Neprilysin is a zinc-dependent endopeptidase. It is ubiquitous in distribution and promiscuous in function, with >50 putative peptide substrates with varying levels of in vitro and/or in vivo ...evidence of functional relevance. In the first part of this review, we discuss the genetic, structural, substrate, and pathophysiological aspects of neprilysin. We incorporate information provided by genetically modified models, as well as pre-clinical and clinical data from investigations of synthetic neprilysin inhibitors. We next highlight the value of neprilysin as a biotarget and weigh the clinical benefits of synthetic neprilysin inhibitors, either alone or in combination with antagonists of the renin-angiotensin system. Finally, we provide evidence about soluble neprilysin as a biomarker surrogate in patients with heart failure and identify important gaps that require further research before soluble neprilysin is used clinically. In sum, neprilysin is a versatile, veteran player returning yet again to center stage after an eventful career spanning >40 years.
Betaine is a major osmolyte, also important in methyl group metabolism. Concentrations of betaine, its metabolite dimethylglycine and analog trimethylamine-N-oxide (TMAO) in blood are cardiovascular ...risk markers. Diabetes disturbs betaine: does diabetes alter associations between betaine-related measures and cardiovascular risk?
Plasma samples were collected from 475 subjects four months after discharge following an acute coronary admission. Death (n = 81), secondary acute MI (n = 87), admission for heart failure (n = 85), unstable angina (n = 72) and all cardiovascular events (n = 283) were recorded (median follow-up: 1804 days).
High and low metabolite concentrations were defined as top or bottom quintile of the total cohort. In subjects with diabetes (n = 79), high plasma betaine was associated with increased frequencies of events; significantly for heart failure, hazard ratio 3.1 (1.2-8.2) and all cardiovascular events, HR 2.8 (1.4-5.5). In subjects without diabetes (n = 396), low plasma betaine was associated with events; significantly for secondary myocardial infarction, HR 2.1 (1.2-3.6), unstable angina, HR 2.3 (1.3-4.0), and all cardiovascular events, HR 1.4 (1.0-1.9). In diabetes, high TMAO was a marker of all outcomes, HR 2.7 (1.1-7.1) for death, 4.0 (1.6-9.8) for myocardial infarction, 4.6 (2.0-10.7) for heart failure, 9.1 (2.8-29.7) for unstable angina and 2.0 (1.1-3.6) for all cardiovascular events. In subjects without diabetes TMAO was only significant for death, HR 2.7 (1.6-4.8) and heart failure, HR 1.9 (1.1-3.4). Adding the estimated glomerular filtration rate to Cox regression models tended to increase the apparent risks associated with low betaine.
Elevated plasma betaine concentration is a marker of cardiovascular risk in diabetes; conversely low plasma betaine concentrations indicate increased risk in the absence of diabetes. We speculate that the difference reflects control of osmolyte retention in tissues. Elevated plasma TMAO is a strong risk marker in diabetes.
Bolide impact and flood volcanism compete as leading candidates for the cause of terminal-Cretaceous mass extinctions. High-precision 40Ar/39Ar data indicate that these two mechanisms may be ...genetically related, and neither can be considered in isolation. The existing Deccan Traps magmatic system underwent a state shift approximately coincident with the Chicxulub impact and the terminal-Cretaceous mass extinctions, after which ∼70% of the Traps' total volume was extruded in more massive and more episodic eruptions. Initiation of this new regime occurred within ∼50,000 years of the impact, which is consistent with transient effects of impact-induced seismic energy. Postextinction recovery of marine ecosystems was probably suppressed until after the accelerated volcanism waned.
The advancement of underrepresented minority and women PhD students to elite postdoctoral and faculty positions in the STEM fields continues to lag that of majority males, despite decades of efforts ...to mitigate bias and increase opportunities for students from diverse backgrounds. In 2015, the National Science Foundation Alliance for Graduate Education and the Professoriate (NSF AGEP) California Alliance (Berkeley, Caltech, Stanford, UCLA) conducted a wide-ranging survey of graduate students across the mathematical, physical, engineering, and computer sciences in order to identify levers to improve the success of PhD students, and, in time, improve diversity in STEM leadership positions, especially the professoriate. The survey data were interpreted via path analysis, a method that identifies significant relationships, both direct and indirect, among various factors and outcomes of interest. We investigated two important outcomes: publication rates, which largely determine a new PhD student's competitiveness in the academic marketplace, and subjective well-being. Women and minority students who perceived that they were well-prepared for their graduate courses and accepted by their colleagues (faculty and fellow students), and who experienced well-articulated and structured PhD programs, were most likely to publish at rates comparable to their male majority peers. Women PhD students experienced significantly higher levels of distress than their male peers, both majority and minority, while both women and minority student distress levels were mitigated by clearly-articulated expectations, perceiving that they were well-prepared for graduate level courses, and feeling accepted by their colleagues. It is unclear whether higher levels of distress in women students is related directly to their experiences in their STEM PhD programs. The findings suggest that mitigating factors that negatively affect diversity should not, in principle, require the investment of large resources, but rather requires attention to the local culture and structure of individual STEM PhD programs.
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