Acetylcholine Receptor Gating: Movement in the α-Subunit Extracellular Domain

Acetylcholine receptor channel gating is a brownian conformational cascade in which nanometer-sized domains (“Φ blocks”) move in staggering sequence to link an affinity change at the transmitter binding sites with a conductance change in the pore. In the α-subunit, the first Φ-block to move during channel opening is comprised of residues near the transmitter binding site and the second is comprised of residues near the base of the extracellular domain. We used the rate constants estimated from single-channel currents to infer the gating dynamics of Y127 and K145, in the inner and outer sheet of the β-core of the α-subunit. Y127 is at the boundary between the first and second Φ blocks, at a subunit interface. αY127 mutations cause large changes in the gating equilibrium constant and with a characteristic Φ-value (Φ = 0.77) that places this residue in the second Φ-block. We also examined the effect on gating of mutations in neighboring residues δI43 (Φ = 0.86), ɛN39 (complex kinetics), αI49 (no effect) and in residues that are homologous to αY127 on the ɛ, β, and δ subunits (no effect). The extent to which αY127 gating motions are coupled to its neighbors was estimated by measuring the kinetic and equilibrium constants of constructs having mutations in αY127 (in both α subunits) plus residues αD97 or δI43. The magnitude of the coupling between αD97 and αY127 depended on the αY127 side chain and was small for both H (0.53 kcal/mol) and C (−0.37 kcal/mol) substitutions. The coupling across the single α–δ subunit boundary was larger (0.84 kcal/mol). The Φ-value for K145 (0.96) indicates that its gating motion is correlated temporally with the motions of residues in the first Φ-block and is not synchronous with those of αY127. This suggests that the inner and outer sheets of the α-subunit β-core do not rotate as a rigid body

Systemic Therapy in Endometrial Cancer: Recent Advances.

Endometrial cancer is a chemosensitive disease. Studies have established a clear benefit of chemotherapy in advanced stages and trials are ongoing to define its role in early stages as well. As more molecular pathways are being elucidated there is increasing role for targeted agents and future looks quite promising. We did an extensive search both online and offline for all the relevant articles including chemotherapy and targeted therapy for endometrial cancer

Glycine Hinges with Opposing Actions at the Acetylcholine Receptor-Channel Transmitter Binding Site □ S

ABSTRACT The extent to which agonists activate synaptic receptor-channels depends on both the intrinsic tendency of the unliganded receptor to open and the amount of agonist binding energy realized in the channel-opening process. We examined mutations of the nicotinic acetylcholine receptor transmitter binding site (␣ subunit loop B) with regard to both of these parameters. ␣Gly147 is an "activation" hinge where backbone flexibility maintains high values for intrinsic gating, the affinity of the resting conformation for agonists and net ligand binding energy. ␣Gly153 is a "deactivation" hinge that maintains low values for these parameters. ␣Trp149 (between these two glycines) serves mainly to provide ligand binding energy for gating. We propose that a concerted motion of the two glycine hinges (plus other structural elements at the binding site) positions ␣Trp149 so that it provides physiologically optimal binding and gating function at the nerve-muscle synapse

Acetylcholine Receptor Gating at Extracellular Transmembrane Domain Interface: the Cys-Loop and M2–M3 Linker

Acetylcholine receptor channel gating is a propagated conformational cascade that links changes in structure and function at the transmitter binding sites in the extracellular domain (ECD) with those at a “gate” in the transmembrane domain (TMD). We used Φ-value analysis to probe the relative timing of the gating motions of α-subunit residues located near the ECD–TMD interface. Mutation of four of the seven amino acids in the M2–M3 linker (which connects the pore-lining M2 helix with the M3 helix), including three of the four residues in the core of the linker, changed the diliganded gating equilibrium constant (Keq) by up to 10,000-fold (P272 > I274 > A270 > G275). The average Φ-value for the whole linker was ∼0.64. One interpretation of this result is that the gating motions of the M2–M3 linker are approximately synchronous with those of much of M2 (∼0.64), but occur after those of the transmitter binding site region (∼0.93) and loops 2 and 7 (∼0.77). We also examined mutants of six cys-loop residues (V132, T133, H134, F135, P136, and F137). Mutation of V132, H134, and F135 changed Keq by 2800-, 10-, and 18-fold, respectively, and with an average Φ-value of 0.74, similar to those of other cys-loop residues. Even though V132 and I274 are close, the energetic coupling between I and V mutants of these positions was small (≤0.51 kcal mol−1). The M2–M3 linker appears to be the key moving part that couples gating motions at the base of the ECD with those in TMD. These interactions are distributed along an ∼16-Å border and involve about a dozen residues

Association Rule Mining on Metrological and Remote Sensing Data With Weka Tool

Drought is one of the major environmental disasters in many parts of the world. There are several possibilities of drought monitoring based on ground measurements, hydrological, climatologically and Remote Sensing data. Drought indices that derived by meteorological data and Remote Sensing data have coarse spatial and temporal resolution. Because of the spatial and temporal variability and multiple impacts of droughts, we need to improve the tools and data available for mapping and monitoring this phenomenon on all scales. In this paper we present discovering knowledge by association rules from metrological and Remote Sensing data and we have also used descriptive modeling. For calculating drought taking metrological data which is extract from metrological department of Pune at Maharastra (India) and Remote Sensing data is extract from National Aeronautics and Space Administration (NASA)

Boiling and Condensation

This chapter contains a brief overview of both boiling and condensation heat transfer phenomena. Boiling and condensation are the two convective heat transfer phenomena that involve phase change from liquid to vapour and vapour to liquid, respectively. The chapter starts with the basis of heat transfer with an emphasis on the boiling and condensation phenomenon. Next, the overview of the boiling phenomenon and its different classifications like pool, flow, and subcooled and saturated boiling are discussed in detail. Different boiling regimes (natural convection boiling, nucleate boiling, transition boiling and film boiling) with the observed heat transfer rate in the case of pool boiling are mentioned in detail using the boiling curve. The heat transfer aspect and basics of condensation with types (drop and film-wise condensation) and application are also presented. The derivation for the calculation of the rate of heat transfer during film condensation with the correlations for heat transfer coefficient on vertical, horizontal and inclined plates is explained. Some numerical for the calculation of the rate of heat transfer and heat transfer coefficient for condensation phenomena has been also been mentioned. Apart from a basic overview, this chapter also includes information about the advanced heat transfer enhancement techniques available for boiling and condensation

Development of an in vitro model to study clot lysis activity of thrombolytic drugs

BACKGROUND: Thrombolytic drugs are widely used for the management of cerebral venous sinus thrombosis patients. Several in vitro models have been developed to study clot lytic activity of thrombolytic drugs, but all of these have certain limitations. There is need of an appropriate model to check the clot lytic efficacy of thrombolytic drugs. In the present study, an attempt has been made to design and develop a new model system to study clot lysis in a simplified and easy way using a thrombolytic drug, streptokinase. METHODS: Whole blood from healthy individuals (n = 20) was allowed to form clots in a pre-weighed sterile microcentrifuge tubes; serum was removed and clot was weighed. After lysis by streptokinase fluid was removed and remnants of clot were again weighed along with the tube. Percentage of Clot lysis was calculated on the basis of the weight difference of microcentrifuge tubes obtained before and after clot lysis. RESULTS: There was a significant percentage of clot lysis observed when streptokinase was used. On the other hand with water (negative control), minimal (2.5%) clot lysis was observed. There was a significant difference between clot lysis done by streptokinase and water. CONCLUSION: Our study could be a rapid and effective methodology to study clot-lytic effect of newly developed drugs as well as known drugs