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PubMed2005

Differential selectivity of hyaluronidase inhibitors toward acidic and basic hyaluronidases.

Hyaluronidase (HAase), a class of enzymes which degrade hyaluronic acid (HA), are involved in the spread of infections/toxins, ovum fertilization, and cancer progression. Thus, HAase inhibitors may have use in disease treatments. We evaluated 21 HAase inhibitors against HYAL-1, testicular, honeybee, and Streptomyces HAases. Among these inhibitors, polymers of poly (styrene-4-sulfonate) (PSS) (i.e., molecular weight 1400-990,000 or PSS 1400-PSS 990,000) and O-sulfated HA (sHA) derivatives (sHA2.0, 2.5, and 2.75) were the most effective. HYAL-1 and bee HAases were the most sensitive, followed by testicular HAase; Streptomyces HAase was resistant to all inhibitors, except PSS 990,000 and VERSA-TL 502 (i.e., PSS 10(6) dalton). The length of the PSS polymer determined their potency (e.g., IC50 for HYAL-1, PSS 990,000: 0.0096 microM; PSS 210 no inhibition; IC50 for testicular HAase, PSS 990,000: 0.042 microM; PSS 210 no inhibition). The presence, but not the number, of sulfate groups on the sHA molecule determined its potency (e.g., IC50 for HYAL-1: sHA2.0, 0.019 microM; sHA2.75, 0.0083 microM). Other known HAase inhibitors, such as gossypol, sodium-aurothiomalate, 1-tetradecane sulfonic acid, and glycerrhizic acid, were not effective. Both PSS and sHA inhibited HAases by a mixed inhibition mechanism (i.e., competitive + uncompetitive) and were 5- to 17-fold better as uncompetitive inhibitors than as competitive inhibitors. These results demonstrate that HAase inhibitors show selectivity toward the different types of HAases, which could be exploited to inhibit specific HAases involved in a variety of pathophysiologic conditions.

Animals↗
PubMedDate not supplied

Membrane binding and transport of N-aminoethyl-1,2-diamino ethane (dien) and N-aminopropyl-1,3-diamino propane (propen) by rat liver mitochondria and their effects on membrane permeability transition.

This investigation is aimed at defining the structural requirements for aliphatic polyamines to interact with mitochondrial binding sites, which are relevant for the regulation of the permeability transition and for mitochondrial polyamine uptake. The triamines N-aminoethyl-1,2-diaminoethane (dien) and N-aminopropyl-1,3-diaminopropane (propen), both symmetric polyamines, are accumulated to differing extents by an energy-dependent mechanism in liver mitochondria. Propen is also able completely to inhibit the permeability transition of mitochondria, induced by Ca2+ plus phosphate, with the same efficacy as the asymmetric ubiquitary triamine spermidine, whereas dien fails to exhibit this effect. The competitive inhibition of both triamines on spermidine transport demonstrates that they bind to the same site(s) of this polyamine and exploit its transport system. The binding of dien and propen to mitochondrial membrane was studied by applying a thermodynamic model of ligand-receptor interactions developed both for equilibrium and far-from-equilibrium binding processes. Results show the presence of two mono-coordinated binding sites, S1 and S2, for propen, and one monocoordinated binding site for dien, all exhibiting high capacity and low affinity. Comparisons of the binding parameters of these polyamines with those of other natural polyamines reveal that, besides flexibility and hydrophilicity, as previously suggested, protonation of the imino group and the symmetry of the molecules for S1, and the presence of an aminobutyl group for S2, also contribute to the polyamine interactions observed in the two sites.

Animals↗
PubMed2005

Crown allometry and growing space efficiency of Norway spruce (Picea abies [L.] Karst.) and European beech (Fagus sylvatica L.) in pure and mixed stands.

In pure and mixed stands of Norway spruce ( Picea abies [L.] Karst.) and European beech ( Fagus sylvatica L.) we have analyzed crown allometry and growing space efficiency at the tree level and have scaled this from tree level to stand level production. Allometry is quantified by the ratio A between the relative growth rates of laterally and vertically oriented tree dimensions. Efficiency parameters, EOC for efficiency in space occupation, EEX for efficiency in space exploitation, and EBI for efficiency in biomass investment, were evaluated, based on quantity and quality of growing space and were measured using crown size and competition index. The evaluation reveals why pure stands of spruce are preferred by foresters, even though the natural vegetation would be dominated by beech. Spruce occupies its share of resources intensively by means of tightly packed pillar-like crowns, whereas beech seizes resources extensively by means of a multi-layered, veil-like canopy. With a given relative biomass increment, beech achieves a 57 % higher increment in crown projection area and a 127 % higher increment in height due to its particular capacity of lateral and vertical expansion. Beech trees are approximately 60 % more efficient in space occupation than spruce trees, however, on average, they are about 70 % less efficient in space exploitation. As a vertical fast growing tree, spruce is efficient in space exploitation under constant conditions, but far more susceptible to disturbances and less well equipped to overcome them when compared with beech. Beech is weaker in terms of space exploitation, while being superior in space occupation, where it encircles competitors and fills gaps after disturbances, which is a successful long-term strategy. A mixture of the two species reduces stand level production by 24 % in comparison to a pure spruce stand, however, when considering enhanced stabilization of the whole stand and risk distribution in the long term, the mixed stand may exceed the production level of pure spruce stands. EEX reflects a strong ontogenetic drift and competition effect that should be considered when scaling from tree to stand level production.

Ecosystem↗
PubMed2003

Variation in the outcome of population interactions: bifurcations and catastrophes.

The nature of the association between two species may vary depending on population abundances, age or size of individuals, or environmental conditions. Interactions may switch between beneficial and detrimental depending on the net balance of costs and benefits involved for each species. We study the repercussion of the ecological setting on the outcomes of conditional or variable interactions by means of a model that incorporates density-dependent interaction coefficients; that is, interaction alpha-functions. These characterize the responsiveness and sensitivity of the association to changes in partner's abundance, and can take positive and negative values. Variable outcomes - and transitions between them - are categorized as homeo- or allo-environmental, that is, occurring under the same ecological setting, or not, respectively. Bifurcation analyses show that these dynamics are moulded by ecological factors that are: intrinsic to the nature of the association (concerning the sensitivity of the interaction), and extrinsic to the association itself (the quality of the environment referred to each species alone). The influence of these factors may be conflicting; consequently, the dynamics involve catastrophic events. In a facultative variable association, stable coexistence is expected when environmental conditions are adverse; otherwise, the exclusion of one species is the likely outcome. Remarkable situations as the switching of victim-exploiter roles illustrate the theoretical perspective.

Animals↗
PubMed1985

A unique type of cyclic AMP-binding protein of Trypanosoma cruzi.

On centrifugation on sucrose density gradients, the cyclic AMP-receptor protein of Trypanosoma cruzi was clearly resolved from the type II regulatory subunit of protein kinase from bovine heart (S20,W = 8.25 and 4.1, respectively). The binding of cyclic [3H]AMP to these two proteins was affected to different extents by several cyclic AMP analogues. Such differences between the cyclic AMP-receptor protein of T. cruzi and cyclic AMP-binding proteins of other eukaryotes might be exploitable by chemotherapy.

Animals↗
PubMed1996

Exploiter-mediated coexistence and frequency-dependent selection in a numerical model of biodiversity.

The key feature of the Daisyworld approach is to explicitly model feedbacks between the competitive dynamics of a planetary biota (daisies with different albedos) and the planet's climate, namely its surface temperature. Self-regulation of surface temperature and stable population dynamics are striking emergent properties of this system, despite increasing energy output from the model's sun. In this paper we attempt to perturb Daisyworld by introducing herbivores endowed with one of four strategies for feeding on daisies in a system rich in daisy diversity, and find that the herbivores only moderately diminish the temperature regulating abilities of the system. Furthermore, we find that the precise trajectory of the system's temperature regulation depends critically on which daisy species the herbivore allows to co-exist, thereby revealing that climate and patterns of biodiversity are highly interrelated in this model, and, possibly, in the real world.

Animals↗
PubMed1993

Specific disengagement of cell-bound anti-LAM-1 (anti-L-selectin) antibodies by aurintricarboxylic acid.

Brief treatment of human peripheral blood lymphocytes with the potential anti-HIV compound aurintricarboxylic acid (ATA) prompts the selective release of already bound L-selectin-specific anti-Leu8 and anti-LAM1-1 antibodies from the cells. Two other anti-LAM1 antibodies, anti-LAM1-3 and anti-LAM1-5 stay antigen-bound at the same time. Interestingly, the ATA-sensitive anti-Leu8 strongly competes with the ATA-resistant anti-LAM1-3 for binding. Photobleaching fluorescence resonance energy transfer (pFRET) measurements on flow-sorted cells suggests that these two antibodies compete for the same epitope, while anti-LAM1-5-FITC and anti-Leu8-PE bind to distinct sites, although they also compete for binding. Combining the data on competition, pFRET and ATA effect, we suggest that the ATA sensitive anti-Leu8 and resistant anti-LAM1-3 bind to overlapping but non-identical epitopes. This remarkably specific effect may be exploited for designing anti-inflammatory drugs that modulate leukocyte adhesion.

Antigen-Antibody Reactions↗
PubMed2006

From genomes to systems: the path with yeast.

Metabolic Control Analysis (MCA) is a conceptual and mathematical formalism that models the relative contributions of individual effectors in a pathway to both the flux through the pathway and the concentrations of individual intermediates within it. To exploit MCA in an initial Systems Biology analysis of the eukaryotic cell, two categories of experiments are required. In category 1 experiments, flux is changed and the impact on the levels of the direct and indirect products of gene action is measured. We have measured the impact of changing the flux on the transcriptome, proteome and metabolome of Saccharomyces cerevisiae. In this whole-cell analysis, flux equates to growth rate. In category 2 experiments, the levels of individual gene products are altered, and the impact on the flux is measured. We have used competition analyses between the complete set of heterozygous yeast deletion mutants to reveal genes encoding proteins with high flux control coefficients. These genes may be exploited, in a top-down analysis, to build a coarse-grained model of the eukaryotic cell, as exemplified by yeast. More detailed modelling requires that 'natural' biological systems be identified. The combination of flux balance analysis with both genetics and metabolomics in the definition of metabolic systems is discussed.

Computational Biology↗
PubMed2000

Development of a cyanovirin-N-HIV-1 gp120 binding assay for high throughput screening of natural product extracts by time-resolved fluorescence.

The unique, high-affinity binding of cyanovirin-N (CV-N), a potent anti-human immunodeficiency virus (HIV) protein, to the HIV envelope glycoprotein gp120, was exploited to develop an HTS assay in an attempt to discover small-molecule mimetics of CV-N. A competition binding assay was developed using CV-N labeled with europium (Eu(3+)). The labeling protocol did not significantly alter the gp120 binding properties or the antiviral activity of CV-N. This report describes the assay development, validation, and results of screening a large library of aqueous and organic natural product extracts. The extracts were incubated with immobilized recombinant gp120 in 96-well plates prior to the addition of Eu(3+)-labeled CV-N. Following a wash step, bound CV-N was measured by dissociation-enhanced time-resolved fluorometry of Eu(3+). The assay proved to be robust, rapid, and reproducible, and was used to screen over 50,000 natural product extracts, and has resulted in the identification of several aqueous natural product extracts that inhibited CV-N-gp120 binding and also had anti-HIV activity.

Anti-HIV Agents↗
PubMed1990

The biology and medicine of sailing.

The physiological demands of sailing are highly specific, varying with wind conditions, type of craft, and crew position. In a light wind, the only physiological variable yet shown to influence performance is the resting blood sugar. Under high wind conditions, the skipper should be light (less than 60 kg), but crew members should be heavy (greater than 80 kg). Height does not seem a great advantage to crew, possibly because they then lack the muscular strength to exploit the added leverage. Muscle strength, endurance and a tolerance of anaerobic metabolism are all desirable attributes of crew, and competitive performance can be improved by a winter training programme that develops these aspects of muscle performance in the abdominal and thigh regions. The skipper must meet intense and prolonged cerebral demands in the face of periodic isometric work; performance may thus be helped by ingestion of carbohydrate over the course of a race. The ability to sustain isometric contractions in the 'hiking' position may also be improved if the muscles are preloaded with glycogen. The combination of a heavy body build, above average age for an athlete and sustained isometric contraction probably makes the yachting enthusiast vulnerable to ischaemic heart disease. Advisors to a sailing team must further take account of the risks presented by immersion in cold water, loss of sleep, circadian variations of performance over an event, and problems of motion sickness in rough weather.

Circadian Rhythm↗
PubMed1975

Inhibition of Bacillus subtilis deoxyribonucleic acid polymerase III by phenylhydrazinopyrimidines. Demonstration of a drug-induced deoxyribonucleic acid-enzyme complex.

The interaction of 6-(phenylhydrazino)-pyrimidines and Bacillus subtilis DNA polymerase III was examined in experiments exploiting agarose gel filtration of mixtures of drug, DNA, and purified enzyme. 6-(p-Hdroxyphenylhydrazino)-uracil and 6-(p-hydroxyphenylhydrazino)-isocytosine were used as model inhibitors; both drugs induced the formation of a distinct polymerase-DNA complex. Comples formation required the inhibitory, hydrazino forms of the drugs and a form of DNA suitable as a primer-template for DNA polymerase III. dGTP and dATP, which respectively, competitively antagonize the inhibitory effects of the uracil and isocytosine derivatives, antagonized in an equally specific manner the respective capacities of these compounds to induce complex formation. Experiments exploiting both wild type and drug-resistant, mutant polymerases indicated that drug concentrations required for the half-maximal induction of complex formation were nearly identical with the apparent inhibitor constants (Ki) determined independently by kinetic analysis of enzyme inhibition. These results and those of experiments exploiting defined homopolymer-oligomer combinations as template-primers support a model of inhibitor action in which arylhydrazinopyrimidine forms a reversible, ternary complex with the enzyme and an appropriate timplate pyrimidine residue in an area adjacent to the 3-hydroxyl primer terminus.

Bacillus subtilis↗
PubMed2002

GPCR drug discovery through the exploitation of allosteric drug binding sites.

G-protein-coupled receptors (GPCRs) represent the most important class of drug targets both in terms of therapeutic benefit and pharmaceutical sales. The majority of current GPCR drugs have been identified in ligand binding assays and interact with the receptor in a competitive manner with the natural ligand. There is increasing evidence that it is possible to identify GPCR agonist and antagonist ligands that do not interact at the natural ligand binding site, rather such compounds interact elsewhere on the receptor to modulate receptor activity. This finding allows the possibility that there may be many as yet uncharacterized drug binding sites within the GPCR that could be exploited for therapeutic intervention. The characterization of such "allosteric" ligand interaction sites, following the identification of molecules capable of interacting at these sites, would be expected to lead to the identification of drug molecules with improved selectivity and efficacy. Such activities may enable the identification of selective ligands at GPCRs for which competitive natural ligand binding screens have been unsuccessful. In this manuscript we review known examples of GPCR allosteric ligands, the functional assay technologies that are being employed to identify further ligands of this type, and the potential benefit that may result from the identification of such ligands.

Allosteric Site↗
PubMed1998

Competitive reversals inside ecological reserves: the role of external habitat degradation.

Habitat degradation is the slow--and often subtle--deterioration in habitat quality that accompanies human activities through increases in road density, pesticide use, hunting pressure, etc. Such degradation is of particular concern in fragmented habitats where economic or jurisdictional boundaries rather than ecological ones determine the level of exploitation adjoining habitat patches endure. To examine the consequences habitat degradation might have on species interactions, we posited a patch of pristine habitat surrounded by "matrix" habitat whose degradation level was variable. Using a coupled pair of diffusive Lotka-Volterra competition equations with Robin (mixed) boundary conditions, we modeled the dynamics of two competing species inhabiting the pristine patch and incorporated matrix degradation through a tunable "hostility" parameter representing species' mortality rates in the matrix. We found that the numerical range of competition coefficients over which one species is the competitive dominant and the other inferior may grow or shrink as matrix quality deteriorates. In some cases, degradation of the exterior habitat would bring about a complete competitive reversal inside the preserve. This result, wherein a formerly inferior species supplants a formerly dominant one--even inside the "protected" remnant patch itself--has policy implications for both nature reserve design and management of human activities outside park boundaries.

Animals↗
PubMed2003

Structures of P. falciparum PfPK5 test the CDK regulation paradigm and suggest mechanisms of small molecule inhibition.

Plasmodium falciparum cell cycle regulators are promising targets for antimalarial drug design. We have determined the structure of PfPK5, the first structure of a P. falciparum protein kinase and the first of a cyclin-dependent kinase (CDK) not derived from humans. The fold and the mechanism of inactivation of monomeric CDKs are highly conserved across evolution. ATP-competitive CDK inhibitors have been developed as potential leads for cancer therapeutics. These studies have identified regions of the CDK active site that can be exploited to achieve significant gains in inhibitor potency and selectivity. We have cocrystallized PfPK5 with three inhibitors that target such regions. The sequence differences between PfPK5 and human CDKs within these inhibitor binding sites suggest that selective inhibition is an attainable goal. Such compounds will be useful tools for P. falciparum cell cycle studies, and will provide lead compounds for antimalarial drug development.

Animals↗
PubMed1999

Consumer information and competition between nonprofit and for-profit nursing homes.

This paper develops implications of Arrow's hypothesis that nonprofit organizations are prevalent in health care because of quality uncertainty. The model analyzes the ability of nonprofits to mitigate market failures created by asymmetric information in an environment characterized by potential competition from both explicitly for-profit firms and for-profits in disguise (profit-motivated firms who obtain nonprofit status in order to exploit the perceived trustworthiness of the nonprofit sector). Under certain conditions, it is shown that nonprofit status can serve as a credible signal of quality and that nonprofits can decrease the underprovision of quality both by providing high quality services and indirectly via a spillover effect on quality in the for-profit sector. Applicability to long-term care and implications for empirical research and policy towards nonprofits in health care are discussed.

Benchmarking↗
PubMed1989

Molecular approaches to problems in biogeochemical cycling.

By using molecular probe techniques in combination with activity and expression measurements, it is possible to estimate bacterial populations in nature. This information can be exploited to study a number of important environmental problems. For instance, it will be possible to study ecosystem perturbation and microbial competition, by altering an ecosystem or a laboratory model of an ecosystem, and assessing corresponding changes in key activities and populations. In addition, regulation of activities in the laboratory can be compared to the response of activities and populations in situ, to develop an understanding of the key parameters that control these processes in nature. These types of approaches are important steps for determining the role of microorganisms in geochemical cycling, in both specific habitats and on a global basis.

Antigens, Bacterial↗
PubMedDate not supplied

Structure-based design of cyclin-dependent kinase inhibitors.

The eukaryotic cell cycle is tightly regulated by the sequential activation and deactivation of the cyclin-dependent kinases (CDKs). Aberrant CDK activity is a common defect in human tumours, and clinically, it often confers a poor prognosis. The strong genetic link between CDKs and the molecular pathology of cancer has provided the rationale for developing small-molecule inhibitors of these kinases. X-ray crystallography recently has revealed the molecular details of CDK regulation by cyclin binding and phosphorylation, and by complex formation with endogenous inhibitors. Knowledge of the structure of CDK2 has been key in driving the design and development of a large number of ATP competitive inhibitors. Crystallography has revealed that the ATP-binding site of CDK2 can accommodate a number of diverse molecular frameworks, exploiting various sites of interaction. In addition, residues outside the main ATP-binding cleft have been identified that could be targeted to increase specificity and potency. These results suggest that it may be possible to design pharmacologically relevant ligands that act as specific and potent inhibitors of CDK activity. We provide a review of the current state of the field, along with an overview of our current inhibitor design studies.

CDC2-CDC28 Kinases↗
PubMed2002

Does natural selection organize ecosystems for the maintenance of high productivity and diversity?

Three types of evidence suggest that natural ecosystems are organized for high productivity and diversity: (i) changes not previously experienced by a natural ecosystem, such as novel human disturbances, tend to diminish its productivity and/or diversity, just as 'random' changes in a machine designed for a function usually impair its execution of that function; (ii) humans strive to recreate properties of natural ecosystems to enhance productivity of artificial ones, as farmers try to recreate properties of natural soils in their fields; and (iii) productivity and diversity have increased during the Earth's history as a whole, and after every major biotic crisis. Natural selection results in ecosystems organized to maintain high productivity of organic matter and diversity of species, just as competition among individuals in Adam Smith's ideal economy favours high production of wealth and diversity of occupations. In nature, poorly exploited energy attracts more efficient users. This circumstance favours the opening of new ways of life and more efficient recycling of resources, and eliminates most productivity-reducing 'ecological monopolies'. Ecological dominants tend to be replaced by successors with higher metabolism, which respond to more stimuli and engage in more varied interactions. Finally, increasingly efficient predators and herbivores favour faster turnover of resources.

Animals↗