Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease

Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-I, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 mu M. Their activities against HIV-1 protease (K-i 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC50 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC50 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 Angstrom (1) and 1.85 Angstrom (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.

Sport-specific practice and the development of expert decision-making in team ball sports

The role of sport-specific practice in the development of decision-making expertise in the sports of field hockey, netball, and basketball was examined. Fifteen expert decision-makers and 13 experienced non-expert athletes provided detailed information about the quantity and type of sport-specific and other related practice activities they had undertaken throughout their careers. Experts accumulated more hours of sport-specific practice from age 12 years onwards than did non-experts, spending on average some 13 years and 4,000 hours on concentrated sport-specific practice before reaching international standard. A significant negative correlation existed between the number of additional activities undertaken and the hours of sportspecific training required before attaining expertise, suggesting a functional role for activities other than sport-specific training in the development of expert decision-making.

Physical Activity and Bone Mineral Accrual During Childhood and Adolescence

The epidemic that is osteoporosis has led to an increasing interest in bone mineral, and the factors that influence the levels of bone mineral, in recent years. While it is unrealistic to try and turn back the clock, a return to an increased level of physical activity may be an important consideration in terms of skeletal health. Peak bone mass is largely determined by heredity, but lifestyle and dietary patterns also influence the level of bone mineral accrued during the growing years. In this review, we summarize the evidence that vigorous weight-bearing physical activity and adequate calcium intake represent the best possibility for enhancing the attainment of an optimal level of bone mineral, within genetic limits.

Exogenous induction of ovarian activity and ovulation and transfer of fresh embryos of domestic cat (Felis catus)

The objective of the present study was the exogenous stimulation of ovarian activity and definition of embryo collection, and transfer protocols, in the domestic cat for potential application in non-domestic endangered species. Sixteen adult queens and two adult male reproducers kept in the experimental cat house at the Morphology sector at the Veterinary Department (DVT), UFV, were used in this study. All the queens received a single application of 150 IU Equine Chorionic Gonadotropin (eCG) in the post estrus to induce ovarian activity and 80 to 84 hours later, received a single application of 100 UI Human Chorionic Gonadotropin (hCG) to induce ovulation. After hCG application, only the donor queens were naturally mated. The receptor queens received extra stimulus for induction of ovulation through manipulation of an intravaginal swab. Five to six days after hCG application, the donor queens were subjected to a laparotomy for embryo collection that was performed by trans-horn uterine washing. On average, six embryos were surgically inovulated. They were classified as type I and III compact morula and blastocysts in four receptor queens. Three animals presented pregnancy confirmed by ultrasound at day 36 and two of these animals gave birth to litters of two and four offsprings, respectively, at 66 and 63 days after induction of ovulation. Except for one still birth, all the offspring developed normally.

Report about the scope and distribution of large urban distressed areas in European cities

LUDA is a research project of Key Action 4 "City of Tomorrow & Cultural Heritage" of the programme "Energy, Environment and Sustainable Development" within the Fifth Framework Programme of the European Commission.

Appraisal of urban rehabilitation literature and projects, including a glossary of terms and a preliminary set of indicators characterising LUDA

LUDA is a research project of Key Action 4 "City of Tomorrow & Cultural Heritage" of the programme "Energy, Environment and Sustainable Development" within the Fifth Framework Programme of the European Commission

Preliminary Overview over Requirements Regarding Tools and Methods Derived from LUDA Cases

LUDA is a research project of Key Action 4 "City of Tomorrow & Cultural Heritage" of the programme "Energy, Environment and Sustainable Development" within the Fifth Framework Programme of the European Commission

Methodology for the Comparative Analysis of Sustainable Evaluation of LUDA

LUDA is a research project of Key Action 4 "City of Tomorrow & Cultural Heritage" of the programme "Energy, Environment and Sustainable Development" within the Fifth Framework Programme of the European Commission

Duration of larval and pupal development stages of Aedes albopictus in natural and artificial containers

Aedes albopictus were reared in different containers: a tree hole, a bamboo stump and an auto tire. The total times from egg hatching to adult emergence were of 19.6,27.3 and 37.5 days, respectively, according to the container. The first, second and third-instar larvae presented growth periods with highly similar durations. The fourth-instar larvae was longer than the others stages. The pupation time was longer than the fourth-instar larvae growth period. The temperature of the breeding sites studied, which was of 18° C to 22° C on average, was also taken into consideration. The mortality of the immature stages was analysed and compared as between the experimental groups; it was lower in the natural containers than in the discarded tire. The average wing length of adult females emerging from tree hole was significantly larger (p < 0.05) than that of those emerging from the tire.

Studies on mosquitoes (Diptera: Culicidae) and anthropic environment: 11 - Biting activity and blood-seeking parity of Anopheles (Kerteszia) in South-Eastern Brazil

An. (Ker.) cruzii and An. (Ker.) bellator were monitored by the use of human bait and Shannon trap collections during a one-year period in 1994. Indoor and outdoor collections were made on human bait and inside the forest environment a Shannon trap was used. Both were undertaken in the evening crepuscular period. Results showed a greater abundance of An. cruzii in the forest, where as An. bellator was more abundant in the domiciliary environment. Through the application of the Polovodova method an age grading was established. Computing the parous and nulliparous females with Christopher's Stage III and above, more than 30.0% of blood-seeking specimens of both anophelines had had a previous blood meal. The higher abundance of An. bellator as compared with that of An. cruzii in the domiciliary environment may be explained by the influence of the neighboring low-lying coastal islands of the estuary system.

Antioxidant activity and cytotoxicity of solubilized C60 and its conjugates with butylated hydroxytoluene

It has been described that fullerenes (C60) present interesting properties with potential application in clinical conditions related to oxidative stress. One of the most prominent features of fullerenes is the ability to quench free radicals. However, because of its poor solubility, this has been studied mostly in organic solutions, while the antioxidant activity and cytotoxicity of fullerenes and their derivates in aqueous medium is not well characterized. The antioxidant capacity of synthesised C60-conjugates has been investigated and its was higher comparing to C60 isolated. The aim of this study was to assess the viability of C60-conjugates by determining its antioxidant activity and cytotoxicity in bio-relevant media.

Influence of wearing an unstable shoe on thigh and leg muscle activity and venous response in upright standing

Purpose: To quantify the effect of unstable shoe wearing on muscle activity and haemodynamic response during standing. Methods: Thirty volunteers were divided into 2 groups: the experimental group wore an unstable shoe for 8 weeks, while the control group used a conventional shoe for the same period. Muscle activity of the medial gastrocnemius, tibialis anterior, rectus femoris and biceps femoris and venous circulation were assessed in quiet standing with the unstable shoe and barefoot. Results: In the first measurement there was an increase in medial gastrocnemius activity in all volunteers while wearing the unstable shoe. On the other hand, after wearing the unstable shoe for eight weeks these differences were not verified. Venous return increased in subjects wearing the unstable shoe before and after training. Conclusions: The unstable shoe produced changes in electromyographic characteristics which were advantageous for venous circulation even after training accommodation by the neuromuscular system.

International sustainable development cooperation of physiotherapy course from Escola Superior de Tecnologia da Saúde de Lisboa

Objectives - To share with delegates the international experience in several Program of Physiotherapy course from Escola Superior de Tecnologia da Saúde de Lisboa (ESTeSL).

Biological activity and cellular uptake of [Ru(eta(5)-C5H5)(PPh3)(Me(2)bpy)][CF3SO3] complex

Anticancer activity of the new [Ru(eta(5)-C5H5)(PPh3)(Me(2)bpy)][CF3SO3] (Me(2)bpy = 4,4'-dimethyl-2,2'-bipyridine) complex was evaluated in vitro against several human cancer cell lines, namely A2780, A2780CisR, HT29, MCF7, MDAMB231 and PC3. Remarkably, the IC50 values, placed in the nanomolar and sub-micromolar range, largely exceeded the activity of cisplatin. Binding to human serum albumin, either HSA (human serum albumin) or HSA(faf) (fatty acid-free human serum albumin) does not affect the complex activity. Fluorescence studies revealed that the present ruthenium complex strongly quench the intrinsic fluorescence of albumin. Cell death by the [Ru(eta(5)-C5H5)(PPh3)(Me(2)bpy)][CF3SO3] complex was reduced in the presence of endocytosis modulators and at low temperature, suggesting an energy-dependent mechanism consistent with endocytosis. On the whole, the biological activity evaluated herein suggests that the complex could be a promising anticancer agent. (C) 2013 Elsevier Inc. All rights reserved.