Background
Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and ...preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF).
Methods and Results
We identified HFpEF cases, HFrEF controls, and no‐HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No‐HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long‐chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no‐HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance.
Conclusions
We identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.
The cross-coupling reactions of allylboronic acid pinacol ester derivatives with aryl and heteroaryl halides occurred with high selectivity (>97%) at the α-carbon of the allylboron reagent in the ...presence of Pd-PEPPSI-IPent precatalyst and 5 M KOH in refluxing THF. In the case of trisubstituted allylboronates with different substituents on the olefin, minor olefin geometry isomerization was observed (E/Z ≈ 80/20).
Boron-derived Lewis acids have been shown to effectively promote the coupling of amide nucleophiles to a wide variety of oxidative addition partners using Pd-NHC catalysts. Through a combination of ...NMR spectroscopy and control studies with and without oxygen and radical scavengers, we propose that boron-imidates form under the basic reaction conditions that aid coordination of nitrogen to Pd(II), which is rate limiting, and directly delivers the intermediate for reductive elimination.
Post-translational histone modifications have a critical role in regulating transcription, the cell cycle, DNA replication and DNA damage repair. The identification of new histone modifications ...critical for transcriptional regulation at initiation, elongation or termination is of particular interest. Here we report a new layer of regulation in transcriptional elongation that is conserved from yeast to mammals. This regulation is based on the phosphorylation of a highly conserved tyrosine residue, Tyr 57, in histone H2A and is mediated by the unsuspected tyrosine kinase activity of casein kinase 2 (CK2). Mutation of Tyr 57 in H2A in yeast or inhibition of CK2 activity impairs transcriptional elongation in yeast as well as in mammalian cells. Genome-wide binding analysis reveals that CK2α, the catalytic subunit of CK2, binds across RNA-polymerase-II-transcribed coding genes and active enhancers. Mutation of Tyr 57 causes a loss of H2B mono-ubiquitination as well as H3K4me3 and H3K79me3, histone marks associated with active transcription. Mechanistically, both CK2 inhibition and the H2A(Y57F) mutation enhance H2B deubiquitination activity of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex, suggesting a critical role of this phosphorylation in coordinating the activity of the SAGA complex during transcription. Together, these results identify a new component of regulation in transcriptional elongation based on CK2-dependent tyrosine phosphorylation of the globular domain of H2A.
Climate affects the timing and magnitude of phytoplankton blooms that fuel marine food webs and influence global biogeochemical cycles. Changes in bloom timing have been detected in some cases, but ...the underlying mechanisms remain elusive, contributing to uncertainty in long-term predictions of climate change impacts. Here we describe a 13-year hourly time series from the New England shelf of data on the coastal phytoplankter Synechococcus, during which the timing of its spring bloom varied by 4 weeks. We show that multiyear trends are due to temperature-induced changes in cell division rate, with earlier blooms driven by warmer spring water temperatures. Synechococcus loss rates shift in tandem with division rates, suggesting a balance between growth and loss that has persisted despite phenological shifts and environmental change.
Vitamin D is a fat-soluble steroid hormone that activates vitamin D receptor to regulate multiple downstream signaling pathways and transcription of various target genes. There is an association ...between vitamin D deficiency and increased risk for cardiovascular disease. However, most of the studies are observational and associative in nature with limited data on clinical application. Thus, there is a need for more prospective randomized controlled studies to determine whether or not vitamin D supplementation provides cardiovascular protection. In this study, we examined the effects of the deficiency and supplementation of vitamin D on coronary restenosis following coronary intervention in atherosclerotic Yucatan microswine. Twelve Yucatan microswine were fed vitamin D-deficient (n = 4) or -sufficient (n = 8) high cholesterol diet for 6-months followed by coronary intervention. Post-intervention, swine in the vitamin D-sufficient high cholesterol diet group received daily oral supplementation of either 1,000 IU (n = 4) or 3,000 IU (n = 4) vitamin D3. Six months later, optical coherence tomography (OCT) was performed to monitor the development of intimal hyperplasia and restenosis. Animals were euthanized to isolate arteries for histomorphometric and immunohistochemical studies. Animals had graded levels of serum 25(OH)D; vitamin D-deficient (15.33 ± 1.45 ng/ml), vitamin D-sufficient + 1,000 IU oral vitamin D post-intervention (32.27 ± 1.20 ng/ml), and vitamin D-sufficient + 3,000 IU oral vitamin D post-intervention (51.00 ± 3.47 ng/ml). Findings from the OCT and histomorphometric studies showed a decrease in intimal hyperplasia and restenosis in vitamin D-supplemented compared to vitamin D-deficient swine. Vitamin D supplementation significantly decreased serum levels of TNF-α and IFN-γ, upregulated serum levels of IL-10, and had no effect on serum IL-6 levels. These findings suggest that vitamin D supplementation limits neointimal formation following coronary intervention in atherosclerotic swine and provide the support for vitamin D supplementation to protect against the development of coronary restenosis.
Here we report electrochemical, spectroscopic, and crystallographic characterization of a redox series of cobalt complexes in five sequential oxidation states. A simple bidentate phosphine ligand, ...cis-1,2-bis(diphenylphosphino)ethylene (dppv), allows for isolation of the 3+, 2+, 1+, 0, and 1– oxidation states of cobaltthe only known example of transition-metal complexes with redox-innocent ligands in five oxidation states. Electrochemistry of Co(dppv)22+ reveals three reversible reductions and one reversible oxidation. Complexes in each oxidation state are characterized using single-crystal X-ray diffraction. The coordination number and geometry of the complex changes as a function of the oxidation state: including acetonitrile ligands, the Co3+ complex is pseudo-octahedral, the Co2+ complex is square-pyramidal, the Co+ complex is pseudo-square-planar, and the Co0 and Co– complexes approach pseudo-tetrahedral, illustrating structures predicted by crystal-field theory of inorganic transition-metal complexes.
Summary
Marine microbes often show a high degree of physiological or ecological diversity below the species level. This microdiversity raises questions about the processes that drive diversification ...and permit coexistence of diverse yet closely related marine microbes, especially given the theoretical efficiency of competitive exclusion. Here, we provide insight with an 8‐year time series of diversity within Synechococcus, a widespread and important marine picophytoplankter. The population of Synechococcus on the Northeast U.S. Shelf is comprised of six main types, each of which displays a distinct and consistent seasonal pattern. With compositional data analysis, we show that these patterns can be reproduced with a simple model that couples differential responses to temperature and light with the seasonal cycle of the physical environment. These observations support the hypothesis that temporal variability in environmental factors can maintain microdiversity in marine microbial populations. We also identify how seasonal diversity patterns directly determine overarching Synechococcus population abundance features.
Circulating high-density lipoprotein particle (HDL-P) subfractions impact atherogenesis, inflammation, and endothelial function, all of which are implicated in the pathobiology of heart failure (HF).
...The authors sought to identify key differences in plasma HDL-P subfractions between patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) to determine their prognostic utility.
Patients with HFrEF (n = 782), HFpEF (n = 1,004), and no HF (n = 4,742) were identified in the CATHGEN (Catheterization Genetics) biorepository of sequential patients undergoing cardiac catheterization. Nuclear magnetic resonance–based lipoprotein profiling was performed on frozen fasting plasma obtained at catheterization. The authors used multivariable analysis of covariance to compare high-density lipoprotein particle (HDL-P) subfractions across groups, and Cox proportional hazards modeling to determine associations between HDL-P subfractions and time to death or major adverse cardiac events.
Mean HDL-P size was greater in HFrEF than HFpEF, both of which were greater than in no HF (all 2-way p < 0.0001). By contrast, concentrations of small HDL-P and total HDL-P were lesser in HFrEF than HFpEF, which were both lesser than no HF (all 2-way p ≤ 0.0002). In both HFrEF and HFpEF, total HDL-P and small HDL-P were inversely associated with time to adverse events. These findings persisted after adjustment for 14 clinical covariates (including high-density lipoprotein cholesterol content, coronary artery disease, and the inflammatory biomarker GlycA), and in sensitivity analyses featuring alternate left ventricular ejection fraction definitions, or stricter inclusion criteria with diastolic dysfunction or left ventricular end-diastolic pressure thresholds.
In the largest analysis of HDL-P subfractions in HF to date, derangements in HDL-P subfractions were identified that were more severe in HFrEF than HFpEF and were independently associated with adverse outcomes. These data may help refine risk assessment and provide new insights into the complex interaction of HDL and HF pathophysiology.
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Negishi revisited: Higher‐order alkyl zincates have been subjected to Negishi coupling with alkyl bromides. For the first time, coupling takes place in straight THF, i.e., without a salt additive and ...a high dielectric co‐solvent. This provides evidence that it is the higher‐order zincate that undergoes transmetalation to Pd, and not mono‐anionic zincates or any of the other species present in the Schlenk equilibrium.
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