Modelling the structure of the calcitonin gene-related peptide

The calcitonin gene-related peptide (CGRP) is a 37 residue neuropeptidewhich causes vasodilatation, increases heart rate and inhibitsbone resorption. These effects make it an interesting lead fordrug discovery. We have combined current structural and biologicalinformation to model the structure of hCGRP-ß to beused as a basis for the rational design of novel analogues.Distinct regions of CGRP have been shown to be responsible forthe activity of the whole molecule. Thus, the structure of thepeptide was modelled in four parts which were finally combined.A random search of conformational space was performed for thefragments CGRP1–8 and CGRP30–37 which have beenshown to be central for receptor activation and binding, respectively.Five low-energy hCGRP-ß structures were obtained frommodelled fragments by molecular dynamics. The relevance of theapproach was verified by comparing the models with NMR structuresof CGRP and calcitonin. The models obtained for the N- and C-terminalfragments should enable the design of novel agonists and antagonistsof the CGRP receptor, respectively. Models of the whole moleculemay be used in the design of peptides with shortened spacersbetween the receptor-bound regions. The approach described isapplicable to several related peptide hormones, like growthhormone-releasing hormone and secretin.     

Urinary excretion of arsenic species after exposure to arsenic present in drinking water

The effects of intravenous MS-551, a new class III antiarrhythmic drug, on atrium and ventricle were evaluated in 6 patients with ventricular tachyarrhythmias (4 males and 2 females; mean age 45 +/- 21 years) in an electrophysiologic study. Two patients had sustained ventricular tachycardia (VT) and 4 patients had ventricular fibrillation (VF). Electrophysiologic study was performed before and after the administration of MS-551 (loading infusion 0.3 mg/kg for 5 min + 0.01 mg/kg/min). The QT and QTc intervals were significantly prolonged by MS-551 from 359 +/- 52 to 411 +/- 63 msec (p = 0.01) and from 410 +/- 36 to 452 +/- 47 (p = 0.0172), respectively. No effect was observed on the sinus cycle length, QRS duration, or AH and HV intervals in sinus rhythm. The effective refractory periods of the right atrium (AERP) were significantly prolonged at paced cycle lengths of 600 (from 222 +/- 19 to 250 +/- 23 msec, p = 0.0009), 400 (from 207 +/- 15 to 228 +/- 15, p < 0.0001) and 300 (from 193 +/- 10 to 205 +/- 8 msec, p = 0.0127) msec. Similarly, the right ventricular ERP (VERP) were significantly prolonged at paced cycle lengths of 600 (from 240 +/- 23 to 268 +/- 23 msec, p < 0.0001), 400 (from 225 +/- 22 to 250 +/- 24 msec, p = 0.0007), and 300 msec (from 213 +/- 14 to 228 +/- 18 msec, p = 0.0071). MS-551 prolonged AERP and VERP in a "reverse" use-dependent manner without changing the conduction time in patients with ventricular tachyarrhythmias. MS-551 prevented the induction of VT in 1 patient and VF in only 1 patient in this electrophysiologic study. Further evaluation of the therapeutic potential of MS-551 using higher dosages is necessary.     

Indoor dispersion of airborne nano and fine particles: Main factors affecting spatial and temporal distribution in the frame of exposure modeling

A particle exposure experiment inside a large climate‐controlled chamber was conducted. Data on spatial and temporal distribution of nanoscale and fine aerosols in the range of mobility diameters 8‐600 nm were collected with high resolution, for sodium chloride, fluorescein sodium, and silica particles. Exposure scenarios studied included constant and intermittent source emissions, different aggregation conditions, high (10 h^?1) and low (3.5 h^?1) air exchange rates (AERs) corresponding to chamber Reynolds number, respectively, equal to 1 × 10⁵ and 3 × 10⁴. Results are presented and analyzed to highlight the main determinants of exposure and to determine whether the assumptions underlying two‐box models hold under various scenarios. The main determinants of exposure found were the source generation rate and the ventilation rate. The effect of particles nature was indiscernible, and the decrease of airborne total number concentrations attributable to surface deposition was estimated lower than 2% when the source was active. A near‐field/far‐field structure of aerosol concentration was always observed for the AER = 10 h^?1 but for AER = 3.5 h^?1, a single‐field structure was found. The particle size distribution was always homogeneous in space but a general shift of particle diameter (?8% to +16%) was observed between scenarios in correlation with the AER and with the source position, presumably largely attributable to aggregation.     

A nonlinear finite element analysis of an ice-strengthened ship shell structure

Finite element method is used to study the nonlinear behaviour of an ice-strengthened ship shell structure. The main object is the plastification and collapse of a frame. The plastic limit load for this frame is determined using the calculated load-deflection curve. The results of the finite element analysis are compared with well-known formulas of plastic design and also with experimental results. The finite element program used in the analysis is ADINA.     

Pipe failure caused by thermal loading in BWR water conditions

This work summarises the results obtained from a failure analysis of a pipe crack in a BWR water clean-up system. The cracking occurred in an AISI 304 steel pipe section area where mixing of the water streams at two different temperatures (280° and 130°C) took place. The temperature difference and turbulence induced a cyclic thermal loading which, together with the environment, caused cracking. Cracking propagated as transgranular brittle cleavage-like fracture, probably on a stress level below yield stress. Cracking was still observed in areas where the cyclic temperature differences caused by turbulence were markedly lower. The AISI 304 steel was in fully solution annealed as-receiv?d condition.     

Stress–strain behavior of polyamide 6 staple fibers of punch-needled press felts under simulated wet-pressing conditions

This study evaluates the specific stress (tenacity) and strain (elongation) of polyamide 6 staple fibers, which were virgin, punch-needled on the press felt, and worn on the press felt under simulated wet-pressing conditions. The staple fibers were distinguished by molecular weights. The fiber deformation and defects were microscopically characterized after the felt preparation and aging. We discovered that the tensile breaking force and elongation of the polyamide 6 staple fibers decreased markedly during the felt preparation and aging. The mechanical reduction of staple fibers reflected their tenacity, work, and modulus values. Surprisingly, the linear density of staple fibers remained unchanged – although fibers strongly deformed and lost their mechanical properties after the felt aging. The results indicate that an increase in molecular weight improves the mechanical durability of staple fibers, the preparation of the press felt (punch-needling) decreases the tenacity and elongation of staple fibers, and humidity provokes their degradation.