55 research outputs found
Applying the extended molecule approach to correlated electron transport: important insight from model calculations
Theoretical approaches of electronic transport in correlated molecules
usually consider an extended molecule, which includes, in addition to the
molecule itself, parts of electrodes. In the case where electron correlations
remain confined within the molecule, and the extended molecule is sufficiently
large, the current can be expressed by means of Laudauer-type formulae.
Electron correlations are embodied into the retarded Green function of a
sufficiently large but isolated extended molecule, which represents the key
quantity that can be accurately determined by means of ab initio quantum
chemical calculations. To exemplify these ideas, we present and analyze
numerical results obtained within full CI calculations for an extended molecule
described by the interacting resonant level model. Based on them, we argue that
for organic electrodes the transport properties can be reliably computed,
because the extended molecule can be chosen sufficiently small to be tackled
within accurate ab initio methods. For metallic electrodes, larger extended
molecules have to be considered in general, but a (semi-)quantitative
description of the transport should still be possible particularly in the
typical cases where electron transport proceeds by off-resonant tunneling. Our
numerical results also demonstrate that, contrary to the usual claim, the ratio
between the characteristic Coulomb strength and the level width due to
molecule-electrode coupling is not the only quantity needed to assess whether
electron correlation effects are strong or weak
Women, autoimmunity, and cancer: a dangerous liaison between estrogen and activation-induced deaminase?
Why women are more susceptible to autoimmune diseases is not completely clear, but new data suggest that the hormone estrogen may play an important role. A new study now shows that estrogen activates the expression of activation-induced deaminase (AID), a protein that drives antibody diversification by deaminating cytosine in DNA to uracil. If estrogen increases the level of AID, increased mutations could transform benign antibodies into anti-self pariahs. AID might also contribute to cancerâparticularly in breast tissue, which is highly responsive to estrogenâby introducing mutations and strand breaks into the genome
XRCC1 suppresses somatic hypermutation and promotes alternative nonhomologous end joining in Igh genes
As revealed using mice heterozygous for the base excision repair (BER) protein XRCC1, BER and mutagenic repair pathways can simultaneously compete for access to single-strand breaks induced by activation-induced deaminase
Roles of the Escherichia coli RecA Protein and the Global SOS Response in Effecting DNA Polymerase Selection In Vivo
The Escherichia coli β sliding clamp protein is proposed to play an important role in effecting switches between different DNA polymerases during replication, repair, and translesion DNA synthesis. We recently described how strains bearing the dnaN159 allele, which encodes a mutant form of the β clamp (β159), display a UV-sensitive phenotype that is suppressed by inactivation of DNA polymerase IV (M. D. Sutton, J. Bacteriol. 186:6738-6748, 2004). As part of an ongoing effort to understand mechanisms of DNA polymerase management in E. coli, we have further characterized effects of the dnaN159 allele on polymerase usage. Three of the five E.coli DNA polymerases (II, IV, and V) are regulated as part of the global SOS response. Our results indicate that elevated expression of the dinB-encoded polymerase IV is sufficient to result in conditional lethality of the dnaN159 strain. In contrast, chronically activated RecA protein, expressed from the recA730 allele, is lethal to the dnaN159 strain, and this lethality is suppressed by mutations that either mitigate RecA730 activity (i.e., ÎrecR), or impair the activities of DNA polymerase II or DNA polymerase V (i.e., ÎpolB or ÎumuDC). Thus, we have identified distinct genetic requirements whereby each of the three different SOS-regulated DNA polymerases are able to confer lethality upon the dnaN159 strain, suggesting the presence of multiple mechanisms by which the actions of the cell's different DNA polymerases are managed in vivo
Co-Stimulation of BCR and Toll-Like Receptor 7 Increases Somatic Hypermutation, Memory B Cell Formation, and Secondary Antibody Response to Protein Antigen
The goal of immunization is to produce both a flood of antibodies to neutralize antigen and memory cells to accelerate the secondary response. To enhance the generation of memory B cells, we examined the effect of co-engaging BCR and toll-like receptor (TLR) 7 receptors by immunizing mice with a hapten-protein antigen, NP-CGG, and a ligand, R837 (imiquimod). During the early and late primary responses, there was no augmentation with R837 on the number of germinal center B cells or serum antibody. However, in the niche of germinal centers, R837 increased somatic hypermutation in the canonical VH1-72 gene that encodes NP-specific antibody. Increased mutation was not due to enhanced expression of activation-induced deaminase, but was likely a result of selection for high-affinity B cells with altered codons in the gene. This correlated with the appearance of antigen-specific B cells with a memory phenotype, which was intrinsic to TLR7 on B cells. To determine if these memory cells produced a recall response after a secondary challenge, spleen cells from mice that were immunized with NP-CGG and R837 were adoptively transferred into muMT recipients, and boosted with NP-CGG. Cells from mice that initially received both antigen and R837 generated a robust increase in germinal center B cells, plasmablasts, plasma cells, and serum antibody, compared with their cohorts who received antigen alone. These results support the use of co-immunization with TLR7 ligands to promote vigorous memory B cell responses to protein antigens
Hijacked DNA repair proteins and unchained DNA polymerases
Somatic hypermutation of immunoglobulin (Ig) genes occurs at a frequency that is a million times greater than the mutation in other genes. Mutations occur in variable genes to increase antibody affinity, and in switch regions before constant genes to cause switching from IgM to IgG. Hypermutation is initiated in activated B cells when the activation-induced deaminase protein deaminates cytosine in DNA to uracil. Uracils can be processed by either a mutagenic pathway to produce mutations or a non-mutagenic pathway to remove mutations. In the mutagenic pathway, we first studied the role of mismatch repair proteins, MSH2, MSH3, MSH6, PMS2 and MLH1, since they would recognize mismatches. The MSH2âMSH6 heterodimer is involved in hypermutation by binding to U:G and other mismatches generated during repair synthesis, but the other proteins are not necessary. Second, we analysed the role of low-fidelity DNA polymerases Ρ, Κ and θ in synthesizing mutations, and conclude that polymerase Ρ is the dominant participant by generating mutations at A:T base pairs. In the non-mutagenic pathway, we examined the role of the Cockayne syndrome B protein that interacts with other repair proteins. Mice deficient in this protein had normal hypermutation and class switch recombination, showing that it is not involved
Role of Escherichia coli DNA Polymerase I in Conferring Viability upon the dnaN159 Mutant Strainâż
The Escherichia coli dnaN159 allele encodes a mutant form of the β-sliding clamp (β159) that is impaired for interaction with the replicative DNA polymerase (Pol), Pol III. In addition, strains bearing the dnaN159 allele require functional Pol I for viability. We have utilized a combination of genetic and biochemical approaches to characterize the role(s) played by Pol I in the dnaN159 strain. Our findings indicate that elevated levels of Pol I partially suppress the temperature-sensitive growth phenotype of the dnaN159 strain. In addition, we demonstrate that the β clamp stimulates the processivity of Pol I in vitro and that β159 is impaired for this activity. The reduced ability of β159 to stimulate Pol I in vitro correlates with our finding that single-stranded DNA (ssDNA) gap repair is impaired in the dnaN159 strain. Taken together, these results suggest that (i) the β clamp-Pol I interaction may be important for proper Pol I function in vivo and (ii) in the absence of Pol I, ssDNA gaps may persist in the dnaN159 strain, leading to lethality of the dnaN159 ÎpolA strain
DNA Breaks in Ig V Regions Are Predominantly Single Stranded and Are Generated by UNG and MSH6 DNA Repair Pathways
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