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At least 919 records · Page 51Linked to original sources
PubMed2006

Calculations of nuclear quadrupole coupling in noble gas-noble metal fluorides: interplay of relativistic and electron correlation effects.

The nuclear quadrupole coupling constants (NQCCs) of noble gas and noble metal nuclei in the recently found noble gas-noble metal fluorides (NgMF, where Ng=Ar,Kr,Xe and M=Cu,Ag,Au) are obtained theoretically by high-level ab initio calculations, where both relativistic and electron correlation effects are included, and compared to experimental results. Fully relativistic four-component Dirac-Hartree-Fock (DHF) calculations are carried out at the basis set limit for electric field gradient that couples with the electric quadrupole moment of the nucleus, and uncorrelated relativistic effects are extracted by comparing DHF results to nonrelativistic (NR) HF calculations. Electron correlation effects are investigated both at fully relativistic second-order Moller-Plesset (DMP2) and at NR MP2 levels of theory, as well as at the NR coupled-cluster singles and doubles with perturbational triples [CCSD(T)] level. The validity of the approximation where relativistic effects, on the one hand, and nonrelativistically obtained correlation effects, on the other hand, are evaluated separately and assumed to be additive, is investigated by comparison with the DMP2 results. Inclusion of relativistic effects is shown to be necessary for obtaining the correct NQCC trends as the nucleus of interest and/or its neighbors become heavier. Electron correlation treatment is needed for approaching quantitative agreement with the experimental NQCCs. The assumption of additive electron correlation and relativistic effects, corresponding to the NR correlation treatment added on top of relativistic DHF data, gives qualitatively correct noble gas NQCCs. For noble metal NQCCs, correlation treatment at the relativistic level of theory is mandatory for reaching agreement with experimental results. Current work also confirms the experimental trends of NQCCs, which have been taken as an indication of nearly covalent interaction between noble gas and noble metal in the heaviest present systems, especially in XeAuF.

Journal Article↗
PubMed2004

Interplay between antibacterial effectors: a macrophage antimicrobial peptide impairs intracellular Salmonella replication.

Antimicrobial peptides have established an important role in the defense against extracellular infections, but the expression of cationic peptides within macrophages as an antibacterial effector mechanism against intracellular pathogens has not been demonstrated. Macrophage expression of the murine cathelicidin-related antimicrobial peptide (CRAMP) was increased after infection by the intracellular pathogen Salmonella typhimurium, and this increase required reactive oxygen intermediates. By using CRAMP-deficient mice or synthetic CRAMP peptide, we found that CRAMP impaired Salmonella cell division in vivo and in vitro, resulting in long filamentous bacteria. This impaired bacterial cell division also depended on intracellular elastase-like serine protease activity, which can proteolytically activate cathelicidins. Macrophage serine protease activity induced filamentation and enhanced the activity of CRAMP in vitro. A peptide-sensitive Salmonella mutant showed enhanced survival within macrophages derived from CRAMP-deficient mice, indicating that Salmonella can sense and respond to cationic peptides in the intracellular environment. Although cationic peptides have been hypothesized to have activity against pathogens within macrophages, this work provides experimental evidence that the antimicrobial arsenal of macrophages includes cathelicidins. These results show that intracellular reactive oxygen intermediates and proteases regulate macrophage CRAMP expression and activity to impair the replication of an intracellular bacterial pathogen, and they highlight the cooperativity between macrophage antibacterial effectors.

Amino Acid Sequence↗
PubMed2004

Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth.

Receptor tyrosine kinases of the Eph family are up-regulated in different types of cancer. EphB4 and its ligand ephrin-B2 have been linked to breast cancer, but little is known about how this receptor-ligand complex may contribute to oncogenesis. The Eph receptors transmit forward signals via their kinase domain and reverse signals via their transmembrane ephrin-B ligands. Therefore, we used EphB4 that were lacking the kinase domain and tagged with EGFP (EphB4 Delta C-EGFP) to differentiate between EphB4 and ephrin-B2 signaling. Interestingly, we found that expression of EphB4 Delta C-EGFP in breast cancer cells increases tumor growth in a mouse xenograft model. Given the undetectable EphB4 activation in the tumor cells, dominant negative effects of EphB4 Delta C-EGFP are unlikely to explain the increased tumor growth. Examination of the tumors revealed that ephrin-B2 is primarily expressed in the vasculature and that the EphB4 Delta C-EGFP tumors have a higher blood content than control tumors, concomitant with increased size of blood vessels. In support of an effect on the vasculature, the extracellular domain of EphB4 attracts endothelial cells in vitro and stimulates endothelial cell invasion, survival, and proliferation, all crucial factors for angiogenesis. These results support a model in which EphB4 promotes tumor growth by stimulating angiogenesis through ephrin-B2.

Animals↗
PubMed2004

Interplay between Drosophila Bloom's syndrome helicase and Ku autoantigen during nonhomologous end joining repair of P element-induced DNA breaks.

P transposable elements in Drosophila are mobilized via a cut-and-paste mechanism. The broken DNA ends generated during transposition can be repaired via the homology-directed synthesis-dependent strand annealing or by nonhomologous end joining (NHEJ). Genetic studies have demonstrated an interaction between the gene (mus309, for mutagen-sensitive) encoding the Drosophila Bloom's syndrome helicase homolog (DmBLM) and the Ku70 gene, which is involved in NHEJ. We have used RNA interference (RNAi) to knock down expression of DmBLM and one or both of the Drosophila Ku subunits, DmKu70 or DmKu80. Our results show that upon reduction of DmKu, an increase in small deletions (1-49 bp) and large deletions (>/=50 bp) flanking the site of P element-induced breaks is observed, and a reduction in large deletions at these sites is found upon reduction of DmBLM. Moreover, double RNAi of DmKu and DmBLM results in an increase in small deletions characteristic of the DmKu RNAi and also partially suppresses the reduction in repair efficiency observed with DmKu RNAi. These results suggest that there are DNA double-strand break recognition and/or processing events involving DmKu and DmBLM that, when eliminated by RNAi, lead to deletions. Finally, these results raise the possibility that, unlike the situation in mammals, where BLM appears to function exclusively in the homologous repair pathway, in Drosophila, DmBLM may be directly involved in, or at least influence the double-strand break recognition that leads to the NHEJ repair pathway.

Adenosine Triphosphatases↗
PubMed2005

The retinal chromophore/chloride ion pair: structure of the photoisomerization path and interplay of charge transfer and covalent states.

Ab initio multi-reference second-order perturbation theory computations are used to explore the photochemical behavior of two ion pairs constituted by a chloride counterion interacting with either a rhodopsin or bacteriorhodopsin chromophore model (i.e., the 4-cis-gamma-methylnona-2,4,6,8-tetraeniminium and all-trans-nona-2,4,6,8-tetraeniminium cations, respectively). Significant counterion effects on the structure of the photoisomerization paths are unveiled by comparison with the paths of the same chromophores in vacuo. Indeed, we demonstrate that the counterion (i) modulates the relative stability of the S0, S1, and S2 energy surfaces leading to an S1 isomerization energy profile where the S1 and S2 states are substantially degenerate; (ii) leads to the emergence of significant S1 energy barriers along all of the isomerization paths except the one mimicking the 11-cis --> all-trans isomerization of the rhodopsin chromophore model; and (iii) changes the nature of the S1 --> S0 decay funnel that becomes a stable excited state minimum when the isomerizing double bond is located at the center of the chromophore moiety. We show that these (apparently very different) counterion effects can be rationalized on the basis of a simple qualitative electrostatic model, which also provides a crude basis for understanding the behavior of retinal protonated Schiff bases in solution.

Alkenes↗
PubMed2005

VEGF-integrin interplay controls tumor growth and vascularization.

Cross-talk between the major angiogenic growth factor, VEGF, and integrin cell adhesion receptors has emerged recently as a critical factor in the regulation of angiogenesis and tumor development. However, the molecular mechanisms and consequences of this intercommunication remain unclear. Here, we define a mechanism whereby integrin alpha v beta3, through activation, clustering, and signaling by means of p66 Shc (Src homology 2 domain containing), regulates the production of VEGF in tumor cells expressing this integrin. Tumors with "activatable" but not "inactive" beta3 integrin secrete high levels of VEGF, which in turn promotes extensive neovascularization and augments tumor growth in vivo. This stimulation of VEGF expression depends upon the ability of alpha v beta3 integrin to cluster and promote phosphorylation of p66 Shc. These observations identify a link between beta3 integrins and VEGF in tumor growth and angiogenesis and, therefore, may influence anti-integrin as well as anti-VEGF therapeutic strategies.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Structure of human Wilson protein domains 5 and 6 and their interplay with domain 4 and the copper chaperone HAH1 in copper uptake.

Human Wilson protein is a copper-transporting ATPase located in the secretory pathway possessing six N-terminal metal-binding domains. Here we focus on the function of the metal-binding domains closest to the vesicular portion of the copper pump, i.e., domain 4 (WLN4), and a construct of domains 5 and 6 (WLN5-6). For comparison purposes, some experiments were also performed with domain 2 (WLN2). The solution structure of apoWLN5-6 consists of two ferredoxin folds connected by a short linker, and (15)N relaxation rate measurements show that it behaves as a unit in solution. An NMR titration of apoWLN5-6 with the metallochaperone Cu(I)HAH1 reveals no complex formation and no copper exchange between the two proteins, whereas titration of Cu(I)HAH1 with WLN4 shows the formation of an adduct that is in fast exchange on the NMR time scale with the isolated protein species as confirmed by (15)N relaxation data. A similar interaction is also observed between Cu(I)HAH1 and WLN2; however, the relative amount of the adduct in the protein mixture is lower. An NMR titration of apoWLN5-6 with Cu(I)WLN4 shows copper transfer, first to WLN6 then to WLN5, without the formation of an adduct. Therefore, we suggest that WLN4 and WLN2 are two acceptors of Cu(I) from HAH1, which then somehow route copper to WLN5-6, before the ATP-driven transport of copper across the vesicular membrane.

Adenosine Triphosphatases↗
PubMed2005

Interplay among coactivator-associated arginine methyltransferase 1, CBP, and CIITA in IFN-gamma-inducible MHC-II gene expression.

Class II major histocompatibility (MHC-II) genes are prototype targets of IFN-gamma. IFN-gamma activates the expression of the non-DNA-binding master regulator of MHC-II, class II transactivator (CIITA), which is crucial for enhanceosome formation and gene activation. This report shows the importance of the histone methyltransferase, coactivator-associated arginine methyltransferase (CARM1/PRMT4), during IFN-gamma-induced MHC-II gene activation. It also demonstrates the coordinated regulation of CIITA, CARM1, and the acetyltransferase cyclic-AMP response element binding (CREB)-binding protein (CBP) during this process. CARM1 synergizes with CIITA in activating MHC-II transcription and synergy is abrogated when an arginine methyltransferase-defective CARM1 mutant is used. Protein-arginine methyltransferase 1 has much less effect on MHC-II transcription. Specific RNA interference reduced CARM1 expression as well as MHC-II expression. The recruitment of CARM1 to the promoter requires endogenous CIITA and results in methylation of histone H3-R17; hence, CIITA is an upstream regulator of histone methylation. Previous work has shown that CARM1 can methylate CBP at three arginine residues. Using wild-type CBP and a mutant of CBP lacking the CARM1-targeted arginine residues (R3A), we show that arginine methylation of CBP is required for IFN-gamma induction of MHC-II. A kinetic analysis shows that CIITA, CARM1, and H3-R17 methylation all precede CBP loading on the MHC-II promoter during IFN-gamma treatment. These results suggest functional and temporal relationships among CIITA, CARM1, and CBP for IFN-gamma induction of MHC-II.

Animals↗
PubMed2006

Interplay between replication and recombination in Escherichia coli: impact of the alternative DNA polymerases.

Homologous recombination (HR) and translesion synthesis (TLS) are two pathways involved in the tolerance of lesions that block the replicative DNA polymerase. However, whereas TLS is frequently error-prone and, therefore, can be deleterious, HR is generally error-free. Furthermore, because the recombination enzymes and alternative DNA polymerases that perform TLS may use the same substrate, their coordination might be important to assure cell fitness and survival. This study aimed to determine whether and how these pathways are coordinated in Escherichia coli cells by using conjugational replication and recombination as a model system. The role of the three alternative DNA polymerases that are regulated by the SOS system was tested in DNA polymerase III holoenzyme-proficient and -deficient mutants. When PolIII is inactive, the alternative DNA polymerases copy DNA in the following order: PolII, PolIV, and PolV. The observed hierarchy corresponds to the selective constraints imposed on the genes coding for alternative DNA polymerases observed in natural populations of E. coli, suggesting that this hierarchy depends on the frequency of specific damages encountered during the evolutionary history of E. coli. We also found that DNA replication and HR are in competition and that they can precede each other. Our results suggest that there is probably not an active choice of which pathway to use, but, rather, the nature and concentration of lesions that lead to formation of ssDNA and the level of SOS induction that they engender might determine the outcome of the competition between HR and alternative DNA polymerases.

Chromosomes, Bacterial↗
PubMed2006

Interplay between PIP3 and calmodulin regulation of olfactory cyclic nucleotide-gated channels.

Phosphatidylinositol-3,4,5-trisphosphate (PIP3) has been proposed to modulate the odorant sensitivity of olfactory sensory neurons by inhibiting activation of cyclic nucleotide-gated (CNG) channels in the cilia. When applied to the intracellular face of excised patches, PIP3 has been shown to inhibit activation of heteromeric olfactory CNG channels, composed of CNGA2, CNGA4, and CNGB1b subunits, and homomeric CNGA2 channels. In contrast, we discovered that channels formed by CNGA3 subunits from cone photoreceptors were unaffected by PIP3. Using chimeric channels and a deletion mutant, we determined that residues 61-90 within the N terminus of CNGA2 are necessary for PIP3 regulation, and a biochemical "pulldown" assay suggests that PIP3 directly binds this region. The N terminus of CNGA2 contains a previously identified calcium-calmodulin (Ca2+/CaM)-binding domain (residues 68-81) that mediates Ca2+/CaM inhibition of homomeric CNGA2 channels but is functionally silent in heteromeric channels. We discovered, however, that this region is required for PIP3 regulation of both homomeric and heteromeric channels. Furthermore, PIP3 occluded the action of Ca2+/CaM on both homomeric and heteromeric channels, in part by blocking Ca2+/CaM binding. Our results establish the importance of the CNGA2 N terminus for PIP3 inhibition of olfactory CNG channels and suggest that PIP3 inhibits channel activation by disrupting an autoexcitatory interaction between the N and C termini of adjacent subunits. By dramatically suppressing channel currents, PIP3 may generate a shift in odorant sensitivity that does not require prior channel activity.

Animals↗
PubMed2006

Structure of the nuclear exosome component Rrp6p reveals an interplay between the active site and the HRDC domain.

The multisubunit eukaryotic exosome is an essential RNA processing and degradation machine. In its nuclear form, the exosome associates with the auxiliary factor Rrp6p, which participates in both RNA processing and degradation reactions. The crystal structure of Saccharomyces cerevisiae Rrp6p displays a conserved RNase D core with a flanking HRDC (helicase and RNase D C-terminal) domain in an unusual conformation shown to be important for the processing function of the enzyme. Complexes with AMP and UMP, the products of the RNA degradation process, reveal how the protein specifically recognizes ribonucleotides and their bases. Finally, in vivo mutational studies show the importance of the domain contacts for the processing function of Rrp6p and highlight fundamental differences between the protein and its prokaryotic RNase D counterparts.

Binding Sites↗
PubMed2003

Interplay of the Arabidopsis nonhost resistance gene NHO1 with bacterial virulence.

It is poorly understood why a particular plant species is resistant to the vast majority of potential pathogens that infect other plant species, a phenomenon referred to as "nonhost" resistance. Here, we show that Arabidopsis NHO1, encoding a glycerol kinase, is required for resistance to and induced by Pseudomonas syringae isolates from bean and tobacco. NHO1 is also required for resistance to the fungal pathogen Botrytis cinerea, indicating that NHO1 is not limited to bacterial resistance. Strikingly, P. s. pv. tomato DC3000, an isolate fully virulent on Arabidopsis, actively suppressed the NHO1 expression. This suppression is abolished in coi1 plants, indicating that DC3000 required an intact jasmonic acid signaling pathway in the plant to suppress NHO1 expression. Constitutive overexpression of NHO1 led to enhanced resistance to this otherwise virulent bacterium. The presence of avrB in DC3000, which activates a cultivar-specific "gene-for-gene" resistance in Arabidopsis, restored the induction of NHO1 expression. Thus, NHO1 is deployed for both general and specific resistance in Arabidopsis and targeted by the bacterium for parasitism.

Amino Acid Sequence↗
PubMed2000

Dynamic interplay between antagonistic pathways controlling the sigma 32 level in Escherichia coli.

The heat-shock response in Escherichia coli depends primarily on the transient increase in the cellular level of heat-shock sigma factor final sigma(32) encoded by the rpoH gene, which results from both enhanced synthesis and transient stabilization of normally unstable final sigma(32). Heat-induced synthesis of final sigma(32) was previously shown to occur at the translation level by melting the mRNA secondary structure formed within the 5' coding sequence of rpoH including the translation initiation region. The subsequent decrease in the final sigma(32) level during the adaptation phase has been thought to involve both shutoff of synthesis (translation) and destabilization of final sigma(32)-mediated by the DnaK-DnaJ chaperones, although direct evidence for translational repression was lacking. We now show that the heat-induced synthesis of final sigma(32) does not shut off at the translation level by using a reporter system involving translational coupling. Furthermore, the apparent shutoff was not observed when the synthesis rate was determined by a very short pulse labeling (15 s). Examination of final sigma(32) stability at 10 min after shift from 30 to 42 degrees C revealed more extreme instability (t(1/2)=20 s) than had previously been thought. Thus, the dynamic change in final sigma(32) stability during the heat-shock response largely accounts for the apparent shutoff of final sigma(32) synthesis observed with a longer pulse. These results suggest a mechanism for maintaining the intricate balance between the antagonistic pathways: the rpoH translation as determined primarily by ambient temperature and the turnover of final sigma(32) as modulated by the chaperone (and presumably protease)-mediated autogenous control.

Amino Acid Sequence↗
PubMed2003

The interplay of glycosylation and disulfide formation influences fibrillization in a prion protein fragment.

It is now accepted that the structural transition from cellular prion protein (PrPC) to proteinase K-resistant prion protein scrapie (PrPSc) is the major event leading to transmissible spongiform encephalopathies. Although the mechanism of this transition remains elusive, glycosylation has been proposed to impede the PrPC to PrPSc conversion. To address the role of glycosylation, we have prepared glycosylated and unglycosylated peptides derived from the 175-195 fragment of the human prion protein. Comparison of the structure, aggregation kinetics, fibril formation capabilities, and redox susceptibility of Cys-179 has shown that the N-linked glycan (at Asn-181) significantly reduces the rate of fibrillization by promoting intermolecular disulfide formation via Cys-179. Further-more, the aggressive fibrillization of a C179S mutant of this fragment highlights the significant role of disulfide stability in retarding the rate of fibril formation. The implications of these studies are discussed in the context of fibril formation in the intact prion protein.

Amino Acid Sequence↗
PubMed2000

Human lung cancer and p53: the interplay between mutagenesis and selection.

It is an almost consensus opinion that the major carcinogenic risk of tobacco smoke is in its direct mutagenic action on DNA of cancer-related genes. The key data supposedly linking smoke-induced mutations to lung cancer were obtained from the adduct spectrum of the p53 tumor suppressor gene. Results of our analysis of p53 mutations compiled from the International Agency for Research on Cancer p53 database (April 1999 update) and from the literature point to a different causative link. Our new analytical tests focused on complementary base substitutions and showed that it is strand-specific repair of primary lesions and site-specific selection of the resultant mutations that determine the lung cancer-specific hot spots of G:C to T:A transversions along the p53 gene and also their increased abundance in lung tissues as compared with smoke-inaccessible tissues. However, on each of the two strands of p53 DNA, our tests revealed no significant difference between smokers and nonsmokers, either in the frequency of different types of mutations or in the frequency of their occurrence along the p53 gene. Moreover, in both smokers and nonsmokers, there was the same frequency of lung tumors with silent p53 mutations. Accordingly, we offer here a selection-based explanation of why lung cancers with nonsilent p53 mutations are more common in smokers than in nonsmokers. We conclude that physiological stresses (not necessarily genotoxic) aggravated by smoking are the leading risk factor in the p53-associated etiology of lung cancer.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2001

Controlling potassium channel activities: Interplay between the membrane and intracellular factors.

Neural signaling is based on the regulated timing and extent of channel opening; therefore, it is important to understand how ion channels open and close in response to neurotransmitters and intracellular messengers. Here, we examine this question for potassium channels, an extraordinarily diverse group of ion channels. Voltage-gated potassium (Kv) channels control action-potential waveforms and neuronal firing patterns by opening and closing in response to membrane-potential changes. These effects can be strongly modulated by cytoplasmic factors such as kinases, phosphatases, and small GTPases. A Kv alpha subunit contains six transmembrane segments, including an intrinsic voltage sensor. In contrast, inwardly rectifying potassium (Kir) channels have just two transmembrane segments in each of its four pore-lining alpha subunits. A variety of intracellular second messengers mediate transmitter and metabolic regulation of Kir channels. For example, Kir3 (GIRK) channels open on binding to the G protein betagamma subunits, thereby mediating slow inhibitory postsynaptic potentials in the brain. Our structure-based functional analysis on the cytoplasmic N-terminal tetramerization domain T1 of the voltage-gated channel, Kv1.2, uncovered a new function for this domain, modulation of voltage gating, and suggested a possible means of communication between second messenger pathways and Kv channels. A yeast screen for active Kir3.2 channels subjected to random mutagenesis has identified residues in the transmembrane segments that are crucial for controlling the opening of Kir3.2 channels. The identification of structural elements involved in potassium channel gating in these systems highlights principles that may be important in the regulation of other types of channels.

Amino Acid Sequence↗
PubMed2001

The interplay of biology and technology.

Technologies for biological research arise in multiple ways-through serendipity, through inspired insights, and through incremental advances-and they are tightly coupled to progress in engineering. Underlying the complex dynamics of technology and biology are the different motivations of those who work in the two realms. Consideration of how methodologies emerge has implications for the planning of interdisciplinary centers and the training of the next generation of scientists.

Biotechnology↗