Timing the Emergence of Resistance to Anti-HIV Drugs with Large Genetic Barriers

New antiretroviral drugs that offer large genetic barriers to resistance, such as the recently approved inhibitors of HIV-1 protease, tipranavir and darunavir, present promising weapons to avert the failure of current therapies for HIV infection. Optimal treatment strategies with the new drugs, however, are yet to be established. A key limitation is the poor understanding of the process by which HIV surmounts large genetic barriers to resistance. Extant models of HIV dynamics are predicated on the predominance of deterministic forces underlying the emergence of resistant genomes. In contrast, stochastic forces may dominate, especially when the genetic barrier is large, and delay the emergence of resistant genomes. We develop a mathematical model of HIV dynamics under the influence of an antiretroviral drug to predict the waiting time for the emergence of genomes that carry the requisite mutations to overcome the genetic barrier of the drug. We apply our model to describe the development of resistance to tipranavir in in vitro serial passage experiments. Model predictions of the times of emergence of different mutant genomes with increasing resistance to tipranavir are in quantitative agreement with experiments, indicating that our model captures the dynamics of the development of resistance to antiretroviral drugs accurately. Further, model predictions provide insights into the influence of underlying evolutionary processes such as recombination on the development of resistance, and suggest guidelines for drug design: drugs that offer large genetic barriers to resistance with resistance sites tightly localized on the viral genome and exhibiting positive epistatic interactions maximally inhibit the emergence of resistant genomes.

Glucosinolate composition and anti-cancer potential of daikon and radish sprouts

Daikon and radish sprouts contain high levels of glucoraphenin, a glucosinolate which hydrolyses to form sulphoraphene. Sulphoraphene, like sulphoraphane from broccoli, is a potent inducer of phase 2 detoxification enzymes and consequently has potential anti-cancer action. Unlike broccoli however, daikon and radish do not possess epithiospecifier protein, a protein that inhibits conversion of glucosinolates to isothiocyanates, and consequently they may represent more suitable sources of phyto-chemicals with anti-cancer potential. Concentrations of glucoraphenin were highest in the seed, declining exponentially with sprout development. The rate of decline was observed to vary considerably between varieties of daikon and radish, with some varieties maintaining significantly high levels of glucoraphenin. Varieties maintaining a high level of glucoraphenin included 'Cherry Belle' and 'French Breakfast'.

Evaluation of transgenic bananas expressing anti-apoptotic genes for resistance against Fusarium wilt

The banana industry worldwide is under threat from a fungal disease known as Fusarium wilt, a disease for which there is no chemical control. Conventional breeding approaches to generate resistant banana varieties are lengthy and very difficult. As such, genetic engineering for disease resistance is considered the most viable control option. In this PhD thesis, genetically modified banana plants were generated using several different stress tolerance genes. When challenged with Fusarium wilt in glasshouse trials, some lines showed increased resistance to the disease. The promising elite lines generated in this study will now require testing in field trials.

Radish sprouts versus broccoli sprouts: a comparison of anti-cancer potential based on glucosinolate breakdown products.

Radish sprouts and broccoli sprouts have been implicated in having a potential chemoprotective effect against certain types of cancer. Each contains a glucosinolate that can be broken down to an isothiocyanate capable of inducing chemoprotective factors known as phase 2 enzymes. In the case of broccoli, the glucosinolate, glucoraphanin, is converted to an isothiocyanate, sulforaphane, while in radish a similar glucosinolate, glucoraphenin, is broken down to form the isothiocyanate, sulforaphene. When sprouts are consumed fresh (uncooked), however, the principal degradation product of broccoli is not the isothiocyanate sulforaphane, but a nitrile, a compound with little anti-cancer potential. By contrast, radish sprouts produce largely the anti-cancer isothiocyanate, sulforaphene. The reason for this difference is likely to be due to the presence in broccoli (and absence in radish) of the enzyme cofactor, epithiospecifier protein (ESP). In vitro induction of the phase 2 enzyme, quinone reductase (QR), was significantly greater for radish sprouts than broccoli sprouts when extracts were self-hydrolysed. By contrast, boiled radish sprout extracts (deactivating ESP) to which myrosinase was subsequently added, induced similar QR activity to broccoli sprouts. The implication is that radish sprouts have potentially greater chemoprotective action against carcinogens than broccoli sprouts when hydrolysed under conditions similar to that during human consumption.

Develop added value uses of high anti-bacterial honey

Honey is valued for its medicinal properties. There interest from industry to develop a rapid method to detect the bioactivity of honey and also to develop value added products from high antibacterial honey.

Protein A: nature's universal anti-antibody

Staphylococcal protein A specifically interacts with immunogobulins. This fact is being used in various disciplines of biology and some of the unique properties of protein A and their applications are summarized in this review.

Anti-bacterial surfaces: Natural agents, mechanisms of action, and plasma surface modification

Strategies that confine antibacterial and/or antifouling property to the surface of the implant, by modifying the surface chemistry and morphology or by encapsulating the material in an antibiotic-loaded coating, are most promising as they do not alter bulk integrity of the material. Among them, plasma-assisted modification and catechol chemistry stand out for their ability to modify a wide range of substrates. By controlling processing parameters, plasma environment can be used for surface nano structuring, chemical activation, and deposition of biologically active and passive coatings. Catechol chemistry can be used for material-independent, highly-controlled surface immobilisation of active molecules and fabrication of biodegradable drug-loaded hydrogel coatings. In this article, we comprehensively review the role plasma-assisted processing and catechol chemistry can play in combating bacterial colonisation on medically relevant coatings, and how these strategies can be coupled with the use of natural antimicrobial agents to produce synthetic antibiotic-free antibacterial surfaces.

Crystallization and preliminary X-ray studies of the anti-T lectin from peanut (Arachis hypogaea)

The anti-T lectin from peanut (Arachis hypogaea) crystallizes in the orthorhombic space group P21212 with one tetrameric molecule (Mr 110,000) in the asymmetric unit in a cell of dimensions a = 129.3 Å, B = 126.9 Å and C = 76.9 Å. The crystals are suitable for high resolution work.

Vegetables containing phytochemicals with potential anti-obesity properties: A review

The incidence of obesity is rising worldwide at an alarming rate and is becoming a major public health concern with incalculable social and economic costs. Studies have exposed the relationship between the adiposity, inflammation and the development of other metabolic disorders, so dietary factors that influence some or all of these are of interest. Dietary phytochemicals appear to be able to target different stages of the adipocyte (fat cell) lifecycle. For example, several classes of polyphenols have been implicated in suppressing the growth of adipose tissue through modifying the adipocyte lifecycle. Many dietary phytochemicals also have strong anti-inflammatory activity, but the amount present in plants varies and may be affected by processing. In this review we summarise the likely mechanisms of action of plant phytochemicals. We highlight the major vegetable sources of polyphenols, including those with possible synergistic attributes, discuss the variation in polyphenol levels and their distribution in cultivars and outline the effects of food processing. The identification and characterisation of the anti-obesogenic properties of phytochemicals in vegetables, as well as an appreciation of the effect of cooking on phytochemical content provide significant new information supporting dietary guidelines that encourage vegetable consumption for the prevention and management of lifestyle related disease.

Structure and conformation of an anti-depressant drug, nitroxazepine hydrochloride monohydrate

CIsH20N3Oa+.C1-.H2 O, M r = 395, orthorhombic, Pn21a, a = 7.710 (4), b = 11.455 (3), c -- 21.199 (3)/k, Z = 4, V = 1872.4/k 3, D m = 1.38, D C = 1.403 g cm -3, F(000) = 832, g(Cu Kct) = 20.94 cm -l. Intensities for 1641 reflections were measured on a Nonius CAD-4 diffractometer; of these, 1470 were significant. The structure was solved by direct methods and refined to an R index of 0.045 using a blockdiagonal least-squares procedure. The angle between the least-squares planes through the benzene rings is 125.0 (5) ° and the side chain is folded similarly to one of the independent molecules of imipramine hydrochloride.

Immunologic studies on nucleic acids and their components. I. An analysis of the specificity of anti-deoxyadenylate antibodies by a membrane-binding technique

Anti-deoxyadenylate antibodies were produced in rabbits by injecting a conjugate of deoxyadenosine 5′-phosphate with bovine serum albumin. The antisera, as analyzed by double diffusion in agar and the quantitative precipitin reaction, showed hapten-specific antibodies. The specific interaction between [3H]deoxyadenylate and antiserum was studied by a sensitive nitrocellulose membrane-binding assay. The specificity of the antibodies was analyzed by measuring the effectiveness of other nucleotides or derivatives to inhibit the hapten-antibody binding. The requirements for recognition by the antibody sites were studied by using a series of naturally occurring nucleic acid components as well as some synthetic derivatives as inhibitors. The antibodies were found to show a high degree of specificity for the whole nucleotide, the base, sugar and phosphate playing almost equally important roles. There was cross reactivity with other mononucleotides, although of a low order. The antibodies were able to react with DNA and tRNA.

Immunologic studies on nucleic acids and their components II. Reversible inhibition of anti-nucleoside antibodies in aqueous pyridine and its application in antibody

The effect of aqueous pyridine on a hapten—antihapten system was investigated by the quantitative precipitin reaction and by the membrane filtration method. It was found that dilute solutions of pyridine inhibited the reaction between isopentenyladenosine and its antiserum. Other solvents examined were less effective. The effect of pyridine was reversible at concentrations where complete inhibition occurred, thus indicating its use for the dissociation of antigen—antibody complexes. The inhibitory effect of pyridine was exploited in a single-step purification method for anti—isopentenyladenosine and antideoxy-adenylate antibodies. In addition, generally applicable methods for linking nucleosides and nucleotides to aminoethyl-Sepharose are described.

Optimisation of resin extraction from an Australian arid grass ‘Triodia pungens’ and its preliminary evaluation as an anti-termite timber coating

Spinifex grasses are the dominant vegetative component in Australian grassland habitats, covering approximately 26% of the Australian landmass. Our ongoing work explores the utility of both the cellulosic and resinous components of this abundant biomass for modern applications and a potential economy for our Aboriginal collaborators. This study is focused on the optimisation of a resin extraction process using solvent, and the subsequent evaluation, via a field trial, of the potential use and efficacy of the resin as an anti-termite coating material. Termiticidal performance was evaluated by re-dissolving the extracted resin in acetone and coating on pine timber blocks. The resin-coated and control blocks were then exposed to a colony of Mastotermes darwiniensis’ (Froggatt) termites, which are the most primitive alive and destructive species in subterranean area, at a trial site in northeast Australia, for six months. The results clearly showed that spinifex resin effectively protected the timber from termite attack, while the uncoated control samples were extensively damaged. By demonstrating an enhanced termite resistance, we here report that plant resins that are produced by arid/semi-arid grasses could be potentially used as treatments to prevent termite attack.