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.

Biomechanical consequences of impairment: A taxonomically valid basis for classification in a unified disability athletics system

Developing a unified classification system to replace four of the systems currently used in disability athletics (i.e., track and field) has been widely advocated. The diverse impairments to be included in a unified system require severed assessment methods, results of which cannot be meaningfully compared. Therefore, the taxonomic basis of current classification systems is invalid in a unified system. Biomechanical analysis establishes that force, a vector described in terms of magnitude and direction, is a key determinant of success in all athletic disciplines. It is posited that all impairments to be included in a unified system may be classified as either force magnitude impairments (FMI) or force control impairments (FCI). This framework would provide a valid taxonomic basis for a unified system, creating the opportunity to decrease the number of classes and enhance the viability of disability athletics.

Reliability and validity of physical fitness field tests for adults aged 55 to 70 years

The aim of this study was to examine the reliability and validity of field tests for assessing physical function in mid-aged and young-old people (55–70 y). Tests were selected that required minimal space and equipment and could be implemented in multiple field settings such as a general practitioner's office. Nineteen participants completed 2 field and 1 laboratory testing sessions. Intra-class correlations showed good reliability for the tests of upper body strength (lift and reach, R= .66), lower body strength (sit to stand, R= .80) and functional capacity (Canadian Step Test, R= .92), but not for leg power (single timed chair rise, R= .28). There was also good reliability for the balance test during 3 stances: parallel (94.7% agreement), semi-tandem (73.7%), and tandem (52.6%). Comparison of field test results with objective laboratory measures found good validity for the sit to stand (cf 1RM leg press, Pearson r= .68, p< .05), and for the step test (cf PWC140, r= −.60, p< .001), but not for the lift and reach (cf 1RM bench press, r= .43, p> .05), balance (r= −.13, −.18, .23) and rate of force development tests (r= −.28). It was concluded that the lower body strength and cardiovascular function tests were appropriate for use in field settings with mid-aged and young-old adults.

Evidence of a spotted fever-like rickettsia and a potential new vector from northeastern Australia

A spotted fever-like rickettsia was identified in a Hemaphysalis tick by polymerase chain reaction (PCR) amplification and sequencing of the 16S rDNA, ompA, and ompB genes. A comparison of these nucleotide sequences with those of other spotted fever group (SFG) rickettsiae revealed that the Hemaphysalis tick rickettsia was distinct from other previously reported strains. Phylogenetic analysis based on both ompA and ompB also indicates that the strain’s closest relatives are the agents of Thai tick typhus (Rickettsia honei strain TT-118) and Flinders Island spotted fever (R. honei). This study represents the first report of an R. honei-like agent from a Hemaphysalis tick in Australia and of a spotted fever group rickettsia from Cape York Peninsula, Queensland.

Determination of Wolbachia genome size by Pulsed-Field Gel Electrophoresis

Genome sizes of six different Wolbachia strains from insect and nematode hosts have been determined by pulsed-field gel electrophoresis of purified DNA both before and after digestion with rare-cutting restriction endonucleases. Enzymes SmaI, ApaI, AscI, and FseI cleaved the studied Wolbachia strains at a small number of sites and were used for the determination of the genome sizes of wMelPop, wMel, and wMelCS (each 1.36 Mb), wRi (1.66 Mb), wBma (1.1 Mb), and wDim (0.95 Mb). The Wolbachia genomes studied were all much smaller than the genomes of free-living bacteria such as Escherichia coli (4.7 Mb), as is typical for obligate intracellular bacteria. There was considerable genome size variability among Wolbachia strains, especially between the more parasitic A group Wolbachia infections of insects and the mutualistic C and D group infections of nematodes. The studies described here found no evidence for extrachromosomal plasmid DNA in any of the strains examined. They also indicated that the Wolbachia genome is circular.

Prospects for control of African trypanosomiasis by tsetse vector manipulation

The extensive antigenic variation phenomena African trypanosomes display in their mammalian host have hampered efforts to develop effective vaccines against trypanosomiasis. Human disease management aims largely to treat infected hosts by chemotherapy, whereas control of animal diseases relies on reducing tsetse populations as well as on drug therapy. The control strategies for animal diseases are carried out and financed by livestock owners, who have an obvious economic incentive. Sustaining largely insecticide-based control at a local level and relying on drugs for treatment of infected hosts for a disease for which there is no evidence of acquired immunity could prove extremely costly in the long run. It is more likely that a combination of several methods in an integrated, phased and area-wide approach would be more effective in controlling these diseases and subsequently improving agricultural output. New approaches that are environmentally acceptable, efficacious and affordable are clearly desirable for control of various medically and agriculturally important insects including tsetse. Here, Serap Aksoy and colleagues discuss molecular genetic approaches to modulate tsetse vector competence.

Wolbachia infection and expression of cytoplasmic incompatibility in Armigeres subalbatus (Diptera: Culicidae)

Polymerase chain reaction screening revealed that Armigeres subalbatus (Coquillett), a vector of filariasis, was infected with the intracellular bacteria Wolbachia. Laboratory crosses between infected males and uninfected females resulted in less than half the number of offspring than control crosses between uninfected individuals when young (2- to 3-d-old) males were used in the cross. However, incompatibility was lost when old (14- to 17-d-old) males were used. Field-collected females did not show detectable cytoplasmic incompatibility, and this may be because of the age at which males mate in the field. We used head pigment fluorescence levels to age field males collected from mating swarms, and found that 25-63% of swarming males were older than 13 d. Male age may be one factor influencing the observed low levels of cytoplasmic incompatibility detected in the field.

Semliki Forest virus as an expression vector in insect cell lines

Studies were undertaken to determine if replication-deficient Semliki Forest virus expression vectors could be successfully used to express foreign gene constructs in insect cell lines. Using green fluorescent protein (GFP) as a marker we recorded infection levels of nearly 100% in the Aedes albopictus cell lines C6/36 and Aa23T, as well as in the Ae. aegypti cell line MOS20. The virus was capable of infecting an Anopheles gambiae cell line MOS55. The amount of GFP protein produced in each cell line was quantified. Northern analysis of viral transcription revealed the presence of novel transcripts in Aa23T, C6/36, and MOS55 cell lines, but not in the BHK or MOS20. The initial characterization of these transcripts is described.

Modification of arthropod vector competence via symbiotic bacteria

Some of the world's most devastating diseases are transmitted by arthropod vectors. Attempts to control these arthropods are currently being challenged by the widespread appearance of insecticide resistance. It is therefore desirable to develop alternative strategies to complement existing methods of vector control. In this review, Charles Beard, Scott O'Neill, Robert Tesh, Frank Richards and Serap Aksoy present an approach for introducing foreign genes into insects in order to confer refractoriness to vector populations, ie. the inability to transmit disease-causing agents. This approach aims to express foreign anti-parasitic or anti-viral gene products in symbiotic bacteria harbored by insects. The potential use of naturally occurring symbiont-based mechanisms in the spread of such refractory phenotypes is also discussed.

A unified and complete construction of all finite dimensional irreducible representations of gl(2|2)

Representations of the non-semisimple superalgebra gl(2/2) in the standard basis are investigated by means of the vector coherent state method and boson-fermion realization. All finite-dimensional irreducible typical and atypical representations and lowest weight (indecomposable) Kac modules of gl(2/2) are constructed explicity through the explicit construction of all gl(2) circle plus gl(2) particle states (multiplets) in terms of boson and fermion creation operators in the super-Fock space. This gives a unified and complete treatment of finite-dimensional representations of gl(2/2) in explicit form, essential for the construction of primary fields of the corresponding current superalgebra at arbitrary level.

Extending teaching and learning initiatives in the cross-disciplinary field of biotechnology

Our AUTC Biotechnology study (Phases 1 and 2) identified a range of areas that could benefit from a common approach by universities nationally. A national network of biotechnology educators needs to be solidified through more regular communication, biennial meetings, and development of methods for sharing effective teaching practices and industry placement strategies, for example. Our aims in this proposed study are to: a. Revisit the state of undergraduate biotechnology degree programs nationally to determine their rate of change in content, growth or shrinkage in student numbers (as the biotech industry has had its ups and downs in recent years), and sustainability within their institutions in light of career movements of key personnel, tightening budgets, and governmental funding priorities. b. Explore the feasibility of a range of initiatives to benefit university biotechnology education to determine factors such as how practical each one is, how much buy-in could be gained from potentially participating universities and industry counterparts, and how sustainable such efforts are. One of many such initiatives arising in our AUTC Biotech study was a national register of industry placements for final-year students. c. During scoping and feasibility study, to involve our colleagues who are teaching in biotechnology – and contributing disciplines. Their involvement is meant to yield not only meaningful insight into how to strengthen biotechnology teaching and learning but also to generate ‘buy-in’ on any initiatives that result from this effort.

Development and evaluation of neural network freeway incident detection models using field data

This paper discusses a multi-layer feedforward (MLF) neural network incident detection model that was developed and evaluated using field data. In contrast to published neural network incident detection models which relied on simulated or limited field data for model development and testing, the model described in this paper was trained and tested on a real-world data set of 100 incidents. The model uses speed, flow and occupancy data measured at dual stations, averaged across all lanes and only from time interval t. The off-line performance of the model is reported under both incident and non-incident conditions. The incident detection performance of the model is reported based on a validation-test data set of 40 incidents that were independent of the 60 incidents used for training. The false alarm rates of the model are evaluated based on non-incident data that were collected from a freeway section which was video-taped for a period of 33 days. A comparative evaluation between the neural network model and the incident detection model in operation on Melbourne's freeways is also presented. The results of the comparative performance evaluation clearly demonstrate the substantial improvement in incident detection performance obtained by the neural network model. The paper also presents additional results that demonstrate how improvements in model performance can be achieved using variable decision thresholds. Finally, the model's fault-tolerance under conditions of corrupt or missing data is investigated and the impact of loop detector failure/malfunction on the performance of the trained model is evaluated and discussed. The results presented in this paper provide a comprehensive evaluation of the developed model and confirm that neural network models can provide fast and reliable incident detection on freeways. (C) 1997 Elsevier Science Ltd. All rights reserved.