Heart failure remains a major public health concern with a 5-year mortality rate higher than that of most cancers. Myocardial disease in heart failure is frequently accompanied by impairment of the specialized electrical conduction system and myocardium. We introduce an epicardial mesh made of electrically conductive and mechanically elastic material, to resemble the innate cardiac tissue and confer cardiac conduction system function, to enable electromechanical cardioplasty. Our epicardium-like substrate mechanically integrated with the heart and acted as a structural element of cardiac chambers. The epicardial device was designed with elastic properties nearly identical to the epicardial tissue itself and was able to detect electrical signals reliably on the moving rat heart without impeding diastolic function 8 weeks after induced myocardial infarction. Synchronized electrical stimulation over the ventricles by the epicardial mesh with the high conductivity of 11,210 S/cm shortened total ventricular activation time, reduced inherent wall stress, and improved several measures of systolic function including increases of 51% in fractional shortening,~90% in radial strain, and 42% in contractility. The epicardial mesh was also capable of delivering an electrical shock to terminate a ventricular tachyarrhythmia in rodents. Electromechanical cardioplasty using an epicardial mesh is a new pathway toward reconstruction of the cardiac tissue and its specialized functions.

The infectious cycle of primate lentiviruses is intimately linked to interactions between cells of the immune system. Nef, a potent virulence factor, alters cellular environments to increase lentiviral replication in the host, yet the mechanisms underlying these effects have remained elusive. Since Nef likely functions as an adaptor protein, we exploited a proteomic approach to directly identify molecules that Nef targets to subvert the signaling machinery in T cells. We purified to near homogeneity a major Nef-associated protein complex from T cells and identified by mass spectroscopy its subunits as DOCK2–ELMO1, a key activator of Rac in antigen- and chemokine-initiated signaling pathways, and Rac. We show that Nef activates Rac in T cell lines and in primary T cells following infection with HIV-1 in the absence of antigenic stimuli. Nef activates Rac by binding the DOCK2–ELMO1 complex, and this interaction is linked to the abilities of Nef to inhibit chemotaxis and promote T cell activation. Our data indicate that Nef targets a critical switch that regulates Rac GTPases downstream of chemokine- and antigen-initiated signaling pathways. This interaction enables Nef to influence multiple aspects of T cell function and thus provides an important mechanism by which Nef impacts pathogenesis by primate lentiviruses.

Heart failure (HF) is an increasing public health problem accelerated by a rapidly aging global population. Despite considerable progress in managing the disease, the development of new therapies for effective treatment of HF remains a challenge. To identify targets for early diagnosis and therapeutic intervention, it is essential to understand the molecular and cellular basis of calcium handling and the signaling pathways governing the functional remodeling associated with HF in humans. Calcium (Ca2+) cycling is an essential mediator of cardiac contractile function, and remodeling of calcium handling is thought to be one of the major factors contributing to the mechanical and electrical dysfunction observed in HF. Active research in this field aims to bridge the gap between basic research and effective clinical treatments of HF. This chapter reviews the most relevant studies of calcium remodeling in failing human hearts and discusses their connections to current and emerging clinical therapies for HF patients.

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Objectives To develop a low-energy electrotherapy that terminates ventricular tachycardia (VT) when anti-tachycardia pacing (ATP) fails. Background High-energy ICD shocks are associated with device failure, significant morbidity and increased mortality. A low-energy alternative to ICD shocks is desirable. Methods Myocardial infarction (MI) was created in 25 dogs. Sustained, monomorphic VT was induced by programmed stimulation. Defibrillation electrodes were placed in the RV apex, and coronary sinus (CS) and LV epicardium (LVP). If ATP failed to terminate sustained VT, the defibrillation thresholds (DFTs) of standard versus experimental electrotherapies were measured. Results Sustained VT ranged from 276–438 bpm (mean 339 bpm). The RV-CS shock vector had lower impedance than RV-LVP (54.4±18.1 Ω versus 109.8±16.9, Ω p<0.001). A single shock required between 0.3±0.2 J to 5.9±2.5 J (mean 2.64±3.22 J; p=0.008) to terminate VT, and varied depending upon the phase of the VT cycle at which it was delivered. In contrast, multiple shocks delivered within 1 VT cycle length were not phase-dependent and achieved lower DFT compared to a single shock (0.13±0.09 J for 3 shocks, 0.08±0.04 J for 5 shocks, 0.09±0.07 J for 7 shocks; p<0.001). Finally, a multi-stage electrotherapy (MSE) achieved significantly lower DFT compared to a single biphasic shock (0.03±0.05 J versus 2.37±1.20 J, respectively, p<0.001). At a peak shock amplitude of 20 V, MSE achieved 91.3% of terminations versus 10.5% for a biphasic shock (p<0.001). Conclusions MSE achieved a major reduction in DFT compared to a single biphasic shock for ATP-refractory monomorphic VT, and represents a novel electrotherapy to reduce high-energy ICD shocks.

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Background-Implantable device therapy of atrial fibrillation (AF) is limited by pain from high-energy shocks. We developed a low-energy multistage defibrillation therapy and tested it in a canine model of AF.

A free energy function, combining molecular mechanics energy with empirical solvation and entropic terms, is used for ranking near-native conformations that occur in the conformational search steps of homology modeling, i.e., side-chain search and loop closure calculations. Correlations between the free energy and RMS deviation from the X-ray structure are established. It is shown that generally both molecular mechanics and solvation/entropic terms should be included in the potential. The identification of near-native backbone conformations is accomplished primarily by the molecular mechanics term that becomes the dominant contribution to the free energy if the backbone is even slightly strained, as frequently occurs in loop closure calculations. Both terms become equally important if a sufficiently accurate backbone conformation is found. Finally, the selection of the best side-chain positions for a fixed backbone is almost completely governed by the solvation term. The discriminatory power of the combined potential is demonstrated by evaluating the free energies of protein models submitted to the first meeting on Critical Assessment of techniques for protein Structure Prediction (CASPI), and comparing them to the free energies of the native conformations.Keywords: free energy; loop closure; protein conformation; side-chain search Identifying native and near-native folds among a set of conformations is an important step in a variety of applications involving conformational search. Here we focus on homology modeling that aims to build the structure of a target protein beginning with the coordinates of a homologue serving as the template. Homology modeling employs search algorithms to determine the structure of certain loop regions and to place nonconserved side chains. Accordingly, this paper deals with the problems of ranking nearnative conformations that are generated by side-chain search and loop closure algorithms, or have been obtained from a template by various homology modeling procedures.As shown by Novotny and co-workers , molecular mechanics energy functions may be unable to distinguish between correct and misfolded conformations. While molecular mechanics is a useful tool for studying the effects of covalent bonding, excluded volumes, and coulombic electrostatics, it is inadequate for a thermodynamical description of stable, compact protein folds that may be heavily influenced by the nature of their solvent exposed surfaces . A further disadvantage of molecular mechanics is its tendency to yield a rugged energy surface with countless local minima, resulting in an exReprint requests to: Sandor Vajda,