Interleukin-7 （IL-7） is an essential cytokine for the development and homeostatic maintenance of T and B lymphocytes. Binding of IL-7 to its cognate receptor, the IL-7 receptor （IL-7R）, activates multiple pathways...Interleukin-7 （IL-7） is an essential cytokine for the development and homeostatic maintenance of T and B lymphocytes. Binding of IL-7 to its cognate receptor, the IL-7 receptor （IL-7R）, activates multiple pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation. There has been much interest in understanding how IL-7 receptor signaling is modulated at multiple interconnected network levels. This review examines how the strength of the signal through the IL-7 receptor is modulated in T and B cells, including the use of shared receptor components, signaling crosstalk, shared interaction domains, feedback loops, integrated gene regulation, multimerization and ligand competition. We discuss how these network control mechanisms could integrate to govern the properties of IL-7R signaling in lymphocytes in health and disease. Analysis of IL-7 receptor signaling at a network level in a systematic manner will allow for a comprehensive approach to understanding the impact of multiple signaling pathways on lymphocyte biology. Cellular ＆ Molecular Immunology.展开更多
As sessile organisms plants must ronmental conditions. To survive cope with ever changing enviplants have evolved elaborate mechanisms to perceive and rapidly respond to a diverse range of abiotic and biotic stresses....As sessile organisms plants must ronmental conditions. To survive cope with ever changing enviplants have evolved elaborate mechanisms to perceive and rapidly respond to a diverse range of abiotic and biotic stresses. Central to this response is the ability to modulate gene expression at both the transcriptional and posttranscriptional levels. This review will focus on recent progress that has been made towards understanding the rapid reprogramming of the transcriptome that occurs in response to stress as well as emerging mechanisms underpinning the reprogramming of gene expression in response to stress,展开更多
Apoptosis and hypertrophy of cardiomyocytes are the primary causes of heart failure （HF）, a global leading cause of death, and are regulated through the complicated intracellular signaling network, limiting the deve...Apoptosis and hypertrophy of cardiomyocytes are the primary causes of heart failure （HF）, a global leading cause of death, and are regulated through the complicated intracellular signaling network, limiting the development of effective treatments due to its complexity. To identify effective therapeutic strategies for HF at a system level, we develop a large-scale comprehensive mathematical model of the cardiac signaling network by integrating all available experimental evidence. Attractor landscape analysis of the network model identifies distinct sets of control nodes that effectively suppress apoptosis and hypertrophy of cardiomyocytes under ischemic or pressure overload-induced HF, the two major types of HF. Intriguingly, our system-level analysis suggests that intervention of these control nodes may increase the efficacy of clinical drugs for HF and, of most importance, different combinations of control nodes are suggested as potentially effective candidate drug targets depending on the types of HF. Our study provides a systematic way of developing mechanism-based therapeutic strategies for HF.展开更多
Protein kinases and phosphatases signal by phosphorylation and dephosphorylation to precisely control the activities of their individual and common substrates for a coordinated cellular outcome. In many situations, a ...Protein kinases and phosphatases signal by phosphorylation and dephosphorylation to precisely control the activities of their individual and common substrates for a coordinated cellular outcome. In many situations, a kinase/phosphatase complex signals dynamically in time and space through their reciprocal regulations and their cooperative actions on a substrate. This complex may be essential for malignant transformation and progression and can therefore be considered as a target for therapeutic intervention. p38γ is a unique MAPK family member that contains a PDZ motif at its C-terminus and interacts with a PDZ domain-containing protein tyrosine phosphatase PTPH1. This PDZcoupled binding is required for both PTPH1 dephosphorylation and inactivation of p38γ and for p38γ phosphorylation and activation of PTPH1. Moreover, the p38γ/PTPH1 complex can further regulate their substrates phosphorylation and dephosphorylation, which impacts Ras transformation, malignant growth and progression, and therapeutic response. This review will use the p38γ/PTPH1 signaling network as an example to discuss the potential of targeting the kinase/phosphatase signaling complex for development of novel targeted cancer therapy.展开更多
Background:Mass cytometry(CyTOF)gives unprecedented opportunity to simultaneously measure up to 40 proteins in single cells,with a theoretical potential to reach 100 proteins.This high-dimensional single-cell informat...Background:Mass cytometry(CyTOF)gives unprecedented opportunity to simultaneously measure up to 40 proteins in single cells,with a theoretical potential to reach 100 proteins.This high-dimensional single-cell information can be very useful in dissecting mechanisms of cellular activity.In particular,measuring abundances of signaling proteins like phospho-proteins can provide detailed information on the dynamics of single-cell signaling processes.However,computational analysis is required to reconstruct such networks with a mechanistic model.Methods:We propose our Mass cytometry Signaling Network Analysis Code(McSNAC),a new software capable of reconstructing signaling networks and estimating their kinetic parameters from CyTOF data.McSNAC approximates signaling networks as a network of first-order reactions between proteins.This assumption often breaks down as signaling reactions can involve binding and unbinding,enzymatic reactions,and other nonlinear constructions.Furthermore,McSNAC may be limited to approximating indirect interactions between protein species,as cytometry experiments are only able to assay a small fraction of protein species involved in signaling.Results:We carry out a series of in silico experiments here to show(1)McSNAC is capable of accurately estimating the ground-truth model in a scalable manner when given data originating from a first-order system;(2)McSNAC is capable of qualitatively predicting outcomes to perturbations of species abundances in simple second-order reaction models and in a complex in silico nonlinear signaling network in which some proteins are unmeasured.Conclusions:These findings demonstrate that McSNAC can be a valuable screening tool for generating models of signaling networks from time-stamped CyTOF data.展开更多
To understand the organization of the biological networks that might potentially govern the pathogenesis of hormone refractory prostate cancer （HRPC）, we investigated the transcriptional circuitry and signaling in a...To understand the organization of the biological networks that might potentially govern the pathogenesis of hormone refractory prostate cancer （HRPC）, we investigated the transcriptional circuitry and signaling in androgen-dependent 22Rvl and MDA PCa 2b cells, androgen- and estrogen-dependent LNCaP cells, and androgen-independent DU 145 and PC-3 prostate cancer （PCa） cell lines. We used microarray analyses, quantitative real-time PCR, pathway prediction analyses, and determination of Transcription Factor Binding Site （TFBS） signatures to dissect HRPC regulatory networks. We generated graphical representations of global topology and local network motifs that might be important in prostate carcinogenesis. Many important putative biomarker ＇target hubs＇ were identified in the current study including AP-1, NF-KB, EGFR, ERK1/2, JNK, p38 MAPK, TGF beta, VEGF, PDGF, CD44, Akt, PI3K, NOTCH1, CASP1, MMP2 and AR. Our results suggest that complex cellular events including autoregulation, feedback loops and cross-talk might govern progression from early lesion to clinically diagnosed PCa, as well as metastatic potential of pre-existent high-grade prostate intraepithelial neoplasia （HG-PIN） and/or advancement to HRPC. The identification of TFBS signatures for TCF/LEF, SOX9 and ELK1 in the regulatory elements suggests additional biomarkers for the potential development of chemopreventive/therapeutic strategies against PCa. Taken together, in this study, we have identified putative biomarker ＇target hubs＇ in the architecture of PCa signaling networks, and investigated TFBS signatures that might enhance our understanding of key regulatory nodes in the progression and pathogenesis of HRPC.展开更多
Inferring causal protein signalling networks from human immune system cell data is a promising approach to unravel the underlying tissue signalling biology and dysfunction in diseased cells,which has attracted conside...Inferring causal protein signalling networks from human immune system cell data is a promising approach to unravel the underlying tissue signalling biology and dysfunction in diseased cells,which has attracted considerable attention within the bioinformatics field.Recently,Bayesian network(BN)techniques have gained significant popularity in inferring causal protein signalling networks from multiparameter single-cell data.However,current BN methods may exhibit high computational complexity and ignore interactions among protein signalling molecules from different single cells.A novel BN method is presented for learning causal protein signalling networks based on parallel discrete artificial bee colony(PDABC),named PDABC.Specifically,PDABC is a score-based BN method that utilises the parallel artificial bee colony to search for the global optimal causal protein signalling networks with the highest discrete K2 metric.The experimental results on several simulated datasets,as well as a previously published multi-parameter fluorescence-activated cell sorter dataset,indicate that PDABC surpasses the existing state-of-the-art methods in terms of performance and computational efficiency.展开更多
Overview of the DNA damage response(DDR)in tumor cells.DDR is a highly coordinated signaling network that repairs DNA damage caused by intrinsic cellular processes and extrinsic insults,thereby preventing genome insta...Overview of the DNA damage response(DDR)in tumor cells.DDR is a highly coordinated signaling network that repairs DNA damage caused by intrinsic cellular processes and extrinsic insults,thereby preventing genome instability.Depending on the type of damage,distinct DNA damage repair and DNA damage tolerance(DDT)pathways are involved and coordinately regulated.展开更多
Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum （ER）. One of the primary mechanisms is the unfolded protein response （UPR）. In this review, we primarily focus on the ...Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum （ER）. One of the primary mechanisms is the unfolded protein response （UPR）. In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein （BiP） interacts with the three sensors （protein kinase RNA-like ER kinase （PERK）, activating transcription factor 6 （ATF6）, and inositol-requiring enzyme la （IREla）） Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor （VEGF）-VEGF receptor （VEGFR）-phospholipase C-~ （PLCy）-mammalian target of rapamycin complex 1 （mTORC1） pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IREla also can be activated by activated RAC-alpha serine/threonine-protein kinase （AKT）. A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species （ROS）, Ca2＋ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase （JNK）, signal transducer and activator of transcription 3 （STAT3）, and P38, when cellular damage exceeds the capacity of this adaptive response.展开更多
We present a staggered buffer connection method that provides flexibility for buffer insertion while designing global signal networks using the tile-based FPGA design methodology. An exhaustive algorithm is used to an...We present a staggered buffer connection method that provides flexibility for buffer insertion while designing global signal networks using the tile-based FPGA design methodology. An exhaustive algorithm is used to analyze the trade-off between area and speed of the global signal networks for this staggered buffer insertion scheme, and the criterion for determining the design parameters is presented. The comparative analytic result shows that the methods in this paper are proven to be more efficient for FPGAs with a large array size.展开更多
An signal noise ratio（ SNR） adaptive sorting algorithm using the time-frequency（ TF）sparsity of frequency-hopping（ FH） signal is proposed in this paper. Firstly,the Gabor transformation is used as TF transformat...An signal noise ratio（ SNR） adaptive sorting algorithm using the time-frequency（ TF）sparsity of frequency-hopping（ FH） signal is proposed in this paper. Firstly,the Gabor transformation is used as TF transformation in the system and a sorting model is established under undetermined condition; then the SNR adaptive pivot threshold setting method is used to find the TF single source. The mixed matrix is estimated according to the TF matrix of single source. Lastly,signal sorting is realized through improved subspace projection combined with relative power deviation of source. Theoretical analysis and simulation results showthat this algorithm has good effectiveness and performance.展开更多
There are various heterogeneous networks for terminals to deliver a better quality of service. Signal system recognition and classification contribute a lot to the process. However, in low signal to noise ratio（SNR）...There are various heterogeneous networks for terminals to deliver a better quality of service. Signal system recognition and classification contribute a lot to the process. However, in low signal to noise ratio（SNR） circumstances or under time-varying multipath channels, the majority of the existing algorithms for signal recognition are already facing limitations. In this series, we present a robust signal recognition method based upon the original and latest updated version of the extreme learning machine（ELM） to help users to switch between networks. The ELM utilizes signal characteristics to distinguish systems. The superiority of this algorithm lies in the random choices of hidden nodes and in the fact that it determines the output weights analytically, which result in lower complexity. Theoretically, the algorithm tends to offer a good generalization performance at an extremely fast speed of learning. Moreover, we implement the GSM/WCDMA/LTE models in the Matlab environment by using the Simulink tools. The simulations reveal that the signals can be recognized successfully to achieve a 95% accuracy in a low SNR（0 dB） environment in the time-varying multipath Rayleigh fading channel.展开更多
Phosphate(Pi)is an essential nutrient for plant growth and development,playing a critical role in key biological processes such as energy metabolism,nucleic acid synthesis,and cellular signaling(Wang et al.,2021;Zhang...Phosphate(Pi)is an essential nutrient for plant growth and development,playing a critical role in key biological processes such as energy metabolism,nucleic acid synthesis,and cellular signaling(Wang et al.,2021;Zhang et al.,2023;Yang et al.,2024).Due to the limited availability and poor accessibility of Pi in soil,plants have evolved complex signaling networks to sense and respond to Pi availability,ensuring the maintenance of normal physiological functions under low-Pi conditions(Wild et al.,2016;Wang et al.,2025).Within this signaling network,inositol pyrophosphates(PP-InsPs),products under Pi repletion,serve as critical signaling molecules in plant cells.When intracellular Pi is sufficient,PP-InsPs bind to SPX-domain proteins,inhibiting the activity of Pi starvation-response transcription factors(PHRs)and thereby suppressing the expression of Pi starvation-related genes.Conversely,PP-InsP levels decrease under Pi-deficient conditions,preventing SPX proteins from inhibiting PHRs(Wild et al.,2016).This results in the activation of PHRs and the initiation of Pi starvation responses,promoting Pi uptake and recycling.This mechanism helps plants to maintain Pi homeostasis in low-Pi environments.展开更多
Online traffic simulation that feeds from online information to simulate vehicle movement in real-time has recently seen substantial advancement in the development of intelligent transportation systems and urban traff...Online traffic simulation that feeds from online information to simulate vehicle movement in real-time has recently seen substantial advancement in the development of intelligent transportation systems and urban traffic management.It has been a challenging problem due to three aspects:1)The diversity of traffic patterns due to heterogeneous layouts of urban intersections;2)The nature of complex spatiotemporal correlations;3)The requirement of dynamically adjusting the parameters of traffic models in a real-time system.To cater to these challenges,this paper proposes an online traffic simulation framework called automated urban traffic operation simulation via meta-learning(AUTOSIM).In particular,simulation models with various intersection layouts are automatically generated using an open-source simulation tool based on static traffic geometry attributes.Through a meta-learning technique,AUTOSIM enables an automated learning process for dynamic model settings of traffic scenarios featured with different spatiotemporal correlations.Besides,AUTOSIM is capable of adapting traffic model parameters according to dynamic traffic information in real-time by using a meta-learner.Through computational experiments,we demonstrate the effectiveness of the meta-learningbased framework that is capable of providing reliable supports to real-time traffic simulation and dynamic traffic operations.展开更多
Studies on cell signaling pay more attention to spatial dynamics and how such diverse organization can relate to high order of cellular capabilities.To overview the specificity of cell signaling,we integrated human re...Studies on cell signaling pay more attention to spatial dynamics and how such diverse organization can relate to high order of cellular capabilities.To overview the specificity of cell signaling,we integrated human receptome data with proteome spatial expression profiles to systematically investigate the specificity of receptors and receptor-triggered transduction networks across 62 normal cell types and 14 cancer types.Six percent receptors showed cell-type-specific expression,and 4% signaling networks presented enriched cell-specific proteins induced by the receptors.We introduced a concept of“response context”to annotate the cell-type dependent signaling networks.We found that most cells respond similarly to the same stimulus,as the“response contexts”presented high functional similarity.Despite this,the subtle spatial diversity can be observed from the difference in network architectures.The architecture of the signaling networks in nerve cells displayed less completeness than that in glandular cells,which indicated cellular-context dependent signaling patterns are elaborately spatially organized.Likewise,in cancer cells most signaling networks were generally dysfunctional and less complete than that in normal cells.However,glioma emerged hyper-activated transduction mechanism in malignant state.Receptor ATP6AP2 and TNFRSF21 induced rennin-angiotensin and apoptosis signaling were found likely to explain the glioma-specific mechanism.This work represents an effort to decipher context-specific signaling network from spatial dimension.Our results indicated that although a majority of cells engage general signaling response with subtle differences,the spatial dynamics of cell signaling can not only deepen our insights into different signaling mechanisms,but also help understand cell signaling in disease.展开更多
The inter-cellular translocation of nutrients in plant is mediated by highly specialized transfer cells （TCs）. TCs share similar functional and structural features across a wide range of plant species, including loc...The inter-cellular translocation of nutrients in plant is mediated by highly specialized transfer cells （TCs）. TCs share similar functional and structural features across a wide range of plant species, including location at plant exchange surfaces, rich in secondary wall ingrowths, facilitation of nutrient flow, and passage of select molecules. The fate of endosperm TCs is determined in the TC fate acquisition stage （TCF）, before the structure features are formed in the TC differentiation stage （TCD）. At present, the molecular basis of TC development in plants remains largely unknown. In this review, we summarize the important roles of the signaling molecules in different development phases, such as sugars in TCF and phytohormones in TCD, and discuss the genetic and epigenetic factors, including TC-specific genes and endogenous plant peptides, and their crosstalk with these signaling molecules as a complex regulatory network in regulation of TC develonment in olants.展开更多
Plants activate complex signaling networks in response to pathogen attacks,orchestrating defense responses both locally and in distant and systemic tissues.The systemic activation of plant immunity,termed systemic acq...Plants activate complex signaling networks in response to pathogen attacks,orchestrating defense responses both locally and in distant and systemic tissues.The systemic activation of plant immunity,termed systemic acquired resistance(SAR),was first observed in the 1960s in tobacco plants infected with the tobacco mosaic virus.A defining feature of SAR is the accumulation of pathogenesis-related(PR)proteins,are sometimes also referred to as the molecular markers for this process(Durrant and Dong,2004).展开更多
The roles of Rho family guanosine triphosphatases(GTPases)of plants(ROPs)in modulating plant growth and development have been well characterized.However,little is known about the roles of ROP signaling pathways in reg...The roles of Rho family guanosine triphosphatases(GTPases)of plants(ROPs)in modulating plant growth and development have been well characterized.However,little is known about the roles of ROP signaling pathways in regulating plant autophagy and autophagosome formation.In this study,we identify a unique ROP signaling mechanism,which mediates developmental to autophagic transition under stress conditions in the model plant Arabidopsis.Loss-of-function mutants of ROP8 showed stress-induced hypersensitive phenotypes and compromised autophagic flux.Similar to other ROPs in the ROP/RAC family,ROP8 exhibits both plasma membrane and cytosolic punctate localization patterns.Upon autophagic induction,active ROP8 puncta colocalize with autophagosomal markers and are degraded inside the vacuole.In human cells,RalB,an RAS subfamily GTPase,engages its effector Exo84 for autophagosome assembly.However,a RalB counterpart is missing in the plant lineage.Intriguingly,we discovered that plant ROP8 promotes autophagy via its downstream effector Sec5.Live-cell super-resolution imaging showed that ROP8 and Sec5 reside on phagophores for autophagosome formation.Taken together,our findings highlight a previously unappreciated role of an ROP8-Sec5 signaling axis in autophagy promotion,providing new insights into how plants utilize versatile ROP signaling networks to coordinate developmental and autophagic responses depending on environmental changes.展开更多
Cancer cell migration enables metastatic spread causing most cancer deaths.Rho-family GTPases control cell migration,but being embedded in a highly interconnected feedback network,the control of their dynamical behavi...Cancer cell migration enables metastatic spread causing most cancer deaths.Rho-family GTPases control cell migration,but being embedded in a highly interconnected feedback network,the control of their dynamical behavior during cell migration remains elusive.To address this question,wereconstructed the Rho-family GTPases signaling network involved in cell migration,and developed a Boolean network model to analyze the different states and emergent rewiring of the Rho-family GTPases signaling network at protrusions and during extracellular matrix-dependent cell migration.Extensive simulations and experimental validations revealed that the bursts of RhoA activity induced at protrusions by EGFare regulated by a negative-feedback module composed of Src,FAK,and CSK.Interestingly,perturbing this module interfered with cyclic Rho activation and extracellular matrix-dependent migration,suggesting that CSK inhibition can be a novel and effective intervention strategy for blocking extracellular matrix-dependent cancer cell migration,while Src inhibition might fail,depending on the genetic background of cells.Thus,this study provides new insights into the mechanisms that regulate the intricate activation states of Rho-family GTPases during extracellular matrix-dependent migration,revealing potential new targets for interfering with extracellular matrix-dependent cancer cell migration.展开更多
Objective： To observe the changes of vascular endothelial functions and general neuroendocrine-immunity （NEI） network under the state of qi-deficiency syndrome induced by excessive idleness and to approach their in...Objective： To observe the changes of vascular endothelial functions and general neuroendocrine-immunity （NEI） network under the state of qi-deficiency syndrome induced by excessive idleness and to approach their internal relevance and illuminate initially the pathophysiological mechanism of vascular lesion induced by excessive idleness. Methods： A total of 100 male Wistar rats were randomly divided into the control group and the qi-deficiency syndrome model group, 50 rats in each group. The qi-deficiency syndrome model was established by feeding the animals with hyper-alimentation diet in combination with restricting movement for 10 weeks. Changes of common chemical signal molecules related to NEI and vascular endothelial functions were measured by the end of the experiment. Furthermore, their internal relevance was analyzed by the method of canonical correlation analysis. Results： The vascular endothelial structure and function were obviously injured in the model group. Compared with the control group, the chemical signal molecules, such as 5-hydroxytryptamine （5-HT）, corticosterone （CORT）, triiodothyronine （T3）, tetraiodothyronine （T4）, angiotensin Ⅱ （Ang Ⅱ）, interleukin-1 （IL-1）, and tumor necrosis factor-α （TNF-α） in peripheral blood of the model group （n=43） were changed significantly （P〈0.05 or P〈0.01）. Canonical correlation analysis showed that vascular endothelial dysfunction was correlated to the changes of these signal molecules in the NEI network. Conclusions： Comfortbased lifestyle induced not only vascular endothelial dysfunction but also an imbalance of the NEI network. Vascular endothelial dysfunction and the imbalanced NEI network interacted with each other, and an imbalance of the NEI network may be the pathophysiologic basis for the genesis and development of vascular endothelial dysfunction, even diseases of the blood vessel.展开更多
文摘Interleukin-7 （IL-7） is an essential cytokine for the development and homeostatic maintenance of T and B lymphocytes. Binding of IL-7 to its cognate receptor, the IL-7 receptor （IL-7R）, activates multiple pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation. There has been much interest in understanding how IL-7 receptor signaling is modulated at multiple interconnected network levels. This review examines how the strength of the signal through the IL-7 receptor is modulated in T and B cells, including the use of shared receptor components, signaling crosstalk, shared interaction domains, feedback loops, integrated gene regulation, multimerization and ligand competition. We discuss how these network control mechanisms could integrate to govern the properties of IL-7R signaling in lymphocytes in health and disease. Analysis of IL-7 receptor signaling at a network level in a systematic manner will allow for a comprehensive approach to understanding the impact of multiple signaling pathways on lymphocyte biology. Cellular ＆ Molecular Immunology.
文摘As sessile organisms plants must ronmental conditions. To survive cope with ever changing enviplants have evolved elaborate mechanisms to perceive and rapidly respond to a diverse range of abiotic and biotic stresses. Central to this response is the ability to modulate gene expression at both the transcriptional and posttranscriptional levels. This review will focus on recent progress that has been made towards understanding the rapid reprogramming of the transcriptome that occurs in response to stress as well as emerging mechanisms underpinning the reprogramming of gene expression in response to stress,
文摘Apoptosis and hypertrophy of cardiomyocytes are the primary causes of heart failure （HF）, a global leading cause of death, and are regulated through the complicated intracellular signaling network, limiting the development of effective treatments due to its complexity. To identify effective therapeutic strategies for HF at a system level, we develop a large-scale comprehensive mathematical model of the cardiac signaling network by integrating all available experimental evidence. Attractor landscape analysis of the network model identifies distinct sets of control nodes that effectively suppress apoptosis and hypertrophy of cardiomyocytes under ischemic or pressure overload-induced HF, the two major types of HF. Intriguingly, our system-level analysis suggests that intervention of these control nodes may increase the efficacy of clinical drugs for HF and, of most importance, different combinations of control nodes are suggested as potentially effective candidate drug targets depending on the types of HF. Our study provides a systematic way of developing mechanism-based therapeutic strategies for HF.
基金R01 NIH CA91576Departments of Veterans Affairs (VA) Merit Review Grant 1I01BX002883+1 种基金Department of Defense Grant BC141898Cancer Center of Medical College of Wisconsin
文摘Protein kinases and phosphatases signal by phosphorylation and dephosphorylation to precisely control the activities of their individual and common substrates for a coordinated cellular outcome. In many situations, a kinase/phosphatase complex signals dynamically in time and space through their reciprocal regulations and their cooperative actions on a substrate. This complex may be essential for malignant transformation and progression and can therefore be considered as a target for therapeutic intervention. p38γ is a unique MAPK family member that contains a PDZ motif at its C-terminus and interacts with a PDZ domain-containing protein tyrosine phosphatase PTPH1. This PDZcoupled binding is required for both PTPH1 dephosphorylation and inactivation of p38γ and for p38γ phosphorylation and activation of PTPH1. Moreover, the p38γ/PTPH1 complex can further regulate their substrates phosphorylation and dephosphorylation, which impacts Ras transformation, malignant growth and progression, and therapeutic response. This review will use the p38γ/PTPH1 signaling network as an example to discuss the potential of targeting the kinase/phosphatase signaling complex for development of novel targeted cancer therapy.
文摘Background:Mass cytometry(CyTOF)gives unprecedented opportunity to simultaneously measure up to 40 proteins in single cells,with a theoretical potential to reach 100 proteins.This high-dimensional single-cell information can be very useful in dissecting mechanisms of cellular activity.In particular,measuring abundances of signaling proteins like phospho-proteins can provide detailed information on the dynamics of single-cell signaling processes.However,computational analysis is required to reconstruct such networks with a mechanistic model.Methods:We propose our Mass cytometry Signaling Network Analysis Code(McSNAC),a new software capable of reconstructing signaling networks and estimating their kinetic parameters from CyTOF data.McSNAC approximates signaling networks as a network of first-order reactions between proteins.This assumption often breaks down as signaling reactions can involve binding and unbinding,enzymatic reactions,and other nonlinear constructions.Furthermore,McSNAC may be limited to approximating indirect interactions between protein species,as cytometry experiments are only able to assay a small fraction of protein species involved in signaling.Results:We carry out a series of in silico experiments here to show(1)McSNAC is capable of accurately estimating the ground-truth model in a scalable manner when given data originating from a first-order system;(2)McSNAC is capable of qualitatively predicting outcomes to perturbations of species abundances in simple second-order reaction models and in a complex in silico nonlinear signaling network in which some proteins are unmeasured.Conclusions:These findings demonstrate that McSNAC can be a valuable screening tool for generating models of signaling networks from time-stamped CyTOF data.
基金National Institutes of Health(Grant No.RO1 CA118947 and RO1 CA152826 to Ah-Ng Tony Kong and R21 CA133675 to Li Cai)
文摘To understand the organization of the biological networks that might potentially govern the pathogenesis of hormone refractory prostate cancer （HRPC）, we investigated the transcriptional circuitry and signaling in androgen-dependent 22Rvl and MDA PCa 2b cells, androgen- and estrogen-dependent LNCaP cells, and androgen-independent DU 145 and PC-3 prostate cancer （PCa） cell lines. We used microarray analyses, quantitative real-time PCR, pathway prediction analyses, and determination of Transcription Factor Binding Site （TFBS） signatures to dissect HRPC regulatory networks. We generated graphical representations of global topology and local network motifs that might be important in prostate carcinogenesis. Many important putative biomarker ＇target hubs＇ were identified in the current study including AP-1, NF-KB, EGFR, ERK1/2, JNK, p38 MAPK, TGF beta, VEGF, PDGF, CD44, Akt, PI3K, NOTCH1, CASP1, MMP2 and AR. Our results suggest that complex cellular events including autoregulation, feedback loops and cross-talk might govern progression from early lesion to clinically diagnosed PCa, as well as metastatic potential of pre-existent high-grade prostate intraepithelial neoplasia （HG-PIN） and/or advancement to HRPC. The identification of TFBS signatures for TCF/LEF, SOX9 and ELK1 in the regulatory elements suggests additional biomarkers for the potential development of chemopreventive/therapeutic strategies against PCa. Taken together, in this study, we have identified putative biomarker ＇target hubs＇ in the architecture of PCa signaling networks, and investigated TFBS signatures that might enhance our understanding of key regulatory nodes in the progression and pathogenesis of HRPC.
基金National Natural Science Foundation of China,Grant/Award Numbers:62106009,62276010R&D Program of Beijing Municipal Education Commission,Grant/Award Numbers:KM202210005030,KZ202210005009。
文摘Inferring causal protein signalling networks from human immune system cell data is a promising approach to unravel the underlying tissue signalling biology and dysfunction in diseased cells,which has attracted considerable attention within the bioinformatics field.Recently,Bayesian network(BN)techniques have gained significant popularity in inferring causal protein signalling networks from multiparameter single-cell data.However,current BN methods may exhibit high computational complexity and ignore interactions among protein signalling molecules from different single cells.A novel BN method is presented for learning causal protein signalling networks based on parallel discrete artificial bee colony(PDABC),named PDABC.Specifically,PDABC is a score-based BN method that utilises the parallel artificial bee colony to search for the global optimal causal protein signalling networks with the highest discrete K2 metric.The experimental results on several simulated datasets,as well as a previously published multi-parameter fluorescence-activated cell sorter dataset,indicate that PDABC surpasses the existing state-of-the-art methods in terms of performance and computational efficiency.
基金the National Natural Science Foundation of China(Grant No.82330090 and Grant No.82341006 to C.G.)the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDA0460403 to C.G.)the Natural Science Foundation of Shanxi Province(Grant No.202203021211155 to X.M.).
文摘Overview of the DNA damage response(DDR)in tumor cells.DDR is a highly coordinated signaling network that repairs DNA damage caused by intrinsic cellular processes and extrinsic insults,thereby preventing genome instability.Depending on the type of damage,distinct DNA damage repair and DNA damage tolerance(DDT)pathways are involved and coordinately regulated.
基金Project supported by the National Basic Research Program(973)of China(No.2012CB518900)the National Natural Science Foundation of China(Nos.31160240 and 31260621)+2 种基金the National Major Scientific and Technological Special Project during the Twelfth Five-year Plan Period of China(No.2012ZX10002006)the Hangzhou Normal University Supporting Project(No.PE13002004042)the Natural Science Foundation of Jiangxi Province(No.20114BAB204016),China
文摘Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum （ER）. One of the primary mechanisms is the unfolded protein response （UPR）. In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein （BiP） interacts with the three sensors （protein kinase RNA-like ER kinase （PERK）, activating transcription factor 6 （ATF6）, and inositol-requiring enzyme la （IREla）） Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor （VEGF）-VEGF receptor （VEGFR）-phospholipase C-~ （PLCy）-mammalian target of rapamycin complex 1 （mTORC1） pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IREla also can be activated by activated RAC-alpha serine/threonine-protein kinase （AKT）. A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species （ROS）, Ca2＋ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase （JNK）, signal transducer and activator of transcription 3 （STAT3）, and P38, when cellular damage exceeds the capacity of this adaptive response.
文摘We present a staggered buffer connection method that provides flexibility for buffer insertion while designing global signal networks using the tile-based FPGA design methodology. An exhaustive algorithm is used to analyze the trade-off between area and speed of the global signal networks for this staggered buffer insertion scheme, and the criterion for determining the design parameters is presented. The comparative analytic result shows that the methods in this paper are proven to be more efficient for FPGAs with a large array size.
基金Supported by the National Natural Science Foundation of China(64601500)
文摘An signal noise ratio（ SNR） adaptive sorting algorithm using the time-frequency（ TF）sparsity of frequency-hopping（ FH） signal is proposed in this paper. Firstly,the Gabor transformation is used as TF transformation in the system and a sorting model is established under undetermined condition; then the SNR adaptive pivot threshold setting method is used to find the TF single source. The mixed matrix is estimated according to the TF matrix of single source. Lastly,signal sorting is realized through improved subspace projection combined with relative power deviation of source. Theoretical analysis and simulation results showthat this algorithm has good effectiveness and performance.
基金supported by the National Science and Technology Major Project of the Ministry of Science and Technology of China(2014 ZX03001027)
文摘There are various heterogeneous networks for terminals to deliver a better quality of service. Signal system recognition and classification contribute a lot to the process. However, in low signal to noise ratio（SNR） circumstances or under time-varying multipath channels, the majority of the existing algorithms for signal recognition are already facing limitations. In this series, we present a robust signal recognition method based upon the original and latest updated version of the extreme learning machine（ELM） to help users to switch between networks. The ELM utilizes signal characteristics to distinguish systems. The superiority of this algorithm lies in the random choices of hidden nodes and in the fact that it determines the output weights analytically, which result in lower complexity. Theoretically, the algorithm tends to offer a good generalization performance at an extremely fast speed of learning. Moreover, we implement the GSM/WCDMA/LTE models in the Matlab environment by using the Simulink tools. The simulations reveal that the signals can be recognized successfully to achieve a 95% accuracy in a low SNR（0 dB） environment in the time-varying multipath Rayleigh fading channel.
基金supported by the National Natural Science Foundation of China(Grant Nos.32300274,32070279)the Project of Priority and Key Areas,Institute of Soil Science,Chinese Academy of Sciences(ISSASIP2222,ISSASIP2206)the Natural Science Foundation of Jiangsu Province(Grant No.BK20221560).
文摘Phosphate(Pi)is an essential nutrient for plant growth and development,playing a critical role in key biological processes such as energy metabolism,nucleic acid synthesis,and cellular signaling(Wang et al.,2021;Zhang et al.,2023;Yang et al.,2024).Due to the limited availability and poor accessibility of Pi in soil,plants have evolved complex signaling networks to sense and respond to Pi availability,ensuring the maintenance of normal physiological functions under low-Pi conditions(Wild et al.,2016;Wang et al.,2025).Within this signaling network,inositol pyrophosphates(PP-InsPs),products under Pi repletion,serve as critical signaling molecules in plant cells.When intracellular Pi is sufficient,PP-InsPs bind to SPX-domain proteins,inhibiting the activity of Pi starvation-response transcription factors(PHRs)and thereby suppressing the expression of Pi starvation-related genes.Conversely,PP-InsP levels decrease under Pi-deficient conditions,preventing SPX proteins from inhibiting PHRs(Wild et al.,2016).This results in the activation of PHRs and the initiation of Pi starvation responses,promoting Pi uptake and recycling.This mechanism helps plants to maintain Pi homeostasis in low-Pi environments.
基金supported by the National Natural Science Foundation of China(62173329)。
文摘Online traffic simulation that feeds from online information to simulate vehicle movement in real-time has recently seen substantial advancement in the development of intelligent transportation systems and urban traffic management.It has been a challenging problem due to three aspects:1)The diversity of traffic patterns due to heterogeneous layouts of urban intersections;2)The nature of complex spatiotemporal correlations;3)The requirement of dynamically adjusting the parameters of traffic models in a real-time system.To cater to these challenges,this paper proposes an online traffic simulation framework called automated urban traffic operation simulation via meta-learning(AUTOSIM).In particular,simulation models with various intersection layouts are automatically generated using an open-source simulation tool based on static traffic geometry attributes.Through a meta-learning technique,AUTOSIM enables an automated learning process for dynamic model settings of traffic scenarios featured with different spatiotemporal correlations.Besides,AUTOSIM is capable of adapting traffic model parameters according to dynamic traffic information in real-time by using a meta-learner.Through computational experiments,we demonstrate the effectiveness of the meta-learningbased framework that is capable of providing reliable supports to real-time traffic simulation and dynamic traffic operations.
基金kindly funded by National Natural Science Foundation of China(Grant No.31070752)in part supported by the National Basic Research Program(973 Program)(Nos 2011CB910204,2010CB529206 and 2010CB912702)+4 种基金Key Infectious Disease Project(No.2012ZX10002012-014)Research Program of Chinese Academy of Sciences(Nos.KSCX2-EW-R-04,KSCX2-YW-R-190 and 2011KIP204)National Natural Science Foundation of China(Grant No.30900272)Chinese Ministry for Science and Technology Grant(No.2008BAI64B01)the National High Technology Research and Development Program(863 Program)(No.2009AA02Z304).
文摘Studies on cell signaling pay more attention to spatial dynamics and how such diverse organization can relate to high order of cellular capabilities.To overview the specificity of cell signaling,we integrated human receptome data with proteome spatial expression profiles to systematically investigate the specificity of receptors and receptor-triggered transduction networks across 62 normal cell types and 14 cancer types.Six percent receptors showed cell-type-specific expression,and 4% signaling networks presented enriched cell-specific proteins induced by the receptors.We introduced a concept of“response context”to annotate the cell-type dependent signaling networks.We found that most cells respond similarly to the same stimulus,as the“response contexts”presented high functional similarity.Despite this,the subtle spatial diversity can be observed from the difference in network architectures.The architecture of the signaling networks in nerve cells displayed less completeness than that in glandular cells,which indicated cellular-context dependent signaling patterns are elaborately spatially organized.Likewise,in cancer cells most signaling networks were generally dysfunctional and less complete than that in normal cells.However,glioma emerged hyper-activated transduction mechanism in malignant state.Receptor ATP6AP2 and TNFRSF21 induced rennin-angiotensin and apoptosis signaling were found likely to explain the glioma-specific mechanism.This work represents an effort to decipher context-specific signaling network from spatial dimension.Our results indicated that although a majority of cells engage general signaling response with subtle differences,the spatial dynamics of cell signaling can not only deepen our insights into different signaling mechanisms,but also help understand cell signaling in disease.
基金supported by the National Natural Science Foundation of China (Grant No.31300241)
文摘The inter-cellular translocation of nutrients in plant is mediated by highly specialized transfer cells （TCs）. TCs share similar functional and structural features across a wide range of plant species, including location at plant exchange surfaces, rich in secondary wall ingrowths, facilitation of nutrient flow, and passage of select molecules. The fate of endosperm TCs is determined in the TC fate acquisition stage （TCF）, before the structure features are formed in the TC differentiation stage （TCD）. At present, the molecular basis of TC development in plants remains largely unknown. In this review, we summarize the important roles of the signaling molecules in different development phases, such as sugars in TCF and phytohormones in TCD, and discuss the genetic and epigenetic factors, including TC-specific genes and endogenous plant peptides, and their crosstalk with these signaling molecules as a complex regulatory network in regulation of TC develonment in olants.
基金supported by a grant from the National Research Foundation of Korea(NRF)funded by the Ministry of Education,Science,and Technology(grant no.RS-2023-00248352)。
文摘Plants activate complex signaling networks in response to pathogen attacks,orchestrating defense responses both locally and in distant and systemic tissues.The systemic activation of plant immunity,termed systemic acquired resistance(SAR),was first observed in the 1960s in tobacco plants infected with the tobacco mosaic virus.A defining feature of SAR is the accumulation of pathogenesis-related(PR)proteins,are sometimes also referred to as the molecular markers for this process(Durrant and Dong,2004).
基金supported by grants from the National Natural Science Foundation of China(31670179 and 91854201)the Research Grants Council of Hong Kong(CUHK14130716,14104716,14102417,14100818,14101219,C4012-16E,C4033-19E,C4002-17G,C4002-20W,R4005-18,and AOE/M-05/12)。
文摘The roles of Rho family guanosine triphosphatases(GTPases)of plants(ROPs)in modulating plant growth and development have been well characterized.However,little is known about the roles of ROP signaling pathways in regulating plant autophagy and autophagosome formation.In this study,we identify a unique ROP signaling mechanism,which mediates developmental to autophagic transition under stress conditions in the model plant Arabidopsis.Loss-of-function mutants of ROP8 showed stress-induced hypersensitive phenotypes and compromised autophagic flux.Similar to other ROPs in the ROP/RAC family,ROP8 exhibits both plasma membrane and cytosolic punctate localization patterns.Upon autophagic induction,active ROP8 puncta colocalize with autophagosomal markers and are degraded inside the vacuole.In human cells,RalB,an RAS subfamily GTPase,engages its effector Exo84 for autophagosome assembly.However,a RalB counterpart is missing in the plant lineage.Intriguingly,we discovered that plant ROP8 promotes autophagy via its downstream effector Sec5.Live-cell super-resolution imaging showed that ROP8 and Sec5 reside on phagophores for autophagosome formation.Taken together,our findings highlight a previously unappreciated role of an ROP8-Sec5 signaling axis in autophagy promotion,providing new insights into how plants utilize versatile ROP signaling networks to coordinate developmental and autophagic responses depending on environmental changes.
基金This work wassupported by the National Research Foundation of Korea(NRF)grants funded by the Korea Government,the Ministry of Science,ICT and Future Planning(2014R1A2A1A10052404 and 2013M3A9A7046303)by the KAIST Future Systems Healthcare Project from the Ministry of Science,ICT and Future Planning.
文摘Cancer cell migration enables metastatic spread causing most cancer deaths.Rho-family GTPases control cell migration,but being embedded in a highly interconnected feedback network,the control of their dynamical behavior during cell migration remains elusive.To address this question,wereconstructed the Rho-family GTPases signaling network involved in cell migration,and developed a Boolean network model to analyze the different states and emergent rewiring of the Rho-family GTPases signaling network at protrusions and during extracellular matrix-dependent cell migration.Extensive simulations and experimental validations revealed that the bursts of RhoA activity induced at protrusions by EGFare regulated by a negative-feedback module composed of Src,FAK,and CSK.Interestingly,perturbing this module interfered with cyclic Rho activation and extracellular matrix-dependent migration,suggesting that CSK inhibition can be a novel and effective intervention strategy for blocking extracellular matrix-dependent cancer cell migration,while Src inhibition might fail,depending on the genetic background of cells.Thus,this study provides new insights into the mechanisms that regulate the intricate activation states of Rho-family GTPases during extracellular matrix-dependent migration,revealing potential new targets for interfering with extracellular matrix-dependent cancer cell migration.
基金Supported by the National Basic Research Program of China (973 Program,No.2005CB523301)the International Science and Technology Cooperation Program(No.2006DFB32460)
文摘Objective： To observe the changes of vascular endothelial functions and general neuroendocrine-immunity （NEI） network under the state of qi-deficiency syndrome induced by excessive idleness and to approach their internal relevance and illuminate initially the pathophysiological mechanism of vascular lesion induced by excessive idleness. Methods： A total of 100 male Wistar rats were randomly divided into the control group and the qi-deficiency syndrome model group, 50 rats in each group. The qi-deficiency syndrome model was established by feeding the animals with hyper-alimentation diet in combination with restricting movement for 10 weeks. Changes of common chemical signal molecules related to NEI and vascular endothelial functions were measured by the end of the experiment. Furthermore, their internal relevance was analyzed by the method of canonical correlation analysis. Results： The vascular endothelial structure and function were obviously injured in the model group. Compared with the control group, the chemical signal molecules, such as 5-hydroxytryptamine （5-HT）, corticosterone （CORT）, triiodothyronine （T3）, tetraiodothyronine （T4）, angiotensin Ⅱ （Ang Ⅱ）, interleukin-1 （IL-1）, and tumor necrosis factor-α （TNF-α） in peripheral blood of the model group （n=43） were changed significantly （P〈0.05 or P〈0.01）. Canonical correlation analysis showed that vascular endothelial dysfunction was correlated to the changes of these signal molecules in the NEI network. Conclusions： Comfortbased lifestyle induced not only vascular endothelial dysfunction but also an imbalance of the NEI network. Vascular endothelial dysfunction and the imbalanced NEI network interacted with each other, and an imbalance of the NEI network may be the pathophysiologic basis for the genesis and development of vascular endothelial dysfunction, even diseases of the blood vessel.
