Associations of HLA DR and DQ molecules with Lyme borreliosis in Latvian patients

ABSTRACT: BACKGROUND: Many autoimmune diseases are associated with variants of HLA genes such as those encoding the MHC complex. This correlation is not absolute, but may help in understanding of the molecular mechanism of disease. The purpose of this study was to determine HLA-DR,-DQ alleles in Latvian patients with Lyme borreliosis and control (healthy) persons. Case patients and control subjects were similar in age, gender and ethnic heritage and differed only as regards the presence of Borrelia burgdorferi infection. The study included 20 patients with clinical stage - erythema migrans and 25 control (healthy) persons. HLA genotyping was performed by PCR with sequence-specific primers. RESULTS: The results show difference in HLA-DRB1 alleles distribution between patients and control subjects. The frequencies of HLA-DRB1 *04 (OR 8.65; p<0.022) and HLA-DRB1 *17 (03) (OR 7.00; p<0.048) were increased in the Lyme disease patients. And the frequency of allele DRB1*13 (OR 0.13; p<0.033) was lower in Borreliosis patients and higher in control group. But, significant differences in frequencies of HLA-DQ alleles we did not detect. CONCLUSIONS: HLA predisposition to Lyme borreliosis appears not to be limited to HLA molecules, but some HLA-DR alleles also have a significant influence, and, may have implications in our understanding of pathogenesis of this disease. In particular, HLA-DRB1*04 and DRB1 *17 (03) may contribute to the Lyme borreliosis development in Latvian population KEYWORDS: Lyme borreliosis, HLA alleles, PCR.     

Assessment of the probabilities for evolutionary structural changes in protein folds

MOTIVATION: The evolution of protein sequences can be described by a stepwise process, where each step involves changes of a few amino acids. In a similar manner, the evolution of protein folds can be at least partially described by an analogous process, where each step involves comparatively simple changes affecting few secondary structure elements. A number of such evolution steps, justified by biologically confirmed examples, have previously been proposed by other researchers. However, unlike the situation with sequences, as far as we know there have been no attempts to estimate the comparative probabilities for different kinds of such structural changes. RESULTS: We have tried to assess the comparative probabilities for a number of known structural changes, and to relate the probabilities of such changes with the distance between protein sequences. We have formalized these structural changes using a topological representation of structures (TOPS), and have developed an algorithm for measuring structural distances that involve few evolutionary steps. The probabilities of structural changes then were estimated on the basis of all-against-all comparisons of the sequence and structure of protein domains from the CATH-95 representative set. The results obtained are reasonably consistent for a number of different data subsets and permit the identification of several 'most popular' types of evolutionary changes in protein structure. The results also suggest that alterations in protein structure are more likely to occur when the sequence similarity is >10% (the average similarity being approximately 6% for the data sets employed in this study), and that the distribution of probabilities of structural changes is fairly uniform within the interval of 15-50% sequence similarity. AVAILABILITY: The algorithms have been implemented on the Windows operating system in C++ and using the Borland Visual Component Library. The source code is available on request from the first author. The data sets used for this study (representative sets of protein domains, matrices of sequence similarities and structural distances) are available on http://bioinf.mii.lu.lv/epsrc_project/struct_ev.html.     

Human metabolic profiles are stably controlled by genetic and environmental variation

¹H Nuclear Magnetic Resonance spectroscopy (¹H NMR) is increasingly used to measure metabolite concentrations in sets of biological samples for top‐down systems biology and molecular epidemiology. For such purposes, knowledge of the sources of human variation in metabolite concentrations is valuable, but currently sparse. We conducted and analysed a study to create such a resource. In our unique design, identical and non‐identical twin pairs donated plasma and urine samples longitudinally. We acquired ¹H NMR spectra on the samples, and statistically decomposed variation in metabolite concentration into familial (genetic and common‐environmental), individual‐environmental, and longitudinally unstable components. We estimate that stable variation, comprising familial and individual‐environmental factors, accounts on average for 60% (plasma) and 47% (urine) of biological variation in ¹H NMR‐detectable metabolite concentrations. Clinically predictive metabolic variation is likely nested within this stable component, so our results have implications for the effective design of biomarker‐discovery studies. We provide a power‐calculation method which reveals that sample sizes of a few thousand should offer sufficient statistical precision to detect ¹H NMR‐based biomarkers quantifying predisposition to disease.     

HSM — a hybrid system based approach for modelling intracellular networks

The paper proposes a hybrid system based approach for modelling of intracellular networks and introduces a restricted subclass of hybrid systems – HSM – with an objective of still being able to provide sufficient power for the modelling of biological systems, while imposing some restrictions that facilitate analysis of systems described by such models.     

Fine-root growth,mortality and heavy metal concentrations in limed and fertilized Pinus silvestris (L.) stands in the vicinity of a Cu-Ni smelter in SW Finland

This study was conducted to assess 1) the growth of fine roots into ingrowth cores and fine root mortality, 2) the effects of liming and correction fertilization on fine-root growth and mortality, and 3) the concentrations of heavy metals in fine roots in control, limed or fertilized Scots pine stands at different distances from a copper-nickel smelter. Fine-root biomass in the ingrowth cores in the control plots varied between 1 (at 0.5 km from the smelter) and 252 and 271 g/m² (at 4 and 8 km, respectively). In the most polluted stand at 0.5 km, 98% of the fine roots that had grown into the ingrowth cores had died before sampling. Corresponding values for the other stands (4 and 8 km) were only 13-18%. At 0.5 km, liming increased the growth and survival of fine roots. The concentrations of Cu and Ni were also smaller in fine roots from the limed plot than those from the control plot. In the correction fertilization treatment at 0.5 km the total ingrowth of fine roots was at the same level as in the control, but less fine roots had died. Thus, the correction fertilizer treatment increased the survival but not the growth of fine roots. At 4 or 8 km, there were no significant differences in the fine-root biomass or necromass or element concentrations between the treatments. This revised version was published online in June 2006 with corrections to the Cover Date.     

Crystal structure of human gamma-butyrobetaine hydroxylase

Gamma-butyrobetaine hydroxylase (GBBH) is a 2-ketoglutarate-dependent dioxygenase that catalyzes the biosynthesis of l-carnitine by hydroxylation of gamma-butyrobetaine (GBB). l-carnitine is required for the transport of long-chain fatty acids into mitochondria for generating metabolic energy. The only known synthetic inhibitor of GBBH is mildronate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate), which is a non-hydroxylatable analog of GBB.To aid in the discovery of novel GBBH inhibitors by rational drug design, we have solved the three-dimensional structure of recombinant human GBBH at 2.0 Å resolution. The GBBH monomer consists of a catalytic double-stranded β-helix (DBSH) domain, which is found in all 2KG oxygenases, and a smaller N-terminal domain. Extensive interactions between two monomers confirm earlier observations that GBBH is dimeric in its biological state. Although many 2KG oxygenases are multimeric, the dimerization interface of GBBH is very different from that of related enzymes.The N-terminal domain of GBBH has a similar fold to the DUF971 superfamily, which consists of several short bacterial proteins with unknown function. The N-terminal domain has a bound Zn ion, which is coordinated by three cysteines and one histidine. Although several other 2KG oxygenases with known structures have more than one domain, none of them resemble the N-terminal domain of GBBH. The N-terminal domain may facilitate dimer formation, but its precise biological role remains to be discovered.The active site of the catalytic domain of GBBH is similar to that of other 2KG oxygenases, and Fe(II)-binding residues form a conserved His-X-Asp-X_n-His triad, which is found in all related enzymes.     

A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection

We have performed a metabolite quantitative trait locus (mQTL) study of the (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1)H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11)相似文献