Is 26S proteasome non-ATPase regulatory subunit 6 a potential molecular target for intrahepatic cholangiocarcinoma?

In this editorial we comment on the article by Tang et al published in the recent issue of World Journal of Hepatology.Drug therapy of intrahepatic cholangiocarcinoma(iCCA)poses an enormous challenge since only a small proportion of patients demonstrate beneficial responses to therapeutic agents.Thus,there has been a sustained search for novel molecular targets for iCCA.The study by Tang et al evaluated the role of 26S proteasome non-ATPase regulatory subunit 6(PSMD6),a 19S regulatory subunit of the proteasome,in human iCCA cells and specimens.The authors employed clustered regularly interspaced short palindromic repeat(CRISPR)knockout screening technology integrated with the computational CERES algorithm,and analyzed the human protein atlas(THPA)database and tissue microarrays.The results show that PSMD6 is a gene essential for the proliferation of 17 iCCA cell lines,and PSMD6 protein was overexpressed in iCCA tissues without a significant correlation with the clinicopathological parameters.The authors conclude that PSMD6 may play a promoting role in iCCA.The major limitations and defects of this study are the lack of detailed information of CRISPR knockout screening,in vivo experiments,and a discussion of plausible mechanistic cues,which,therefore,dampen the significance of the results.Further studies are required to verify PSMD6 as a molecular target for developing novel therapeutics for iCCA.In addition,the editorial article summarizes the latest advances in molecular targeted drugs and recently emerging immunotherapy in the clinical management of iCCA,development of proteasome inhibitors for cancer therapy,and advantages of CRISPR screening technology,computational methods,and THPA database as experimental tools for fighting cancer.We hope that these comments may provide some clues for those engaged in the field of basic and clinical research into iCCA.

Multilevel analysis of the central-peripheral-target organ pathway:contributing to recovery after peripheral nerve injury

Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes at individual injury sites,neglecting multilevel pathological analysis of the overall nervous system and target organs.This has led to restrictions on current therapeutic approaches.In this paper,we first summarize the potential mechanisms of peripheral nerve injury from a holistic perspective,covering the central nervous system,peripheral nervous system,and target organs.After peripheral nerve injury,the cortical plasticity of the brain is altered due to damage to and regeneration of peripheral nerves;changes such as neuronal apoptosis and axonal demyelination occur in the spinal cord.The nerve will undergo axonal regeneration,activation of Schwann cells,inflammatory response,and vascular system regeneration at the injury site.Corresponding damage to target organs can occur,including skeletal muscle atrophy and sensory receptor disruption.We then provide a brief review of the research advances in therapeutic approaches to peripheral nerve injury.The main current treatments are conducted passively and include physical factor rehabilitation,pharmacological treatments,cell-based therapies,and physical exercise.However,most treatments only partially address the problem and cannot complete the systematic recovery of the entire central nervous system-peripheral nervous system-target organ pathway.Therefore,we should further explore multilevel treatment options that produce effective,long-lasting results,perhaps requiring a combination of passive(traditional)and active(novel)treatment methods to stimulate rehabilitation at the central-peripheral-target organ levels to achieve better functional recovery.

Pyroptosis,ferroptosis,and autophagy in spinal cord injury:regulatory mechanisms and therapeutic targets

Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.

Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

Safety Evaluation of Myricetin and Crude Extract from Myrica rubra Leaves on Non-target Organisms

[ Objective] The study aimed to supply important basis for developing environment-friendly pesticides with myricetin and crude extract of Myrica rubra leaves as effective components. [ Method] According to ＂Test guidelines for environmental safety evaluation on chemical pesticides＂, the toxicity of myricetin and crude extract of M. rubra leaves on non-target organisms was determined and the safety evaluation was carried out. [Result] MyriceUn and crude extract of M. rubra leaves had low toxicity on non-target organisms, such as earthworm, silkworm and soil microbes. Myricetin showed low toxicity and the crude extract of M. rubra leaves showed middle toxicity on tadpole. The high-concentration crude extract of M. rubra leaves had some antifeedant effect on silkworm. [ Conclusion] Myricetin and crude extract of M. rubra leaves had low toxicity on non-tar- get organisms in environment and they were relatively safe.

Robust detector for range-spread targets in non-Gaussian background

Based on the target scatterer density, the range-spread target detection of high-resolution radar is addressed in additive non-Gaussian clutter, which is modeled as a spherically invariant random vector. Firstly, for sparse scatterer density, the detection of target scatterer in each range cell is derived, and then an M/K detector is proposed to detect the whole range-spread target. Se- condly, an integrating detector is devised to detect a range-spread target with dense scatterer density. Finally, to make the best of the advantages of M/K detector and integrating detector, a robust detector based on scatterer density （DBSD） is designed, which can reduce the probable collapsing loss or quantization error ef- fectively. Moreover, the density decision factor of DBSD is also determined. The formula of the false alarm probability is derived for DBSD. It is proved that the DBSD ensures a constant false alarm rate property. Furthermore, the computational results indi- cate that the DBSD is robust to different clutter one-lag correlations and target scatterer densities. It is also shown that the DBSD out- performs the existing scatterer-density-dependent detector.

Targeted Antimicrobial Therapy Against Streptococcus mutans Establishes Protective Non-cariogenic Oral Biofilms and Reduces Subsequent Infection

Aim Dental biofilms are complex communities composed largely of harmless bacteria. Certain pathogenic species including Streptococcus mutans （S. mutans） can become predominant when host factors such as dietary sucrose intake imbalance the biofilm ecology. Current approaches to control S. mutans infection are not pathogen-specific and eliminate the entire oral community along with any protective benefits provided. Here, we tested the hypothesis that removal of S. mutans from the oral community through targeted antimicrobial therapy achieves protection against subsequent S. mutans colonization. Methodology Controlled amounts of S. mutans were mixed with S. mutans-free saliva, grown into biofilms and visualized by antibody staining and cfu quantization. Two specifically-targeted antimicrobial peptides （STAMPs） against S. mutans were tested for their ability to reduce S. mutans biofilm incorporation upon treatment of the inocula. The resulting biofilms were also evaluated for their ability to resist subsequent exogenous S. mutans colonization. Results S. mutans colonization was considerably reduced （9 ± 0.4 fold reduction, P=0.01） when the surface was preoccupied with saliva-derived biofilms. Furthermore, treatment with S. mutans-specific STAMPs yielded S. mutans-deficient biofilms with significant protection against further S. mutans colonization （5 minutes treatment： 38 ± 13 fold reduction P=0.01; 16 hours treatment： 96 ± 28 fold reduction P=0.07）. Conclusion S. mutans infection is reduced by the pre- sence of existing biofilms. Thus maintaining a healthy or ＂normal＂ biofilm through targeted antimicrobial therapy （such as the STAMPs） could represent an effective strategy for the treatment and prevention of S. mutans colonization in the oral cavity and caries progression.

Particle filter initialization in non-linear non-Gaussian radar target tracking

When particle filter is applied in radar target tracking, the accuracy of the initial particles greatly effects the results of filtering. For acquiring more accurate initial particles, a new method called “competition strategy algorithm” is presented. In this method, initial measurements give birth to several particle groups around them, regularly. Each of the groups is tested several times, separately, in the beginning periods, and the group that has the most number of efficient particles is selected as the initial particles. For this method, sample initial particles selected are on the basis of several measurements instead of only one first measurement, which surely improves the accuracy of initial particles. The method sacrifices initialization time and computation cost for accuracy of initial particles. Results of simulation show that it greatly improves the accuracy of initial particles, which makes the effect of filtering much better.

Design of a Non-cooperative Target Capture Mechanism

A passive compliant non-cooperative target capture mechanism is designed to maintain the non-cooperative target on-orbit. When the relative position between capture mechanism and satellite is confirmed,a pair of four-bar linkages lock the docking ring,which is used for connecting the satellite and the rocket. The mathematical model of capture mechanism and capture space is built by the Denavit-Hartenberg(D-H)method,and the torque of each joint is analyzed by the Lagrange dynamic equation. Besides,the capture condition and the torque of every joint under different capture conditions are analyzed by simulation in MSC. Adams. The results indicate that the mechanism can capture the non-cooperative target satellite in a wide range. During the process of capture,the passive compliant mechanism at the bottom can increase capture space,thereby reducing the difficulty and enhance stability of the capture.

Non-fluctuating target detection in low-grazing angle with MIMO radar

The non-fluctuating target detection in low-grazing angle using multiple-input multiple-output(MIMO) radar systems was studied, where the multipath effects are very abundant. The performance of detection can be improved via utilizing the multipath echoes. First, the reflection coefficient considering the curved earth effect is derived. Then, the general signal model for MIMO radar is introduced for non-fluctuating target in low-grazing angle. Using the generalized likelihood ratio test(GLRT) criterion, the detector of non-fluctuating target with multipath was analyzed. The simulation results demonstrate that the MIMO radar outperforms the conventional radar in non-fluctuating target detection and show that the performance can be enhanced markedly when the multipath effects are considered.

Review of the current targeted therapies for non-small-cell lung cancer

The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer(NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor(EGFR), and crizotinib which targets anaplastic lymphoma kinase(ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790 Mtargeted agents CO-1686 and AZD9291, and the ALKtargeted agents ceritinib(LDK378), AP26113, alectinib(CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.

Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma

Non-small-cell lung cancer(NSCLC)remains the leading cause of cancer-related death in both men and women in the United States.Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease.Improvements in overall survival and quality of life have been modest.Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics,thus changing the treatment paradigm for many NSCLC patients.In this review,we present a summary of many of the currently investigated biologic targets in NSCLC,discuss their current clinical trial status,and also discuss the potential for development of other targeted agents.

Impedance control of multi-arm space robot for the capture of non-cooperative targets

Robotic systems are expected to play an increasingly important role in future space activities. The robotic on-orbital service, whose key is the capturing technology, becomes a research hot spot in recent years. This paper studies the dynamics modeling and impedance control of a multi-arm free-flying space robotic system capturing a non-cooperative target. Firstly, a control-oriented dynamics model is essential in control algorithm design and code realization. Unlike a numerical algorithm, an analytical approach is suggested. Using a general and a quasi-coordinate Lagrangian formulation, the kinematics and dynamics equations are derived.Then, an impedance control algorithm is developed which allows coordinated control of the multiple manipulators to capture a target.Through enforcing a reference impedance, end-effectors behave like a mass-damper-spring system fixed in inertial space in reaction to any contact force between the capture hands and the target. Meanwhile, the position and the attitude of the base are maintained stably by using gas jet thrusters to work against the manipulators' reaction. Finally, a simulation by using a space robot with two manipulators and a free-floating non-cooperative target is illustrated to verify the effectiveness of the proposed method.

Optical polarization imaging for underwater target detection with non-scatter background

For conventional optical polarization imaging of underwater target,the polarization degree of backscatter should be pre-measured by averaging the pixel intensities in the no target region of the polarization images,and the polarization property of the target is assumed to be completely depolarized.When the scattering background is unseen in the field of view or the target is polarized,conventional method is helpless in detecting the target.An improvement is to use lots of co-polarization and cross polarization detection components.We propose a polarization subtraction method to estimate depolarization property of the scattering noise and target signal.And experiment in a quartz cuvette container is performed to demonstrate the effectiveness of the proposed method.The results show that the proposed method can work without scattering background reference,and further recover the target along with smooth surface for polarization preserving response.This study promotes the development of optical polarization imaging systems in underwater environments.

Pathophysiological mechanisms involved in non-alcoholic steatohepatitis and novel potential therapeutic targets

Non-alcoholic fatty liver disease(NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as nonalcoholic fatty liver(NAFL) or simple steatosis,and non-alcoholic steatohepatitis(NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms,such as,insulin resistance(IR),lipotoxicity,inflammation,oxidative stress,and recently the gut-liver axis interaction has been described. Incretin-based therapies could play a role in the treatment of NAFLD. Glucagon-like peptide-1(GLP-1) is an intestinal mucosa-derived hormone which is secreted into the bloodstream in response to nutrient ingestion; it favors glucose-stimulated insulin secretion,inhibition of postprandial glucagon secretion and delayed gastric emptying. It also promotes weight loss and is involved in lipid metabolism. Once secreted,GLP-1 is quickly degraded by dipeptidyl peptidase-4(DPP-4). Therefore,DPP-4 inhibitors are able to extend the activity of GLP-1. Currently,GLP-1 agonists and DPP-4 inhibitors represent attractive options for the treatment of NAFLD and NASH. The modulation of lipid and glucose metabolism through nuclear receptors,such as the farsenoid X receptor,also constitutes an attractive therapeutic target. Obeticholic acid is a potent activator of the farnesoid X nuclear receptor and reduces liver fat content and fibrosis in animal models. Ursodeoxycholic acid(UDCA) is a hydrophilic bile acid with immunomodulatory,antiinflammatory,antiapoptotic,antioxidant and antifibrotic properties. UDCA can improve IR and modulate lipid metabolism through its interaction with nuclear receptors such as,TGR5,farnesoid X receptor-a,or the small heterodimeric partner. Finally,pharmacologic modulation of the gut microbiota could have a role in the therapy of NAFLD and NASH. Probiotics prevent bacterial translocation and epithelial invasion,inhibit mucosal adherence by bacteria,and stimulate host immunity. In animal models,probiotics prevent obesity,decrease transaminase levels,and improve IR and liver histology in NASH.

Targeting FGFR in non-small cell lung cancer:implications from the landscape of clinically actionable aberrations of FGFR kinases

Objective:Dysfunction in fibroblast growth factor receptor(FGFR)signaling has been reported in diverse cancer types,including non-small cell lung cancer(NSCLC).The frequency of FGFR aberrations in Chinese NSCLC patients is therefore of great clinical significance.Methods:A total of 10,966 NSCLC patients whose tumor specimen and/or circulating cell-free DNA(cf DNA)underwent hybridization capture-based next-generation sequencing were reviewed.Patients'clinical characteristics and treatment histories were also evaluated.Results:FGFR aberrations,including mutations,fusions,and gene amplifications,were detected in 1.9%(210/10,966)of the population.FGFR abnormalities were more frequently observed in lung squamous cell carcinomas(6.8%,65/954)than lung adenocarcinomas(1.3%,128/9,596).FGFR oncogenic mutations were identified in 19 patients(~0.17%),of which,68%were male lung squamous cell carcinoma patients.Eleven out of the 19 patients(58%)had concurrent altered PI3 K signaling,thus highlighting a potential combination therapeutic strategy of dual-targeting FGFR and PI3 K signaling in such patients.Furthermore,FGFR fusions retaining the intact kinase domain were identified in 12 patients(0.11%),including 9 FGFR3-TACC3,1 FGFR2-INA,1 novel FGFR4-RAPGEFL1,and 1 novel fusion between the FGFR1 and SLC20 A25′-untranslated regions,which may have caused FGFR1 overexpressions.Concomitant EGFR mutations or amplifications were observed in 6 patients,and 4 patients received anti-EGFR inhibitors,in whom FGFR fusions may have mediated resistance to anti-EGFR therapies.FGFR amplification was detected in 24 patients,with the majority being FGFR1 amplifications.Importantly,FGFR oncogenic mutations,fusions,and gene amplifications were almost always mutually exclusive events.Conclusions:We report the prevalence of FGFR anomalies in a large NSCLC population,including mutations,gene amplifications,and novel FGFR fusions.

Design of a Flexible Capture Mechanism Inspired by Sea Anemone for Non-cooperative Targets

Robotic grippers have been used in industry as end-effectors but are usually limited to operations in pre-defined workspace.However,few devices can capture irregularly shaped dynamic targets in space,underwater and other unstructured environments.In this paper,a novel continuum arm group mechanism inspired by the morphology and motions of sea anemones is proposed.It is able to dissipate and absorb the kinetic energy of a fast moving target in omni-direction and utilize multiple arms to wrap and lock the target without accurate positioning control.Wire-driven actuation systems are implemented in the individual continuum arms,achieving both bending motion and stiffness regulation.Through finite element method,the influence of different configurations of the continuum arm group on the capture performance is analyzed.A robotic prototype is constructed and tested,showing the presented arm group mechanism has high adaptability to capture targets with different sizes,shapes,and incident angles.

Sequential quadratic programming-based non-cooperative target distributed hybrid processing optimization method

The distributed hybrid processing optimization problem of non-cooperative targets is an important research direction for future networked air-defense and anti-missile firepower systems. In this paper, the air-defense anti-missile targets defense problem is abstracted as a nonconvex constrained combinatorial optimization problem with the optimization objective of maximizing the degree of contribution of the processing scheme to non-cooperative targets, and the constraints mainly consider geographical conditions and anti-missile equipment resources. The grid discretization concept is used to partition the defense area into network nodes, and the overall defense strategy scheme is described as a nonlinear programming problem to solve the minimum defense cost within the maximum defense capability of the defense system network. In the solution of the minimum defense cost problem, the processing scheme, equipment coverage capability, constraints and node cost requirements are characterized, then a nonlinear mathematical model of the non-cooperative target distributed hybrid processing optimization problem is established, and a local optimal solution based on the sequential quadratic programming algorithm is constructed, and the optimal firepower processing scheme is given by using the sequential quadratic programming method containing non-convex quadratic equations and inequality constraints. Finally, the effectiveness of the proposed method is verified by simulation examples.

Subspace detection for range-spread target to suppress interference:exploiting persymmetry in non-homogeneous scenario

This paper deals with subspace detection for rangespread target in non-homogeneous clutter with unknown covariance matrix where structured interference is presented in the received data.Through exploiting the persymmetry of the clutter covariance matrix,we propose two adaptive target detectors,which are referred to as persymmetric subspace Rao to suppress interference and persymmetric subspace Wald to suppress interference("PS-Rao-I"and"PS-Wald-I"),respectively.The persymmetry-based design brings in the advantage of easy implementation for small training sample support.The signal flow analysis of the two detectors shows that the PS-Rao-I rejects interference and integrates signals successively through separated matrix projection,while the PS-Wald-I jointly achieves interference elimination and signal combination via oblique projection.In addition,both detectors are shown to be constant false alarm rate detectors,significantly improving the detection performance with other competing detectors under the condition of limited training.

Non-cooperative target pose estimation based on improved iterative closest point algorithm

For localisation of unknown non-cooperative targets in space,the existence of interference points causes inaccuracy of pose estimation while utilizing point cloud registration.To address this issue,this paper proposes a new iterative closest point(ICP)algorithm combined with distributed weights to intensify the dependability and robustness of the non-cooperative target localisation.As interference points in space have not yet been extensively studied,we classify them into two broad categories,far interference points and near interference points.For the former,the statistical outlier elimination algorithm is employed.For the latter,the Gaussian distributed weights,simultaneously valuing with the variation of the Euclidean distance from each point to the centroid,are commingled to the traditional ICP algorithm.In each iteration,the weight matrix W in connection with the overall localisation is obtained,and the singular value decomposition is adopted to accomplish high-precision estimation of the target pose.Finally,the experiments are implemented by shooting the satellite model and setting the position of interference points.The outcomes suggest that the proposed algorithm can effectively suppress interference points and enhance the accuracy of non-cooperative target pose estimation.When the interference point number reaches about 700,the average error of angle is superior to 0.88°.