Gene-gene Interaction Between EPAS1 and EGLN1 in Patients with High-Altitude Pulmonary Edema

Article信州医学雑誌 63(3):157-165 (2015)journal articl

The association of Toll-like receptor 4 gene polymorphisms with the development of emphysema in Japanese subjects: a case control study

<p>Abstract</p> <p>Background</p> <p>The principal role of Toll-like receptor 4 (TLR4) is the induction of immune responses to lipopolysaccharides. Previously, mice deficient in the <it>TLR4 </it>gene exhibited up-regulation of the NADPH oxidase system in the lungs. This resulted in increased oxidant generation and elastolytic activity, which led to pulmonary emphysema. It was suggested that TLR4 might maintain constitutive lung integrity by modulating oxidant generation. We investigated whether single nucleotide polymorphisms (SNPs) in the <it>TLR4 </it>gene were associated with the emphysema phenotype in Japanese subjects with chronic obstructive pulmonary disease (COPD).</p> <p>Results</p> <p>Seven SNPs in the <it>TLR4 </it>gene (<it>rs10759930</it>, <it>rs1927914</it>, <it>rs12377632</it>, <it>rs2149356, rs11536889</it>, <it>rs7037117</it>, and <it>rs7045953</it>) were genotyped with allelic discrimination assays. The frequencies of SNPs were compared between 106 patients with the emphysema phenotype of COPD and 137 healthy smokers. We found that the positivity of the individuals with the major G allele of <it>rs11536889 </it>was significantly less in the emphysema group than the control group (<it>p </it>= 0.019). The frequencies of the minor C allele and the distribution of the CC genotype as well as the frequency of the major haplotype that carried the minor C allele of <it>rs11536889 </it>were all significantly higher in the emphysema group than the control group (<it>p </it>= 0.0083, 0.019, and 0.004, respectively). Furthermore, the strength of the association of the CC genotype with the emphysema phenotype was in an odds ratio of 2.60 with 95% confidence intervals from 1.17 to 5.78. However, these significances were not apparent after adjust for age and smoking history by logistic regression. No associations were observed between the <it>rs11536889 </it>and the low attenuation area score, the forced expiratory volume, and the carbon monoxide diffusion capacity in the emphysema group.</p> <p>Conclusions</p> <p>The minor C allele of the <it>rs11536889 </it>SNP in the <it>TLR4 </it>gene is likely associated with the risk of developing emphysema in the Japanese population.</p

Endobronchial Ultrasound-guided Transbronchial Needle Aspiration for the Diagnosis of Intrathoracic Lesions : Experience of a Single Academic Medical Center

Article信州医学雑誌 60(5): 249-255(2012)journal articl

Nanodisc-to-Nanofiber Transition of Noncovalent Peptide–Phospholipid Assemblies

We report a novel molecular architecture of peptide–phospholipid coassemblies. The amphiphilic peptide Ac-18A-NH₂ (18A), which was designed to mimic apolipoprotein α-helices, has been shown to form nanodisc structures with phospholipid bilayers. We show that an 18A peptide cysteine substitution at residue 11, 18A­[A11C], forms fibrous assemblies with 1-palmitoyl-2-oleoyl-phosphatidylcholine at a lipid-to-peptide (L/P) molar ratio of 1, a fiber diameter of 10–20 nm, and a length of more than 1 μm. Furthermore, 18A­[A11C] can form nanodiscs with these lipid bilayers at L/P ratios of 4–6. The peptide adopts α-helical structures in both the nanodisc and nanofiber assemblies, although the α-helical bundle structures were evident only in the nanofibers, and the phospholipids of the nanofibers were not lamellar. Fluorescence spectroscopic analysis revealed that the peptide and lipid molecules in the nanofibers exhibited different solvent accessibility and hydrophobicity from those of the nanodiscs. Furthermore, the cysteine substitution at residue 11 did not result in disulfide bond formation, although it was responsible for the nanofiber formation, suggesting that this free sulfhydryl group has an important functional role. Alternatively, the disulfide dimer of 18A­[A11C] preferentially formed nanodiscs, even at an L/P ratio of 1. Interconversions of these discoidal and fibrous assemblies were induced by the stepwise addition of free 18A­[A11C] or liposomes into the solution. Furthermore, these structural transitions could also be induced by the introduction of oxidative and reductive stresses to the assemblies. Our results demonstrate that heteromolecular lipid–peptide complexes represent a novel approach to the construction of controllable and functional nanoscale assemblies