EMERGING ROLES OF PLATELET-DERIVED GROWTH FACTOR RECEPTOR ALPHA IN CHRONIC LIVER INJURY: POTENTIAL THERAPEUTIC TARGET IN HEPATIC FIBROSIS

Platelet-derived growth factor receptor (PDGFR) is a tyrosine kinase receptor that plays a role in cell survival, proliferation, and differentiation, and is involved in liver development, regeneration and chronic liver injury states such as hepatic fibrosis and cirrhosis. Hepatic stellate cells (HSCs) are the primary mediators of hepatic fibrosis through their activation from a quiescent state in response to the presence of pro-fibrotic growth factors such as PDGFs. Proliferation and migration are key outcomes of this transition, facilitating collagen deposition and migration of activated HSCs to sites of liver injury. We confirm the upregulation of PDGFRα in pericentral hepatocytes in CCl4-induced liver injury as well as HSCs/myofibroblasts in carbon tetrachloride (CCl4), bile duct ligation (BDL), and 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury. After ruling out a significant contribution of hepatocyte PDGFRα in hepatic fibrosis using Alb-Cre and FoxA3-Cre Pdgfra-/- animals, we examine PDGFRα signaling in primary human HSCs (HHSteCs) in combination with human PDGFRα–specific inhibitory monoclonal antibody Olaratumab to test the hypothesis that PDGFRα signaling in HSCs promotes hepatic fibrosis. Olaratumab-mediated PDGFRα inhibition resulted in decreased HHSteC proliferation and motility, while lacking an effect on transcriptional expression of fibrosis-associated genes. Furthermore, Olaratumab reduced activation of downstream signaling effectors involved in proliferation and motility including Akt, mTOR, Erk1/2, FAK, and p38 MAPK suggesting that PDGFRα contributes to mitogenesis and actin reorganization through diverse downstream mediators. This evidence was corroborated with findings that HSC-specific Lrat-Cre Pdgfra-/- mice showed reduced CCl4-induced fibrosis after 4 weeks (early fibrosis) followed by reduced ALT/AST levels at 8 weeks (advanced fibrosis). This was accompanied by increased macrophage infiltration and increased TUNEL-positive HSCs/myofibroblasts concomitant with a decrease in TUNEL-positive hepatocytes, suggesting that PDGFRα loss in HSCs may promote injury resolution in advanced fibrosis by limiting HSC/myofibroblast survival. These findings support a distinct pro-fibrotic role of PDGFRα in HSCs during chronic liver injury in both mice and human primary cells and provides an important pre-clinical foundation for the future testing of therapeutic PDGFRα inhibition in hepatic fibrosis

Phase field model of premelting of grain boundaries

We present a phase field model of solidification which includes the effects of the crystalline orientation in the solid phase. This model describes grain boundaries as well as solid-liquid boundaries within a unified framework. With an appropriate choice of coupling of the phase field variable to the gradient of the crystalline orientation variable in the free energy, we find that high angle boundaries undergo a premelting transition. As the melting temperature is approached from below, low angle grain boundaries remain narrow. The width of the liquid layer at high angle grain boundaries diverges logarithmically. In addition, for some choices of model coupling, there may be a discontinuous jump in the width of the fluid layer as function of temperature.Comment: 6 pages, 9 figures, RevTeX

Differential responses of seabirds to climate variability over two years in the southeast Bering Sea

第6回極域科学シンポジウム分野横断セッション：[IA] 急変する北極気候システム及びその全球的な影響の総合的解明―GRENE北極気候変動研究事業研究成果報告2015―11月19日（木）　国立極地研究所１階交流アトリウ

Phosphatase-Dependent Regulation of Epithelial Mitogen-Activated Protein Kinase Responses to Toxin-Induced Membrane Pores

Diverse bacterial species produce pore-forming toxins (PFT) that can puncture eukaryotic cell membranes. Host cells respond to sublytic concentrations of PFT through conserved intracellular signaling pathways, including activation of mitogen-activated protein kinases (MAPK), which are critical to cell survival. Here we demonstrate that in respiratory epithelial cells p38 and JNK MAPK were phosphorylated within 30 min of exposure to pneumolysin, the PFT from Streptococcus pneumoniae. This activation was tightly regulated, and dephosphorylation of both MAPK occurred within 60 min following exposure. Pretreatment of epithelial cells with inhibitors of cellular phosphatases, including sodium orthovanadate, calyculin A, and okadaic acid, prolonged and intensified MAPK activation. Specific inhibition of MAPK phosphatase-1 did not affect the kinetics of MAPK activation in PFT-exposed epithelial cells, but siRNA-mediated knockdown of serine/threonine phosphatases PP1 and PP2A were potent inhibitors of MAPK dephosphorylation. These results indicate an important role for PP1 and PP2A in termination of epithelial responses to PFT and only a minor contribution of dual-specificity phosphatases, such as MAPK phosphatase-1, which are the major regulators of MAPK signals in other cell types. Epithelial regulation of MAPK signaling in response to membrane disruption involves distinct pathways and may require different strategies for therapeutic interventions

繁殖期間中、夜間に深い海域のハダカイワシを表層で採るアカアシミツユビカモメ

第6回極域科学シンポジウム分野横断セッション：[IA] 急変する北極気候システム及びその全球的な影響の総合的解明―GRENE北極気候変動研究事業研究成果報告2015―11月19日（木）　国立極地研究所１階交流アトリウ

Auditory sequence processing reveals evolutionarily conserved regions of frontal cortex in macaques and humans.

An evolutionary account of human language as a neurobiological system must distinguish between human-unique neurocognitive processes supporting language and evolutionarily conserved, domain-general processes that can be traced back to our primate ancestors. Neuroimaging studies across species may determine whether candidate neural processes are supported by homologous, functionally conserved brain areas or by different neurobiological substrates. Here we use functional magnetic resonance imaging in Rhesus macaques and humans to examine the brain regions involved in processing the ordering relationships between auditory nonsense words in rule-based sequences. We find that key regions in the human ventral frontal and opercular cortex have functional counterparts in the monkey brain. These regions are also known to be associated with initial stages of human syntactic processing. This study raises the possibility that certain ventral frontal neural systems, which play a significant role in language function in modern humans, originally evolved to support domain-general abilities involved in sequence processing

Cloud optical depth retrievals from the Aerosol Robotic Network (AERONET) cloud mode observations

Cloud optical depth is one of the most poorly observed climate variables. The new “cloud mode” capability in the Aerosol Robotic Network (AERONET) will inexpensively yet dramatically increase cloud optical depth observations in both number and accuracy. Cloud mode optical depth retrievals from AERONET were evaluated at the Atmospheric Radiation Measurement program’s Oklahoma site in sky conditions ranging from broken clouds to overcast. For overcast cases, the 1.5 min average AERONET cloud mode optical depths agreed to within 15% of those from a standard ground‐based flux method. For broken cloud cases, AERONET retrievals also captured rapid variations detected by the microwave radiometer. For 3 year climatology derived from all nonprecipitating clouds, AERONET monthly mean cloud optical depths are generally larger than cloud radar retrievals because of the current cloud mode observation strategy that is biased toward measurements of optically thick clouds. This study has demonstrated a new way to enhance the existing AERONET infrastructure to observe cloud optical properties on a global scale

Influence of extended dynamics on phase transitions in a driven lattice gas

Monte Carlo simulations and dynamical mean-field approximations are performed to study the phase transition in a driven lattice gas with nearest-neighbor exclusion on a square lattice. A slight extension of the microscopic dynamics with allowing the next-nearest-neighbor hops results in dramatic changes. Instead of the phase separation into high- and low-density regions in the stationary state the system exhibits a continuous transition belonging to the Ising universality class for any driving. The relevant features of phase diagram are reproduced by an improved mean-field analysis.Comment: 3 pages, 3 figure

Magnetic-Field Induced First-Order Transition in the Frustrated XY Model on a Stacked Triangular Lattice

The results of extensive Monte Carlo simulations of magnetic-field induced transitions in the xy model on a stacked triangular lattice with antiferromagnetic intraplane and ferromagnetic interplane interactions are discussed. A low-field transition from the paramagnetic to a 3-state (Potts) phase is found to be very weakly first order with behavior suggesting tricriticality at zero field. In addition to clarifying some long-standing ambiguity concerning the nature of this Potts-like transition, the present work also serves to further our understanding of the critical behavior at $T_N$, about which there has been much controversy.Comment: 10 pages (RevTex 3.0), 4 figures available upon request, CRPS-93-0

Complexation of lanthanides, actinides and transition metal cations with a 6-(1,2,4-triazin-3-yl)-2,2’:6’,2’’-terpyridine ligand: implications for actinide(III) /lanthanide(III) partitioning

The quadridentate N-heterocyclic ligand 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzotriazin-3-yl)-2,2’:6’,2’’-terpyridine (CyMe4-hemi-BTBP) has been synthesized and its interactions with Am(III), U(VI), Ln(III) and some transition metal cations have been evaluated by X-ray crystallographic analysis, Am(III)/Eu(III) solvent extraction experiments, UV absorption spectrophotometry, NMR studies and ESI-MS. Structures of the 1:1 complexes with Eu(III), Ce(III) and the linear uranyl (UO22+) ion were obtained by X-ray crystallographic analysis, and showed similar coordination behavior to related BTBP complexes. In methanol, the stability constants of the Ln(III) complexes are slightly lower than those of the analogous quadridentate bis-triazine BTBP ligands, while the stability constant for the Yb(III) complex is higher. 1H NMR titrations and ESI-MS with lanthanide nitrates showed that the ligand forms only 1:1 complexes with Eu(III), Ce(III) and Yb(III), while both 1:1 and 1:2 complexes were formed with La(III) and Y(III) in acetonitrile. A mixture of isomeric chiral 2:2 helical complexes was formed with Cu(I), with a slight preference (1.4:1) for a single directional isomer. In contrast, a 1:1 complex was observed with the larger Ag(I) ion. The ligand was unable to extract Am(III) or Eu(III) from nitric acid solutions into 1-octanol, except in the presence of a synergist at low acidity. The results show that the presence of two outer 1,2,4-triazine rings is required for the efficient extraction and separation of An(III) from Ln(III) by quadridentate N-donor ligand