Effect of Hole Doping on the Electronic Structure of Tl2201

We discuss doping dependencies of the electronic structure and Fermi surface of the monolayer Tl$_{2-x}$Cu$_x$Ba$_2$CuO$_{6+\delta}$ (Tl2201). The TlO bands are found to be particularly sensitive to doping in that these bands rapidly move to higher energies as holes are added into the system. Such doping effects beyond the rigid band picture should be taken into account in analyzing and modeling the electronic spectra of the cuprates.Comment: 2 pages, Submitted to Physica C / Proceedings of the M2S-HTSC-VIII Conferenc

Possible Microscopic Doping Mechanism in Tl-2201

X-ray absorption spectroscopy on oxygen-annealed, self-flux-grown single crystals of Tl-2201 suggests a microscopic doping mechanism whereby interstitial oxygens are attracted to copper substituted on the thallium site, contributing holes to both the planes and to these coppers, and typically promoting only one hole to the plane rather than two. These copper substituents would provide an intrinsic hole doping. The evidence for this is discussed, along with an alternative interpretation.Comment: 2 pages, 1 figure, submitted as conference proceedings for M2S-IX, Toky

Molecular characterization of the first missense mutation in the fibrinogen Aalpha-chain gene identified in a compound heterozygous afibrinogenemic patient

AbstractCongenital afibrinogenemia is a rare coagulopathy characterized by extremely low levels of functional and immunoreactive fibrinogen in plasma, associated with a hemorrhagic phenotype of variable severity. It is transmitted as an autosomal recessive trait and is invariantly associated with mutations affecting 1 of the 3 fibrinogen genes (FGA, FGB, and FGG, coding for Aα, Bβ, and γ chain, respectively). Most genetic defects causing afibrinogenemia are truncating mutations, whereas only few missense mutations (6) have been identified so far, all located in FGB.In this study, the mutational screening of an afibrinogenemic Italian male identified the first missense mutation (Met51Arg) in FGA leading to afibrinogenemia. The patient was a compound heterozygote for a previously described frameshift mutation (1215delT) in the same gene. Met51Arg involves a residue located at the very beginning of the coiled-coil domain, in a region demonstrated to play a pivotal role in hexamer formation. In-vitro expression experiments showed that Met51Arg strongly reduces secretion of hexameric fibrinogen, whereas traces of not completely assembled trimeric intermediate were found in conditioned media. Western blot analysis on the proband's plasma confirmed the presence in vivo of the trimeric fibrinogen, supporting the hypothesis that Met51Arg prevents the final step of fibrinogen assembly

Inhibition of surface induced coagulation by preadsorption of albumin-heparin conjugates

Surface coatings of the albumin-heparin conjugates were developed to improve the blood compatibility of polymeric materials. Glass, PVC, Biomer and cellulose acetate were coated with albumin-heparin conjugate and its adsorption and desorption behavior on glass in particular was studied using 3H and 51Cr radiolabeled conjugates. Precoated materials showed a significant prolongation of the Lee-White clotting time as compared with noncoated ones. It was demonstrated that the prolonged clotting time for pretreated glass was due to surface bound conjugate. Prolonged recalcification times of plasma exposed to glass, Biomer, and PVC were obtained using albumin-heparin conjugate precoated surfaces. Albumin-heparin conjugates with high affinity for antithrombin III gave more prolonged clotting times as low affinity conjugates when used as coatings for glass. This indicates that the behaviour of heparin in preadsorbed conjugates resembles that of heparin in solution

Encapsulated Single Crystal Growth and Annealing of the High-Temperature Superconductor Tl-2201

Highly-perfect platelet single crystals of Tl_2Ba_2CuO_{6+d} (Tl-2201) were grown by a self-flux technique. A novel encapsulation scheme allowed the precursors to react prior to the sealing required to contain volatile thallium oxides, and permitted the removal of melt at the conclusion of growth, reproducibly producing high yields of clean crystals. The crystals were annealed under well-controlled oxygen partial pressures, then characterised. They have sharp superconducting transitions, narrow X-ray rocking curves and a low 4% substitution of thallium by copper, all evidence of their high perfection and homogeneity. The crystals are orthorhombic at most dopings, and a previously unreported commensurate superlattice distortion is observed.Comment: 8 pages, 5 figures, submitted to Journal of Crystal Growt

Impact of a functional polymorphism in the PAR-1 gene promoter in COPD and COPD exacerbations.

Proteinase-activated receptor-1 (PAR-1) plays a key role in mediating the interplay between coagulation and inflammation in response to injury. The aim of this study was to investigate the role of the promoter single-nucleotide polymorphism (SNP) rs2227744G>A in modulating PAR-1/F2R gene expression in the context of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. The function of the rs2227744G>A SNP was investigated by using reporter gene assays. The frequency of the polymorphism in the UK population was assessed by genotyping 8,579 healthy individuals from the Whitehall II and English Longitudinal Study of Ageing cohorts. The rs2227744G>A SNP was genotyped in a carefully phenotyped cohort of 203 COPD cases and matched controls. The results were further replicated in two different COPD cohorts. The minor allele of the rs2227744G>A polymorphism was found to increase F2R expression by 2.6-fold (P A SNP was not significantly associated with COPD, or with lung function, in all cohorts. The minor allele of the SNP was found to be associated with protection from frequent exacerbations (P = 0.04) in the cohort of COPD patients for which exacerbation frequency was available. Considering exacerbations as a continuous variable, the presence of the minor allele was associated with a significantly lower COPD exacerbation rate (3.03 vs. 1.98 exacerbations/year, Mann-Whitney U-test P = 0.04). Taken together, these data do not support a role for the rs2227744G>A F2R polymorphism in the development of COPD but suggest a protective role for this polymorphism from frequent exacerbations. Studies in separate cohorts to replicate these findings are warranted

Role of a functional polymorphism in the F2R gene promoter in sarcoidosis

Sarcoidosis is a multisystem granulomatous disease of unknown aetiology characterized by increased inflammation, and results from gene-environment interactions. Proteinase-activated receptor-1 mediates the interplay between coagulation and inflammation. The rs2227744G > A promoter single nucleotide polymorphism has been linked to inflammation, cardiovascular disease and chronic obstructive pulmonary disease exacerbations. Using a case-control study (184 cases with sarcoidosis and 368 controls), we show that the rs2227744A allele significantly associates with protection from sarcoidosis (P = 0.003, OR = 0.68 (0.52-0.88))

TGFβ upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells.

The major high-affinity thrombin receptor, proteinase activated receptor-1 (PAR-1) is expressed at low levels by the normal epithelium but is upregulated in many types of cancer, including lung cancer. The thrombin-PAR-1 signalling axis contributes to the activation of latent TGFβ in response to tissue injury via an αvβ6 integrin-mediated mechanism. TGFβ is a pleiotropic cytokine that acts as a tumour suppressor in normal and dysplastic cells but switches into a tumour promoter in advanced tumours. In this study we demonstrate that TGFβ is a positive regulator of PAR-1 expression in A549 lung adenocarcinoma cells, which in turn increases the sensitivity of these cells to thrombin signalling. We further demonstrate that this effect is Smad3-, ERK1/2- and Sp1-dependent. We also show that TGFβ-mediated PAR-1 upregulation is accompanied by increased expression of integrin αv and β6 subunits. Finally, TGFβ pre-stimulation promotes increased migratory potential of A549 to thrombin. These data have important implications for our understanding of the interplay between coagulation and TGFβ signalling responses in lung cancer.Medical Research Council UK (MRC) CASE studentship with Novartis awarded to RCC, MRC Centenary Award awarded to NS and RCC, and MRC Career Development Award G0800340 to CJS

Quantum oscillations in underdoped YBa_2Cu_3O_6.5

Shubnikov-de Haas and de Haas-van Alphen effects have been measured in the underdoped high temperature superconductor YBa$_2$Cu$_3$O$_{6.51}$. Data are in agreement with the standard Lifshitz-Kosevitch theory, which confirms the presence of a coherent Fermi surface in the ground state of underdoped cuprates. A low frequency $F = 530 \pm 10$ T is reported in both measurements, pointing to small Fermi pocket, which corresponds to 2% of the first Brillouin zone area only. This low value is in sharp contrast with that of overdoped Tl$_2$Ba$_2$CuO$_{6+\delta}$, where a high frequency $F = 18$ kT has been recently reported and corresponds to a large hole cylinder in agreement with band structure calculations. These results point to a radical change in the topology of the Fermi surface on opposing sides of the cuprate phase diagram.Comment: proceeding of the ECRYS-200

Impact of a functional polymorphism in the PAR-1 gene promoter in COPD and COPD exacerbations

Proteinase-activated receptor-1 (PAR-1) plays a key role in mediating the interplay between coagulation and inflammation in response to injury. The aim of this study was to investigate the role of the promoter single-nucleotide polymorphism (SNP) rs2227744G&gt;A in modulating PAR-1/ F2R gene expression in the context of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. The function of the rs2227744G&gt;A SNP was investigated by using reporter gene assays. The frequency of the polymorphism in the UK population was assessed by genotyping 8,579 healthy individuals from the Whitehall II and English Longitudinal Study of Ageing cohorts. The rs2227744G&gt;A SNP was genotyped in a carefully phenotyped cohort of 203 COPD cases and matched controls. The results were further replicated in two different COPD cohorts. The minor allele of the rs2227744G&gt;A polymorphism was found to increase F2R expression by 2.6-fold ( P &lt; 0.001). The rs2227744G&gt;A SNP was not significantly associated with COPD, or with lung function, in all cohorts. The minor allele of the SNP was found to be associated with protection from frequent exacerbations ( P = 0.04) in the cohort of COPD patients for which exacerbation frequency was available. Considering exacerbations as a continuous variable, the presence of the minor allele was associated with a significantly lower COPD exacerbation rate (3.03 vs. 1.98 exacerbations/year, Mann-Whitney U-test P = 0.04). Taken together, these data do not support a role for the rs2227744G&gt;A F2R polymorphism in the development of COPD but suggest a protective role for this polymorphism from frequent exacerbations. Studies in separate cohorts to replicate these findings are warranted. </jats:p