The folding pathway of an engineered circularly permuted PDZ domain

To understand the role of sequence connectivity in the folding pathway of a multi-state protein, we have analysed the folding kinetics of an engineered circularly permuted PDZ domain. This variant has been designed with the specific aim of posing two of the strands participating in the stabilisation of an early folding nucleus as contiguous elements in the primary structure. Folding of the circularly permuted PDZ2 has been explored by a variety of different experimental approaches including stopped-flow and continuous-flow kinetics, as well as ligand-induced folding experiments. Data reveal that although circular permutation introduces a significant destabilisation of the native state, a folding intermediate is stabilised and accumulated prior folding. Furthermore, quantitative analysis of the observed kinetics indicates an acceleration of the early folding events by more than two orders of magnitude. The results support the importance of sequence connectivity both in the mechanism and the speed of protein folding.     

Crystallization and morphology of the trigonal form in random propene/1-pentene copolymers

The melting and crystallization behaviour of a series of isotactic propene/1-pentene random copolymers, with 1-pentene contents up to 50 mol%, was investigated by DSC and temperature resolved WAXD/SAXS. The role of the 1-pentene comonomer in the development of the trigonal modification (δ-form) of i-PP was studied and the results were compared with those reported in the literature for PP copolymers with 1-hexene. The crystallizing capability of the δ-form, which develops in the composition range between ca. 10 and 50 mol% of 1-pentene content, only slightly decreases with concentration of 1-pentene. This result is correlated with the limits imposed to cell expansion by the crystal density. The crystallinity degree calculated from the deconvolution of the WAXD patterns is in fair agreement with the results of the DSC analysis, from which the value of the melting enthalpy of the perfect i-PP δ-form has been estimated to be around 140 J/g. The crystallization kinetics of the trigonal modification is characterized by a composition-dependent induction time followed by a relatively fast development of structural order. The sharp WAXD reflections combined with the SAXS data suggest that, notwithstanding the intrinsic intrachain structural disorder, thin and wide lamellae characterize the morphology of the δ-form crystallites.     

Anti-inflammatory activity of a new class of nitric oxide synthase inhibitors that release nitric oxide

Nitric oxide (NO) is a gaseous mediator that exerts key regulatory functions in mammalian cells. Low levels of NO exert homeostatic functions and counteract inflammation, whereas high amounts of NO cause tissue destruction and cellular death. Herein we describe a new class of nitric oxide synthase (NOS) inhibitor NO-donating drugs (NI-NODs). Human endothelial cells and human monocyte-based activity screening showed that NI-NODs inhibit IL-1beta production, modulate PGE(2) production, and protect against apoptosis. In a rodent model of colitis, NI-NOD1 and NI-NOD2 potently decreased inflammation. These data show that NI-NODs are effective in both in vitro and in vivo models of inflammation, mimicking the positive effects of low levels of NO and suppressing NOS-induced NO production.     

Eudragit and hydrotalcite-like anionic clay composite system for diclofenac colonic delivery

In this paper, the microencapsulation of the MgAl-hydrotalcite (HTlc) and diclofenac (DIK) intercalation product (HTlc-DIK) was realized in order to obtain a composite system for colonic drug delivery. Eudragit^® S or Eudragit^® L were used as polymers for preparation of microparticles (MPs). MPs were prepared by using a properly modified oil-in-oil solvent evaporation method. A 1:5 or 1:10 w/w HTlc-DIK/polymer ratios were employed. An experimental design was applied in order to assess the preparation variable effects on the qualitative MP appearance. Improved MP preparations were achieved when 7–13 ml of acetone-ethanol solution was employed at both HTlc-DIK/polymer ratios. The MPs were tested for in vitro drug release. DIK release from Eudragit^® L MPs at pH 6.8 reached 26–35% within 25–30 min at both HTlc-DIK/polymer ratios and no further increase was observed when the pH was shifted to 7.5. DIK release from Eudragit^® S MPs at pH 7.5 reached for both ratios 70% after 6–8 h.The obtained results showed that hydrotalcite intercalation compound can be microencapsulated without missing the intercalated compound and the resulted composite MPs showed good characteristics. Besides HTlc-DIK/Eudragit^® S MPs possess improved features with respect to HTlc-DIK/Eudragit^® L MPs. For this reason, HTlc-DIK/Eudragit^® S MPs could be promising for drug delivery either to the distal part of small intestine or to the colon.     

Thermodynamic analysis of fatty acid esterification for fatty acid alkyl esters production

The development of renewable energy source alternatives has become a planet need because of the unavoidable fossil fuel scarcity and for that reason biodiesel production has attracted growing interest over the last decade. The reaction yield for obtaining fatty acid alkyl esters varies significantly according to the operating conditions such as temperature and the feed reactants ratio and thus investigation of the thermodynamics involved in such reactional systems may afford important knowledge on the effects of process variables on biodiesel production. The present work reports a thermodynamic analysis of fatty acid esterification reaction at low pressure. For this purpose, Gibbs free energy minimization was employed with UNIFAC and modified Wilson thermodynamic models through a nonlinear programming model implementation. The methodology employed is shown to reproduce the most relevant investigations involving experimental studies and thermodynamic analysis.     

Ultracapacitors for fuel saving in small size hybrid vehicles

The main purpose of the paper is to describe a small size hybrid vehicle having ultracapacitors as on-board storage unit. The vehicle on-board main power supply is achieved by a genset being formed of a 250 cm³ internal combustion engine and a permanent magnet synchronous electric generator, whereas 4 16V-500F ultracapacitors modules are connected in series in order to supply as well as to store the power peaks during respectively acceleration and braking vehicle modes of operation. The traction power is provided by a permanent magnet synchronous electric motor, whereas a distributed power electronic interface is in charge of all the required electronic conversions as well of controlling the operating conditions for each power unit. The paper discusses the implemented control strategy and shows experimental results on the modes of operation of both generation unit and storage unit.     

A fully integrated 0.18-/spl mu/m CMOS direct conversion receiver front-end with on-chip LO for UMTS

This paper presents a 0.18-/spl mu/m CMOS direct-conversion IC realized for the Universal Mobile Telecommunication System (UMTS). The chip comprises a variable gain low-noise amplifier, quadrature mixers, variable gain amplifiers, and local oscillator generation circuits. The solution is based on very high dynamic range front-end blocks, a low-power superharmonic injection-locking technique for quadrature generation and continuous-time dc offset removal. Measured performances are an overall gain variable between 21 and 47 dB, 5.6 dB noise figure, -2 dBm out-of-band IIP3, -10 dBm in-band IIP3, 44.8-dBm minimum IIP2, and -155-dBc/Hz phase noise at 135 MHz from carrier frequency, while drawing 21 mA from a 1.8-V supply.     

A comparative evaluation of nonlinear dynamics methods for time series prediction

A key problem in time series prediction using autoregressive models is to fix the model order, namely the number of past samples required to model the time series adequately. The estimation of the model order using cross-validation may be a long process. In this paper, we investigate alternative methods to cross-validation, based on nonlinear dynamics methods, namely Grassberger–Procaccia, Kégl, Levina–Bickel and False Nearest Neighbors algorithms. The experiments have been performed in two different ways. In the first case, the model order has been used to carry out the prediction, performed by a SVM for regression on three real data time series showing that nonlinear dynamics methods have performances very close to the cross-validation ones. In the second case, we have tested the accuracy of nonlinear dynamics methods in predicting the known model order of synthetic time series. In this case, most of the methods have yielded a correct estimate and when the estimate was not correct, the value was very close to the real one.     

Blame culture and defensive medicine

Introduction  

Defensive medicine takes place when healthcare personnel (doctors and nurses) order unnecessary treatments (positive defensive medicine) or avoid high-risk procedures or patients (negative defensive medicine) with the principle—though not exclusive—aim of reducing their expose to damages claims. This phenomenon is directly related to the significant growth in medical malpractice litigation over recent years. Defensive medicine increases the cost of healthcare and may expose patients to unnecessary risks. In fact, the large number of legal initiatives taken by patients have induced many doctors to set in place a defensive “strategy” so as to avoid placing their careers at risk. The threat of medical malpractice litigation constitutes a major obstacle to improving the reliability of healthcare organizations and patient safety.     

Delays andQswitching in semiconductor lasers--Still an open question

A critical review is made of the available experimental data and the proposed theoretical explanations regarding long delays andQswitching in semiconductor lasers. It is shown that no model is completely satisfactory in explaining all the available data. Guidelines for developing a better theory are presented.