plasma Pro-Endothelin-1 Peptide Concentrations Rise in Chronic Kidney Disease and Following Selective Endothelin A Receptor Antagonism

The new analyses described in this article were funded by the Medical Research Council (Grant G0801509). Additional funding was from the British Heart Foundation (Project Grant PG/05/91), Encysive Pharmaceuticals, and Pfizer. Dr Dhaun is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/13/30/29994)

IgA nephropathy genetic risk score to estimate the prevalence of IgA nephropathy in UK Biobank.

This is the final version. Available fromElsevier via the DOI in this record. BACKGROUND: IgA nephropathy (IgAN) is the commonest glomerulonephritis worldwide. Its prevalence is difficult to estimate, as people with mild disease do not commonly receive a biopsy diagnosis. We aimed to generate an IgA nephropathy genetic risk score (IgAN-GRS) and estimate the proportion of people with hematuria who had IgAN in the UK Biobank (UKBB). METHODS: We calculated an IgAN-GRS using 14 single-nucleotide polymorphisms (SNPs) drawn from the largest European Genome-Wide Association Study (GWAS) and validated the IgAN-GRS in 464 biopsy-proven IgAN European cases from the UK Glomerulonephritis DNA Bank (UKGDB) and in 379,767 Europeans in the UKBB. We used the mean of IgAN-GRS to calculate the proportion of potential IgAN in 14,181 with hematuria and other nonspecific renal phenotypes from 379,767 Europeans in the UKBB. RESULTS: The IgAN-GRS was higher in the IgAN cohort (4.30; 95% confidence interval [95% CI: 4.23-4.38) than in controls (3.98; 3.97-3.98; P < 0.0001). The mean GRS in UKBB participants with hematuria (n = 12,858) was higher (4.04; 4.02-4.06) than UKBB controls (3.98; 3.97-3.98; P < 0.0001) and higher in those with hematuria, hypertension, and microalbuminuria (n = 1323) (4.07; 4.02-4.13) versus (3.98; 3.97-3.98; P = 0.0003). Using the difference in these means, we estimated that IgAN accounted for 19% of noncancer hematuria and 28% with hematuria, hypertension, and microalbuminuria in UKBB. CONCLUSIONS: We used an IgAN-GRS to estimate the prevalence of IgAN contributing to common phenotypes that are not always biopsied. The noninvasive use of polygenic risk in this setting may have further utility to identify likely etiology of nonspecific renal phenotypes in large population cohorts.Diabetes UKDiabetes UKWellcome TrustNational Institute for Health Researc

Smooth Muscle Endothelin B Receptors Regulate Blood Pressure but Not Vascular Function or Neointimal Remodeling

The role of smooth muscle endothelin$_{B}$ (ET$_{B}$) receptors in regulating vascular function, blood pressure (BP), and neointimal remodeling has not been established. Selective knockout mice were generated to address the hypothesis that loss of smooth muscle ET$_{B}$ receptors would reduce BP, alter vascular contractility, and inhibit neointimal remodeling. ET$_{B}$ receptors were selectively deleted from smooth muscle by crossing floxed ET$_{B}$ mice with those expressing cre-recombinase controlled by the transgelin promoter. Functional consequences of ET$_{B}$ deletion were assessed using myography. BP was measured by telemetry, and neointimal lesion formation induced by femoral artery injury. Lesion size and composition (day 28) were analyzed using optical projection tomography, histology, and immunohistochemistry. Selective deletion of ET$_{B}$ was confirmed by genotyping, autoradiography, polymerase chain reaction, and immunohistochemistry. ET$_{B}$-mediated contraction was reduced in trachea, but abolished from mesenteric veins, of knockout mice. Induction of ET$_{B}$-mediated contraction in mesenteric arteries was also abolished in these mice. Femoral artery function was unaltered, and baseline BP modestly elevated in smooth muscle ET$_{B}$ knockout compared with controls (+4.2±0.2 mm Hg; $\textit{P}$<0.0001), but salt-induced and ET$_{B}$ blockade-mediated hypertension were unaltered. Circulating endothelin-1 was not altered in knockout mice. ET$_{B}$-mediated contraction was not induced in femoral arteries by incubation in culture medium or lesion formation, and lesion size was not altered in smooth muscle ET$_{B}$ knockout mice. In the absence of other pathology, ET$_{B}$ receptors in vascular smooth muscle make a small but significant contribution to ET$_{B}$-dependent regulation of BP. These ET$_{B}$ receptors have no effect on vascular contraction or neointimal remodeling.This work was funded by the British Heart Foundation (Project Grant PG/08/068/25461, P.W.F. Hadoke and D.J. Webb; Intermediate Clinical Research Fellowship FS/13/30/29994, N. Dhaun; and Centre of Research Excellence Award) and the Wellcome Trust (107715/Z/15/Z, A.P. Davenport and R.E. Kuc)

IgA Nephropathy Genetic Risk Score to Estimate the Prevalence of IgA Nephropathy in UK Biobank

Background: IgA nephropathy (IgAN) is the commonest glomerulonephritis worldwide. Its prevalence is difficult to estimate, as people with mild disease do not commonly receive a biopsy diagnosis. We aimed to generate an IgA nephropathy genetic risk score (IgAN-GRS) and estimate the proportion of people with hematuria who had IgAN in the UK Biobank (UKBB). Methods: We calculated an IgAN-GRS using 14 single-nucleotide polymorphisms (SNPs) drawn from the largest European Genome-Wide Association Study (GWAS) and validated the IgAN-GRS in 464 biopsy-proven IgAN European cases from the UK Glomerulonephritis DNA Bank (UKGDB) and in 379,767 Europeans in the UKBB. We used the mean of IgAN-GRS to calculate the proportion of potential IgAN in 14,181 with hematuria and other nonspecific renal phenotypes from 379,767 Europeans in the UKBB. Results: The IgAN-GRS was higher in the IgAN cohort (4.30; 95% confidence interval [95% CI: 4.23–4.38) than in controls (3.98; 3.97–3.98; P < 0.0001). The mean GRS in UKBB participants with hematuria (n = 12,858) was higher (4.04; 4.02–4.06) than UKBB controls (3.98; 3.97–3.98; P < 0.0001) and higher in those with hematuria, hypertension, and microalbuminuria (n = 1323) (4.07; 4.02–4.13) versus (3.98; 3.97–3.98; P = 0.0003). Using the difference in these means, we estimated that IgAN accounted for 19% of noncancer hematuria and 28% with hematuria, hypertension, and microalbuminuria in UKBB. Conclusions: We used an IgAN-GRS to estimate the prevalence of IgAN contributing to common phenotypes that are not always biopsied. The noninvasive use of polygenic risk in this setting may have further utility to identify likely etiology of nonspecific renal phenotypes in large population cohorts

Does 'Political Bias' Undermine the Korea Investment Corporation?

Based on “in-depth study”, the aim of the chapter is to analyze Korea Investment Corporation (KIC), a non-commodity Sovereign Wealth Fund, in order to investigate its investment strategies over the time (2005-2012) and evaluate any form of ‘political bias’. Our results suggest that KIC pursues financial objectives, aiming to maximize the portfolio risk/return relationship, as it manages foreign excess reserves of those managed by Bank of Korea. We also argue that a form of ‘internal political bias’ affects investment process, as most of the financial resources are managed in-house. Overall, we support the hypothesis that in Korea Investment Corporation both financial and political objectives coexist

Sequences of two related multiple antibiotic resistance virulence plasmids sharing a unique IS26-related molecular signature isolated from different Escherichia coli pathotypes from different hosts

Enterohemorrhagic Escherichia coli (EHEC) and atypical enteropathogenic E. coli (aEPEC) are important zoonotic pathogens that increasingly are becoming resistant to multiple antibiotics. Here we describe two plasmids, pO26-CRL125 (125 kb) from a human O26:H- EHEC, and pO111-CRL115 (115kb) from a bovine O111 aEPEC, that impart resistance to ampicillin, kanamycin, neomycin, streptomycin, sulfathiazole, trimethoprim and tetracycline and both contain atypical class 1 integrons with an identical IS26-mediated deletion in their 3'-conserved segment. Complete sequence analysis showed that pO26-CRL125 and pO111-CRL115 are essentially identical except for a 9.7 kb fragment, present in the backbone of pO26-CRL125 but absent in pO111-CRL115, and several indels. The 9.7 kb fragment encodes IncI-associated genes involved in plasmid stability during conjugation, a putative transposase gene and three imperfect repeats. Contiguous sequence identical to regions within these pO26-CRL125 imperfect repeats was identified in pO111-CRL115 precisely where the 9.7 kb fragment is missing, suggesting it may be mobile. Sequences shared between the plasmids include a complete IncZ replicon, a unique toxin/antitoxin system, IncI stability and maintenance genes, a novel putative serine protease autotransporter, and an IncI1 transfer system including a unique shufflon. Both plasmids carry a derivate Tn21 transposon with an atypical class 1 integron comprising a dfrA5 gene cassette encoding resistance to trimethoprim, and 24 bp of the 3'-conserved segment followed by Tn6026, which encodes resistance to ampicillin, kanymycin, neomycin, streptomycin and sulfathiazole. The Tn21-derivative transposon is linked to a truncated Tn1721, encoding resistance to tetracycline, via a region containing the IncP-1 alpha oriV. Absence of the 5 bp direct repeats flanking Tn3-family transposons, indicates that homologous recombination events played a key role in the formation of this complex antibiotic resistance gene locus. Comparative sequence analysis of these closely related plasmids reveals aspects of plasmid evolution in pathogenic E. coli from different hosts