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PubMed1989

A new strategy for the generation of catalytic antibodies.

The high binding affinity and specificity of antibodies for a wide range of ligands has recently been exploited in the generation of catalysts for acyl-transfer reactions, carbon-carbon bond forming and carbon-carbon bond cleaving reactions. In addition, a number of strategies are emerging for the generation of catalytic antibodies including transition state stabilization, catalysis by approximation, and the introduction of catalytic groups or cofactors into antibody combining sites. An important goal in the design of catalytic antibodies is the development of general rules relating hapten structure to the corresponding catalytic groups in the antibody combining site. We report here that electrostatic interactions between a hapten and the complementary antibody can be exploited to generate catalytic amino-acid side chains in an antibody-combining site. The antibody-catalysed reaction, a beta-elimination reaction, exhibits saturation kinetics, substrate specificity, competitive inhibition by hapten, and specific inactivation by a reagent that modifies carboxylate residues.

Antibodies↗

PubMed2003

Importance of Gram-positive naphthalene-degrading bacteria in oil-contaminated tropical marine sediments.

AIMS: The aim of this study was to isolate, characterize and evaluate the importance of naphthalene-degrading bacterial strains from oil-contaminated tropical marine sediments. METHODS AND RESULTS: Three Gram-positive naphthalene-degrading bacteria were isolated from oil-contaminated tropical intertidal marine sediments by direct isolation or enrichment using naphthalene as the sole source of carbon and energy. Bacillus naphthovorans strain MN-003 can also grow on benzene, toluene, xylene and diesel fuel while Micrococcus sp. str. MN-006 can also grow on benzene. Staphylococcus sp. str. MN-005 can only degrade naphthalene and was not able to use the other aromatic hydrocarbons tested. Strain MN-003 possessed the highest maximal specific growth rate with naphthalene as sole carbon source. An enrichment culture fed with naphthalene as sole carbon source exhibited a significant increase in the relative abundances of the three isolates after 21 days of incubation. The three isolates constituted greater than 69% of the culturable naphthalene-degrading microbial community. Strain MN-003 outcompeted and dominated the other two isolates in competition studies involving batch cultures inoculated with equal cell densities of the three isolates and incubated with between 1 and 10 mg l-1 of naphthalene. CONCLUSIONS: Three Gram-positive naphthalene-degrading bacteria were successfully isolated from oil-contaminated tropical marine sediments. Gram-positive bacteria might play an important role in naphthalene degradation in the highly variable environment of oil-contaminated tropical intertidal marine sediments. Among the three isolates, strain MN-003 has the highest maximal specific growth rate when grown on naphthalene, and outgrew the other two isolates in competition experiments. SIGNIFICANCE AND IMPACT OF THE STUDY: This research will aid in the development of bioremediation schemes for oil-contaminated marine environments. Strain MN-003 could potentially be exploited in such schemes.

Bacillus↗

PubMed2002

Competition among cooperators: altruism and reciprocity.

Levine argues that neither self-interest nor altruism explains experimental results in bargaining and public goods games. Subjects' preferences appear also to be sensitive to their opponents' perceived altruism. Sethi and Somanathan provide a general account of reciprocal preferences that survive under evolutionary pressure. Although a wide variety of reciprocal strategies pass this evolutionary test, Sethi and Somanthan conjecture that fewer are likely to survive when reciprocal strategies compete with each other. This paper develops evolutionary agent-based models to test their conjecture in cases where reciprocal preferences can differ in a variety of games. We confirm that reciprocity is necessary but not sufficient for optimal cooperation. We explore the theme of competition among reciprocal cooperators and display three interesting emergent organizations: racing to the "moral high ground," unstable cycles of preference change, and, when we implement reciprocal mechanisms, hierarchies resulting from exploiting fellow cooperators. If reciprocity is a basic mechanism facilitating cooperation, we can expect interaction that evolves around it to be complex, non-optimal, and resistant to change.

Altruism↗

PubMed2001

Recent developments in the employment and retirement of older workers in Germany.

Against a background of an aging population, rising social security costs, and foreseeable labor and skill shortages, there have been public policy changes affecting older workers in Germany. Labor-market related initiatives aim at an increase of labor force participation among this group. Enterprise-related, active age-management strategies aim at improving occupational conditions of aging workers. In this context, prolonging the working life must be seen as one option of "active aging." Another view of the current retirement discussion is the question of how the unused potential of Germany's younger, early-retired seniors can be exploited. Active aging has become a social duty nowadays, with the intention that older persons contribute to society to avoid generational conflicts. In the future, active aging will preserve the competitiveness of enterprises and of the entire economy, despite an aging labor force. But gerontological research points out that different options to carry out individual life plans of active aging are also required. This article reviews the changes in public policies towards older workers and includes the findings of a project that illustrates good practice to combat age barriers in the labor world.

Aged↗

PubMed1998

Building a quality future.

How can healthcare leaders stay ahead of the curve? What can they do to see what the future holds and to secure a place for their employees and their organizations? They must begin doing today what they need to do to survive tomorrow. Furthermore, they must take wise action today or there will be no tomorrow. This article looks into the future and connects it with what we must see and do today. The article begins with a glimpse of the future and with an exploration of what people really want from health and healthcare. Next, it examines what appear to be inexorable megatrends and healthcare trends that are sweeping through society. This leads us to consider the quality and value imperatives that must be faced to secure a stake in the healthcare delivery. We will discuss a model for managing care for individual patients and small populations by focusing on where patients, populations, and caregivers meet--at the front lines of patients care. We conclude with some advice on how to build sustainable organizations by exploiting the inevitable.

Delivery of Health Care↗

PubMed2005

Genetic diversity and kinetic properties of Trypanosoma cruzi dihydroorotate dehydrogenase isoforms.

Dihydroorotate dehydrogenase (DHOD) is the fourth enzyme in the de novo pyrimidine biosynthetic pathway and is essential in Trypanosoma cruzi, the parasitic protist causing Chagas' disease. T. cruzi and human DHOD have different biochemical properties, including the electron acceptor capacities and cellular localization, suggesting that T. cruzi DHOD may be a potential chemotherapeutic target against Chagas' disease. Here, we report nucleotide sequence polymorphisms of T. cruzi DHOD genes and the kinetic properties of the recombinant enzymes. T. cruzi Tulahuen strain possesses three DHODgenes: DHOD1 and DHOD2, involved in the pyrimidine biosynthetic (pyr) gene cluster on an 800 and a 1000 kb chromosomal DNA, respectively, and DHOD3, located on an 800 kb DNA. The open reading frames of all three DHOD genes are comprised of 942 bp, and encode proteins of 314 amino acids. The three DHOD genes differ by 26 nucleotides, resulting in replacement of 8 amino acid residues. In contrast, all residues critical for constituting the active site are conserved among the three proteins. Recombinant T. cruzi DHOD1 and DHOD2 expressed in E. coli possess similar enzymatic properties, including optimal pH, optimal temperature, Vmax, and Km for dihydroorotate and fumarate. In contrast, DHOD3 had a higher Vmax and Km for both substrates. Orotate competitively inhibited all three DHOD enzymes to a comparable level. These results suggest that, despite their genetic variations, kinetic properties of the three T. cruziDHODs are conserved. Our findings facilitate further exploitation of T. cruzi DHOD inhibitors, as chemotherapeutic agents against Chagas' disease.

Animals↗

PubMed2002

Biochemical and preliminary crystallographic characterization of the vitamin D sterol- and actin-binding by human vitamin D-binding protein.

Vitamin D-binding protein (DBP), a multi-functional serum glycoprotein, has a triple-domain modular structure. Mutation of Trp145 (in Domain I) to Ser decreased 25-OH-D(3)-binding by 80%. Furthermore, recombinant Domain I (1-203) and Domain I + II (1-330) showed specific and strong binding for 25-OH-D(3), but Domain III (375-427) did not, suggesting that only Domains I and II might be required for vitamin D sterol-binding. Past studies have suggested that Domain III is independently capable of binding G-actin. We exploited this apparently independent ligand-binding property of DBP to purify DBP-actin complex from human serum and rabbit muscle actin by 25-OH-D(3) affinity chromatography. Competitive (3)H-25-OH-D(3) binding curves for native DBP and DBP-actin complex were almost identical, further suggesting that vitamin D sterol- and actin-binding activities by DBP might be largely independent of each other. Trypsin treatment of DBP produced a prominent 25 kDa band (Domain I, minus 5 amino acids in N-terminus), while actin was completely fragmented by such treatment. In contrast, tryptic digestion of purified DBP-actin complex showed two prominent bands, 52 (DBP, minus 5 amino acids in the N-terminus) and 34 kDa (actin, starting with amino acid position 69) indicating that DBP, particularly its Domains II and III were protected from trypsin cleavage upon actin-binding. Similarly, actin, except its N-terminus, was also protected from tryptic digestion when complexed with DBP. These results provided the basis for our studies to crystallize DBP-actin complex, which produced a 2.5 A crystal, primitive orthorhombic with unit cell dimensions a=80.2A, b=87.3A, and c=159.6A, P2(1)2(1)2(1) space group, V(m)=2.9. Soaking of crystals of actin-DBP in crystallization buffer containing various concentrations of 25-OH-D(3) resulted in cracking of the crystal, which was probably a reflection of a ligand-induced conformational change in the complex, disrupting crystal contacts. In conclusion, we have provided data to suggest that although binding of 25-OH-D(3) to DBP might result in discrete conformational changes in the holo-protein to influence actin-binding, these binding processes are largely independent of each other in solution.

Actins↗

PubMed2002

A case study of human migration and the sea cucumber crisis in the Galapagos Islands.

The sea cucumber fishing crisis in Galapagos is an example of the potential consequences of rapid migration, growing economic competition, and weak regulatory mechanisms. In a short period of time sea cucumber fishing has become the most inflammatory issue in the Galapagos. The key factors that allowed for the efficient exploitation of the new resource were not the fishermen themselves but rather the new fishing techniques and access to credit and markets. This suggests that the annual sea cucumber crisis is due to factors more complex than simply more fishermen generating greater sea cucumber catches. This paper examines census data and fisher registries to analyze population growth in the islands. A public opinion survey is used to determine the population's attitudes toward sea cucumber fishing and regulations. Qualitative interviews explore the history of the sea cucumber boom. Information from the sea cucumber monitoring program provides estimates for the annual sea cucumber catches.

Animals↗

PubMed1990

N-myristyl-Lys-Arg-Thr-Leu-Arg: a novel protein kinase C inhibitor.

In view of the critical role that the Ca2+- and phospholipid-dependent enzyme protein kinase C (PKC) plays in mediating proliferative responses to a number of growth factors, hormones, and tumor promoters, it is thought that selective PKC inhibitors may provide a new class of antiproliferative drugs. Established PKC inhibitors include three major classes of agents: agents that compete with the substrate ATP, agents that compete with the protein substrate, and agents that both compete with ATP and interact with the cofactor phosphatidylserine (PS). In this report, we have characterized the interactions between PKC and N-myristyl-Lys-Arg-Thr-Leu-Arg, a myristylated analogue of a synthetic peptide substrate of PKC. We determined that the myristylated peptide was a novel PKC inhibitor that interacted with PS as well as competed with the protein substrate of PKC. The inhibitory activity of the peptide was conferred by myristylation. We found that the myristylated peptide antagonized Ca2+- and PS-activated PKC with an IC50 of 75 microns, whereas the nonmyristylated peptide lacked this inhibitory activity. A fully active, Ca2+- and PS-independent catalytic fragment of PKC can be generated by limited proteolysis. Although the myristylated peptide was a very poor PKC substrate, this peptide inhibited the catalytic fragment of PKC by apparent competition with the phosphoacceptor substrate histone IIIS with an IC50 of 200 microM, whereas the nonmyristylated peptide showed no inhibitory activity against the catalytic fragment. Thus, the myristylated peptide may serve as a model for the development of selective PKC inhibitors, because its inhibitory mechanism exploits the substrate specificity of PKC, as well as the novel regulation of the enzyme. Furthermore, since endogenous PKC substrates include acylated proteins, the observations that we report here concerning a myristylated synthetic peptide suggest that acylation of proteins may be important in the regulation of PKC activity in vivo.

Amino Acid Sequence↗

PubMed2003

Diversity of core antigen epitopes of hepatitis B virus.

Core antigen (cAg), the viral capsid, is one of the three major clinical antigens of hepatitis B virus. cAg has been described as presenting either one or two conformational epitopes involving the "immunodominant loop." We have investigated cAg antigenicity by cryo-electron microscopy at approximately 11-A resolution of capsids labeled with monoclonal Fabs, combined with molecular modeling, and describe here two conformational epitopes. Both Fabs bind to the dimeric external spikes, and each epitope has contributions from the loops on both subunits, explaining their discontinuous nature: however, their binding aspects and epitopes differ markedly. To date, four cAg epitopes have been characterized: all are distinct. Although only two regions of the capsid surface are accessible to antibodies, local clustering of the limited number of exposed peptide loops generates a potentially extensive set of discontinuous epitopes. This diversity has not been evident from competition experiments because of steric interference effects. These observations suggest an explanation for the distinction between cAg and e-antigen (an unassembled form of capsid protein) and an approach to immunodiagnosis, exploiting the diversity of cAg epitopes.

Cryoelectron Microscopy↗

PubMed1992

Four-amino acid segment in steroid 5 alpha-reductase 1 confers sensitivity to finasteride, a competitive inhibitor.

The 4-azasteroid 17 beta-(N-t-butyl)carbamoyl-4-aza-5 alpha-androst-1-en-3-one (finasteride) is 100-fold more potent as a competitive inhibitor of the rat NADPH:delta 4-3-oxosteroid-5-alpha- oxidoreductase (steroid 5 alpha-reductase) type 1 enzyme (Ki = 3-5 nM) than of the human type 1 enzyme (Ki greater than or equal to 300 nM). In this study, we exploit this differential sensitivity to map a major determinant of finasteride sensitivity in steroid 5 alpha-reductase. Chimeric steroid 5 alpha-reductase cDNAs composed of different combinations of rat and human exon sequences were created by genetic engineering, expressed in human embryonic kidney 293 cells, and assayed for their sensitivity to finasteride. Hybrid proteins containing sequences encoded by rat exon 1 were found to be as sensitive to finasteride as the parental enzyme. The exchange of progressively smaller protein segments encoded within exon 1 identified a tetrapeptide sequence (Val-Ser-Ile-Val) in the rat enzyme that conferred sensitivity to finasteride. The analogous sequence in the human enzyme (Ala-Val-Phe-Ala) conferred partial resistance to the drug. Finasteride was a competitive inhibitor of the native and all chimeric enzymes tested, suggesting that the tetrapeptide segments form a portion of the substrate-binding domain of steroid 5 alpha-reductase.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1988

Fast kinetics analysis of the peroxidatic reaction catalysed by horse liver alcohol dehydrogenase.

The kinetics of the enzymatic step of the peroxidatic reaction between NAD and hydrogen peroxide, catalysed by horse liver alcohol dehydrogenase (alcohol:NAD+ oxidoreductase, EC 1.1.1.1), has been investigated at pH 7 at high enzyme concentration. Under such conditions no burst phase has been observed, thus indicating that the rate-limiting step in the process, which converts NAD into Compound I, either precedes or coincides with the chemical step responsible for the observed spectroscopic change. Kinetic analysis of the data, performed according to a simplified reaction scheme suggests that the rate-limiting step is coincident with the spectroscopic (i.e., chemical) step itself. Furthermore, the absence of a proton burst phase indicates the proton release step does not precede the chemical step, in contrast with the case of ethanol oxidation. A kinetic effect of different premixing conditions on the reaction rate has been observed and attributed to the presence of NADH formed in the 'blank reaction' between NAD and residual ethanol tightly bound to alcohol dehydrogenase. A molecular mechanism for the enzymatic peroxidation step is finally proposed, exploiting the knowledge of the much better known reaction of ethanol oxidation. Inhibition of this reaction by NADH has been investigated with respect to H2O2 (noncompetitive, Ki about 10 microM) and to NAD (competitive, Ki about 0.7 microM). The effect of temperature on the steady-state reaction state (about 65 kJ/mol activation energy) has also been studied.

Alcohol Dehydrogenase↗

PubMed2004

Dissecting physiological roles of estrogen receptor alpha and beta with potent selective ligands from structure-based design.

The distinct roles of the two estrogen receptor (ER) isotypes, ERalpha and ERbeta, in mediating the physiological responses to estrogens are not completely understood. Although knockout animal experiments have been aiding to gain insight into estrogen signaling, additional information on the function of ERalpha and ERbeta will be provided by the application of isotype-selective ER agonists. Based on the crystal structure of the ERalpha ligand binding domain and a homology model of the ERbeta-ligand binding domain, we have designed steroidal ligands that exploit the differences in size and flexibility of the two ligand binding cavities. Compounds predicted to bind preferentially to either ERalpha or ERbeta were synthesized and tested in vitro using radio-ligand competition and transactivation assays. This approach directly led to highly ER isotype-selective (approximately 200-fold) and potent ligands. To unravel physiological roles of the two receptors, in vivo experiments with rats were conducted using the ERalpha- and ERbeta-selective agonists in comparison to 17beta-estradiol. The ERalpha agonist induced uterine growth, caused bone-protective effects, reduced LH and FSH plasma levels, and increased angiotensin I, whereas the ERbeta agonist did not at all or only at high doses lead to such effects, despite high plasma levels. It can thus be concluded that estrogen effects on the uterus, pituitary, bone, and liver are primarily mediated via ERalpha. Simultaneous administration of the ERalpha and ERbeta ligand did not lead to an attenuation of ERalpha-mediated effects on the uterus, pituitary, and liver parameters.

Amino Acid Sequence↗

PubMed1990

AIDS and its impact on medical work: the culture and politics of the shop floor.

AIDS, together with other institutional factors, is changing the "shop-floor" culture of house officers and students in urban, academic medical centers. These medical workers complained of powerlessness and exploitation prior to the epidemic, but they felt pride in scoring clinical coups and chagrin in their clinical defeats, characteristic of an adolescent sense of invulnerability. The HIV epidemic, dovetailing with the intensely competitive economic environment in medical settings, subjects house officers to increasingly demanding schedules, heightens their sense of powerlessness, and limits their sense of professional achievement. Fear of contagion, moreover, is erasing their perception of invulnerability.

Academic Medical Centers↗

PubMed2001

Moving upward in a downturn.

As the recent bursting of the new economy bubble has shown, business cycles are still wih us. The question, then, is, what executives should do to help their companies weather these downturns. As in so many instances, there are conventional approaches that appear to make sense in the short term. But while these approaches seem reasonable in the heat of the moment, they can eventually damage competitive positions and financial performance. Drawing on extensive research of Fortune 500 companies that have lived through industry downturns and economic recessions over the past two decades, Darrell Rigby, a director of Bain & Company, reveals how companies need to go against the grain of convention and exploit industry downturns to harness their unique opportunities for upward mobility. The author explains that every downturn goes through three phases. He examines each phase and shows how successful players navigate the huge waves of a downturn. Smart executives, he says, don't panic: they look bad news in the eye and institutionalize an approach to detecting storms. Rather than hedge their bets through diversification, they focus on their core businesses and spend to gain market share. They manage costs relentlessly during good times and bad. They keep a long-term view and strive to maintain the loyalty of employees, suppliers, and customers. And coming out of the downturn, they maintain momentum in their businesses to stay ahead of the competition they've already surpassed. Every industry will face periodic downturns of varying severity, says Rigby. But executives with the vision and ingenuity to take unconventional approaches can buoy their companies to new heights.

Commerce↗

PubMed2005

Learning and decision making in monkeys during a rock-paper-scissors game.

Game theory provides a solution to the problem of finding a set of optimal decision-making strategies in a group. However, people seldom play such optimal strategies and adjust their strategies based on their experience. Accordingly, many theories postulate a set of variables related to the probabilities of choosing various strategies and describe how such variables are dynamically updated. In reinforcement learning, these value functions are updated based on the outcome of the player's choice, whereas belief learning allows the value functions of all available choices to be updated according to the choices of other players. We investigated the nature of learning process in monkeys playing a competitive game with ternary choices, using a rock-paper-scissors game. During the baseline condition in which the computer selected its targets randomly, each animal displayed biases towards some targets. When the computer exploited the pattern of animal's choice sequence but not its reward history, the animal's choice was still systematically biased by the previous choice of the computer. This bias was reduced when the computer exploited both the choice and reward histories of the animal. Compared to simple models of reinforcement learning or belief learning, these adaptive processes were better described by a model that incorporated the features of both models. These results suggest that stochastic decision-making strategies in primates during social interactions might be adjusted according to both actual and hypothetical payoffs.

Algorithms↗

PubMed2003

Side-chain-to-tail thiolactone peptide inhibitors of the staphylococcal quorum-sensing system.

The expression of many staphylococcal virulence factors are regulated by the agr locus via a two-component signal transduction system (TCSTS), which is activated in response to a secreted autoinducer peptide (AIP). By exploiting the unique chemical architecture of the naturally occurring AIP-1, several potent inhibitors of staphylococcal TCSTS were designed and synthesized using either a linear or branched solid-phase approach. These inhibitors are competitive binders and contain the crucial 16-membered side-chain-to-tail thiolactone peptide pharmacophore.

4-Butyrolactone↗

PubMed2025

A novel regulation on the developmental checkpoint protein Sda that controls sporulation and biofilm formation in Bacillus subtilis.

UNLABELLED: Biofilm formation by Bacillus subtilis is triggered by an unusually simple environmental sensing mechanism. Certain serine codons, the four TCN codons (N for A, T, C, or G), in the gene for the biofilm repressor SinR caused lowered SinR translation and subsequent biofilm induction during transition from exponential to stationary growth. Global ribosome profiling showed that ribosomes pause when translating the four UCN (U for T on the mRNA) serine codons on mRNA, but not the two AGC/AGU serine codons. We proposed a serine codon hierarchy (AGC/AGT vs TCN) in that genes enriched in the TCN serine codons may experience reduced translation efficiency when serine is limited. In this study, we designed an algorithm to score all protein-coding genes in B. subtilis NCIB3610 based on the serine codon hierarchy. We generated a short list of 50 genes that could be subject to regulation by this novel mechanism. We further investigated one such gene from the list, sda, which encodes a developmental checkpoint protein regulating both sporulation and biofilm formation. We showed that synonymously switching the TCN serine codons to AGC in sda led to delayed biofilm formation and sporulation. This engineered strain also outgrew strains with other synonymously substituted sda alleles (TCN) in competition assays for biofilm formation and sporulation. Finally, we showed that the AGC serine codon substitutions in sda elevated the Sda protein levels. This serine codon hierarchy-based novel signaling mechanism could be exploited by bacteria in adapting to stationary phase and regulating important biological processes. IMPORTANCE: Genome-wide ribosome profiling in Bacillus subtilis shows that under serine limitation, ribosomes pause on the four TCN (N for A, C, G, and T), but not AGC/AGT serine codons, during translation at a global scale. This serine codon hierarchy (AGC/T vs TCN) differentially influences the translation efficiency of genes enriched in certain serine codons. In this study, we designed an algorithm to score all 4,000+ genes in the B. subtilis genome and generated a list of 50 genes that could be subject to this novel serine codon hierarchy-mediated regulation. We further investigated one such gene, sda, encoding a developmental checkpoint protein. We show that sda and cell developments controlled by Sda are also regulated by this novel mechanism.

Bacillus subtilis↗