Selenoprotein GPX3 is a novel prognostic indicator for stomach adenocarcinoma and brain low-grade gliomas: Evidence from an integrative pan-cancer analysis.

Background: The antioxidant enzyme GPX3 is a selenoprotein that transports selenium in blood and maintains its levels in peripheral tissues. Aberrant GPX3 expression is strongly linked to the development of some tumors. However, there is a scarcity of studies examining the pan-cancer expression patterns and prognostic relevance of GPX3. Methods: GPX3 expression levels in normal tissues and multiple tumors were analyzed using TCGA, CCLE, GTEx, UALCAN and HPA databases. Forest plots and KM survival curves were utilized to evaluate the correlation between GPX3 expression and the outcome of tumor patients. The prognostic value of GPX3 in LGG was assessed utilizing the CGGA datasets, and that in STAD was tested by TCGA and GEO databases. A nomogram was then constructed to predict OS in STAD using R software. Additionally, the impact of GPX3 on post-chemoradiotherapy OS in patients with LGG and STAD was evaluated using the KM method. The multiplicative interaction of GPX3 expression, chemotherapy and radiotherapy on STAD and LGG was analyzed using logistic regression models. The correlation of GPX3 with the immune infiltration, immune neoantigens and MMR genes were investigated in TCGA cohort. Results: GPX3 exhibited downregulation across 21 tumor types, including STAD, with its decreased expression significantly associated with improved OS, DFS, PFS and DSS. Conversely, in LGG, low levels of GPX3 expression were indicative of a poorer prognosis. Univariate and multivariate Cox models further identified GPX3 as an independent predictor of STAD, and a nomogram based on GPX3 expression and other independent factors showed high level of predictive accuracy. Moreover, low GPX3 expression and chemotherapy prolonged the survival of STAD. In LGG patients, chemoradiotherapy, GPX3 and chemotherapy, and GPX3 and chemoradiotherapy may improve prognosis. Our observations reveal a notable connection between GPX3 and immune infiltration, immune neoantigens, and MMR genes. Conclusions: The variations in GPX3 expression are linked to the controlling tumor development and could act as a promising biomarker that impacts the prognosis of specific cancers like STAD and LGG.

Characterization of bamboo shoots dietary fiber modified by ball milling and its role in altering the physicochemical properties of shrimp surimi.

A simple but robust strategy of ball milling (20 Hz, 30 Hz for 30 s, 60 s, 120 s, 180 s) was utilized to modify bamboo shoots fiber (BSDF) in shrimp surimi. The water holding capacity, swelling capacity, and oil binding capacity of 30 Hz-60 s milled BSDF exhibited the highest values of 5.61 g/g, 3.13 mL/g, and 6.93 g/g, significantly higher (P < 0.05) than untreated one (3.65 g/g, 2.03 mL/g, 4.57 g/g). Ball-milled BSDF exhibited a small-sized structure with the relative crystallinity decreased from 40.44 % (control) to 11.12 % (30 Hz-180 s). The myosin thermal stability, gelation properties of surimi were significantly enhanced by incorporating 20 Hz-120 s and 30 Hz-60 s BSDF via promoting protein unfolding, covalent hydrophobic interactions, and hydrogen bonding. A matrix-reinforcing and water entrapping effect was observed, exhibiting reinforced networks with down-sized water tunnels. However, BSDF modified at 180 s contributed to over-aggregated networks with fractures and enlarged gaps. Appropriate ball-milled BSDF (20 Hz-120 s, and 30 Hz-60 s) resulted in a significant decrease in α-helix (P < 0.05), accompanied by an increase of ß-sheets and ß-turn. This work could bring some insights into the applications of modified BSDF and its roles in the gelation of surimi-based food.

Soil selenium enhanced the resistance of oilseed rape to Sclerotinia sclerotiorum by optimizing the plant microbiome.

Plant can recruit beneficial microbes to enhance their ability to resist disease. Selenium is well established as a beneficial element in plant growth, but its role in mediating microbial disease resistance remained poorly understood. Here, we investigated the correlation between selenium, oilseed rape rhizosphere microbes and Sclerotinia sclerotiorum. Soil application of 0.5 and 1.0 mg/kg selenium significantly increased the resistance of oilseed rape to Sclerotinia sclerotiorum compared with no selenium application, and the disease inhibition rate was higher than 20%. The disease resistance of oilseed rape was related to rhizosphere microorganisms, and beneficial bacteria isolated from the rhizosphere inhibited Sclerotinia stem rot. Burkholderia cepacia, and synthetic community enhanced plant disease resistance through transcriptional regulation and activated plant-induced systemic resistance to protect plants. Besides, inoculation of isolated bacteria optimized the bacterial community structure of leaves and enriched beneficial microorganisms such as Bacillus, Pseudomonas and Sphingomonas. Bacillus isolated from the leaves were sprayed on the detached leaves, and it also performed a significant inhibition effect on Sclerotinia sclerotiorum. Overall, our results suggested that selenium drive plant rhizosphere microorganisms to increase resistance to Sclerotinia sclerotiorum in oilseed rape.

Matrimeres are systemic nanoscale mediators of tissue integrity and function.

Tissue barriers must be rapidly restored after injury to promote regeneration. However, the mechanism behind this process is unclear, particularly in cases where the underlying extracellular matrix is still compromised. Here, we report the discovery of matrimeres as constitutive nanoscale mediators of tissue integrity and function. We define matrimeres as non-vesicular nanoparticles secreted by cells, distinguished by a primary composition comprising at least one matrix protein and DNA molecules serving as scaffolds. Mesenchymal stromal cells assemble matrimeres from fibronectin and DNA within acidic intracellular compartments. Drawing inspiration from this biological process, we have achieved the successful reconstitution of matrimeres without cells. This was accomplished by using purified matrix proteins, including fibronectin and vitronectin, and DNA molecules under optimal acidic pH conditions, guided by the heparin-binding domain and phosphate backbone, respectively. Plasma fibronectin matrimeres circulate in the blood at homeostasis but exhibit a 10-fold decrease during systemic inflammatory injury in vivo . Exogenous matrimeres rapidly restore vascular integrity by actively reannealing endothelial cells post-injury and remain persistent in the host tissue matrix. The scalable production of matrimeres holds promise as a biologically inspired platform for regenerative nanomedicine.

Selenium and Bacillus proteolyticus SES increased Cu-Cd-Cr uptake by ryegrass: highlighting the significance of key taxa and soil enzyme activity.

Many studies have focused their attention on strategies to improve soil phytoremediation efficiency. In this study, a pot experiment was carried out to investigate whether Se and Bacillus proteolyticus SES promote Cu-Cd-Cr uptake by ryegrass. To explore the effect mechanism of Se and Bacillus proteolyticus SES, rhizosphere soil physiochemical properties and rhizosphere soil bacterial properties were determined further. The findings showed that Se and Bacillus proteolyticus SES reduced 23.04% Cu, 36.85% Cd, and 9.85% Cr from the rhizosphere soil of ryegrass. Further analysis revealed that soil pH, organic matter, soil enzyme activities, and soil microbial properties were changed with Se and Bacillus proteolyticus SES application. Notably, rhizosphere key taxa (Bacteroidetes, Actinobacteria, Firmicutes, Patescibacteria, Verrucomicrobia, Chloroflexi, etc.) were significantly enriched in rhizosphere soil of ryegrass, and those taxa abundance were positively correlated with soil heavy metal contents (P < 0.01). Our study also demonstrated that in terms of explaining variations of soil Cu-Cd-Cr content under Se and Bacillus proteolyticus SES treatment, soil enzyme activities (catalase and acid phosphatase) and soil microbe properties showed 42.5% and 12.2% contributions value, respectively. Overall, our study provided solid evidence again that Se and Bacillus proteolyticus SES facilitated phytoextraction of soil Cu-Cd-Cr, and elucidated the effect of soil key microorganism and chemical factor.

Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity.

BACKGROUND: Mitochondrial dysfunction is a primary driver of cardiac contractile failure; yet, the cross talk between mitochondrial energetics and signaling regulation remains obscure. Ponatinib, a tyrosine kinase inhibitor used to treat chronic myeloid leukemia, is among the most cardiotoxic tyrosine kinase inhibitors and causes mitochondrial dysfunction. Whether ponatinib-induced mitochondrial dysfunction triggers the integrated stress response (ISR) to induce ponatinib-induced cardiotoxicity remains to be determined. METHODS: Using human induced pluripotent stem cells-derived cardiomyocytes and a recently developed mouse model of ponatinib-induced cardiotoxicity, we performed proteomic analysis, molecular and biochemical assays to investigate the relationship between ponatinib-induced mitochondrial stress and ISR and their role in promoting ponatinib-induced cardiotoxicity. RESULTS: Proteomic analysis revealed that ponatinib activated the ISR in cardiac cells. We identified GCN2 (general control nonderepressible 2) as the eIF2α (eukaryotic translation initiation factor 2α) kinase responsible for relaying mitochondrial stress signals to trigger the primary ISR effector-ATF4 (activating transcription factor 4), upon ponatinib exposure. Mechanistically, ponatinib treatment exerted inhibitory effects on ATP synthase activity and reduced its expression levels resulting in ATP deficits. Perturbed mitochondrial function resulting in ATP deficits then acts as a trigger of GCN2-mediated ISR activation, effects that were negated by nicotinamide mononucleotide, an NAD+ precursor, supplementation. Genetic inhibition of ATP synthase also activated GCN2. Interestingly, we showed that the decreased abundance of ATP also facilitated direct binding of ponatinib to GCN2, unexpectedly causing its activation most likely because of a conformational change in its structure. Importantly, administering an ISR inhibitor protected human induced pluripotent stem cell-derived cardiomyocytes against ponatinib. Ponatinib-treated mice also exhibited reduced cardiac function, effects that were attenuated upon systemic ISRIB administration. Importantly, ISRIB does not affect the antitumor effects of ponatinib in vitro. CONCLUSIONS: Neutralizing ISR hyperactivation could prevent or reverse ponatinib-induced cardiotoxicity. The findings that compromised ATP production potentiates GCN2-mediated ISR activation have broad implications across various cardiac diseases. Our results also highlight an unanticipated role of ponatinib in causing direct activation of a kinase target despite its role as an ATP-competitive kinase inhibitor.

Robust Synthesis of GO-PtNPs Nanocomposites: A Highly Selective Colorimetric Sensor for Mercury Ion (II) Detection.

Due to their high toxicity and ongoing bioaccumulation, mercury ions (Hg2+) can cause significant harm to both the environment and human health. Therefore, rapid, accurate, and selective methods for Hg2+ detection are highly desirable. Herein, we present a simple method for depositing platinum nanoparticles (PtNPs) on graphene oxide (GO) to obtain graphene oxide-PtNPs (GO-PtNPs). The fabricated GO-PtNPs exhibit excellent peroxidase-like activity and high stability. Further, the GO-PtNPs nanozymes preferentially reduced Hg2+, thereby inhibiting the catalytic activity. By monitoring the color change in the chromogenic substrate, Hg2+ can be detected within 15 min. With a detection limit of 88.3 pM, the GO-PtNPs system may be employed to detect Hg2+ in a linear range of 0.1 nM to 10 µM. The simplicity and low cost of the proposed approach as well as its applicability to complicated samples demonstrate its capacity for mercury sensing in environmental samples.

Recent Advances in Design and Application of Nanomaterials-Based Colorimetric Biosensors for Agri-food Safety Analysis.

A colorimetric sensor detects an analyte by utilizing the optical properties of the sensor unit, such as absorption or reflection, to generate a structural color that serves as the output signal to detect an analyte. Detecting the refractive index of an analyte by recording the color change of the sensor structure on its surface has several advantages, including simple operation, low cost, suitability for onsite analysis, and real-time detection. Colorimetric sensors have drawn much attention owing to their rapidity, simplicity, high sensitivity and selectivity. This Review discusses the use of colorimetric sensors in the food industry, including their applications for detecting food contaminants. The Review also provides insight into the scope of future research in this area.

sNASP Mutation Aggravates to the TLR4-Mediated Inflammation in SLE by TAK1 Pathway.

Genetic factors play an important role in the pathogenesis of systemic lupus erythematosus (SLE), and abnormal Toll-like receptor (TLR) signaling pathways are closely related to the onset of SLE. In previous studies, we found that the mutant somatic nuclear autoantigenic sperm protein (sNASP) gene in the mouse lupus susceptibility locus Sle2 can promote the development of lupus model mice, but the mechanism is still unclear. Here, we stimulated mouse peritoneal macrophages with different concentrations of lipopolysaccharide. The results showed that sNASP gene mutations can promote the response of the TLR4-TAK1 signaling pathway but have no significant effect on the TLR4-TBK1 signaling pathway. sNASP mutations enhanced TLR4-mediated nuclear factor-κ-gene binding and mitogen-activated protein kinase activation and IL-6, tumor necrosis factor secretion in murine peritoneal macrophages. Collectively, our study revealed the impact of sNASP gene mutation on the sensitivity of TLR4 receptors in mouse peritoneal macrophages and shed light on potential mechanisms underlying inflammation in autoimmune diseases.

Integrin ß3 directly inhibits the Gα13-p115RhoGEF interaction to regulate G protein signaling and platelet exocytosis.

The integrins and G protein-coupled receptors are both fundamental in cell biology. The cross talk between these two, however, is unclear. Here we show that ß3 integrins negatively regulate G protein-coupled signaling by directly inhibiting the Gα13-p115RhoGEF interaction. Furthermore, whereas ß3 deficiency or integrin antagonists inhibit integrin-dependent platelet aggregation and exocytosis (granule secretion), they enhance G protein-coupled RhoA activation and integrin-independent secretion. In contrast, a ß3-derived Gα13-binding peptide or Gα13 knockout inhibits G protein-coupled RhoA activation and both integrin-independent and dependent platelet secretion without affecting primary platelet aggregation. In a mouse model of myocardial ischemia/reperfusion injury in vivo, the ß3-derived Gα13-binding peptide inhibits platelet secretion of granule constituents, which exacerbates inflammation and ischemia/reperfusion injury. These data establish crucial integrin-G protein crosstalk, providing a rationale for therapeutic approaches that inhibit exocytosis in platelets and possibly other cells without adverse effects associated with loss of cell adhesion.

Epileptic seizures worsen the gait and motor abnormalities in adult patients with Dravet syndrome (with a case report and literature review).

Dravet syndrome (DS), previously known as severe myoclonic epilepsy in infancy (SMEI), is considered the most serious "epileptic encephalopathy." Here, we present a man with a de novo SCN1A mutation who was diagnosed with DS at the age of 29. In addition to pharmaco-resistant seizures and cognitive delay, he also developed moderate to severe motor and gait problems, such as crouching gait and Pisa syndrome. Moreover, it deteriorated significantly following an epileptic seizure. The patient presented with severe flexion of the head and trunk in the sagittal plane and fulfilled the diagnostic criteria for camptocormia and antecollis. After a week, it spontaneously alleviated partially. We applied levodopa to the patient and had a good response. Functional Gait Assessment (FGA) was assessed at three different times: 4 days after the seizure, 1 week after the seizure, and after taking levodopa for 2 years. The results were 4, 12, and 19 points, respectively. We postulated that: (1) gait and motor deficits are somehow influenced by recurrent epileptic episodes;(2) the nigrostriatal dopamine system is involved. To our knowledge, we were the ones who first reported this phenomenon.

A Critical Role for ERO1α in Arterial Thrombosis and Ischemic Stroke.

BACKGROUND: Platelet adhesion and aggregation play a crucial role in arterial thrombosis and ischemic stroke. Here, we identify platelet ERO1α (endoplasmic reticulum oxidoreductase 1α) as a novel regulator of Ca2+ signaling and a potential pharmacological target for treating thrombotic diseases. METHODS: Intravital microscopy, animal disease models, and a wide range of cell biological studies were utilized to demonstrate the pathophysiological role of ERO1α in arteriolar and arterial thrombosis and to prove the importance of platelet ERO1α in platelet activation and aggregation. Mass spectrometry, electron microscopy, and biochemical studies were used to investigate the molecular mechanism. We used novel blocking antibodies and small-molecule inhibitors to study whether ERO1α can be targeted to attenuate thrombotic conditions. RESULTS: Megakaryocyte-specific or global deletion of Ero1α in mice similarly reduced platelet thrombus formation in arteriolar and arterial thrombosis without affecting tail bleeding times and blood loss following vascular injury. We observed that platelet ERO1α localized exclusively in the dense tubular system and promoted Ca2+ mobilization, platelet activation, and aggregation. Platelet ERO1α directly interacted with STIM1 (stromal interaction molecule 1) and SERCA2 (sarco/endoplasmic reticulum Ca2+-ATPase 2) and regulated their functions. Such interactions were impaired in mutant STIM1-Cys49/56Ser and mutant SERCA2-Cys875/887Ser. We found that ERO1α modified an allosteric Cys49-Cys56 disulfide bond in STIM1 and a Cys875-Cys887 disulfide bond in SERCA2, contributing to Ca2+ store content and increasing cytosolic Ca2+ levels during platelet activation. Inhibition of Ero1α with small-molecule inhibitors but not blocking antibodies attenuated arteriolar and arterial thrombosis and reduced infarct volume following focal brain ischemia in mice. CONCLUSIONS: Our results suggest that ERO1α acts as a thiol oxidase for Ca2+ signaling molecules, STIM1 and SERCA2, and enhances cytosolic Ca2+ levels, promoting platelet activation and aggregation. Our study provides evidence that ERO1α may be a potential target to reduce thrombotic events.

A new noninvasive and patient-specific hemodynamic index for the severity of renal stenosis and outcome of interventional treatment.

Renal arterial stenosis (RAS) often causes renovascular hypertension, which may result in kidney failure and life-threatening consequences. Direct assessment of the hemodynamic severity of RAS has yet to be addressed. In this work, we present a computational concept to derive a new, noninvasive, and patient-specific index to assess the hemodynamic severity of RAS and predict the potential benefit to the patient from a stenting therapy. The hemodynamic index is derived from a functional relation between the translesional pressure indicator (TPI) and lumen volume reduction (S) through a parametric deterioration of the RAS. Our in-house computational platform, InVascular, for image-based computational hemodynamics is used to compute the TPI at given S. InVascular integrates unified computational modeling for both image processing and computational hemodynamics with graphic processing unit parallel computing technology. The TPI-S curve reveals a pair of thresholds of S indicating mild or severe RAS. The TPI at S = 0 represents the pressure improvement following a successful stenting therapy. Six patient cases with a total of 6 aortic and 12 renal arteries are studied. The computed blood pressure waveforms have good agreements with the in vivo measured ones and the systolic pressure is statistical equivalence to the in-vivo measurements with p < .001. Uncertainty quantification provides the reliability of the computed pressure through the corresponding 95% confidence interval. The severity assessments of RAS in four cases are consistent with the medical practice. The preliminary results inspire a more sophisticated investigation for real medical insights of the new index. This computational concept can be applied to other arterial stenoses such as iliac stenosis. Such a noninvasive and patient-specific hemodynamic index has the potential to aid in the clinical decision-making of interventional treatment with reduced medical cost and patient risks.

Signaling mechanisms of the platelet glycoprotein Ib-IX complex.

The glycoprotein Ib-IX (GPIb-IX) complex mediates initial platelet adhesion to von Willebrand factor (VWF) immobilized on subendothelial matrix and endothelial surfaces, and transmits VWF binding-induced signals to stimulate platelet activation. GPIb-IX also functions as part of a mechanosensor to convert mechanical force received via VWF binding into intracellular signals, thereby greatly enhancing platelet activation. Thrombin binding to GPIb-IX initiates GPIb-IX signaling cooperatively with protease-activated receptors to synergistically stimulate the platelet response to low-dose thrombin. GPIb-IX signaling may also occur following the binding of other GPIb-IX ligands such as leukocyte integrin αMß2 and red cell-derived semaphorin 7A, contributing to thrombo-inflammation. GPIb-IX signaling requires the interaction between the cytoplasmic domains of GPIb-IX and 14-3-3 protein and is mediated through Src family kinases, the Rho family of small GTPases, phosphoinositide 3-kinase-Akt-cGMP-mitogen-activated protein kinase, and LIM kinase 1 signaling pathways, leading to calcium mobilization, integrin activation, and granule secretion. This review summarizes the current understanding of GPIb-IX signaling.

[Expression of Glutathione Peroxidases and Its Effect on Clinical Prognosis in Glioma Patients].

Objective To investigate the relationship between the expression of glutathione peroxidase(GPX)genes and the clinical prognosis in glioma patients,and to construct and evaluate the model for predicting the prognosis of glioma. Methods The clinical information and GPX expression of 663 patients,including 153 patients of glioblastoma(GBM)and 510 patients of low-grade glioma(LGG),were obtained from The Cancer Genome Atlas(TCGA)database.The relationship between GPX expression and patient survival was analyzed.The key GPX affecting the prognosis of glioma was screened out by single- and multi-factor Cox's proportional-hazards regression models and validated by least absolute shrinkage and selection operator(Lasso)regression.Finally,we constructed the model for predicting the prognosis of glioma with the screening results and then used concordance index and calibration curve respectively to evaluate the discrimination and calibration of model. Results Compared with those in the control group,the expression levels of GPX1,GPX3,GPX4,GPX7,and GPX8 were up-regulated in glioma patients(all P<0.001).Moreover,the expression levels of other GPX except GPX3 were higher in GBM patients than in LGG patients(all P<0.001).The Kaplan-Meier curves showed that the progression-free survival of GBM with high expression of GPX1(P=0.013)and GPX4(P=0.040),as well as the overall survival,disease-specific survival,and progression-free survival of LGG with high expression of GPX1,GPX7,and GPX8,was shortened(all P<0.001).GPX7 and GPX8 were screened out as the key factors affecting the prognosis of LGG.The results were further used to construct a nomogram model,which suggested GPX7 was the most important variable.The concordance index of the model was 0.843(95%CI=0.809-0.853),and the calibration curve showed that the predicted and actual results had good consistency. Conclusion GPX7 is an independent risk factor affecting the prognosis of LGG,and the nomogram model constructed with it can be used to predict the survival rate of LGG.

A Bioinformatic Analysis: The Overexpression and Prognostic Potential of GPX7 in Lower-Grade Glioma.

Purpose: Glutathione peroxidase-7 (GPX7) is a newly discovered non-selenium-containing protein with glutathione peroxidase activity, which mainly protects the organism from oxidative damage and is very important for basic biology studies. This study aims to reveal the expression pattern of GPX7 and its prognosis potential from a pan-cancer perspective. Methods: Expression levels of GPX7 in human tumor tissues and normal tissues were evaluated using Human Protein Atlas (HPA), the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and UALCAN databases. The prognostic potential of GPX7 for 33 TCGA tumors was evaluated by Kaplan-Meier analysis and Cox regression analysis. Subsequently, the Chinese Glioma Genome Atlas (CGGA) dataset was used to further verify the expression of GPX7 and its prognostic potential in glioma. We explored the correlation between GPX7 and immune infiltration, tumor mutational burden (TMB) and microsatellite instability (MSI). Furthermore, a nomogram lower-grade glioma (LGG) was constructed to verify the prognostic outcome of patients. Finally, the relationship between GPX7 and treatment regimens for LGG was also explored. Results: GPX7 was overexpressed in multiple tumors. Elevated expression of GPX7 was associated with poor prognosis of LGG patients (OS hazard ratio (HR) = 1.044, P < 0.0001; DFS HR = 1.035, P < 0.0001; PFS HR = 1.045, P < 0.0001). GPX7 was proved to be an independent prognostic factor of LGG through univariate and multivariate Cox analysis. The nomogram confirmed a better predictability (Concordance index (C-index): 0.845; 95% CI, 0.825-0.865). GPX7 was positively correlated with TMB in LGG. GPX7 expression was negatively correlated with half-maximal inhibitory concentration (IC50) of temozolomide (TMZ) (spearman= -0.59, P =1.3e-48). Conclusion: GPX7 was upregulated in multiple tumors, and it was a potential prognostic biomarker in LGG. High-expressed GPX7 can predict the sensitivity of TMZ in LGG patients.

Explaining the Frequency Dependence of the DC-Biased Dielectric Response of Polar Nanoregions by Field-Enhanced Correlation Length.

Understanding the effects of polar nanoregions (PNRs) dynamics on dielectric properties is a complex question of essential importance for both fundamental studies of relaxor ferroelectrics and their applications to electro-optic devices. The frequency dependence of dielectric response to the bias electric field opens a brand new window for the study of this problem. A novel model from mesoscopic to macroscopic, revealing the relationship between the dielectric permittivity to the applied electric field, temperature, and PNRs, was established based on mean field approximation and the theory of continuum percolation, and not only validates the field-induced percolation and the relaxation time divergency at the freezing temperature, but also predicts the frequency dependence of dielectric response. Unexpectedly, the model reveals the field-enhanced correlation length results in the nonmonotonic behavior of dielectric response, and implies that the increased orientation consistency of dipolar clusters and coercive fields originated from inherent inhomogeneity slow down the relaxation time of PNR reorientation. Considering the multi-scale heterogeneity of PNRs in relaxor, we found that the increased heterogeneity degree reduces the dielectric permittivity, but changes the slope of dielectric response to the bias electric field.