SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Aside from the demonstration that individual molecular traits of enzymes can be evolutionarily optimised, the discovery that several traits can be simultaneously optimised is a major advance. The first observations of the effects of evolutionary optimisation at the structural level, through X-ray crystallography, reinforce the view that enzymes are best optimised by evolution and not by design.
We report the development of a solid polymer electrolyte film from hydrogen bonding layer-by-layer (LBL) assembly that outperforms previously reported LBL assembled films and approaches battery integration capability. Films were fabricated by alternating deposition of poly(ethylene oxide) (PEO) and poly(acrylic acid) (PAA) layers from aqueous solutions. Film quality benefits from increasing PEO molecular weight even into the 10(6) range due to the intrinsically low PEO/PAA cross-link density. Assembly is disrupted at pH near the PAA ionization onset, and a potential mechanism for modulating PEO:PAA ratio within assembled films by manipulating pH is discussed. Ionic conductivity of 5 x 10(-5) S/cm is achievable after short exposure to 100% relative humidity (RH) for plasticization. Adding free ions by exposing PEO/ PAA films to lithium salt solutions enhanced conductivity to greater than 10(-5) S/cm at only 52% RH and tentatively greater than 10(-4) S/cm at 100% RH. The excellent stability of PEO/PAA films even when exposed to 1.0 M salt solutions led to an exploration of LBL assembly with added electrolyte present in the adsorption step. Fortuitously, the modulation of PEO/PAA assembly by ionic strength is analogous to that of electrostatic LBL assembly and can be attributed to electrolyte interactions with PEO and PAA. Dry ionic conductivity was enhanced in films assembled in the presence of salt as compared to films that were merely exposed to salt after assembly, implying different morphologies. These results reveal clear directions for the evolution of these promising solid polymer electrolytes into elements appropriate for electrochemical power storage and generation applications.
Enzymes are the subset of proteins that catalyse the chemistry of life, transforming both macromolecular substrates and small molecules. The precise three-dimensional architecture of enzymes permits almost unerring selectivity in physical and chemical steps to impose remarkable rate accelerations and specificity in product-determining reactions. Many enzymes are members of families that carry out related chemical transformations and offer opportunities for directed in vitro evolution, to tailor catalytic properties to particular functions.
Electrostatic coupling between particles is important in many microscopic phenomena found in nature. The interaction between two isolated point charges is described by the bare Coulomb potential, but in many-body systems this interaction is modified as a result of the collective response of the screening cloud surrounding each charge carrier. One such system involves ultrafast interactions between quasi-free electrons in semiconductors-which are central to high-speed and future quantum electronic devices. The femtosecond kinetics of nonequilibrium Coulomb systems has been calculated using static and dynamical screening models that assume the instantaneous formation of interparticle correlations. However, some quantum kinetic theories suggest that a regime of unscreened bare Coulomb collisions might exist on ultrashort timescales. Here we monitor directly the temporal evolution of the charge-charge interactions after ultrafast excitation of an electron-hole plasma in GaAs. We show that the onset of collective behaviour such as Coulomb screening and plasmon scattering exhibits a distinct time delay of the order of the inverse plasma frequency, that is, several 10(-14) seconds.
Explore the source record for details and available documents.
Isolated neutron stars are highly magnetized, fast-rotating objects that form as an end point of stellar evolution. They are directly observable in X-ray emission, because of their high surface temperatures. Features in their X-ray spectra could in principle reveal the presence of atmospheres, or be used to estimate the strength of their magnetic fields through the cyclotron process, as is done for X-ray binaries. Almost all isolated neutron star spectra observed so far appear as featureless thermal continua. The only exception is 1E1207.4-5209 (refs 7-9), where two deep absorption features have been detected, but with insufficient definition to permit unambiguous interpretation. Here we report a long X-ray observation of the same object in which the star's spectrum shows three distinct features, regularly spaced at 0.7, 1.4 and 2.1 keV, plus a fourth feature of lower significance, at 2.8 keV. These features vary in phase with the star's rotation. The logical interpretation is that they are features from resonant cyclotron absorption, which allows us to calculate a magnetic field strength of 8 x 10(10) G, assuming the absorption arises from electrons.
When massive stars exhaust their fuel, they collapse and often produce the extraordinarily bright explosions known as core-collapse supernovae. On occasion, this stellar collapse also powers an even more brilliant relativistic explosion known as a long-duration gamma-ray burst. One would then expect that these long gamma-ray bursts and core-collapse supernovae should be found in similar galactic environments. Here we show that this expectation is wrong. We find that the gamma-ray bursts are far more concentrated in the very brightest regions of their host galaxies than are the core-collapse supernovae. Furthermore, the host galaxies of the long gamma-ray bursts are significantly fainter and more irregular than the hosts of the core-collapse supernovae. Together these results suggest that long-duration gamma-ray bursts are associated with the most extremely massive stars and may be restricted to galaxies of limited chemical evolution. Our results directly imply that long gamma-ray bursts are relatively rare in galaxies such as our own Milky Way.
We report an RNA molecule that exhibits activity analogous to that of alcohol dehydrogenase (ADH). Directed in vitro evolution was used to enrich nicotinamide adenine dinucleotide (NAD+)-dependent redox-active RNAs from a combinatorial pool. The most active ribozyme in the population forms a compact pseudoknotted structure and oxidizes an alcohol seven orders of magnitude faster than the estimated spontaneous rate. Moreover, this ADH RNA was coupled with a redox relay between NADH and flavin adenine dinucleotide to give a NAD+-regeneration system. Our demonstration of the redox ability of RNA adds support to an RNA-based metabolic system in ancient life.
Originally identified in Drosophila melanogaster, the Warts(Wts)/Lats protein kinase has been proposed to function with two other Drosophila proteins, Hippo (Hpo) and Salvador (Sav), in the regulation of cell cycle exit and apoptosis. In mammals, two candidate Warts/Lats homologs, termed Lats1 and Lats2, have been described, and the targeted disruption of LATS1 in mice increases tumor formation. Little, however, is known about the function and regulation of human Lats kinases. Here we report that human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2. Deletion analysis revealed that regulation of Lats1 occurs through the C-terminal, catalytic domain. Within this domain, two regulatory phosphorylation sites were identified by mass spectrometry. These sites, S909 in the activation loop and T1079 within a hydrophobic motif, have been highly conserved during evolution. Moreover, a direct interaction was observed between Mst2 and hWW45, a putative ortholog of Drosophila Sav. These results indicate that Mst2-like kinases regulate Lats kinase activities in an evolutionarily conserved regulatory pathway. Although the function of this pathway remains poorly understood in mammals, it is intriguing that, in Drosophila, it has been linked to development and tissue homeostasis.
An improved pulse sequence for measuring diffusion-ordered COSY spectra is achieved by incorporating the diffusion encoding directly into the evolution and detection periods of a gradient-enhanced COSY sequence, giving improved sensitivity and a 32-fold reduction in minimum experiment time.
In order to survive in an oxygen environment, aerobic organisms have developed numerous mechanisms to protect against oxygen radicals and singlet oxygen. One such mechanism, which appears to have attained particular significance during primate evolution, is the direct scavenging of oxygen radicals, singlet oxygen, oxo-haem oxidants and hydroperoxyl radicals by uric acid. In the present paper we demonstrate that another important 'antioxidant' property of uric acid is the ability to form stable co-ordination complexes with iron ions. Formation of urate-Fe3+ complexes dramatically inhibits Fe3+-catalysed ascorbate oxidation, as well as lipid peroxidation in liposomes and rat liver microsomal fraction. In contrast with antioxidant scavenger reactions, the inhibition of ascorbate oxidation and lipid peroxidation provided by urate's ability to bind iron ions does not involve urate oxidation. Association constants (Ka) for urate-iron ion complexes were determined by fluorescence-quenching techniques. The Ka for a 1:1 urate-Fe3+ complex was found to be 2.4 X 10(5), whereas the Ka for a 1:1 urate-Fe2+ complex was determined to be 1.9 X 10(4). Our experiments also revealed that urate can form a 2:1 complex with Fe3+ with an association constant for the second urate molecule (K'a) of approx. 4.5 X 10(5). From these data we estimate an overall stability constant (Ks approximately equal to Ka X K'a) for urate-Fe3+ complexes of approx. 1.1 X 10(11). Polarographic measurements revealed that (upon binding) urate decreases the reduction potential for the Fe2+/Fe3+ half-reaction from -0.77 V to -0.67 V. Thus urate slightly diminishes the oxidizing potential of Fe3+. The present results provide a mechanistic explanation for our previous report that urate protects ascorbate from oxidation in human blood. The almost saturating concentration of urate normally found in human plasma (up to 0.6 mM) represents 5-10 times the plasma ascorbate concentration, and is orders of magnitude higher than the 'free' iron ion concentration. These considerations point to the physiological significance of our findings.
The description of the fourth stage larva of W. bancrofti provides an indication of the direction of morphological evolution in the genus showing in particular that W. kalimantani is more highly evolved than W. bancrofti and constitutes a "capture" by Presbytis of the species parasitic in man. No morphological character of adult W. bancrofti distinguishes the geographic origin of the different collections studied. By contrast, the morphological characters of the microfilariae and their biological features are significantly different, but are not inter-correlated. It therefore appears that in the genus Wuchereria, as in the other viviparous filarioids, the phenomenon of speciation is evident first of all in the morphology of the microfilaria, the stage most susceptible to selection pressures.
In the last decades of the twentieth century, interest in effects of consciousness on health and illness generated several lines of investigation into effects on cancer. Animal studies showed sensitivity of some cancers to hormonal and stressful influences. However, those findings did not translate into effects on humans, nor did they lead to advances in understanding of human cancer. The proposal that emotional state or stress, mediated through psycho-neuro-immunologic mechanisms would affect cancer generation or growth, resulted in conflicting information. Major surveys found no relationship. The proposal of a cancer personality (Type C) also was not confirmed. Initial observations that depression and stress affected human cancer seem to have best been explained by misinterpretations of cause and effect. By the mid 1990s, a remaining thesis--effect of psychosocial support on longevity and the course of cancer--was yet to be resolved. Initial positive results, especially findings in two popularly quoted studies, were not confirmed; they seem to have been due to inadequate numbers (chance) or to artifacts in study design or implementation. Psychosocial support may result in better adjustment and quality of life, but it does not directly affect the evolution of human cancer.
Type 1 diabetes is the clinical manifestation of aberrant leukocytic infiltration of the pancreatic islets; it is usually diagnosed only very late in disease progression, after the critical autoimmune phenomena have mostly played out. A noninvasive means of directly monitoring the evolution of islet infiltrates would have important research and clinical applications. We have exploited fluorescence and MRI of long-circulating magnetofluorescent nanoparticles to visualize micro-vascular leakage, as an indicator of inflammation, in pancreata of mouse models of type 1 diabetes ex vivo or in vivo. We could detect the onset and evolution of insulitis in vivo and in real time, permitting us to study the natural history of diabetes in individual animals.
Methanosarcina acetivorans produces acetate, formate, and methane when cultured with CO as the growth substrate [Rother M, Metcalf WW (2004) Proc Natl Acad Sci USA 101:], which suggests novel features of CO metabolism. Here we present a genome-wide proteomic approach to identify and quantify proteins differentially abundant in response to growth on CO versus methanol or acetate. The results indicate that oxidation of CO to CO2 supplies electrons for reduction of CO2 to a methyl group by steps and enzymes of the pathway for CO2 reduction determined for other methane-producing species. However, proteomic and quantitative RT-PCR results suggest that reduction of the methyl group to methane involves novel methyltransferases and a coenzyme F420H2:heterodisulfide oxidoreductase system that generates a proton gradient for ATP synthesis not previously described for pathways reducing CO2 to methane. Biochemical assays support a role for the oxidoreductase, and transcriptional mapping identified an unusual operon structure encoding the oxidoreductase. The proteomic results further indicate that acetate is synthesized from the methyl group and CO by a reversal of initial steps in the pathway for conversion of acetate to methane that yields ATP by substrate level phosphorylation. The results indicate that M. acetivorans utilizes a pathway distinct from all known CO2 reduction pathways for methane formation that reflects an adaptation to the marine environment. Finally, the pathway supports the basis for a recently proposed primitive CO-dependent energy-conservation cycle that drove and directed the early evolution of life on Earth.
Butterflies in the large Palearctic genus Agrodiaetus (Lepidoptera: Lycaenidae) are extremely uniform and exhibit few distinguishing morphological characters. However, these insects are distinctive in one respect: as a group they possess among the greatest interspecific karyotype diversity in the animal kingdom, with chromosome numbers (n) ranging from 10 to 125. The monophyly of Agrodiaetus and its systematic position relative to other groups within the section Polyommatus have been controversial. Characters from the mitochondrial genes for cytochrome oxidases I and II and from the nuclear gene for elongation factor 1 alpha were used to reconstruct the phylogeny of Agrodiaetus using maximum parsimony and Bayesian phylogenetic methods. Ninety-one individuals, encompassing most of the taxonomic diversity of Agrodiaetus, and representatives of 14 related genera were included in this analysis. Our data indicate that Agrodiaetus is monophyletic. Representatives of the genus Polyommatus (sensu stricto) are the closest relatives. The sequences of the Agrodiaetus taxa in this analysis are tentatively arranged into 12 clades, only 1 of which corresponds to a species group traditionally recognized in Agrodiaetus. Heterogeneous substitution rates across a recovered topology were homogenized with a nonparametric rate-smoothing algorithm before the application of a molecular clock. Two published estimates of substitution rates dated the origin of Agrodiaetus between 2.51 and 3.85 million years ago. During this time, there was heterogeneity in the rate and direction of karyotype evolution among lineages within the genus. Karyotype instability has evolved independently three times in the section Polyommatus, within the lineages Agrodiaetus, Lysandra, and Plebicula. Rapid karyotype diversification may have played a significant role in the radiation of the genus Agrodiaetus.
The bacterial cell cycle is simpler and different than that of the typical eukaryotic cell cycle. The selective pressure during evolution has been directed to achieve optimal growth of the individual free-living microbial cell instead of a variety of replication rates of the differentiated cell within an entire multicellular organism. This means that for most bacterial cells division depends more critically on their success in acquiring and using resources than is the case for most eukaryotic cells. The further implication is that bacterial cells somehow measure their own success in growth and from this 'decide' when they should attempt cell cycle events such as cell division and chromosome replication. On the assumption that bacterial division is responsive, directly or indirectly, to cell size, the cell cycle is analyzed here through Monte Carlo simulations. The results are used to consider the possibility of generating bacterial cultures growing synchronous. Because the precision of the size-at-division is surprisingly good, it appears that some organisms, at least, have a sensory mechanism that responds to their success in cell growth. It is known that the division size of some strains, however, is more precisely regulated than in others. Also, some strains are more precise in dividing the mother's cell cytoplasm to give the same sized daughters. Because some strains are much more precise than others, the possibility is raised that useful synchrony could be obtained with selected strains that are precise in these two aspects. These cultures would useful in studying other aspect of the physiology of cell growth.
Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of "negatively associated" or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.