Comparative molecular field analysis of colchicine inhibition and tubulin polymerization for combretastatins binding to the colchicine binding site on beta-tubulin

A molecular modeling study using Comparative Molecular Field Analysis (CoMFA) was undertaken to develop a predictive model for combretastatin binding to the colchicine binding site of tubulin. Furthermore, we examined the potential contribution of lipophilicity (log P) and molecular dipole moment and were unable to correlate these properties to the observed biological data. In this study we first confirmed that tubulin polymerization inhibition (IC50) correlated (R2 = 0.92) with [3H]colchicine displacement. Although these data correlated quite well, we developed two independent models for each set of data to quantify structural features that may contribute to each biological property independently. To develop our predictive model we first examined a series of molecular alignments for the training set and ultimately found that overlaying the respective trimethoxyphenyl rings (A ring) of the analogues generated the best correlated model. The CoMFA yielded a cross-validated R2 = 0.41 (optimum number of components equal to 5) for the tubulin polymerization model and an R2 = 0.38 (optimum number of components equal to 5) for [3H]colchicine inhibition. Final non-cross-validation generated models for tubulin polymerization (R2 of 0.93) and colchicine inhibition (R2 of 0.91). These models were validated by predicting both biological properties for compounds not used in the training set. These models accurately predicted the IC50 for tubulin polymerization with an R2 of 0.88 (n = 6) and those of [3H]colchicine displacement with an R2 of 0.80 (n = 7). This study represents the first predictive model for the colchicine binding site over a wide range of combretastatin analogues.     

Vaccination with inactivated virus but not viral DNA reduces virus load following challenge with a heterologous and virulent isolate of feline immunodeficiency virus

It has been shown that cats can be protected against infection with the prototypic Petaluma strain of feline immunodeficiency virus (FIV(PET)) using vaccines based on either inactivated virus particles or replication-defective proviral DNA. However, the utility of such vaccines in the field is uncertain, given the absence of consistent protection against antigenically distinct strains and the concern that the Petaluma strain may be an unrepresentative, attenuated isolate. Since reduction of viral pathogenicity and dissemination may be useful outcomes of vaccination, even in the absence of complete protection, we tested whether either of these vaccine strategies ameliorates the early course of infection following challenge with heterologous and more virulent isolates. We now report that an inactivated virus vaccine, which generates high levels of virus neutralizing antibodies, confers reduced virus loads following challenge with two heterologous isolates, FIV(AM6) and FIV(GL8). This vaccine also prevented the marked early decline in CD4/CD8 ratio seen in FIV(GL8)-infected cats. In contrast, DNA vaccines based on either FIV(PET) or FIV(GL8), which induce cell-mediated responses but no detectable antiviral antibodies, protected a fraction of cats against infection with FIV(PET) but had no measurable effect on virus load when the infecting virus was FIV(GL8). These results indicate that the more virulent FIV(GL8) is intrinsically more resistant to vaccinal immunity than the FIV(PET) strain and that a broad spectrum of responses which includes virus neutralizing antibodies is a desirable goal for lentivirus vaccine development.     

The effects of arable field margin management on the abundance and species richness of Araneae (spiders)

The effects of ten different management regimes on the abundance and species richness of Araneae on pre-existing and newly expanded zones of field margins surrounding arable fields are compared in a large-scale experiment conducted between 1987 and 1991. Most of the management regimes involved varying the Liming and frequency with which the field margins were cut. There was no evidence of consistent temporal trends in the abundance and species richness of Araneae on either the existing or expanded zones of the field margins during the first four years of the experiment. However, lowest numbers were recorded before expansion of the margins in 1987, and highest numbers in the final sample, in 1991. Araneae remained less abundant, and less species rich, on the newly expanded than on the existing zones of the field margins four years after they were set-aside'. Culling reduced both abundance and species richness. Regimes which included culling in mid-summer had a greater impact which persisted for longer than did those involving cutting in spring and autumn. Removal of cut material was associated with lower species richness than leaving it in situ. Sowing the margins with a wild flower seed mixture was associated with increased abundance and species richness of Araneae. Annual spraying with a broad-spectrum, non-persistent herbicide reduced the abundance of Araneae but the effect was not detectable until several months after the application of the spray. Both the species richness and abundance of Araneae were positively correlated with a measure of vegetation height made on the field margins in September, on both the pre-existing and newly expanded zones of the margins. The extent to which management practices which benefit Araneae are compatible with both the management requirements for various other taxa. and the overriding constraint of effective pernicious weed control on field margins, is discussed.     

Rabies in Zimbabwe: reservoir dogs and the implications for disease control.

Using detailed field study observations of the side-striped jackal (Canis adustus) and a simple stochastic model of the transmission dynamics of the virus and host demography, we discuss the epidemiology of rabies virus infection in the jackal population of Zimbabwe. Of the two jackal species in Zimbabwe, the other being the black-backed jackal (Canis mesomelas), the bulk of notified rabies cases are in side-striped jackals. Specifically, we show that the side-striped jackal population itself does not seem able to support rabies infection endemically, i.e. without frequent reintroduction from outside sources of infection. We argue that this is probably because the overall average jackal population density is too low to maintain the chain of infection. This study suggests that the disease is regularly introduced to jackals by rabid dogs from populations associated with human settlements. Given the rapidly rising dog population in Zimbabwe, estimates are derived of the future incidence of jackal rabies based on different dog-vaccination scenarios.     

Incidence and levels of fumonisin contamination in Colombian corn and corn products

A survey was conducted to determine the levels of fumonisins B1 and B2 in corn and corn-based products available in Colombia for human and animal consumption. A total of 120 samples were analyzed by acetonitrile-water extraction, cleanup with a strong-anion-exchange column, and liquid chromatography with o-phthaldialdehyde-2-mercaptoethanol derivatization and fluorescence detection. The samples of corn and corn-based products for animal intake were taken at different feed manufacturing plants, whereas the samples used for human foods where purchased from local retail stores. The number of positive samples for fumonisin B1 was 20.0% higher in corn and corn-based products for animal intake (75.0%) than in corn and corn-based products for human consumption (55.0%). The levels of fumonisin B1 were also higher in corn and corn-based products for animal intake (mean = 694 μg/kg; range = 32–2964 μg/kg), than in corn and corn-based products for human intake (mean = 218 μg/kg; range = 24–2170 μg/ kg). The incidence and levels of fumonisin B2 were lower than those for fumonisin B1. Corn and corn-based products for animal consumption had an incidence of fumonisin B2 of 58.3%, with a mean value of 283 μg/kg, and a range of 44–987 μg/kg. The incidence of fumonisin B2 in corn-based products for human intake was 35.0%, with a mean value of 118 μg/kg and a range of 21–833 μg/kg. The highest incidence and levels of fumonisins were found in samples of hominy feed, with concentrations ranging from 86 to 2964 μg/kg fumonisin B1 and 57 to 987 μg/kg fumonisin B2.     

Translational Activation of Oskar mRNA: Reevaluation of the Role and Importance of a 5' Regulatory Element

Local translation of oskar (osk) mRNA at the posterior pole of the Drosophila oocyte is essential for axial patterning of the embryo, and is achieved by a program of translational repression, mRNA localization, and translational activation. Multiple forms of repression are used to prevent Oskar protein from accumulating at sites other than the oocyte posterior. Activation is mediated by several types of cis-acting elements, which presumably control different forms of activation. We characterize a 5'' element, positioned in the coding region for the Long Osk isoform and in the extended 5'' UTR for translation of the Short Osk isoform. This element was previously thought to be essential for osk mRNA translation, with a role in posterior-specific release from repression. From our work, which includes assays which separate the effects of mutations on RNA regulatory elements and protein coding capacity, we find that the element is not essential, and conclude that there is no evidence supporting a role for the element only at the posterior of the oocyte. The 5'' element has a redundant role, and is only required when Long Osk is not translated from the same mRNA. Mutations in the element do disrupt the anchoring function of Long Osk protein through their effects on the amino acid sequence, a confounding influence on interpretation of previous experiments.     

Systematic Review of the Measurement Properties of Tools Used to Measure Behaviour Problems in Young Children with Autism

Background

Behaviour problems are common in young children with autism spectrum disorder (ASD). There are many different tools used to measure behavior problems but little is known about their validity for the population.

Objectives

To evaluate the measurement properties of behaviour problems tools used in evaluation of intervention or observational research studies with children with ASD up to the age of six years.

Methods

Behaviour measurement tools were identified as part of a larger, two stage, systematic review. First, sixteen major electronic databases, as well as grey literature and research registers were searched, and tools used listed and categorized. Second, using methodological filters, we searched for articles examining the measurement properties of the tools in use with young children with ASD in ERIC, MEDLINE, EMBASE, CINAHL, and PsycINFO. The quality of these papers was then evaluated using the COSMIN checklist.

Results

We identified twelve tools which had been used to measure behaviour problems in young children with ASD, and fifteen studies which investigated the measurement properties of six of these tools. There was no evidence available for the remaining six tools. Two questionnaires were found to be the most robust in their measurement properties, the Child Behavior Checklist and the Home Situations Questionnaire—Pervasive Developmental Disorders version.

Conclusions

We found patchy evidence on reliability and validity, for only a few of the tools used to measure behaviour problems in young children with ASD. More systematic research is required on measurement properties of tools for use in this population, in particular to establish responsiveness to change which is essential in measurement of outcomes of intervention.

PROSPERO Registration Number

CRD42012002223