The Membrane-Associated Adaptor Protein DOK5 Is Upregulated in Systemic Sclerosis and Associated with IGFBP-5-Induced Fibrosis

Systemic sclerosis (SSc) is characterized by excessive fibrosis of the skin and internal organs due to fibroblast proliferation and excessive production of extracellular matrix (ECM). We have shown that insulin-like growth factor binding protein (IGFBP)-5 plays an important role in the development of fibrosis in vitro, ex vivo, and in vivo. We identified a membrane-associated adaptor protein, downstream of tyrosine kinase/docking protein (DOK)5, as an IGFBP-5-regulated target gene using gene expression profiling of primary fibroblasts expressing IGFBP-5. DOK5 is a tyrosine kinase substrate associated with intracellular signaling. Our objective was to determine the role of DOK5 in the pathogenesis of SSc and specifically in IGFBP-5-induced fibrosis. DOK5 mRNA and protein levels were increased in vitro by endogenous and exogenous IGFBP-5 in primary human fibroblasts. DOK5 upregulation required activation of the mitogen-activated protein kinase (MAPK) signaling cascade. Further, IGFBP-5 triggered nuclear translocation of DOK5. DOK5 protein levels were also increased in vivo in mouse skin and lung by IGFBP-5. To determine the effect of DOK5 on fibrosis, DOK5 was expressed ex vivo in human skin in organ culture. Expression of DOK5 in human skin resulted in a significant increase in dermal thickness. Lastly, levels of DOK5 were compared in primary fibroblasts and lung tissues of patients with SSc and healthy donors. Both DOK5 mRNA and protein levels were significantly increased in fibroblasts and skin tissues of patients with SSc compared with those of healthy controls, as well as in lung tissues of SSc patients. Our findings suggest that IGFBP-5 induces its pro-fibrotic effects, at least in part, via DOK5. Furthermore, IGFBP-5 and DOK5 are both increased in SSc fibroblasts and tissues and may thus be acting in concert to promote fibrosis

Hyperfine Interactions in the Heavy Fermion CeMIn_5 Systems

The CeMIn_5 heavy fermion compounds have attracted enormous interest since their discovery six years ago. These materials exhibit a rich spectrum of unusual correlated electron behavior, and may be an ideal model for the high temperature superconductors. As many of these systems are either antiferromagnets, or lie close to an antiferromagnetic phase boundary, it is crucial to understand the behavior of the dynamic and static magnetism. Since neutron scattering is difficult in these materials, often the primary source of information about the magnetic fluctuations is Nuclear Magnetic Resonance (NMR). Therefore, it is crucial to have a detailed understanding of how the nuclear moments interact with conduction electrons and the local moments present in these systems. Here we present a detailed analysis of the hyperfine coupling based on anisotropic hyperfine coupling tensors between nuclear moments and local moments. Because the couplings are symmetric with respect to bond axes rather than crystal lattice directions, the nuclear sites can experience non-vanishing hyperfine fields even in high symmetry sites.Comment: 15 pages, 5 figure

Anomalous radon emanation linked to preseismic electromagnetic phenomena

International audienceAnomalous emanation of radon (222Rn) was observed preceding large earthquakes and is considered to be linked to preseismic electromagnetic phenomena (e.g. great changes of atmospheric electric field and ionospheric disturbances). Here we analyze atmospheric radon concentration and estimate changes of electrical conditions in atmosphere due to preseismic radon anomaly. The increase of radon emanation obeys crustal damage evolution, following a power-law of time-to-earthquake. Moreover, the radon emanation decreases the atmospheric electric field by 40%, besides influencing the maximum strength of atmospheric electric field by 104?105 V/m enough to trigger ionospheric disturbances. These changes are within the ranges observed or explaining electromagnetic phenomena associated with large earthquakes

Effects of carbon incorporation on doping state of YBa2Cu3Oy

Effects of carbon incorporation on the doping state of YBa2Cu3Oy (Y-123) were investigated. Quantitative carbon analysis revealed that carbon could be introduced into Y-123 from both the precursor and the sintering gas. Nearly carbon-free (< 200 ppm) samples were prepared from a vacuum-treated precursor by sintered at 900 &#730;C and cooling with 20 &#730;C /min in flowing oxygen gas. The lower Tc (= 88 K) and higher oxygen content (y = 6.98) strongly suggested the overdoping state, which was supported by the temperature dependence of resisitivity and thermoelectric power. The nuclear quadrapole resonance spectra and the Raman scattering spectra indicated that there was almost no oxygen defect in the Cu-O chain in these samples. On the other hand, in the same cooling condition, the samples sintered in air stayed at optimal doping level with Tc = 93 K, and the intentionally carbon-doped sample was in the underdoping state. It is revealed that about 60% of incorporated carbon was substituted for Cu at the chain site in the form of CO32+, and the rest remains at the grain boundary as carbonate impurities. Such incorporation affected the oxygen absorption process in Y-123. It turned out that the oxygen content in Y-123 cannot be controlled only by the annealing temperature and the oxygen partial pressure but also by the incorporated carbon concentration.Comment: 16pages, 9figure

Magnetization under High Pressure in MnSi

The magnetization M(H) has been measured in the weakly helimagnetic itinerant compound MnSi under high pressure up to 10.2 kbar and high magnetic field up to 9 Tesla. We interpret the simultaneous decrease under pressure of the saturated magnetization, $p_s$, and the Curie temperature, $$ in the frame of the self-consistent renormalization theory (SCR) of spin fluctuations. From the analysis of the so-called Arrot-plot ($H/p [ H,T ]$ versus $p^2[ H,T ]$) and the respective volume dependence of $p_s$ and $T_c$, we estimate the evolution of the characteristic spin fluctuation temperatures, $T_0$ and $T_A$ when the system approaches its critical pressure, $P_c$=15 kbar, corresponding to the disappearance of the long range magnetic order at T=0.Comment: 12 pages, 5 figures. Submitted to Phys. Rev.

Transport, magnetic and superconducting properties of RuSr2RCu2O8 (R= Eu, Gd) doped with Sn

Ru{1-x}Sn{x}Sr2EuCu2O8 and Ru{1-x}Sn{x}Sr2GdCu2O8 have been comprehensively studied by microwave and dc resistivity and magnetoresistivity and by the dc Hall measurements. The magnetic ordering temperature T_m is considerably reduced with increasing Sn content. However, doping with Sn leads to only slight reduction of the superconducting critical temperature T_c accompanied with the increase of the upper critical field B_c2, indicating an increased disorder in the system and a reduced scattering length of the conducting holes in CuO2 layers. In spite of the increased scattering rate, the normal state resistivity and the Hall resistivity are reduced with respect to the pure compound, due to the increased number of itinerant holes in CuO2 layers, which represent the main conductivity channel. Most of the electrons in RuO2 layers are presumably localized, but the observed negative magnetoresistance and the extraordinary Hall effect lead to the conclusion that there exists a small number of itinerant electrons in RuO$_2$ layers that exhibit colossal magnetoresistance.Comment: 10 pages, 9 figure

Nuclear spin-spin coupling in La_{2-x}Sr_{x}CuO_{4} studied by stimulated echo decay

We have performed copper NQR experiments in high temperature superconductors YBa_{2}Cu_{4}O_{8}, YBa_{2}Cu_{3}O_{7}, and La_{2-x}Sr_{x}CuO_{4} (x=0.12 and 0.15), using the stimulated echo technique. The stimulated echo intensity is analyzed by a model that includes the spin-lattice relaxation process (T_ {1 }-process) and the fluctuating local field due to nuclear spin-spin coupling. The model gives quantitative account of the experimental results in Y-based compounds using the known values of 1/T_{1} and 1/T_{2G}, the gaussian decay rate of the spin echo intensity. The same model applied to LSCO enables us to extract the value of T_{2G}. Our results indicate that T_{1}T/T_{2G} is independent of temperature, implying that the dynamic exponent is one in La_{2-x}Sr_{x}CuO_{4}.Comment: 14 pages, 11 fugures, The bibliography field is correcte

Cu Nuclear Quadrupole Resonance Study of Site-Disorder and Chemical Pressure Effects on Y(Ba1-xSrx)2Cu4O8

We report a zero-field Cu nuclear quadrupole resonance (NQR) study on the effects of nonmagnetic Sr substitution for high-Tc superconductors, Y(Ba1-xSrx)2Cu4O8 (Tc=82-80 K for x=0-0.4), using a spin-echo technique. The site-disordering and chemical pressure effects associated with doping Sr were observed in the broadened, shifted Cu NQR spectra. Nevertheless, the site disorder did not significantly affect the homogeneity of Cu electron spin dynamics, in contrast to the in-plane impurity. The peak shift of Cu NQR spectrum due to Sr was different between the chain- and the plane-Cu sites, more remarkably than those under a hydrostatic physical pressure, suggesting anisotropic or nonuniform local structural strains. The small decrease of Tc due to Sr can be traced back to either a cancellation effect on Tc between the disorder and the pressure, or an anisotropic or nonuniform chemical pressure effect on Tc.Comment: 4 pages, 5 figure

Emergent Weyl fermion excitations in TaP explored by 181Ta quadrupole resonance

T. K., Y. K., and H. T. appreciate the financial support from JSPS KAKENHI Grants (No. 15K21732 and No. 15H05885). D. K. acknowledges funding via FOR 1346 from the Deutsche Forschungsgemeinschaft.The 181Ta quadrupole resonance [nuclear quadrupole resonance (NQR)] technique is utilized to investigate the microscopic magnetic properties of the Weyl semimetal TaP. We find three zero-field NQR signals associated with the transition between the quadrupole split levels for Ta with I=7/2 nuclear spin. A quadrupole coupling constant, νQ=19.250 MHz, and an asymmetric parameter of the electric field gradient, η=0.423, are extracted, in good agreement with band structure calculations. In order to examine the magnetic excitations, the temperature dependence of the spin-lattice relaxation rate (1/T1T) is measured for the f2 line (±5/2↔±3/2 transition). We find that there exist two regimes with quite different relaxation processes. Above T∗≈30 K, a pronounced (1/T1T) α T2 behavior is found, which is attributed to the magnetic excitations at the Weyl nodes with temperature-dependent orbital hyperfine coupling. Below T∗, the relaxation is mainly governed by a Korringa process with 1/T1T=const, accompanied by an additional T-1/2-type dependence to fit our experimental data. We show that Ta NQR is a novel probe for the bulk Weyl fermions and their excitations.PostprintPeer reviewe

Neuropilin-2 expression in breast cancer: correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression

<p>Abstract</p> <p>Background</p> <p>Neuropilin-2 (Nrp2) is a receptor for vascular endothelial growth factor-C (VEGF-C), which is a well-known lymphangiogenic factor and plays an important role in lymph node metastasis of various human cancers, including breast cancer. Recently, Nrp2 was shown to play a role in cancer by promoting tumor cell metastasis. CXC chemokine receptor 4 (CXCR4) also promotes tumor metastasis. In the previous studies, we demonstrated that VEGF-C and cytoplasmic CXCR4 expressions were correlated with poorer patient prognosis (BMC Cancer 2008,8:340; Breast Cancer Res Treat 2005, 91:125–132).</p> <p>Methods</p> <p>The relationship between Nrp2 expression and lymph node metastasis, VEGF-C expression, CXCR4 expression, and other established clinicopathological variables (these data were cited in our previous papers), including prognosis, was analyzed in human breast cancer. Effects of neutralizing anti-Nrp2 antibody on CXCR4 expression and chemotaxis were assessed in MDA-MB-231 breast cancer cells.</p> <p>Results</p> <p>Nrp2 expression was observed in 53.1% (60 of 113) of the invasive breast carcinomas. Nrp2 expression was significantly correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Survival curves determined by the Kaplan-Meier method showed that Nrp2 expression was associated with reduced overall survival. In multivariate analysis, Nrp2 expression emerged as a significant independent predictor for overall survival. Neutralizing anti-Nrp2 antibody blocks cytoplasmic CXCR4 expression and CXCR4-induced migration in MDA-MB-231 cells.</p> <p>Conclusion</p> <p>Nrp2 expression was correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Nrp2 expression may serve as a significant prognostic factor for long-term survival in breast cancer. Our data also showed a role for Nrp2 in regulating cytoplasmic CXCR4 expression <it>in vitro</it>.</p