Protein Flexibility in Drug Discovery: From Theory to Computation

Nowadays it is widely accepted that the mechanisms of biomolecular recognition are strongly coupled to the intrinsic dynamic of proteins. In past years, this evidence has prompted the development of theoretical models of recognition able to describe ligand binding assisted by protein conformational changes. On a different perspective, the need to take into account protein flexibility in structure‐based drug discovery has stimulated the development of several and extremely diversified computational methods. Herein, on the basis of a parallel between the major recognition models and the simulation strategies used to account for protein flexibility in ligand binding, we sort out and describe the most innovative and promising implementations for structure‐based drug discovery.     

Mono- and polyclonal antibodies as probes to study vitellin processing in embryos of the stick insect Carausius morosus

OBJECTIVE: To investigate the effects of paternal age on fertility and progeny outcome using the Brown Norway rat model. DESIGN: Controlled prospective study. SETTING: McIntyre Animal Centre, McGill University, Montreal, Quebec, Canada. INTERVENTION(S): Brown Norway male rats of increasing age were mated to young Sprague-Dawley females. MAIN OUTCOME MEASURE(S): Pregnancy outcome was assessed by counting the numbers of corpora lutea, resorptions, and live fetuses on day 20 of gestation. To evaluate progeny outcome, pups were examined for external malformations and weighed daily for 2 months. RESULT(S): There were no significant changes in the numbers of resorptions, offspring, or in the incidence of external malformations. However, there was an increase in preimplantation loss (corpora lutea minus implantation sites) in litters fathered by older males. Furthermore, a significant decrease in the average fetal weight was found with increasing paternal age. A significant increase in neonatal deaths for progeny fathered by older males also was found. CONCLUSION(S): These results indicate that the quality of spermatozoa decreases as males age.     

The use of massive bone allografts for intercalary reconstruction and arthrodeses after tumor resection. A multicentric European study

A multicentric study was conducted by the European Musculoskeletal Oncology Society on 113 cases of resection for tumors of the major long bones and reconstruction with massive allografts, as intercalary diaphyseal or for arthrodesis. The follow-up was at least 12 months. There was a 14% incidence of infection, with a higher frequency (18.5%) in intercalary grafts as compared to arthrodeses (7%). Fracture of the graft occurred in 15.5% of the cases with a prevalence in the humerus (28.5%) as compared to the tibia (21.4%) and femur (14.7%). Fracture constantly occurred after osteosynthesis with screws, in 16% of the cases after osteosynthesis with a plate, and in 12.5% of the cases after osteosynthesis with an intramedullary nail. It was observed in 32% of the grafts preserved at -30 degrees, in 17% of those irradiated, and in 7% and 7.6% of those preserved at -180 degrees and -80 degrees, respectively. Delayed union and non-union was observed in 57% of the cases: 63% in intercalary grafts, 48% in arthrodeses. Final results after treatment of complications were excellent and good in 63% of the entire series. The results should, however, be evaluated after 3 years, as during this period of time important transformation phenomena of the graft occur. Complications are observed in 75% of the cases, but they may be reduced if planning is correct and surgery is accurate. Each complication may be dealt with and resolved without high risks for preservation of the limb.     

Optimization and extensions of a fuzzy multicriteria decision making method and applications to selection of touristic destinations

The aim of the present paper is to optimize and extend the recent method in Chu and Lin (2009). We simplify the calculus taking into account the expected value of a fuzzy number can be expressed by using its α-cut sets. A collateral benefit is that the discussed method becomes applicable in any structure of data as triangular fuzzy numbers. Then, to cover a wider range of data - performances of alternatives versus criteria and importance weights of criteria - we extend the optimized method to trapezoidal fuzzy numbers and to the cases of importance weights of criteria/ratings of alternatives expressed by real numbers and ratings of alternatives/importance weights of criteria expressed by fuzzy numbers. Each theoretical development is illustrated by examples. The importance of the method to the selection of the best touristic destinations is discussed too.     

Hydrological Characterization of an Ice-Contact Lake: Miage Lake (Monte Bianco,Italy)

The Miage Lake is an ice-contact lake located on a side of the Miage glacier (Monte Bianco Massif, Alps), the third Italy’s largest glacier, and is characterized by rapid drawdown episodes that have occurred with varying frequency in the lake’s history. The emptying episode of September 2004 gave the possibility of performing many activities, up to the filling phases which occurred during spring and summer 2005. In situ tests and measurements and laboratory tests lead to a reliable reconstruction of the path of water recharge and draining and to the development of a numerical model of unsaturated-saturated groundwater flow to evaluate natural losses through the lake bed sediments. Results show that material at the bed of the lake has a low permeability and can be responsible for water losses of a few litres per second, very far from the discharge calculated during the rapid drawdown episodes. These results gave the experimental and numerical evidences to support the hypothesis that identifies sudden and temporary failure in the ice floor as the only possible cause of the rapid draining events historically occurred in Miage Lake. In the monitoring period the hydrological balance has also been assessed to evaluate the factors affecting the main recharge phase of the year. Calving was found to be the most important factor contributing to recharge, followed by direct melting and precipitation while water losses occurring through the lake bed sediments and evapotranspiration are much smaller even if not negligible.     

A new ternary mixed oxide catalyst for ammoxidation of propane: Sn/V/Sb

The catalytic properties of a Sn/V/Sb mixed oxide for propane ammoxidation to acrylonitrile are studied in this paper. In particular the antimony and vanadium amounts were changed in order to optimize the relative atomic ratio. The ternary sample with the best catalytic performance was compared with the analogous binary samples (Sn/Sb and Sb/V). The results obtained indicate that vanadium is responsible for the paraffin activation, nevertheless much vanadium produces a lot of carbon oxides. Antimony is responsible for the insertion of nitrogen in the molecule (it can be considered as an acrylonitrile selectivity modulator); nevertheless, too much antimony deactivates the catalyst. Tin does not act only as a dispersive matrix for the active sites, but leads to the formation of a polyfunctional catalyst, increasing the rate of acrylonitrile formation from the intermediate propene. From a structural point of view, this catalytic system can be described as a homogeneous system, containing microfields of rutile type oxide (SnO₂), promoted with antimony and vanadium in substitutional solid solution, dispersed in an excess of amorphous antimony oxide. This revised version was published online in July 2006 with corrections to the Cover Date.     

Failures induced on analog integrated circuits by conveyed electromagnetic interferences: A review

Failures induced on analog integrated circuits by electromagnetic interference (EMI) will be analyzed with particular emphasis on integrated operational amplifiers built with different technologies. Additionally, the correlation found between EMI susceptibility and large-signal opamp behavior will be discussed. Some criteria for the design of low EMI susceptibility opamps will be derived. Finally, as an application example, the design of a BiCMOS opamp with an extremely low-probability EMI-induced failure will be presented.     

In situ monitoring of film deposition with an ellipsometer based on a four-detector photopolarimeter

Ellipsometry is a sensitive and noninvasive technique for the characterization of thin films. A recently developed ellipsometer, based on the four-detector photopolarimeter, was arranged outside a UHV chemical vapor deposition chamber for the in situ monitoring of film growth processes. The instrument showed a sensitivity in the submonolayer range when used to follow the growth of germanium thin films deposited on silicon substrates. As the main instrument drawback is represented by the need to have precise alignment, an effective positioning procedure was developed to obtain a positioning error smaller than 0.1°.