Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Increased selenium and decreased iron levels in relation to risk of coronary artery disease in patients with diabetes

BackgroundObservational studies have reported inconsistent associations between micronutrient levels and the risk of coronary artery disease (CAD) in diabetic patients. We aim to explore the causal association between genetically predicted concentrations of micronutrients (phosphorus, magnesium, selenium, iron, zinc, and copper) and CAD in patients with diabetes.MethodsSingle nucleotide polymorphisms (SNPs) connected to serum micronutrient levels were extracted from the corresponding published genome-wide association studies (GWASs). Summary-level statistics for CAD in diabetic patients were obtained from a GWAS of 15,666 patients with diabetes. The primary analysis was carried out with the inverse variance weighted approach, and sensitivity analyses using other statistical methods were further employed to assess the robustness of the results.ResultsGenetically predicted selenium level was causally associated with a higher risk of CAD in diabetic patients (odds ratio [OR]: 1.25; 95% confidence interval [CI]: 1.10–1.42; p = 5.01 × 10−4). While, genetically predicted iron concentrations in patients with diabetes were inversely associated with the risk of CAD (OR: 0.82; 95% CI: 0.75–0.90; p = 2.16 × 10−5). The association pattern kept robust in most sensitivity analyses. Nominally significant associations were observed for magnesium and copper with the risk of CAD in patients with diabetes. No consistent evidence was found for the causal associations between phosphorus and zinc levels, and the risk of CAD in patients with diabetes.ConclusionWe provide consistent evidence for the causal effect of increased selenium and decreased iron levels on CAD in patients with diabetes, highlighting the necessity of micronutrient monitoring and application in these patients

A Mechanosensor Mechanism Controls the G-Quadruplex/i-Motif Molecular Switch in the MYC Promoter NHE III 1

MYC is overexpressed in many different cancer types and is an intensively studied oncogene because of its contributions to tumorigenesis. The regulation of MYC is complex, and the NHE III1 and FUSE elements rely upon noncanonical DNA structures and transcriptionally induced negative superhelicity. In the NHE III1 only the G-quadruplex has been extensively studied, whereas the role of the i-motif, formed on the opposite C-rich strand, is much less understood. We demonstrate here that the i-motif is formed within the 4CT element and is recognized by hnRNP K, which leads to a low level of transcription activation. For maximal hnRNP K transcription activation, two additional cytosine runs, located seven bases downstream of the i-motif-forming region, are also required. To access these additional runs of cytosine, increased negative superhelicity is necessary, which leads to a thermodynamically stable complex between hnRNP K and the unfolded i-motif. We also demonstrate mutual exclusivity between the MYC G-quadruplex and i-motif, providing a rationale for a molecular switch mechanism driven by SP1-induced negative superhelicity, where relative hnRNP K and nucleolin expression shifts the equilibrium to the on or off state.National Science Foundation [CH-1609514, CHE-1415883]; National Institutes of Health [5R01CA153821, 1R01GM085585]; National Foundation for Cancer Research [VONHOFF-15-01]12 month embargo. First available online 26 September 2016.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

A Mechanosensor Mechanism Controls the G‑Quadruplex/i-Motif Molecular Switch in the <i>MYC</i> Promoter NHE III₁

<i>MYC</i> is overexpressed in many different cancer types and is an intensively studied oncogene because of its contributions to tumorigenesis. The regulation of <i>MYC</i> is complex, and the NHE III₁ and FUSE elements rely upon noncanonical DNA structures and transcriptionally induced negative superhelicity. In the NHE III₁ only the G-quadruplex has been extensively studied, whereas the role of the i-motif, formed on the opposite C-rich strand, is much less understood. We demonstrate here that the i-motif is formed within the 4CT element and is recognized by hnRNP K, which leads to a low level of transcription activation. For maximal hnRNP K transcription activation, two additional cytosine runs, located seven bases downstream of the i-motif-forming region, are also required. To access these additional runs of cytosine, increased negative superhelicity is necessary, which leads to a thermodynamically stable complex between hnRNP K and the unfolded i-motif. We also demonstrate mutual exclusivity between the <i>MYC</i> G-quadruplex and i-motif, providing a rationale for a molecular switch mechanism driven by SP1-induced negative superhelicity, where relative hnRNP K and nucleolin expression shifts the equilibrium to the on or off state

Ag Decorated Co3O4-Nitrogen Doped Porous Carbon as the Bifunctional Cathodic Catalysts for Rechargeable Zinc-Air Batteries

The use of transition metals as bifunctional catalysts for rechargeable zinc-air batteries has recently attracted much attention. Due to their multiple chemical valence states, the cobalt oxides are considered to be promising catalysts for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). In this work, bifunctional Ag-decorated Co3O4-nitrogen doped porous carbon composite (Co3O4-NC&amp;Ag) catalysts were synthesized by annealing ZIF-67 in N2 and O2, respectively, followed by Ag deposition using chemical bath deposition. Due to the decoration of Ag nanoparticles and high specific surface area (46.9 m2 g&minus;1), the electrochemical activity of Co3O4 increased significantly. The optimized Co3O4-NC&amp;Ag catalysts possessed superior ORR performance with a half-wave potential of 0.84 V (vs. RHE) and OER activity with an overpotential of 349 mV at 10 mA cm&minus;2. The open circuit voltage of the Co3O4-NC&amp;Ag-based zinc-air battery was 1.423 V. Meanwhile, the power density reached 198 mW cm&minus;2 with a specific discharge capacity of 770 mAh g&minus;1 at 10 mA cm&minus;2, which was higher than that of Pt/C-based zinc-air battery (160 mW cm&minus;2 and 705 mAh g&minus;1). At a current density of 10 mA cm&minus;2, the charge-discharge performance was stable for 120 h (360 cycles), exhibiting better long-term stability than the Pt/C&amp;RuO2 counterpart

Ag Decorated Co₃O₄-Nitrogen Doped Porous Carbon as the Bifunctional Cathodic Catalysts for Rechargeable Zinc-Air Batteries

The use of transition metals as bifunctional catalysts for rechargeable zinc-air batteries has recently attracted much attention. Due to their multiple chemical valence states, the cobalt oxides are considered to be promising catalysts for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). In this work, bifunctional Ag-decorated Co3O4-nitrogen doped porous carbon composite (Co3O4-NC&Ag) catalysts were synthesized by annealing ZIF-67 in N2 and O2, respectively, followed by Ag deposition using chemical bath deposition. Due to the decoration of Ag nanoparticles and high specific surface area (46.9 m2 g−1), the electrochemical activity of Co3O4 increased significantly. The optimized Co3O4-NC&Ag catalysts possessed superior ORR performance with a half-wave potential of 0.84 V (vs. RHE) and OER activity with an overpotential of 349 mV at 10 mA cm−2. The open circuit voltage of the Co3O4-NC&Ag-based zinc-air battery was 1.423 V. Meanwhile, the power density reached 198 mW cm−2 with a specific discharge capacity of 770 mAh g−1 at 10 mA cm−2, which was higher than that of Pt/C-based zinc-air battery (160 mW cm−2 and 705 mAh g−1). At a current density of 10 mA cm−2, the charge-discharge performance was stable for 120 h (360 cycles), exhibiting better long-term stability than the Pt/C&RuO2 counterpart

Mutually Exclusive Formation of G‑Quadruplex and i‑Motif Is a General Phenomenon Governed by Steric Hindrance in Duplex DNA

G-Quadruplex and i-motif are tetraplex structures that may form in opposite strands at the same location of a duplex DNA. Recent discoveries have indicated that the two tetraplex structures can have conflicting biological activities, which poses a challenge for cells to coordinate. Here, by performing innovative population analysis on mechanical unfolding profiles of tetraplex structures in double-stranded DNA, we found that formations of G-quadruplex and i-motif in the two complementary strands are mutually exclusive in a variety of DNA templates, which include human telomere and promoter fragments of hINS and hTERT genes. To explain this behavior, we placed G-quadruplex- and i-motif-hosting sequences in an offset fashion in the two complementary telomeric DNA strands. We found simultaneous formation of the G-quadruplex and i-motif in opposite strands, suggesting that mutual exclusivity between the two tetraplexes is controlled by steric hindrance. This conclusion was corroborated in the BCL-2 promoter sequence, in which simultaneous formation of two tetraplexes was observed due to possible offset arrangements between G-quadruplex and i-motif in opposite strands. The mutual exclusivity revealed here sets a molecular basis for cells to efficiently coordinate opposite biological activities of G-quadruplex and i-motif at the same dsDNA location

Conditioned medium from bone marrow-derived mesenchymal stem cells inhibits vascular calcification through blockade of the BMP2–Smad1/5/8 signaling pathway

Abstract Background Arterial calcification is associated with cardiovascular disease as a complication of advanced atherosclerosis and is a significant contributor to cardiovascular morbidity and mortality. Osteoblastic differentiation of vascular smooth muscle cells (VSMCs) plays an important role in arterial calcification and is characterized by cellular necrosis, inflammation, and lipoprotein and phospholipid complexes, especially in atherosclerotic calcification. The conditioned medium from bone marrow-derived mesenchymal stem cells (MSC-CM) is well known as a rich source of autologous cytokines and is universally used for tissue regeneration in current clinical medicine. Here, we demonstrate that MSC-CM inhibits beta-glycerophosphate (β-GP)-induced vascular calcification through blockade of the bone morphogenetic protein-2 (BMP2)–Smad1/5/8 signaling pathway. Methods VSMC calcification was induced by β-GP followed by treatment with MSC-CM. Mineral deposition was assessed by Alizarin Red S staining. Intracellular calcium content was determined colorimetrically by the o-cresolphthalein complexone method and alkaline phosphatase (ALP) activity was measured by the para-nitrophenyl phosphate method. Expression of BMP2, BMPR1A, BMPR1B, BMPR2, msh homeobox 2 (Msx2), Runt-related transcription factor 2 (Runx2), and osteocalcin (OC), representative osteoblastic markers, was assessed using real-time polymerase chain reaction analysis while the protein expression of BMP2, Runx2, and phosphorylated Smad1/5/8 was detected by western blot analysis. Results Our data demonstrated that MSC-CM inhibits osteoblastic differentiation and mineralization of VSMCs as evidenced by decreased calcium content, ALP activity, and decreased expression of BMP-2, Runx2, Msx2, and OC. MSC-CM suppressed the expression of phosphorylated Smad1/5/8 and the β-GP-induced translocation from the cytoplasm to the nucleus. Further study demonstrated that human recombinant BMP-2 overcame the suppression of VSMC calcification by MSC-CM. Conclusion MSC-CM may act as a novel therapy for VSMC calcification by mediating the BMP2–Smad1/5/8 signaling pathwa

Mechanical properties of DNA origami nanoassemblies are determined by Holliday junction mechanophores

DNA nanoassemblies have demonstrated wide applications in various fields including nanomaterials, drug delivery and biosensing. In DNA origami, single-stranded DNA template is shaped into desired nanostructure by DNA staples that form Holliday junctions with the template. Limited by current methodologies, however, mechanical properties of DNA origami structures have not been adequately characterized, which hinders further applications of these materials. Using laser tweezers, here, we have described two mechanical properties of DNA nanoassemblies represented by DNA nanotubes, DNA nanopyramids and DNA nanotiles. First, mechanical stability of DNA origami structures is determined by the effective density of Holliday junctions along a particular stress direction. Second, mechanical isomerization observed between two conformations of DNA nanotubes at 10–35 pN has been ascribed to the collective actions of individual Holliday junctions, which are only possible in DNA origami with rotational symmetric arrangements of Holliday junctions, such as those in DNA nanotubes. Our results indicate that Holliday junctions control mechanical behaviors of DNA nanoassemblies. Therefore, they can be considered as ‘mechanophores’ that sustain mechanical properties of origami nanoassemblies. The mechanical properties observed here provide insights for designing better DNA nanostructures. In addition, the unprecedented mechanical isomerization process brings new strategies for the development of nano-sensors and actuators