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• Develop a framework including both stability analysis and implementation constraints for traffic platoon control via sparse autonomous vehicles. • Identify the number of human-driven vehicles that can be stabilized by one single autonomous vehicle. • Establish error dynamics in traffic platoon considering multiple disturbances and error composition. • Propose a novel ring string stability that is flexible and applicable to mixed ring traffic. The emergence of autonomous vehicles (AVs) is expected to revolutionize road transportation and it has been demonstrated that AVs can be employed as mobile actuators to effectively dissipate stop and go waves. This paper proposes a comprehensive theoretical framework including stability and implementation considerations for analyzing traffic platoon control via sparse AVs and discussing the number of HDVs that can be stabilized by one AV. Considering multiple disturbance sources, we first discuss the output error composition and analyze traffic dynamics in a platoon system. Then we discuss the Lyapunov asymptotic stability (LAS) of the system based on eigenvalue analysis and propose a novel ring string stability (RSS), which ensures the boundedness of disturbance error and guarantees that the effect of disturbance will not be amplified over a lap. The proposed RSS is flexible and applicable to mixed traffic, since the string instability for predecessor-follower pairs are allowed, provided they can be compensated by AVs. In addition, the practical constraints including driving safety and vehicle physical limitations are modeled. The worst-case evaluation of constraints is conducted to reproduce the critical scenarios in real life. Finally, we conduct numerical experiments and analyze the traffic platoon control from the aspects of both stability and practical implementations. New findings include: (1) The introduction of AVs is beneficial to dampen the waves and stabilize the HDV flow. (2) Considering the implementation issues, there is an upper bound of HDVs that can be stabilized by one single AV. (3) As the number and amplitudes of exogenous disturbances increase, it will be more challenging for sparse AVs to ensure stability and meanwhile satisfy the practical constraints. [ABSTRACT FROM AUTHOR]

Due to the tumor heterogeneity, the velocity of blood flow is significantly different in either various malignancy types or in diversified positioning within a certain tumor. However, despite the nanodrugs administered in a systemic manner are transported into tumors through complicated vessel network, the effects of intratumoral blood velocity on the intratumoral accumulation of nanocarriers and its underlying mechanisms still remain largely unexplored so far. Consequently, we herein constructed several animal models with diverse intratumoral blood velocity via regulating the intratumoral coagulation environment (ICE), and subsequently evaluated the instrumental roles they played on intratumoral accumulation and penetration of nanocarriers and drugs. Interestingly, we discovered when the ICE featured an anti-coagulable state, the blood velocity in tumor vessels was consequently increased, leading to the high frequency of nanocarriers flowing through tumor vessels, improved intratumoral penetration of nanocarriers as well as the promoted intratumoral drug concentrations. On the other hand, when the ICE became a hypercoagulable state, the blood velocity in tumor vessels was prominently decreased correspondingly, generating the low frequency of nanocarriers flowing through tumor vessels and massed retention of nanodrugs in tumor vessels, which increased the number of drugs within tumor as well. Therefore, the evidence indicated that the variation in blood flow velocity caused by modifying ICE have different advantages in improving the efficiency of tumor-targeted nano drugs, which might propose a new perspective to consider how tumor-targeting nanodrugs enter solid tumors and further exert efficacious tumor-killing effectiveness under disparate tumor vascular microenvironment. [Display omitted] • Construct several solid tumor models with diverse blood velocities in mice by altering ICE for the first time. • The augment of the blood velocity in tumor vessels contributed to the penetration of nanocarriers into the interstitial space within tumor and the opposite situation induced the accumulation of nanocarriers in tumor vessels. • Intratumoral drug concentration was prominently increased in both cases mentioned above, which may be conducive to diversiform tumor-targeted therapies. [ABSTRACT FROM AUTHOR]

World shipping activities are operated in a complex and risky environment. The global marine casualty governance and shipping safety problems are issues of common concern of all maritime countries. Total-loss marine casualties are the nightmares and the most serious shipping accidents to the world, which may cause huge economic losses, the loss of lives, and severe marine environmental pollution. This study develops a fuzzy matter element method to analyse the main contributing factors of world total-loss marine casualty, the evolution trend of the total losses caused by different contributors is also evaluated with the proposed models. In this paper, according to the practice of the world shipping industry, we firstly select ten main contributors of the world shipping total losses, and the evaluation framework and mathematical models are established based on fuzzy matter element theory. Then the paper introduces the detailed evaluation procedures and methods. Finally, we select the historical data of world total-loss marine casualty from 2001 to 2015 for an empirical study of the proposed models, verifying practicability and validity of the method introduced in this paper. The results of this study are beneficial to government departments and policy makers in proposing reasonable and effective strategy to control and prevent the total-loss marine casualty in world shipping industry. [ABSTRACT FROM AUTHOR]

Acute lung injury / acute respiratory distress syndrome (ALI/ARDS) or pulmonary fibrosis (PF) has been regarded as a global health issue with high mortality and limited drug therapy. Clinical evidence suggests that undesired macrophage polarization (M) is the main factor driving the development of ALI/ARDS, and endoplasmic reticulum stress (ERS) has been considered an important determinant of M polarization. Accordingly, we proposed a hypothesis that restoration of ER homeostasis would effectively balance the homeostasis of M and prevent ALI from progressing to pulmonary fibrosis (PF). To this end, we designed a multistage targeted nanomicelle mainly based on hyaluronic acid (HA) and α-tocopherol succinate (α-TOS) (named as HSST or pHSST with peptide modified) to load ERS inhibitor (KIRA6, K) and anti-inflammatory drug (Dexamethasone, Dex) respectively. When inflammation occurred, K-loaded pHSST (K@pHSST) and Dex-loaded HSST (Dex@HSST) firstly achieved lung targeting by "hitchhiking" myeloid M and neutrophils (Neu) that patrol in the blood and then achieved inflammation-associated cells targeting through a CD44 receptor-ligand-mediated mode by HA. For K@pHSST, at the same time, the ER-targeting molecule (Pardaxin, Par) was used to modify the nanomicelles for tertiary ER-targeting effect and specifically delivering of the K to ER. While in response to high-level intracellular reactive oxygen species (ROS), Dex@HSST disintegrated due to the reductive α-tocopherol succinate (α-TOS) and disulfide bond. The released Dex exerted anti-inflammatory effects and promoted type 2 M cells (M2) polarization via activating intracellular glucocorticoid receptors. Through the combined administration of Dex@HSST and K@pHSST, this strategy could effectively reduce ROS, limit cytokine storm, restore ER homeostasis, reverse imbalanced M polarization, and fundamentally resolve ALI and prevent PF. [Display omitted] • Multi-functional nanomicelles with precise ER-targeting were prepared. • Inhibition of ERS can effectively reverse the hyperpolarization of M1 and alleviate ALI-mice symptoms. • Maintenance of ER homeostasis combined with the activation of hormone receptors contribute the treatment of PF. [ABSTRACT FROM AUTHOR]

In this paper, the route recommendation provided by the traffic management authority, rather than the uncontrollable bifurcation splitting rate, is directly considered as the control variable in the route guidance system; a real-time en-route diversion control strategy with multiple objectives is designed in a Model Predictive Control (MPC) framework with regard to system uncertainties and disturbances. The objectives include not only traffic efficiency, but also emission reduction and fuel economy, which respectively correspond to minimizing the total time spent (TTS), total amount of emissions and fuel consumption for all vehicles moving through a network. In the MPC framework, the routing control problem is transformed to be a constrained combinational optimization, which is solved by the parallel Tabu Search algorithm. Two representative traffic scenarios are tested, and the simulation results show: (1) The room for improvement in each objective by means of route diversion control is not consistent with each other and varies with the utilized traffic scenario. In the peak hour, the routing control can lead to significant improvements in TTS and fuel economy, while a relatively small improvement in emission reduction is achieved; in the off-peak hour, however, it is opposite, which indicates that routing is possibly dispensable from the aspect of improving traffic efficiency, but is required from the aspect of emission reduction. (2) The conflict among the multiple objectives varies with the utilized traffic scenario in route diversion control. Improving traffic efficiency often conflicts with emission reduction in both scenarios. For the objectives of traffic efficiency and fuel economy, they are not conflicting in peak hour, while in the off-peak hour, the two objectives are likely conflicting, and the improvement in one objective can lead to the degradation in the other objective. (3) Regardless of the scenarios of peak hour or off-peak hour, the proposed control strategy can result in a proper trade-off among the three chosen objectives. [ABSTRACT FROM AUTHOR]

[Display omitted] • Previous studies using voxel-based morphometry (VBM) analysis have reported brain morphological changes in visual and cognitive related brain regions between TAO group and control group, however not taking into account the different developing phases of TAO. Our study was divided into detailed groups, including active TAO group, inactive TAO group and healthy controls group. • There were significant changes in the active TAO group compared to the inactive TAO group and healthy controls group. No significant differences were found between the inactive TAO group and healthy controls. This may suggest that there may be a corresponding process of self-repair and remodeling of the brain structure as the disease progresses into the inactive phase. • ROC curve analysis showed that the mean GMV of left SFG achieved the best classification performance for discriminating active TAO from inactive TAO patients and healthy controls. Mean GMV of the left SFG has potential utility as a diagnostic biomarker. The left SFG is a core brain region for cognitive control and emotional regulation. • Our study also correlated the changed regional mean GMV with TAO's clinical parameters which may suggest future directions for prevention or intervention. To explore the morphological brain changes among active thyroid-associated ophthalmopathy (TAO) patients, inactive TAO patients and healthy controls and to investigate the neuropathological relationship of TAO using magnetic resonance imaging (MRI) data. In this observational case-control study, we included 35 inactive TAO patients, 37 active TAO patients and 23 healthy controls. Voxel-based morphometry (VBM) analysis was conducted to evaluate the gray matter volume (GMV) changes among groups, and the correlations between GMV alterations and clinical parameters in active and inactive TAO groups were investigated. Active TAO patients showed significantly increased GMV in the right inferior frontal gyrus, left superior frontal gyrus (SFG), orbital superior frontal gyrus, orbital middle frontal gyrus, precuneus and postcentral gyrus compared with controls and significantly increased GMV in the right middle temporal gyrus, left SFG and precuneus compared with the inactive TAO group. No significant differences were observed between the inactive TAO group and healthy controls. Notably, the receiver operating characteristic (ROC) curve analysis demonstrated altered GMV among groups and significantly (p < 0.001) differentiated active TAO from inactive TAO and healthy controls. In addition, the mean GMV in precuneus and postcentral gyrus were significantly associated with clinical parameters in active TAO. Our findings suggested the localized GMV alterations among groups were associated with the pathophysiology of TAO and served as a potential discriminative pattern to detect clinical phases of TAO at the individual level. The altered brain morphometry may suggest a corresponding process of self-repair and remodeling of the brain structure as the disease progresses in TAO. [ABSTRACT FROM AUTHOR]

• We here generated a KIRA6 loaded α-Tocopherol nanoemulsion (KT-NE) to relieve oxidative stress and ER of malfunctioned DCs. • Our KT-NE reinvigorates the dysfunctional dendritic cells in tumor microenvironment. • Both KT-NE treated TIDCs and KT-NE itself significantly restore the efficacy of DC-mediated immunotherapy. • Treated with KT-NE, tumor bearing hosts can evoke robust anti-tumor immunity. [Display omitted] In immunosuppressive tumor microenvironment (TME), tumor-infiltrating DCs (TIDCs) feature a redundant lipid accumulation, overwhelming reactive oxygen species (ROS), and hyperactivated endoplasmic reticulum (ER) stress. Herein, we revealed that our KIRA6 loaded α-Tocopherol nanoemulsion (KT-NE) significantly blocked lipid accumulation and revived TIDCs by concurrent inhibition of ER stress and ROS, which might contribute centrally to reset the systemic anti-tumor immune landscape and abrogate tumor progression ultimately. Dendritic cells (DCs), particularly tumor-infiltrating DCs (TIDCs), are critical to the orchestration of T cell-dependent anti-tumor immune response. However, immunosuppressive tumor microenvironment (TME) conspires to pose multifarious challenges that hinder the function of TIDCs and promote the development of immune evasion. The TIDCs with functional defects usually accumulate excessive lipid, characterized with both aberrantly endoplasmic reticulum (ER) stress and oxidative stress. In this study, we generate a KIRA6 loaded α-Tocopherol nanoemulsion (KT-NE), which concurrently inhibits ER stress sensor inositol-requiring kinase 1α (IRE1α)-X-box binding protein 1 (XBP1) and reactive oxygen species (ROS) in dysfunctional lipid-laden TIDCs. As a result, KT-NE prominently mitigates the XBP1- and ROS-triggered lipid accumulation of TIDCs, which reactivates TIDCs and rehabs their capacity of expanding and stimulating tumor-specific T cells. Moreover, both KT-NE treated TIDCs (adoptive transfer) and KT-NE itself could significantly restore the efficacy of DC-mediated immunotherapy and ease tumor burden in malignant ovarian cancer (OvCa)-bearing mice. In conclusion, co-inhibiting hyperactivated XBP1 and redundant intracellular ROS though KT-NE may be a potent therapeutic strategy to ameliorate the ineffective DCs, reverse hostile TME, evoke robust anti-tumor immunity, and extend host progression-free survival ultimately. [ABSTRACT FROM AUTHOR]

[Display omitted] Gastrointestinal cancers (GICs) are highly prevalent cancers that threaten human health worldwide. The Wnt/β-catenin signaling pathway has been reported to play a pivotal role in the carcinogenesis of GICs. Numerous interventions targeting the Wnt/β-catenin signaling in GICs are currently being tested in clinical trials with promising results. Unfortunately, there are no clinically approved drugs that effectively target this pathway. This comprehensive review aims to evaluate the impact of clinical therapies targeting the Wnt/β-catenin signaling pathway in GICs. By integrating data from bioinformatics databases and recent literature from the past five years, we examine the heterogeneous expression and regulatory mechanisms of Wnt/β-catenin pathway genes and proteins in GICs. Specifically, we focus on expression patterns, mutation frequencies, and clinical prognoses to understand their implications for treatment strategies. Additionally, we discuss recent clinical trial efforts targeting this pathway. Understanding the inhibitors currently under clinical investigation may help optimize foundational research and clinical strategies. We hope that elucidating the current status of precision therapeutic stratification for patients targeting the Wnt/β-catenin pathway will guide future innovations in precision medicine for GICs. [ABSTRACT FROM AUTHOR]

Transshipment ports are important constituents of the global and regional container shipping networks. Betweenness centrality is often used to identify transshipment ports by focusing on the global topology of the shipping network without adequate consideration of local topologies of ports' ego shipping networks, and therefore some ports that are playing intermediary roles as hubs within the regional scopes may not be recognized sufficiently. The structural hole theory is introduced to detect regional transshipment ports by paying more attention on local topologies. The results show that the structural hole-based approach can effectively identify some relatively small transshipment ports at the regional level, which are important supplementaries to the detected ports based on betweenness centralities. Las Palmas Port is taken as an illustration to explain how a port occupying the position of a structural hole is likely to become the regional hub by functioning as a connecting bridge. Several policy implications are further elaborated for relevant decision-makers such as liner companies, port authorities and international port operators. • Transshipment ports are constituents of container shipping networks. • Structural hole-based method can effectively identify regional transshipment ports. • Structural hole approach is supplementary to the betweenness centrality method. [ABSTRACT FROM AUTHOR]

Tumor vaccine inducing effective and perdurable antitumor immunity has a great potential for cancer prevention and therapy. The key indicator for a successful tumor vaccine is boosting the immune system to produce more memory T cells. Although many tumor vaccines have been designed, few of them involve in actively regulating immune memory CD8+T cells. Here a tumor vaccine vector (TA-Met@MS) by encapsulating tumor antigen (TA), metformin (Met) and Hollow gold nanospheres (HAuNS) into poly (lactic-co-glycolic acid) (PLGA) microspheres was presented. TA via the treatment of photothermal therapy (PTT) showed high immunogenicity and immune-adjuvant effectiveness. And NIR light-mediated photothermal effect can lead to a pulsed-release behavior of TA and Met from the microspheres. The released TA can regulate primary T cell expansion and contraction, and stimulate the production of effector T cells at the early immunization stage. The metabolic behavior of the cells is then intervened from glycolysis into fatty acids oxidation (FAO) through the activation of AMPK mediated by Met, which can enhance T cell survival and facilitate the differentiation of memory CD8+T cells. This study may present a valuable insight to design tumor vaccine for enhanced cancer prevention and therapy. [ABSTRACT FROM AUTHOR]

Abstract Chemotherapy has become a critical treatment for many cancer types. However, its efficacy is hindered by chemoresistance and limited drug accumulation induced by the hypoxic tumor environment. Therefore, there is an urgent need for useful strategies to alleviate tumor hypoxia and enhance chemotherapy response in solid tumors. Herein, we report the development of a multifunctional liposome simultaneously loading an oxygen carrier (hemoglobin, Hb) and an anti-tumor drug (doxorubicin, DOX) to enhance chemotherapeutic effects against hypoxic tumors. The liposomes, DOX-Hb-lipo (DHL), showed efficient loading of oxygen and site-specific oxygen delivery into tumors, inducing the reversal of tumor hypoxia. Furthermore, the O 2 interference capacity increased the uptake of the drug into hypoxic cancer cells, inducing a remarkably increased toxicity of the drug against cancer cells. Interestingly, the obtained DHL showed a significantly enhanced internalization into cancer cells and accumulation in tumors compared to DL (DOX loaded liposomes without Hb), while the enhanced effect did not occur in normal cells. The specific delivery of DHL into cancer cells should be attributed to the mediation of Hb on the surface of the liposomes. In addition, DHL considerably increased reactive oxygen species (ROS) production in a hypoxic environment and promoted the ROS-mediated cytotoxicity of DOX. Based on the elevated drug accumulation in the tumor sites, increased internalization into cancer cells and enhanced oxygen levels in tumor regions, DHL reversed hypoxia-induced chemoresistance and exhibited stronger antitumor effects. Thus, DHL might be a promising alternative strategy for cancer treatment. Graphical abstract A synchronous oxygen and DOX delivery liposome that could increase drug accumulation and reverse hypoxia-induced chemoresistance. Image 1 [ABSTRACT FROM AUTHOR]

Mutations in the tubulin beta 8 class VIII ( TUBB8 ) gene have been proven to cause oocyte maturation arrest. The aim of this study was to describe newly discovered mutations in TUBB8 and to investigate the prevalence of TUBB8 mutations in our cohort. Nine women with oocyte maturation arrest and 100 fertile female controls were recruited. Sanger sequencing of the coding regions of TUBB8 revealed a heterozygous variant c.535G > A (p.V179M) in two unrelated affected individuals and a heterozygous variant c.5G > T (p.R2M) in one affected individual. These TUBB8 variants were inherited from the unaffected fathers and were absent in 100 fertile female control individuals. In total, 33.33% (3/9) of the affected individuals in our cohort obtained a clear genetic diagnosis through sequencing of the TUBB8 gene. These two novel variants extend the spectrum of TUBB8 mutations and this study confirmed that TUBB8 mutations occur in a high proportion of infertile women with oocyte maturation arrest. [ABSTRACT FROM AUTHOR]

• Hyperspectral reflectance at canopy-scale of apple-trees was measured using the portable spectroradiometer. • The spectra of apple tree canopy affected by floating dust particles were well preprocessed by SNV-FD. • Random frog (Rfrog) was used to extract feature bands for estimating leaf N content in apple-trees. • The combination of SNV-FD, Rfrog and ELM was feasible and reliable for estimating the leaf N content in apple-trees. Rapid estimation of crop nitrogen (N) status is helpful for achieving precise N fertilizer management, so as to promote the collaborative improvement of yield, quality and N use efficiency. To establish a method for rapidly estimating N status of apple-trees based on hyperspectral remote sensing, a field experiment on apple trees with four levels of N application were conducted in Luochuan, Yan'an, China in 2018 and 2019. Hyperspectral data at apple tree canopy scale were obtained at different phenological stages. The outliers in the dataset were detected by Monte-Carlo cross-validation (MCCV). A total of 15 forms of spectral data were analyzed, including the raw spectrum (RS), Savitzky-Golay (SG) smoothing, normalization by the mean (NME), standard normal transformation (SNV), multiplicative scatter correction (MSC) and their combination with the first-order derivative (FD) or second-order derivative (SD). The results showed that SNV-FD was the best preprocessing method for apple tree canopy spectral data on the Loess Plateau. For SNV-FD data, competitive adaptive reweighted sampling (CARS), successive projection algorithm (SPA), random frog (Rfrog), and partial least squares (PLS) were used to extract feature variables. The feature wavelengths extracted by CARS, SPA and Rfrog were widely distributed in visible and near-infrared (VIS/NIR) range. The feature variables extracted by PLS were fewer, but had a strong interpretation. Based on these feature variables, linear and nonlinear models including partial least squares regression (PLSR), support vector machine (SVM), back-propagation artificial neural network (BPANN), extreme learning machine (ELM) and random forest (RF), were used to establish the prediction model. Among all the models, four nonlinear modeling methods were superior to the linear method. The model by Rfrog-ELM achieved the best results (R2 P = 0.843, RMSEP = 2.461 g·kg−1, RPD = 2.508). This study demonstrated that the combination of SNV-FD, Rfrog and ELM was feasible and reliable for estimating the leaf N content in apple-trees on the Loess Plateau, China. [ABSTRACT FROM AUTHOR]

The treatment of metastatic cancer is a huge challenge at the moment. Highly precise targeting delivery and drug release in tumor have always been our pursuit in cancer therapy, especially to advance cancer with metastasis, for increasing the efficacy and biosafety. We established a smart nanosized micelle, formed by tocopherol succinate (TOS) conjugated hyaluronic acid (HA) using a disulfide bond linker. The micelle (HA-SS-TOS, HSST) can highly specifically bind with CD44 receptor over-expressed tumor, and response selectively to high GSH level in the cells, inducing disulfide bond breakage and the release of the payload (paclitaxel, PTX). To predict the antitumor efficacy of the micelles more clinically, we established an orthotopic colon cancer model with high metastasis rate, which could be visualized by the luciferase bioluminescence. Our data confirmed CD44 high expression in the colon cancer cells. Highly matching between the micellar fluorescence and bioluminescence of cancer cells in intestines demonstrated an exact recognition of our micelles to orthotopic colon tumor and its metastatic cells, attributing to the mediation of CD44 receptors. Furthermore, the fluorescence of the released Nile Red from the micelles was found only in the tumor and its metastatic cells, and almost completely overlapped with the bioluminescence of the cancer cells, indicating a highly selective drug release. Our micelles presented an excellent therapeutic effect against metastatic colon cancer, and induced significantly prolonged survival time for the mice, which might become a promising nanomedicine platform for the future clinical application against advanced cancers with high CD44 receptor expression. [ABSTRACT FROM AUTHOR]

CO 2 emission generated by yard tractors at container terminals have been proven to be one of the main sources of pollution from maritime transportation. This paper aims to offer a method for evaluating the emissions from yard tractors during loading. First, an assignment model of export containers is built to capture the behavior of tractor arrivals at each block when the loading begins and the queuing theory is used to model the congestion happening in the yard. Second, emissions from yard tractors are evaluated based on the forecast arrivals. The emissions are categorized into two types: one from those tractors which are moving at normal speed and the other from those tractors sitting in traffic jam or at the stop-and-go state. Terminals with different calls and diversified storage utilization are simulated to show the performance of the proposed method and identify potential measures for traffic management aiming to reduce transport emissions. It is shown that the emissions from the yard tractors are closely related to the location of export containers and should be a main concern in operating a busy terminal. [ABSTRACT FROM AUTHOR]

Transplantation is the most effective, and sometimes the only resort for end-stage organ failure. However, allogeneic graft suffers greatly from lymphocyte-mediated immunorejection, which bears close relationship with a hyperactivation of endoplasmic reticulum (ER) stress response in host lymphocytes, especially in CD8+ T cells (T-8). Therefore, regulating lymphocytic ER unfolded protein response (UPR) might be a potential therapeutic breakthrough in alleviating graft rejection. Here, ER-targetable liposome is prepared via the surface modification of ER-targeting peptide (Pardaxin), which efficiently loads and directly delivers small molecule inhibitor of UPR sensor IRE1α into the ER of lymphocytes, inducing a systemic immunosuppression that facilitates tumorigenesis and metastasis in the tumor inoculation challenge in vivo. And in vitro , a stage-differential dependency of IRE1α in the phase transition of T-8 is identified. Specifically, inhibiting IRE1α at the early responding stages of T-8, especially at the activation phase, results in a shrunk proliferation, impaired effector function, and limited memory commitment, which might contribute centrally to the induced overall immunosuppression. Based on this, a classical acute rejection model, murine full-thickness trunk skin allograft that primary arises from the hyperactivity of T-lymphocyte, is used. Results suggest that lymphocytic IRE1α inactivation attenuates transplant rejection and prolongs graft survival, with a limited effector function and memory commitment of host T-8. Moreover, an even higher immunosuppressive effect is obtained when IRE1α inhibition is used in combination with immunosuppressant tacrolimus (FK506), which might owe to a synergistic regulation of inflammatory transcription factors. These findings provide a deeper insight into the biological polarization and stress response of lymphocytes, which might guide the future development of allogeneic transplantation. We here reveal that endoplasmic reticulum (ER)-targeted abrogation of lymphocytic ER-stress transducer IRE1ɑ induces a systemic immunosuppression to alleviate skin allograft rejection, which displays synergism with immunosuppressant tacrolimus (FK506), probably due to a cooperative regulation over inflammatory transcription factors. Further exploration identified a stage-differential dependency of IRE1ɑ in the phase transition of CD8+ T cells (T-8), which might contribute centrally to the negative immunoregulation of lymphocytic IRE1ɑ inhibition. [Display omitted] [ABSTRACT FROM AUTHOR]