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New type of carbon nanotubes-narrow nanotubes-has recently been observed with diameters of 4-5 A. It has been postulated that the narrow nanotubes are closed by fullerene fragments of C(20) and C(36). This paper presents computational results on related model nanotubes with stoichiometries such as C(80), C(84), C(96), C(108), or C(120). The computations were carried out at the PM3, AM1, SAM1, HF/3-21G, HF/4-31G, and B3LYP/6-31G(*) levels. Two C(36) fullerenes were considered, D(6h) and D(2d). At the PM3 level and with the C(84) nanotube stoichiometry, the D(2d) cage closure gave a lower energy (by 185 kcal/mol and a diameter of 5.42 A). There is another possible candidate, a C(32) cage with D(4d) symmetry (two four-membered rings). At the PM3 level and with the C(96) nanotube stoichiometry, the D(4d) closure (with a diameter of 5.43 A) had energy lower by 210 kcal/mol than that of the D(6h) nanotube closure. On the other hand, four-membered rings should not play a significant role for narrow nanotubes with a diameter of 4 A, where the dodecahedron-related closure should be exclusive. Still narrower nanotubes are briefly discussed.
J Mol Graph Model 2003 Jun
PMID:Computations of model narrow nanotubes closed by fragments of smaller fullerenes and quasi-fullerenes. 1267 38

Reactive oxygen species (ROS) can act as signaling molecules to stimulate either hypertrophy or apoptosis in cardiac myocytes. We tested the hypothesis that the phenotypic effects of ROS are due to differential, concentration-dependent activation of specific kinase signaling pathways. Adult rat ventricular myocytes were exposed to H(2)O(2) over a broad concentration range (10-1000 microM). Low concentrations of H(2)O(2) (10-30 microM) increased protein synthesis without affecting survival. Higher concentrations of H(2)O(2) (100-200 microM) increased apoptosis (assessed by TUNEL). Still higher concentrations of H(2)O(2) (300-1000 microM) caused both apoptosis and necrosis. A hypertrophic concentration of H(2)O(2) (10 microM) increased the activity of ERK1/2, but not that of JNK, p38 kinase or Akt. An apoptotic concentration of H(2)O(2) (100 microM) activated JNK, p38 kinase and Akt, and further activated ERK1/2. The MEK1/2 inhibitor U0126 prevented the hypertrophic effect of 10 microM H(2)O(2). The apoptotic effect of 100 microM H(2)O(2) was inhibited bya dominant-negative JNK adenovirus, and was potentiated by U0126 or an Akt inhibitor. Thus, the concentration-dependent effects of ROS on myocyte hypertrophy and growth are due, at least in part, to the differential activation of specific kinase signaling pathways that regulate hypertrophy and apoptosis.
J Mol Cell Cardiol 2003 Jun
PMID:H(2)O(2) regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways. 1278 76

The alpha(2)-adrenergic receptors (alpha(2)-ARs) belong to the large family of rhodopsinlike G-protein-coupled receptors that share a common structure of seven transmembrane (TM) alpha-helices. The aims of this study were (1) to determine the number of alpha(2)-AR genes in a teleost fish, the zebrafish (Danio rerio), (2) to study the gene duplication events that generated the alpha(2)-AR subtypes, and (3) to study changes in receptor structure that have occurred since the divergence of the mammalian and fish lineages. Here, we report the cloning and chromosomal mapping of fish orthologs for all three mammalian alpha(2)-ARs. In addition, we identified a fourth alpha(2)-AR subtype with two duplicates in zebrafish. Chromosomal mapping showed that the zebrafish alpha(2)-AR genes are located within conserved chromosomal segments, consistent with the origin of the four alpha(2)-AR subtypes by two rounds of chromosome or block duplication before the divergence of the ray fin fish and tetrapod lineages. Thus, the fourth subtype has apparently been present in the common ancestor of vertebrates but has been deleted or is yet to be identified in mammals. The overall percentage identity between the fish and mammalian orthologs is 53% to 67%, and in the TM regions 80% to 87%. These values are clearly lower than what is observed between mammalian orthologs. Still, all of the residues thought to be important for alpha(2)-adrenergic ligand binding are conserved across species and subtypes, and even the most divergent regions of the fish receptors show clear "molecular fingerprints" typical for orthologs of a given subtype.
Mol Biol Evol 2004 Jan
PMID:Identification of duplicated fourth alpha2-adrenergic receptor subtype by cloning and mapping of five receptor genes in zebrafish. 1294 38

Apolipoprotein E (apoE) remains the most important genetic risk factor for the development of Alzheimer's disease (AD). Still elusive, the role of apoE is under intense investigation. We propose that proteolysis of apoE in the brain leads to two major fragments, N- and C-terminal apoE, each of which would drive a different neuropathological pathway. N-terminal fragments of apoE are implicated in neurotoxicity, and C-terminal fragments might play a role in amyloid deposition and plaque formation. The greater risk of AD associated with the E4 isoform might relate to its greater neurotoxicity. Drugs that either directly inhibit the toxic effects of apoE or prevent the production of apoE fragments may provide novel therapeutic approaches to the treatment of AD and other disorders in which apoE is implicated.
J Mol Neurosci 2003
PMID:Apolipoprotein E-related neurotoxicity as a therapeutic target for Alzheimer's disease. 1450 Oct 16

In recent years, our understanding of biological nitrogen fixation has been bolstered by a diverse array of scientific techniques. Still, the origin and extant distribution of nitrogen fixation has been perplexing from a phylogenetic perspective, largely because of factors that confound molecular phylogeny such as sequence divergence, paralogy, and horizontal gene transfer. Here, we make use of 110 publicly available complete genome sequences to understand how the core components of nitrogenase, including NifH, NifD, NifK, NifE, and NifN proteins, have evolved. These genes are universal in nitrogen fixing organisms-typically found within highly conserved operons-and, overall, have remarkably congruent phylogenetic histories. Additional clues to the early origins of this system are available from two distinct clades of nitrogenase paralogs: a group composed of genes essential to photosynthetic pigment biosynthesis and a group of uncharacterized genes present in methanogens and in some photosynthetic bacteria. We explore the complex genetic history of the nitrogenase family, which is replete with gene duplication, recruitment, fusion, and horizontal gene transfer and discuss these events in light of the hypothesized presence of nitrogenase in the last common ancestor of modern organisms, as well as the additional possibility that nitrogen fixation might have evolved later, perhaps in methanogenic archaea, and was subsequently transferred into the bacterial domain.
Mol Biol Evol 2004 Mar
PMID:The natural history of nitrogen fixation. 1469 78

Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) elicit proliferation, migration, and differentiation in a wide spectrum of cell types through various signal transduction pathways. These activities are attenuated by receptor internalization, intracellular trafficking through endosomes, and degradation in lysosomes, resulting in decreased receptor expression. However, there is now considerable evidence that EGFRs continue to signal in endosomes, forcing us to reevaluate the outcomes of receptor trafficking. An exciting revelation is that internalized receptors extend some signaling activities but not others, suggesting that certain responses, such as cell motility, must be mediated at the cell surface. Still, only when the effects of decreased receptor populations and signaling compartmentalization are integrated can we hope to understand and manipulate receptor function at the molecular level.
Mol Interv 2002 Sep
PMID:Localization of receptor-mediated signal transduction pathways: the inside story. 1499 84

Chromosome fragmentation (CF) constitutes one means of manipulating eukaryotic genomes and provides a powerful tool for examining both the structure and function of chromosomes. During the past 15 yr, CF, which is based on the use of transfection, has been widely used in yeast and mammals to elucidate the functional elements required for normal chromosome maintenance. However, in view of the relatively late development of parasite genome projects, this strategy has only been used recently in parasites. Here, we describe basic methods for CF (except telomere-mediated fragmentation) experiments and analysis in Leishmania. Current limitations of this methodology are precisely the lack of knowledge of the nature of centromeres and autonomously replicating sequences in this and other protozoa, the poor understanding of precise recombination mechanisms, as well as the fact that the deletion of unknown genes essential to parasite survival may interfere with recombination events and chromosomal rearrangements. Still, this powerful method has enriched our basic knowledge of chromosomal structure and maintenance.
Methods Mol Biol 2004
PMID:Chromosome fragmentation in leishmania. 1515 39

The meiosis of mammalian oocytes begins during the fetal life and stops at the dictyate stage. This study has assessed the role of specific phosphodiesterase (PDE) inhibitors on the control of meiotic resumption in porcine oocytes investigating the influence of PMSG-hCG and cAMP stimulation. Cumulus-oocytes complexes (COCs) and denuded oocytes (DOs) were collected from gilt ovaries obtained at a local slaughterhouse. Oocytes were cultured in NCSU23 with different PDE inhibitors. The EC(50) for oocytes maintained in germinal vesicle (GV) stage was evaluated using different doses of both cilostamide (CIL), PDE3 inhibitor and 3-isobutyl-1-methylxanthine (IBMX), a nonspecific PDE inhibitor. In presence of PMSG-hCG, meiotic resumption is observed after 24 hr of culture. Both CIL and IBMX reversibly blocked meiotic resumption. In absence of PMSG-hCG, meiotic resumption is reduced after 24 hr of culture. After 48 hr of culture, only CIL significantly blocked meiotic resumption. Still in absence of PMSG-hCG, significant effect of treatment was only observed in COCs using the combination of CIL and rolipram (PDE3 and PDE4 inhibitor, respectively) compared to the use of IBMX. To assess the contribution of cAMP synthesis, a low dose of an adenylyl cyclase (AC) stimulator, forskolin, has been used in combination with CIL showing a significant effect of this combination. In CIL-treated COCs and DOs, significant higher percentages of oocytes were maintained in GV stage when cultured in combination with forskolin instead of PMSG-hCG. In conclusion, these results demonstrate that the control of meiotic resumption in porcine oocytes is highly regulated by cAMP. Both the degradation by specific PDE3 enzyme and the synthesis by an active AC are highly involved.
Mol Reprod Dev 2005 Mar
PMID:Fundamental significance of specific phosphodiesterases in the control of spontaneous meiotic resumption in porcine oocytes. 1562 97

The question of whether or not the high rates (mu) of mutation that occur for some hypervariable markers can affect commonly used empirical measures of spatial structure of genetic variation within populations is addressed. The results show that values of these measures are approximately halved when mu is 10(-2). Finest spatial-scale correlations, measured by either Moran's I-statistics or conditional kinship, are reduced by 30%-50%. When the mutation rate is 10 times lower, much smaller reductions result, e.g. averaging 7% for the finest scale correlations. Still smaller orders of magnitude of mu cause negligible changes in spatial structure, where any effects normally would not be detectable. The reductions are caused by forward mutations, and when the reductions are measured as percentages, they are nearly independent of the amount of structure produced sans mutation, except when dispersal is nearly minimal. The percent reductions are also nearly independent of the number of alleles and of back mutations, hence of the nature of the mutation process (e.g. stepwise or not). The results demonstrate that some hypervariable loci should have reduced spatial structuring, and that marker choice may affect the values observed in experimental surveys. Moreover, if fine-scale correlations are used to indirectly estimate dispersal distances, then mutation at high rates could inflate estimates, easily up to two- to three-fold.
Mol Ecol 2005 Mar
PMID:Mutation at high rates reduces spatial structure within populations. 1572 62

Type II restriction endonucleases are components of restriction modification systems that protect bacteria and archaea against invading foreign DNA. Most are homodimeric or tetrameric enzymes that cleave DNA at defined sites of 4-8 bp in length and require Mg2+ ions for catalysis. They differ in the details of the recognition process and the mode of cleavage, indicators that these enzymes are more diverse than originally thought. Still, most of them have a similar structural core and seem to share a common mechanism of DNA cleavage, suggesting that they evolved from a common ancestor. Only a few restriction endonucleases discovered thus far do not belong to the PD...D/ExK family of enzymes, but rather have active sites typical of other endonuclease families. The present review deals with new developments in the field of Type II restriction endonucleases. One of the more interesting aspects is the increasing awareness of the diversity of Type II restriction enzymes. Nevertheless, structural studies summarized herein deal with the more common subtypes. A major emphasis of this review will be on target site location and the mechanism of catalysis, two problems currently being addressed in the literature.
Cell Mol Life Sci 2005 Mar
PMID:Type II restriction endonucleases: structure and mechanism. 1577 Apr 20


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