Membrane Biophysics

Membranes are the unique biological structures maintaining the intra- and extracellular partition. In unicellular organisms they define the living interior from the nonliving exterior. In case of eukaryotes, membranes also help in separation of different intracellular milieus. Membranes also play roles as the site of active exchange of information between intra- and extracellular environments in various ways. Here in this chapter, we first visit the structural aspects of biological membranes. Then, we discuss in details the various types of transport mechanisms that occur across membranes. We also describe the different types of ion channels and pumps with special emphasis of Na+/K+ ATPase and Ca2+ ATPases. We have paid special attention about diseases that are associated with dysfunction of ion channels and pumps. This chapter is designed for the readers to build a sound background on the functioning of biological membranes from the structural perspectives

High gender -specific susceptibility to curare- a neuromuscular blocking agent

Curare, a selective skeletal muscle relaxant, has been used clinically to reduce shivering and as an anesthetic auxiliary in abdominal surgery. It is also widely used in animal experiments to block neuromuscular junction activity. Effective doses of curare diminish muscle contraction without affecting brain function, but at higher doses it is known to be lethal. However, the exact dose of curare initiating muscle relaxation vs. lethal effect has not been fully characterized in mice. In this study we carefully examined the dose-response for achieving muscle inactivity over lethality in both male and female mice (C57BL6/J). The most striking finding of this study is that female mice were highly susceptible to curare; both the EDm and LDm were at least 3-fold lower than male littermates. This study shows that gender-specific differences can be an important factor when administering skeletal muscle relaxants, particularly curare or other analogous agents targeted to the neuromuscular junction

Identification of new inhibitors against human Great wall kinase using in silico approaches

Microtubule associated serine/threonine kinase (MASTL) is an important Ser/Thr kinase belonging to the family of AGC kinases. It is the human orthologue of Greatwall kinase (Gwl) that plays a significant role in mitotic progression and cell cycle regulation. Upregulation of MASTL in various cancers and its association with poor patient survival establishes it as an important drug target in cancer therapy. Nevertheless, the target remains unexplored with the paucity of studies focused on identification of inhibitors against MASTL, which emphasizes the relevance of our present study. We explored various drug databases and performed virtual screening of compounds from both natural and synthetic sources. A list of promising compounds displaying high binding characteristics towards MASTL protein is reported. Among the natural compounds, we found a 6-hydroxynaphthalene derivative ZINC85597499 to display best binding energy value of −9.32 kcal/mol. While among synthetic compounds, a thienopyrimidinone based tricyclic derivative ZINC53845290 compound exhibited best binding affinity of value −7.85 kcal/mol. MASTL interactions with these two compounds were further explored using molecular dynamics simulations. Altogether, this study identifies potential inhibitors of human Gwl kinase from both natural and synthetic origin and calls for studying these compounds as potential drugs for cancer therapy

Pulmonary artery banding alters the expression of Ca2+ transport proteins in the right atrium in rabbits

Following pulmonary artery banding (PAB), the contractile function of right ventricle diminishes over time. Subsequently, the right atrium (RA) has to contract against a higher afterload, but it is unknown to what extent ventricular dysfunction has an effect on the atrial contractility. We hypothesized that right ventricular pressure overload may have an affect on atrial contractility and Ca2+ transport protein expression. Therefore, we induced pressure overload of the right ventricle by PAB for 10 wk in rabbits and examined the changes in the expression of Ca2+ transport proteins in the atrium. We demonstrate that PAB significantly decreased the expression of sarco(endo)plasmic reticulum Ca2+-ATPase (Serca) 2a while expression of Na+/Ca2+ exchanger-1 was significantly upregulated in the RA but not in the left atria of rabbit hearts, indicating that pressure is the major trigger. A decrease in Serca2a expression was concomitant with a significant decrease in sarcolipin (SLN), possibly indicating a compensatory role of SLN. The decreased expression of SLN was unable to completely restore sarcoplasmic reticulum Ca2+ uptake function of Serca2a. Functional contractile assessments in isolated trabeculae showed no difference between PAB- and sham-operated rabbits at 1 Hz but displayed an enhanced force development at higher frequencies and in the presence of isoproterenol, while twitch timing was unaffected. Our results indicate that right ventricular mechanical overload due to PAB affects the expression of the Ca2+-handling proteins in the RA in rabbits

Metabolic dysfunction and altered mitochondrial dynamics in the utrophin-dystrophin deficient mouse model of duchenne muscular dystrophy.

The utrophin-dystrophin deficient (DKO) mouse model has been widely used to understand the progression of Duchenne muscular dystrophy (DMD). However, it is unclear as to what extent muscle pathology affects metabolism. Therefore, the present study was focused on understanding energy expenditure in the whole animal and in isolated extensor digitorum longus (EDL) muscle and to determine changes in metabolic enzymes. Our results show that the 8 week-old DKO mice consume higher oxygen relative to activity levels. Interestingly the EDL muscle from DKO mouse consumes higher oxygen per unit integral force, generates less force and performs better in the presence of pyruvate thus mimicking a slow twitch muscle. We also found that the expression of hexokinase 1 and pyruvate kinase M2 was upregulated several fold suggesting increased glycolytic flux. Additionally, there is a dramatic increase in dynamin-related protein 1 (Drp 1) and mitofusin 2 protein levels suggesting increased mitochondrial fission and fusion, a feature associated with increased energy demand and altered mitochondrial dynamics. Collectively our studies point out that the dystrophic disease has caused significant changes in muscle metabolism. To meet the increased energetic demand, upregulation of metabolic enzymes and regulators of mitochondrial fusion and fission is observed in the dystrophic muscle. A better understanding of the metabolic demands and the accompanied alterations in the dystrophic muscle can help us design improved intervention therapies along with existing drug treatments for the DMD patients

NMR assignment of peptidyl-tRNA hydrolase from Mycobacterium tuberculosis H37Rv

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