Resistance Noise Scaling in a Dilute Two-Dimensional Hole System in GaAs

We have measured the resistance noise of a two-dimensional (2D)hole system in a high mobility GaAs quantum well, around the 2D metal-insulator transition (MIT) at zero magnetic field. The normalized noise power $S_R/R^2$ increases strongly when the hole density p_s is decreased, increases slightly with temperature (T) at the largest densities, and decreases strongly with T at low p_s. The noise scales with the resistance, $S_R/R^2 \sim R^{2.4}$, as for a second order phase transition such as a percolation transition. The p_s dependence of the conductivity is consistent with a critical behavior for such a transition, near a density p* which is lower than the observed MIT critical density p_c.Comment: 4 pages, 4 figures, to be published in Phys. Rev. Let

An analysis of growth, differentiation and apoptosis genes with risk of renal cancer

We conducted a case-control study of renal cancer (987 cases and 1298 controls) in Central and Eastern Europe and analyzed genomic DNA for 319 tagging single-nucleotide polymorphisms (SNPs) in 21 genes involved in cellular growth, differentiation and apoptosis using an Illumina Oligo Pool All (OPA). A haplotype-based method (sliding window analysis of consecutive SNPs) was used to identify chromosome regions of interest that remained significant at a false discovery rate of 10%. Subsequently, risk estimates were generated for regions with a high level of signal and individual SNPs by unconditional logistic regression adjusting for age, gender and study center. Three regions containing genes associated with renal cancer were identified: caspase 1/5/4/ 12(CASP 1/5/4/12), epidermal growth factor receptor (EGFR), and insulin-like growth factor binding protein-3 (IGFBP3). We observed that individuals with CASP1/5/4/12 haplotype (spanning area upstream of CASP1 through exon 2 of CASP5) GGGCTCAGT were at higher risk of renal cancer compared to individuals with the most common haplotype (OR:1.40, 95% CI:1.10-1.78, p-value = 0.007). Analysis of EGFR revealed three strong signals within intron 1, particularly a region centered around rs759158 with a global p = 0.006 (GGG: OR:1.26, 95% CI:1.04-1.53 and ATG: OR:1.55, 95% CI:1.14-2.11). A region in IGFBP3 was also associated with increased risk (global p = 0.04). In addition, the number of statistically significant (p-value 0.05) SNP associations observed within these three genes was higher than would be expected by chance on a gene level. To our knowledge, this is the first study to evaluate these genes in relation to renal cancer and there is need to replicate and extend our findings. The specific regions associated with risk may have particular relevance for gene function and/or carcinogenesis. In conclusion, our evaluation has identified common genetic variants in CASP1, CASP5, EGFR, and IGFBP3 that could be associated with renal cancer risk

On the violation of the Fermi-liquid picture in two-dimensional systems owing to the Van-Hove singularities

We consider the two-dimensional t-t' Hubbard model with the Fermi level being close to the van Hove singularities. The phase diagram of the model is discussed. In a broad energy region the self-energy at the singularity points has a nearly-linear energy dependence. The corresponding correction to the density of states is proportional to ln^3(e). Both real- and imaginary part of the self-energy increase near the quantum phase transition into magnetically ordered or superconducting phase which implies violation of the Fermi-liquid behavior. The application of the results to cuprates is discussed.Comment: 16 pages, RevTeX, 5 figures; The errors of the published version (PRB 64, 205105, 2001) are correcte

Rare Copy Number Variants Observed in Hereditary Breast Cancer Cases Disrupt Genes in Estrogen Signaling and TP53 Tumor Suppression Network

Breast cancer is the most common cancer in women in developed countries, and the contribution of genetic susceptibility to breast cancer development has been well-recognized. However, a great proportion of these hereditary predisposing factors still remain unidentified. To examine the contribution of rare copy number variants (CNVs) in breast cancer predisposition, high-resolution genome-wide scans were performed on genomic DNA of 103 BRCA1, BRCA2, and PALB2 mutation negative familial breast cancer cases and 128 geographically matched healthy female controls; for replication an independent cohort of 75 similarly mutation negative young breast cancer patients was used. All observed rare variants were confirmed by independent methods. The studied breast cancer cases showed a consistent increase in the frequency of rare CNVs when compared to controls. Furthermore, the biological networks of the disrupted genes differed between the two groups. In familial cases the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity, including DNA double-strand break repair (P = 0.0211). Biological network analysis in the two independent breast cancer cohorts showed that the disrupted genes were closely related to estrogen signaling and TP53 centered tumor suppressor network. These results suggest that rare CNVs represent an alternative source of genetic variation influencing hereditary risk for breast cancer

Pathway Analysis for Genome-Wide Association Study of Basal Cell Carcinoma of the Skin

Recently, a pathway-based approach has been developed to evaluate the cumulative contribution of the functionally related genes for genome-wide association studies (GWASs), which may help utilize GWAS data to a greater extent.In this study, we applied this approach for the GWAS of basal cell carcinoma (BCC) of the skin. We first conducted the BCC GWAS among 1,797 BCC cases and 5,197 controls in Caucasians with 740,760 genotyped SNPs. 115,688 SNPs were grouped into gene transcripts within 20 kb in distance and then into 174 Kyoto Encyclopedia of Genes and Genomes pathways, 205 BioCarta pathways, as well as two positive control gene sets (pigmentation gene set and BCC risk gene set). The association of each pathway with BCC risk was evaluated using the weighted Kolmogorov-Smirnov test. One thousand permutations were conducted to assess the significance.Both of the positive control gene sets reached pathway p-values<0.05. Four other pathways were also significantly associated with BCC risk: the heparan sulfate biosynthesis pathway (p  =  0.007, false discovery rate, FDR  =  0.35), the mCalpain pathway (p  =  0.002, FDR  =  0.12), the Rho cell motility signaling pathway (p  =  0.011, FDR  =  0.30), and the nitric oxide pathway (p  =  0.022, FDR  =  0.42).We identified four pathways associated with BCC risk, which may offer new insights into the etiology of BCC upon further validation, and this approach may help identify potential biological pathways that might be missed by the standard GWAS approach

FTO gene polymorphisms and obesity risk: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>The pathogenesis of obesity is reportedly related to variations in the fat mass and an obesity-associated gene (<it>FTO</it>); however, as the number of reports increases, particularly with respect to varying ethnicities, there is a need to determine more precisely the effect sizes in each ethnic group. In addition, some reports have claimed ethnic-specific associations with alternative SNPs, and to that end there has been a degree of confusion.</p> <p>Methods</p> <p>We searched PubMed, MEDLINE, Web of Science, EMBASE, and BIOSIS Preview to identify studies investigating the associations between the five polymorphisms and obesity risk. Individual study odds ratios (OR) and their 95% confidence intervals (CI) were estimated using per-allele comparison. Summary ORs were estimated using a random effects model.</p> <p>Results</p> <p>We identified 59 eligible case-control studies in 27 articles, investigating 41,734 obesity cases and 69,837 healthy controls. Significant associations were detected between obesity risk and the five polymorphisms: rs9939609 (OR: 1.31, 95% CI: 1.26 to 1.36), rs1421085 (OR: 1.43, 95% CI: 1.33 to 1.53), rs8050136 (OR: 1.25, 95% CI: 1.13 to 1.38), rs17817449 (OR: 1.54, 95% CI: 1.41 to 1.68), and rs1121980 (OR: 1.34, 95% CI: 1.10 to 1.62). Begg's and Egger's tests provided no evidence of publication bias for the polymorphisms except rs1121980. There is evidence of higher heterogeneity, with <it>I</it>²test values ranging from 38.1% to 84.5%.</p> <p>Conclusions</p> <p>This meta-analysis suggests that <it>FTO </it>may represent a low-penetrance susceptible gene for obesity risk. Individual studies with large sample size are needed to further evaluate the associations between the polymorphisms and obesity risk in various ethnic populations.</p

Reduced Lentivirus Susceptibility in Sheep with TMEM154 Mutations

Visna/Maedi, or ovine progressive pneumonia (OPP) as it is known in the United States, is an incurable slow-acting disease of sheep caused by persistent lentivirus infection. This disease affects multiple tissues, including those of the respiratory and central nervous systems. Our aim was to identify ovine genetic risk factors for lentivirus infection. Sixty-nine matched pairs of infected cases and uninfected controls were identified among 736 naturally exposed sheep older than five years of age. These pairs were used in a genome-wide association study with 50,614 markers. A single SNP was identified in the ovine transmembrane protein (TMEM154) that exceeded genome-wide significance (unadjusted p-value 3×10−9). Sanger sequencing of the ovine TMEM154 coding region identified six missense and two frameshift deletion mutations in the predicted signal peptide and extracellular domain. Two TMEM154 haplotypes encoding glutamate (E) at position 35 were associated with infection while a third haplotype with lysine (K) at position 35 was not. Haplotypes encoding full-length E35 isoforms were analyzed together as genetic risk factors in a multi-breed, matched case-control design, with 61 pairs of 4-year-old ewes. The odds of infection for ewes with one copy of a full-length TMEM154 E35 allele were 28 times greater than the odds for those without (p-value<0.0001, 95% CI 5–1,100). In a combined analysis of nine cohorts with 2,705 sheep from Nebraska, Idaho, and Iowa, the relative risk of infection was 2.85 times greater for sheep with a full-length TMEM154 E35 allele (p-value<0.0001, 95% CI 2.36–3.43). Although rare, some sheep were homozygous for TMEM154 deletion mutations and remained uninfected despite a lifetime of significant exposure. Together, these findings indicate that TMEM154 may play a central role in ovine lentivirus infection and removing sheep with the most susceptible genotypes may help eradicate OPP and protect flocks from reinfection

Emerging Roles of PAR-1 and PAFR in Melanoma Metastasis

Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor–ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1 and PAFR, contribute to the acquisition of the metastatic phenotype of melanoma is presented and discussed