RESUMEN

Short surfactant-like amphiphilic peptide, A3K, resembling a surfactant with a hydrophobic tail (A3) and a polar headgroup (K), is experimentally determined to form a membrane. Although the peptides are known to exist as ß-strands, the exact packing architecture stabilizing the membrane is unknown. Earlier simulation studies have reported successful packing configurations through trial and error. In this work, we present a systematic protocol to identify the best peptide configurations for different packing patterns. The influence of stacking peptides in square and hexagonal packing geometry with the neighboring peptides in parallel and antiparallel orientations was explored. The best peptide configurations were determined from the free energy of bringing 2-4 peptides together as a bundle that can be stacked into a membrane. The stability of the assembled bilayer membrane was further investigated through molecular dynamics simulation. The role of peptide tilting, interpeptide distance, the nature and the extent of interactions, and the conformational degrees of freedom on the stability of the membrane is discussed. The consistency with the experimental findings suggests hexagonal antiparallel as the most relevant molecular architecture.

Asunto(s)

RESUMEN

INTRODUCTION: Left bundle branch pacing (LBBP) involves the deployment of the lead deep inside the septum. Penetration of the septum by the lead depends on the texture of the septum, rapidity of rotations, operator experience, and implantation tools. OBJECTIVES: The aim of our study was to assess the behavior of the lumenless lead during rapid rotations and the physiological property of the interventricular septum(IVS) during LBBP. METHODS: Patients undergoing LBBP between January 2021 and December 2022 were retrospectively included in the study. RESULTS: Among 255 attempted patients, 20 (7.9%) had procedural failure(no LBB capture-four, inability to penetrate septum-seven, and dislodgements after sheath removal-nine). Septal penetration achieved in 248/255 patients (97.2%). Lead movement inside the IVS was assessed by lead traverse time. Based on the behavior of the IVS (n = 255), three different responses were noted. Type-I response(normal/firm septum) in 93.7% (n = 239) characterized by constant and progressive movement of lead. Neither perforation nor further change in premature-ventricular-complex morphology beyond M-beat were observed despite additional few unintentional rotations indicating the protective mechanism of LV-endocardium. Type-II response(soft/cheesy septum) in 3.5% (n = 9) characterized by hyper-movement of lead without resistance due to altered texture of septum and poor LV subendocardial barrier resulting in perforation. No patients in this group had LV dysfunction or associated coronary artery disease. In type-III response, seen in 2.8% (n = 7), lead could not be penetrated due to scar in IVS. CONCLUSION: Three different patterns of responses were observed during LBBP. The most distinct type-ll response was associated with soft/cheesy septum with hyper-movement of the lead predisposing for future dislodgments in patients without structural heart disease.

Asunto(s)

RESUMEN

Alanine-rich tetrapeptides like A3K dominantly exist as polyproline II helices in dilute aqueous solutions. However, during self-assembly, based on the free energy calculation in implicit solvent for various peptide conformations, only the peptides in the ß-strand conformation can be packed closely. This necessitates the conformational transition to the ß-strand commonly observed during peptide self-assembly such as in amyloid fibril formation. In fact, the closest interpeptide distance of 4.8 Å is consistent with the interstrand distance determined from the X-ray diffraction pattern of many amyloid fibrils. The position of free energy minimum obtained from implicit solvent calculation matches exactly with the explicit solvent simulation through umbrella sampling when the peptide conformations are restrained, demonstrating the applicability of the former for rapid screening of peptide configurations favorable for self-assembly. The barrier in the free energy profile in the presence of water arises out of the entropic restriction on the interstitial water molecules while satisfying the hydrogen bonding of both the peptides by forming water mediated hydrogen bond bridge. Further, the high energy barrier observed for the ß-strand suggests that peptides initially tend to self-assemble in the polyproline II structure to mitigate the desolvation energy cost; the transition to the ß-strand would happen only in the later stage after crossing the barrier. The umbrella sampling simulations with peptides allowed to change conformations, relative to each other, confirm the dynamic conformational transition during the course of the self-assembly supporting the "dock and lock" mechanism suggested for amyloid fibrillar growth.

Asunto(s)

RESUMEN

BACKGROUND: Cardiac resynchronization therapy (CRT) is a class I indication for left ventricular ejection fraction (LVEF) ≤35% and heart failure (HF). Left bundle branch block (LBBB)-associated nonischemic cardiomyopathy (LB-NICM) with minimal or no scar by cardiac magnetic resonance (CMR) imaging may be associated with excellent prognosis following CRT. Left bundle branch pacing (LBBP) can achieve excellent resynchronization in LBBB patients. OBJECTIVES: The purpose of this study was to prospectively assess the feasibility and efficacy of LBBP with or without a defibrillator in patients with LB-NICM and LVEF ≤35%, risk stratified by CMR. METHODS: Patients with LB-NICM, LVEF ≤35%, and HF were prospectively enrolled from 2019 to 2022. If the scar burden was <10% by CMR then LBBP only (group I) and if ≥10% then LBBP + implantable cardioverter-defibrillator (ICD) (group II) was performed. Primary endpoints were (1) echocardiographic response (ER) [ΔLVEF ≥15%] at 6 months; and (2) composite of time to death, heart failure hospitalization (HFH), or sustained ventricular tachycardia (VT)/ventricular fibrillation (VF). Secondary endpoints were (1) echocardiographic hyperresponse (EHR) [LVEF ≥50% or ΔLVEF ≥20%] at 6 and 12 months; and (2) indication for ICD upgrade [persistent LVEF <35% at 12 months or sustained VT/VF]. RESULTS: One hundred twenty patients were enrolled. CMR showed <10% scar burden in 109 patients (90.8%). Four patients opted for LBBP+ICD and withdrew. LBBP-optimized dual-chamber pacemaker (LOT-DDD-P) was performed in 101 patients and LOT-CRT-P in 4 patients (group I; n = 105). Eleven patients with scar burden ≥10% underwent LBBP+ICD (group II). During mean-follow-up of 21 ± 12 months, the primary endpoint of ER was observed in 80% (68/85 patients) in group I vs 27% (3/11 patients) in group II (P = .0001). Primary composite endpoint of death, HFH, or VT/VF occurred in 3.8% in group I vs 33.3% in group II (P <.0001). Secondary endpoint of EHR (LVEF≥50%) was observed in 39.5% vs 0%, 61.2% vs 9.1%, and 80% vs 33.3% at 3, 6, and 12 months in groups I and II, respectively. CONCLUSION: CMR-guided CRT using LOT-DDD-P seems to be a safe and feasible approach in LB-NICM and has the potential to reduce health care costs.

Asunto(s)

RESUMEN

Drug repurposing has been gaining increasing interest recently due to the reduction in development cost and reduced development timelines. Here, we report the antibacterial activity of the anticancer drug etoposide investigated in combination with the eggshell-derived hydroxyapatite (EHA). Hydroxyapatite (HA) is a well-known bioactive material with enhanced osteoconductivity and possesses superior drug delivery properties. In the present work, we have synthesized etoposide-loaded EHA by the wet precipitation method. The physicochemical characterization of the samples confirmed the composition and amount of drug encapsulation. Screening for antibacterial activity confirmed the antibacterial effect of etoposide against Staphylococcus aureus. Biofilm formation test on pristine and etoposide-loaded samples showed the inhibition of biofilm formation on etoposide loading, which was further studied by confocal laser scanning microscopy (CLSM) and colony forming units (CFUs). It has been found that etoposide-loaded HA exhibited a sustained release of the drug upto 168 h. Analysis of the inhibition mechanism of etoposide against S. aureus revealed damage to the cell membrane and has been quantified using flow cytometry by the uptake of propidium iodide. Etoposide-loaded eggshell-derived HA (EHA-ET) exhibited excellent bioactivity and cytocompatibility against mouse fibroblast cells (L929) and supressed the growth of osteosarcoma cells (MG-63). Our studies reveal that the EHA-ET has a great potential for treating osteosarcoma and osteomyelitis.

Asunto(s)

Asunto(s)