Probing the fibrate binding specificity of rat liver fatty acid binding protein

Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.

Ribosome inactivating proteins (RIPs) from momordica charantia for anti viral therapy

This review describes the nature and applications of ribosome inactivating proteins (RIPs) from Momordica charantia (bitter melon). RIPs from the plant kingdom have received much attention in biomedical research because they target conserved host protein synthesis machinery and show specificity towards human and animal cell targets. Recent studies aimed at unravelling the enzymatic activities of the M charantia RIPs provide a structural basis for their activities. It has been reported that RIPs are member of the single chain ribosome inactivating protein (SCRIP) family which act irreversibly on ribosome by removing adenine residue from eukaryotic ribosomal RNA. Various activities of RIPs include anti-tumor, broad anti-viral, ribonuclease and deoxyribonuclease. MAP30 (Momordica Anti-HIV Protein), alpha- and beta-momorcharins inhibit HIV replication in acutely and chronically infected cells and thus are considered potential therapeutic agent in HIV infection and AIDS. Further, MAP30 improved the efficacy of anti-HIV therapy when used in combination with other anti-viral drugs. MAP30 holds therapeutic promise over other RIPs because not only it is active against infection and replication of both HSV and HIV but is non toxic to normal cells. Here we review the nature, action, structure function relationship and applications of RIPs from Momordica charantia and evaluate their potential for anti-cancer and anti-viral therapy.

The before and after effect of the Olympic games on the host city's property market : the Sydney experience

This research evaluated the impact of the Olympic Games on the host city's residential property market, both before and after the Games. Using a time  series approach between 1990 and 2003, this paper examines various indicators to measure the effect of the 2000 Olympics on the Sydney property market. The research shows that although the Olympics were held for only ten days, its influence on the surrounding market in a direct and indirect manner was substantial. It appears that the lasting effect of the Games on the property market remained strongest in the general vicinity of the Olympic Village, and then gradually weakened over time in areas located further away from this precinct. It emphasised the role of urban planning both before and after the event, and how to use a major sporting event to gentrify a suburb.

Dealing with corruption/bribery in a host country

Multinational business managers and companies with an ethical bent of mind find it difficult to navigate bribery/corruption in a host country which has systemic or large scale corruption and often end up debating such decisions. This paper proposes the ‘stakeholder compliance approach’ as a decision-making guideline to assist the managerial decision making process in such situations.

Host intra-clutch variation, cuckoo egg matching and egg rejection by great reed warblers

Prevailing theory predicts that lower levels of intra-clutch variation in host eggs facilitate the detection of brood parasitism. We assessed egg matching using both human vision and UV-VIS spectrophotometry and then followed the nest fate of great reed warblers naturally parasitised by European cuckoos. Rejection was predicted by the following three variables: matching between cuckoo and host eggs on the main chromatic variable defined by principal components analysis of the egg spectra (which has a strong loading in the UV); the number of host eggs in the nest; and human estimates of intra-clutch variation. The first variable is not correlated to human estimates of matching, which do not predict rejection. In line with another recent study, rejection rates were predicted by higher levels of intra-clutch variation in the host eggs, suggesting that higher rather than lower levels of intra-clutch variation can facilitate the discrimination of cuckoo eggs by hosts. We suggest that the importance of intra-clutch variation is context dependent, with intra-clutch variation being important when there is good matching between the host and the cuckoo eggs. Our results also suggest that both spectrometric and human visual assessments of egg matching and intra-clutch variation are prudent: the former provide the best method of estimating reflectance variation, whereas the latter include some assessment of patterns of maculation.

Do cuckoos choose nests of great reed warblers on the basis of host egg appearance?

Prevailing theory assumes cuckoos lay at random among host nests within a population, although it has been suggested that cuckoos could choose large nests and relatively active pairs within host populations. We tested the hypothesis that egg matching could be improved by cuckoos choosing nests in which host eggs more closely match their own, by assessing matching and monitoring nest fate in great reed warblers naturally or experimentally parasitized by eggs of European cuckoos. A positive correlation between cuckoo and host egg visual features suggests that cuckoos do not lay at random within a population, but choose nests and this improves egg matching: naturally parasitized cuckoo eggs were more similar to host eggs as perceived by humans and as measured by spectrophotometry. Our results suggest a hitherto overlooked step in cuckoo-host evolutionary arms races, and have nontrivial implications for the common experimental practice of artificially parasitizing clutches.

Plasmodium falciparum induces reorganization of host membrane proteins during intraerythrocytic growth

The virulence of the malaria parasite, Plasmodium falciparum, is due in large part to the way in which it modifies the membrane of its erythrocyte host. In this work we have used confocal microscopy and fluorescence recovery after photo-bleaching to examine the lateral mobility of host membrane proteins in erythrocytes infected with P falciparum at different stages of parasite growth. The erythrocyte membrane proteins band 3 and glycophorin show a marked decrease in mobility during the trophozoite stage of growth. Erythrocytes infected with a parasite strain that does not express the knob-associated histidine-rich protein show similar effects, indicating that this parasite protein does not contribute to the immobilization of the host proteins. Erythrocytes infected with ring-stage parasites exhibit intermediate mobility indicating that the parasite is able to modify its host prior to its active feeding stage.

Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6

CYP2B6 is mainly expressed in the liver that has been thought historically to play an insignificant role in human drug metabolism. However, increased interest in this enzyme has been stimulated by the discovery of polymorphic and ethnic differences in CYP2B6 expression, identification of additional substrates for CYP2B6, and evidence for co-regulation with CYP3A4. This paper updates our knowledge about the structure, function, regulation and polymorphism of CYP2B6. CYP2B6 can metabolise approximately 8% of clinically used drugs (n > 60), including cyclophosphamide, ifosfamide, tamoxifen, ketamine, artemisinin, nevirapine, efavirenz, bupropion, sibutramine, and propofol. CYP2B6 is one of the CYP enzymes that bioactivate several procarcinogens and toxicants. This enzyme also metabolizes arachidonic acid, lauric acid, 17beta-estradiol, estrone, ethinylestradiol, and testosterone. Typical substrates of CYP2B6 are non-planar molecules, neutral or weakly basic, highly lipophilic with one or two hydrogen-bond acceptors. The crystal structure of CYP2B6 has not been resolved, while several pharmacophore and homology models of human CYP2B6 have been reported. Human CYP2B6 is closely regulated by constitutive androstane receptor (CAR/NR1I3) which can activate CYP2B6 expression upon ligand binding. Pregnane X receptor and glucocorticoid receptor also play a role in the regulation of CYP2B6. Induction of CYP2B6 may partially explain some clinical drug interactions observed. For example, coadministered carbamazepine decreases the systemic exposure of bupropion. There is a wide interindividual variability in the expression and activity of CYP2B6. Such a large variability is probably due to effects of genetic polymorphisms and exposure to drugs that are inducers or inhibitors of CYP2B6. To date, at least 28 allelic variants and some subvariants of CYP2B6 (*1B through *29) have been described and some of them have been shown to have important functional impact on drug clearance and drug response. For example, the efavirenz plasma levels in African-American subjects with the CYP2B6 homozygous 516T/T genotype are approximately 3-fold higher than individuals carrying the homozygous G/G genotype. The CYP2B6 516T/T genotype is associated with 1.7-fold greater plasma levels of nevirapine in HIV-infected patients. Smokers with the 1459C>T (R487C) variant of CYP2B6 may be more vulnerable to abstinence symptoms and relapse following treatment with bupropion as a smoking cessation agent. Further studies in the structure, function, regulation and polymorphism of CYP2B6 are warranted.

The TOC-ABC choice debate for product mix decisions : introducing asset specificity as an alternate explanation

Though constructed with different purposes, the theory of constraints and activity based costing systems pose a choice problem in respect of product mix decisions. We believe that the existing explanation of short versus long run criterion to explain firms' choice between these two systems is incomplete and offer an alternate explanation based on asset specificity. We argue that the extent to which specialized resources are deployed to make products in a mix determines the choice. We present a 2*2 matrix stating that when asset specificity is high, a firm is likely to choose ABC instead of TOC since ABC makes a large portion of costs visible to enable control. However, the choice is likely to be a TOC-ABC combination when the manufacture of asset specific products is also constrained by bottlenecks.