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The long-term benefits of human generosity in indirect reciprocity.

Among the theories that have been proposed to explain the evolution of altruism are direct reciprocity and indirect reciprocity. The idea of the latter is that helping someone or refusing to do so has an impact on one's reputation within a group. This reputation is constantly assessed and reassessed by others and is taken into account by them in future social interactions. Generosity in indirect reciprocity can evolve if and only if it eventually leads to a net benefit in the long term. Here, we show that this key assumption is met. We let 114 students play for money in an indirect and a subsequent direct reciprocity game. We found that although being generous, i.e., giving something of value to others, had the obvious short-term costs, it paid in the long run because it builds up a reputation that is rewarded by third parties (who thereby themselves increase their reputation). A reputation of being generous also provided an advantage in the subsequent direct reciprocity game, probably because it builds up trust that can lead to more stable cooperation.

Altruism↗

Fitness effects of fixed beneficial mutations in microbial populations.

Beneficial mutations are intuitively relevant to understanding adaptation, yet not all beneficial mutations are of consequence to the long-term evolutionary outcome of adaptation. Many beneficial mutations-mostly those of small effect-are lost due either to (1) genetic drift or to (2) competition among clones carrying different beneficial mutations, a phenomenon called the "Hill-Robertson effect" for sexual populations and "clonal interference" for asexual populations. Competition among clones becomes more prevalent with increasing genetic linkage and increasing population size, and it is thus generally characteristic of microbial populations. Together, these two phenomena suggest that only those beneficial mutations of large fitness effect should achieve fixation, despite the fact that most beneficial mutations produced are predicted to have very small fitness effects. Here, we confirm this prediction-both empirically and theoretically-by showing that fitness effects of fixed beneficial mutations follow a distribution whose mode is positive.

Adaptation, Physiological↗

The counterforce.

Explore the source record for details and available documents.

Directed Molecular Evolution↗

Loss of oxyR in Mycobacterium tuberculosis.

The loss of the putative regulator oxyR and the associated dysfunction of oxidative stress response in Mycobacterium tuberculosis may have coincided with, or directly participated in, the evolution of this microorganism into the potent contemporary human pathogen. These phenomena may have implications for host-pathogen interactions in tuberculosis and for M. tuberculosis sensitivity to the front-line antituberculosis agent isoniazid.

Antitubercular Agents↗

Attempts to obtain more efficient GAC-cleaving hammerhead ribozymes by in vitro selection.

An in vitro selection was carried out to identify hammerhead ribozymes cleaving 3' to GAC triplets more efficiently than the wild type ribozyme. A double-stranded DNA containing the sequence for the hammerhead ribozyme with 10 randomizations in the catalytic core, designed for in cis cleavage, was transcribed and the cleavage product amplified by reverse transcription and PCR. After seven selection cycles, the DNA was cloned and 50 colonies sequenced. One sequence, appearing six times, was active for in cis cleavage of GAC. It was identical to the consensus sequence except for a mutation at position 7. Another cleaved GUC and two more, cleaved GUA. The cleavage rates of these ribozymes for in trans cleavage were slower than the rate of the consensus ribozyme. Interestingly, the consensus sequence was not found in the selection. This strongly suggests that the consensus hammerhead ribozyme has evolved to an optimal sequence.

Base Sequence↗

Comparison of in vivo selection and rational design of heterodimeric coiled coils.

To investigate how electrostatic interactions restrict the associations of coiled coils, we improved a heterodimeric coiled coil (WinZip-A1B1) by in vivo selection and, alternatively, by rational design. Selection from libraries encoding variable edge (g and e) residues enriched g/e' ion pairs, but the optimum selected heterodimers unexpectedly retained two predicted repulsive g/e' pairs. The best genetically selected heterodimer displayed similar thermodynamic stability and specificity as a rationally designed dimer with predicted ion pairs at all edge positions. This rationally designed pair, however, was less effective than the best genetically selected pair in mediating dimerization in vivo. Thus, the effects of predicted charge pairs depend on sequence context, and complementary charges at the edge positions rationalize only a fraction of the sequences that form stable, specific coiled coils.

Cell Division↗

The expanded role of minimally invasive coronary grafting.

The evolution of minimally invasive direct coronary artery bypass (MIDCAB) grafting has extended the role of this approach for limited coronary revascularization. MIDCAB techniques can now be used to address isolated stenoses in the inferior and lateral coronary distributions. MIDCAB techniques are increasingly being used in the reoperative setting, and multiple vessels can be bypassed during a single operation. This article reviews the expanded role of MIDCAB grafting in the treatment of coronary artery disease.

Coronary Artery Bypass↗

Light regulation of cyclic-AMP levels in the red macroalga Porphyra leucosticta.

Total cyclic-3'-5'-adenosine monophosphate (cAMP) levels were measured in the gametophyte of the red macroalga Porphyra leucosticta under different light conditions in order to study its regulation by phytochrome or photosynthesis. cAMP levels were relatively low when samples were incubated in darkness, or exposed to red or far-red light. Irradiation with red+far-red light induced a moderate increase in cAMP levels, while white light induced a pronounced increase in cAMP levels. When incubated under increasing white light irradiance, cAMP levels closely followed the increase in photosynthetic oxygen evolution rate, suggesting a direct relationship between photosynthesis and cAMP accumulation. cAMP levels were not dependent on cellular ATP concentration, as inhibitors of ATP synthesis did not significantly affect cAMP levels in light. We conclude that cAMP depends on photosynthetic activity regardless of ATP synthesis and concentration or phytochrome activity.

Adenosine Triphosphate↗

RNA-catalyzed RNA ligation on an external RNA template.

Variants of the hc ligase ribozyme, which catalyzes ligation of the 3' end of an RNA substrate to the 5' end of the ribozyme, were utilized to evolve a ribozyme that catalyzes ligation reactions on an external RNA template. The evolved ribozyme catalyzes the joining of an oligonucleotide 3'-hydroxyl to the 5'-triphosphate of an RNA hairpin molecule. The ribozyme can also utilize various substrate sequences, demonstrating a largely sequence-independent mechanism for substrate recognition. The ribozyme also carries out the ligation of two oligonucleotides that are bound at adjacent positions on a complementary template. Finally, it catalyzes addition of mononucleoside 5'-triphosphates onto the 3' end of an oligonucleotide primer in a template-dependent manner. The development of ribozymes that catalyze polymerase-type reactions contributes to the notion that an RNA world could have existed during the early history of life on Earth.

Directed Molecular Evolution↗

Lipases as practical biocatalysts.

Lipases are the most used enzymes in synthetic organic chemistry, catalyzing the hydrolysis of carboxylic acid esters in aqueous medium or the reverse reaction in organic solvents. Recent methodological advancements regarding practical factors affecting lipase activity and enantioselectivity are reviewed. Select practical examples concerning the use of lipases in the production of chiral intermediates are also highlighted.

Catalysis↗

Protein engineering of oxygenases for biocatalysis.

Oxygenase enzymes have seen limited practical applications because of their complexity, poor stabilities, and often low catalytic rates. However, their ability to perform difficult chemistry with high selectivity and specificity has kept oxygenases at the forefront of engineering efforts. Growing understanding of structure-function relationships and improved protein engineering methods are paving the way for applications of oxygenases in chemical synthesis and bioremediation.

Animals↗

Controlling lipase enantioselectivity for organic synthesis.

Lipases are used frequently as chiral catalysts in the synthesis of various fine chemicals and intermediates. The increasing need of compounds with high stereochemical purity requires catalysts with an improved and controlled performance. This overview emphasizes some important aspects for the control of lipase enantioselectivity and some examples where the enantioselectivity has been altered or reversed are highlighted. However, in several of these cases the complete explanation for the altered or reversed enantioselectivity remains unclear and needs to be solved. Three different strategies (engineering of the reaction medium, the substrate molecule, and the enzyme) for exploring lipase enantioselectivity at a molecular level are discussed and summarized. These three different approaches represent powerful tools for understanding the molecular basis for lipase enantioselective catalysis and can guide the rational improvement and tailoring of catalyst performance. By combining approaches from chemistry and biology much is learnt about the most important parameters controlling lipase enantioselectivity for organic synthesis.

Chemistry, Organic↗

Stigma and mental disorder: conceptions of illness, public attitudes, personal disclosure, and social policy.

The end of the last millennium witnessed an unprecedented degree of public awareness regarding mental disorder as well as motivation for policy change. Like Sartorius, we contend that the continued stigmatization of mental illness may well be the central issue facing the field, as nearly all attendant issues (e.g., standards of care, funding for basic and applied research efforts) emanate from professional, societal, and personal attitudes towards persons with aberrant behavior. We discuss empirical and narrative evidence for stigmatization as well as historical trends regarding conceptualizations of mental illness, including the field's increasing focus on genetic and neurobiological causes and determinants of mental disorder. We next define stigma explicitly, noting both the multiple levels (community, societal, familial, individual) through which stigma operates to dehumanize and delegitimize individuals with mental disorders and the impact of stigma across development. Key developmental psychopathology principles are salient in this regard. We express concern over the recent oversimplification of mental illness as "brain disorder," supporting instead transactional models which account for the dynamic interplay of genes, neurobiology, environment, and self across development and which are consistent with both compassion and societal responsibility. Finally, we consider educational and policy-related initiatives regarding the destigmatization of mental disorder. We conclude that attitudes and policy regarding mental disorder reflect, in microcosmic form, two crucial issues for the next century and millennium: (a) tolerance for diversity (vs. pressure for conformity) and (b) intentional direction of our species' evolution, given fast-breaking genetic advances.

Attitude to Health↗

In vitro selection of novel RNA ligands that bind human cytomegalovirus and block viral infection.

Ribonuclease-resistant RNA molecules that bind to infectious human cytomegalovirus (HCMV) were isolated in vitro from a pool of randomized sequences after 16 cycles of selection and amplification. The two ligands (L13 and L19) characterized exhibited high HCMV-binding affinity in vitro and effectively inhibited viral infection in tissue culture. Their antiviral activity was also specific as they only reacted with two different strains of HCMV but not with the related herpes simplex virus 1 and human cells. These two ligands appeared to function as antivirals by blocking viral entry. Ultraviolet (UV) crosslinking studies suggested that L13 and L19 bind to HCMV essential glycoproteins B and H, respectively. Thus, RNA ligands that bind to different surface antigens of HCMV can be simultaneously isolated by the selection procedure. Our study demonstrates the feasibility of using these RNA ligands as a research tool to identify viral proteins required for infectivity and as an antiviral agent to block viral infection.

Antiviral Agents↗

A selection system for identifying accessible sites in target RNAs.

Although ribozymes offer tremendous potential for posttranscriptionally controlling expression of targeted genes, their utility is often limited by the accessibility of the targeted regions within the RNA transcripts. Here we describe a method that identifies RNA regions that are accessible to oligonucleotides. Based on this selection protocol, we show that construction of hammerhead ribozymes targeted to the identified regions results in catalytic activities that are consistently and substantially greater than those of ribozymes designed on the basis of computer modeling. Identification of accessible sites should also be widely applicable to design of antisense oligonucleotides and DNAzymes.

Base Sequence↗

Sequence-specific interaction between HIV-1 matrix protein and viral genomic RNA revealed by in vitro genetic selection.

The human immunodeficiency virus type-1 matrix protein (HIV-1 MA) is a multifunctional structural protein synthesized as part of the Pr55 gag polyprotein. We have used in vitro genetic selection to identify an RNA consensus sequence that specifically interacts with MA (Kd = 5 x 10(-7) M). This 13-nt MA binding consensus sequence bears a high degree of homology (77%) to a region (nt 1433-1446) within the POL open reading frame of the HIV-1 genome (consensus sequence from 38 HIV-1 strains). Chemical interference experiments identified the nucleotides within the MA binding consensus sequence involved in direct contact with MA. We further demonstrate that this RNA-protein interaction is mediated through a stretch of basic amino acids within MA. Mutations that disrupt the interaction between MA and its RNA binding site within the HIV-1 genome resulted in a measurable decrease in viral replication.

Base Sequence↗

Optimization and optimality of a short ribozyme ligase that joins non-Watson-Crick base pairings.

A small ribozyme ligase (L1) selected from a random sequence population appears to utilize non-Watson-Crick base pairs at its ligation junction. Mutational and selection analyses confirmed the presence of these base pairings. Randomization of the L1 core and selection of active ligases yielded highly active variants whose rates were on the order of 1 min(-1). Base-pairing covariations confirmed the general secondary structure of the ligase, and the most active ligases contained a novel pentuple sequence covariation. The optimized L1 ligases may be optimal within their sequence spaces, and minimal ligases that span less than 60 nt in length have been engineered based on these results.

Base Pairing↗