Modeling the Role of Negative Cooperativity in Metabolic Regulation and Homeostasis

A significant proportion of enzymes display cooperativity in binding ligand molecules, and such effects have an important impact on metabolic regulation. This is easiest to understand in the case of positive cooperativity. Sharp responses to changes in metabolite concentrations can allow organisms to better respond to environmental changes and maintain metabolic homeostasis. However, despite the fact that negative cooperativity is almost as common as positive, it has been harder to imagine what advantages it provides. Here we use computational models to explore the utility of negative cooperativity in one particular context: that of an inhibitor binding to an enzyme. We identify several factors which may contribute, and show that acting together they can make negative cooperativity advantageous.     

Control ofThrips tabaci [Thysanoptera: Thripidae] on glasshouse cucumber using large introductions of predatory mitesAmblyseius barkeri [Acarina: Phytoseiidae]

The phytoseiid miteAmblyseius barkeri (Hughes) (=Amblyseius mckenziei Sch. & Pr.) was used for biological control ofThrips tabaci Lind. in 7 commercial glasshouses with cucumber (a total of 5780 m²). Predatory mites were introduced 3–4 times in densities ranging from 40 to 300/m² at each release. In 6 of the 7 glasshouses, control of thrips was satisfactory throughout the growing season. Thrips densities were kept below 15 individuals per leaf. In 1 glasshouse, thrips damage was seen on the fruits at densities of 25 thrips per leaf, but the thrips population was quickly reduced and remained at low densities for the next 3 months.      

Highly regioselective hydrolysis of tricarballylates (“retro-fats”) and citrates by subtilisin

Trimethyl and triethyl esters of tricarballylic acid and citric acid were hydrolysed with porcine liver esterase(PLE) to the isomeric diesters. In all cases the hydrolysis took place with poor regioselectivity (maximum 50% excess). However, the hydrolysis of trimethyl and triethyl esters of tricarballylic acid and of the triethyl ester of citric acid with subtilisin was absolutely regioselective and the symmetric 1,5-diester was obtained.     

Construction of immunogens for synthetic malaria vaccines

The immunogenicity of a peptide consisting of eight repeats of the tetrapeptide sequence NANP (Asn-Ala-Asn-Pro) contained in the circumsporozoite protein of Plasmodium falciparum was investigated in mice under different modes of presentation. This peptide was able to produce biologically active antibodies when administered with adjuvant and linked to a protein carrier. However, a (NANP) peptide polymerized by carbodiimide was found to be immunogenic in the absence of protein carrier in H-2b mice. In contrast, the (NANP)8 peptide polymerized by glutaraldehyde was not immunogenic in the same strain. Furthermore, the efficacy of murabutide in saline, as an immunological adjuvant, was compared to the efficacy of Freund's complete adjuvant.     

Oxidative destruction of DNA by the adriamycin-iron complex

The 2:1 adriamycin-Fe(III) complex is able to bind to DNA and to catalyze its oxidative destruction. The binding of the drug-metal complex to DNA is indicated by characteristic spectral changes which are different from those seen with adriamycin intercalation and by the propensity of the drug-metal complex to precipitate DNA. Furthermore, intercalated adriamycin appears not to be available for iron binding. The resulting ternary complex is quite stable: it is not disrupted by incubation in the presence of EDTA and can be isolated by using Sephadex G-50 column chromatography. Disruption of the ternary complex requires vigorous conditions (extraction with phenol at 60 degrees C). The adriamycin-iron complex in free solution has the capacity to catalyze the reduction of oxygen by thiols. The DNA-bound drug-metal complex preserves this capacity over a wide range of complex/DNA ratios. As a consequence of this thiol-dependent oxygen reduction, DNA is cleaved. This thiol-dependent DNA cleavage has been shown to require hydrogen peroxide as an intermediate product. These results have led us to propose that the thiol-dependent DNA cleavage reaction has two stages involving (1) reduction of oxygen leading to hydrogen peroxide and then (2) peroxide-dependent DNA cleavage. An unusual property of this reaction is that the cleavage is not random but gives rise to a defined 2300 base pair fragment.     

Teaching of Fertility Regulation in Medical Schools: A Survey in the United States and Canada, 1964

Fertility regulation is taught didactically in 82 of 94 medical school departments of obstetrics and gynecology in the United States and Canada, but students are given clinical experience in only 59 medical schools, according to a survey conducted in 1964 by a committee of the American Public Health Association. Legal prohibitions impeded teaching in 1964 in two States and in all of Canada. Nearly all schools teach that help with fertility regulation should be offered for medical and socioeconomic stress, and most teach that it should be offered routinely in premarital counselling and in the postpartum period, but only two-thirds teach that this help should be given to unmarried adults and only one-third teach that any person requesting help with fertility regulation should receive it.     

A Study of the Chronic Effects of Insecticides in Man

Signs of possible chronic intoxication due to insecticides were sought among 441 apple-growers. A group of 170 persons living in the same environment and 162 other persons having no contact with insecticides were used as controls. It was the first attempt to determine signs of chronic intoxication by organic phosphate and chlorinated hydrocarbon insecticides. The greater incidence of leukopenia and of neurologic manifestations found among the subjects suggest that insecticides may have some chronic effects in man. This assumption is reinforced by the similarities in the findings between the subjects and the environments, and by the parallelism between the duration of exposure to insecticides and the number of affected subjects. The repetition of this study at five-year intervals seems desirable until a sufficient number of apple-growers have been studied who have been exposed to large doses of insecticides for 10, 15 or 20 years.