Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi-Ethnic Study of Atherosclerosis).

BACKGROUND:APOL1 genetic variants confer an increased risk for kidney disease. Their associations with cardiovascular disease (CVD) are less certain. We aimed to compare the prevalence of subclinical CVD and incidence of atherosclerotic CVD and heart failure by APOL1 genotypes among self-identified black participants of MESA (Multi-Ethnic Study of Atherosclerosis). METHODS AND RESULTS:Cross-sectional associations of APOL1 genotypes (high-risk=2 alleles; low-risk=0 or 1 allele) with coronary artery calcification, carotid-intimal media thickness, and left ventricular mass were evaluated using logistic and linear regression. Longitudinal associations of APOL1 genotypes with incident myocardial infarction, stroke, coronary heart disease, and congestive heart failure were examined using Cox regression. We adjusted for African ancestry, age, and sex. We also evaluated whether hypertension or kidney function markers explained the observed associations. Among 1746 participants with APOL1 genotyping (mean age 62 years, 55% women, mean cystatin C-based estimated glomerular filtration rate 89 mL/min per 1.73 m2, 12% with albuminuria), 12% had the high-risk genotypes. We found no difference in prevalence or severity of coronary artery calcification, carotid-intimal media thickness, or left ventricular mass by APOL1 genotypes. The APOL1 high-risk group was 82% more likely to develop incident heart failure compared with the low-risk group (95% confidence interval, 1.01-3.28). Adjusting for hypertension (hazard ratio, 1.80; 95% confidence interval, 1.00-3.24) but not markers of kidney function (hazard ratio, 1.86; 95% confidence interval, 1.03-3.35) slightly attenuated this association. The APOL1 high-risk genotypes were not significantly associated with other clinical CVD outcomes. CONCLUSIONS:Among blacks without baseline CVD, the APOL1 high-risk variants may be associated with increased risk for incident heart failure but not subclinical CVD or incident clinical atherosclerotic CVD

Small-polaron hopping conductivity in bilayer manganite La1.2_{1.2}Sr1.8_{1.8}Mn2_{2}O7_{7}

We report anisotropic resistivity measurements on a La$_{1.2}$Sr$_{1.8}$Mn$_{2}$O$_{7}$ single crystal over a temperature $T$ range from 2 to 400 K and in magnetic fields $H$ up to 14 T. For $T\geq 218$ K, the temperature dependence of the zero-field in-plane $\rho_{ab}(T)$ resistivity obeys the adiabatic small polaron hopping mechanism, while the out-of-plane $\rho_{c}(T)$ resistivity can be ascribed by an Arrhenius law with the same activation energy. Considering the magnetic character of the polarons and the close correlation between the resistivity and magnetization, we developed a model which allows the determination of $\rho_{ab,c}(H,T)$. The excellent agreement of the calculations with the measurements indicates that small polarons play an essential role in the electrical transport properties in the paramagnetic phase of bilayer manganites.Comment: 4 pages, 3 figures, to appear in Physical Review

Smad3 Mediates Activin-Induced Transcription of Follicle-Stimulating Hormone β-Subunit Gene

Synthesis of FSH by the anterior pituitary is regulated by activin, a member of the TGFβ superfamily of ligands. Activin signals through a pathway that involves the activation of the transcriptional coregulators Smad2 and Smad3. Previous work from our laboratory demonstrated that Smad3, and not Smad2, is sufficient for stimulation of the rat FSHβ promoter in a pituitary-derived cell line LβT2. Here, we used RNA interference technology to independently decrease the expression of Smad proteins in LβT2 cells to further investigate Smad2 and Smad3 roles in activin-dependent regulation of the FSHβ promoter. Down-regulation of Smad2 protein by small interfering RNA duplexes affects only basal transcription of FSHβ, whereas decreased expression of Smad3 abrogates activin-mediated stimulation of FSHβ transcription. Although highly related, Smad2 and Smad3 differ in their Mad homolog (MH) 1 domains, where the Smad2 protein contains two additional stretches of amino acids that prevent this factor from binding to DNA. We investigated whether these structural features contribute to differential FSHβ transactivation by Smad2 and Smad3. A variety of Smad chimera constructs were generated and used in transient transfection studies to address this question. Only cotransfection of chimera constructs that contain the MH1 domain of Smad3 results in activin-mediated stimulation of the rat FSHβ promoter. Furthermore, the insertion of Smad2 loops into Smad3 protein renders it inactive, suggesting that DNA binding is necessary for Smad3-mediated stimulation of the rat FSHβ promoter. Taken together, these results indicate that the functional differences between Smad2 and Smad3 in their ability to transactivate the rat FSHβ promoter lie primarily within the MH1 domain and involve structural motifs that affect DNA binding

Thermal/Electronic Transport Properties and Two-Phase Mixtures in La_{5/8-x}Pr_{x}Ca_{3/8}MnO_{3}

We measured thermal conductivity, k, thermoelectric power, S, and dc electric conductivity, sigma, of La_{5/8-x}Pr_{x}Ca_{3/8}MnO_{3}, showing an intricate interplay between metallic ferromagnetism (FM) and charge ordering (CO) instability. The change of k, S and sigma with temperature (T) and x agrees well with the effective medium theories for binary metal-insulator mixtures. This agreement clearly demonstrates that with the variation of T as well as x, the relative volumes of FM and CO phases drastically change and percolative metal-insulator transition occurs in the mixture of FM and CO domains.Comment: 8 pages, 4 eps figures included, to appear in Phys. Rev. Let

Spin-wave scattering at low temperatures in manganite films

The temperature $T$ and magnetic field $H$ dependence of the resistivity $\rho$ has been measured for La$_{0.8-y}$Sr$_{0.2}$MnO$_{3}$ (y=0 and 0.128) films grown on (100) SrTiO$_{3}$ substrates. The low-temperature $\rho$ in the ferromagnetic metallic region follows well $\rho (H,T)=\rho _{0}(H)+A(H)\omega_{s}/\sinh (\hbar \omega_{s}/2k_{B}T)+B(H)T^{7/2}$ with $\rho _{0}$ being the residual resistivity. We attribute the second and third term to small-polaron and spin-wave scattering, respectively. Our analysis based on these scattering mechanisms also gives the observed difference between the metal-insulator transition temperatures of the films studied. Transport measurements in applied magnetic field further indicate that spin-wave scattering is a key transport mechanism at low temperatures.Comment: 5 pages, 4 figures. to appear in Phys. Rev.

RelB Expression Determines the Differential Effects of Ascorbic Acid in Normal and Cancer Cells

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced injury. We found that the NF-κB transcription factor RelB is a pivotal determinant in the differential radiosensitization effects of ascorbic acid in prostate cancer cells and normal prostate epithelial cells. Mechanistically, high reactive oxygen species concentrations suppress RelB in cancer cells. RelB suppression decreases expression of the sirtuin SIRT3 and the powerful antioxidant MnSOD, which in turn increases oxidative and metabolic stresses in prostate cancer cells. In contrast, ascorbic acid enhances RelB expression in normal cells, improving antioxidant and metabolic defenses against radiation injury. In addition to showing how RelB mediates the differential effects of ascorbic acid on cancer and normal tissue radiosensitivities, our work also provides a proof of concept for the existence of redox modulators that can improve the efficacy of radiotherapy while protecting against normal tissue injury in cancer settings

Anomalous field-dependent specific heat in charge-ordered Pr1−x_{1-x}Cax_xMnO3_3 and La0.5_{0.5}Ca0.5_{0.5}MnO3_3

We report low temperature specific heat measurements of Pr$_{1-x}$Ca$_{x}$MnO$_{3}$ ($0.3\leq x \leq 0.5$) and La$_{0.5}$Ca$_{0.5}$MnO$_{3}$ with and without applied magnetic field. An excess specific heat, $C^{\prime}(T)$, of non-magnetic origin associated with charge ordering is found for all the samples. A magnetic field sufficient to induce the transition from the charge-ordered state to the ferromagnetic metallic state does not completely remove the $C^{\prime}$ contribution. This suggests that the charge ordering is not completely destroyed by a "melting" magnetic field. In addition, the specific heat of the Pr$_{1-x}$Ca$_{x}$MnO$_{3}$ compounds exhibit a large contribution linear in temperature ($\gamma T$) originating from magnetic and charge disorder.Comment: submitted to PRL 5 pages, 3 figures include