N-myristoyltransferase inhibitor protein is homologous to heat shock cognate protein 70

Many of viral and eukaryotic proteins are required for signal transduction and regulatory functions which undergo a lipid modification by the enzyme N-myristoyltransferase (NMT). In this study, we demonstrated that heat shock cognate protein 70 (HSC70) is homologous to NMT inhibitor protein (NIP71), which was discovered in our laboratory, based on MALDI-TOF mass spectrometric analysis. The purified bovine cytosolic HSC70 and particulate NIP71 produced a dose-dependent inhibition of human NMT having half maximal inhibitions of 235 and 230 nM, respectively. Further, Western blot analysis revealed that the purified particulate NIP71 and cytosolic HSC70 cross-reacted with both anti-NIP71 and anti-HSC70 antibodies. The results we obtained imply that molecular chaperones could be involved in the regulation of NMT in normal and cancerous cells. Further studies directed to revealing the role of HSC70 in the regulation of NMT may lead to the development of gene based therapies of colon cancer.     

Sequential cytotoxicity: a theory examined using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines and related phosphonic acids

The concept of sequential cytotoxicity, which states that successive chemical attacks on cellular constituents can be more deleterious to neoplasms than normal cells, was evaluated using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines 1 and related phosphonic acids 2, which were screened against a panel of malignant and normal cell lines. The compounds proved to be not only potent cytotoxins (71% of the CC(50) figures are submicromolar) but to display greater cytotoxicity to the neoplastic cells. QSAR revealed that both cytotoxic potencies and selective toxicity were increased by a rise in the electron-withdrawing properties and a decrease in the hydrophobicity of the aryl substituents. Utilisation of the PL10 concept and evaluation of druglike properties revealed 1c as the lead tumour-specific cytotoxin. This molecule activated caspase-3 in HL-60 cells but not in the HSC-2 cell line. While 1c caused internucleosomal DNA fragmentation in HL-60 cells, it did not elicit this effect in either HSC-2 and HSC-4 cells. Clearly 1c exerts its cytotoxic potencies by different mechanisms and such pleiotropy is likely the principal reason for the remarkable display of preferential toxicity towards malignant cells of the compounds in series 1 and 2.     

Serological and biochemical factors in bovine ephemeral fever

Clinical signs of ephemeral fever, which were observed in individual cattle during two successive epidemics in 1973 and 1976, were related to biochemical, cellular and serological changes in the blood. The rise in peripheral blood neutrophil counts in samples collected from 12 sentinel cattle on a daily basis before, during and after natural disease in the two epidemics to mean peaks of 9.6-12.5 X 10(9) per litre, and fall in counts of lymphocytes to a trough of 5-7 X 10(9) per litre was found to occur on the same day as the fever peak. A fall in serum calcium levels from a normal mean of 2.55 mmol/l to 2.0 mmol/l occurred on the day clinical signs were most pronounced. Serum magnesium levels were affected to only a minor degree. Plasma fibrinogen rose from a normal mean of 5.0 milligrams to a peak of 18 milligrams on the second day of disease and fell towards normal in the week after recovery. Neutralizing antibodies to bovine ephemeral fever virus were detected up to 63 days prior to clinical disease, and the rise of antibody after recovery was secondary in pattern. Serological evidence of a prior infection with an antigenically related virus, Kimberley virus, was found in these animals. In more severe clinical cases of ephemeral fever serum calcium levels were as low as 1.95 mmol/l. Treatment of cattle showing clinical signs of the disease with phenylbutazone and calcium borogluconate was favourable.     

Molecular structure--activity relationship of hydrazides inhibiting glutamic acid decarboxylase, GABA-alpha-oxoglutarate aminotransferase, and monoamine oxidase activities in chick brain.

Several aryl and heteroaryl hydrazides were synthesized and evaluated for their inhibitory effects on glutamic acid decarboxylase (GAD), GABA-alpha-oxoglutarate aminotransferase (GABA-T), and monoamine oxidase (MAO) enzyme systems in chick brain 24 h after their intramuscular administration (0.75 mmol/kg). All compounds produced a reduction in GAD, GABA-T, and MAO activity. Structure-activity relationships indicated that the ring structure had a greater influence on the degree of GAD and GABA-T inhibition than did the N'-terminal group. In contrast, structural requirements for MAO inhibition were much more restrictive. The intramuscular administration of benzoic acid hydrazide to chicks 24 h prior to their being exposed to oxygen at high pressure provided significant protection against the onset of the hyperbaric oxygen-induced seizures.     

Defective Interfering Influenza Virus RNAs: Time To Reevaluate Their Clinical Potential as Broad-Spectrum Antivirals?

Defective interfering (DI) RNAs are highly deleted forms of the infectious genome that are made by most families of RNA viruses. DI RNAs retain replication and packaging signals, are synthesized preferentially over infectious genomes, and are packaged as DI virus particles which can be transmitted to susceptible cells. Their ability to interfere with the replication of infectious virus in cell culture and their potential as antivirals in the clinic have long been known. However, until now, no realistic formulation has been described. In this review, we consider the early evidence of antiviral activity by DI viruses and, using the example of DI influenza A virus, outline developments that have led to the production of a cloned DI RNA that is highly active in preclinical studies not only against different subtypes of influenza A virus but also against heterologous respiratory viruses. These data suggest the timeliness of reassessing the potential of DI viruses as a novel class of antivirals that may have general applicability.     

In the Water with White Sharks (Carcharodon carcharias): Participants’ Beliefs toward Cage-diving in Australia

White shark (Carcharodon carcharias) cage-diving tourism is a controversial activity that provokes emotional and often opposing points of view. With increasing demand for shark tourism since the 1990s, the un- derlying determinants driving this growth in participation remain unclear. This paper adopts a qualitative approach to investigate beliefs underlying tourists’ choice to observe white sharks while cage-diving at the Neptune Islands, South Australia. Elicitation surveys gathered responses from a sample (n = 86) of cage-diving participants. Content analysis of the responses revealed the decision to cage-dive with white sharks is driven by factors including education and the perceived naturalness of the experience. The findings of this study indicate an opportunity for cage-dive operators to pro- vide in situ education and interpretation with potential for increased tourist satisfaction and shark conservation outcomes.