ACTH and Polymorphisms at Steroidogenic Loci as Determinants of Aldosterone Secretion and Blood Pressure

The majority of genes contributing to the heritable component of blood pressure remain unidentified, but there is substantial evidence to suggest that common polymorphisms at loci involved in the biosynthesis of the corticosteroids aldosterone and cortisol are important. This view is supported by data from genome-wide association studies that consistently link the CYP17A1 locus to blood pressure. In this review article, we describe common polymorphisms at three steroidogenic loci (CYP11B2, CYP11B1 and CYP17A1) that alter gene transcription efficiency and levels of key steroids, including aldosterone. However, the mechanism by which this occurs remains unclear. While the renin angiotensin system is rightly regarded as the major driver of aldosterone secretion, there is increasing evidence that the contribution of corticotropin (ACTH) is also significant. In light of this, we propose that the differential response of variant CYP11B2, CYP11B1 and CYP17A1 genes to ACTH is an important determinant of blood pressure, tending to predispose individuals with an unfavourable genotype to hypertension.</p

Joint actions with large partners and small-firm ambidexterity in asymmetric alliances:The mediating role of relational identification

This study investigates the role of relational identification in the relation between joint actions and small-firm ambidexterity in asymmetric alliances. Using survey data on Chinese high-technology firms, we find that joint problem-solving and joint sensemaking are both positively associated with small firm's relational identification. We also find a positive relationship between small firm's relational identification and knowledge exploration and exploitation. More importantly, we show that relational identification mediates the relationships between joint actions (i.e., joint problem-solving and joint sensemaking) and small-firm ambidexterity, except for the relationship between joint sensemaking and small-firm knowledge exploitation. This study advances our understanding of the association between joint actions and ambidexterity by providing a social identification explanation

Alterations in vascular function in primary aldosteronism - a cardiovascular magnetic resonance imaging study

Introduction: Excess aldosterone is associated with increased cardiovascular risk. Aldosterone has a permissive effect on vascular fibrosis. Cardiovascular magnetic resonance imaging (CMR) allows study of vascular function by measuring aortic distensibility. We compared aortic distensibility in primary aldosteronism (PA), essential hypertension (EH) and normal controls and explored the relationship between aortic distensibility and pulse wave velocity (PWV).&lt;p&gt;&lt;/p&gt; Methods: We studied PA (n=14) and EH (n=33) subjects and age-matched healthy controls (n=17) with CMR, including measurement of aortic distensibility, and measured PWV using applanation tonometry. At recruitment, PA and EH patients had similar blood pressure and left ventricular mass.&lt;p&gt;&lt;/p&gt; Results: Subjects with PA had significantly lower aortic distensibilty and higher PWV compared to EH and healthy controls. These changes were independent of other factors associated with reduced aortic distensibility, including aging. There was a significant relationship between increasing aortic stiffness and age in keeping with physical and vascular aging. As expected, aortic distensibility and PWV were closely correlated.&lt;p&gt;&lt;/p&gt; Conclusion: These results demonstrate that PA patients display increased arterial stiffness compared to EH, independent of vascular aging. The implication is that aldosterone invokes functional impairment of arterial function. The long-term implications of arterial stiffening in aldosterone excess require further study.&lt;p&gt;&lt;/p&gt

Resistance to the antimicrobial agent fosmidomycin and an FR900098 prodrug through mutations in the deoxyxylulose phosphate reductoisomerase gene (dxr)

There is a pressing need for new antimicrobial therapies to combat globally important drug-resistant human pathogens, including Plasmodium falciparum malarial parasites, Mycobacterium tuberculosis, and Gram-negative bacteria, including Escherichia coli. These organisms all possess the essential methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, which is not found in humans. The first dedicated enzyme of the MEP pathway, 1-deoxy-d-xylulose 5-phosphate reductoisomerase (Dxr), is inhibited by the phosphonic acid antibiotic fosmidomycin and its analogs, including the N-acetyl analog FR900098 and the phosphoryl analog fosfoxacin. In order to identify mutations in dxr that confer resistance to these drugs, a library of E. coli dxr mutants was screened at lethal fosmidomycin doses. The most resistant allele (with the S222T mutation) alters the fosmidomycin-binding site of Dxr. The expression of this resistant allele increases bacterial resistance to fosmidomycin and other fosmidomycin analogs by 10-fold. These observations confirm that the primary cellular target of fosmidomycin is Dxr. Furthermore, cell lines expressing Dxr-S222T will be a powerful tool to confirm the mechanisms of action of future fosmidomycin analogs

My Life and Times at Iowa State University

https://lib.dr.iastate.edu/carver_narratives/1025/thumbnail.jp

4-H Programming for Urban Youth in Des Moines, Iowa

Within Polk County, Iowa there existed a need for additional 4-H programming in the Des Moines Metro area geared toward middle and high school aged youth. Information was gathered in regards to the barriers this age group experienced which has led to their lack of participation. Through this Creative Component I identified two key barriers, location and cost, and, along with utilizing the Positive Youth Development concepts of belonging and mastery, developed youth programming for this particular group. Once the information was gathered I created 15 hours of relevant curriculum on the topics of STEM, Cooking, and Communication and Interview skills to be delivered to middle and high school youth in Des Moines at no cost

The evolution of entrepreneurial finance – 10 years after the global financial crisis [Editorial]

In the period following the global financial crisis, as banks and private equity investors withdrew from early stage entrepreneurial finance markets in the United Kingdom and developed economies (Mac an Bhaird, 2014; Wilson and Silver, 2013), there was a profusion in supply of alternative sources of early stage entrepreneurial finance (World Bank, 2013). These new financing options for firms partly alleviated the adverse effects of pro-cyclical provision of entrepreneurial finance (Mac an Bhaird et al., 2019). The large increase in provision of nontraditional sources of finance for the real economy was viewed as revolutionary (Harrison, 2013) and potentially transformative (Bruton et al., 2015), and its sustained use over more than a decade suggests that it is more than a passing fad. The amount of finance procured from these sources has grown significantly in a very short time period and is estimated to surpass investment from traditional sources of funding in the near future (Barnett, 2015). These developments have significant implications in relation to the supply of, and demand for, entrepreneurial finance, including well-established issues which primarily stem from information asymmetries, such as agency, signalling, moral hazard and adverse selection. The emergence of new sources of alternative finance introduces additional concerns in relation to regulation, investor protection, ownership and governance, among other issues (Bruton et al., 2015). The significant increase in the supply and use of alternative sources of finance has been facilitated to a large extent by the expansion of the Internet and use of social media. The increase in supply of, and demand for, alternative sources of finance has been accompanied by a burgeoning literature on the subject, due primarily to the availability of data that are accessible from the online platforms and websites. Over a decade has passed since the increased provision and use of alternative finance in its various forms and amounts, providing us with an opportunity to assess and analyse its adoption and to appraise how its provision may be improved for the benefit of investors and borrowers. At this juncture, we should have adequate evidence to increase the efficiency of provision from alternative sources, in order to improve the supply of finance in private debt and equity markets and to provide greater diversification and depth in financial markets. The International Journal of Entrepreneurship and Innovation has been to the forefront in publishing innovative studies on topical issues at the nexus of entrepreneurship and innovation (e.g. Volume 19, Issue 1, ‘Green innovation – connecting governance, practices and outcomes’). This special issue continues in that tradition, publishing state-of-the-art studies on a variety of issues related to innovations in entrepreneurial finance. This special issue is significantly different from other journal special issues on this subject (e.g. Baldock and Mason, 2015; Harrison, 2015; Owen et al., 2019) in the range and breadth of issues investigated and analysed. The studies represent a broad geographic spread, including New Zealand, the United Kingdom, France, and the United States. A broad range of financing innovations are also considered, including blockchain, peer-to-peer (P2P) lending, equity-based crowdfunding and mobile payment systems. Each article provides a unique contribution to our knowledge of entrepreneurial finance, and a brief summary is provided in the following section. [...

Common Polymorphisms at the <i>CYP17A1 </i>Locus Associate With Steroid Phenotype:Support for Blood Pressure Genome-Wide Association Study Signals at This Locus

Genome-wide association studies implicate the CYP17A1 gene in human blood pressure regulation although the causative polymorphisms are as yet unknown. We sought to identify common polymorphisms likely to explain this association. We sequenced the CYP17A1 locus in 60 normotensive individuals and observed 24 previously identified single-nucleotide polymorphisms with minor allele frequency &gt;0.05. From these, we selected, for further studies, 7 polymorphisms located ≤2 kb upstream of the CYP17A1 transcription start site. In vitro reporter gene assays identified 3 of these (rs138009835, rs2150927, and rs2486758) as having significant functional effects. We then analyzed the association between the 7 polymorphisms and the urinary steroid metabolites in a hypertensive cohort (n=232). Significant associations included that of rs138009835 with aldosterone metabolite excretion; rs2150927 associated with the ratio of tetrahydrodeoxycorticosterone to tetrahydrodeoxycortisol, which we used as an index of 17α-hydroxylation. Linkage analysis showed rs138009835 to be the only 1 of the 7 polymorphisms in strong linkage disequilibrium with the blood pressure–associated polymorphisms identified in the previous studies. In conclusion, we have identified, characterized, and investigated common polymorphisms at the CYP17A1 locus that have functional effects on gene transcription in vitro and associate with corticosteroid phenotype in vivo. Of these, rs138009835—which we associate with changes in aldosterone level—is in strong linkage disequilibrium with polymorphisms linked by genome-wide association studies to blood pressure regulation. This finding clearly has implications for the development of high blood pressure in a large proportion of the population and justifies further investigation of rs138009835 and its effects

Analysis of nuclear fiber cell compaction in transparent and cataractous diabetic human lenses by scanning electron microscopy

BACKGROUND: Compaction of human ocular lens fiber cells as a function of both aging and cataractogenesis has been demonstrated previously using scanning electron microscopy. The purpose of this investigation is to quantify morphological differences in the inner nuclear regions of cataractous and non-cataractous human lenses from individuals with diabetes. The hypothesis is that, even in the presence of the osmotic stress caused by diabetes, compaction rather than swelling occurs in the nucleus of diabetic lenses. METHODS: Transparent and nuclear cataractous lenses from diabetic patients were examined by scanning electron microscopy (SEM). Measurements of the fetal nuclear (FN) elliptical angles (anterior and posterior), embryonic nuclear (EN) anterior-posterior (A-P) axial thickness, and the number of EN fiber cell membrane folds over 20 μm were compared. RESULTS: Diabetic lenses with nuclear cataract exhibited smaller FN elliptical angles, smaller EN axial thicknesses, and larger numbers of EN compaction folds than their non-cataractous diabetic counterparts. CONCLUSION: As in non-diabetic lenses, the inner nuclei of cataractous lenses from diabetics were significantly more compacted than those of non-cataractous diabetics. Little difference between diabetic and non-diabetic compaction levels was found, suggesting that diabetes does not affect the degree of compaction. However, consistent with previous proposals, diabetes does appear to accelerate the formation of cataracts that are similar to age-related nuclear cataracts in non-diabetics. We conclude that as scattering increases in the diabetic lens with cataract formation, fiber cell compaction is significant

Analysis of nuclear fiber cell compaction in transparent and cataractous diabetic human lenses by scanning electron microscopy

BACKGROUND: Compaction of human ocular lens fiber cells as a function of both aging and cataractogenesis has been demonstrated previously using scanning electron microscopy. The purpose of this investigation is to quantify morphological differences in the inner nuclear regions of cataractous and non-cataractous human lenses from individuals with diabetes. The hypothesis is that, even in the presence of the osmotic stress caused by diabetes, compaction rather than swelling occurs in the nucleus of diabetic lenses. METHODS: Transparent and nuclear cataractous lenses from diabetic patients were examined by scanning electron microscopy (SEM). Measurements of the fetal nuclear (FN) elliptical angles (anterior and posterior), embryonic nuclear (EN) anterior-posterior (A-P) axial thickness, and the number of EN fiber cell membrane folds over 20 μm were compared. RESULTS: Diabetic lenses with nuclear cataract exhibited smaller FN elliptical angles, smaller EN axial thicknesses, and larger numbers of EN compaction folds than their non-cataractous diabetic counterparts. CONCLUSION: As in non-diabetic lenses, the inner nuclei of cataractous lenses from diabetics were significantly more compacted than those of non-cataractous diabetics. Little difference between diabetic and non-diabetic compaction levels was found, suggesting that diabetes does not affect the degree of compaction. However, consistent with previous proposals, diabetes does appear to accelerate the formation of cataracts that are similar to age-related nuclear cataracts in non-diabetics. We conclude that as scattering increases in the diabetic lens with cataract formation, fiber cell compaction is significant