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Delayed graft function due to transplant ischemia/reperfusion injury adversely affects up to 50% of deceased-donor kidney transplant recipients. However, key factors contributing to the severity of ischemia/reperfusion injury remain unclear. Here, using a clinically relevant mouse model of delayed graft function, we demonstrated that donor genetic background and kidney-intrinsic MyD88/Trif-dependent innate immunity were key determinants of delayed graft function. Functional deterioration of kidney grafts directly corresponded with the duration of cold ischemia time. The graft dysfunction became irreversible after cold ischemia time exceeded six hours. When cold ischemia time reached four hours, kidney grafts displayed histological features reflective of delayed graft function seen in clinical kidney transplantation. Notably, kidneys of B6 mice exhibited significantly more severe histological and functional impairment than kidneys of C3H or BALB/c mice, regardless of recipient strains or alloreactivities. Furthermore, allografts of B6 mice also showed an upregulation of IL-6, neutrophil gelatinase-associated lipocalin, and endoplasmic reticulum stress genes, as well as an increased influx of host neutrophils and memory CD8 T-cells. In contrast, donor MyD88/Trif deficiency inhibited neutrophil influx and decreased the expression of IL-6 and endoplasmic reticulum stress genes, along with improved graft function and prolonged allograft survival. Thus, kidney-intrinsic factors involving genetic characteristics and innate immunity serve as critical determinants of the severity of delayed graft function. This preclinical murine model allows for further investigations of the mechanisms underlying delayed graft function.

Limb transplant in particular and vascularized composite allotransplant (VCA) in general have wide therapeutic promise that have been stymied by current limitations in immunosuppression and functional neuromotor recovery. Many animal models have been developed for studying unique features of VCA, but here we present a robust reproducible model of orthotopic hind limb transplant in rats designed to simultaneously investigate both aspects of current VCA limitation: immunosuppression strategies and functional neuromotor recovery. At the core of the model rests a commitment to meticulous, time-tested microsurgical techniques such as hand sewn vascular anastomoses and hand sewn neural coaptation of the femoral nerve and the sciatic nerve. This approach yields durable limb reconstructions that allow for longer lived animals capable of rehabilitation, resumption of daily activities, and functional testing. With short-term treatment of conventional immunosuppressive agents, allotransplanted animals survived up to 70 days post-transplant, and isotransplanted animals provide long lived controls beyond 200 days post-operatively. Evidence of neurologic functional recovery is present by 30 days post operatively. This model not only provides a useful platform for interrogating immunological questions unique to VCA and nerve regeneration, but also allows for in vivo testing of new therapeutic strategies specifically tailored for VCA.

Objective Active antibody-mediated rejection (aABMR), particularly late aABMR, remains a major challenge for long-term renal allograft survival. This single-center retrospective study aimed to compare clinical features between early vs late aABMR and to identify risk factors for allograft failure among patients with aABMR. Method Forty-one patients diagnosed with aABMR at our hospital were included and were divided into 2 groups: early aABMR (≤6 months; n = 10) vs late aABMR (>6 months; n = 31) based on the time from transplant to diagnosis. Their clinical and pathologic data were compared. This study was performed in compliance with the Helsinki Congress and the Declaration of Istanbul. Results Of 10 patients with early aABMR, none had allograft failure, whereas 8 of 31 patients with late aABMR had developed allograft failure at the time of follow-up (25.8%). At the time of biopsy, patients with early aABMR had higher positive grade in urine occult blood test than patients with late aABMR (P = .01); however, the late aABMR group displayed more intensive interstitial fibrosis and tubular atrophy (P = .03) and more frequent HLA-DQ-type donor-specific antibodies. Interestingly, donor-specific antibody conversion from positive to negative was not associated with C4d grade but was correlated with time from transplant to biopsy. Multivariate Cox regression analysis indicated that high levels of serum creatinine or proteinuria and concomitant T-cell-mediated rejection were independent risk factors for allograft failure in patients with aABMR. Conclusion These data not only confirm that early aABMR has better clinical outcomes than late aABMR but highlight the importance of early diagnostic biopsy and early therapeutic interventions in ABMR, particularly in patients with high levels of serum creatinine or proteinuria in the early posttransplant phase.

Subjective well-being is a comprehensive psychological indicator for measuring quality of life. Studies have found that emotional measurement methods and measurement accuracy are important for well-being-related research. Academic emotion is an emotion description in the field of education. The subjective well-being of learners in an online learning environment can be studied by analyzing academic emotions. However, in a large-scale online learning environment, it is extremely challenging to classify learners&rsquo, academic emotions quickly and accurately for specific comment aspects. This study used literature analysis and data pre-analysis to build a dimensional classification system of academic emotion aspects for students&rsquo, comments in an online learning environment, as well as to develop an aspect-oriented academic emotion automatic recognition method, including an aspect-oriented convolutional neural network (A-CNN) and an academic emotion classification algorithm based on the long short-term memory with attention mechanism (LSTM-ATT) and the attention mechanism. The experiments showed that this model can provide quick and effective identification. The A-CNN model accuracy on the test set was 89%, and the LSTM-ATT model accuracy on the test set was 71%. This research provides a new method for the measurement of large-scale online academic emotions, as well as support for research related to students&rsquo, well-being in online learning environments.

Aim To investigate whether the parameters of machine perfusion could predict the quality of kidneys from donation after circulatory death(DCD) donors and expanded criteria donors (ECD) . Methods 58 kidneys from DCD/ECD donors were harvested in our hospital from July 2011 to August 2014. All kidneys were preserved with machine perfusion(Life Port), and parameters of machine perfusion were collected. All kidneys were biopsied before transplantation. The primary endpoints were delayed graft function(DGF), graft loss and patient death. Results After kidney transplantation, 26 patients(44.8%) had DGF. We chose 1-hour RI as a predictive parameter to predict DGF after transplant, and made the ROC curve. The ROC curve showed that 1-hour RI = 0.4 was the best cut-off point for predicting DGF after transplant. The sensitivity was 61.54% , and the specificity was 81.25%. 58 recipients were divided into two groups according to 1-hour RI of machine perfusion. 22 cases in high RI group (RI > 0.4) and 36 cases in low RI group( RI ≤0.4). DGF rate was significantly higher in the high RI group(72.7% vs. 27.8%). 1-year serum creatinine levels were also significantly higher in the high RI group(p

Summary Peritransplant infusion of ethylene carbodiimide-fixed donor splenocytes (ECDI-SPs) induces protection of islet and cardiac allografts. However, pro-inflammatory cytokine production during the peritransplantation period may negate the effect of ECDI-SPs. Therefore, we hypothesized that blocking pro-inflammatory cytokine secretion while increasing levels of anti-inflammatory cytokines would enhance the tolerance-induced efficacy of ECDI-SPs. The objective of this study was to determine the effectiveness of using ECDI-SPs combined with a short course of α1-antitrypsin (AAT) for induction of tolerance. Using a mice cardiac transplant model, we demonstrated that ECDI-SPs + AAT effectively induced indefinite mice cardiac allograft protection in a donor-specific fashion. This effect was accompanied by modulation of cytokines through decreasing levels of pro-inflammatory cytokines (including IFN-γ, TNF-α, IL-1β, IL-6, IL-17, and IL-23) and increasing levels of anti-inflammatory cytokines (including IL-10, IL-13, and TGF-β), and by inhibition of effector T cells (Teff) and expansion of regulatory T cells (Tregs). Therefore, we concluded that combined ECDI-SPs and AAT appeared to modulate the expression of cytokines and regulate the Teff:Treg balance to create a support milieu for graft protection. Our strategy of combining ECDI-SPs and AAT provides a promising approach for inducing donor-specific transplant tolerance.

Ischemia/reperfusion injury (IRI) is inherent to all transplanted organs and is adversely associated with early renal graft function and graft longevity. Despite the progress in immunosuppressive regimens and perioperative care, no FDA-approved treatment for kidney transplant IRI is available to date. In recent years, by utilizing the modified and clinically-relevant mouse models of kidney transplantation (KTx) in which extended IRI is induced by the prolonged warm or cold ischemic time, studies have identified several potential therapeutic approaches for KTx IRI, including the hormone supplement, promoting tubular repair and regeneration, and targeting complement system, inflammation, and necroptosis. This review describes some of the lessons learned from mouse models of KTx with regard to factors that influence the severity of transplant IRI and the potential therapeutic targets.

Reactivation of latent cytomegalovirus remains an important complication after transplant. Although immunosuppression (IS) has been implicated as a primary cause, we have previously shown that the implantation response of a kidney allograft can lead to early transcriptional activation of latent murine cytomegalovirus (MCMV) genes in an immune-competent host and to MCMV reactivation and dissemination to other organs in a genetically immune-deficient recipient. We now describe a model that allows us to separately analyze the impact of the implantation effect vs that of a clinically relevant IS regimen. Treatment with IS of latently infected mice alone does not induce viral reactivation, but transplant of latently infected allogeneic kidneys combined with IS facilitates MCMV reactivation in the graft and dissemination to other organs. The IS regimen effectively dampens allo-immune inflammatory pathways and depletes recipient anti-MCMV but does not affect ischemia-reperfusion injury pathways. MCMV reactivation similar to that seen in allogeneic transplants combined with also occurs after syngeneic transplants. Thus, our data strongly suggest that while ischemia-reperfusion injury of the implanted graft is sufficient and necessary to initiate transcriptional reactivation of latent MCMV ("first hit"), IS is permissive to the first hit and facilitates dissemination to other organs ("second hit").

The urgent unmet need of improving the outcomes of cancer patients is to develop novel treatment strategies that can reduce the systemic toxicity of chemotherapy and overcome the multiple drug resistance (MDR). Developing effective combination treatment regimens is an ideal approach to improve the efficiency of chemotherapy. Bruton's tyrosine kinase (BTK) is a key component of the B-cell receptor (BCR) signaling pathway and plays an essential role in B-cell maturation and lymphomagenesis. The development of BTK inhibitors and their application in clinic represent the major advance in the treatment of hematological malignancies. Recently, extensive studies have demonstrated that the aberrant activation of the BTK signaling pathway has been involved in MDR. Targeting the BTK signaling pathway could sensitize the cancer cells resistant to various chemotherapy drugs including paclitaxel, cisplatin, doxorubicin, proteasome inhibitors, Bcl-2 antagonists, and HDAC inhibitors. The combination treatment strategies using the BTK inhibitor, ibrutinib, and other chemotherapy agents have been proven effective in targeting resistant cell lines. Some of the combination treatment regimens are currently tested in clinical trials. In this chapter, the mechanisms, applications, as well as the efficacy of BTK inhibitors acting as sensitizing agents in cancer chemotherapy are discussed.

A digital image correlation technique with non-fixed camera is developed for deformation measurement in the field since it is difficult to fix cameras when the deformations of a large number of areas need to be measured. Multiple reference and target images of the specimen surface and a feature template are captured from different orientations and corrected before the correlation calculation. The relative positions of the specimen surface and the camera are obtained by the camera calibration method. The specimen surface is divided to several meshes to reconstruct the speckle patterns. The technique is more flexible and convenient than traditional digital image correlation method in measuring the deformation of high altitude facilities such as bridges. In order to test the accuracy of this method, the deformations of an aluminum plate under different loading forces are measured and compared to the values recorded by the tensile tester.

Transplantation tolerance is achieved when recipients are unresponsive to donor alloantigen yet mobilize against third-party antigens, including virus. After transplantation, cytomegalovirus (CMV) reactivation in latently-infected transplants reduces allograft viability. To determine if pre-tolerized recipients are resistant to viral dissemination in this setting, we transfused chemically-fixed donor splenocytes (1-ethyl-3- (3&prime, dimethyl-aminopropyl)-carbo-diimide (ECDI)-treated splenocytes (ECDIsp)) to induce donor antigen tolerance without immunosuppression. In parallel, we implanted donor islet cells to validate operational tolerance. These pre-tolerized recipients were implanted with murine CMV (MCMV) latently-infected donor kidneys (a validated model of CMV latency) to monitor graft inflammation and viral dissemination. Our results indicate that tolerance to donor islets was sustained in recipients after implantation of donor kidneys. In addition, kidney allografts implanted after ECDIsp and islet implantation exhibited low levels of fibrosis and tubulitis. In contrast, kidney cellular and innate immune infiltrates trended higher in the CMV group and exhibited increased markers of CD8+ T cell activation. Tolerance induction was unable to prevent increases in MCMV-specific CD8+ T cells or dissemination of viral IE-1 DNA. Our data suggest that latently-infected allografts are inherently more susceptible to inflammation that is associated with viral dissemination in pre-tolerized recipients. Thus, CMV latently-infected allografts require enhanced strategies to protect allograft integrity and viral spread.