Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis

BACKGROUND AND AIMS: The MDR1 gene encodes P-glycoprotein 170, an efflux transporter that is highly expressed in intestinal epithelial cells. The MDR1 exonic single nucleotide polymorphisms (SNPs) C3435T and G2677T have been shown to correlate with activity/expression of P-glycoprotein 170.METHODS: This was a case-control analysis of MDR1 C3435T and G2677T SNPs in a large well-characterized Scottish white cohort (335 with ulcerative colitis [UC], 268 with Crohn's disease [CD], and 370 healthy controls). We conducted 2-locus haplotype and detailed univariate and multivariate genotypic-phenotypic analyses.RESULTS: The MDR1 3435 TT genotype (34.6% vs 26.5%; P = .04; odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.04-2.44) and T-allelic frequencies (58.2% vs 52.8%; P = .02; OR, 1.28; 95% CI, 1.03-1.58) were significantly higher in patients with UC compared with controls. No association was seen with CD. The association was strongest with extensive UC (TT genotype: 42.4% vs 26.5%; P = .003; OR, 2.64; 95% CI, 1.34-4.99; and T allele: 63.9% vs 52.8%; P = .009; OR, 1.70; 95% CI, 1.24-2.29), and this was also confirmed on multivariate analysis ( P = .007). The G2677T SNP was not associated with UC or CD. These 2 SNPs lie in linkage disequilibrium in our population (D', .8-.9; r 2 , .7-.8). Two-locus haplotypes showed both positive (3435T/G2677 haplotype: P = .03; OR, 1.44) and negative (C3435/2677T haplotype: P = .002; OR, .35) associations with UC. Homozygotes for the haplotype 3435T/G2677 were significantly increased in UC ( P = .017; OR, 8.88; 95% CI, 1.10-71.45).CONCLUSIONS: Allelic variations of the MDR1 gene determine disease extent as well as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the need for further detailed haplotypic studies.</p

The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn's disease

Background and Aims: Recent data suggest that polymorphisms in the organic cation transporter (OCTN) genes OCTN1 (SLC22A4) and OCTN2 (SLC22A5) represent disease-causing mutations within the IBD5 locus (chromosome 5q31). We investigated associations with disease susceptibility, phenotype, and evidence for epistasis with CARD15 in 679 patients with Crohn’s disease (CD) or ulcerative colitis (UC). Methods: A total of 374 patients with CD, 305 patients with UC, and 294 healthy controls (HCs) were studied. Genotyping for single nucleotide polymorphisms IGR2096, IGR2198, and IGR2230, OCTN1 variant (SLC22A4 1672C→T), and OCTN2 variant (SLC22A5 −207G→C) was performed using the TaqMan system. Results: The IBD5 OCTN1 and OCTN2 polymorphisms were in strong linkage disequilibrium (D′, >0.959). IGR2198 variant allele frequency (49.1% vs 40.8%; P = .0046) and homozygosity (21% vs 14.8%; P = .044) were associated with CD versus HCs. Variant allelic frequency of OCTN1 (53.6% vs 43%; P = .0008) and OCTN2 (56.1% vs 48.4%; P = .0092) polymorphisms and homozygosity for the OCTN1/2-TC haplotype (28.4% vs 16%; P = .0042) were associated with CD versus HCs. IGR2198 homozygosity and TC homozygosity were associated with stricturing/penetrating disease at follow-up (P = .011 and P = .011, respectively) and disease progression (P = .038 and P = .049, respectively) on univariate analysis and with need for surgery on multivariate analysis (P = .016 and P = .004, respectively). In the absence of the IBD5 risk haplotype, no association of OCTN1/2 variants with CD was detected. No associations were seen with UC. Conclusions: The IBD5 locus influences susceptibility, progression, and need for surgery in CD. However, the contribution of OCTN1/2 variants is not independent of the IBD5 haplotype; a causative role for these genes remains plausible but is not yet proven. Further genetic, functional, and expression data are now required. </p

Physical Properties of (2) Pallas

We acquired and analyzed adaptive-optics imaging observations of asteroid (2) Pallas from Keck II and the Very Large Telescope taken during four Pallas oppositions between 2003 and 2007, with spatial resolution spanning 32-88 km (image scales 13-20 km/pix). We improve our determination of the size, shape, and pole by a novel method that combines our AO data with 51 visual light-curves spanning 34 years of observations as well as occultation data. The shape model of Pallas derived here reproduces well both the projected shape of Pallas on the sky and light-curve behavior at all the epochs considered. We resolved the pole ambiguity and found the spin-vector coordinates to be within 5 deg. of [long, lat] = [30 deg., -16 deg.] in the ECJ2000.0 reference frame, indicating a high obliquity of ~84 deg., leading to high seasonal contrast. The best triaxial-ellipsoid fit returns radii of a=275 km, b= 258 km, and c= 238 km. From the mass of Pallas determined by gravitational perturbation on other minor bodies [(1.2 +/- 0.3) x 10-10 Solar Masses], we derive a density of 3.4 +/- 0.9 g.cm-3 significantly different from the density of C-type (1) Ceres of 2.2 +/- 0.1 g.cm-3. Considering the spectral similarities of Pallas and Ceres at visible and near-infrared wavelengths, this may point to fundamental differences in the interior composition or structure of these two bodies. We define a planetocentric longitude system for Pallas, following IAU guidelines. We also present the first albedo maps of Pallas covering ~80% of the surface in K-band. These maps reveal features with diameters in the 70-180 km range and an albedo contrast of about 6% wrt the mean surface albedo.Comment: 16 pages, 8 figures, 6 table

Observations of Persistent Leonid Meteor Trails. 1. Advection of the Diamond Ring

From a single image of a persistent trail left by a -1.5 magnitude Leonid meteor on November 17, 1998, the relative winds between 92.5 and 98 km altitude are derived, where the altitudes are determined by a sodium lidar. These are converted to true winds 82 sec after the appearance of the meteor by fixing the winds at 98 km to match the results of following the trail with the lidar for twelve minutes. The image and winds reveal a fine example of the effects of a gravity wave having a vertical wavelenth of 5.50 ± 0.02 km, a horizontal wavelength of 2650 ± 60 kin, an intrinsic period of 19.5 ± 0.4 hours, and an observed period of 8.6 ± 0.1 hours. Effects of the gravity wave are still present in the wind field 70 rain later

Quantum dynamics in ultra-cold atomic physics

We review recent developments in the theory of quantum dynamics in ultra-cold atomic physics, including exact techniques, but focusing on methods based on phase-space mappings that are appli- cable when the complexity becomes exponentially large. These phase-space representations include the truncated Wigner, positive-P and general Gaussian operator representations which can treat both bosons and fermions. These phase-space methods include both traditional approaches using a phase-space of classical dimension, and more recent methods that use a non-classical phase-space of increased dimensionality. Examples used include quantum EPR entanglement of a four-mode BEC, time-reversal tests of dephasing in single-mode traps, BEC quantum collisions with up to 106 modes and 105 interacting particles, quantum interferometry in a multi-mode trap with nonlinear absorp- tion, and the theory of quantum entropy in phase-space. We also treat the approach of variational optimization of the sampling error, giving an elementary example of a nonlinear oscillator

Scalar Electrodynamics and Primordial Magnetic Fields

A primordial magnetic field may be generated during an inflationary period if conformal invariance is broken. We reexamine and generalize previous results about the magnetic field produced by couplings of the form $R^n F_{\mu\nu}F^{\mu\nu}$. We show that the amplitude of the magnetic field depends strongly on $n$. For adequate values of $n$ the field produced can serve as seed for galactic magnetic fields. We also compute the effective interaction between the electromagnetic field and the geometry in the context of scalar QED (with and without classical conformal invariance). In both cases, the amplitude of the magnetic field is too small to be of astrophysical interest.Comment: 16 pages, LaTeX, no figure

Observations of persistent Leonid meteor trails 3. The ‘‘Glowworm’’

A spectacular, well-observed Leonid meteor of visual magnitude -14.3 appeared on 17 November 1998 and left a lingering trail, dubbed the Glowworm, that was well studied. From a location on Kirtland Air Force Base, near Albuquerque, New Mexico, we obtained CCD images of the trail from 94 to 203 s after the meteor and recorded a video with an intensified camera for even longer. From information obtained with a sodium lidar half an hour after the meteor, we have determined that a gravity wave with a vertical wavelength of 2.4 km was responsible for the right-angled appearance of the trail. The trail ended abruptly at 85 km, and its uppermost altitude may have been no greater than 91 km. We designate the Glowworm a Type I trail: one that is wide (1 km), cloudy in appearance, has high diffusion rates (800m2 s-1), high total line emission rates (1.5 x 1018 photons m-1 s-1), and is optically thicker than Type II trails. The lower parts of the Diamond Ring, another Leonid lingering trail that appeared 38 min earlier than the Glowworm, define the Type II trails, which appear as narrow, optically thinner parallel trails, with low diffusion rates (12 m2 s-1) and total line emission rates (1–3 x 1016 photons m1 s-1). No explanation is offered for the two orders of magnitude difference in these quantities. The Glowworm meteor produced infrasound [ReVelle and Whitaker, 1999], from which a meteoroid mass estimate of 522 g was made. We compare our photometry to a detailed numerical modeling of the shape of the trail and emission from the Glowworm made by Zinn et al. [1999], who find that the largest contributors to emission recorded by our CCD and video cameras are atmospheric O2 vibrational bands. Compared to our measurements, their calculated emission is too high by two orders of magnitude, but since most of O2 emission may be absorbed by atmospheric O2 before it reaches the ground, this may indeed be the primary contributor to the observed flux. Although the calculations of Zinn et al. lead to a hollow cylinder appearance which may be appropriate for the Glowworm, it is not pronounced enough to account for the complete darkness between the parallel structures seen in Type II trails. An upper limit to backscattering from dust of 3.7 x 10-5 of the expected return was found from directing a 180 W copper vapor laser at the Glowworm

Quantum delocalization in photon-pair generation

The generation of correlated photon pairs is a key to the production of entangled quantum states, which have a variety of applications within the area of quantum information. In spontaneous parametric down-conversion—the primary method of generating correlated photon pairs—the associated photon annihilation and creation events are generally thought of as being colocated: The correlated pair of photons is localized with regards to the pump photon and its positional origin. A detailed quantum electrodynamical analysis highlights a mechanism exhibiting the possibility of a delocalized origin for paired output photons: The spatial extent of the region from which the pair is generated can be much larger than previously thought. The theory of both localized and nonlocalized degenerate down-conversion is presented, followed by a quantitative analysis using discrete-volume computational methods. The results may have significant implications for quantum information and imaging applications, and the design of nonlinear optical metamaterials

Coalescent-based species delimitation in the sand lizards of the Liolaemus wiegmannii complex (Squamata: Liolaemidae)

Coalescent-based algorithms coupled with the access to genome-wide data have become powerful tools forassessing questions on recent or rapid diversification, as well as delineating species boundaries in the absence of reciprocal monophyly. In southern South America, the diversification of Liolaemus lizards during the Pleistocene is well documented and has been attributed to the climatic changes that characterized this recent period of time. Past climatic changes had harsh effects at extreme latitudes, including Patagonia, but habitat changes at intermediate latitudes of South America have also been recorded, including expansion of sand fields over northern Patagonia and Pampas). In this work, we apply a coalescent-based approach to study the diversification of the Liolaemus wiegmannii species complex, a morphologically conservative clade that inhabits sandy soils across northwest and south-central Argentina, and the south shores of Uruguay. Using four standard sequence markers (mitochondrial DNA and three nuclear loci) along with ddRADseq data we inferred species limits and a time calibrated species tree for the L. wiegmannii complex in order to evaluate the influence of Quaternary sand expansion/retraction cycles on diversification. We also evaluated the evolutionary independence of the recently described L. gardeli and inferred its phylogenetic position relative to L. wiegmannii. We find strong evidence for six allopatric candidate species within L. wiegmannii, which diversified during the Pleistocene. The Great Patagonian Glaciation (∼1 million years before present) likely split the species complex into two main groups: one composed of lineages associated with sub-Andean sedimentary formations, and the other mostly related to sand fields in the Pampas and northern Patagonia. We hypothesize that early speciation within L. wiegmannii was influenced by the expansion of sand dunes throughout central Argentina and Pampas. Finally, L. gardeli is supported as a distinct lineage nested within the L. wiegmannii complex.Fil: Villamil, Joaquín. Universidad de la República. Facultad de Ciencias; UruguayFil: Avila, Luciano Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico para el Estudio de los Ecosistemas Continentales; ArgentinaFil: Morando, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico para el Estudio de los Ecosistemas Continentales; ArgentinaFil: Sites, Jack W.. University Brigham Young; Estados UnidosFil: Leaché, Adam D.. University of Washington; Estados UnidosFil: Maneyro, Raúl. Universidad de la República. Facultad de Ciencias; UruguayFil: Camargo Bentaberry, Arley. Universidad de la República; Urugua

Analysis of Germline GLI1 Variation Implicates Hedgehog Signalling in the Regulation of Intestinal Inflammatory Pathways

Charlie Lees and colleagues identify a reduced-function variant of the hedgehog signaling pathway protein GLI1 that associates with inflammatory bowel disease, and investigate its role in a mouse model of colitis