Store-Operated Ca^(2+) Channels in Mesangial Cells Inhibit Matrix Protein Expression

Accumulation of extracellular matrix derived from glomerular mesangial cells is an early feature of diabetic nephropathy. Ca^(2+) signals mediated by store–operated Ca^(2+) channels regulate protein production in a variety of cell types. The aim of this study was to determine the effect of store–operated Ca^(2+) channels in mesangial cells on extracellular matrix protein expression. In cultured human mesangial cells, activation of store–operated Ca^(2+) channels by thapsigargin significantly decreased fibronectin protein expression and collagen IV mRNA expression in a dose-dependent manner. Conversely, inhibition of the channels by 2-aminoethyl diphenylborinate significantly increased the expression of fibronectin and collagen IV. Similarly, overexpression of stromal interacting molecule 1 reduced, but knockdown of calcium release–activated calcium channel protein 1 (Orai1) increased fibronectin protein expression. Furthermore, 2-aminoethyl diphenylborinate significantly augmented angiotensin II–induced fibronectin protein expression, whereas thapsigargin abrogated high glucose– and TGF-β1–stimulated matrix protein expression. In vivo knockdown of Orai1 in mesangial cells of mice using a targeted nanoparticle siRNA delivery system resulted in increased expression of glomerular fibronectin and collagen IV, and mice showed significant mesangial expansion compared with controls. Similarly, in vivo knockdown of stromal interacting molecule 1 in mesangial cells by recombinant adeno–associated virus–encoded shRNA markedly increased collagen IV protein expression in renal cortex and caused mesangial expansion in rats. These results suggest that store–operated Ca^(2+) channels in mesangial cells negatively regulate extracellular matrix protein expression in the kidney, which may serve as an endogenous renoprotective mechanism in diabetes

Mixing of superconducting dx2−y2d_{x^2-y^2} state with s-wave states for different filling and temperature

We study the order parameter for mixed-symmetry states involving a major $d_{x^2-y^2}$ state and various minor s-wave states ($s$, $s_{xy}$, and $s_{x^2+y^2}$) for different filling and temperature for mixing angles 0 and $\pi/2$. We employ a two-dimensional tight-binding model incorporating second-neighbor hopping for tetragonal and orthorhombic lattice. There is mixing for the symmetric $s$ state both on tetragonal and orthorhombic lattice. The $s_{xy}$ state mixes with the $d_{x^2-y^2}$ state only on orthorhombic lattice. The $s_{x^2+y^2}$ state never mixes with the $d_{x^2-y^2}$ state. The temperature dependence of the order parameters is also studied.Comment: 10 pages, 9 figures, accepted in Physica

Enhancement of superconducting transition temperature by the additional second neighbor hopping t' in the t-J model

Within the kinetic energy driven superconducting mechanism, the effect of the additional second neighbor hopping t' on the superconducting state of the t-J model is discussed. It is shown that t' plays an important role in enhancing the superconducting transition temperature of the t-J model. It is also shown that the superconducting-state of cuprate superconductors is the conventional Bardeen-Cooper-Schrieffer like, so that the basic Bardeen-Cooper-Schrieffer formalism is still valid in quantitatively reproducing the doping dependence of the superconducting gap parameter and superconducting transition temperature, and electron spectral function at $(\pi,0)$ point, although the pairing mechanism is driven by the kinetic energy by exchanging dressed spin excitations.Comment: 8 pages, 4 figures, added discussions and references, accepted for publication in Physics Letters

Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology

Human phenotype ontology; Prenatal diagnosis; Prenatal phenotypingOntología del fenotipo humano; Diagnóstico prenatal; Fenotipado prenatalOntologia del fenotip humà; Diagnòstic prenatal; Fenotipat prenatalTechnological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal-perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype-driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care.European Commission; National Human Genome Research Institute; NIH Office of the Director; The European Union's EIT-Health Innovation Program bp2020-2022, Grant/Award Numbers: #211015, #20062; NIH Office of the Director (OD), the European Union's Horizon 2020 research and innovation program, Grant/Award Number: 779257; NHGRI, Grant/Award Numbers: 2R24OD011883-05A1, 1U24HG011449-01A

Store Operated Calcium Entry Suppressed TGF-β1/SMAD3 Signaling Pathway in Glomerular Mesangial Cells

Our previous study demonstrated that the abundance of extracellular matrix proteins was suppressed by store-operated Ca^(2+) entry (SOCE) in mesangial cells (MCs). The present study was conducted to investigate the underlying mechanism focused on the transforming growth factor-β1 (TGF-β1)/Smad3 pathway, a critical pathway for ECM expansion in diabetic kidneys. We hypothesized that SOCE suppressed ECM protein expression by inhibiting this pathway in MCs. In cultured human MCs, we observed that TGF-β1 (5 ng/ml for 15 h) significantly increased Smad3 phosphorylation, as evaluated by immunoblot. However, this response was markedly inhibited by thapsigargin (1 µM), a classical activator of store-operated Ca^(2+) channels. Consistently, both immunocytochemistry and immunoblot showed that TGF-β1 significantly increased nuclear translocation of Smad3, which was prevented by pretreatment with thapsigargin. Importantly, the thapsigargin effect was reversed by lanthanum (La^(3+); 5 µM) and GSK-7975A (10 µM), both of which are selective blockers of store-operated Ca^(2+) channels. Furthermore, knockdown of Orai1, the pore-forming subunit of the store-operated Ca^(2+) channels, significantly augmented TGF-β1-induced Smad3 phosphorylation. Overexpression of Orai1 augmented the inhibitory effect of thapsigargin on TGF-β1-induced phosphorylation of Smad3. In agreement with the data from cultured MCs, in vivo knockdown of Orai1 specific to MCs using a targeted nanoparticle small interfering RNA delivery system resulted in a marked increase in abundance of phosphorylated Smad3 and in nuclear translocation of Smad3 in the glomerulus of mice. Taken together, our results indicate that SOCE in MCs negatively regulates the TGF-β1/Smad3 signaling pathway

Negative regulation of Smad1 pathway and collagen IV expression by store-operated Ca^(2+) entry in glomerular mesangial cells

Collagen IV (Col IV) is a major component of expanded glomerular extracellular matrix in diabetic nephropathy and Smad1 is a key molecule regulating Col IV expression in mesangial cells (MCs). The present study was conducted to determine if Smad1 pathway and Col IV protein abundance were regulated by store-operated Ca^(2+) entry (SOCE). In cultured human MCs, pharmacological inhibition of SOCE significantly increased the total amount of Smad1 protein. Activation of SOCE blunted high-glucose-increased Smad1 protein content. Treatment of human MCs with ANG II at 1 µM for 15 min, high glucose for 3 days, or TGF-β1 at 5 ng/ml for 30 min increased the level of phosphorylated Smad1. However, the phosphorylation of Smad1 by those stimuli was significantly attenuated by activation of SOCE. Knocking down Smad1 reduced, but expressing Smad1 increased, the amount of Col IV protein. Furthermore, activation of SOCE significantly attenuated high-glucose-induced Col IV protein production, and blockade of SOCE substantially increased the abundance of Col IV. To further verify those in vitro findings, we downregulated SOCE specifically in MCs in mice using small-interfering RNA (siRNA) against Orai1 (the channel protein mediating SOCE) delivered by the targeted nanoparticle delivery system. Immunohistochemical examinations showed that expression of both Smad1 and Col IV proteins was significantly greater in the glomeruli with positively transfected Orai1 siRNA compared with the glomeruli from the mice without Orai1 siRNA treatment. Taken together, our results indicate that SOCE negatively regulates the Smad1 signaling pathway and inhibits Col IV protein production in MCs

Mid-infrared supercontinuum generation using dispersion-engineered Ge11.5As24Se64.5 chalcogenide channel waveguide

We numerically investigate mid-infrared supercontinuum (SC) generation in dispersion-engineered, air-clad, Ge11.5As24Se64.5 chalcogenide-glass channel waveguides employing two different materials, Ge11.5As24S64.5 or MgF2 glass for their lower cladding. We study the effect of waveguide parameters on the bandwidth of the SC at the output of 1-cm-long waveguide. Our results show that output can vary over a wide range depending on its design and the pump wavelength employed. At the pump wavelength of 2 µm the SC never extended beyond 4.5 µm for any of our designs. However, supercontinuum could be extended to beyond 5 µm for a pump wavelength of 3.1 µm. A broadband SC spanning from 2 µm to 6 µm and extending over 1.5 octave could be generated with a moderate peak power of 500 W at a pump wavelength of 3.1 µm using an air-clad, all-chalcogenide, channel waveguide. We show that SC can be extended even further when MgF2 glass is used for the lower cladding of chalcogenide waveguide. Our numerical simulations produced SC spectra covering the wavelength range 1.8-7.7 µm (> two octaves) by using this geometry. Both ranges exceed the broadest SC bandwidths reported so far. Moreover, we realize it using 3.1 µm pump source and relatively low peak power pulses. By employing the same pump source, we show that SC spectra can cover a wavelength range of 1.8-11 µm (> 2.5 octaves) in a channel waveguide employing MgF2 glass for its lower cladding with a moderate peak power of 3000 W

Phase transition from a dx2−y2d_{x^2-y^2} to dx2−y2+dxyd_{x^2-y^2}+d_{xy} superconductor

We study the phase transition from a $d_{x^2-y^2}$ to $d_{x^2-y^2}+d_{xy}$ superconductor using the tight-binding model of two-dimensional cuprates. As the temperature is lowered past the critical temperature $T_c$, first a $d_{x^2-y^2}$ superconducting phase is created. With further reduction of temperature, the $d_{x^2-y^2}+d_{xy}$ phase is created at temperature $T=T_{c1}$. We study the temperature dependencies of the order parameter, specific heat and spin susceptibility in these mixed-angular-momentum states on square lattice and on a lattice with orthorhombic distortion. The above-mentioned phase transitions are identified by two jumps in specific heat at $T_c$ and $T_{c1}$.Comment: Latex file, 5 pages, 6 postscript figures, Accepted in Physical Review

Heterogeneity of tibial plateau cartilage in response to a physiological compressive strain rate

Knowledge of the extent to which tibial plateau cartilage displays non‐uniform mechanical topography under physiologically relevant loading conditions is critical to evaluating the role of biomechanics in knee osteoarthritis. Cartilage explants from 21 tibial plateau sites of eight non‐osteoarthritic female cadaveric knees (age: 41–54; BMI: 14–20) were tested in unconfined compression at 100% strain/s. The elastic tangent modulus at 10% strain ( E 10% ) was calculated for each site and averaged over four geographic regions: not covered by meniscus (I); covered by meniscus—anterior (II); covered by meniscus—exterior (III); and covered by meniscus—posterior (IV). A repeated‐measures mixed model analysis of variance was used to test for effects of plateau, region, and their interaction on E 10% . Effect sizes were calculated for each region pair. E 10% was significantly different ( p  < 0.05) for all regional comparisons, except I–II and III–IV. The regional pattern of variation was consistent across individuals. Moderate to strong effect sizes were evident for regional comparisons other than I–II on the lateral side and III–IV on both sides. Healthy tibial cartilage exhibits significant mechanical heterogeneity that manifests in a common regional pattern across individuals. These findings provide a foundation for evaluating the biomechanical mechanisms of knee osteoarthritis. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 370–375, 2013Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96249/1/22226_ftp.pd

Orthorhombicity mixing of s- and d- gap components in YBa2Cu3O7YBa_2Cu_3O_7 without involving the chains

Momentum decoupling develops when forward scattering dominates the pairing interaction and implies tendency for decorrelation between the physical behavior in the various regions of the Fermi surface. In this regime it is possible to obtain anisotropic s- or d-wave superconductivity even with isotropic pairing scattering. We show that in the momentum decoupling regime the distortion of the $CuO_2$ planes is enough to explain the experimental reports for s- mixing in the dominantly d-wave gap of $YBa_2Cu_3O_7$. In the case of spin fluctuations mediated pairing instead, a large part of the condensate must be located in the chains in order to understand the experiments.Comment: LATEX file and 3 Postscript figure