Ab initio theory of helix-coil phase transition

In this paper we suggest a theoretical method based on the statistical mechanics for treating the alpha-helix-random coil transition in alanine polypeptides. We consider this process as a first-order phase transition and develop a theory which is free of model parameters and is based solely on fundamental physical principles. It describes essential thermodynamical properties of the system such as heat capacity, the phase transition temperature and others from the analysis of the polypeptide potential energy surface calculated as a function of two dihedral angles, responsible for the polypeptide twisting. The suggested theory is general and with some modification can be applied for the description of phase transitions in other complex molecular systems (e.g. proteins, DNA, nanotubes, atomic clusters, fullerenes).Comment: 24 pages, 3 figure

Device Therapies Among Patients Receiving Primary Prevention Implantable Cardioverter-Defibrillators in the Cardiovascular Research Network

BACKGROUND: Primary prevention implantable cardioverter-defibrillators (ICDs) reduce mortality in selected patients with left ventricular systolic dysfunction by delivering therapies (antitachycardia pacing or shocks) to terminate potentially lethal arrhythmias; inappropriate therapies also occur. We assessed device therapies among adults receiving primary prevention ICDs in 7 healthcare systems. METHODS AND RESULTS: We linked medical record data, adjudicated device therapies, and the National Cardiovascular Data Registry ICD Registry. Survival analysis evaluated therapy probability and predictors after ICD implant from 2006 to 2009, with attention to Centers for Medicare and Medicaid Services Coverage With Evidence Development subgroups: left ventricular ejection fraction, 31% to 35%; nonischemic cardiomyopathy \u3c9 \u3emonths\u27 duration; and New York Heart Association class IV heart failure with cardiac resynchronization therapy defibrillator. Among 2540 patients, 35% wereold, 26% were women, and 59% were white. During 27 (median) months, 738 (29%) received ≥1 therapy. Three-year therapy risk was 36% (appropriate, 24%; inappropriate, 12%). Appropriate therapy was more common in men (adjusted hazard ratio [HR], 1.84; 95% confidence interval [CI], 1.43-2.35). Inappropriate therapy was more common in patients with atrial fibrillation (adjusted HR, 2.20; 95% CI, 1.68-2.87), but less common among patients ≥65 years old versus younger (adjusted HR, 0.72; 95% CI, 0.54-0.95) and in recent implants (eg, in 2009 versus 2006; adjusted HR, 0.66; 95% CI, 0.46-0.95). In Centers for Medicare and Medicaid Services Coverage With Evidence Development analysis, inappropriate therapy was less common with cardiac resynchronization therapy defibrillator versus single chamber (adjusted HR, 0.55; 95% CI, 0.36-0.84); therapy risk did not otherwise differ for Centers for Medicare and Medicaid Services Coverage With Evidence Development subgroups. CONCLUSIONS: In this community cohort of primary prevention patients receiving ICD, therapy delivery varied across demographic and clinical characteristics, but did not differ meaningfully for Centers for Medicare and Medicaid Services Coverage With Evidence Development subgroups

Comparison of Inappropriate Shocks and Other Health Outcomes Between Single- and Dual-Chamber Implantable Cardioverter-Defibrillators for Primary Prevention of Sudden Cardiac Death: Results from the Cardiovascular Research Network Longitudinal Study of Implantable Cardioverter-Defibrillators

Background In US clinical practice, many patients who undergo placement of an implantable cardioverter‐defibrillator (ICD) for primary prevention of sudden cardiac death receive dual‐chamber devices. The superiority of dual‐chamber over single‐chamber devices in reducing the risk of inappropriate ICD shocks in clinical practice has not been established. The objective of this study was to compare risk of adverse outcomes, including inappropriate shocks, between single‐ and dual‐chamber ICDs for primary prevention. Methods and Results We identified patients receiving a single‐ or dual‐chamber ICD for primary prevention who did not have an indication for pacing from 15 hospitals within 7 integrated health delivery systems in the Longitudinal Study of Implantable Cardioverter‐Defibrillators from 2006 to 2009. The primary outcome was time to first inappropriate shock. ICD shocks were adjudicated for appropriateness. Other outcomes included all‐cause hospitalization, heart failure hospitalization, and death. Patient, clinician, and hospital‐level factors were accounted for using propensity score weighting methods. Among 1042 patients without pacing indications, 54.0% (n=563) received a single‐chamber device and 46.0% (n=479) received a dual‐chamber device. In a propensity‐weighted analysis, device type was not significantly associated with inappropriate shock (hazard ratio, 0.91; 95% confidence interval, 0.59–1.38 [P=0.65]), all‐cause hospitalization (hazard ratio, 1.03; 95% confidence interval, 0.87–1.21 [P=0.76]), heart failure hospitalization (hazard ratio, 0.93; 95% confidence interval, 0.72–1.21 [P=0.59]), or death (hazard ratio, 1.19; 95% confidence interval, 0.93–1.53 [P=0.17]). Conclusions Among patients who received an ICD for primary prevention without indications for pacing, dual‐chamber devices were not associated with lower risk of inappropriate shock or differences in hospitalization or death compared with single‐chamber devices. This study does not justify the use of dual‐chamber devices to minimize inappropriate shocks

Alpha helix-coil phase transition: analysis of ab initio theory predictions

In the present paper we present results of calculations obtained with the use of the theoretical method described in our preceding paper [1] and perform detail analysis of alpha helix-random coil transition in alanine polypeptides of different length. We have calculated the potential energy surfaces of polypeptides with respect to their twisting degrees of freedom and construct a parameter-free partition function of the polypeptide using the suggested method [1]. From the build up partition function we derive various thermodynamical characteristics for alanine polypeptides of different length as a function of temperature. Thus, we analyze the temperature dependence of the heat capacity, latent heat and helicity for alanine polypeptides consisting of 21, 30, 40, 50 and 100 amino acids. Alternatively, we have obtained same thermodynamical characteristics from the use of molecular dynamics simulations and compared them with the results of the new statistical mechanics approach. The comparison proves the validity of the statistical mechanic approach and establishes its accuracy.Comment: 34 pages, 12 figure

Folding Pathways of Prion and Doppel

The relevance of various residue positions for the stability and the folding characteristics of the prion protein are investigated by using molecular dynamics simulations of models exploiting the topology of the native state. Highly significant correlations are found between the most relevant sites in our analysis and the single point mutations known to be associated with the arousal of the genetic forms of prion disease (caused by the conformational change from the cellular to the scrapie isoform). Considerable insight into the conformational change is provided by comparing the folding process of prion and doppel (a newly discovered protein) sharing very similar native state topology: the folding pathways of the former can be grouped in two main classes according to which tertiary structure contacts are formed first enroute to the native state. For the latter a single class of pathways leads to the native state. Our results are consistent and supportive of the recent experimental findings that doppel lacks the scrapie isoform and that such remarkably different behavior results from differences in the region containing the two $\beta-$strands and the intervening helix.Comment: 16 pages, 2 tables, 5 figure

Folding of the Protein Domain hbSBD

The folding of the alpha-helice domain hbSBD of the mammalian mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex is studied by the circular dichroism technique in absence of urea. Thermal denaturation is used to evaluate various thermodynamic parameters defining the equilibrium unfolding, which is well described by the two-state model with the folding temperature T_f = 317.8 K and the enthalpy change Delta H_g = 19.67 kcal/mol. The folding is also studied numerically using the off-lattice coarse-grained Go model and the Langevin dynamics. The obtained results, including the population of the native basin, the free energy landscape as a function of the number of native contacts and the folding kinetics, also suggest that the hbSBD domain is a two-state folder. These results are consistent with the biological function of hbSBD in BCKD.Comment: 25 pages, 7 figures, 1 table, published in Biophysical Journa

The intermediate learner’s choice of self-as-a-model strategies and the eight-session practice in learning of the front crawl swim

The aim of this study was to investigate the intermediate learners’ choice of self-as-a-model strategies for learning the front crawl swim by extending the amount of practice. Participants (n=40) were divided into three groups: choice (free to choose to watch a video footage of their best or overall performance anytime during a practice), yoked (paired to the learners of the choice group), and control group (did not watch any video). Experimental design also involved a pretest, eigh tacquisition blocks, and a 48-hour retention test. The measures included a qualitative analysis of the front crawl swim and the rate of self-efficacy belief questionnaire. Results showed better learning of the front crawl swim for the choice group in comparison to the yoked and control group. It was also verified that the belief of self-efficacy improved in the choice and yoked groups. Most learners chose self-observation of their overall performance during the entire practice. The rest of learners waved in their choices. Self-observation of either the best or overall performance had similar effects on learning the front crawl swim. In conclusion, to provide learners with freedom of choice during the extended acquisition phase was positive for motor learning, regardless of whether or not there were changes in their choices

Protein Dynamics: From Molecules, to Interactions, to Biology

Proteins have a remarkably rich diversity of dynamical behaviors, and the articles in this issue of the International Journal of Molecular Sciences are a testament to that fact. From the picosecond motions of single sidechains probed by NMR or fluorescence spectroscopy, to aggregation processes at interfaces that take months, all time scales play a role. Proteins are functional molecules, so by their nature they always interact with their environment. This environment includes water, other biomolecules, or larger cellular structures. In a sense, it also includes the protein molecule itself: proteins are large enough to fold and interact with themselves. These interactions have been honed by evolution to produce behaviors completely different from those of random polymers

Phytohormone cytokinin guides microtubule dynamics during cell progression from proliferative to differentiated stage

Cell production and differentiation for the acquisition of specific functions are key features of living systems. The dynamic network of cellular microtubules provides the necessary platform to accommodate processes associated with the transition of cells through the individual phases of cytogenesis. Here, we show that the plant hormone cytokinin fine‐tunes the activity of the microtubular cytoskeleton during cell differentiation and counteracts microtubular rearrangements driven by the hormone auxin. The endogenous upward gradient of cytokinin activity along the longitudinal growth axis in Arabidopsis thaliana roots correlates with robust rearrangements of the microtubule cytoskeleton in epidermal cells progressing from the proliferative to the differentiation stage. Controlled increases in cytokinin activity result in premature re‐organization of the microtubule network from transversal to an oblique disposition in cells prior to their differentiation, whereas attenuated hormone perception delays cytoskeleton conversion into a configuration typical for differentiated cells. Intriguingly, cytokinin can interfere with microtubules also in animal cells, such as leukocytes, suggesting that a cytokinin‐sensitive control pathway for the microtubular cytoskeleton may be at least partially conserved between plant and animal cells