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At least 469 records · Page 26Linked to original sources
PubMed1997

Thrombin-mediated focal adhesion plaque reorganization in endothelium: role of protein phosphorylation.

Endothelial cell (EC) gap formation and barrier function are subject to dual regulation by (1) axial contractile forces, regulated by myosin light chain kinase activity, and (2) tethering forces, represented by cell-cell and cell-substratum adhesions. We examined whether focal adhesion plaque proteins (vinculin and talin) and focal adhesion kinase, p125FAK (FAK), represent target regulatory sites involved in thrombin-mediated EC barrier dysfunction. Histologically, thrombin produced dramatic rearrangement of EC actin, vinculin, and FAK in parallel with the evolution of gap formation and barrier dysfunction. Vinculin and talin were in vitro substrates for phosphorylation by EC PKC, a key effector enzyme involved in thrombin-induced EC barrier dysfunction. Although vinculin and talin were phosphorylated in situ under basal conditions in 32P-labeled EC, thrombin failed to alter the basal level of phosphorylation of these proteins. Phosphotyrosine immunoblotting showed that neither vinculin nor talin was significantly phosphorylated in situ on tyrosine residues in unstimulated ECs, and this was not further increased after thrombin. In contrast, both thrombin and the thrombin receptor-activating peptide (TRAP) produced an increase in FAK phosphotyrosine levels (corrected for immunoreactive FAK content) present in EC immunoprecipitates. Ionomycin, which produces EC barrier dysfunction in a myosin light chain kinase-independent manner, was used to increase intracellular Ca2+ and evaluate the Ca2+ sensitivity of this observation. In contrast to thrombin, ionomycin effected a dramatic decrease in the phosphotyrosine-to-immunoreactive FAK ratios, suggesting distinct effects of the two agents on FAK phosphorylation and function. These data indicate that modulation of cell tethering via phosphorylation of focal adhesion proteins is complex, agonist-specific, and may be a relevant mechanism of EC barrier dysfunction in permeability models that do not depend on an increase in myosin 20-kD regulatory light chain phosphorylation.

Animals↗
PubMed2004

A novel method for protein secondary structure prediction using dual-layer SVM and profiles.

A high-performance method was developed for protein secondary structure prediction based on the dual-layer support vector machine (SVM) and position-specific scoring matrices (PSSMs). SVM is a new machine learning technology that has been successfully applied in solving problems in the field of bioinformatics. The SVM's performance is usually better than that of traditional machine learning approaches. The performance was further improved by combining PSSM profiles with the SVM analysis. The PSSMs were generated from PSI-BLAST profiles, which contain important evolution information. The final prediction results were generated from the second SVM layer output. On the CB513 data set, the three-state overall per-residue accuracy, Q3, reached 75.2%, while segment overlap (SOV) accuracy increased to 80.0%. On the CB396 data set, the Q3 of our method reached 74.0% and the SOV reached 78.1%. A web server utilizing the method has been constructed and is available at http://www.bioinfo.tsinghua.edu.cn/pmsvm.

Computational Biology↗
PubMed2003

A modified ESID approach to studying mental illness and homelessness.

This paper describes 15 years of research on homelessness using a modified ESID approach. The article summarizes the results of several needs assessment studies; describes the development and evolution of alternative treatment models to assist homeless individuals with severe mental illness; summarizes results of three outcome evaluation studies; and discusses issues of treatment implementation, treatment diffusion, and dissemination.

Black or African American↗
PubMed1997

The non-standard genetic code of Candida spp.: an evolving genetic code or a novel mechanism for adaptation?

A number of yeasts of the genus Candida translate the standard leucine-CUG codon as serine. This unique genetic code change is the only known alteration to the universal genetic code in cytoplasmic mRNAs, of either eukaryotes or prokaryotes, which involves reassignment of a sense codon. Translation of CUG as serine in these species is mediated by a novel serine-tRNA (ser-tRNACAG), which uniquely has a guanosine at position 33, 5' to the anticodon, a position that is almost invariably occupied by a pyrimidine (uridine in general) in all other tRNAs. We propose that G-33 has two important functions: lowering the decoding efficiency of the ser-tRNACAG and preventing binding of the leucyl-tRNA synthetase. This implicates this nucleotide as a key player in the evolutionary reassignment of the CUG codon. In addition, the novel ser-tRNACAG has 1-methylguanosine (m1G-37) at position 37, 3' to the anticodon, which is characteristic of leucine, but not serine tRNAs. Remarkably, m1G-37 causes leucylation of the ser-tRNACAG both in vitro and in vivo, making the CUG codon an ambiguous codon: the polysemous codon. This indicates that some Candida species tolerate ambiguous decoding and suggests either that (i) the genetic code change has not yet been fully established and is evolving at different rates in different Candida species; or (ii) CUG ambiguity is advantageous and represents the final stage of the reassignment. We propose that such dual specificity indicates that reassignment of the CUG codon evolved through a mechanism that required codon ambiguity and that ambiguous decoding evolved to generate genetic diversity and allow for rapid adaptation to environmental challenges.

Adaptation, Physiological↗
PubMed2004

Mode transition induced by low-frequency current in dual-frequency capacitive discharges.

The mode transition induced by varying the low-frequency current in low-pressure dual-frequency discharges in argon is found through particle-in-cell or Monte Carlo simulations. As the low-frequency (2 MHz) current increases for the fixed high-frequency (27 MHz) current, the electron distribution function (EDF) changes from Druyvesteyn to bi-Maxwellian (in alpha mode) or Maxwellian-type (in gamma mode), along with the significant drop in the effective electron temperature. It is shown that this EDF evolution is attributed to the transition from collisional to collisionless property (but not stochastic heating) of the low-energy electrons as well as the alpha-gamma transition.

Journal Article↗
PubMed1999

High-frequency homologous genetic recombination of an arterivirus, lactate dehydrogenase-elevating virus, in mice and evolution of neuropathogenic variants.

On the basis of genome nucleotide differences between a nonneuropathogenic and a neuropathogenic lactate dehydrogenase-elevating virus (LDV) quasispecies (LDV-P and LDV-C, respectively), we have designed sets of primers for polymerase chain reaction (PCR) amplification that can detect recombinants between them in a 1276-nt-long segment ranging from ORF 5 to ORF 7. Mice were infected with large amounts of both LDVs and bled at various times postinfection (p.i.). RNA was extracted from plasma samples and reverse transcribed and the first-strand products were PCR amplified with four sets of sense and antisense primers that discriminate between parental (P/P and C/C) and recombinant (P/C and C/P) genomic segments. Both P/C and C/P recombinants were detected in plasma from six different mice at 1 day p.i. No recombinant products were generated with in vitro mixtures of LDV-P and LDV-C. End-point dilution experiments indicated that the generation of P/C and C/P recombinants varied between mice but that in some mice the frequency of recombination in the 1276-nt-long genome segment was as high as 5%. Sequence analyses of clones of some recombinants indicated that recombination had occurred at 26- to 43-nt-long stretches of homology between the LDV-P and the LDV-C genomes. Sequence analyses of the 3157-nt-long 3' end of the genomes of the neuropathogenic LDV-v and of a newly discovered nonneuropathogenic quasispecies, LDV-vx, showed that LDV-v is a natural recombinant of LDV-vx that has specifically acquired by a double recombination about 400 nt of the 5' end of ORF 5 of the neuropathogenic LDV-C and thereby the unique properties of LDV-C, neuropathogenicity and high sensitivity to antibody neutralization. In dual infections of mice with LDV-P and LDV-C all genetic recombinants, like the LDV-C parent itself, had been lost by 7 days p.i., and only LDV-P persisted. The results further support the view that LDV-P and LDV-vx have evolved to a highly stable relationship with their host, the mouse.

Animals↗
PubMed2003

Functional evolution of the HIV-1 envelope glycoprotein 120 association site of glycoprotein 41.

Protein-protein interaction surfaces can exhibit structural plasticity, a mechanism whereby an interface adapts to mutations as binding partners coevolve. The HIV-1 envelope glycoprotein gp120-gp41 complex, which is responsible for receptor attachment and membrane fusion, represents an extreme example of a coevolving complex as up to 35% amino acid sequence divergence has been observed in these proteins among HIV-1 isolates. In this study, the function of conserved gp120 contact residues, Leu593, Trp596, Gly597, Lys601, and Trp610 within the disulfide-bonded region of gp41, was examined in envelope glycoproteins derived from diverse HIV-1 isolates. We found that the gp120-gp41 association function of the disulfide-bonded region is conserved. However, the contribution of individual residues to gp41 folding and/or stability, gp120-gp41 association, membrane fusion function, and viral entry varied from isolate to isolate. In gp120-gp41 derived from the dual-tropic isolate, HIV-189.6, the importance of Trp596 for fusion function was dependent on the chemokine receptor utilized as a fusion cofactor. Thus, the engagement of alternative chemokine receptors may evoke distinct fusion-activation signals involving the site of gp120-gp41 association. An examination of chimeric glycoproteins revealed that the isolate-specific functional contributions of particular gp120-contact residues are influenced by the sequence of gp120 hypervariable regions 1, 2, and 3. These data indicate that the gp120-gp41 association site is structurally and functionally adaptable, perhaps to maintain a functional glycoprotein complex in a setting of host selective pressures driving the rapid coevolution of gp120 and gp41.

Amino Acid Sequence↗
PubMed1999

Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts.

Proteolytic degradation of extracellular matrix (ECM) components during tissue remodeling plays a pivotal role in normal and pathological processes including wound healing, inflammation, tumor invasion, and metastasis. Proteolytic enzymes in tumors may activate or release growth factors from the ECM or act directly on the ECM itself, thereby facilitating angiogenesis or tumor cell migration. Fibroblast activation protein (FAP) is a cell surface antigen of reactive tumor stromal fibroblasts found in epithelial cancers and in granulation tissue during wound healing. It is absent from most normal adult human tissues. FAP is conserved throughout chordate evolution, with homologues in mouse and Xenopus laevis, whose expression correlates with tissue remodeling events. Using recombinant and purified natural FAP, we show that FAP has both dipeptidyl peptidase activity and a collagenolytic activity capable of degrading gelatin and type I collagen; by sequence, FAP belongs to the serine protease family rather than the matrix metalloprotease family. Mutation of the putative catalytic serine residue of FAP to alanine abolishes both enzymatic activities. Consistent with its in vivo expression pattern determined by immunohistochemistry, FAP enzyme activity was detected by an immunocapture assay in human cancerous tissues but not in matched normal tissues. This study demonstrates that FAP is present as an active cell surface-bound collagenase in epithelial tumor stroma and opens up investigation into physiological substrates of its novel, tumor-associated dipeptidyl peptidase activity.

Adult↗
PubMed1997

Positive and negative MHC class I recognition by rat NK cells.

The prompt rejection of transplanted allogeneic lymphocytes by rat NK cells in non-sensitized recipients (allogeneic lymphocyte cytotoxicity or ALC) is determined by MHC genes as well as by genes located in the NK complex. The same genetic control is found when NK alloreactivity is measured by an in vitro assay, and we have employed this assay to delineate the specificity of NK cells for the MHC. The MHC of the rat, RT1, contains class I genes situated on either side of the class II/class III region. The majority of these class I genes are located in the RT1.C region and expressed class I products usually behave as non-classical (class Ib) molecules. They do not serve as restriction elements for the vast majority of conventional alpha/beta T-cells, in contrast to those class I molecules encoded by one or more loci in the classical (class Ia) region, RT1.A. However, NK cells appear to recognize the products of either class I region. Immunogenetic studies suggest that NK cells are inhibited by RT1. A molecules, whereas RT1.C region molecules may have a dual role in regulating NK cytolytic activity, i.e. they either inhibit or activate natural killing. Based on these premises, a model is proposed in which identification of a target as self or non-self depends on different receptors for class I in single NK cells, interpreting coincident positive and negative signals from the various target class I molecules. The putative role of peptides presented by class I, the biological implications, and the evolution of the NK receptors and their ligands are discussed.

Animals↗
PubMed1998

Bone mineral density in French Canadian women.

This cross-sectional study investigated bone mineral density (BMD) at the lumbar spine (L2-4) and femoral neck in French Canadian women residing in the Quebec city area. Data collection was initiated in 1988 and completed in 1994. A total of 747 French Canadian Caucasian women (16-79 years of age) with no metabolic bone disease were evaluated. BMD measurements were obtained using dual-photon absorptiometry (DPA) or dual-energy X-ray absorptiometry (DXA). Anthropometric measures such as weight, height and body mass index (BMI) were recorded. Medical files provided information on demographic characteristics, hormonal profile and lifestyle habits. Results show a curvilinear trend of BMD with aging. Furthermore, the peak BMD at the lumbar spine (L2-4) was reached at 29 years followed by a stable phase until 35 years, after which BMD started to decrease. The pattern of bone evolution at the femoral neck was different, peak BMD being achieved earlier, at 21 years, while after age 26 years a significant decrease was already observed. Women older than 60 years showed the lowest BMD. Regression analysis showed that age, weight and height are determinants of BMD at the lumbar spine and explained 33.9% of inter-individual variation. At the femoral neck, 29.1% of variation was explained by age and height only. In conclusion, our data suggest that French Canadian women have a different pattern of bone loss at the femoral neck compared with the lumbar spine, according to their mean BMD values.

Adolescent↗
PubMed2005

The dual nature of homologous recombination in plants.

Homologous recombination creates covalent linkages between DNA in regions of highly similar or identical sequence. Recent results from several laboratories, many of them based on forward and reverse genetics in Arabidopsis, give insights into the mechanisms of the enzymatic machinery and the involvement of chromatin in somatic and meiotic DNA recombination. Also, signaling pathways and interconnections between repair pathways are being discovered. In addition, recent work shows that biotic and abiotic influences from the environment can dramatically affect plant genomes. The resulting changes in the DNA sequence, exerted at the level of somatic or meiotic tissue, might contribute to evolution.

Arabidopsis↗
PubMed1999

Evolution of remission as the new standard in the treatment of depression.

Epidemiologic and clinical data support the goal of treating depressed patients to wellness or full remission. Many patients improve but fail to achieve full remission with antidepressant treatment and continue to have residual symptoms, which cause distress and dysfunction. These residual symptoms may meet criteria for subsyndromal and minor depression. Patients who have these milder syndromes after treatment have a greater risk of relapse and recurrence than do those who remain symptom-free. Clinical trials of antidepressants have shown lower rates of remission than of responses that fall short of remission, although some dual-acting antidepressants (e.g., serotonin-norepinephrine reuptake inhibitors) may have higher remission rates than other agents. Treatment with such robust dual-acting antidepressants may result in higher rates of remission and fewer residual symptoms than treatment with selective serotonin reuptake inhibitors.

Antidepressive Agents↗
PubMed1989

[The dual-nature of the retina of mammals].

Using the literary review and author's data the morphologic criterion in the distinction of cones and rods is being discussed. It is based on a distinction of the chromatin structure in the photoreceptor kernels. The rod chromatin is organized by one or a few large blocks which disguise a nucleolus. The cone chromatin is a crumbly grain. One or two nucleoli can be seen clearly. Obviously, the manner of the chromatin condensation reflects the physiological and biochemical distinctions of cones and rods. Even nocturnal or diurnal mammals have mixed double retina. These facts contradict to the Walls' theory of evolution in photoreceptors (transmutation theory) and agree to the Dollo's low. Double-natured retina is a significant condition for its plastic and private adaptation in changing of ecological conditions.

Animals↗
PubMed1983

Natural evolution of atrioventricular conduction in patients with sick sinus syndrome treated by atrial demand pacing. A study of 26 cases.

The authors have followed up 26 patients with sinus node disease who were treated by atrial pacing. The follow-up duration varies between 10 months and 3 years. Assessment of A.V. conduction was performed repeatedly by atrial pacing at increasing rates. Nine patients showed a progressive, sometimes early, deterioration of their A.V. conduction system; five (19%) developed second degree A.V. block of Mobitz type I for pacing rates lower than 100 beats/min. In three of them, the pace-maker had to be replaced by a dual chamber stimulator. Deterioration of A.V. conduction seems to be more frequent in subjects with antecedents of myocardial infarction (4/5) than in others (5/21: p less than 0.05). Deterioration of A.V. conduction is not uncommon among patients with sinus node dysfunction, especially after myocardial infarction. This constitutes a serious limitation to the use of atrial pacing.

Adult↗
PubMed2004

The enhancement of histone H4 and H2A serine 1 phosphorylation during mitosis and S-phase is evolutionarily conserved.

Histone phosphorylation has long been associated with condensed mitotic chromatin; however, the functional roles of these modifications are not yet understood. Histones H1 and H3 are highly phosphorylated from late G2 through telophase in many organisms, and have been implicated in chromatin condensation and sister chromatid segregation. However, mutational analyses in yeast and biochemical experiments with Xenopus extracts have demonstrated that phosphorylation of H1 and H3 is not essential for such processes. In this study, we investigated additional histone phosphorylation events that may have redundant functions to H1 and H3 phosphorylation during mitosis. We developed an antibody to H4 and H2A that are phosphorylated at their respective serine 1 (S1) residues and found that H4S1/H2AS1 are highly phosphorylated in the mitotic chromatin of worm, fly, and mammals. Mitotic H4/H2A phosphorylation has similar timing and localization as H3 phosphorylation, and closely correlates with the chromatin condensation events during mitosis. We also detected a lower level of H4/H2A phosphorylation in 5-bromo-2-deoxyuridine-positive S-phase cells, which corroborates earlier studies that identified H4S1 phosphorylation on newly synthesized histones during S-phase. The evolutionarily conserved phosphorylation of H4/H2A during the cell cycle suggests that they may have a dual purpose in chromatin condensation during mitosis and histone deposition during S-phase.

Amino Acid Sequence↗
PubMed2005

PCR analysis of egyptian respiratory adenovirus isolates, including identification of species, serotypes, and coinfections.

Eighty-eight adenovirus (Ad) isolates and associated clinical data were collected from walk-in patients with influenza-like illness in Egypt during routine influenza surveillance from 1999 through 2002. Respiratory Ad distributions are geographically variable, and serotype prevalence has not been previously characterized in this region. Serotype identity is clinically relevant because it predicts vaccine efficacy and correlates strongly with both clinical presentation and epidemiological pattern. Species and serotype identities were determined using several well-validated multiplex PCR protocols culled from the literature and supplemented with a few novel primer sets designed to identify rare types. The isolates included common species B1 serotypes (Ad3 and Ad7), common species C serotypes (Ad1, Ad2, and Ad5), the less common species B2 serotype Ad11, and three isolates of the rare species B1 serotype Ad16. Two isolates that appear to be variant Ad16 were also identified. Fifteen coinfections of multiple adenoviral types, primarily AdB/AdC and Ad3/Ad7 dual infections, were detected. The majority of these were verified using redundant PCR tests targeted at multiple genes. PCR is able to resolve coinfections, in contrast to traditional serum neutralization tests. PCR is also comparatively rapid and requires very little equipment. Application of the method allowed an inclusive determination of the serotypes found in the Egyptian respiratory sample set and demonstrated that coinfections are common and may play a previously unrecognized role in adenovirus pathogenesis, evolution, and epidemiology. In particular, coinfections may influence adenoviral evolution, as interserotypic recombination has been identified as a source of emerging strains.

Adenovirus Infections, Human↗
PubMed2004

Evolutionary relationships of Aurora kinases: implications for model organism studies and the development of anti-cancer drugs.

BACKGROUND: As key regulators of mitotic chromosome segregation, the Aurora family of serine/threonine kinases play an important role in cell division. Abnormalities in Aurora kinases have been strongly linked with cancer, which has lead to the recent development of new classes of anti-cancer drugs that specifically target the ATP-binding domain of these kinases. From an evolutionary perspective, the species distribution of the Aurora kinase family is complex. Mammals uniquely have three Aurora kinases, Aurora-A, Aurora-B, and Aurora-C, while for other metazoans, including the frog, fruitfly and nematode, only Aurora-A and Aurora-B kinases are known. The fungi have a single Aurora-like homolog. Based on the tacit assumption of orthology to human counterparts, model organism studies have been central to the functional characterization of Aurora kinases. However, the ortholog and paralog relationships of these kinases across various species have not been rigorously examined. Here, we present comprehensive evolutionary analyses of the Aurora kinase family. RESULTS: Phylogenetic trees suggest that all three vertebrate Auroras evolved from a single urochordate ancestor. Specifically, Aurora-A is an orthologous lineage in cold-blooded vertebrates and mammals, while structurally similar Aurora-B and Aurora-C evolved more recently in mammals from a duplication of an ancestral Aurora-B/C gene found in cold-blooded vertebrates. All so-called Aurora-A and Aurora-B kinases of non-chordates are ancestral to the clade of chordate Auroras and, therefore, are not strictly orthologous to vertebrate counterparts. Comparisons of human Aurora-B and Aurora-C sequences to the resolved 3D structure of human Aurora-A lends further support to the evolutionary scenario that vertebrate Aurora-B and Aurora-C are closely related paralogs. Of the 26 residues lining the ATP-binding active site, only three were variant and all were specific to Aurora-A. CONCLUSIONS: In this study, we found that invertebrate Aurora-A and Aurora-B kinases are highly divergent protein families from their chordate counterparts. Furthermore, while the Aurora-A family is ubiquitous among all vertebrates, the Aurora-B and Aurora-C families in humans arose from a gene duplication event in mammals. These findings show the importance of understanding evolutionary relationships in the interpretation and transference of knowledge from studies of model organism systems to human cellular biology. In addition, given the important role of Aurora kinases in cancer, evolutionary analysis and comparisons of ATP-binding domains suggest a rationale for designing dual action anti-tumor drugs that inhibit both Aurora-B and Aurora-C kinases.

Amino Acid Sequence↗
PubMed2026

The genetic code at the balance point of error and demand.

The origin and organizing principles of the genetic code remain central problems in molecular evolution. The low probability of the natural codon-to-amino acid mapping arising by chance has spurred the hypothesis that its structure is optimized for robustness to mutations and translational errors. For the construction of effective molecular machines, the repertoire of encoded amino acids must also be diverse enough in physicochemical features. Here, we examine whether the standard genetic code can be understood as a near-optimal solution balancing these two objectives: minimizing error load and aligning codon assignments with the naturally occurring amino acid composition. Using simulated annealing, we explore this trade-off across a broad range of parameters. We find that the standard genetic code resides near an optimum in the fitness landscape of possible genetic codes. The degeneracy of the code plays a dual role, minimizing mistranslation errors while matching codon multiplicity to amino acid usage frequencies. As a result, uniform codon usage alone is sufficient to recover the empirical amino acid composition, without any additional bias. It is a highly effective solution that balances fidelity against resource availability constraints. A comparative analysis of natural variants also reveals a functional decoupling: error robustness acts as a rigid global constraint determined by code topology, whereas compositional alignment serves as a more flexible variable that adapts to lineage-specific demands. These results support a multi-objective optimization framework in which the genetic code reflects a balance between translational fidelity and proteomic demand.

Genetic Code↗