Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis

Objectives: The aim of the current study was to determine the contribution of interleukin (IL) 1 gene cluster polymorphisms previously implicated in susceptibility for ankylosing spondylitis (AS) to AS susceptibility in different populations worldwide. Methods: Nine polymorphisms in the IL1 gene cluster members IL1A (rs2856836, rs17561 and rs1894399), IL1B (rs16944), IL1F10 (rs3811058) and IL1RN (rs419598, the IL1RA VNTR, rs315952 and rs315951) were genotyped in 2675 AS cases and 2592 healthy controls recruited in 12 different centres in 10 countries. Association of variants with AS was tested by Mantel-Haenszel random effects analysis. Results: Strong association was observed with three single nucleotide polymorphisms (SNPs) in the IL1A gene (rs2856836, rs17561, rs1894399, p = 0.0036, 0.000019 and 0.0003, respectively). There was no evidence of significant heterogeneity of effects between centres, and no evidence of non-combinability of findings. The population attributable risk fraction of these variants in Caucasians is estimated at 4-6%. Conclusions: This study confirms that IL1A is associated with susceptibility to AS. Association of the other IL1 gene complex members could not be excluded in specific populations. Prospective meta-analysis is a useful tool in confirmation studies of genes associated with complex genetic disorders such as AS, providing sufficiently large sample sizes to produce robust findings often not achieved in smaller individual cohorts.

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1–3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4, 5, 6, 7, 8, 9, 10, 11. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression...

Role of TATATAA element in the regulation of tRNA(1)(Gly) gene expression in Bombyx mori is position dependent

Transcription of tRNA genes by RNA polymerase III is controlled by the internal conserved sequences within the coding region and the immediate upstream flanking sequences. A highly transcribed copy of glycyl tRNA gene tRNA1(Gly)-1 from Bombyx mori is down regulated by sequences located much farther upstream in the region -150 to -300 nucleotides (nt), with respect to the +1 nt of tRNA. The negative regulatory effect has been narrowed down to a sequence motif 'TATATAA', a perfect consensus recognised by the TATA binding protein, TBP. This sequence element, when brought closer to the transcription start point, on the other hand, exerts a positive effect by promoting transcription of the gene devoid of other cis regulatory elements. The identity of the nuclear protein interacting with this 'TATATAA' element to TBP has been established by antibody and mutagenesis studies. The 'TATATAA' element thus influences the transcription of tRNA genes positively or negatively in a position-dependent manner either by recruitment or sequestration of TBP from the transcription machinery.

Structure of tri-1-naphthylborane-benzene (1/1) complex, c30h21b.c6h6

M r= 470.46, rhombohedral, R3, a =8.710(4)A, a=91.10(3) o, V= 660.4 (9) A 3, Z= 1,D m= 1.170 (flotation in KI solution), D x=1.183 Mg m -a, Mo Kct, 2 = 0.7107/~,, /t =0.033 mm -1, F(000) - 248.0, T= 293 K, R -- 4.6%(481 unique reflections). The molecule has C a symmetry and is propeller shaped, the angle of twist about the B-C bond being 41.5 (7) °. The space group being chiral, this is yet another example of spontaneous resolution. The results of a thermal-motion analysis are discussed.

Paracrine action of sFLT-1 secreted by stably-transfected Ehrlich ascites tumor cells and therapy using sFLT-1 inhibits ascites tumor growth in vivo

Background Vascular endothelial growth factor (VEGF) is known to play a major role in angiogenesis. A soluble form of Flt-1, a VEGF receptor, is potentially useful as an antagonist of VEGF, and accumulating evidence suggests the applicability of sFlt-1 in tumor suppression. In the present study, we have developed and tested strategies targeted specifically to VEGF for the treatment of ascites formation.Methods As an initial strategy, we produced recombinant sFLT-1 in the baculovirus expression system and used it as a trap to sequester VEGF in the murine ascites carcinoma model. The effect of the treatment on the weight of the animal, cell number, ascites volume and proliferating endothelial cells was studied. The second strategy involved, producing Ehrlich ascites tumor (EAT) cells stably transfected with vectors carrying cDNA encoding truncated form of Flt-1 and using these cells to inhibit ascites tumors in a nude mouse model. Results The sFLT-1 produced by the baculovirus system showed potent antiangiogenic activity as assessed by rat cornea and tube formation assay. sFLT-1 treatment resulted in reduced peritoneal angiogenesis with a concomitant decrease in tumor cell number, volume of ascites, amount of free VEGF and the number of invasive tumor cells as assayed by CD31 staining. EAT cells stably transfected with truncated form of Flt-1 also effectively reduced the tumor burden in nude mice transplanted with these cells, and demonstrated a reduction in ascites formation and peritoneal angiogenesis. Conclusions The inhibition of peritoneal angiogenesis and tumor growth by sequestering VEGF with either sFlt-1 gene expression by recombinant EAT cells or by direct sFLT-1 protein therapy is shown to comprise a potential therapy. Copyright (C) 2009 John Wiley & Sons, Ltd.

Determination of the thermodynamic properties of xMgO + (1 x)MnO (s, sln) from a solid-electrolyte galvanic cell in the temperature range 1163 to 1318 K

The thermodynamic activities of MgO in the NaCl-type solid solutions which can exist in xMgO + (1 x)MnO have been determined in the temperature range 1163 to 1318 K from a solid-state galvanic cell incorporating MgF2 as the solid electrolyte. The activities of MnO have been calculated by a graphical Gibbs-Duhem integration method. The activities of both the components exhibit positive deviations from ideality over the entire composition range. The excess molar enthalpies are found to be positive. Further, xMgO + (1 - x)MnO does not conform to regular-solution behaviour. The origin of the excess thermodynamic properties is discussed in relation to the cationic size disparity and the crystal-field effects.

Row spacing and planting density effects on the growth and yield of sugarcane. 1. Responses in fumigated and non-fumigated soil.

It has been reported that high-density planting of sugarcane can improve cane and sugar yield through promoting rapid canopy closure and increasing radiation interception earlier in crop growth. It is widely known that the control of adverse soil biota through fumigation (removes soil biological constraints and improves soil health) can improve cane and sugar yield. Whether the responses to high-density planting and improved soil health are additive or interactive has important implications for the sugarcane production system. Field experiments established at Bundaberg and Mackay, Queensland, Australia, involved all combinations of 2-row spacings (0.5 and 1.5 m), two planting densities (27 000 and 81 000 two-eyed setts/ha), and two soil fumigation treatments (fumigated and non-fumigated). The Bundaberg experiment had two cultivars (Q124, Q155), was fully irrigated, and harvested 15 months after planting. The Mackay experiment had one cultivar (Q117), was grown under rainfed conditions, and harvested 10 months after planting. High-density planting (81 000 setts/ha in 0.5-m rows) did not produce any more cane or sugar yield at harvest than low-density planting (27 000 setts/ha in 1.5-m rows) regardless of location, crop duration (15 v. 10 months), water supply (irrigated v. rainfed), or soil health (fumigated v. non-fumigated). Conversely, soil fumigation generally increased cane and sugar yields regardless of site, row spacing, and planting density. In the Bundaberg experiment there was a large fumigation x cultivar x density interaction (P<0.01). Cultivar Q155 responded positively to higher planting density in non-fumigated soil but not in fumigated soil, while Q124 showed a negative response to higher planting density in non-fumigated soil but no response in fumigated soil. In the Mackay experiment, Q117 showed a non-significant trend of increasing yield in response to increasing planting density in non-fumigated soil, similar to the Q155 response in non-fumigated soil at Bundaberg. The similarity in yield across the range of row spacings and planting densities within experiments was largely due to compensation between stalk number and stalk weight, particularly when fumigation was used to address soil health. Further, the different cultivars (Q124 and Q155 at Bundaberg and Q117 at Mackay) exhibited differing physiological responses to the fumigation, row spacing, and planting density treatments. These included the rate of tiller initiation and subsequent loss, changes in stalk weight, and propensity to lodging. These responses suggest that there may be potential for selecting cultivars suited to different planting configurations.

Cr3+ electron paramagnetic resonance study of Sn(1-x)CrxO(2) (0.00 <= x <= 0.10)

This paper reports on the liquid-helium-temperature (5 K) electron paramagnetic resonance (EPR) spectra of Cr3+ ions in the nanoparticles of SnO2 synthesized at 600 degrees C with concentrations of 0%, 0.1%, 0.5%, 1%, 1.5%, 2.0%, 2.5%, 3.0%, 5.0%, and 10%. Each spectrum may be simulated as overlap of spectra due to four magnetically inequivalent Cr3+ centers characterized by different values of the spin-Hamiltonian parameters. Three of these centers belong to Cr3+ ions in orthorhombic sites, situated near oxygen vacancies, characterized by very large zero-field splitting parameters D and E, presumably due to the presence of nanoparticles in the samples. The fourth EPR spectrum belongs to the Cr3+ ions situated at sites with tetragonal symmetry, substituting for the Sn4+ ion, characterized by a very small value of D. In addition, there appears a ferromagnetic resonance line due to oxygen defects for samples with Cr3+ concentrations of <= 2.5%. Further, in samples with Cr3+ concentrations of >2.5%, there appears an intense and wide EPR line due to the interactions among the Cr3+ ions in the clusters formed due to rather excessive doping; the intensity and width of this line increase with increasing concentration. The Cr3+ EPR spectra observed in these nanopowders very different from those in bulk SnO2 crystals.

Structure of the disodium salt of glucose 1-phosphate hydrate, 2Na+.C6H11O9P2-.3.5H2O

Mr= 367.2, monoclinic, C2, a = 8.429 (1),b= 10.184(2), c= 16.570(2)A, /~= 99.18 (1) °, U= 1404.2 A 3, z = 4, D m = 1.73, D x = 1.74 Mg m -3,Cu K~, 2 = 1.5418 A, g = 2.99 mm -1, F(000) = 764,T= 300K, final R for 1524 observed reflections is0.069. The endocyclic C-O bonds in the glucose ring are nearly equal with C(5)-O(5)= 1.445 (10) and C(1)-O(5)= 1.424(10). The pyranose sugar ring adopts a 4C 1 chair conformation. The conformation about the exocyclic C(5)-C(6) bond is gauche-gauche, in contrast to gauche-trans observed in the structure of the dipotassium salt of glucose 1-phosphate. The phosphate ester bond, P-O(1), is 1.641 (6)A, slightly longer than the 'high-energy' P-,.O bond in the monopotassium salt of phosphoenolpyruvate [1.612 (6)A]. Two sodium ions are six coordinated while the third has only five neighbours.

Structure of ethyl 1,2,2-tricyano 3-(4-nitrophenyl)-cyclopropane-1-carboxylate

C15HIoN404, monoclinic, P2~/c, a = 10.694(8), b = 11.743 (8), c - 12.658 (8) A, fl = 113.10 (7) °, V = 1462.1 A 3, Z = 4, O m = 1 "38, O c = 1.408 g cm -3, t,t(MoKa, ~, = 0.7107 ]~) = 0.99 cm -i, F(000) = 640. The structure was solved by direct methods and refined to an R value of 0.054 using 1398 intensity measurements. The relative magnitudes of interaction of the substituents and the extent to which a ring can accommodate interactions with substituents are discussed.

Determination of mode 1 notch stress intensity factor by the photoelastic technique

The structural integrity of any member subjected to a load gets impaired due to the presence of cracks or crack-like defects. The notch severity is one of the several parameters that promotes the brittle fracture. The most severe one is an ideal crack with infinitesimal width and infinitesimal or zero root radius. Though analytical investigations can handle an ideal crack, experimental work, either to validate the analytical conclusions or to impose the bounds, needs to be carried out on models or specimens containing the cracks which are far from the ideal ones. Thus instead of an ideal crack with infinitesimal width the actual model will have a slot or a slit of finite width and instead of a crack ending in zero root radius, the model contains a slot having a finite root radius. Another factor of great significance at the root is the notch angle along which the transition from the slot to the root takes place. This paper is concerned with the photoelastic determination of the notch stress intensity factor in the case of a “crack” subjected to Mode 1 deformation.

Familial aggregation of type 1 diabetes and diabetic nephropathy in Finland

Type 1 diabetes (T1D) is a common, multifactorial disease with strong familial clustering. In Finland, the incidence of T1D among children aged 14 years or under is the highest in the world. The increase in incidence has been approximately 2.4% per year. Although most new T1D cases are sporadic the first-degree relatives are at an increased risk of developing the same disease. This study was designed to examine the familial aggregation of T1D and one of its serious complications, diabetic nephropathy (DN). More specifically the study aimed (1) to determine the concordance rates of T1D in monozygotic (MZ) and dizygotic (DZ) twins and to estimate the relative contributions of genetic and environmental factors to the variability in liability to T1D as well as to study the age at onset of diabetes in twins; (2) to obtain long-term empirical estimates of the risk of T1D among siblings of T1D patients and the factors related to this risk, especially the effect of age at onset of diabetes in the proband and the birth cohort effect; (3) to establish if DN is aggregating in a Finnish population-based cohort of families with multiple cases of T1D, and to assess its magnitude and particularly to find out whether the risk of DN in siblings is varying according to the severity of DN in the proband and/or the age at onset of T1D: (4) to assess the recurrence risk of T1D in the offspring of a Finnish population-based cohort of patients with childhood onset T1D, and to investigate potential sex-related effects in the transmission of T1D from the diabetic parents to their offspring as well as to study whether there is a temporal trend in the incidence. The study population comprised of the Finnish Young Twin Cohort (22,650 twin pairs), a population-based cohort of patients with T1D diagnosed at the age of 17 years or earlier between 1965 and 1979 (n=5,144) and all their siblings (n=10,168) and offspring (n=5,291). A polygenic, multifactorial liability model was fitted to the twin data. Kaplan-Meier analyses were used to provide the cumulative incidence for the development of T1D and DN. Cox s proportional hazards models were fitted to the data. Poisson regression analysis was used to evaluate temporal trends in incidence. Standardized incidence ratios (SIRs) between the first-degree relatives of T1D patients and background population were determined. The twin study showed that the vast majority of affected MZ twin pairs remained discordant. Pairwise concordance for T1D was 27.3% in MZ and 3.8% in DZ twins. The probandwise concordance estimates were 42.9% and 7.4%, respectively. The model with additive genetic and individual environmental effects was the best-fitting liability model to T1D, with 88% of the phenotypic variance due to genetic factors. The second paper showed that the 50-year cumulative incidence of T1D in the siblings of diabetic probands was 6.9%. A young age at diagnosis in the probands considerably increased the risk. If the proband was diagnosed at the age of 0-4, 5-9, 10-14, 15 or more, the corresponding 40-year cumulative risks were 13.2%, 7.8%, 4.7% and 3.4%. The cumulative incidence increased with increasing birth year. However, SIR among children aged 14 years or under was approximately 12 throughout the follow-up. The third paper showed that diabetic siblings of the probands with nephropathy had a 2.3 times higher risk of DN compared with siblings of probands free of nephropathy. The presence of end stage renal disease (ESRD) in the proband increases the risk three-fold for diabetic siblings. Being diagnosed with diabetes during puberty (10-14) or a few years before (5-9) increased the susceptibility for DN in the siblings. The fourth paper revealed that of the offspring of male probands, 7.8% were affected by the age of 20 compared with 5.3% of the offspring of female probands. Offspring of fathers with T1D have 1.7 times greater risk to be affected with T1D than the offspring of mothers with T1D. The excess risk in the offspring of male fathers manifested itself through the higher risk the younger the father was when diagnosed with T1D. Young age at onset of diabetes in fathers increased the risk of T1D greatly in the offspring, but no such pattern was seen in the offspring of diabetic mothers. The SIR among offspring aged 14 years or under remained fairly constant throughout the follow-up, approximately 10. The present study has provided new knowledge on T1D recurrence risk in the first-degree relatives and the risk factors modifying the risk. Twin data demonstrated high genetic liability for T1D and increased heritability. The vast majority of affected MZ twin pairs, however, remain discordant for T1D. This study confirmed the drastic impact of the young age at onset of diabetes in the probands on the increased risk of T1D in the first-degree relatives. The only exception was the absence of this pattern in the offspring of T1D mothers. Both the sibling and the offspring recurrence risk studies revealed dynamic changes in the cumulative incidence of T1D in the first-degree relatives. SIRs among the first-degree relatives of T1D patients seems to remain fairly constant. The study demonstrates that the penetrance of the susceptibility genes for T1D may be low, although strongly influenced by the environmental factors. Presence of familial aggregation of DN was confirmed for the first time in a population-based study. Although the majority of the sibling pairs with T1D were discordant for DN, its presence in one sibling doubles and presence of ESRD triples the risk of DN in the other diabetic sibling. An encouraging observation was that although the proportion of children to be diagnosed with T1D at the age of 4 or under is increasing, they seem to have a decreased risk of DN or at least delayed onset.

Statistical analysis of the associations of hereditary factors with the risk of Type 1 diabetes and Diabetic Nephropathy based on the familial data collected through ascertaiment from population-based registers

In genetic epidemiology, population-based disease registries are commonly used to collect genotype or other risk factor information concerning affected subjects and their relatives. This work presents two new approaches for the statistical inference of ascertained data: a conditional and full likelihood approaches for the disease with variable age at onset phenotype using familial data obtained from population-based registry of incident cases. The aim is to obtain statistically reliable estimates of the general population parameters. The statistical analysis of familial data with variable age at onset becomes more complicated when some of the study subjects are non-susceptible, that is to say these subjects never get the disease. A statistical model for a variable age at onset with long-term survivors is proposed for studies of familial aggregation, using latent variable approach, as well as for prospective studies of genetic association studies with candidate genes. In addition, we explore the possibility of a genetic explanation of the observed increase in the incidence of Type 1 diabetes (T1D) in Finland in recent decades and the hypothesis of non-Mendelian transmission of T1D associated genes. Both classical and Bayesian statistical inference were used in the modelling and estimation. Despite the fact that this work contains five studies with different statistical models, they all concern data obtained from nationwide registries of T1D and genetics of T1D. In the analyses of T1D data, non-Mendelian transmission of T1D susceptibility alleles was not observed. In addition, non-Mendelian transmission of T1D susceptibility genes did not make a plausible explanation for the increase in T1D incidence in Finland. Instead, the Human Leucocyte Antigen associations with T1D were confirmed in the population-based analysis, which combines T1D registry information, reference sample of healthy subjects and birth cohort information of the Finnish population. Finally, a substantial familial variation in the susceptibility of T1D nephropathy was observed. The presented studies show the benefits of sophisticated statistical modelling to explore risk factors for complex diseases.

Synthesis and biological evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives and their precursors as antileukemic agents

We report here the synthesis and preliminary evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives 6(a–k) and their precursors 5(a–k) as potential chemotherapeutic agents. In each case, the structures of the compounds were determined by FTIR, 1H NMR and mass spectroscopy. Among the synthesized molecules, methyl 1-(4-methoxyphenethyl)-2-(4-fluoro-3-nitrophenyl)-1H-benzimidazole-5-carboxylate (5a) induced maximum cell death in leukemic cells with an IC50 value of 3 μM. Using FACS analysis we show that the compound 5a induces S/G2 cell cycle arrest, which was further supported by the observed down regulation of CDK2, Cyclin B1 and PCNA. The observed downregulation of proapoptotic proteins, upregulation of antiapoptotic proteins, cleavage of PARP and elevated levels of DNA strand breaks indicated the activation of apoptosis by 5a. These results suggest that 5a could be a potent anti-leukemic agent.