Identification of diabetes susceptibility loci in db mice by combined quantitative trait loci analysis and haplotype mapping

To identify the disease-susceptibility genes of type 2 diabetes, we performed quantitative trait loci (QTL) analysis in F2 populations generated from a BKS.Cg-m+/+Leprdb and C3H/HeJ intercross, taking advantage of genetically determined obesity and diabetes traits associated with the db gene. A genome-wide scan in the F2 populations divided by sex and db genotypes identified 14 QTLs in total and 3 major QTLs on chromosome (Chr) 3 (LOD 5.78) for fat pad weight, Chr 15 (LOD 6.64) for body weight, and Chr 16 (LOD 8.15) for blood glucose concentrations. A linear-model-based genome scan using interactive covariates allowed us to consider sex- or sex-by db-specific effects of each locus. For the most significant QTL on Chr 16, the high-resolution haplotype comparison between BKS and C3H strains reduced the critical QTL interval from 20 to 4.6 Mb by excluding shared haplotype regions and identified 11 nonsynonymous single-nucleotide polymorphisms in six candidate genes

Experimental validation of blood flow derived from pulse oximeter wave signals in beagles

Purpose Pulse oximeter wave reflects blood volume changes in tissue, suggesting the possibility of monitoring changes in tissue blood flow. Thus, our aim was to examine the correlation between tissue blood flow derived from pulse oximeter wave signals (Q_pulse) at a toe and the arterial flow measured by a Doppler probe at the femoral artery (Q_Doppler).Methods Six beagles under general anesthesia were studied. A 24-G catheter was placed in the proximal femoral artery for drug infusion and an ultrasonic transit-time flow probe applied to the artery to measure Q_Doppler. The pulse oximeter signals from the right toe were processed with in-house-developed software to obtain Q_pulse. Three saline solutions containing respectively the vasodilators isosorbide dinitrate (20μg/mL), adenosine (20μg/mL), and nicardipine (10μg/mL) were infused at increasing rates of 0, 2.5, 5.0, 10, or 20 mL/h for 8 minutes into the femoral artery with a syringe pump. Results Both Q_Doppler and Q_pulse increased fourfold with increasing rates of infusion of the three vasodilators. Plotting of Q_Doppler and Q_pulse across the three vasodilators in each animal revealed linear correlations (R^2 = 0.17-0.76). Overall regression analysis showed a less strong but still statistically significant linear relation (y=3.68x + 18.5, R^2 = 0.25, P < 0.01). Conclusions We found a linear correlation between Q_Doppler and Q_pulse in a wide range of femoral arterial blood flow measures induced by different vasodilators in each animal. Arterial flow wave derived from pulse oximetry was quantitatively validated

Diagnostic Utility of SOX4 Expression in Adult T-Cell Leukemia/Lymphoma

Differentiation between adult T-cell leukemia/lymphoma (ATLL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is often challenging based on pathological findings alone. Although serum anti-HTLV-1 antibody positivity is required for ATLL diagnosis, this information is often not available at the time of pathological diagnosis. Therefore, we examined whether the expression of SOX4 and p16 would be helpful for differentiating the two disease entities. We immunohistochemically examined SOX4 and p16 expression (which have been implicated in ATLL carcinogenesis) in 11 ATLL patients and 20 PTCL-NOS patients and classified them into four stages according to the percentage of positive cells. Among the ATLL cases, 8/11 (73%) were SOX4-positive, while only 2/20 (10%) PTCL-NOS cases expressed SOX4. The mean total score was 4.2 (standard deviation (SD): 0.61) in the ATLL group and 0.50 (SD: 0.46) in the PTCL-NOS group (p < 0.001). Positive expression of p16 was noted in 4/11 (36%) patients with ATLL and 3/20 (15%) patients with PTCL-NOS, with mean total scores of 1.9 (SD: 0.64) and 0.70 (SD: 0.48) in the ATLL and PTCL-NOS groups, respectively (p = 0.141). These results suggest that SOX4 may be strongly expressed in ATLL compared to PTCL-NOS cases. Therefore, it may be helpful to perform immunohistochemical staining of SOX4 when pathologists face challenges discriminating between ATLL and PTCL-NOS

Lack of association of genetic variation in chromosome region 15q14-22.1 with type 2 diabetes in a Japanese population

Background: Chromosome 15q14-22.1 has been linked to type 2 diabetes (T2D) and its related traits in Japanese and other populations. The presence of T2D disease susceptibility variant(s) was assessed in the 21.8 Mb region between D15S118 and D15S117 in a Japanese population using a region-wide case-control association test. Methods: A two-stage association test was performed using Japanese subjects: The discovery panel (Stage 1) used 372 cases and 360 controls, while an independent replication panel (Stage 2) used 532 cases and 530 controls. A total of 1,317 evenly-spaced, common SNP markers with minor allele frequencies > 0.10 were typed for each stage. Captured genetic variation was examined in HapMap JPT SNPs, and a haplotype-based association test was performed. Results: SNP2140 (rs2412747) (C/T) in intron 33 of the ubiquitin protein ligase E3 component n-recognin 1 (UBR1) gene was selected as a landmark SNP based on repeated significant associations in Stage 1 and Stage 2. However, the marginal p value (p = 0.0043 in the allelic test, OR = 1.26, 95% CI = 1.07–1.48 for combined samples) was weak in a single locus or haplotype-based association test. We failed to find any significant SNPs after correcting for multiple testing. Conclusion: The two-stage association test did not reveal a strong association between T2D and any common variants on chromosome 15q14-22.1 in 1,794 Japanese subjects. A further association test with a larger sample size and denser SNP markers is required to confirm these observations

Heterozygous B beta-chain C-terminal 12 amino acid elongation variant, B beta X462W (Kyoto VI), showed dysfibrinogenemia

A heterozygous patient with dysfibrinogenemia with slight bleeding and no thrombotic complications was diagnosed with fibrinogen Kyoto VI (K-VI). To elucidate the genetic mutation(s) and characterize the variant protein, we performed the following experiments and compared with identical and similar variants that have already been reported. The proposita's PCR-amplified DNA was analyzed by sequencing and her purified plasma fibrinogen underwent SDS-PAGE followed by immunoblotting, fibrin polymerization, and scanning electron microscopic observation of fibrin clot and fibers. Sequence analyses showed that K-VI fibrinogen substituted W (TGG) for terminal codon (TAG), resulting in 12 amino acid elongation 462-473 (WSPIRRFLLFCM) in the B beta-chain. Protein analyses indicated that the presence of some albumin-binding variant fibrinogens and a dimeric molecule of variant fibrinogens reduced fibrin polymerization, with a thinner fiber and aberrant fibrin network. These results are almost the same as for the identical variant of Magdeburg, however, different from the similar variant of Osaka VI [ 12 amino acid elongation 462-473 (KSPIRRFLLFCM) in the B beta-chain] in the presence of variant forms and clot structure. We speculate the side-chain difference at 462 residues, W in K-VI, K in Osaka VI, and/or the difference in the presence of disulfide bridged forms of variant fibrinogens, led to the notable difference in the fibrin bundle network. Although a strong evolutional and structural association between B beta-chain and gamma-chain molecules is established, the corresponding recombinant 15 residue elongation variants of the fibrinogen gamma-chain showed reduced assembly and secretion.ArticleBLOOD COAGULATION & FIBRINOLYSIS. 23(1):87-90 (2012)journal articl

First Results of Axion Dark Matter Search with DANCE

Axions are one of the well-motivated candidates for dark matter, originally proposed to solve the strong CP problem in particle physics. Dark matter Axion search with riNg Cavity Experiment (DANCE) is a new experimental project to broadly search for axion dark matter in the mass range of $10^{-17}~\mathrm{eV} < m_a < 10^{-11}~\mathrm{eV}$. We aim to detect the rotational oscillation of linearly polarized light caused by the axion-photon coupling with a bow-tie cavity. The first results of the prototype experiment, DANCE Act-1, are reported from a 24-hour observation. We found no evidence for axions and set 95% confidence level upper limit on the axion-photon coupling $g_{a \gamma} \lesssim 8 \times 10^{-4}~\mathrm{GeV^{-1}}$ in $10^{-14}~\mathrm{eV} < m_a < 10^{-13}~\mathrm{eV}$. Although the bound did not exceed the current best limits, this optical cavity experiment is the first demonstration of polarization-based axion dark matter search without any external magnetic field.Comment: 9 pages, 8 figure

Visualization of Neural Activity in Insect Brains Using a Conserved Immediate Early Gene, Hr38

Many insects exhibit stereotypic instinctive behavior [1-3], but the underlying neural mechanisms are not well understood due to difficulties in detecting brain activity in freely moving animals. Immediate early genes (IEGs), such as c-fos, whose expression is transiently and rapidly upregulated upon neural activity, are powerful tools for detecting behavior-related neural activity in vertebrates [4, 5]. In insects, however, this powerful approach has not been realized because no conserved IEGs have been identified. Here, we identified Hr38 as a novel IEG that is transiently expressed in the male silkmoth Bombyx mori by female odor stimulation. Using Hr38 expression as an indicator of neural activity, we mapped comprehensive activity patterns of the silkmoth brain in response to female sex pheromones. We found that Hr38 can also be used as a neural activity marker in the fly Drosophila melanogaster. Using Hr38, we constructed a neural activity map of the fly brain that partially overlaps with fruitless (fru)-expressing neurons in response to female stimulation. These findings indicate that Hr38 is a novel and conserved insect neural activity marker gene that will be useful for a wide variety of neuroethologic studies. © 2013 Elsevier Ltd. All rights reserved

Material properties of a low contraction and resistivity silicon-aluminum composite for cryogenic detectors

We report on the cryogenic properties of a low-contraction silicon-aluminum composite, namely Japan Fine Ceramics SA001, to use as a packaging structure for cryogenic silicon devices. SA001 is a silicon--aluminum composite material (75% silicon by volume) and has a low thermal expansion coefficient ($\sim$1/3 that of aluminum). The superconducting transition temperature of SA001 is measured to be 1.18 K, which is in agreement with that of pure aluminum, and is thus available as a superconducting magnetic shield material. The residual resistivity of SA001 is 0.065 $\mathrm{\mu \Omega m}$, which is considerably lower than an equivalent silicon--aluminum composite material. The measured thermal contraction of SA001 immersed in liquid nitrogen is $\frac{L_{293\mathrm{K}}-L_{77\mathrm{K}}}{L_{293\mathrm{K}}}=0.12$%, which is consistent with the expected rate obtained from the volume-weighted mean of the contractions of silicon and aluminum. The machinability of SA001 is also confirmed with a demonstrated fabrication of a conical feedhorn array, with a wall thickness of 100 $\mathrm{\mu m}$. These properties are suitable for packaging applications for large-format superconducting detector devices.Comment: 8 pages, 4 figures, 1 table, accepted for the Journal of Low Temperature Physics for the LTD19 special issu