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At least 667 records · Page 37Linked to original sources
PubMed1999

Unexpected divergence of enzyme function and sequence: "N-acylamino acid racemase" is o-succinylbenzoate synthase.

A protein identified as "N-acylamino acid racemase" from Amycolaptosis sp. is an inefficient enzyme (kcat/Km = 3.7 x 10(2) M-1 s-1). Its sequence is 43% identical to that of an unidentified protein encoded by the Bacillus subtilis genome. Both proteins efficiently catalyze the o-succinylbenzoate synthase reaction in menaquinone biosynthesis (kcat/Km = 2.5 x 10(5) and 7.5 x 10(5) M-1 s-1, respectively), suggesting that this is their "correct" metabolic function. Their membership in the mechanistically diverse enolase superfamily provides an explanation for the catalytic promiscuity of the protein from Amycolaptosis. The adventitious promiscuity may provide an example of a protein poised for evolution of a new enzymatic function in the enolase superfamily. This study demonstrates that the correct assignment of function to new proteins in functional and structural genomics may require an understanding of the metabolism of the organism.

Actinobacteria↗
PubMed1997

Divergent activity and function of superoxide dismutases in Pasteurella haemolytica serotypes A1 and A2 and Pasteurella trehalosi serotype T10.

Representative strains of Pasteurella haemolytica serotypes A1 and A2 and Pasteurella trehalosi serotype T10 were examined for the presence of superoxide dismutase. Visualisation of superoxide dismutase enzyme activity on polyacrylamide gels, and specific inhibition with potassium cyanide verified a copper/zinc (Cu/Zn) superoxide dismutase only in serotype A2 whereas serotypes A1 and T10 showed other superoxide dismutase activity. Using a simple freeze-thaw method the cellular location of superoxide dismutase enzyme activity was determined in all three serotypes. In serotypes A1 and A2 but not T10 superoxide dismutases were located in the periplasm. The viability of serotypes A2 and T10 cells in the presence of exogenous superoxide was unchanged over a 30 min period, whereas serotype A1 cells declined in viability between 15 and 30 min. Purified immunoglobulin from sheep convalescent serum did not reduce superoxide dismutase activity in the serotypes in an in vitro assay. The presence of this enzyme within the pasteurellae suggests a supportive role in the virulence of this major pathogen of ruminants.

Animals↗
PubMed2005

The plasmodial surface anion channel is functionally conserved in divergent malaria parasites.

The plasmodial surface anion channel (PSAC), a novel ion channel induced on human erythrocytes infected with Plasmodium falciparum, mediates increased permeability to nutrients and presumably supports intracellular parasite growth. Isotope flux studies indicate that other malaria parasites also increase the permeability of their host erythrocytes, but the precise mechanisms are unknown. Channels similar to PSAC or alternative mechanisms, such as the upregulation of endogenous host transporters, might fulfill parasite nutrient demands. Here we evaluated these possibilities with rhesus monkey erythrocytes infected with Plasmodium knowlesi, a parasite phylogenetically distant from P. falciparum. Tracer flux and osmotic fragility studies revealed dramatically increased permeabilities paralleling changes seen after P. falciparum infection. Patch-clamp of P. knowlesi-infected rhesus erythrocytes revealed an anion channel with striking similarities to PSAC: its conductance, voltage-dependent gating, pharmacology, selectivity, and copy number per infected cell were nearly identical. Our findings implicate a family of unusual anion channels highly conserved on erythrocytes infected with various malaria parasites. Together with PSAC's exposed location on the host cell surface and its central role in transport changes after infection, this conservation supports development of antimalarial drugs against the PSAC family.

Animals↗
PubMed2006

A search for genes that may confer divergent morphology and function in the carotid body between two strains of mice.

The carotid body (CB) is the primary hypoxic chemosensory organ. Its hypoxic response appears to be genetically controlled. We have hypothesized that: 1) genes related to CB function are expressed less in the A/J mice (low responder to hypoxia) compared with DBA/2J mice (high responder to hypoxia); and 2) gene expression levels of morphogenic and trophic factors of the CB are significantly lower in the A/J mice than DBA/2J mice. This study utilizes microarray analysis to test these hypotheses. Three sets of CBs were harvested from both strains. RNA was isolated and used for global gene expression profiling (Affymetrix Mouse 430 v2.0 array). Statistically significant gene expression was determined as a minimum six counts of nine pairwise comparisons, a minimum 1.5-fold change, and P <or= 0.05. Our results demonstrated that 793 genes were expressed less and that 568 genes were expressed more in the A/J strain vs. the DBA/2J strain. Analysis of individual genes indicates that genes encoding ion channels are differentially expressed between the two strains. Genes related to neurotransmitter metabolism, synaptic vesicles, and the development of neural crest-derived cells are expressed less in the A/J CB vs. the DBA/2J CB. Through pathway analysis, we have constructed a model that shows gene interactions and offers a roadmap to investigate CB development and hypoxic chemosensing/chemotransduction processes. Particularly, Gdnf, Bmp2, Kcnmb2, Tph1, Hif1a, and Arnt2 may contribute to the functional differences in the CB between the two strains. Bmp2, Phox2b, Dlx2, and Msx2 may be important for the morphological differences.

Animals↗
PubMed2006

Divergent expression and function of glucocorticoid receptor beta in human monocytes and T cells.

Glucocorticoid (GC) insensitivity is a significant problem in the treatment of immune-mediated diseases. The current study examined whether T cells and monocytes differed in their response to GC and the potential molecular basis for their variation in response to steroids. Functional studies revealed that dexamethasone (DEX) inhibited phorbol 12-myristate 13-acetate/ionomycin-induced tumor necrosis factor alpha and interleukin-6 production to a significantly lesser extent in monocytes than T cells. In parallel, a significantly longer period of time was required for DEX to induce the steroid-responsive gene, mitogen-activated protein kinase phosphatase-1 (MKP-1), in human monocytes as compared with T cells. It is interesting that such differences were not observed between murine T cells and monocytes. GC receptor beta (GCRbeta) is a splicing variant of the classic GCR, GCRalpha, which functions as a dominant-negative inhibitor of GCRalpha in humans, not mice (as mice do not express GCRbeta mRNA as a result of a difference in the murine GCR 9b exon sequence). It was found that human monocytes had a significantly higher level of GCRbeta than T cells. Furthermore, GCRbeta was found in the cytoplasm and nucleus of monocytes, and GCRbeta was localized to the nucleus of T cells. This raised the possibility that GCRbeta in the cytoplasm could affect GCRalpha cellular shuttling in response to DEX. Indeed, we found that DEX-induced nuclear translocation of GCRalpha was decreased in monocytes as compared with T cells. Specific RNA silencing of GCRbeta in human monocytes resulted in enhanced steroid-induced GCRalpha transactivation and transrepression. Our data suggest that GCRbeta contributes to variation in the GC responses of monocytes versus T cells.

Animals↗
PubMed2001

Genetic evidence for early divergence of small functioning and nonfunctioning endocrine pancreatic tumors: gain of 9Q34 is an early event in insulinomas.

The malignant potential among endocrine pancreatic tumors (EPTs) varies greatly and can frequently not be predicted using histopathological parameters. Thus, molecular markers that can predict the biological behavior of EPTs are required. In a previous comparative genomic hybridization study, we observed marked genetic differences between the various EPT subtypes and a correlation between losses of 3p and 6 and gains of 14q and Xq and metastatic disease. To search for genetic alterations that play a role during early tumor development, we have studied 38 small (< or =2 cm) EPTs, including 24 insulinomas and 10 nonfunctioning EPTs. Small EPTs are usually classified as clinically benign tumors in the absence of histological signs of malignancy. Using comparative genomic hybridization, we identified chromosomal aberrations in 27 EPTs (mean, 4.1). Interestingly, the number of gains differed strongly between nonfunctioning and functioning EPTs (3.4 versus 1.5, respectively; P = 0.0526), as did the number of aberrations in the benign (n = 30) and malignant (n = 8) tumors (3 versus 8.4, respectively; P = 0.0022). In the insulinomas, 9q gain (common region of involvement: 9q34) was most common (50%) and in nonfunctioning EPTs, gain of 4p was most common (40%). Most frequent losses in insulinomas involved 1p (20.8%), 1q, 4q, 11q, Xq, and Y (all 16.7%) and in nonfunctioning EPTs, 6q. Losses of 3pq and 6q and gains of 17pq and 20q proved to be strongly associated with malignant behavior in all of the small EPTs (P < or = 0.0219). Our results demonstrate marked genetic differences between small functioning and nonfunctioning EPTs, indicating that these subtypes evolve along different genetic pathways. In addition, our study endorses the importance of chromosomes 3 and 6q losses to discriminate EPTs with a malignant behavior from benign ones.

Adolescent↗
PubMed1981

[Convergence and divergence of interneuronal functional connections].

Multiunit activity was recorded in the auditory and motor cortex of cats with implanted electrodes, impulses with highest and lowest amplitudes being isolated by means of an amplitude discriminator. Crossinterval histograms were obtained for two simultaneous records. Functional relationships between neurons under different electrodes were evaluated by statistical interdependence of isolated trains. In the auditory cortex, neurons with high amplitude spikes mainly produced connections of excitatory type whereas neurons with low amplitude spikes produced connections of inhibitory type. In the motor cortex neurons producing heterogenous effect were predominant.

Animals↗
PubMed1983

Divergent T gamma cell functions in antigen-induced blastogenesis: facilitory interactions with Tnon gamma cells and participation in monocyte- and prostaglandin-mediated suppression.

The contribution of T gamma cells, i.e., T cells bearing surface receptors for the Fc portion of IgG, to the immunologic response to antigen has not been assessed in health or disease. We examined the role of T gamma cells in antigen-induced blastogenesis of T cells from healthy subjects and characterized their participation in monocyte- and prostaglandin-mediated suppression. Cell fractions enriched in the depleted of T gamma cells were prepared from nonadherent T cells by preparative rosetting with IgG-sensitized ox erythrocytes; antigen-induced blastogenesis was assayed as 3H-thymidine incorporation (3H-TdR), by microculture techniques. Removal of T gamma cells resulted in a Tnon gamma cell fraction whose in vitro response to soluble antigen was a mean 40% +/- 8 less than the response of the unseparated T cells from the same donors. Antigen did not induce 3H-TdR in cultures of T gamma cells; however, in cell-mixing experiments, addition of autologous T gamma cells reconstituted the antigen responsiveness of the Tnon gamma cell fraction. Monocytes (MN) added to cell cultures at a ratio known to be suppressive in vitro (MN to T = 1:4) significantly decreased antigen-induced 3H-TdR of unseparated T cells but did not alter the antigen responses of Tnon gamma cells. MN-dependent suppression was abrogated by co-culture with indomethacin. Exogenous prostaglandin E2, an immunosuppressive cyclooxygenase product of MN, selectively decreased antigen-induced 3H-TdR of cell cultures containing T gamma cells but did not affect antigen responses of Tnon gamma cell fraction. Thus these studies show that MN and their cyclooxygenase products modulate T gamma cells to function in a suppressive mode. This demonstration of divergent T gamma cell functions indicates that the contribution of an expanded T gamma cell population to altered antigen reactivity in disease can be determined only by careful functional studies.

Adult↗
PubMed2001

Divergent evolution of enzymatic function: mechanistically diverse superfamilies and functionally distinct suprafamilies.

The protein sequence and structure databases are now sufficiently representative that strategies nature uses to evolve new catalytic functions can be identified. Groups of divergently related enzymes whose members catalyze different reactions but share a common partial reaction, intermediate, or transition state (mechanistically diverse superfamilies) have been discovered, including the enolase, amidohydrolase, thiyl radical, crotonase, vicinal-oxygen-chelate, and Fe-dependent oxidase superfamilies. Other groups of divergently related enzymes whose members catalyze different overall reactions that do not share a common mechanistic strategy (functionally distinct suprafamilies) have also been identified: (a) functionally distinct suprafamilies whose members catalyze successive transformations in the tryptophan and histidine biosynthetic pathways and (b) functionally distinct suprafamilies whose members catalyze different reactions in different metabolic pathways. An understanding of the structural bases for the catalytic diversity observed in super- and suprafamilies may provide the basis for discovering the functions of proteins and enzymes in new genomes as well as provide guidance for in vitro evolution/engineering of new enzymes.

Amidohydrolases↗
PubMed1995

Differences in divergent thinking as a function of handedness and sex.

The relationship between handedness and divergent thinking was explored in four studies. Experiment 1 (N = 556) used the Alternate Uses Test, Experiment 2 (N = 941) tested object synthesis, and Experiment 3 (N = 965) tested ideational flexibility. No difference as a function of handedness was found in Experiment 1, but in Experiments 2 and 3 divergent thinking was significantly related to handedness in males. Left-handed males had higher divergent thinking scores, and the scores rose systematically with increasing sinistrality. Handedness was not related to divergent thinking ability in females. Experiment 4 (N = 1,548) showed that these differences were not associated with superiority by left-handed individuals in convergent thinking. Interpretations based on altered neurological development due to factors such as fetal testosterone exposure are discussed.

Adolescent↗
PubMed1995

Nonaccommodative factors of refractive accommodative esotropia.

The clinical characteristics of 45 cases of refractive accommodative esotropia were compared with 31 cases of the control group who remained orthotropic in the presence of uncorrected same degree of hypermetropia. In addition to the general ophthalmologic and orthoptic examinations, the accommodative convergence/accommodation (AC/A) ratio, fusional vergences and random dot stereopsis were investigated. The hypermetropic patients without esotropia were found to have a lower AC/A ratio and normal fusional function, while in cases with refractive accommodative esotropia, their AC/A ratios were normal and their fusional functions were decreased, especially significant being the divergent fusional function. In both groups, their stereopsis was defective or absent. It is suggested that esotropia be not simply caused by excessive accommodation due to uncorrected hypermetropia, and the range of divergent fusional function and the level of AC/A ratio be the two factors which determine the causation of esotropia in cases with uncorrected hypermetropia.

Accommodation, Ocular↗
PubMed1997

Molecular keys to speciation: DNA polymorphism and the control of genetic exchange in enterobacteria.

Speciation involves the establishment of genetic barriers between closely related organisms. The extent of genetic recombination is a key determinant and a measure of genetic isolation. The results reported here reveal that genetic barriers can be established, eliminated, or modified by manipulating two systems which control genetic recombination, SOS and mismatch repair. The extent of genetic isolation between enterobacteria is a simple mathematical function of DNA sequence divergence. The function does not depend on hybrid DNA stability, but rather on the number of blocks of sequences identical in the two mating partners and sufficiently large to allow the initiation of recombination. Further, there is no obvious discontinuity in the function that could be used to define a level of divergence for distinguishing species.

Biological Evolution↗
PubMed2006

Evolutionary conservation of protein backbone flexibility.

Internal protein dynamics is essential for biological function. During evolution, protein divergence is functionally constrained: properties more relevant for function vary more slowly than less important properties. Thus, if protein dynamics is relevant for function, it should be evolutionary conserved. In contrast with the well-studied evolution of protein structure, the evolutionary divergence of protein dynamics has not been addressed systematically before, apart from a few case studies. X-Ray diffraction analysis gives information not only on protein structure but also on B-factors, which characterize the flexibility that results from protein dynamics. Here we study the evolutionary divergence of protein backbone dynamics by comparing the C(alpha) flexibility (B-factor) profiles for a large dataset of homologous proteins classified into families and superfamilies. We show that C(alpha) flexibility profiles diverge slowly, so that they are conserved at family and superfamily levels, even for pairs of proteins with nonsignificant sequence similarity. We also analyze and discuss the correlations among the divergences of flexibility, sequence, and structure.

Amino Acid Sequence↗
PubMed2007

Contribution of divergent thinking to community functioning in schizophrenia.

Fluency deficits have been associated with poor community functioning in patients with schizophrenia. In our previous study we demonstrated that the ability to generate higher-quality responses on tasks of divergent thinking as measured by several fluency tests was impaired in patients with schizophrenia. The purpose of the present study was to investigate the contribution of the deficits in divergent thinking to community dysfunction in schizophrenia. Forty Japanese outpatients with schizophrenia and 32 healthy control subjects were recruited for this study and assessed over a broad spectrum of the neurocognitive domain. Their capacity for divergent thinking was assessed by idea, design, and word fluency tests. Community functioning was assessed by using the Global Assessment of Functioning (GAF), the Life Assessment Scale for the Mentally Ill (LASMI), and the Social Functioning Scale (SFS). The results confirmed the qualitative deficits of divergent thinking in schizophrenia. Stepwise multiple regressions using neurocognitive and demographic/clinical variables as predictors revealed that the higher-quality response scores on the tasks of divergent thinking significantly contributed to community functioning. Moreover, the deficit on the verbal task of divergent thinking significantly contributed to impairment in the area of daily living, and the deficit on the nonverbal task of divergent thinking significantly contributed to impairment in the area of interpersonal relations. The results of this study reveal the importance and the possibility of cognitive remediation and cognitive training with strategies that target capacity for divergent thinking to improve community functioning in patients with schizophrenia.

Adult↗
PubMed2005

Divergence, recombination and retention of functionality during protein evolution.

We have only a vague idea of precisely how protein sequences evolve in the context of protein structure and function. This is primarily because structural and functional contexts are not easily predictable from the primary sequence, and evaluating patterns of evolution at individual residue positions is also difficult. As a result of increasing biodiversity in genomics studies, progress is being made in detecting context-dependent variation in substitution processes, but it remains unclear exactly what context-dependent patterns we should be looking for. To address this, we have been simulating protein evolution in the context of structure and function using lattice models of proteins and ligands (or substrates). These simulations include thermodynamic features of protein stability and population dynamics. We refer to this approach as 'ab initio evolution' to emphasise the fact that the equilibrium details of fitness distributions arise from the physical principles of the system and not from any preconceived notions or arbitrary mathematical distributions. Here, we present results on the retention of functionality in homologous recombinants following population divergence. A central result is that protein structure characteristics can strongly influence recombinant functionality. Exceptional structures with many sequence options evolve quickly and tend to retain functionality--even in highly diverged recombinants. By contrast, the more common structures with fewer sequence options evolve more slowly, but the fitness of recombinants drops off rapidly as homologous proteins diverge. These results have implications for understanding viral evolution, speciation and directed evolutionary experiments. Our analysis of the divergence process can also guide improved methods for accurately approximating folding probabilities in more complex but realistic systems.

Evolution, Molecular↗
PubMed1996

Pseudogenes in ribonuclease evolution: a source of new biomacromolecular function?

Bovine seminal ribonuclease (RNase) diverged from pancreatic RNase after a gene duplication ca. 35 million years ago. Members of the seminal RNase gene family evidently remained as unexpressed pseudogene for much of its evolutionary history. Between 5 and 10 million years ago, however, after the divergence of kudu but before the divergence of ox, evidence suggests that the pseudogene was repaired and expressed. Intriguingly, detailed analysis of the sequences suggests that the repair may have involved gene conversion, transfer of information from the pancreatic gene to the RNase pseudogene. Further, the ratio of non-silent to silent substitutions suggests that the pancreatic RNases are divergently evolving under functional constraints, the seminal RNase pseudogenes are diverging under no functional constraints, while the genes expressed in the seminal plasma are evolving extremely rapidly in their amino acid sequences, as if to fulfil a new physiological role.

Amino Acid Sequence↗