225 research outputs found
The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population
Background: The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of Pck1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. \ud
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Methods: We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. \ud
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Results: Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). \ud
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Conclusion: This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group. \ud
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Trial registration: UKADS Trial Registration: ISRCTN38297969
The Transition from Atomic to Molecular Hydrogen in Interstellar Clouds: 21cm Signature of the Evolution of Cold Atomic Hydrogen in Dense Clouds
We have investigated the time scale for formation of molecular clouds by
examining the conversion of HI to H2 using a time-dependent model. H2 formation
on dust grains and cosmic ray and photo destruction are included in
one-dimensional model slab clouds which incorporate time-independent density
and temperature distributions. We calculate 21cm spectral line profiles seen in
absorption against a background provided by general Galactic HI emission, and
compare the model spectra with HI Narrow Self-Absorption, or HINSA, profiles
absorbed in a number of nearby molecular clouds. The time evolution of the HI
and H2 densities is dramatic, with the atomic hydrogen disappearing in a wave
propagating from the central, denser regions which have a shorter H2 formation
time scale, to the edges, where the density is lower and the time scale for H2
formation longer. The model 21cm spectra are characterized by very strong
absorption at early times, when the HI column density through the model clouds
is extremely large. The minimum time required for a cloud to have evolved to
its observed configuration, based on the model spectra, is set by the
requirement that most of the HI in the outer portions of the cloud, which
otherwise overwhelms the narrow absorption, be removed. The characteristic time
that has elapsed since cloud compression and initiation of the HI to H2
conversion is a few x 10^{14} s or ~ 10^7 yr. This sets a minimum time for the
age of these molecular clouds and thus for the star formation that may take
place within them
Multiwavelength study of the transient X-ray binary IGR J01583+6713
We have investigated multiband optical photometric variability and stability
of the H line profile of the transient X-ray binary IGR J01583+6713. We
set an upper limit of 0.05 mag on photometric variations in the {\it V} band
over a time scale of 3 months. The H line is found to consist of
non-Gaussian profile and quite stable for a duration of 2 months. We have
identified the spectral type of the companion star to be B2 IVe while distance
to the source is estimated to be 4.0 kpc. Along with the optical
observations, we have also carried out analysis of X-ray data from three short
observations of the source, two with the {\it Swift}--XRT and one with the {\it
RXTE}--PCA. We have detected a variation in the absorption column density, from
a value of 22.0 10 cm immediately after the outburst
down to 2.6 10 cm four months afterwards. In the
quiescent state, the X-ray absorption is consistent with the optical reddening
measurement of E(B - V) = 1.46 mag. From one of the {\it Swift} observations,
during which the X-ray intensity was higher, we have a possible pulse detection
with a period of 469.2 s. For a Be X-ray binary, this indicates an orbital
period in the range of 216--561 days for this binary system.Comment: 22 pages, 8 figures, accepted for publication in MNRA
The Oxford-Dartmouth Thirty Degree Survey II: Clustering of Bright Lyman Break Galaxies - Strong Luminosity Dependent Bias at z=4
We present measurements of the clustering properties of bright ()
z4 Lyman Break Galaxies (LBGs) selected from the Oxford-Dartmouth Thirty
Degree Survey (ODT). We describe techniques used to select and evaluate our
candidates and calculate the angular correlation function which we find best
fitted by a power law, with
(with in arcseconds), using a constrained slope of . Using
a redshift distribution consistent with photometric models, we deproject this
correlation function and find a comoving
h Mpc in a flat cosmology for
. This corresponds to a linear bias value of
(assuming ). These data show a
significantly larger and than previous studies at . We
interpret this as evidence that the brightest LBGs have a larger bias than
fainter ones, indicating a strong luminosity dependence for the measured bias
of an LBG sample. Comparing this against recent results in the literature at
fainter (sub-) limiting magnitudes, and with simple models describing
the relationship between LBGs and dark matter haloes, we discuss the
implications on the implied environments and nature of LBGs. It seems that the
brightest LBGs (in contrast with the majority sub- population), have
clustering properties, and host dark matter halo masses, that are consistent
with them being progenitors of the most massive galaxies today.Comment: Accepted for Publication in MNRAS. 15 Pages, 13 Figure
Multi-Jet Event Rates in Deep Inelastic Scattering and Determination of the Strong Coupling Constant
Jet event rates in deep inelastic ep scattering at HERA are investigated
applying the modified JADE jet algorithm. The analysis uses data taken with the
H1 detector in 1994 and 1995. The data are corrected for detector and
hadronization effects and then compared with perturbative QCD predictions using
next-to-leading order calculations. The strong coupling constant alpha_S(M_Z^2)
is determined evaluating the jet event rates. Values of alpha_S(Q^2) are
extracted in four different bins of the negative squared momentum
transfer~\qq in the range from 40 GeV2 to 4000 GeV2. A combined fit of the
renormalization group equation to these several alpha_S(Q^2) values results in
alpha_S(M_Z^2) = 0.117+-0.003(stat)+0.009-0.013(syst)+0.006(jet algorithm).Comment: 17 pages, 4 figures, 3 tables, this version to appear in Eur. Phys.
J.; it replaces first posted hep-ex/9807019 which had incorrect figure 4
Measurement of Leading Proton and Neutron Production in Deep Inelastic Scattering at HERA
Deep--inelastic scattering events with a leading baryon have been detected by
the H1 experiment at HERA using a forward proton spectrometer and a forward
neutron calorimeter. Semi--inclusive cross sections have been measured in the
kinematic region 2 <= Q^2 <= 50 GeV^2, 6.10^-5 <= x <= 6.10^-3 and baryon p_T
<= MeV, for events with a final state proton with energy 580 <= E' <= 740 GeV,
or a neutron with energy E' >= 160 GeV. The measurements are used to test
production models and factorization hypotheses. A Regge model of leading baryon
production which consists of pion, pomeron and secondary reggeon exchanges
gives an acceptable description of both semi-inclusive cross sections in the
region 0.7 <= E'/E_p <= 0.9, where E_p is the proton beam energy. The leading
neutron data are used to estimate for the first time the structure function of
the pion at small Bjorken--x.Comment: 30 pages, 9 figures, 2 tables, submitted to Eur. Phys.
HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44<sup>+</sup> Natural Killer Cells in Ulcerative Colitis
Background & Aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. Methods: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. Results: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401–NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. Conclusions: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype–dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell–mediated destruction of the intestinal epithelium in UC.</p
HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44<sup>+</sup> Natural Killer Cells in Ulcerative Colitis
Background & Aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. Methods: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. Results: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401–NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. Conclusions: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype–dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell–mediated destruction of the intestinal epithelium in UC.</p
Aquatic Ecotoxicity of Microplastics and Nanoplastics: Lessons Learned from Engineered Nanomaterials
Rheumatoid arthritis - treatment: 180. Utility of Body Weight Classified Low-Dose Leflunomide in Japanese Rheumatoid Arthritis
Background: In Japan, more than 20 rheumatoid arthritis (RA) patients died of interstitial pneumonia (IP) caused by leflunomide (LEF) were reported, but many of them were considered as the victims of opportunistic infection currently. In this paper, efficacy and safety of low-dose LEF classified by body weight (BW) were studied. Methods: Fifty-nine RA patients were started to administrate LEF from July 2007 to July 2009. Among them, 25 patients were excluded because of the combination with tacrolimus, and medication modification within 3 months before LEF. Remaining 34 RA patients administered 20 to 50 mg/week of LEF were followed up for 1 year and enrolled in this study. Dose of LEF was classified by BW (50 mg/week for over 50 kg, 40 mg/week for 40 to 50 kg and 20 to 30 mg/week for under 40 kg). The average age and RA duration of enrolled patients were 55.5 years old and 10.2 years. Prednisolone (PSL), methotrexate (MTX) and etanercept were used in 23, 28 and 2 patients, respectively. In case of insufficient response or adverse effect, dosage change or discontinuance of LEF were considered. Failure was defined as dosages up of PSL and MTX, or dosages down or discontinuance of LEF. Last observation carried forward method was used for the evaluation of failed patients at 1 year. Results: At 1 year after LEF start, good/ moderate/ no response assessed by the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score, including a 28-joint count (DAS28)-C reactive protein (CRP) were showed in 14/ 10/ 10 patients, respectively. The dosage changes of LEF at 1 year were dosage up: 10, same dosage: 5, dosage down: 8 and discontinuance: 11 patients. The survival rate of patients in this study was 23.5% (24 patients failed) but actual LEF continuous rate was 67.6% (11 patients discontinued) at 1 year. The major reason of failure was liver dysfunction, and pneumocystis pneumonia was occurred in 1 patient resulted in full recovery. One patient died of sepsis caused by decubitus ulcer infection. DAS28-CRP score was decreased from 3.9 to 2.7 significantly. Although CRP was decreased from 1.50 to 0.93 mg/dl, it wasn't significant. Matrix metalloproteinase (MMP)-3 was decreased from 220.0 to 174.2 ng/ml significantly. Glutamate pyruvate transaminase (GPT) was increased from 19 to 35 U/l and number of leukocyte was decreased from 7832 to 6271 significantly. DAS28-CRP, CRP, and MMP-3 were improved significantly with MTX, although they weren't without MTX. Increase of GPT and leukopenia were seen significantly with MTX, although they weren't without MTX. Conclusions: It was reported that the risks of IP caused by LEF in Japanese RA patients were past IP history, loading dose administration and low BW. Addition of low-dose LEF is a potent safe alternative for the patients showing unsatisfactory response to current medicines, but need to pay attention for liver function and infection caused by leukopenia, especially with MTX. Disclosure statement: The authors have declared no conflicts of interes
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