Generation and Analysis of Interaction Energy Maps of p-Substituted Benzoic Acid [(5-Nitro-thiophen-2-yl)-methylene]-Hydrazides Active against MRSA

In this preliminary study eighteen p-substituted benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazides with antimicrobial activity were evaluated against multidrug-resistant Staphylococcus aureus, correlating the three-dimensional characteristics of the ligands with their respective bioactivities. The computer programs Sybyl and CORINA were used, respectively, for the design and three-dimensional conversion of the ligands. Molecular interaction fields were calculated using GRID program. Calculations using Volsurf resulted in a statistically consistent model with 48 structural descriptors showing that hydrophobicity is a fundamental property in the analyzed biological response.

Crystal and molecular structures of dichloro((Z)-2-chloro-2-phenylvinyl)(organo)tellurium(IV) for organo = n-butyl and phenyl

In each of the title compounds, R[Ph(Cl)C=(H)C]TeCl(2), R = nBu (1) and Ph (2), the primary geometry about the Te(IV) atom is a pseudo-trigonal-bipyramidal arrangement, with two Cl atoms in apical positions, and the lone pair of electrons and C atoms in the equatorial plane. As the Te(IV) is involved in two, an intra- and an inter-molecular, Te center dot center dot center dot Cl interactions the coordination geometry might be considered as a Psi-pentagonal bipyramid in each case. In addition, in (2) there is a hint of a Te center dot center dot center dot pi interaction (Te center dot center dot center dot C = 3.911(3) A). The key feature in the crystal structure of both compounds is the formation of supramolecular chains mediated by Te center dot center dot center dot Cl contacts. (1): C(12)H(15)Cl(3)Te, triclinic, P (1) over bar, a = 5.9471 (11), b = 10.7826(22), c = 11.7983(19) angstrom, alpha = 75.416(12), beta = 78.868(13), gamma = 80.902(14)degrees, V = 713.6(2) angstrom(3), Z = 2, R(1) = 0.021; (2): C14HIIC13Te, orthorhombic, Pcab, a=7.7189(10), b=17.415(2), c=21.568(3)angstrom, V = 2899.3(6) angstrom(3), Z = 8, R(1) = 0.027.

Comparative analysis of the gas-phase reactions of cylindrospermopsin and the difference in the alkali metal cation mobility

Cylindrospermopsin (CYN) belongs to a group of toxins produced by several strains of freshwater cyanobacteria. It is a compact zwitterionic molecule composed of a uracil section and a tricyclic guanidinium portion with a primarily hepatotoxic effect. Using low multi-stage and high-resolution mass spectrometry, the gas-phase reactions of this toxin have been investigated. Our data show that collision-induced dissociation (CID) spectra of CYN are dominated by neutral losses, and three major initial fragmentation pathways are clearly distinguishable. Interestingly, comparative analysis of protonated and cationizated molecules showed a significant difference in the balance of the SO(3) and terminal ring elimination. These data indicate that the differential ion mobility of H(+), Li(+), Na(+) and K(+) leads to different fragmentation pathways, giving rise to mass spectra with different profiles. Copyright (C) 2008 John Wiley & Sons, Ltd.

Cubebin and derivatives as inhibitors of mitochondrial complex I. Proposed interaction with subunit B8

The effects on mitochondrial respiration and complex I NADH oxidase activity of cubebin and derivatives were evaluated. The compounds inhibited the state 3 glutamate/malate-supported respiration of hamster liver mitochondria with IC50 values ranging from 12.16 to 83.96M. NADH oxidase reaction was evaluated in submitochondrial particles. The compounds also inhibited this activity, showing the same order of potency observed for effects on state 3 respiration, as well as a tendency towards a non-competitive type of inhibition (KI values ranging from 0.62 to 16.1M). A potential binding mode of these compounds with complex I subunit B8, assessed by docking calculations, is proposed.

Molecular dynamics, density functional, ADMET predictions, virtual screening, and molecular interaction field studies for identification and evaluation of novel potential CDK2 inhibitors in cancer therapy

In this work, we have used molecular dynamics, density functional theory, virtual screening, ADMET predictions, and molecular interaction field studies to design and propose eight novel potential inhibitors of CDK2. The eight molecules proposed showed interesting structural characteristics that are required for inhibiting the CDK2 activity and show potential as drug candidates for the treatment of cancer. The parameters related to the Rule of Five were calculated, and only one of the molecules violated more than one parameter. One of the proposals and one of the drug-like compounds selected by virtual screening indicated to be promising candidates for CDK2-based cancer therapy.

Use of virtual screening, flexible docking, and molecular interaction fields to design novel HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia

Dietary changes associated with drug therapy can reduce high serum cholesterol levels and dramatically decrease the risk of coronary artery disease, stroke, and overall mortality. Statins are hypolipemic drugs that are effective in the reduction of cholesterol serum levels, attenuating cholesterol synthesis in liver by competitive inhibition regarding the substrate or molecular target HMG-CoA reductase. We have herewith used computer-aided molecular design tools, i.e., flexible docking, virtual screening in large data bases, molecular interaction fields to propose novel potential HMG-CoA reductase inhibitors that are promising for the treatment of hypercholesterolemia.

Fluoride increases lead concentrations in whole blood and in calcified tissues from lead-exposed rats

Higher blood lead (BPb) levels have been reported in children living in communities that receive fluoride-treated water. Here, we examined whether fluoride co-administered with lead increases BPb and lead concentrations in calcified tissues in Wistar rats exposed to this metal from the beginning of gestation. We exposed female rats and their offspring to control water (Control Group), 100 mg/L of fluoride (F Group), 30 mg/L of lead (Pb Group), or 100 mg/L of fluoride and 30 mg/L of lead (F+ Pb Group) from 1 week prior to mating until offspring was 81 days old. Blood and calcified tissues (enamel, dentine, and bone) were harvested at day 81 for lead and fluoride analyses. Higher BPb concentrations were found in the F+ Pb Group compared with the Pb Group (76.7 +/- 11.0 mu g/dL vs. 22.6 +/- 8.5 mu g/dL, respectively: p <0.001). Two-to threefold higher lead concentrations were found in the calcified tissues in the F+ Pb Group compared with the Pb Group (all p <0.001). Fluoride concentrations were similar in the F and in the F+ Pb Groups. These findings show that fluoride consistently increases BPb and calcified tissues Pb concentrations in animals exposed to low levels of lead and suggest that a biological effect not yet recognized may underlie the epidemiological association between increased BPb lead levels in children living in water-fluoridated communities. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Metal embryotoxicity from urban particles in Sao Paulo city: An experimental study in chicken embryos

Chicken eggs were inoculated with suspensions of ambient air particles (<= 10 mu m, PM(10)) from Sao Paulo city in 3, 0.3 or 0.03 mu g doses on one of the four early days of embryo development. On the eleventh day of development alterations were observed on embryos inoculated with PM(10) 3 mu g on the third day. Particles analysis showed high content of metals. Hence, embryos were also inoculated with PM(10) (3 mu g) combined with metal chelating EDTA. PM(10) (3 mu g) embryos presented underdevelopment (stage 29.44 +/- 11.4) compared to vehicle and positive controls (stage 36.44 +/- 0.51 Saline and stage 31.20 +/- 9.7 Cyclophosphamide, p <= 0.05); higher (47%) mortality rate (23% Saline and 42% Cyclophosphamide) and low (68%) viability (100% Saline and 70% Cyclophosphamide, p = 0.04). Effects were attenuated when embryos received PM(10) + EDTA (stage 33.63 +/- 0.94, 18.9% mortality rate and 82% viability). PM(10) from Sao Paulo city is embryotoxic and metal may be implicated in the toxic mechanism. (C) 2010 Elsevier Inc. All rights reserved.

Molecular dynamics, flexible docking, virtual screening, ADMET predictions, and molecular interaction field studies to design novel potential MAO-B inhibitors

Monoamine oxidase is a flavoenzyme bound to the mitochondrial outer membranes of the cells, which is responsible for the oxidative deamination of neurotransmitter and dietary amines. It has two distinct isozymic forms, designated MAO-A and MAO-B, each displaying different substrate and inhibitor specificities. They are the well-known targets for antidepressant, Parkinson`s disease, and neuroprotective drugs. Elucidation of the x-ray crystallographic structure of MAO-B has opened the way for the molecular modeling studies. In this work we have used molecular modeling, density functional theory with correlation, virtual screening, flexible docking, molecular dynamics, ADMET predictions, and molecular interaction field studies in order to design new molecules with potential higher selectivity and enzymatic inhibitory activity over MAO-B.

Bixin and lycopene modulation of free radical generation induced by cisplatin-DNA interaction

This work evaluated the Modulation of reactive oxygen species (ROS) produced by the cisplatin-human DNA interaction in a cell-free experimental model by the carotenoids bixin and lycopene extracted from, natural dietary Sources and purified through luminol- and Cypridina luciferin methoxy-analogue (MCLA)- enhanced chemiluminescence assays. The results showed that the ROS generation by DNA-cisplatin interaction was inhibited by both lycopene and bixin in a concentration-dependent manner. At a concentration of 100 mu M, lycopene and bixin inhibited Superoxide anion (O center dot(2)) generation at 90% and 82%, respectively, and the total ROS generation at 44% and 42%, respectively. The formation of significant amounts of isomers or degradation products of both carotenoids was not observed after ROS scavenging, as evaluated by high-performance liquid chromatography. Taken together, these results Suggest that carotenoids can be helpful to Modulate the oxidative stress found in cancer therapy with cisplatin. (c) 2008 Elsevier Ltd. All rights reserved.

Environmental Risk Factors for Parkinson's Disease

Parkinson’s disease (PD) is a progressive, degenerative, neurological disease. The progressive disability associated with PD results in substantial burdens for those with the condition, their families and society in terms of increased health resource use, earnings loss of affected individuals and family caregivers, poorer quality of life, caregiver burden, disrupted family relationships, decreased social and leisure activities, and deteriorating emotional well-being. Currently, no cure is available and the efficacy of available treatments, such as medication and surgical interventions, decreases with longer duration of the disease. Whilst the cause of PD is unknown, genetic and environmental factors are believed to contribute to its aetiology. Descriptive and analytical epidemiological studies have been conducted in a number of countries in an effort to elucidate the cause, or causes, of PD. Rural residency, farming, well water consumption, pesticide exposure, metals and solvents have been implicated as potential risk factors for PD in some previous epidemiological studies. However, there is substantial disagreement between the results of existing studies. Therefore, the role of environmental exposures in the aetiology of PD remains unclear. The main component of this thesis consists of a case-control study that assessed the contribution of environmental exposures to the risk of developing PD. An existing, previously unanalysed, dataset from a local case-control study was analysed to inform the design of the new case-control study. The analysis results suggested that regular exposure to pesticides and head injury were important risk factors for PD. However, due to the substantial limitations of this existing study, further confirmation of these results was desirable with a more robustly designed epidemiological study. A new exposure measurement instrument (a structured interviewer-delivered questionnaire) was developed for the new case-control study to obtain data on demographic, lifestyle, environmental and medical factors. Prior to its use in the case-control study, the questionnaire was assessed for test-retest repeatability in a series of 32 PD cases and 29 healthy sex-, age- and residential suburb-matched electoral roll controls. High repeatability was demonstrated for lifestyle exposures, such as smoking and coffee/tea consumption (kappas 0.70-1.00). The majority of environmental exposures, including use of pesticides, solvents and exposure to metal dusts and fumes, also showed high repeatability (kappas >0.78). A consecutive series of 163 PD case participants was recruited from a neurology clinic in Brisbane. One hundred and fifty-one (151) control participants were randomly selected from the Australian Commonwealth Electoral Roll and individually matched to the PD cases on age (± 2 years), sex and current residential suburb. Participants ranged in age from 40-89 years (mean age 67 years). Exposure data were collected in face-to-face interviews. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression for matched sets in SAS version 9.1. Consistent with previous studies, ever having been a regular smoker or coffee drinker was inversely associated with PD with dose-response relationships evident for packyears smoked and number of cups of coffee drunk per day. Passive smoking from ever having lived with a smoker or worked in a smoky workplace was also inversely related to PD. Ever having been a regular tea drinker was associated with decreased odds of PD. Hobby gardening was inversely associated with PD. However, use of fungicides in the home garden or occupationally was associated with increased odds of PD. Exposure to welding fumes, cleaning solvents, or thinners occupationally was associated with increased odds of PD. Ever having resided in a rural or remote area was inversely associated with PD. Ever having resided on a farm was only associated with moderately increased odds of PD. Whilst the current study’s results suggest that environmental exposures on their own are only modest contributors to overall PD risk, the possibility that interaction with genetic factors may additively or synergistically increase risk should be considered. The results of this research support the theory that PD has a multifactorial aetiology and that environmental exposures are some of a number of factors to contribute to PD risk. There was also evidence of interaction between some factors (eg smoking and welding) to moderate PD risk.

The effects of viscous loading of the human forearm flexors on the stability of coordination

This experiment investigated whether the stability of rhythmic unimanual movements is primarily a function of perceptual/spatial orientation or neuro-mechanical in nature. Eight participants performed rhythmic flexion and extension movements of the left wrist for 30 s at a frequency of 2.25 Hz paced by an auditory metronome. Each participant performed 8 flex-on-the-beat trials and 8 extend-on-the-beat trials in one of two load conditions, loaded and unload. In the loaded condition, a servo-controlled torque motor was used to apply a small viscous load that resisted the flexion phase of the movement only. Both the amplitude and frequency of the movement generated in the loaded and unloaded conditions were statistically equivalent. However, in the loaded condition movements in which participants were required to flex-on-the-beat became less stable (more variable) while extend-on-the-beat movements remained unchanged compared with the unload condition. The small alteration in required muscle force was sufficient to result in reliable changes in movement stability even a situation where the movement kinematics were identical. These findings support the notion that muscular constraints, independent of spatial dependencies, can be sufficiently strong to reliably influence coordination in a simple unimanual task.

The interaction between technologies and society: Lessons learnt from 160 evolutionary years of online news services

In mapping the evolutionary process of online news and the socio-cultural factors determining this development, this paper has a dual purpose. First, in reworking the definition of “online communication”, it argues that despite its seemingly sudden emergence in the 1990s, the history of online news started right in the early days of the telegraphs and spread throughout the development of the telephone and the fax machine before becoming computer-based in the 1980s and Web-based in the 1990s. Second, merging macro-perspectives on the dynamic of media evolution by DeFleur and Ball-Rokeach (1989) and Winston (1998), the paper consolidates a critical point for thinking about new media development: that something technically feasible does not always mean that it will be socially accepted and/or demanded. From a producer-centric perspective, the birth and development of pre-Web online news forms have been more or less generated by the traditional media’s sometimes excessive hype about the power of new technologies. However, placing such an emphasis on technological potentials at the expense of their social conditions not only can be misleading but also can be detrimental to the development of new media, including the potential of today’s online news.

Spontaneous transitions in the coordination of a whole body task

This paper describes an example of spontaneous transitions between qualitatively different coordination patterns during a cyclic lifting and lowering task. Eleven participants performed 12 trials of repetitive lifting and lowering in a ramp protocol in which the height of the lower shelf was raised or lowered 1 cm per cycle between 10 and 50 cm. Two distinct patterns of coordination were evident: a squat technique in which moderate range of hip, knee and ankle movement was utilised and ankle plantar-flexion occurred simultaneously with knee and hip extension; and a stoop technique in which the range of knee movement was reduced and knee and hip extension was accompanied by simultaneous ankle dorsi-flexion. Abrupt transitions from stoop to squat techniques were observed during descending trials, and from squat to stoop during ascending trials. Indications of hysteresis was observed in that transitions were more frequently observed during descending trials, and the average shelf height at the transition was 5 cm higher during ascending trials. The transitions may be a consequence of a trade-off between the biomechanical advantages of each technique and the influence of the lift height on this trade-off.

Interaction between Normative Systems and Cognitive Agents in Temporal Modal Defeasible Logic

While some recent frameworks on cognitive agents addressed the combination of mental attitudes with deontic concepts, they commonly ignore the representation of time. An exception is [1]that manages also some temporal aspects both with respect to cognition and normative provisions. We propose in this paper an extension of the logic presented in [1]with temporal intervals.