Non-inherited maternal HLA alleles are associated with rheumatoid arthritis

Background. Rheumatoid arthritis (RA) is strongly associated with a series of HLA-DRB1 alleles that encode a conserved sequence of amino acids (70Q/R K/R R A A74) in the DRβ1 chain, known as the shared epitope (SE). However 30% of patients are negative for DRB1*04 and 15% are SE-negative. Exposure to these alleles as non-inherited maternal antigens (NIMA) might explain this discrepancy. We undertook a family study to investigate the role of NIMA in RA. Methods. One hundred families, including the RA proband and both parents, were recruited. HLA-DRB1 genotyping was performed using an allele-specific polymerase chain reaction by standard methods. The frequencies of NIMA and non-inherited paternal antigens (NIPA) were compared using contingency tables and a two-tailed P test. We then reviewed four previously published studies of NIMA in RA and conducted an analysis of the combined data Results. We identified 36 families in which the proband was DRB1*04-negative and 13 in which the proband lacked the SE. There was an excess of DRB1*04 and SE NIMA (P=0.05) compared with NIPA. Combined analysis with previous studies showed that 53/231 mothers (23%) versus 25/205 fathers (12%) had a non-inherited DRB1*04 (P=0.003) and 30/99 mothers versus 18/101 fathers had a non-inherited SE allele (P=0.03). Conclusion. A role for HLA NIMA in RA is suggested by these results.

HLA-DR/DQ haplotype in rheumatoid arthritis: Novel allelic associations in UK Caucasians

Objective. To elucidate the relative importance of the HLA-DR and HLA-DQ loci in conferring genetic predisposition to rheumatoid arthritis (RA). Methods. HLA-DRB1 and HLA-DQB1 alleles were typed in a set of 685 patients with RA using sequence-specific polymerase chain reaction. Allele and phenotype frequencies were compared with those in 2 large sets of historical, ethnically matched healthy controls, using the relative predispositional effect method. Results. Positive association was confirmed with the shared epitope positive HLA-DRB1 alleles associated with RA in Caucasians. A significant susceptibility effect was observed with HLA-DRB1*09, described in other ethnically diverse populations but not in Caucasians. A significant underrepresentation of the HLA-DRB1*0103 variant was noted among the RA cases, supporting the proposed protective role of the DERAA motif at residues 70-74 of the DRβ molecule. No HLA-DRB1 independent association of the HLA-DQB1 alleles, implicated in predisposing to RA, was evident. Conclusion. These data corroborate the shared epitope hypothesis of susceptibility to RA and provide strong evidence for the DRB1 locus as the primary RA susceptibility factor in the HLA region.

Polymorphism in codon 17 of the CTLA-4 gene (+49 A/G) is not associated with susceptibility to rheumatoid arthritis in British Caucasians

The role of the CTLA-4 antigen in the development of autoimmune diseases is well documented, with several autoimmune disorders showing association or linkage with the CTLA-4 locus. Its role in the aetiology of rheumatoid arthritis (RA) however, remains unclear, as the functional studies of the B7-CTLA-4 pathway in mouse models of RA and genetic studies in humans have given contrasting results. We have studied the single nucleotide polymorphism at position +49 (A/G) of the CTLA-4 gene, in a cohort of 421 RA cases and 452 healthy controls from the UK. Despite the high statistical power to detect even a weak susceptibility effect, no significant association was found. We also analysed the distribution of the allele and genotype frequencies with respect to the presence of the shared epitope (a known RA susceptibility factor) and found no statistically significant differences. We conclude that, although the importance of the B7-CTLA-4 interaction in the development of RA can not be excluded, the CTLA-4 gene is unlikely to be a predisposing factor to this disease.

Finite volume evolution Galerkin method for hyperbolic conservation laws with spatially varying flux functions

We present a generalization of the finite volume evolution Galerkin scheme [M. Lukacova-Medvid'ova,J. Saibertov'a, G. Warnecke, Finite volume evolution Galerkin methods for nonlinear hyperbolic systems, J. Comp. Phys. (2002) 183 533-562; M. Luacova-Medvid'ova, K.W. Morton, G. Warnecke, Finite volume evolution Galerkin (FVEG) methods for hyperbolic problems, SIAM J. Sci. Comput. (2004) 26 1-30] for hyperbolic systems with spatially varying flux functions. Our goal is to develop a genuinely multi-dimensional numerical scheme for wave propagation problems in a heterogeneous media. We illustrate our methodology for acoustic waves in a heterogeneous medium but the results can be generalized to more complex systems. The finite volume evolution Galerkin (FVEG) method is a predictor-corrector method combining the finite volume corrector step with the evolutionary predictor step. In order to evolve fluxes along the cell interfaces we use multi-dimensional approximate evolution operator. The latter is constructed using the theory of bicharacteristics under the assumption of spatially dependent wave speeds. To approximate heterogeneous medium a staggered grid approach is used. Several numerical experiments for wave propagation with continuous as well as discontinuous wave speeds confirm the robustness and reliability of the new FVEG scheme.

On the relationship between finger width, velocity, and fluxes in thermohaline convection

Double-diffusive finger convection occurs in many natural processes.The theories for double-diffusive phenomena that exist at present consider systems with linear stratification in temperature and salinity. The double-diffusive systems with step change in salinity and temperature are, however, not amenable to simple stability analysis. Hence factors that control the width of the finger, velocity, and fluxes in systems that have step change in temperature and salinity have not been understood so far. In this paper we provide new physical insight regarding factors that influence finger convection in two-layer double-diffusive system through two-dimensional numerical simulations. Simulations have been carried out for density stability ratios (R-rho) from 1.5 to 10. For each density stability ratio, the thermal Rayleigh number (Ra-T) has been systematically varied from 7x10(3) to 7x10(8). Results from these simulations show how finger width, velocity, and flux ratios in finger convection are interrelated and the influence of governing parameters such as density stability ratio and the thermal Rayleigh number. The width of the incipient fingers at the time of onset of instability has been shown to vary as Ra-T-1/3. Velocity in the finger varies as Ra(T)1/3/R-rho. Results from simulation agree with the scale analysis presented in the paper. Our results demonstrate that wide fingers have lower velocities and flux ratios compared to those in narrow fingers. This result contradicts present notions about the relation between finger width and flux ratio. A counterflow heat-exchanger analogy is used in understanding the dependence of flux ratio on finger width and velocity.

Axially homogeneous, zero mean flow buoyancy-driven turbulence in a vertical pipe

We report an experimental study of a new type of turbulent flow that is driven purely by buoyancy. The flow is due to an unstable density difference, created using brine and water, across the ends of a long (length/diameter = 9) vertical pipe. The Schmidt number Sc is 670, and the Rayleigh number (Ra) based on the density gradient and diameter is about 10(8). Under these conditions the convection is turbulent, and the time-averaged velocity at any point is `zero'. The Reynolds number based on the Taylor microscale, Re-lambda, is about 65. The pipe is long enough for there to be an axially homogeneous region, with a linear density gradient, about 6-7 diameters long in the midlength of the pipe. In the absence of a mean flow and, therefore, mean shear, turbulence is sustained just by buoyancy. The flow can be thus considered to be an axially homogeneous turbulent natural convection driven by a constant (unstable) density gradient. We characterize the flow using flow visualization and particle image velocimetry (PIV). Measurements show that the mean velocities and the Reynolds shear stresses are zero across the cross-section; the root mean squared (r.m.s.) of the vertical velocity is larger than those of the lateral velocities (by about one and half times at the pipe axis). We identify some features of the turbulent flow using velocity correlation maps and the probability density functions of velocities and velocity differences. The flow away from the wall, affected mainly by buoyancy, consists of vertically moving fluid masses continually colliding and interacting, while the flow near the wall appears similar to that in wall-bound shear-free turbulence. The turbulence is anisotropic, with the anisotropy increasing to large values as the wall is approached. A mixing length model with the diameter of the pipe as the length scale predicts well the scalings for velocity fluctuations and the flux. This model implies that the Nusselt number would scale as (RaSc1/2)-Sc-1/2, and the Reynolds number would scale as (RaSc-1/2)-Sc-1/2. The velocity and the flux measurements appear to be consistent with the Ra-1/2 scaling, although it must be pointed out that the Rayleigh number range was less than 10. The Schmidt number was not varied to check the Sc scaling. The fluxes and the Reynolds numbers obtained in the present configuration are Much higher compared to what would be obtained in Rayleigh-Benard (R-B) convection for similar density differences.

targetTB: A target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis

Background: Tuberculosis still remains one of the largest killer infectious diseases, warranting the identification of newer targets and drugs. Identification and validation of appropriate targets for designing drugs are critical steps in drug discovery, which are at present major bottle-necks. A majority of drugs in current clinical use for many diseases have been designed without the knowledge of the targets, perhaps because standard methodologies to identify such targets in a high-throughput fashion do not really exist. With different kinds of 'omics' data that are now available, computational approaches can be powerful means of obtaining short-lists of possible targets for further experimental validation. Results: We report a comprehensive in silico target identification pipeline, targetTB, for Mycobacterium tuberculosis. The pipeline incorporates a network analysis of the protein-protein interactome, a flux balance analysis of the reactome, experimentally derived phenotype essentiality data, sequence analyses and a structural assessment of targetability, using novel algorithms recently developed by us. Using flux balance analysis and network analysis, proteins critical for survival of M. tuberculosis are first identified, followed by comparative genomics with the host, finally incorporating a novel structural analysis of the binding sites to assess the feasibility of a protein as a target. Further analyses include correlation with expression data and non-similarity to gut flora proteins as well as 'anti-targets' in the host, leading to the identification of 451 high-confidence targets. Through phylogenetic profiling against 228 pathogen genomes, shortlisted targets have been further explored to identify broad-spectrum antibiotic targets, while also identifying those specific to tuberculosis. Targets that address mycobacterial persistence and drug resistance mechanisms are also analysed. Conclusion: The pipeline developed provides rational schema for drug target identification that are likely to have high rates of success, which is expected to save enormous amounts of money, resources and time in the drug discovery process. A thorough comparison with previously suggested targets in the literature demonstrates the usefulness of the integrated approach used in our study, highlighting the importance of systems-level analyses in particular. The method has the potential to be used as a general strategy for target identification and validation and hence significantly impact most drug discovery programmes.

Scheme of squares: Part I. Systems formalism for potentiostatic studies

The so-called “Scheme of Squares”, displaying an interconnectivity of heterogeneous electron transfer and homogeneous (e.g., proton transfer) reactions, is analysed. Explicit expressions for the various partial currents under potentiostatic conditions are given. The formalism is applicable to several electrode geometries and models (e.g., semi-infinite linear diffusion, rotating disk electrodes, spherical or cylindrical systems) and the analysis is exact. The steady-state (t→∞) expressions for the current are directly given in terms of constant matrices whereas the transients are obtained as Laplace transforms that need to be inverted by approximation of numerical methods. The methodology employs a systems approach which replaces a system of partial differential equations (governing the concentrations of the several electroactive species) by an equivalent set of difference equations obeyed by the various partial currents.

Magnetic-properties of quasi-2-dimensional la1-xsr1+xmno4 and the evolution of itinerant electron ferromagnetism in the sro.(la1-xsrxmno3)n system

Quasi-two-dimensional oxides of the La,+,Sr,+,Mn04 system, possessing the KZNiF4 structure, show no evidence for ferromagnetic ordering in contrast to the corresponding three-dimensional La,+.Sr,MnO~ perovskites. Instead, there is an increasing tendency toward antiferromagnetic ordering with mcreasmg x m La,+,Sr,,, MnOp. Furthermore, these oxides are relatively high-resistivity materials over the entire compositional range. Substitution of Ba for Sr in La&r,.5Mn04 decreases the ferromagnetic interaction. Increasing the number of perovskite layers in SrO (La,-,Sr,MnO& causes an increase in electrical conductivity as well as ferromagnetic interaction. The oxide becomes a highly conducting ferromagnet when n 2 2.

Observations sur les termes culinaires dans deux San-Antonio de Frédéric Dard

Pro gradu-työni aihe on ruokaterminologiaa käsittelevät ranskan puhekielen ja Pariisin slangin lainasanat sekä kirjailija Frédéric Dardin alias San-Antonion (1921-2000) luomat, ruokatermistöön kuuluvat uudissanat ja -sanonnat kahdessa San-Antonio-romaanissa C'est mort et ça ne sait pas sekä Le fil à couper le beurre. Näissä ns. kioskikirjallisuutta edustavissa rikosromaaneissa seikkailee puheenparttaan ruoka-alan termeillä höystävä, "erikoistehtäviä" hoitava komisario ja naistenmies, San-Antonio. Ranskankielisessä arjen kielenkäytössä vilisee ruokaan liittyviä sanoja ja sanontoja muissakin kuin varsinaisissa ruuanvalmistus- ja ateriointiyhteyksissä. Halusin tarkastella, millaisena tämä yleisesti havaitsemani ilmiö todentuu Frédéric Dardin kahdessa romaanissa, jotka olen valinnut aineistokseni. Frédéric Dard käyttää romaaneissaan varsin omaperäistä kieltä: sekä puhekieltä että Pariisin slangia. Korpukseni koostuu romaaneista poimimistani ruoka-alan termistöä sisältävistä esimerkeistä, joita valmiiseen työhön tuli 228 kappaletta. Jaoin kaikki korpuksesta löytämäni ruokatermit kahteen luokkaan sen mukaan, oliko kirjailija lainannut käyttämänsä sanan tai ilmauksen puhekielestä tai Pariisin slangista (lainatermit), vai oliko hän luonut termin tai ilmauksen itse (neologismit). Määrittelin termin tai ilmauksen neologismiksi, jos se ei esiintynyt joko laisinkaan tai ainakaan kirjailijan tarkoittamassa merkityksessä seuraavissa sanakirjoissa: Le Dictionnaire du français argotique, populaire et familier; Le Dictionnaire de l'argot moderne; Le Dictionnaire du français non conventionnel; Le Dictionnaire de l'argot; Le Dictionnaire du français argotique et populaire; L'argot chez les vrais de vrai ja Trésor de la langue française. Varsinainen tutkimus perustuu sanojen ja ilmausten merkitysten selvittämiseen ja analysointiin. Lainatermien analyysillä tarkoitan lainatermien merkitysten selvitystä em. sanakirjojen avulla. Neologismit analysoin tarkemmin käyttäen em. sanakirjoja sekä tukeutuen gastronomisten ja erityisesti kielitieteellisten lähdeteosteni tarjoamiin rakenteellisiin ja semanttisiin muodostustapoihin ja tekemällä niistä tarvittavat yhteenvedot oikean merkityksen selvittämiseksi. Käsittelin aineiston kaikki ruokatermit. Niiden valtavan lukumäärän vuoksi analysoitavien esimerkkien määrää piti rajoittaa niin, että valmiiseen työhön jäi jokaisesta termistä enintään kaksi esimerkkiä kummastakin korpuksen kirjasta eli yhteensä 228 esimerkkiä. Muut esimerkit luetteloin työn lopusta löytyvään liitteeseen. Neologismianalyysissä selvisi, että Frédéric Dard suosi erityisesti semanttisia muodostustapoja eli olemassa olevan merkityksen muuttamista metaforien ja kielikuvien avulla. Dardin rikas terminologia ja hänen humoristiset oivalluksensa ovat osaltaan rikastuttaneet ranskan puhekieltä.Työssäni totean, että Pariisin slangia ja puhekieltä on totuttu pitämään sosiaalisesti sopimattomana, marginaalisten ryhmien kielenä, vaikka sen ilmauksia saattaa nykyisin kuulla jopa akateemikkojen käyttävän, ja ilmauksia on siirtynyt slangi- ja puhekielestä yleiskieleen. Toivon työni edistävän kiinnostusta kielitaidon parantamiseen San-Antonion tyyliin tutustumisen avulla sekä herättävän mielenkiintoa ranskan kielen vivahteikkuuteen ja monimuotoisuuteen muullakin kuin yleiskielen tasolla. Kielessä ei mielestäni voi olla sellaisia osa-alueita, joiden opiskelu ja osaaminen olisi tarpeetonta.

Relation between high-tc superconductivity and structure - a study of la3-xba3+xcu6o14+delta and yba2cu3o7-delta systems

Superconductivity is found in tetragonal La3−x Ba3+x Cu6O14+δ and La, Ba)6−x Sr x Cu6O14+δ even though they do not possess Cu-O chains or the K2NiF4 structure. Resistivity measurements confirm the occurrence of a transformation from chain-superconductivity to sheet-superconductivity in YBa2Cu3O7−δ as δ is varied in the range 0.0–0.5.

High-temperature superconductivity in La- and Lu-substituted YBa2,Cu3,O7, and related oxides

The perovskites, Y0.75La0.25Ba2Cu3O7 and Y0.75Lu0.25Ba2Cu3O7, show high-Tc superconductivity (with zero resistance at or above 80 K), just as the parent compound YBa2Cu3O7. The Lu-substituted oxide, with the smallest unit-cell parameters, shows the highest Tc besides exhibiting a 100% Meissner effect. Hc1, in these oxides is around 25 mT, but the Hc2, is large. The thermopower of YBa2Cu3O7 shows a sharp transition to zero at the superconducting transition, reinforcing the bulk nature of the superconductivity. Preliminary studies show that ErBa2Cu3O7 and Er0.5Y0.5Ba2Cu3O7 are both high-temperature superconductors with zero resistance in the 82-90 K range.

High-Tc superconductivity in the Er---Ba---Cu---O and related systems

ErBa2Cu3O7 and Er0.5Y0.5Ba2Cu3O7 are both high-Tc superconductors attaining zero resistance above 80 K. Preliminary studies indicate that Yb1−xYxBa2Cu3O7 also exhibits zero resistance above 77 K.

HIGH-Tc superconductivity in perovskite oxides of the Y-Ba-Cu-O system

Several biphasic compositions of the type Y3-xBa3+xCu6O14 show an onset of superconductivity in the 90-115K range, attaining zero resistance in the 70-85K range. The phase responsible for superconductivity in these compositions is a perovskite oxide of composition YBa2Cu3 O7. This oxide annealed in oxygen shows the onset of superconductivity at 120K and zero resistance at 87K. YBa2,Cu3O7 shows the highest Meissner effect of all oxide superconductors. The superconducting behaviour of the two perovskite oxides, Y0.95Ba1.95,Cu3O7 and Y1.05Ba1.95Cu3O7 show interesting features; a marked decrease in resistivity is observed from room temperature itself in the former oxide with zero resistance at 89K. Electron microscopy and infrared spectra of these oxides are briefly discussed.