GPR35 antagonist CID-2745687 attenuates anchorage-independent cell growth by inhibiting YAP/TAZ activity in colorectal cancer cells.

Background and purpose: GPR35, a member of the orphan G-protein-coupled receptor, was recently implicated in colorectal cancer (CRC). However, whether targeting GPR35 by antagonists can inhibit its pro-cancer role has yet to be answered. Experimental approach: We applied antagonist CID-2745687 (CID) in established GPR35 overexpressing and knock-down CRC cell lines to understand its anti-cell proliferation property and the underlying mechanism. Key results: Although GPR35 did not promote cell proliferation in 2D conditions, it promoted anchorage-independent growth in soft-agar, which was reduced by GPR35 knock-down and CID treatment. Furthermore, YAP/TAZ target genes were expressed relatively higher in GPR35 overexpressed cells and lower in GPR35 knock-down cells. YAP/TAZ activity is required for anchorage-independent growth of CRC cells. By detecting YAP/TAZ target genes, performing TEAD4 luciferase reporter assay, and examining YAP phosphorylation and TAZ protein expression level, we found YAP/TAZ activity is positively correlated to GPR35 expression level, which CID disrupted in GPR35 overexpressed cells, but not in GPR35 knock-down cells. Intriguingly, GPR35 agonists did not promote YAP/TAZ activity but ameliorated CID's inhibitory effect; GPR35-promoted YAP/TAZ activity was only partly attenuated by ROCK1/2 inhibitor. Conclusion and implications: GPR35 promoted YAP/TAZ activity partly through Rho-GTPase with its agonist-independent constitutive activity, and CID exhibited its inhibitory effect. GPR35 antagonists are promising anti-cancer agents that target hyperactivation and overexpression of YAP/TAZ in CRC.

Aminosalicylates target GPR35, partly contributing to the prevention of DSS-induced colitis.

GPR35, a class A G-protein-coupled receptor, is considered an orphan receptor; the endogenous ligand and precise physiological function of GPR35 remain obscure. GPR35 is expressed relatively highly in the gastrointestinal tract and immune cells. It plays a role in colorectal diseases like inflammatory bowel diseases (IBDs) and colon cancer. More recently, the development of GPR35 targeting anti-IBD drugs is in solid request. Nevertheless, the development process is in stagnation due to the lack of a highly potent GPR35 agonist that is also active comparably in both human and mouse orthologs. Therefore, we proposed to find compounds for GPR35 agonist development, especially for the human ortholog of GPR35. As an efficient way to pick up a safe and effective GPR35 targeting anti-IBD drug, we screened Food and Drug Administration (FDA)-approved 1850 drugs using a two-step DMR assay. Interestingly, we found aminosalicylates, first-line medicine for IBDs whose precise target remains unknown, exhibited activity on both human and mouse GPR35. Among these, pro-drug olsalazine showed the most potency on GPR35 agonism, inducing ERK phosphorylation and ß-arrestin2 translocation. In dextran sodium sulfate (DSS)-induced colitis, the protective effect on disease progression and inhibitory effect on TNFα mRNA expression, NF-κB and JAK-STAT3 pathway of olsalazine are compromised in GPR35 knock-out mice. The present study identified a target for first-line medicine aminosalicylates, highlighted that uncleaved pro-drug olsalazine is effective, and provided a new concept for the design of aminosalicylic GPR35 targeting anti-IBD drug.

Voluntary Assist-as-Needed Controller for an Ankle Power-Assist Rehabilitation Robot.

OBJECTIVE: Although existing assist-as-needed (AAN) controllers have been designed to adapt the robotic assistance to patients' movement performance, they ignore patient's active participation. This study proposed a voluntary AAN (VAAN) controller considering both movement performance and active participation for an ankle rehabilitation robot. METHODS: According to the trajectory tracking error of the human-robot cooperation movement, the controller can switch among four working modes, including robot-resist, free, robot-assist, and robot-dominant mode. In order to reflect patients' active participation, the voluntary torque of the ankle joint was estimated by an EMG-driven musculoskeletal model. The control torque in robot-resist, free, and robot-assist mode was determined by the voluntary torque of ankle joint multiplied by an assistance ratio to encourage subjects' active participation, and a stiff torque was provided in robot-dominant mode. The controller was evaluated with 2 healthy subjects and 5 stroke patients on an ankle rehabilitation robot to investigate the clinical impact on the stroke patients. RESULTS: The experiment results showed that as patients' disability level increased, the trajectory tracking error increased and the proportion of human-dominant time and the voluntary torque of ankle joint decreased. Moreover, the results showed that the proposed VAAN controller achieved higher human contribution ratio than that of previous studies. CONCLUSION: The proposed VAAN controller can adapt the working mode to the movement performance and promote the subjects to participate actively. SIGNIFICANCE: Based on its performance, the proposed VAAN controller has potential for use in robot-assisted rehabilitation.

Continuous mode adaptation for cable-driven rehabilitation robot using reinforcement learning.

Continuous mode adaptation is very important and useful to satisfy the different user rehabilitation needs and improve human-robot interaction (HRI) performance for rehabilitation robots. Hence, we propose a reinforcement-learning-based optimal admittance control (RLOAC) strategy for a cable-driven rehabilitation robot (CDRR), which can realize continuous mode adaptation between passive and active working mode. To obviate the requirement of the knowledge of human and robot dynamics model, a reinforcement learning algorithm was employed to obtain the optimal admittance parameters by minimizing a cost function composed of trajectory error and human voluntary force. Secondly, the contribution weights of the cost function were modulated according to the human voluntary force, which enabled the CDRR to achieve continuous mode adaptation between passive and active working mode. Finally, simulation and experiments were conducted with 10 subjects to investigate the feasibility and effectiveness of the RLOAC strategy. The experimental results indicated that the desired performances could be obtained; further, the tracking error and energy per unit distance of the RLOAC strategy were notably lower than those of the traditional admittance control method. The RLOAC strategy is effective in improving the tracking accuracy and robot compliance. Based on its performance, we believe that the proposed RLOAC strategy has potential for use in rehabilitation robots.

Hawk: Rapid Android Malware Detection Through Heterogeneous Graph Attention Networks.

Android is undergoing unprecedented malicious threats daily, but the existing methods for malware detection often fail to cope with evolving camouflage in malware. To address this issue, we present Hawk, a new malware detection framework for evolutionary Android applications. We model Android entities and behavioral relationships as a heterogeneous information network (HIN), exploiting its rich semantic meta-structures for specifying implicit higher order relationships. An incremental learning model is created to handle the applications that manifest dynamically, without the need for reconstructing the whole HIN and the subsequent embedding model. The model can pinpoint rapidly the proximity between a new application and existing in-sample applications and aggregate their numerical embeddings under various semantics. Our experiments examine more than 80,860 malicious and 100,375 benign applications developed over a period of seven years, showing that Hawk achieves the highest detection accuracy against baselines and takes only 3.5 ms on average to detect an out-of-sample application, with the accelerated training time of 50x faster than the existing approach.

Identification and Characterization of Robust Hepatocellular Carcinoma Prognostic Subtypes Based on an Integrative Metabolite-Protein Interaction Network.

Metabolite-protein interactions (MPIs) play key roles in cancer metabolism. However, our current knowledge about MPIs in cancers remains limited due to the complexity of cancer cells. Herein, the authors construct an integrative MPI network and propose a MPI network based hepatocellular carcinoma (HCC) subtyping and mechanism exploration workflow. Based on the expressions of hub proteins on the MPI network, two prognosis-distinctive HCC subtypes are identified. Meanwhile, multiple interdependent features of the poor prognostic subtype are observed, including hypoxia, DNA hypermethylation of metabolic pathways, fatty acid accumulation, immune pathway up-regulation, and exhausted T-cell infiltration. Notably, the immune pathway up-regulation is probably induced by accumulated unsaturated fatty acids which are predicted to interact with multiple immune regulators like SRC and TGFB1. Moreover, based on tumor microenvironment compositions, the poor prognostic subtype is further divided into two sub-populations showing remarkable differences in metabolism. The subtyping shows a strong consistency across multiple HCC cohorts including early-stage HCC. Overall, the authors redefine robust HCC prognosis subtypes and identify potential MPIs linking metabolism to immune regulations, thus promoting understanding and clinical applications about HCC metabolism heterogeneity.

High performance of filter capacitor based on nitrogen-doped carbon nanotube supercapacitor.

The high-performance filter capacitor is a hot research topic in the field of filter circuits for flexible and wearable devices, whereas traditional aluminum electrolytic capacitors still experience widespread problems in terms of large error factors and poor stability. To avoid these disadvantages, in this work, we have developed a liquid dual-layer supercapacitor (SC). When it is employed as the filter capacitor in a filter circuit, any waveform signal can be transformed into a linear signal. The maximum fluctuation of the output signal is less than 16 mV; the SC also demonstrates excellent filtering stability in a frequency range of 1 ∼ 100 000 Hz, as well as an amplitude window of 0 ∼ 10 V. In this framework, our filter SC demonstrates unparalleled processing properties, and can greatly improve the stability and extend the lifetime of the entire electronic circuit. The fact that the requirements of high-end electronic products can be fulfilled due to the contribution of this filter SC are particularly significant.

Synthesis and bioevaluation of radioiodinated nitroimidazole hypoxia imaging agents by one-pot click reaction.

Eight radioiodinated 2-nitroimidazole derivatives for use as hypoxia imaging agents were synthesized by one-pot click reaction using four azides, two alkynes, and [131I]iodide ions and evaluated by hypoxic cellular uptake and biodistribution experiments. The results suggested that radiotracers with suitable partition coefficients (log P: -0.2-1.2) were more likely to have higher hypoxic cellular uptake. Among these eight molecules, [131I]15 ([131I]-(5-iodo-1-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethyl)-4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazole)) had a suitable log P (0.05 ± 0.03) and contained two 2-nitroimidazole groups. The hypoxic/aerobic cellular uptake ratio of [131I]15 was 4.4 ± 0.5, and the tumor/blood (T/B) and tumor/muscle (T/M) ratios were 2.03 ± 0.45 and 6.82 ± 1.70, respectively. These results suggested that [131I]15 was a potential hypoxia imaging agent.

Preparation and Characterization of Bletilla striata Polysaccharide/Polylactic Acid Composite.

Polylactic acid (PLA) is limited in its application due to its high price, high brittleness and low glass-transition temperature. Modification methods are currently used to overcome these shortcomings. In this study, Bletilla striata polysaccharide (BSP) was blended with PLA by a solvent method. DMA data showed that the BSP/PLA film had a higher glass-transition temperature, and the glass-transition temperature of the film showed an extreme value of 68 °C when the proportion of the chalk polysaccharide was 0.8%. TG data indicates that the composite film material has good thermal stability. Tensile tests show that the composite film is improved in rigidity and elasticity compared to the pure PLA film. The blending modification of PLA with white peony polysaccharide not only reduces the cost of PLA, but also improves the thermal and mechanical properties of PLA.

Preparation, In Vivo and In Vitro Release of Polyethylene Glycol Monomethyl Ether-Polymandelic Acid Microspheres Loaded Panax Notoginseng Saponins.

In order to enrich the types of Panax notoginseng saponins (PNS) sustained-release preparations and provide a new research idea for the research and development of traditional Chinese medicine sustained-release formulations, a series of Panax notoginseng saponins microspheres was prepared by a double emulsion method using a series of degradable amphiphilic macromolecule materials polyethylene glycol monomethyl ether-polymandelic acid (mPEG-PMA) as carrier. The structure and molecular weight of the series of mPEG-PMA were determined by nuclear magnetic resonance spectroscopy (1 HNMR) and gel chromatography (GPC). The results of the appearance, particle size, drug loading and encapsulation efficiency of the drug-loaded microspheres show that the mPEG10000-PMA (1:9) material is more suitable as a carrier for loading the total saponins of Panax notoginseng. The particle size was 2.51 ± 0.21 µm, the drug loading and encapsulation efficiency were 8.54 ± 0.16% and 47.25 ± 1.64%, respectively. The drug-loaded microspheres were used for in vitro release and degradation experiments to investigate the degradation and sustained release behaviour of the drug-loaded microspheres. The biocompatibility of the microspheres was studied by haemolytic, anticoagulant and cytotoxicity experiments. The pharmacological activity of the microspheres was studied by anti-inflammatory and anti-tumour experiments. The results showed that the drug-loaded microspheres could be released stably for about 12 days and degraded within 60 days. At the same time, the microspheres had good biocompatibility, anti-inflammatory and anti-tumour activities.

Preparation and In Vitro Release of Total Alkaloids from Alstonia Scholaris Leaves Loaded mPEG-PLA Microspheres.

Total alkaloids of Alstonia scholaris leaves (ASAs) are extracted from the lamp leaves, which have positive anti-inflammatory activity and remarkable effects in treating bronchitis. Due to its short half-life, we used a degradable mPEG-PLA to physically encapsulate the total alkali of the lamp stage, and prepared a sustained-release microsphere by double-emulsion method. The ASAs-loaded mPEG10000-PLA microspheres were screened for better performance by testing the morphology, average particle size, embedding rate and drug loading of different molecular weight mPEG-PLA microspheres, which can stably and continuously release for 15 days at 37 °C. The results of cytotoxicity and blood compatibility indicated that the drug-loaded microspheres have beneficial biocompatibility. Animal experiments showed that the drug-loaded microspheres had a beneficial anti-inflammatory effect. These results all indicated that mPEG-PLA is a controlled release carrier material suitable for ASAs.