Amplifying colorectal cancer progression: impact of a PDIA4/SP1 positive feedback loop by circPDIA4 sponging miR-9-5p

Objective:Colorectal cancer(CRC)is a prevalent malignant tumor with a high fatality rate.CircPDIA4 has been shown to have a vital role in cancer development by acting as a facilitator.Nevertheless,the impact of the circPDIA4/miR-9-5p/SP1 axis on development of CRC has not been studied.Methods:Western blot,immunohistochemistry,and reverse transcription-quantitative polymerase chain reaction assays were used to analyze gene expression.The CCK-8 assay was used to assess cell growth.The Transwell assay was used to detect invasion and migration of cells.The luciferase reporter and RNA immunoprecipitation tests were used to determine if miR-9-5p and circPDIA4(or SP1)bind to one another.An in vivo assay was used to measure tumor growth.Results:It was shown that circPDIA4 expression was greater in CRC cell lines and tissues than healthy cell lines and tissues.CircPDIA4 knockdown prevented the invasion,migration,and proliferation of cells in CRC.Additionally,the combination of circPDIA4 and miR-9-5p was confirmed,as well as miR-9-5p binding to SP1.Rescue experiments also showed that the circPDIA4/miR-9-5p/SP1 axis accelerated the development of CRC.In addition,SP1 combined with the promoter region of circPDIA4 and induced circPDIA4 transcription.CircPDIA4 was shown to facilitate tumor growth in an in vivo assay.Conclusions:The circPDIA4/miR-9-5p/SP1 feedback loop was shown to aggravate CRC progression.This finding suggests that the ceRNA axis may be a promising biomarker for CRC patient treatment.

Dynamics simulation of the belt conveyor possessing feedback loop during starting

Synthesizing the mechanical models of the belt, the driver and the take-up device, the dynamics model was established on the longitudinal vibration of the overall belt conveyor system with finite elemental method, and S-function simulation block of asynchronous motor owing feedback function was built in Matlab/Simulink software, the simulation block indicates that motor rotation speed and its output moment vary with load and time, and the motor is a dynamic feedback system in working process. The state space block was adopted to express model of the belt. Thus it created simulation model of established dynamic model of overall belt conveyor system with Mat- lab/Simulink software, and simulates the course of starting by properly setting simulation parameters, and processes data for visualization.

Stochastic Resonance in a Bistable System with Time-Delayed Feedback Loops

The phenomenon of stochastic resonance of a bistable system subjected to linear time-delayed feedback loops driven by multiplieative Gaussian coloured noise and additive Gaussian white noise is investigated. Firstly, the analytic expression of the quasi-steady distribution function Ps （x, t） is derived by applying the unified coloured noise approximation and the Novikov Theorem; Secondly, the expression of the signal-to-noise ratio （SNR） is obtained in the adiabatic limit to quantify the stochastic resonance. Finally, tile effects of the linear coefficient a, the nonlinear coefficient b, the linear time-delayed feedback coefficient c and the delay time r on Ps（x,t） and SNR^± are discussed. It is found that the effects of the linear coefficient and the nonlinear coefficient, the positive linear time-delayed feedback coefficient and the negative linear time-delayed feedback coefficient, the positive delayed time and the negative delayed time on Ps（x,t） and SNR^± are different, respectively. This discussion would be helpful to the study of the system reliability and controlling stochastic resonance.

Accelerating the Feedback Loop in Scanning Probe Microscopes without Loss of Height Measurement Accuracy by Using Pixel Forecast Methods

Scanning probe microscopes (SPM) are limited in their speed of data acquisition by the mechanical stability of the scanner. Therefore many types of scanners have been developed to achieve a rigid setup while maintaining an acceptable image size. We have followed here a different path to accelerate data acquisition by improving the feedback loop to achieve the same SPM image quality in a shorter time. While the feedback loop in a scanning probe microscope typically starts to probe a new pixel starting from the previous position, we have reduced the total control time by using an improved starting point for the feedback loop at each pixel. By exploiting the information of the already scanned pixels a forecast for the new pixel is created. We have successfully used several simple methods for a prognosis in MATLAB simulations like one dimensional linear or cubic extrapolation and others. Only scanning tunnelling microscope data from real experiments were used to test the forecasts. A doubling of the speed was achieved in the most favourable cases.

A warm temperature-released negative feedback loop fine-tunes PIF4-mediated thermomorphogenesis in Arabidopsis

Plants can sense temperature changes and adjust their growth accordingly.In Arabidopsis,high ambient temperatures stimulate stem elongation by activating a key thermoresponsive regulator,PHYTOCHROME INTERACTING FACTOR 4(PIF4).Here,we show that warmth promotes the nighttime transcription of GI,which is necessary for the high temperature-induced transcription of TOC1.Genetic analyses suggest that GI prevents excessive thermoresponsive growth by inhibiting PIF4,with this regulatory mechanism be-ing partially reliant on TOC1.GI transcription is repressed by ELF3 and HY5,which concurrently inhibit PIF4 expression and activity.Temperature elevation causes the deactivation or degradation of ELF3 and HY5,leading to PIF4 activation and relief of GI transcriptional repression at high temperatures.This allows PIF4 to further activate GI transcription in response to elevated temperatures.GI,in turn,inhibits PIF4,es-tablishing a negative feedback loop thatfine-tunes PIF4 activity.In addition,we demonstrate that ELF3,HY5,and PIF4 regulate GI transcription by modulating the enrichment of histone variant H2A.Z at the GI lo-cus.Together,ourfindings suggest that thermal release of a negative feedback loopfinely adjusts plant thermomorphogenesis.

A positive feedback loop between PLD1 and NF-κB signaling promotes tumorigenesis of nasopharyngeal carcinoma

Phospholipase D(PLD)lipid-signaling enzyme superfamily has been widely implicated in various human malignancies,but its role and underlying mechanism remain unclear in nasopharyngeal carcinoma(NPC).Here,we analyze the expressions of 6 PLD family members between 87 NPC and 10 control samples through transcriptome analysis.Our findings reveal a notable upregulation of PLD1 in both NPC tumors and cell lines,correlating with worse disease-free and overall survival in NPC patients.Functional assays further elucidate the oncogenic role of PLD1,demonstrating its pivotal promotion of critical tumorigenic processes such as cellproliferation and migration in vitro,as well as tumor growth in vivo.Notably,our study uncovers a positive feedback loop between PLD1 and the NF-κB signaling pathway to render NPC progression.Specifically,PLD1 enhances NF-kB activity by facilitating the phosphorylation and nuclear translocation of RELA,which in turn binds to the promoter of PLD1,augmenting its expression.Moreover,RELA over-expression markedly rescues the inhibitory effects in PLD1-depleted NPC cells.Importantly,the application of the PLD1 inhibitor,VU0155069,substantially inhibits NPC tumorigenesis in a patient-derived xenograft model.Together,our findings identify PLD1/NF-κB signaling as a positive feedback loop with promising therapeutic and prognostic potential in NPC.

The anti-neoplastic activities of aloperine in HeLa cervical cancer cells are associated with inhibition of the IL-6-JAK1-STAT3 feedback loop

Cervical cancer(CC)is recognized as the most common neoplasm in the female reproductive system worldwide.The lack of chemotherapeutic agents with outstanding effectiveness and safety severely compromises the anti-cipated prognosis of patients.Aloperine(ALO)is a natural quinolizidine alkaloid with marked anti-cancer effects on multiple malignancies as well as favorable activity in relieving inflammation,allergies and infection.However,its therapeutic efficacy and underlying mechanism in CC are still unclear.In the current study,MTT assay was employed to evaluate the viability of HeLa cells exposed to ALO to preliminarily estimate the effectiveness of ALO in CC.Then,the effects of ALO on the proliferation and apoptosis of HeLa cells were further investigated by plate colony formation and flow cytometry,respectively,while the migration and invasion of ALO-treated HeLa cells were evaluated using Transwell assay.Moreover,nude mice were subcutaneously inoculated with HeLa cells to demonstrate the anti-CC properties of ALO in vivo.The molecular mechanisms underlying these effects of ALO were evaluated by Western blot and immunohistochemical analysis.This study experimentally demonstrated that ALO inhibited the proliferation of HeLa cells via G2 phase cell cycle arrest.Simultaneously,ALO promoted an increase in the percentage of apoptotic HeLa cells by increasing the Bax/Bcl-2 ratio.Additionally,the migration and invasion of HeLa cells were attenuated by ALO treatment,which was considered to result from inhibition of epithelial-to-mesenchymal transition.For molecular mechanisms,the expression and activation of the IL-6-JAK1-STAT3 feedback loop were markedly suppressed by ALO treatment.This study indicated that ALO markedly suppresses the proliferation,migration and invasion and enhances the apoptosis of HeLa cells.In addition,these prominent anti-CC properties of ALO are associated with repression of the IL-6-JAK1-STAT3 feedback loop.

PLEK2 promotes cancer stemness and tumorigenesis of head and neck squamous cell carcinoma via the c-Myc-mediated positive feedback loop

Background:Head and neck squamous cell carcinoma(HNSCC)is one of the most frequent malignancies worldwide and is characterized by unfavorable prognosis,high lymph node metastasis and early recurrence.However,the molecular events regulating HNSCC tumorigenesis remain poorly understood.Therefore,uncovering the underlying mechanisms is urgently needed to identify novel and promising therapeutic targets for HNSCC.In this study,we aimed to explore the role of pleckstrin-2(PLEK2)in regulating HNSCC tumorigenesis.Methods:The expression pattern of PLEK2 and its clinical significance in HNSCC were determined by analyzing publicly assessable datasets and our own independent HNSCC cohort.In vitro and in vivo experiments,including cell proliferation,colony formation,Matrigel invasion,tumor sphere formation,ALDEFLUOR,Western blotting assays and xenograft mouse models,were used to investigate the role of PLEK2 in regulating the malignant behaviors of HNSCC cells.The underlying molecular mechanisms for the tumor-promoting role of PLEK2 were elucidated using co-immunoprecipitation,cycloheximide chase analysis,ubiquitination assays,chromatin immunoprecipitation-quantitative polymerase chain reaction,luciferase reporter assays and rescue experiments.Results:The expression levels of PLEK2 mRNA and protein were significantly increased in HNSCC tissues,and PLEK2 overexpression was strongly associated with poor overall survival and therapeutic resistance.Additionally,PLEK2 was important for maintaining the proliferation,invasion,epithelial-mesenchymal transition,cancer stemness and tumorigenesis of HNSCC cells and could alter the cellular metabolism of the cancer cells.Mechanistically,PLEK2 interacted with c-Myc and reduced the association of F-box and WD repeat domain containing 7(FBXW7)with c-Myc,thereby avoiding ubiquitination and subsequent proteasome-mediated degradation of c-Myc.Moreover,the c-Myc signaling activated by PLEK2 was important for sustaining the aggressive malignant phenotypes and tumorigenesis of HNSCC cells.c-Myc also directly bounded to the PLEK2 promoter and activated its transcription,forming a positive feedback loop.Conclusions:Collectively,these findings uncover a previously unknown molecular basis of PLEK2-enhanced c-Myc signaling in HNSCC,suggesting that PLEK2 may represent a promising therapeutic target for treating HNSCC.

Meiotic nuclear divisions 1(MND1)fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma

Background:Considering the increase in the proportion of lung adenocarcinoma(LUAD)cases among all lung cancers and its considerable contribution to cancer-related deaths worldwide,we sought to identify novel oncogenes to provide potential targets and facilitate a better understanding of the malignant progression of LUAD.Methods:The results from the screening of transcriptome and survival analyses according to the integrated Gene Expression Omnibus(GEO)datasets and The Cancer Genome Atlas(TCGA)data were combined,and a promising risk biomarker called meiotic nuclear divisions 1(MND1)was selectively acquired.Cell viability assays and subcutaneous xenograftmodelswere used to validate the oncogenic role ofMND1 in LUADcell proliferation and tumor growth.Aseries of assays,including mass spectrometry,co-immunoprecipitation(Co-IP),and chromatin immunoprecipitation(ChIP),were performed to explore the underlying mechanism.Results:MND1 up-regulation was identified to be an independent risk factor for overall survival in LUAD patients evaluated by both tissue microarray staining and third party data analysis.In vivo and in vitro assays showed that MND1 promoted LUAD cell proliferation by regulating cell cycle.The results of the Co-IP,ChIP and dual-luciferase reporter assays validated that MND1 competitively bound to tumor suppressor Kruppel-like factor 6(KLF6),and thereby protecting E2F transcription factor 1(E2F1)from KLF6-induced transcriptional repression.Luciferase reporter and ChIP assays found that E2F1 activated MND1 transcription by binding to its promoter in a feedback manner.Conclusions:MND1,KLF6,and E2F1 form a positive feedback loop to regulate cell cycle and confer DDP resistance in LUAD.MND1 is crucial for malignant progression and may be a potential therapeutic target in LUAD patients.

The repression of oncoprotein SET by the tumor suppressor p53 reveals a p53-SET-PP2A feedback loop for cancer therapy

The oncoprotein SET is frequently overexpressed in many types of tumors and contributes to malignant initiation and progression through multiple mechanisms,including the hijacking of the tumor suppressors p53 and PP2A.Targeting aberrant SET represents a promising strategy for cancer intervention.However,the mechanism by which endogenous SET is regulated in cancer cells remains largely unknown.Here,we identified the tumor suppressor p53 as a key regulator that transcriptionally repressed the expression of SET in both normal and cancer cells.In addition,p53 stimulated PP2A phosphatase activity via p53-mediated transcriptional repression of SET,whereby SET-mediated inhibition of PP2A was alleviated.Moreover,targeting the interaction between SET and PP2A catalytic subunit(PP2Ac)with FTY720 enhanced stress-induced p53 activation via PP2A-mediated dephosphorylation of p53 on threonine 55(Thr55).Therefore,our findings uncovered a previously unknown p53-SETPP2A regulatory feedback loop.To functionally potentiate this feedback loop,we designed a combined therapeutic strategy by simultaneously administrating a p53 activator and SET antagonist in cancer cells and observed a dramatic synergistic effect on tumor suppression.Our study reveals mechanistic insight into the regulation of the oncoprotein SET and raises a potential strategy for cancer therapy by stimulating the p53-SET-PP2A feedback loop.

An HGF-dependent positive feedback loop between bladder cancer cells and fibroblasts mediates lymphangiogenesis and lymphatic metastasis

Background Cancer-associated fibroblasts (CAFs) play a vital role in facilitating tumor progression through extensive reciprocal interplay with cancer cells. Tumor-derived extracellular vesicles (EVs) are the critical mediators involved in the crosstalk between cancer cells and stromal cells, contributing to the metastasis of cancers. Yet, the biological mechanisms of tumor-derived EVs in triggering CAFs phenotype to stimulate the lymph node (LN) metastasis of bladder cancer (BCa) are largely unknown. Here, we aimed to explore the effects and molecular mechanisms of tumor-derived EV-mediated CAFs phenotype in regulating BCa LN metastasis. Methods The high-throughput sequencing was utilized to identify the crucial long non-coding RNA (lncRNA) associated with CAF enrichment in BCa. The functional role of the transition of fibroblasts to CAFs induced by LINC00665-mediated EVs was investigated through the in vitro and in vivo assays. Chromatin isolation by RNA purification assays, fluorescence resonance energy transfer assays, cytokine profiling and patient-derived xenograft (PDX) model were performed to explore the underlying mechanism of LINC00665 in the LN metastasis of BCa. Results We found that CAFs are widely enriched in the tumor microenvironment of BCa, which correlated with BCa lymphangiogenesis and LN metastasis. We then identified a CAF-associated long non-coding RNA, LINC00665, which acted as a crucial mediator of CAF infiltration in BCa. Clinically, LINC00665 was associated with LN metastasis and poor prognosis in patients with BCa. Mechanistically, LINC00665 transcriptionally upregulated RAB27B expression and induced H3K4me3 modification on the promoter of RAB27B through the recruitment of hnRNPL. Moreover, RAB27B-induced EVs secretion endowed fibroblasts with the CAF phenotype, which reciprocally induced LINC00665 overexpression to form a RAB27B-HGF-c-Myc positive feedback loop, enhancing the lymphangiogenesis and LN metastasis of BCa. Importantly, we demonstrated that blocking EV-transmitted LINC00665 or HGF broke this loop and impaired BCa lymphangiogenesis in a PDX model. Conclusion Our study uncovers a precise mechanism that LINC00665 sustains BCa LN metastasis by inducing a RAB27B-HGF-c-Myc positive feedback loop between BCa cells and fibroblasts, suggesting that LINC00665 could be a promising therapeutic target for patients with LN metastatic BCa.

A Pd1-Ps-P1 Feedback Loop Controls Pubescence Density in Soybean

Trichomes are universally present in plants and their development is delicately regulated.Trichomes are responsible for pubescence,whose density is associated with some agronomic traits such as insect resis-tance,evapotranspiration,and yield.Almost a century ago,three dominant alleles related to pubescence density in soybean,namely Pd1(dense pubescence),Ps(sparse pubescence),and P1(glabrous),were iden-tified.However,their molecular identity and genetic relationships remain unclear.In this study,through a genome-wide association study and map-based cloning,we determined the genetic basis of these three traits.The sparse-pubescence phenotype of Ps was attributed to a copy-number variation of a 25.6-kb sequence that includes a gene encoding a protein with WD40 and RING domains.The dense-pubescence phenotype of Pd1 was attributed to a T-C transition in the last exon of an HD-Zip transcription factor gene,and the glabrous phenotype of P1 was caused by a G-A transition in the first exon of a lipid transfer protein gene.Genetic and biochemical analyses revealed that Pd1 functions as a transcriptional activator that can bind the promoters of the P1 and Ps genes to induce their expression;Interestingly,Pd1 can also bind its own promoter and inhibit its gene transcription.In addition,Ps can interact with Pd1 and weaken the tran-scriptional activity of Pd1.Taken together,our results demonstrate that Pd1,Ps,and P1 form a complex feedback loop to regulate pubescence formation in soybean.

All-Optical WDM Buffer System Realized by NOLM and Feedback Loop Structure

We propose an all-optical WDM buffer for optical packet switching system, which consists of NOLM and feedback loop. The proposed structure provides more than 40 turn buffering and nice output of buffered data when selected by control signal.

Dual loop feedback pre-distortion in satellite communication

Since the satellite communication goes in the trend of high-frequency and fast speed, the coefficients updating and the precision of the traditional pre-distortion feedback methods need to be further improved. On this basis, this paper proposes dual loop feedback pre-distortion, which uses two first-order Volterra filter models to reduce the computing complexity and a dynamic error adjustment model to construct a revised feedback to ensure a better pre-distortion performance. The computation complexity, iterative convergence speed and precision of the proposed method are theoretically analyzed. Simulation results show that this dual loop feedback pre-distortion can speed the updating of coefficients and ensure the linearity of the amplifier output.

Accuracy Compensation Technology of Closed⁃Loop Feedback of Industrial Robot Joints

The existing kinematic parameter calibration method cannot further improve the absolute positioning accuracy of the robot due to the uncertainty of positioning error caused by robot joint backlash.In view of this problem,a closed‑loop feedback accuracy compensation method for robot joints was proposed.Firstly,a Chebyshev polynomial error estimation model was established which took geometric error and non‑geometric error into account.In addition,the absolute linear grating scale was installed at each joint of the robot and the positioning error of the robot end was mapped to the joint angle.And the joint angle corrected value was obtained.Furthermore,the closed‑loop feedback of robot joints was established to realize the online correction of the positioning error.Finally,an experiment on the KUKA KR210 industrial robot was conducted to demonstrate the effectiveness of the method.The result shows that the maximum absolute positioning error of the robot is reduced by 75%from 0.76 mm to 0.19 mm.This method can compensate the robot joint backlash effectively and further improve the absolute positioning accuracy of the robot.

Reliability Analysis on Repairable System with Dual Input Closed-Loop Feedback Link Considering Shutdown Correlation Based on Goal Oriented Methodology

Goal oriented( GO) methodology is a kind of success oriented system reliability analysis method and has been used widely.The repairable system with dual input closed-loop feedback link( DICLFL) considering shutdown correlation didn't make reliability analysis accurately based on existing GO methodology. So, a reliability analysis method used to deal with DICLFL considering shutdown correlation is provided based on GO methodology.Firstly, a new operator, which is used to describe DICLFL considering shutdown correlation,whose number is 1,is created and named as Type 9C operator. And then,the formulas of type 9C operator are derived based on Markov process theory. Finally,the new method presented in this paper is adopted to conduct the reliability analysis of an electro-hydraulic servo speed control system. The analysis result is compared with those of Monte Carlo simulation and fault tree analysis( FTA). The comparison results show that this new reliability analysis method based on GO methodology is feasible and meaningful for reliability analysis of repairable systems with DICLFL considering shutdown correlation.Meantime,it will be useful for more other applications.

Control of Spiral Waves in an Excitable Medium by Applying Close Loop Feedback Scheme

In this paper, a scheme of close-loop feedback is proposed to induce transition of spiral pattern in the excitable media, which is described with the modified FitzHugh-Nagumo model. The numerical simulation results confirm that the stable rotating spiral wave is removed and the whole media becomes homogeneous when appropriate intensity of feedback is used no matter whether the coupling feedback is imposed on the whole media or the sites in one line in the media.

基于非负稀疏编码的位置细胞反馈环路学习模型

为了探究大脑导航编码的神经机制,聚焦内嗅皮层与海马体之间的神经连接进行模型研究。生理学证据显示,内嗅皮层与海马体之间存在显著的反馈回路连接,两者的空间编码细胞在导航行为中表现出高度关联性。基于这一基础,建立了反馈循环网络模型,将内嗅皮层的栅格细胞与弱空间细胞作为网络输入,连接到海马体的位置细胞与颗粒细胞,并采用非负稀疏编码进行学习。实验结果表明:该反馈学习模型可以快速捕获细胞的空间调谐特性,仅使用弱空间细胞作为输入,也可以通过反馈环路学习到海马位置细胞对空间的单峰选择性,说明反馈编码机制在优化空间表示中发挥着关键作用。总之,该模型可能是大脑导航系统生成精确空间编码的重要细胞机制之一。

Analysis and improvement of missile three-loop autopilots

The non-minimum phase feature of tail-controlled missile airframes is analyzed. Three selection strategies for desired performance indexes are presented. An acceleration autopilot design methodology based on output feedback and optimization is proposed. Performance and robustness comparisons between the two-loop and classical three-loop topologies are made. Attempts to improve the classical three-loop topology are discussed. Despite the same open-loop structure, the classical three-loop autopilot shows distinct characteristics from a two-loop autopilot with PI compensator. Both the two-loop and three-loop topologies can stabilize a static unstable missile. However, the finite actuator resource is the crucial factor dominating autopilot function.