Replica-Exchange Method in van der Waals Radius Space: Overcoming Steric Restrictions for Biomolecules

We present a new type of the Hamiltonian replica-exchange method, in which not temperatures but the van der Waals radius parameter is exchanged. By decreasing the van der Waals radii that control spatial sizes of atoms, this Hamiltonian replica-exchange method overcomes the steric restrictions and energy barriers. Furthermore, the simulation based on this method escapes from the local-minimum free-energy states and realizes effective sampling in the conformational space. We applied this method to an alanine dipeptide in aqueous solution and showed the effectiveness of the method by comparing the results with those obtained from the conventional canonical method.Comment: 14 pages, (Revtex4), 11 figure

Monte Carlo Simulations in Multibaric-Multithermal Ensemble

We propose a new generalized-ensemble algorithm, which we refer to as the multibaric-multithermal Monte Carlo method. The multibaric-multithermal Monte Carlo simulations perform random walks widely both in volume space and in potential energy space. From only one simulation run, one can calculate isobaric-isothermal-ensemble averages at any pressure and any temperature. We test the effectiveness of this algorithm by applying it to the Lennard-Jones 12-6 potential system with 500 particles. It is found that a single simulation of the new method indeed gives accurate average quantities in isobaric-isothermal ensemble for a wide range of pressure and temperature.Comment: 8 pages, (RevTeX), 5 figure

Human mast cell activation through Fc receptors and Toll-like receptors

ABSTRACTMast cells express high-affinity IgE receptors (FcεRI) on their surface and can be activated to secrete a variety of biologically active mediators by cross-linking of receptor-bound IgE. Recent studies in animal models indicate that mouse mast cells may play a protective role in host defense against bacteria through the production of tumor necrosis factor-α, mainly as a result of Toll-like receptor (TLR) 4- or CD48-mediated activation. Moreover, several recent observations in animal models have indicated that mast cells may also play a pivotal role in coordinating the early phases of autoimmune diseases, particularly those involving auto-antibodies. We recently identified functional TLR4 and FcγRI on human mast cells, in which their expression had been upregulated by interferon-γ. We compared each of the receptor-mediated gene expression profiles with the FcεRI-mediated gene expression profile using high-density oligonucleotide probe arrays and discovered that human mast cells may modulate the immune system in a receptor-specific manner

Kheper, a Novel ZFH/δEF1 Family Member, Regulates the Development of the Neuroectoderm of Zebrafish (Danio rerio)

AbstractKheper is a novel member of the ZFH (zinc-finger and homeodomain protein)/δEF1 family in zebrafish. kheper transcripts are first detected in the epiblast of the dorsal blastoderm margin at the early gastrula stage and kheper is expressed in nearly all the neuroectoderm at later stages. kheper expression was expanded in noggin RNA-injected embryos and also in swirl mutant embryos and was reduced in bmp4 RNA-injected embryos and chordino mutant embryos, suggesting that kheper acts downstream of the neural inducers Noggin and Chordino. Overexpression of Kheper elicited ectopic expansion of the neuroectoderm-specific genes fkd3, hoxa-1, and eng3, and the ectopic expression of hoxa-1 was not inhibited by BMP4 overexpression. Kheper interacted with the transcriptional corepressors CtBP1 and CtBP2. Overexpression of a Kheper mutant lacking the homeodomain or of a VP16–Kheper fusion protein disturbed the development of the neuroectoderm and head structures. These data underscore the role of Kheper in the development of the neuroectoderm and indicate that Kheper acts as a transcriptional repressor

Prognostic significance of nonsustained ventricular tachycardia in patients receiving cardiac resynchronization therapy for primary prevention: Analysis of the Japan cardiac device treatment registry database

BackgroundWhether nonsustained ventricular tachycardia (NSVT) is a marker of increased risk of sustained ventricular tachyarrhythmias (VTAs) remains to be established in patients receiving cardiac resynchronization therapy with a defibrillator (CRT‐D) for primary prevention.MethodsAmong the follow‐up data of the Japan cardiac device treatment registry (JCDTR) with an implantation date between January 2011 and August 2015, information regarding a history of NSVT before the CRT‐D implantation for primary prevention had been registered in 269 patients. Outcomes were compared between two groups with and without NSVT: NSVT group (n = 179) and No NSVT group (n = 90).ResultsThere was no significant difference with regard to age, gender, and NYHA class between the two groups. Left ventricular ejection fraction (LVEF) was 25.6% in the NSVT group and 28.0% in the No NSVT group (P = .046). The rate of appropriate therapy at 24 months was 26.0% and 18.4% in the NSVT and No NSVT groups (P = .22), respectively. Survival free from heart failure death was reduced in the NSVT group, as compared with the No NSVT group, with the rate of 90.2% vs 97.2% at 24 months (P = .030). A multivariate analysis identified a history of NSVT, anemia, and no use of angiotensin‐converting enzyme inhibitor (ACEI) or angiotensin‐receptor blocker (ARB) as predictors of heart failure death.ConclusionsNSVT appears to be a surrogate marker of severe heart failure rather than a substrate for subsequent sustained VTAs in patients with CRT‐D for primary prevention

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