Serum uric acid (UA) is taken up by endothelial cells and reduces the level of nitric oxide (NO) by inhibiting its production and accelerating its degradation. Cytosolic and plasma xanthine oxidase ...(XO) generates superoxide and also decreases the NO level. Thus, hyperuricemia is associated with impaired endothelial function. Hyperuricemia is often associated with vascular diseases such as chronic kidney disease (CKD) and cardiovascular disease (CVD). It has long been debated whether hyperuricemia is causally related to the development of these diseases. The 2020 American College of Rheumatology Guideline for the Management of Gout (ACR2020) does not recommend pharmacological treatment of hyperuricemia in patients with CKD/CVD. In contrast, the Japanese Guideline on Management of Hyperuricemia and Gout (JGMHG), 3rdedition, recommends pharmacological treatment of hyperuricemia in patients with CKD. In a FREED study on Japanese hyperuricemic patients with CVD, an XO inhibitor, febuxostat, improved the primary composite endpoint of cerebro-cardio-renovascular events, providing a rationale for the use of urate-lowering agents (ULAs). Since a CARES study on American gout patients with CVD treated with febuxostat revealed increased mortality, ACR2020 recommends switching to different ULAs. However, there was no difference in the mortality of Japanese patients between the febuxostat-treated group and the placebo or allopurinol-treated groups in either the FEATHER or FREED studies.
Estimating large and sparse inverse covariance matrix plays a fundamental role in modern multivariate analysis, because the zero entries capture the conditional independence between pairs of ...variables given all other variables. This estimation task can be realized by penalizing the maximum likelihood estimation with an adaptive group lasso penalty imposed directly on the elements of the inverse, which allows the estimated to have a blockwise sparse structure that is particularly useful in some applications. In the paper, we are particularly interested in studying the implementation of optimization algorithms for minimizing a class of log-determinant model. This considered minimization model, one the one hand, contains a large number of popular sparse models as special cases, but on the other hand, it poses more challenges especially in high-dimensional situations. Instead of targeting the challenging optimization problem directly, we employ the symmetric Gauss–Seidel (sGS) iteration based alternating direction method of multipliers (ADMM) to tackle the 3-block nonsmooth dual program. By choosing an appropriate proximal term, it was shown that the implemented sGS-ADMM is equivalent to the 2-block ADMM, so its convergence is followed directly from some existing theoretical results. Numerical experiments on synthetic data and real data sets, including the performance comparisons with the directly extended ADMM, demonstrate that the implemented algorithm is effective in estimating large and sparse inverse covariance matrices.
A Ge-doped dual-core dispersion compensation photonic crystal fiber (DC-DCPCF) is proposed. The small diameters of two layers' air holes make DC-DCPCF form a dual-core structure, which is conducive ...to broadband dispersion compensation. Low Ge-doped silica as the only background material reduces the preparation difficulty and cost. It is inversely designed by using artificial neural network (ANN) combined with differential evolution algorithm (DE) to obtain target dispersion compensation. ANN replaces the finite element method to accomplish fast forward prediction of DC-DCPCF properties. DE solves the single solution problem of single or cascade network that makes it flexible and reproducible. The results demonstrate that the designed DC-DCPCF can not only compensate 45 and 25 times its length of Corning single-mode fiber 28 (SMF28) in S+C+L+U bands and E+S+C+L+U bands respectively, but also accurately compensate the residual dispersion with effective dispersion compensation being only +0.005∼+0.842ps/(nm·km) and -0.03∼+1.31ps/(nm·km), respectively. In addition, the kappa values of DCP-PCF are well matched with SMF28 in the broadband wavelength range. It takes only about 10 seconds to complete the inverse design of the target DC-DCPCF. It provides a design method for custom DC-DCPCF and an efficient inverse design solution for photonic automation in fiber optical communication systems.
Background: Intracellular uric acid is known to increase the protein level and channel current of atrial Kv1.5; however, mechanisms of the uric acid-induced enhancement of Kv1.5 expression remain ...unclear. Methods and Results: The effects of uric acid on mRNA and protein levels of Kv1.5, as well as those of Akt, HSF1 and Hsp70, in HL-1 cardiomyocytes were studied by using qRT-PCR and Western blotting. The uptake of uric acid was measured using radio-labeled uric acid. The Kv1.5-mediated channel current was also measured by using patch clamp techniques. Uric acid up-taken by HL-1 cells significantly increased the level of Kv1.5 proteins in a concentration-dependent manner, with this increase abolished by an uric acid transporter inhibitor. Uric acid slowed degradation of Kv1.5 proteins without altering its mRNA level. Uric acid enhanced phosphorylation of Akt and HSF1, and thereby increased both transcription and translation of Hsp70; these effects were abolished by a PI3K inhibitor. Hsp70 knockdown abolished the uric acid-induced increases of Kv1.5 proteins and channel currents. Conclusions: Intracellular uric acid could stabilize Kv1.5 proteins through phosphorylation of Akt and HSF1 leading to enhanced expression of Hsp70.
Strengthening the interfacial contact between the reactive components effectively boosts the energy release of energetic materials. In this study, we aimed to create a close-knit interfacial contact ...condition between aluminum nanoparticles (Al NPs) and Polyvinylidene fluoride-hexafluoropropylene (P(VDF-HFP)) through hydrolytic adsorption and assembling 1H, 1H, 2H, 2H-Perfluorododecyltrichlorosilane (FTCS) on the surface of Al NPs. Leveraging hydrogen bonding between –CF and –CH and the interaction between C–F⋯F–C groups, the adsorbed FTCS directly leads to the growth of the P(VDF-HFP) coating layer around the treated Al NPs, yielding Al@FTCS/P(VDF-HFP) energetic composites. In comparison with the ultrasonically processed Al/P(VDF-HFP) mixture, thermal analysis reveals that Al@FTCS/P(VDF-HFP) exhibits a 57 °C lower reaction onset temperature and a 1646 J/g increase in heat release. Associated combustion tests demonstrate a 52% shorter ignition delay, 62% shorter combustion time, and a 288% faster pressurization rate. These improvements in energetic characteristics stem from the reactivity activation of FTCS towards Al NPs by the etching effect to the surface Al2O3. Moreover, enhanced interfacial contact facilitated by the FTCS-directed growth of P(VDF-HFP) around Al NPs further accelerates the whole reaction process.
Broadband optical frequency comb (OFC) generation based on a single electro-absorption modulator (EAM) is proposed. The EAM is driven by a radio frequency (RF) multi-frequency signal generated by a ...multiplication coupler composed of an electrical power splitter and an arithmetic circuit. Thus the number of comb-lines of the generated OFC can be increased. A complete theoretical model of OFC generation by an EAM driven by nth power of the RF source is established, and the performance of the OFC is analyzed by using OptiSystem software. The results show that, the number of comb-lines of the OFC is positively correlated with the number of multiplication of the RF source signal. The frequency spacing of the comb-lines is twice the frequency of the RF source signal and is tunable by adjusting the frequency of the RF source signal. Increasing chirp factor and modulation index of EAM could increase the number of comb-lines of the generated OFC. The amplitude of the RF source signal had little impact on the flatness of the OFC and the average OFC power. The scheme developed is not only simple and low-cost, but also can produce a large number of comb-lines.
Fungal pathogens typically use secreted effector proteins to suppress host immune activators to facilitate invasion. However, there is rarely evidence supporting the idea that fungal secretory ...proteins contribute to pathogenesis by transactivating host genes that suppress defense. We previously found that pathogen Magnaporthe oryzae induces rice Bsr-d1 to facilitate infection and hypothesized that a fungal effector mediates this induction. Here, we report that MoSPAB1 secreted by M. oryzae directly binds to the Bsr-d1 promoter to induce its expression, facilitating pathogenesis. Amino acids 103-123 of MoSPAB1 are required for its binding to the Bsr-d1 promoter. Both MoSPAB1 and rice MYBS1 compete for binding to the Bsr-d1 promoter to regulate Bsr-d1 expression. Furthermore, MoSPAB1 homologues are highly conserved among fungi. In particular, Colletotrichum fructicola CfSPAB1 and Colletotrichum sublineola CsSPAB1 activate kiwifruit AcBsr-d1 and sorghum SbBsr-d1 respectively, to facilitate pathogenesis. Taken together, our findings reveal a conserved module that may be widely utilized by fungi to enhance pathogenesis.
This study investigated the effects of adipose-derived stem cell sheets on a rat model of detrusor underactivity.
Adipose-derived stem cell sheets were prepared from the subcutaneous adipose tissue ...of male Lewis rats. Female Lewis rats were assigned into four groups: control, sham operation, cryo-injury, and cryo-injury+sheet (n = 8 per group). Rats in the cryo-injury+sheet group were implanted with ASC sheets 3 days after cryo-injury induction and underwent cystometry 7 days later. Subsequently, reverse transcription-polymerase chain reaction (RT-PCR) and histopathological examinations were performed. Cell sheets expressing the green fluorescent protein were prepared and transplanted to confirm the viability and differentiation of the sheets. Fluorescence was confirmed using a fluorescence stereomicroscope on days 3, 7, 14, 21, and 28 after sheet implantation, and tissue immunostaining was performed.
Cystometry showed that sheet implantation improved the maximum intravesical pressure (P = 0.009) and the residual urine volume (P = 0.011). Furthermore, RT-PCR indicated that the mRNA levels of the angiogenic factors vascular endothelial growth factor and hepatocyte growth factor were significantly higher in the cryo-injury+sheet group than in the cryo-injury group (P = 0.045, P = 0.037, respectively). Histologically, sheet implantation resulted in an improvement in inflammation and increased the number of blood vessels. Green fluorescent protein-positive cells fused with von Willebrand factor-positive cells and differentiated into blood vessels 7 days after sheet implantation.
Adipose-derived stem cell sheets transplanted into the bladder of cryo-injured rats differentiated into blood vessels and restored bladder contractile function 7 days after transplantation.
To characterize long-term repopulation of peripheral immune cells following alemtuzumab-induced lymphopenia in relapsing-remitting MS (RRMS), with a focus on regulatory cell types, and to explore ...associations with clinical outcome measures.
The project was designed as a multicenter add-on longitudinal mechanistic study for RRMS patients enrolled in CARE-MS II, CARE-MS II extension at the University of Southern California and Stanford University, and an investigator-initiated study conducted at the Universities of British Columbia and Chicago. Methods involved collection of blood at baseline, prior to alemtuzumab administration, and at months 5, 11, 17, 23, 36, and 48 post-treatment. T cell, B cell, and natural killer (NK) cell subsets, chemokine receptor expression in T cells, in vitro cytokine secretion patterns, and regulatory T cell (Treg) function were assessed. Clinical outcomes, including expanded disability status score (EDSS), relapses, conventional magnetic resonance imaging (MRI) measures, and incidents of secondary autoimmunity were tracked.
Variable shifts in lymphocyte populations occurred over time in favor of CD4+ T cells, B cells, and NK cells with surface phenotypes characteristic of regulatory subsets, accompanied by reduced ratios of effector to regulatory cell types. Evidence of increased Treg competence was observed after each treatment course. CD4+ and CD8+ T cells that express CXCR3 and CCR5 and CD8+ T cells that express CDR3 and CCR4 were also enriched after treatment, indicating heightened trafficking potential in activated T cells. Patterns of repopulation were not associated with measures of clinical efficacy or secondary autoimmunity, but exploratory analyses using a random generalized estimating equation (GEE) Poisson model provide preliminary evidence of associations between pro-inflammatory cell types and increased risk for gadolinium (Gd+) enhancing lesions, while regulatory subsets were associated with reduced risk. In addition, the risk for T2 lesions correlated with increases in CD3+CD8+CXCR3+ cells.
Lymphocyte repopulation after alemtuzumab treatment favors regulatory subsets in the T cell, B cell, and NK cell compartments. Clinical efficacy may reflect the sum of interactions among them, leading to control of potentially pathogenic effector cell types. Several immune measures were identified as possible biomarkers of lesion activity. Future studies are necessary to more precisely define regulatory and effector subsets and their contributions to clinical efficacy and risk for secondary autoimmunity in alemtuzumab-treated patients, and to reveal new insights into mechanisms of immunopathogenesis in MS.
Parent trials for this study are registered with ClinicalTrials.gov: CARE-MS II: NCT00548405, CARE-MS II extension: NCT00930553 and ISS: NCT01307332.
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