The scaffold protein c-Jun NH2-terminal kinase-associated leucine zipper protein regulates cell migration through interaction wity the G protein Gα13

Division of Molecular Cell Signalin

Serum levels of toxic AGEs (TAGE) may be a promising novel biomarker in development and progression of NASH

a b s t r a c t Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leads to fibrosis and potentially cirrhosis, liver failure, and hepatocellular carcinoma, and is one of the most common causes of liver disease worldwide. NAFLD has also been implicated in other medical conditions such as insulin resistance, obesity, metabolic syndrome, hyperlipemia, hypertension, cardiovascular disease, and diabetes. Continuous hyperglycemia has been implicated in the pathogenesis of diabetic micro-and macro-vascular complications via various metabolic pathways, and numerous hyperglycemiainduced metabolic and hemodynamic conditions exist, including the increased generation of various types of advanced glycation end-products (AGEs). We recently demonstrated that glyceraldehyde-derived AGEs (Glycer-AGEs), the predominant components of toxic AGEs (TAGE), played an important role in the pathogenesis of angiopathy in diabetic patients. Moreover, a growing body of evidence suggests that the interaction between TAGE and the receptor for AGEs may alter intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicits the generation of oxidative stress in numerous types of cells including hepatocytes and hepatic stellate cells. Serum levels of TAGE were significantly higher in NASH patients than in those with simple steatosis and healthy controls. Moreover, serum levels of TAGE inversely correlated with adiponectin (adiponectin is produced by adipose tissue and is an anti-inflammatory adipokine that can increase insulin sensitivity). Furthermore, immunohistochemical staining of TAGE showed intense staining in the livers of patients with NASH. Serum levels of TAGE may be a useful biomarker for discriminating NASH from simple steatosis. The administration of atorvastatin (10 mg daily) for 12 months significantly improved NASH-related metabolic parameters and significantly decreased serum levels of TAGE. The steatosis grade and NAFLD activity score were also significantly improved. These results demonstrated that atorvastatin decreased the serum levels of TAGE in NASH patients with dyslipidemia and suggest the usefulness of TAGE as a biomarker for the attenuation of NASH. Serum levels of TAGE were significantly higher in non-B or non-C hepatocellular carcinoma (NBNC-HCC) patients than in NASH subjects without HCC or control subjects. TAGE may be involved in the pathogenesis of NBNC-HCC, and could, therefore, be a biomarker that could discriminate NBNC-HCC from NASH. We propose that serum levels of TAGE are promising novel targets for the diagnosis of and therapeutic interventions against NASH

Characterizing Low-Mass Binaries From Observation of Long Time-scale Caustic-crossing Gravitational Microlensing Events

Despite astrophysical importance of binary star systems, detections are limited to those located in small ranges of separations, distances, and masses and thus it is necessary to use a variety of observational techniques for a complete view of stellar multiplicity across a broad range of physical parameters. In this paper, we report the detections and measurements of 2 binaries discovered from observations of microlensing events MOA-2011-BLG-090 and OGLE-2011-BLG-0417. Determinations of the binary masses are possible by simultaneously measuring the Einstein radius and the lens parallax. The measured masses of the binary components are 0.43 $M_{\odot}$ and 0.39 $M_{\odot}$ for MOA-2011-BLG-090 and 0.57 $M_{\odot}$ and 0.17 $M_{\odot}$ for OGLE-2011-BLG-0417 and thus both lens components of MOA-2011-BLG-090 and one component of OGLE-2011-BLG-0417 are M dwarfs, demonstrating the usefulness of microlensing in detecting binaries composed of low-mass components. From modeling of the light curves considering full Keplerian motion of the lens, we also measure the orbital parameters of the binaries. The blended light of OGLE-2011-BLG-0417 comes very likely from the lens itself, making it possible to check the microlensing orbital solution by follow-up radial-velocity observation. For both events, the caustic-crossing parts of the light curves, which are critical for determining the physical lens parameters, were resolved by high-cadence survey observations and thus it is expected that the number of microlensing binaries with measured physical parameters will increase in the future.Comment: 8 pages, 5 figures, 4 table

MOA-2011-BLG-293Lb: A test of pure survey microlensing planet detections

Because of the development of large-format, wide-field cameras, microlensing surveys are now able to monitor millions of stars with sufficient cadence to detect planets. These new discoveries will span the full range of significance levels including planetary signals too small to be distinguished from the noise. At present, we do not understand where the threshold is for detecting planets. MOA-2011-BLG-293Lb is the first planet to be published from the new surveys, and it also has substantial followup observations. This planet is robustly detected in survey+followup data (Delta chi^2 ~ 5400). The planet/host mass ratio is q=5.3+/- 0.2*10^{-3}. The best fit projected separation is s=0.548+/- 0.005 Einstein radii. However, due to the s-->s^{-1} degeneracy, projected separations of s^{-1} are only marginally disfavored at Delta chi^2=3. A Bayesian estimate of the host mass gives M_L = 0.43^{+0.27}_{-0.17} M_Sun, with a sharp upper limit of M_L < 1.2 M_Sun from upper limits on the lens flux. Hence, the planet mass is m_p=2.4^{+1.5}_{-0.9} M_Jup, and the physical projected separation is either r_perp = ~1.0 AU or r_perp = ~3.4 AU. We show that survey data alone predict this solution and are able to characterize the planet, but the Delta chi^2 is much smaller (Delta chi^2~500) than with the followup data. The Delta chi^2 for the survey data alone is smaller than for any other securely detected planet. This event suggests a means to probe the detection threshold, by analyzing a large sample of events like MOA-2011-BLG-293, which have both followup data and high cadence survey data, to provide a guide for the interpretation of pure survey microlensing data.Comment: 29 pages, 6 figures, Replaced 7/3/12 with the version accepted to Ap

MMP-15 Is Upregulated in Preeclampsia, but Does Not Cleave Endoglin to Produce Soluble Endoglin

Preeclampsia is a major pregnancy complication, characterized by severe endothelial dysfunction, hypertension and maternal end-organ damage. Soluble endoglin is an anti-angiogenic protein released from placenta and thought to play a central role in causing the endothelial dysfunction and maternal organ injury seen in severe preeclampsia. We recently reported MMP-14 was the protease producing placentally-derived soluble endoglin by cleaving full-length endoglin present on the syncytiotrophoblast surface. This find identifies a specific drug target for severe preeclampsia; interfering with MMP-14 mediated cleavage of endoglin could decrease soluble endoglin production, ameliorating clinical disease. However, experimental MMP-14 inhibition alone only partially repressed soluble endoglin production, implying other proteases might have a role in producing soluble endoglin. Here we investigated whether MMP-15–phylogenetically the closest MMP relative to MMP-14 with 66% sequence similarity–also cleaves endoglin to produce soluble endoglin. MMP-15 was localized to the syncytiotrophoblast layer of the placenta, the same site where endoglin was localized. Interestingly, it was significantly (p = 0.03) up-regulated in placentas from severe early-onset preeclamptic pregnancies (n = 8) compared to gestationally matched preterm controls (n = 8). However, siRNA knockdown of MMP-15 yielded no significant decrease of soluble endoglin production from either HUVECs or syncytialised BeWo cells in vitro. Importantly, concurrent siRNA knockdown of both MMP-14 and MMP-15 in HUVECS did not yield further decrease in soluble endoglin production compared to MMP-14 siRNA alone. We conclude MMP-15 is up-regulated in preeclampsia, but does not cleave endoglin to produce soluble endoglin

Microlensing discovery of a population of very tight, very low mass binary brown dwarfs

Although many models have been proposed, the physical mechanisms responsible for the formation of low-mass brown dwarfs (BDs) are poorly understood. The multiplicity properties and minimum mass of the BD mass function provide critical empirical diagnostics of these mechanisms. We present the discovery via gravitational microlensing of two very low mass, very tight binary systems. These binaries have directly and precisely measured total system masses of 0.025 M· and 0.034 M·, and projected separations of 0.31 AU and 0.19 AU, making them the lowest-mass and tightest field BD binaries known. The discovery of a population of such binaries indicates that BD binaries can robustly form at least down to masses of 0.02 M·. Future microlensing surveys will measure a mass-selected sample of BD binary systems, which can then be directly compared to similar samples of stellar binaries. © 2013. The American Astronomical Society. All rights reserved