Limited Lifespan of Fragile Regions in Mammalian Evolution

An important question in genome evolution is whether there exist fragile regions (rearrangement hotspots) where chromosomal rearrangements are happening over and over again. Although nearly all recent studies supported the existence of fragile regions in mammalian genomes, the most comprehensive phylogenomic study of mammals (Ma et al. (2006) Genome Research 16, 1557-1565) raised some doubts about their existence. We demonstrate that fragile regions are subject to a "birth and death" process, implying that fragility has limited evolutionary lifespan. This finding implies that fragile regions migrate to different locations in different mammals, explaining why there exist only a few chromosomal breakpoints shared between different lineages. The birth and death of fragile regions phenomenon reinforces the hypothesis that rearrangements are promoted by matching segmental duplications and suggests putative locations of the currently active fragile regions in the human genome

Association Between CNDP1 Genotype and Diabetic Nephropathy Is Sex Specific

OBJECTIVE-The 5-5 homozygous CNDP1 (carnosinase) genotype is associated with a reduced risk of diabetic nephropathy. We investigated whether this association is sex specific and independent of susceptibility for type 2 diabetes. RESEARCH DESIGN AND METHODS-Three separate groups of 114, 90, and 66 patients with type 2 diabetes and diabetic nephropathy were included in this study and compared with 93 patients with type 2 diabetes for >15 years without diabetic nephropathy and 472 population control subjects. The diabetes control group was used to determine an association in the three patient groups separately, and the population control group was used to estimate the genotype risk [odds ratio (CI)] for the population in a pooled analysis. The population control subjects were also compared with 562 patients with type 2 diabetes without diabetic nephropathy to determine whether the association was independent of type 2 diabetes. The CNDP1 genotype was determined by fragment analysis after PCR amplification. RESULTS-The frequency of the 5-5 homozygous genotype was 28, 36, and 41% in the three diabetic nephropathy patient groups and 43 and 42% in the diabetic and population control subjects, respectively. The 5-5 homozygous genotype occurred significantly less frequently in women in all three patient groups compared with diabetic control subjects. The genotype risk for the population was estimated to be 0.5 (0.30-0.68) in women and 1.2 (0.77-1.69) in men. The 562 patients with type 2 diabetes without diabetic nephropathy did not differ from the general population (P = 0.23). CONCLUSIONS-This study suggests that the association between the CNDP1 gene and diabetic nephropathy is sex specific and independent of susceptibility for type 2 diabetes. Diabetes 59:1555-1559, 201

HbA1c levels in schoolchildren with type 1 diabetes are seasonally variable and dependent on weather conditions

Aims/hypothesis: We evaluated seasonal HbA$_{1c}$ changes in children with type 1 diabetes and its relation with measures of weather conditions. Methods: HbA$_{1c}$ changes over more than 3 years were evaluated in type 1 diabetic patients who were younger than 18 years and had diabetes duration of more than 12 months, and correlated with measures of weather conditions (ambient temperature, hours of sunshine and solar irradiance). After comparison of autocorrelation patterns, patterns of metabolic control and meteorological data were evaluated using Spearman rank correlation. Results: A total of 3,935 HbA$_{1c}$ measurements in 589 school (≥7 years) and 88 preschool (<7 years) children were analysed. Mean (±SD) HbA$_{1c}$ level for the whole study period was 7.65±1.12%. The lowest HbA$_{1c}$ levels were observed in late summer and the highest in winter months, with differences consistently exceeding 0.44%. Autocorrelation analysis of HbA$_{1c}$ levels in schoolchildren showed a sine-wave pattern with a cycle length of roughly 12 months, which mirrored changes in ambient temperature. Strong negative correlations of HbA$_{1c}$ with ambient temperature (R=−0.56; p=0.0002), hours of sunshine (R=−0.52; p=0.0007) and solar irradiance (R=−0.52; p=0.0006) were present in schoolchildren, but not in preschoolers (p≥0.29 for each correlation). Conclusions/interpretation: Seasonal changes of HbA$_{1c}$ levels in schoolchildren with type 1 diabetes are a significant phenomenon and should be considered in patient education and diabetes management. They may potentially affect the results of clinical trials using HbA$_{1c}$ levels as their primary outcome, as well as HbA$_{1c}$-based diagnosis of diabetes

Contrast-enhanced whole-heart coronary MRA at 3.0T for the evaluation of cardiac venous anatomy

This study was designed to evaluate the value of contrast-enhanced whole-heart coronary MRA (CMRA) at 3.0T in depicting the cardiac venous anatomy. In cardiac resynchronization therapy (CRT), left ventricular (LV) pacing is achieved by positioning the LV lead in one of the tributaries of the coronary sinus (CS). Pre-implantation knowledge of the venous anatomy may help determine whether transvenous LV lead placement for CRT is feasible. Images of 51 subjects undergoing contrast-enhanced whole-heart CMRA at 3.0T were retrospectively analyzed. Data acquisition was performed using electrocardiography-triggered, navigator-gated, inversion-recovery prepared, segmented gradient-echo sequence. A 32-element cardiac coil was used for data acquisition. The visibility of the cardiac veins was graded visually using a 4-point scale (1: poor–4: excellent). The paired Student t test was used to evaluate differences in diameters of the ostium of the CS in anteroposterior and superoinferior direction. The cardiac veins were finally evaluated in 48 subjects with three anatomic variations. The diameter of the CS ostium in the superoinferior direction (1.13 ± 0.26 cm) was larger than in the anteroposterior direction (0.82 ± 0.19 cm) (P < 0.05). The mean visibility score of CS, posterior interventricular vein, posterior vein of the left ventricle, left marginal vein, and anterior interventricular vein was 4.0 ± 0.0, 3.4 ± 0.5, 3.4 ± 0.5, 3.0 ± 0.8, and 3.3 ± 0.5, respectively. In conclusion, contrast-enhanced whole-heart CMRA at 3.0T can depict the normal and variant cardiac venous anatomy

Are ribosomal DNA clusters rearrangement hotspots? A case study in the genus Mus (Rodentia, Muridae)

<p>Abstract</p> <p>Background</p> <p>Recent advances in comparative genomics have considerably improved our knowledge of the evolution of mammalian karyotype architecture. One of the breakthroughs was the preferential localization of evolutionary breakpoints in regions enriched in repetitive sequences (segmental duplications, telomeres and centromeres). In this context, we investigated the contribution of ribosomal genes to genome reshuffling since they are generally located in pericentromeric or subtelomeric regions, and form repeat clusters on different chromosomes. The target model was the genus <it>Mus </it>which exhibits a high rate of karyotypic change, a large fraction of which involves centromeres.</p> <p>Results</p> <p>The chromosomal distribution of rDNA clusters was determined by <it>in situ </it>hybridization of mouse probes in 19 species. Using a molecular-based reference tree, the phylogenetic distribution of clusters within the genus was reconstructed, and the temporal association between rDNA clusters, breakpoints and centromeres was tested by maximum likelihood analyses. Our results highlighted the following features of rDNA cluster dynamics in the genus <it>Mus</it>: i) rDNA clusters showed extensive diversity in number between species and an almost exclusive pericentromeric location, ii) a strong association between rDNA sites and centromeres was retrieved which may be related to their shared constraint of concerted evolution, iii) 24% of the observed breakpoints mapped near an rDNA cluster, and iv) a substantial rate of rDNA cluster change (insertion, deletion) also occurred in the absence of chromosomal rearrangements.</p> <p>Conclusions</p> <p>This study on the dynamics of rDNA clusters within the genus <it>Mus </it>has revealed a strong evolutionary relationship between rDNA clusters and centromeres. Both of these genomic structures coincide with breakpoints in the genus <it>Mus</it>, suggesting that the accumulation of a large number of repeats in the centromeric region may contribute to the high level of chromosome repatterning observed in this group. However, the elevated rate of rDNA change observed in the chromosomally invariant clade indicates that the presence of these sequences is insufficient to lead to genome instability. In agreement with recent studies, these results suggest that additional factors such as modifications of the epigenetic state of DNA may be required to trigger evolutionary plasticity.</p

Common Variants of Inflammatory Cytokine Genes Are Associated with Risk of Nephropathy in Type 2 Diabetes among Asian Indians

BACKGROUND: Inflammatory cytokine genes have been proposed as good candidate genes for conferring susceptibility to diabetic nephropathy. In the present study, we examined the combined effect of multiple alleles of pro inflammatory cytokine genes for determining the risk of nephropathy in type 2 diabetic patients. METHODOLOGY/PRINCIPAL FINDINGS: Eight single nucleotide polymorphisms (SNPs) of pro-inflammatory cytokine genes (CCL2, TGFB1, IL8, CCR5, and MMP9) were genotyped in two independently ascertained type 2 diabetic cohorts with (DN) and without nephropathy (DM); consisting of patients from North India (n = 495) and South India (n = 188). Genotyping was carried out using PCR, allele specific oligonucleotide-PCR (ASO-PCR), PCR-RFLP and TaqMan allelic discrimination assays and the gene-gene interaction among genetic variants were determined by multi dimensional reduction (MDR) software. Serum high sensitive CRP (hs-CRP) levels were measured by ELISA. The hs-CRP levels were significantly higher in DN as compared to the DM group (p<0.05). The CCL2, IL8, CCR5 and MMP9 polymorphisms were found to be associated with the risk of diabetic nephropathy. Frequency of CCL2 II, IL8 -251AA, CCR5 59029AA and MMP9 279Gln/Gln genotypes were significantly higher in DN than in DM group (p<0.05) and associated with an increased risk of nephropathy in both North and South Indian cohorts. CCR5 DD and IL8 -251AA genotypes were more prevalent in North Indian DN group only. The co-occurrence of risk associated genotypes (II, -2518GG (CCL2), DD (CCR5) and 279Gln/Gln (MMP9) conferred a tenfold increased risk of nephropathy among type 2 diabetics (p<0.0002). CONCLUSION: The present study highlights that common variants of inflammatory cytokine genes exert a modest effect on risk of DN and a combination of risk alleles confer a substantial increased risk of nephropathy in type 2 diabetes among Asian Indians

Differential regulation of serum microRNA expression by HNF1β and HNF1α transcription factors.

We aimed to identify microRNAs (miRNAs) under transcriptional control of the HNF1β transcription factor, and investigate whether its effect manifests in serum.This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text via the publisher's site.Published (Open Access

Exclusive dielectron production in ultraperipheral Pb+Pb collisions at √sNN = 5.02 TeV with ATLAS

Exclusive production of dielectron pairs, γγ → e+e−, is studied using Lint = 1.72 nb−1 of data from ultraperipheral collisions of lead nuclei at √sNN = 5.02 TeV recorded by the ATLAS detector at the LHC. The process of interest proceeds via photon–photon interactions in the strong electromagnetic fields of relativistic lead nuclei. Dielectron production is measured in the fiducial region defined by following requirements: electron transverse momentum peT &gt; 2.5 GeV, absolute electron pseudorapidity |ηe| &lt; 2.5, dielectron invariant mass mee &gt; 5 GeV, and dielectron transverse momentum peeT &lt; 2 GeV. Differential cross-sections are measured as a function of mee, average peT , absolute dielectron rapidity |yee|, and scattering angle in the dielectron rest frame, |cos θ*|, in the inclusive sample, and also with a requirement of no activity in the forward direction. The total integrated fiducial cross-section is measured to be 215±1(stat.)+23−20(syst.)±4(lumi.) μb. Within experimental uncertainties the measured integrated cross-section is in good agreement with the QED predictions from the Monte Carlo programs STARLIGHT and SUPERCHIC, confirming the broad features of the initial photon fluxes. The differential cross-sections show systematic differences from these predictions which are more pronounced at high |yee| and |cos θ*| values