Patient-specific modeling of dyssynchronous heart failure: A case study

The development and clinical use of patient-specific models of the heart is now a feasible goal. Models have the potential to aid in diagnosis and support decision-making in clinical cardiology. Several groups are now working on developing multi-scale models of the heart for understanding therapeutic mechanisms and better predicting clinical outcomes of interventions such as cardiac resynchronization therapy. Here we describe the methodology for generating a patient-specific model of the failing heart with a myocardial infarct and left ventricular bundle branch block. We discuss some of the remaining challenges in developing reliable patient-specific models of cardiac electromechanical activity, and identify some of the main areas for focusing future research efforts. Key challenges include: efficiently generating accurate patient-specific geometric meshes and mapping regional myofiber architecture to them; modeling electrical activation patterns based on cellular alterations in human heart failure, and estimating regional tissue conductivities based on clinically available electrocardiographic recordings; estimating unloaded ventricular reference geometry and material properties for biomechanical simulations; and parameterizing systemic models of circulatory dynamics from available hemodynamic measurements.     

Effect of thermostable mutations on the neurotensin receptor 1 (NTSR1) activation state

Abstract

Neurotensin (NTS) is a 13-amino acid neuropeptide with neuroendocrine and vasoactive functions that is widely expressed in the central nervous system and gastrointestinal tract. NTS is sensed by a multiple cell surface proteins including two G protein-coupling receptors (GPCRs): NTS receptors 1 and 2 (NTSR₁ and NTSR₂). Crystal structures of NTSR₁ have successfully elucidated agonist binding within the orthosteric pocket of receptor but have not revealed the full activation state of the receptor. Recent studies have attempted to address this challenge by improving NTSR₁ crystal formation via thermostable mutants; unfortunately, these mutations exhibit functional defects in the G protein coupling of NTSR₁. Here, we have used molecular dynamics simulations to gain greater insights into how the amino acid substitutions used in these thermostable mutants (E166A, L310A and F358A) impact receptor activation. Our simulations indicate that wild-type NTSR₁ in complex with NTS_8-13 shows more active-like features including a 17.7?Å shift in TM6, reflecting a network of polar and aromatic interactions orchestrating agonist-induced receptor conformational changes. We also provide evidence indicating that F358 is a precursor to the rotamer change observed in W321, and our collective analysis also suggests that mutations E166A and F358A are less impactful to G protein coupling than L310A. Furthermore, we believe that our findings can be used to design future NTSR₁ mutants that do not interfere with agonist-induced conformational changes and downstream G protein coupling and thus produce structures that will allow visualization of the fully activated receptor conformation.     

Characterization of two host-specific genes, mannose-sensitive hemagglutinin (mshA) and uridyl phosphate dehydrogenase (UDPDH) that are involved in the Vibrio fischeri–Euprymna tasmanica mutualism

While much has been known about the mutualistic associations between the sepiolid squid Euprymna tasmanica and the luminescent bacterium, Vibrio fischeri , less is known about the connectivity between the microscopic and molecular basis of initial attachment and persistence in the light organ. Here, we examine the possible effects of two symbiotic genes on specificity and biofilm formation of V. fischeri in squid light organs. Uridine diphosphate glucose-6-dehydrogenase (UDPDH) and mannose-sensitive hemagglutinin ( mshA ) mutants were generated in V. fischeri to determine whether each gene has an effect on host colonization, specificity, and biofilm formation. Both squid light organ colonization assays and transmission electron microscopy confirmed differences in host colonization between wild-type and mutant strains, and also demonstrated the importance of both UDPDH and mshA gene expression for successful light organ colonization. This furthers our understanding of the genetic factors playing important roles in this environmentally transmitted symbiosis.     

Advanced Glycation End Products: key player of the pathogenesis of atherosclerosis

Glycoconjugate Journal - Atherosclerosis is the most common type of cardiovascular disease, and it causes intima thickening, plaque development, and ultimate blockage of the artery lumen. Advanced...     

UV-A induced lipid peroxidation in liposomal membrane

UV-A (365 nm) produced a dose-dependent linear increase of lipid peroxidation, as detected by the assay of malondialdehyde (MDA). MDA formation was inversely related to the UV-A dose rate. Sodium formate and ethylenediaminetetra acetic acid (EDTA) could not inhibit by any significant degree the UV-A induced MDA formation. While butylated hydroxy toluene (BHT) caused about 85% inhibition, sodium azide and L-histidine produced 45-50% inhibition of MDA formation. The involvement of singlet oxygen (1O2) in the UV-A induced lipid peroxidation is discussed.     

Protective Impact of Edaravone Against ZnO NPs-induced Oxidative Stress in the Human Neuroblastoma SH-SY5Y Cell Line

Cellular and Molecular Neurobiology - Extensive applications of ZnO NPs (zinc oxide nanoparticles) in daily life have created concern about their biotoxicity. Zinc oxide nanoparticles induce...