Autophagy is a conserved lysosomal degradation process that has important roles in both normal human physiology and disease. However, the function of autophagy in bone homeostasis is not well understood. Here, we report that autophagy is activated during osteoblast differentiation. Ablation of FIP200 (focal adhesion kinase family interacting protein of 200 kD), an essential component of mammalian autophagy, led to multiple autophagic defects in osteoblasts including aberrantly increased p62 expression, deficient LC3-II conversion, defective autophagy flux, absence of GFP-LC3 puncta in FIP200-null osteoblasts expressing transgenic GFP-LC3 and absence of autophagosome-like structures by electron microscope examination. Osteoblast-specific deletion of FIP200 led to osteopenia in mice. Histomorphometric analysis revealed that the osteopenia was due to cell-autonomous effects of FIP200 deletion on osteoblasts. FIP200 deletion led to defective osteoblast terminal differentiation in both primary bone marrow and calvarial osteoblasts in vitro. Interestingly, both proliferation and differentiation were not adversely affected by FIP200 deletion in early cultures. However, FIP200 deletion led to defective osteoblast nodule formation after initial proliferation and differentiation. Furthermore, treatment with autophagy inhibitors recapitulated the effects of FIP200 deletion on osteoblast differentiation. Taken together, these data identify FIP200 as an important regulator of bone development and reveal a novel role of autophagy in osteoblast function through its positive role in supporting osteoblast nodule formation and differentiation.

Measurement-device-independent quantum key distribution (MDIQKD) protocol is immune to all attacks on detection and guarantees the information-theoretical security even with imperfect single-photon detectors. Recently, several proof-of-principle demonstrations of MDIQKD have been achieved. Those experiments, although novel, are implemented through limited distance with a key rate less than 0.1  bit/s. Here, by developing a 75 MHz clock rate fully automatic and highly stable system and superconducting nanowire single-photon detectors with detection efficiencies of more than 40%, we extend the secure transmission distance of MDIQKD to 200 km and achieve a secure key rate 3 orders of magnitude higher. These results pave the way towards a quantum network with measurement-device-independent security.

Multidrug resistance (MDR) in tumor cells is a significant obstacle to the success of chemotherapy in many cancers. The purpose of this research is to test the possibility of docetaxel-loaded poly (ε-caprolactone)/Pluronic F68 (PCL/Pluronic F68) nanoparticles to overcome MDR in docetaxel-resistance human breast cancer cell line. Docetaxel-loaded nanoparticles were prepared by modified solvent displacement method using commercial PCL and self-synthesized PCL/Pluronic F68, respectively. PCL/Pluronic F68 nanoparticles were found to be of spherical shape with a rough and porous surface. The nanoparticles had an average size of around 200 nm with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a biphasic release pattern. There was an increased level of uptake of PCL/Pluronic F68 nanoparticles in docetaxel-resistance human breast cancer cell line, MCF-7 TAX30, when compared with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxotere®in the MCF-7 TAX30 cell culture, but the differences were not significant (p > 0.05). However, the PCL/Pluronic F68 nanoparticles achieved significantly higher level of cytotoxicity than both of PCL nanoparticles and Taxotere®(p < 0.05), indicating docetaxel-loaded PCL/Pluronic F68 nanoparticles could overcome multidrug resistance in human breast cancer cells and therefore have considerable potential for treatment of breast cancer.

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Existing anti-angiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here we report a novel role for the sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased proliferation, adhesion, chemotaxis and endothelial tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector function in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo. The TGFβ1-SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical specimens of HCC, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development.

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Phase-locked loops (PLLs) are widely used for clock generation in modern digital systems. All-digital PLLs have been proposed to address design issues in conventional analog PLLs. However, current all-digital PLLs require custom circuit design, and therefore cannot fully leverage advanced automated digital design flows. While fully synthesizable PLLs [1,2,3] have been reported, they suffer from high power consumption and large area. This arises because each stage of the ring needs to have a large number of parallel tristate buffers/inverters in order to achieve the necessary frequency resolution. Moreover, custom-designed cells are required in prior synthesizable PLLs [2, 3], introducing additional place-and-route (P&R) steps, leading to poor portability, integration, and scalability. To address these issues, this paper proposes a fully synthesizable PLL based solely on a standard digital library, with a currentoutput digital-to-analog converter (DAC) for maintaining frequency linearity and duty balance, an interpolative phase-coupled oscillator for minimizing the output phase imbalance from automatic P&R, as well as an edge injection technique for avoiding injection-pulse width issues.A block diagram of the proposed PLL with a DAC and an interpolative phasecoupled oscillator is given in Fig. 15.1.1. All circuits that makeup the PLL, including the DAC and DCO, are implemented using standard cells and an automated design flow. A dual-loop PLL architecture [5] is employed and improved in this design to provide continuous tracking of voltage/temperature variations and to avoid the timing problems associated with conventional injection-locked PLLs. The frequencies of two oscillators are digitized by two counters. A signed adder/subtractor compares the digitized frequencies with a predefined frequency-control word (FCW) and provides a frequency difference to a digital loop filter consisting of a proportional path and an integral path. The filter output determines whether to increase, decrease, or hold the DCO oscillation frequency. In addition, an edge-injection technique is incorporated into this design. Figure 15.1.2 illustrates the proposed oscillator architecture that is used in both the main and replica VCOs. In order to relieve the oscillator output phase imbalance caused by the automatic P&R, an interpolative phase-coupled oscillator built by three 3-stage oscillators is developed, based on the concept in [6]. Due to its internal feedback and feed-forward control using phase interpolators for the oscillator, the phase difference within the ring and between all adjacent rings will remain fixed in time, leading to balanced output phases. To maintain the control-code resolution and extend the operating frequency range, the oscillator is designed to operate with a coarse, medium, and fine tuning. A standard cell-based DAC controls the coarse tuning of the oscillator. As shown in Fig. 15.1.2, a digitally-controlled varactor using NAND gates is adopted in the medium-tuning circuitry. The fine-tuning circuitry is real...

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