Interferon-gamma inducible protein 10 (IP10) induced cisplatin resistance of HCC after liver transplantation through ER stress signaling pathway.

Tumor recurrence remains an obstacle after liver surgery, especially in living donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC). The acute-phase liver graft injury might potentially induce poor response to chemotherapy in recurrent HCC after liver transplantation. We here intended to explore the mechanism and to identify a therapeutic target to overcome such chemoresistance. The associations among graft injury, overexpression of IP10 and multidrug resistant genes were investigated in a rat liver transplantation model, and further validated in clinical cohort. The role of IP10 on HCC cell proliferation and tumor growth under chemotherapy was studied both in vitro and in vivo. The underlying mechanism was revealed by detecting the activation of endoplasmic reticulum (ER) stress signaling pathways. Moreover, the effect of IP10 neutralizing antibody sensitizing cisplatin treatment was further explored. In rat liver transplantation model, significant up-regulation of IP10 associated with multidrug resistant genes was found in small-for-size liver graft. Clinically, high expression of circulating IP10 was significant correlated with tumor recurrence in HCC patients underwent LDLT. Overexpression of IP10 promoted HCC cell proliferation and tumor growth under cisplatin treatment by activation of ATF6/Grp78 signaling. IP10 neutralizing antibody sensitized cisplatin treatment in nude mice. The overexpression of IP10, which induced by liver graft injury, may lead to cisplatin resistance via ATF6/Grp78 ER stress signaling pathway. IP10 neutralizing antibody could be a potential adjuvant therapy to sensitize cisplatin treatment

HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation

SummaryAcute myeloid leukemia (AML) is driven and sustained by leukemia stem cells (LSCs) with unlimited self-renewal capacity and resistance to chemotherapy. Mutation in the TP53 tumor suppressor is relatively rare in de novo AML; however, p53 can be regulated through post-translational mechanisms. Here, we show that p53 activity is inhibited in inv(16)+ AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8). HDAC8 aberrantly deacetylates p53 and promotes LSC transformation and maintenance. HDAC8 deficiency or inhibition using HDAC8-selective inhibitors (HDAC8i) effectively restores p53 acetylation and activity. Importantly, HDAC8 inhibition induces apoptosis in inv(16)+ AML CD34+ cells, while sparing the normal hematopoietic stem cells. Furthermore, in vivo HDAC8i administration profoundly diminishes AML propagation and abrogates leukemia-initiating capacity of both murine and patient-derived LSCs. This study elucidates an HDAC8-mediated p53-inactivating mechanism promoting LSC activity and highlights HDAC8 inhibition as a promising approach to selectively target inv(16)+ LSCs

Mixed-Traffic Intersection Management Utilizing Connected and Autonomous Vehicles as Traffic Regulators

Connected and autonomous vehicles (CAVs) can realize many revolutionary applications, but it is expected to have mixed-traffic including CAVs and human-driving vehicles (HVs) together for decades. In this paper, we target the problem of mixed-traffic intersection management and schedule CAVs to control the subsequent HVs. We develop a dynamic programming approach and a mixed integer linear programming (MILP) formulation to optimally solve the problems with the corresponding intersection models. We then propose an MILP-based approach which is more efficient and real-time-applicable than solving the optimal MILP formulation, while keeping good solution quality as well as outperforming the first-come-first-served (FCFS) approach. Experimental results and SUMO simulation indicate that controlling CAVs by our approaches is effective to regulate mixed-traffic even if the CAV penetration rate is low, which brings incentive to early adoption of CAVs

Increased functional connectivity of the posterior cingulate cortex with the lateral orbitofrontal cortex in depression

To analyze the functioning of the posterior cingulate cortex (PCC) in depression, we performed the first fully voxel-level resting state functional-connectivity neuroimaging analysis of depression of the PCC, with 336 patients with major depressive disorder and 350 controls. Voxels in the PCC had significantly increased functional connectivity with the lateral orbitofrontal cortex, a region implicated in non-reward and which is thereby implicated in depression. In patients receiving medication, the functional connectivity between the lateral orbitofrontal cortex and PCC was decreased back towards that in the controls. In the 350 controls, it was shown that the PCC has high functional connectivity with the parahippocampal regions which are involved in memory. The findings support the theory that the non-reward system in the lateral orbitofrontal cortex has increased effects on memory systems, which contribute to the rumination about sad memories and events in depression. These new findings provide evidence that a key target to ameliorate depression is the lateral orbitofrontal cortex

A Safety-Guaranteed Framework for Neural-Network-Based Planners in Connected Vehicles under Communication Disturbance

Neural-network-based (NN-based) planners have been increasingly used to enhance the performance of planning for autonomous vehicles. However, it is often difficult for NN-based planners to balance efficiency and safety in complicated scenarios, especially under real-world communication disturbance. To tackle this challenge, we present a safety-guaranteed framework for NN-based planners in connected vehicle environments with communication disturbance. Given any NN-based planner with no safety-guarantee, the framework generates a robust compound planner embedding the NN-based planner to ensure overall system safety. Moreover, with the aid of an information filter for imperfect communication and an aggressive approach for the estimation of the unsafe set, the compound planner could achieve similar or better efficiency than the given NN-based planner. A comprehensive case study of unprotected left turn and extensive simulations demonstrate the effectiveness of our framework

Fingertip‐skin‐inspired highly sensitive and multifunctional sensor with hierarchically structured conductive graphite/polydimethylsiloxane foams

Fingertip skin exhibits high sensitivity in a broad pressure range, and can detect diverse stimuli, including textures, temperature, humidity, etc. Despite adopting diverse microstructures and functional materials, achieving skin sensor devices possessing high pressure sensitivity over a wide linear range and with multifunctional sensing capabilities is still challenging. Herein, inspired by the microstructures of fingertip skin, a highly sensitive skin sensor is demonstrated with a linear response over a broad pressure range and multifunctional sensing capabilities. The porous sensing layer is designed with hierarchical microstructures on the surface. By optimizing the porosity and the graphite concentration, a fabricated skin sensor device exhibits a superior sensitivity of 245 kPa−1 over a broad linear pressure range from 5 Pa to 120 kPa. For practical application demonstrations, the sensor devices are utilized to monitor subtle wrist pulse and diverse human motions including finger bending, wrist bending, and feet movement. Furthermore, this novel sensor device demonstrates potential applications in recognizing textures and detecting environmental temperatures, thereby marking an important progress for constructing advanced electronic skin

Targeting a ribonucleoprotein complex containing the caprin-1 protein and the c-Myc mRNA suppresses tumor growth in mice: an identification of a novel oncotarget

Tylophorine compounds have been the focus of drug development for decades. Tylophorine derivatives exhibit anti-cancer activities but their cellular targets remain unknown. We used a biotinylated tylophorine derivative to probe for the interacting cellular target(s) of tylophorine. Tylophorine directly binds to caprin-1 and consequently enhances the recruitment of G3BP1, c-Myc mRNA, and cyclin D2 mRNA to form a ribonucleoprotein complex. Subsequently, this tylophorine targeted ribonucleoprotein complex is sequestered to the polysomal fractions and the protein expressions of the associated mRNA-transcripts are repressed. Caprin-1 depleted carcinoma cells become more resistant to tylophorine, associated with decreased formation of the ribonucleoprotein complex targeted by tylophorine. Consequently, tylophorine downregulates c-Myc and cyclins D1/D2, causing hypophosphorylation of Rb and suppression of both processing-body formation and the Warburg effect. Gene expression profiling and gain-of-c-Myc-function experiments also revealed that the downregulated c-Myc contributes to the anti-oncogenic effects of tylophorine compounds. Furthermore, the potent tylophorine derivative dibenzoquinoline-33b elicited a similar effect, as c-Myc protein levels were also decreased in xenograft tumors treated with dibenzoquinoline-33b. Thus, tylophorine compounds exert anti-cancer activity predominantly by targeting and sequestering the caprin-1 protein and c-Myc mRNA associated ribonucleoprotein complex

Bioinspired, self-powered, and highly sensitive electronic skin for sensing static and dynamic pressures

Flexible piezoresistive pressure sensors obtain global research interest owing to their potential applications in healthcare, human–robot interaction, and artificial nerves. However, an additional power supply is usually required to drive the sensors, which results in increased complexity of the pressure sensing system. Despite the great efforts in pursuing self-powered pressure sensors, most of the self-powered devices can merely detect the dynamic pressure and the reliable static pressure detection is still challenging. With the help of redox-induced electricity, a bioinspired graphite/polydimethylsiloxane piezoresistive composite film acting both as the cathode and pressure sensing layer, a neoteric electronic skin sensor is presented here to detect not only the dynamic forces but also the static forces without an external power supply. Additionally, the sensor exhibits a fascinating pressure sensitivity of ∼103 kPa–1 over a broad sensing range from 0.02 to 30 kPa. Benefiting from the advanced performance of the device, various potential applications including arterial pulse monitoring, human motion detecting, and Morse code generation are successfully demonstrated. This new strategy could pave a way for the development of next-generation self-powered wearable devices