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

Tensor network and (pp-adic) AdS/CFT

We use the tensor network living on the Bruhat-Tits tree to give a concrete realization of the recently proposed $p$-adic AdS/CFT correspondence (a holographic duality based on the $p$-adic number field $\mathbb{Q}_p$). Instead of assuming the $p$-adic AdS/CFT correspondence, we show how important features of AdS/CFT such as the bulk operator reconstruction and the holographic computation of boundary correlators are automatically implemented in this tensor network.Comment: 59 pages, 18 figures; v3: improved presentation, added figures and reference

On the Performance Gain of NOMA over OMA in Uplink Communication Systems

In this paper, we investigate and reveal the ergodic sum-rate gain (ESG) of non-orthogonal multiple access (NOMA) over orthogonal multiple access (OMA) in uplink cellular communication systems. A base station equipped with a single-antenna, with multiple antennas, and with massive antenna arrays is considered both in single-cell and multi-cell deployments. In particular, in single-antenna systems, we identify two types of gains brought about by NOMA: 1) a large-scale near-far gain arising from the distance discrepancy between the base station and users; 2) a small-scale fading gain originating from the multipath channel fading. Furthermore, we reveal that the large-scale near-far gain increases with the normalized cell size, while the small-scale fading gain is a constant, given by $\gamma$ = 0.57721 nat/s/Hz, in Rayleigh fading channels. When extending single-antenna NOMA to $M$-antenna NOMA, we prove that both the large-scale near-far gain and small-scale fading gain achieved by single-antenna NOMA can be increased by a factor of $M$ for a large number of users. Moreover, given a massive antenna array at the base station and considering a fixed ratio between the number of antennas, $M$, and the number of users, $K$, the ESG of NOMA over OMA increases linearly with both $M$ and $K$. We then further extend the analysis to a multi-cell scenario. Compared to the single-cell case, the ESG in multi-cell systems degrades as NOMA faces more severe inter-cell interference due to the non-orthogonal transmissions. Besides, we unveil that a large cell size is always beneficial to the ergodic sum-rate performance of NOMA in both single-cell and multi-cell systems. Numerical results verify the accuracy of the analytical results derived and confirm the insights revealed about the ESG of NOMA over OMA in different scenarios.Comment: 51 pages, 7 figures, invited paper, submitted to IEEE Transactions on Communication