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.

IDENTIFICATION OF THE STATE OF A WET SPOUTED BED THROUGH TIME-FREQUENCY ANALYSIS OF PRESSURE FLUCTUATION TIME SERIES

The feasibility of detecting instability in wet spouted beds via pressure fluctuation (PF) time-series analyses was investigated. Experiments were carried out in a cylindrical Plexiglas column of diameter 150 mm with a conical base of internal angle 60 degrees, an inlet orifice diameter of 25 mm and glass beads of diameter 2.4 mm. Transducers at several axial positions measured PF time series with incremental addition of aqueous sucrose solutions of different concentrations. Liquid addition affected the spouted bed dynamics, causing irregular spouting, increased voidage in the annulus, increased fountain height, irregular annulus height, channelling, agglomeration, and adhesion of particles to the column walls. Autocorrelations indicated the appearance of periodicities in the PF signals with increasing sucrose addition. Dominant peaks in power-spectral density developed at low frequencies with changing system dynamics. The results indicate that PF signals furnish relevant information on system dynamics, useful for monitoring and control of spouted bed operations such as particle coating and drying of paste-like materials.

Antiviral and antiparasite properties of an L-amino acid oxidase from the Snake Bothrops jararaca: Cloning and identification of a complete cDNA sequence (Retracted article. See vol. 80, pg. 288, 2010)

L-Amino acid oxidases (LAAOs, EC 1.4.3.2) are flavoenzymes that catalyze the stereospecific oxidative deamination of an L-amino acid substrate to the corresponding a-ketoacid with hydrogen peroxide and ammonia production. The present work describes the first report on the antiviral (Dengue virus) and antiprotozoal (trypanocidal and leishmanicide) activities of a Bothrops jararaca L-amino acid oxidase (BjarLAAO-I) and identify its cDNA sequence. Antiparasite effects were inhibited by catalase, suggesting that they are mediated by H(2)O(2) production. Cells infected with DENV-3 virus previously treated with BjarLAAO-I, showed a decrease in viral titer (13-83-fold) when compared with cells infected with untreated viruses. Untreated and treated promastigotes (T. cruzi and L. amazonensis) were observed by transmission electron microscopy with different degrees of damage. Its complete cDNA sequence, with 1452 bp, encoded an open reading frame of 484 amino acid residues with a theoretical molecular weight and pl of 54,771.8 and 5.7, respectively. The cDNA-deduced amino acid sequence of BjarLAAO shows high identity to LAAOs from other snake venoms. Further investigations will be focused on the related molecular and functional correlation of these enzymes. Such a study should provide valuable information for the therapeutic development of new generations of microbicidal drugs. (C) 2008 Elsevier Inc. All rights reserved.

Evaluation of curcumin and cisplatin-induced DNA damage in PC12 cells by the alkaline comet assay

A very appropriate method for antigenotoxicity evaluation of antioxidants is the comet assay, since this analytical method detects initial DNA lesions that are still subject to repair; in other words, lesions that are very associated to damages resulting from the generation and subsequent action of reactive species. However, a solid evaluation should be developed in order to avoid inexact interpretations. In our study, besides the association of curcumin with cisplatin, curcumin and cisplatin agents were also tested separately. Classical genotoxic compounds, when tested by the comet assay, present an increase in the nucleoid tail; however, the cisplatin treatment has resulted in a decrease of DNA migration. This was an expected effect, as the cross-links between cisplatin and DNA decrease the DNA electrophoretic mobility. A similar effect was observed with the curcumin treatment, which decreased the nucleoid tail. Such effect was not expected and reinforced the necessity of including in the study, separate treatment groups with potentially antigenotoxic substances. The comet assay results have been analyzed using specific software for image analysis, as well as the classical visual analysis, and we have observed that the effect of decrease in DNA electrophoretic mobility was more easily observed when the data were analyzed by the software.

Paracoccin from Paracoccidioides brasiliensis; purification through affinity with chitin and identification of N-acetyl-beta-D-glucosaminidase activity

The dimorphic fungus Paracoccidioides brasiliensis is the causative agent of paracoccidioidomycosis, the most frequent systemic mycosis in Latin America. Our group has been working with paracoccin, a P. brasiliensis lectin with MM 70 kDa. which is purified by affinity, with immobilized N-acetylglucosamine (GlcNAc). Paracoccin has been described to play a role in fungal adhesion to extracellular matrix components and to induce high and persistent levels or TNF alpha. and nitric oxide production by macrophages. In the cell wall, paracoccin colocalizes with the beta-1,4-homopolymer of GlcNAc into the budding sites of the P. brasiliensis yeast cell. In this paper we present a protocol for the chitin-affinity purification or paracoccin. This procedure provided higher yields than those achieved by means of the technique based oil the affinity of this lectin with GlcNAc and had an impact on downstream assays. SDS-PAGE and Western blot analysis revealed similarities between the N-acetylglucosamine- and chitin-bound fractions, confirmed by MALDI-TOF-MS of trypsinic peptides. Western blot of two-dimensional gel electrophoresis of the yeast extract showed a major spot with M(r) 70000 and pl approximately 5.63. Moreover, an N-acetyl-beta-D-glucosaminidase activity was reported for paracoccin, thereby providing new insights into the mechanisms that lead to cell wall remodelling and opening new perspectives for its structural characterization. Copyright (C) 2009 John Wiley & Sons. Ltd.

Computer-aided drug design and ADMET predictions for identification and evaluation of novel potential farnesyltransferase inhibitors in cancer therapy

We have used various computational methodologies including molecular dynamics, density functional theory, virtual screening, ADMET predictions and molecular interaction field studies to design and analyze four novel potential inhibitors of farnesyltransferase (FTase). Evaluation of two proposals regarding their drug potential as well as lead compounds have indicated them as novel promising FTase inhibitors, with theoretically interesting pharmacotherapeutic profiles, when Compared to the very active and most cited FTase inhibitors that have activity data reported, which are launched drugs or compounds in clinical tests. One of our two proposals appears to be a more promising drug candidate and FTase inhibitor, but both derivative molecules indicate potentially very good pharmacotherapeutic profiles in comparison with Tipifarnib and Lonafarnib, two reference pharmaceuticals. Two other proposals have been selected with virtual screening approaches and investigated by LIS, which suggest novel and alternatives scaffolds to design future potential FTase inhibitors. Such compounds can be explored as promising molecules to initiate a research protocol in order to discover novel anticancer drug candidates targeting farnesyltransferase, in the fight against cancer. (C) 2009 Elsevier Inc. All rights reserved.

Constraints on the spatiotemporal accuracy of interceptive action: effects of target size on hitting a moving object

Results of two experiments are reported that examined how people respond to rectangular targets of different sizes in simple hitting tasks. If a target moves in a straight line and a person is constrained to move along a linear track oriented perpendicular to the targetrsquos motion, then the length of the target along its direction of motion constrains the temporal accuracy and precision required to make the interception. The dimensions of the target perpendicular to its direction of motion place no constraints on performance in such a task. In contrast, if the person is not constrained to move along a straight track, the targetrsquos dimensions may constrain the spatial as well as the temporal accuracy and precision. The experiments reported here examined how people responded to targets of different vertical extent (height): the task was to strike targets that moved along a straight, horizontal path. In experiment 1 participants were constrained to move along a horizontal linear track to strike targets and so target height did not constrain performance. Target height, length and speed were co-varied. Movement time (MT) was unaffected by target height but was systematically affected by length (briefer movements to smaller targets) and speed (briefer movements to faster targets). Peak movement speed (Vmax) was influenced by all three independent variables: participants struck shorter, narrower and faster targets harder. In experiment 2, participants were constrained to move in a vertical plane normal to the targetrsquos direction of motion. In this task target height constrains the spatial accuracy required to contact the target. Three groups of eight participants struck targets of different height but of constant length and speed, hence constant temporal accuracy demand (different for each group, one group struck stationary targets = no temporal accuracy demand). On average, participants showed little or no systematic response to changes in spatial accuracy demand on any dependent measure (MT, Vmax, spatial variable error). The results are interpreted in relation to previous results on movements aimed at stationary targets in the absence of visual feedback.

Hitting a moving target: Perception and action in the timing of rapid interceptions

Different interceptive tasks and modes of interception (hitting or capturing) do not necessarily involve similar control processes. Control based on preprogramming of movement parameters is possible for actions with brief movement times but is now widely rejected; continuous perceptuomotor control models are preferred for all types of interception. The rejection of preprogrammed control and acceptance of continuous control is evaluated for the timing of rapidly executed, manual hitting actions. It is shown that a preprogrammed control model is capable of providing a convincing account of observed behavior patterns that avoids many of the arguments that have been raised against it. Prominent continuous perceptual control models are analyzed within a common framework and are shown to be interpretable as feedback control strategies. Although these models can explain observations of on-line adjustments to movement, they offer only post hoc explanations for observed behavior patterns in hitting tasks and are not directly supported by data. It is proposed that rapid manual hitting tasks make up a class of interceptions for which a preprogrammed strategy is adopted-a strategy that minimizes the role of visual feedback. Such a strategy is effective when the task demands a high degree of temporal accuracy.

A randomized and controlled trial of a participative ergonomics intervention to reduce injuries associated with manual tasks: physical risk and legislative

A participative ergonomics approach to reducing injuries associated with manual tasks is widely promoted; however only limited evidence from uncontrolled trials has been available to support the efficacy of such an approach. This paper reports on a randomized and controlled trial of PErforM, a participative ergonomics intervention designed to reduce the risks of injury associated with manual tasks. One hundred and seventeen small to medium sized food, construction, and health workplaces were audited by government inspectors using a manual tasks risk assessment tool (ManTRA). Forty-eight volunteer workplaces were then randomly assigned to Experimental and Control groups with the Experimental group receiving the PErforM program. Inspectors audited the workplaces again, 9 months following the intervention. The results showed a significant decrease in estimates of manual task risk and suggested better legal compliance in the Experimental group.

Visual Display Height

We examined the influence of backrest inclination and vergence demand on the posture and gaze angle that-workers adopt to view visual targets placed in different vertical locations. In the study 12 participants viewed a small video monitor placed in 7 locations around a 0.65-m radius arc (from 650 below to 300 above horizontal eye height). Trunk posture was manipulated by changing the backrest inclination of an adjustable chair. Vergence demand was manipulated by using ophthalmic lenses and prisms to mimic the visual consequences of varying target distance. Changes in vertical target location caused large changes in atlantooccipital posture and gaze angle. Cervical posture was altered to a lesser extent by changes in vertical target location. Participants compensated for changes in backrest inclination by changing cervical posture, though they did not significantly alter atlanto-occipital posture and gaze angle. The posture adopted to view any target represents a compromise between visual and musculoskeletal demands. These results provide support for the argument that the optimal location of visual targets is at least 15 below horizontal eye level. Actual or potential applications of this work include the layout of computer workstations and the viewing of displays from a seated posture.

Measurement Function Design for Visual Tracking Applications

Extracting human postural information from video sequences has proved a difficult research question. The most successful approaches to date have been based on particle filtering, whereby the underlying probability distribution is approximated by a set of particles. The shape of the underlying observational probability distribution plays a significant role in determining the success, both accuracy and efficiency, of any visual tracker. In this paper we compare approaches used by other authors and present a cost path approach which is commonly used in image segmentation problems, however is currently not widely used in tracking applications.

Identification of two novel mutations in the hydroxymethylbilane synthase gene in three patients from two unrelated families with acute intermittent porphyria

We have screened the hydroxymethylbilane synthase cDNAs of 3 patients from 2 families suffering from acute intermittent porphyria (AIP) from Scotland and South Africa using heteroduplex and chemical cleavage of mismatch analyses, Direct sequencing was used to characterise the mutations, The two novel mutations identified were a missense mutation at nucleotide position 64 in exon 3 (R22C) and a single base-pair deletion in exon 15, These mutations are predicted to affect the normal function of the enzyme and, therefore, are expected to be the primary cause of disease in these patients.

The relationship between multiple birth children's early phonological skills and later literacy

Previous studies have shown that multiple ; birth children (MBC) are prone to early phonological ;difficulties and later literacy problems. However, to date, ;there has been no systematic long-term follow-up of MBC with phonological difficulties in the preschool years to determine whether these difficulties predict later literacy problems. In this study, 20 MBC whose early speech and language skills had been previously documented were compared to normative data and 20 singleton controls on tasks assessing phonological ; processing and literacy. The major findings indicated that MBC performed significantly more poorly on some tasks :df phonological processing than singleton controls did. Further, the early phonological skills of MBC (i.e., the number of inappropriate phonological processes used) correlated with poor performance on visual rhyme recognition, word repetition, and phoneme detection tasks 5 years later. There was no significant relationship between early biological factors (birth weight and gestation period) and performance on the phonological processing and literacy-related subtests. These results cl-support the hypothesis that MBC's early speech and language difficulties are not merely a transient phase;of; development, but a real disorder, with consequences for later academic achievement.

Gaze angle: a possible mechanism of visual stress in virtual reality headsets

It is known that some Virtual Reality (VR) head-mounted displays (HMDs) can cause temporary deficits in binocular vision. On the other hand, the precise mechanism by which visual stress occurs is unclear. This paper is concerned with a potential source of visual stress that has not been previously considered with regard to VR systems: inappropriate vertical gaze angle. As vertical gaze angle is raised or lowered the 'effort' required of the binocular system also changes. The extent to which changes in vertical gaze angle alter the demands placed upon the vergence eye movement system was explored. The results suggested that visual stress may depend, in part, on vertical gaze angle. The proximity of the display screens within an HMD means that a VR headset should be in the correct vertical location for any individual user. This factor may explain some previous empirical results and has important implications for headset design. Fortuitously, a reasonably simple solution exists.