Natriuretic peptides are cardiac-derived hormones with a range of protective functions, including natriuresis, diuresis, vasodilation, lusitropy, lipolysis, weight loss, and improved insulin ...sensitivity. Their actions are mediated through membrane-bound guanylyl cyclases that lead to production of the intracellular second-messenger cyclic guanosine monophosphate. A growing body of evidence demonstrates that genetic and acquired deficiencies of the natriuretic peptide system can promote hypertension, cardiac hypertrophy, obesity, diabetes mellitus, the metabolic syndrome, and heart failure. Clinically, natriuretic peptides are robust diagnostic and prognostic markers, and augmenting natriuretic peptides is a target for therapeutic strategies in cardiometabolic disease. This review will summarize current understanding and highlight novel aspects of natriuretic peptide biology. (Circ J 2015; 79: 1647–1655)
Objectives This study sought to determine the frequency and magnitude of impaired systolic deformation in heart failure with preserved ejection fraction (HFpEF). Background Although diastolic ...dysfunction is widely considered a key pathophysiologic mediator of HFpEF, the prevalence of concomitant systolic dysfunction has not been clearly defined. Methods We assessed myocardial systolic and diastolic function in 219 HFpEF patients from a contemporary HFpEF clinical trial. Myocardial deformation was assessed using a vendor-independent 2-dimensional speckle-tracking software. The frequency and severity of impaired deformation was assessed in HFpEF, and compared to 50 normal controls free of cardiovascular disease and to 44 age- and sex-matched hypertensive patients with diastolic dysfunction (hypertensive heart disease) but no HF. Among HFpEF patients, clinical, echocardiographic, and biomarker correlates of left ventricular strain were determined. Results The HFpEF patients had preserved left ventricular ejection fraction and evidence of diastolic dysfunction. Compared to both normal controls and hypertensive heart disease patients, the HFpEF patients demonstrated significantly lower longitudinal strain (LS) (−20.0 ± 2.1 and −17.07 ± 2.04 vs. −14.6 ± 3.3, respectively, p < 0.0001 for both) and circumferential strain (CS) (−27.1 ± 3.1 and −30.1 ± 3.5 vs. −22.9 ± 5.9, respectively; p < 0.0001 for both). In HFpEF, both LS and CS were related to LVEF (LS, R = −0.46; p < 0.0001; CS, R = −0.51; p < 0.0001) but not to standard echocardiographic measures of diastolic function (E' or E/E'). Lower LS was modestly associated with higher NT-proBNP, even after adjustment for 10 baseline covariates including LVEF, measures of diastolic function, and LV filling pressure (multivariable adjusted p = 0.001). Conclusions Strain imaging detects impaired systolic function despite preserved global LVEF in HFpEF that may contribute to the pathophysiology of the HFpEF syndrome. (LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction; NCT00887588 )
Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in ...patients with multiple myeloma (MM) receiving PIs.
Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide BNP, and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs.
Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib (
= .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8;
< .001). Elevated natriuretic peptides occurring mid-first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0;
< .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank
= .01) and overall survival (log-rank
< .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications.
CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.
IMPORTANCE: Polygenic risk scores comprising millions of single-nucleotide polymorphisms (SNPs) could be useful for population-wide coronary heart disease (CHD) screening. OBJECTIVE: To determine ...whether a polygenic risk score improves prediction of CHD compared with a guideline-recommended clinical risk equation. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of the predictive accuracy of a previously validated polygenic risk score was assessed among 4847 adults of white European ancestry, aged 45 through 79 years, participating in the Atherosclerosis Risk in Communities (ARIC) study and 2390 participating in the Multi-Ethnic Study of Atherosclerosis (MESA) from 1996 through December 31, 2015, the final day of follow-up. The performance of the polygenic risk score was compared with that of the 2013 American College of Cardiology and American Heart Association pooled cohort equations. EXPOSURES: Genetic risk was computed for each participant by summing the product of the weights and allele dosage across 6 630 149 SNPs. Weights were based on an international genome-wide association study. MAIN OUTCOMES AND MEASURES: Prediction of 10-year first CHD events (including myocardial infarctions, fatal coronary events, silent infarctions, revascularization procedures, or resuscitated cardiac arrest) assessed using measures of model discrimination, calibration, and net reclassification improvement (NRI). RESULTS: The study population included 4847 adults from the ARIC study (mean SD age, 62.9 5.6 years; 56.4% women) and 2390 adults from the MESA cohort (mean SD age, 61.8 9.6 years; 52.2% women). Incident CHD events occurred in 696 participants (14.4%) and 227 participants (9.5%), respectively, over median follow-up of 15.5 years (interquartile range IQR, 6.3 years) and 14.2 (IQR, 2.5 years) years. The polygenic risk score was significantly associated with 10-year CHD incidence in ARIC with hazard ratios per SD increment of 1.24 (95% CI, 1.15 to 1.34) and in MESA, 1.38 (95% CI, 1.21 to 1.58). Addition of the polygenic risk score to the pooled cohort equations did not significantly increase the C statistic in either cohort (ARIC, change in C statistic, −0.001; 95% CI, −0.009 to 0.006; MESA, 0.021; 95% CI, −0.0004 to 0.043). At the 10-year risk threshold of 7.5%, the addition of the polygenic risk score to the pooled cohort equations did not provide significant improvement in reclassification in either ARIC (NRI, 0.018, 95% CI, −0.012 to 0.036) or MESA (NRI, 0.001, 95% CI, −0.038 to 0.076). The polygenic risk score did not significantly improve calibration in either cohort. CONCLUSIONS AND RELEVANCE: In this analysis of 2 cohorts of US adults, the polygenic risk score was associated with incident coronary heart disease events but did not significantly improve discrimination, calibration, or risk reclassification compared with conventional predictors. These findings suggest that a polygenic risk score may not enhance risk prediction in a general, white middle-aged population.
Plant genomes are complex and contain large amounts of repetitive DNA including microsatellites that are distributed across entire genomes. Whole genome sequences of several monocot and dicot plants ...that are available in the public domain provide an opportunity to study the origin, distribution and evolution of microsatellites, and also facilitate the development of new molecular markers. In the present investigation, a genome-wide analysis of microsatellite distribution in monocots (Brachypodium, sorghum and rice) and dicots (Arabidopsis, Medicago and Populus) was performed. A total of 797,863 simple sequence repeats (SSRs) were identified in the whole genome sequences of six plant species. Characterization of these SSRs revealed that mono-nucleotide repeats were the most abundant repeats, and that the frequency of repeats decreased with increase in motif length both in monocots and dicots. However, the frequency of SSRs was higher in dicots than in monocots both for nuclear and chloroplast genomes. Interestingly, GC-rich repeats were the dominant repeats only in monocots, with the majority of them being present in the coding region. These coding GC-rich repeats were found to be involved in different biological processes, predominantly binding activities. In addition, a set of 22,879 SSR markers that were validated by e-PCR were developed and mapped on different chromosomes in Brachypodium for the first time, with a frequency of 101 SSR markers per Mb. Experimental validation of 55 markers showed successful amplification of 80% SSR markers in 16 Brachypodium accessions. An online database 'BraMi' (Brachypodium microsatellite markers) of these genome-wide SSR markers was developed and made available in the public domain. The observed differential patterns of SSR marker distribution would be useful for studying microsatellite evolution in a monocot-dicot system. SSR markers developed in this study would be helpful for genomic studies in Brachypodium and related grass species, especially for the map based cloning of the candidate gene(s).
Generation of hydrogen sulfide (H2S) is challenging and few methods are capable of localized delivery of this gas. Here, a boron dipyrromethene-based carbamothioate (BDP-H2S) that is uncaged by ...visible light of 470 nm to generate carbonyl sulfide (COS), which is rapidly hydrolyzed to H2S in the presence of carbonic anhydrase, a widely prevalent enzyme, is reported.
Diabetic kidney disease (DKD) is one of the most common complications of diabetes and is clinically featured by progressive albuminuria, consequent to glomerular destruction that involves podocyte ...senescence. Burgeoning evidence suggests that ketosis, in particular β-hydroxybutyrate, exerts a beneficial effect on aging and on myriad metabolic or chronic diseases, including obesity, diabetes and chronic kidney diseases. Its effect on DKD is largely unknown. In vitro in podocytes exposed to a diabetic milieu, β-hydroxybutyrate treatment substantially mitigated cellular senescence and injury, as evidenced by reduced formation of γH2AX foci, reduced staining for senescence-associated-β-galactosidase activity, diminished expression of key mediators of senescence signaling like p16INK4A and p21, and preserved expression of synaptopodin. This beneficial action of β-hydroxybutyrate coincided with a reinforced transcription factor Nrf2 antioxidant response. Mechanistically, β-hydroxybutyrate inhibition of glycogen synthase kinase 3β (GSK3β), a convergent point for myriad signaling pathways regulating Nrf2 activity, seems to contribute. Indeed, trigonelline, a selective inhibitor of Nrf2, or ectopic expression of constitutively active mutant GSK3β abolished, whereas selective activation of Nrf2 was sufficient for the anti-senescent and podocyte protective effects of β-hydroxybutyrate. Moreover, molecular modeling and docking analysis revealed that β-hydroxybutyrate is able to directly target the ATP-binding pocket of GSK3β and thereby block its kinase activity. In murine models of streptozotocin-elicited DKD, β-hydroxybutyrate therapy inhibited GSK3β and reinforced Nrf2 activation in glomerular podocytes, resulting in lessened podocyte senescence and injury and improved diabetic glomerulopathy and albuminuria. Thus, our findings may pave the way for developing a β-hydroxybutyrate-based novel approach of therapeutic ketosis for treating DKD.
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•A novel metallization design strategy for CPV solar cells is presented.•Optimized metallization patterns enable significantly higher power output.•Our method allows tailoring ...metallization design for specific illumination profiles.•We show that contact resistance should not be ignored in CPV solar cell modeling.
Concentrated photovoltaics (CPV) has recently gained popularity due to its ability to deliver significantly more power at relatively lower absorber material costs. In CPVs, lenses and mirrors are used to concentrate illumination over a small solar cell, thereby increasing the incident light by several folds. This leads to non-uniform illumination and temperature distribution on the front side of the cell, which reduces performance. A way to limit this reduction is to optimize the metallization design of the solar cell for certain non-uniform illumination and temperature profiles. Most of the existing metallization optimization methods are restricted to the conventional H-pattern, which limits the achievable improvements. Topology optimization alleviates such restrictions and is capable of generating complex metallization patterns, which cannot be captured by the traditional optimization methods. In this paper, the application of topology optimization is explored for concentrated illumination conditions. A finite element model that includes all relevant resistances combined with topology optimization method is presented and the applicability is demonstrated on non-uniform illumination and temperature profiles. The finite element model allows accurate modeling of the current density and voltage distributions. Metallization designs obtained by topology optimization significantly improve the power output of concentrating solar cells.
•A comparative LCA of Rice straw utilization practices in India.•Four scenarios studied were use as, fertilizer, fodder, electricity and biogas.•Scope of the study starts from collection of straw to ...the end use of the products.•System expansion is used for accounting emissions from the replaced product.•Electricity and biogas give highest benefits in most of the environmental impacts.
The aim of this study is to find potential utilization practice of rice straw in India from an environmental perspective. Life cycle assessment (LCA) is conducted for four most realistic utilization practices of straw including: (1) incorporation into the field as fertilizer (2) animal fodder (3) electricity (4) biogas. The results show that processing of 1 ton straw to electricity and biogas resulted in net reduction of 1471 and 1023kg CO2 eq., 15.0 and 3.4kg SO2 eq. and 6.7 and 7.1kg C2H6 eq. emissions in global warming, acidification and photochemical oxidation creation potential respectively. Electricity production from straw replaces the coal based electricity and resulted in benefits in most of the environmental impacts whereas use as an animal fodder resulted in eutrophication benefits. The burning of straw is a harmful practice of managing straw in India which can be avoided by utilizing straw for bioenergy.
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