Ixazomib enhances parathyroid hormone-induced β-catenin/T-cell factor signaling by dissociating β-catenin from the parathyroid hormone receptor.

The anabolic action of PTH in bone is mostly mediated by cAMP/PKA and Wnt-independent activation of β-catenin/T-cell factor (TCF) signaling. β-Catenin switches the PTH receptor (PTHR) signaling from cAMP/PKA to PLC/PKC activation by binding to the PTHR. Ixazomib (Izb) was recently approved as the first orally administered proteasome inhibitor for the treatment of multiple myeloma; it acts in part by inhibition of pathological bone destruction. Proteasome inhibitors were reported to stabilize β-catenin by the ubiquitin-proteasome pathway. However, how Izb affects PTHR activation to regulate β-catenin/TCF signaling is poorly understood. In the present study, using CRISPR/Cas9 genome-editing technology, we show that Izb reverses β-catenin-mediated PTHR signaling switch and enhances PTH-induced cAMP generation and cAMP response element-luciferase activity in osteoblasts. Izb increases active forms of β-catenin and promotes β-catenin translocation, thereby dissociating β-catenin from the PTHR at the plasma membrane. Furthermore, Izb facilitates PTH-stimulated GSK3β phosphorylation and β-catenin phosphorylation. Thus Izb enhances PTH stimulation of β-catenin/TCF signaling via cAMP-dependent activation, and this effect is due to its separating β-catenin from the PTHR. These findings provide evidence that Izb may be used to improve the therapeutic efficacy of PTH for the treatment of osteoporosis and other resorptive bone diseases

Transport Coefficients for Holographic Hydrodynamics at Finite Energy Scale

We investigate the relations between black hole thermodynamics and holographic transport coefficients in this paper. The formulae for DC conductivity and diffusion coefficient are verified for electrically single-charged black holes. We examine the correctness of the proposed expressions by taking charged dilatonic and single-charged STU black holes as two concrete examples, and compute the flows of conductivity and diffusion coefficient by solving the linear order perturbation equations. We then check the consistence by evaluating the Brown-York tensor at a finite radial position. Finally, we find that the retarded Green functions for the shear modes can be expressed easily in terms of black hole thermodynamic quantities and transport coefficients.Comment: 33 pages,4 figures,to appear in Advances in High Energy Physic

BOOST: A fast approach to detecting gene-gene interactions in genome-wide case-control studies

Gene-gene interactions have long been recognized to be fundamentally important to understand genetic causes of complex disease traits. At present, identifying gene-gene interactions from genome-wide case-control studies is computationally and methodologically challenging. In this paper, we introduce a simple but powerful method, named `BOolean Operation based Screening and Testing'(BOOST). To discover unknown gene-gene interactions that underlie complex diseases, BOOST allows examining all pairwise interactions in genome-wide case-control studies in a remarkably fast manner. We have carried out interaction analyses on seven data sets from the Wellcome Trust Case Control Consortium (WTCCC). Each analysis took less than 60 hours on a standard 3.0 GHz desktop with 4G memory running Windows XP system. The interaction patterns identified from the type 1 diabetes data set display significant difference from those identified from the rheumatoid arthritis data set, while both data sets share a very similar hit region in the WTCCC report. BOOST has also identified many undiscovered interactions between genes in the major histocompatibility complex (MHC) region in the type 1 diabetes data set. In the coming era of large-scale interaction mapping in genome-wide case-control studies, our method can serve as a computationally and statistically useful tool.Comment: Submitte

Individual position diversity in dependence socioeconomic networks increases economic output

The availability of big data recorded from massively multiplayer online role-playing games (MMORPGs) allows us to gain a deeper understanding of the potential connection between individuals' network positions and their economic outputs. We use a statistical filtering method to construct dependence networks from weighted friendship networks of individuals. We investigate the 30 distinct motif positions in the 13 directed triadic motifs which represent microscopic dependences among individuals. Based on the structural similarity of motif positions, we further classify individuals into different groups. The node position diversity of individuals is found to be positively correlated with their economic outputs. We also find that the economic outputs of leaf nodes are significantly lower than that of the other nodes in the same motif. Our findings shed light on understanding the influence of network structure on economic activities and outputs in socioeconomic system.Comment: 19 pages, 5 figure

Corneal layer plate removal with Fluconazole injected corneal stroma and autologous conjunctival transplantation for keratomycosis

AIM: To investigate the clinical effect of corneal layer plate removal with Fluconazole injected corneal stroma and autologous conjunctival transplantation for keratomycosis.<p>METHODS: There were 168 cases suffered keratomycosis that the focus located shallow of the cornea and was not obvious to drug, who registered in our hospital from March 2005 to June 2010. In surgery we removed plate layer to cormea clear, the region was greater than focus for 0.5mm,then we injected fluconazole which is 2g/L density in corneal stroma to make the edema area greater than Removal of area for 0.5mm. At last we took pedicle conjunctival flap to cover the plant bed by continuous suture. Postoperative day use drug to drop eye and to observe that whether recurrent of the keratomycosis and how was the edema degrade, the blood supply of conjunctival graft pieces, how about the stimulating signs of the surgery eye, the vision.<p>RESULTS: The improvement rate was 96.2% after surgery for seven days and the cure rate was 95.5% after surgery for one months. We found in 157 eyes accepted trigeminy surgery there were 6 eyes recurrence and the recurrence rate was 3.8%. The mean time of corneal stromal edema faded away was 13.4 hours. After surgery for one month there were 39 eyes(24.8%)whose vision removed than preoperative, there were 91 eyes(58.0%)whose vision were same as preoperative and there were 27 eyes(17.2%)whose vision lower than preoperative. In these operations the loss ratio of corneal endothelium was from 0%-8%, the mean was 2.9%. The irritative symptoms postoperative were mild for 87%, moderate for 10% and severe for 3%. By this surgery the mean length of stay was 7.3 days so the mean hospitalization expenses only were 2160 RMB. Three months after surgery, 4 cases were slight corneal ectasia.<p>CONCLUSION: This operation combined corneal layer plate removal, Fluconazole injected corneal stroma and autologous conjunctival transplantation for keratomycosis which was in early-to-mid was affordable and curative effect. So which could be used in some district which shortage the cornea donor

catena-Poly[[iodidocopper(I)]-μ-4,4′,6,6′-tetra­methyl-2,2′-(ethyl­enedithio)dipyrimidine-κ2 N:N′]

In the title coordination polymer, [CuI(C14H18N4S2)]n, the CuI center is trigonally coordinated by two pyrimidine N-atom donors from two distinct dithio­ether ligands and one iodide anion. The Cu and I atoms are located on a twofold axis, whereas the midpoint of the central C—C bond of the dithio­ether ligand is located on an inversion center. Each organic ligand, acting in a bidentate mode, bridges two CuI ions, resulting in the formation of polymeric zigzag chains. The dihedral angle between the two pyrimidine units bonded to the metal center is 88.01 (2)°. The crystal packing is mainly stabilized by van der Waals forces and π–π stacking inter­actions, with an inter­planar distance between the pyrimidine rings of adjacent chains of 3.638 (3) Å