π-Lewis Base Activation of Carbonyls and Hexafluorobenzene.

We report hitherto elusive side-on η2-bonded palladium(0) carbonyl (anthraquinone, benzaldehyde) and arene (benzene, hexa-fluorobenzene) palladium(0) complexes and present the catalytic hydrodefluorination of hexafluorobenzene by cyclohexene. The comparison with respective cyclohexene, pyridine and tetrahydrofuran complexes reveals that the experimental ligand binding strengths follow the order THF < C6H6 < C6F6 < cyclohexene < pyridine < benzaldehyde < anthraquinone. To understand this surprising order, the complexes' electronic structures were elucidated by nuclear magnetic resonance (NMR), single crystal X-Ray diffraction (sc-XRD), ultraviolet/visible (UV/Vis) electronic absorption, infrared (IR) vibrational, Pd L3-edge X-ray absorption (XAS), and X-ray photoelectron (XP) spectroscopic techniques, complemented by Density Functional Theory (DFT) calculations including energy decomposition (EDA-NOCV) and effective oxidation state (EOS) analyses.

Cardiac cGMP Regulation and Therapeutic Applications.

cGMP plays a central role in cardiovascular regulation in health and disease. It is synthesized by NO or natriuretic peptide activated cyclases and hydrolyzed to 5'GMP by select members of the PDEs (phosphodiesterase) superfamily. The primary downstream effector is cGMP-dependent protein kinase, primarily cGK-1a also known as protein kinase G 1a in the heart and vasculature.

Design of a randomised controlled hybrid trial of nintedanib in patients with progressive myositis-associated interstitial lung disease.

Background: The Myositis Interstitial Lung Disease Nintedanib Trial (MINT) is a hybrid trial, which is enrolling patients both at local sites and remotely via a decentralised site. The trial will investigate the efficacy and safety of nintedanib in patients with progressive myositis-associated interstitial lung disease (MA-ILD).

Methods/design: MINT is an exploratory, prospective randomised placebo-controlled trial.

Cardiomyocyte myofilament function in common animal models of heart failure with preserved ejection fraction.

Human cardiomyocytes from very obese patients with heart failure and preserved ejection fraction (HFpEF) have markedly depressed calcium-activated tension and increased resting stiffness. To test if either are recapitulated by obese-HFpEF animal models, tension‑calcium and tension-sarcomere length relations were measured in myocytes from mice on a high fat diet (HFD) with L-NAME, ZSF1 rats, and Göttingen minipigs on HFD + DOCA (MP). Only MP myocytes displayed reduced Ca-activated tension, and none exhibited increased resting stiffness versus respective controls.

A bis-Phenolate Carbene-Supported bis-μ-Oxo Iron(IV/IV) Complex with a [Fe(μ-O)Fe] Diamond Core Derived from Dioxygen Activation.

The diiron(II) complex, [(OCO)Fe(MeCN)] (, MeCN = acetonitrile), supported by the bis-phenolate carbene pincer ligand, 1,3-bis(3,5-di--butyl-2-hydroxyphenyl)benzimidazolin-2-ylidene (OCO), was synthesized and characterized by single-crystal X-ray diffraction, H nuclear magnetic resonance, infrared (IR) vibrational, ultraviolet/visible/near-infrared (UV/vis/NIR) electronic absorption, Fe Mössbauer, X-band electron paramagnetic resonance (EPR) and SQUID magnetization measurements. Complex activates dioxygen to yield the diferric, μ-oxo-bridged complex [(OCO)Fe(py)(μ-O)Fe(O(C═O)O)(py)] () that was isolated and fully characterized. In , one of the iron-carbene bonds was oxidized to give a urea motif, resulting in an O(C═O)O binding site, while the other Fe(OCO) unit remained unchanged.

Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics.

Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides. While the 11 PDE subfamilies share common features, key differences confer signaling specificity. The differences include substrate selectivity, enzymatic activity regulation, tissue expression, and subcellular localization.

Landscape of glycolytic metabolites and their regulating proteins in myocardium from human heart failure with preserved ejection fraction.

Aims: Heart failure (HF) with preserved ejection fraction (HFpEF) reflects half of all clinical HF yet has few therapies. Obesity and diabetes are now common comorbidities which have focused attention towards underlying myocardial metabolic defects. The profile of a major metabolic pathway, glycolytic intermediates and their regulating enzymes and ancillary pathways, remains unknown.

A Bioinspired Nonheme Fe-(O)-Cu Complex with an = 1 Ground State.

Cytochrome oxidase (CcO) is a heme copper oxidase (HCO) that catalyzes the natural reduction of oxygen to water. A profound understanding of some of the elementary steps leading to the intricate 4e/4H reduction of O is presently lacking. A total spin = 1 Fe-(O)-Cu () intermediate is proposed to reduce the overpotentials associated with the reductive O-O bond rupture by allowing electron transfer from a tyrosine moiety without the necessity of any spin-surface crossing.

Assessment of prevalence of elevated blood lead levels and risk factors among children and pregnant women in Bihar, India.

Background: While modeled estimates and studies in contaminated areas indicate high lead exposure among children in Bihar, India, local data on lead exposure in the child population is limited.

Objectives: To characterize lead exposure, and assess potential sources of lead exposure among a state-representative sample of children and their pregnant mothers residing in Bihar.

Methods: Blood samples were collected from 697 children under five and 55 pregnant women from eight districts in Bihar.

ATP Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance And Is Depressed in Human Heart Failure.

Background: ATP-citrate lyase (ACLY) converts citrate into acetyl-CoA and oxaloacetate in the cytosol. It plays a prominent role in lipogenesis and fat accumulation coupled to excess glucose, and its inhibition is approved for treating hyperlipidemia. In RNAseq analysis of human failing myocardium, we found ACLY gene expression is reduced; however the impact this might have on cardiac function and/or metabolism has not been previously studied.

A Systems Map of the Challenges of Climate Communication.

Over the past sixty years, scientists have been warning about climate change and its impacts on human health, but evidence suggests that many may not be heeding these concerns. This raises the question of whether new communication approaches are needed to overcome the unique challenges of communicating what people can do to slow or reverse climate change. To better elucidate the challenges of communicating about the links between human activity, climate change and its effects, and identify potential solutions, we developed a systems map of the factors and processes involved based on systems mapping sessions with climate change and communication experts.

Origin of Unprecedented Formation and Reactivity of Fe═O Species via Oxygen Activation: Role of Noncovalent Interactions and Magnetic Coupling.

Emulating the capabilities of the soluble methane monooxygenase (sMMO) enzymes, which effortlessly activate oxygen at diiron(II) centers to form a reactive diiron(IV) intermediate Q, which then performs the challenging oxidation of methane to methanol, poses a significant challenge. Very recently, one of us reported the mononuclear complex [(cyclam)Fe(CHCN)] (), which performed a rare bimolecular activation of the molecule of O to generate two molecules of Fe═O without the requirement of external proton or electron sources, similar to sMMO. In the present study, we employed the density functional theory (DFT) calculations to investigate this unique mechanism of O activation.

Relationship Between Myocardial NPPB Expression and Serum NT-proBNP in Heart Failure With Preserved Ejection Fraction.

“Low serum NT-proBNP in obese #HFpEF is related to lower myocardial synthesis at same hemodynamic load. #HFpEF thresholds for serum proBNP bias towards worse renal dz, less severe #obesity, worse #PH, impacting efficacy/generalizability.”

The efficacy of a virtual and in-person mindfulness-based intervention course on university students' during COVID-19 pandemic.

: The purpose of this research was to evaluate the impact of a mindfulness-based intervention (MBI) on university students during the COVID-19 pandemic. There were 53 participants who voluntarily enrolled in a mindfulness course at a regional state university (24 virtual and 29 in-person) and 56 in the control group. Participants completed surveys at the beginning and end of the course on mindfulness, life satisfaction, and resilience.

Design of the STRIVE-IPF trial- study of therapeutic plasma exchange, rituximab, and intravenous immunoglobulin for acute exacerbations of idiopathic pulmonary fibrosis.

Background: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) affect a significant proportion of patients with IPF. There are limited data to inform therapeutic strategies for AE-IPF, despite its high mortality. We discuss the rationale and design of STRIVE-IPF, a randomized, multi-center, open-label Phase IIb clinical trial to determine the efficacy of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG), in comparison to treatment as usual (TAU), among patients with acute IPF exacerbations.

Design of the STRIVE-IPF Trial- Study of Therapeutic Plasma Exchange, Rituximab, and Intravenous Immunoglobulin for Acute Exacerbations of Idiopathic Pulmonary Fibrosis.

Background: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) affect a significant proportion of patients with IPF. There are limited data to inform therapeutic strategies for AEIPF, despite its high mortality. We discuss the rationale and design of STRIVE-IPF, a randomized, multi-center, open-label Phase IIb clinical trial to determine the efficacy of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG), in comparison to treatment as usual (TAU), among patients with acute IPF exacerbations.

The structural OFF and ON states of myosin can be decoupled from the biochemical super- and disordered-relaxed states.

There is a growing awareness that both thick-filament and classical thin-filament regulations play central roles in modulating muscle contraction. Myosin ATPase assays have demonstrated that under relaxed conditions, myosin may reside either in a high-energy-consuming disordered-relaxed (DRX) state available for binding actin to generate force or in an energy-sparing super-relaxed (SRX) state unavailable for actin binding. X-ray diffraction studies have shown that the majority of myosin heads are in a quasi-helically ordered OFF state in a resting muscle and that this helical ordering is lost when myosin heads are turned ON for contraction.

Trapping of a phenoxyl radical at a non-haem high-spin iron(II) centre.

The activation of dioxygen at haem and non-haem metal centres, and subsequent functionalization of unactivated C‒H bonds, has been a focal point of much research. In iron-mediated oxidation reactions, O binding at an iron(II) centre is often accompanied by an oxidation of the iron centre. Here we demonstrate dioxygen activation by sodium tetraphenylborate and protons in the presence of an iron(II) complex to form a reactive radical species, whereby the iron oxidation state remains unaltered in the presence of a highly oxidizing phenoxyl radical and O.