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Although most [CD8.sup.+] T cells are equipped to kill infected or transformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CD8 lineage that is instructed to differentiate into CD8 T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self- peptides. Recognition and elimination of pathogenic target cells that express these Qa-1- self-peptide complexes selectively inhibits pathogenic antibody responses without generalized immune suppression. Immunization with synthetic agonist peptides that mobilize CD8 Tregs in vivo efficiently inhibit antigraft antibody responses and markedly prolong heart and kidney organ graft survival. Definition of TCR-dependent differentiation and target recognition by this lineage of CD8 Tregs may open the way to new therapeutic approaches to inhibit pathogenic antibody responses., Introduction The immune system has evolved complex mechanisms that allow efficient destruction of microbial pathogens while sparing the host's own tissues. Maintenance of this balance depends, in part, on regulatory [...]

Grape skin serves as a reservoir for many bacteria and fungi, which can affect grape health, quality, and safety. However, grape skin microbiota and mycobiota of table grapes remain largely understudied. This study investigated bacterial and fungal communities residing on different table grapevine cultivars ('Summer Black' and 'Kyoho') as well as the impact of potential contributors thereby, via culture-dependent and culture-independent (analysis of 16S rRNA gene and internal transcribed spacer sequences) methods with different purposes. Microbiota of both grapevine cultivars were dominated by Cladosporium, Alternaria, Aspergillus, Thauera, and Pantoea. In addition, yeast strains belonging to Hanseniaspora opuntiae, Pichia terricola, Rhodotorula mucilaginosa, Candida stellimalicola, and Kodamaea ohmeri were enriched from the studied grapes, while some strains were considered as health-threatening pathogens. Differences in grapevine cultivars did not significantly affect their mycobiota and microbiota profiles. Nevertheless, their mycobiota exhibited significant variations across different grape-sampling sites in Shanghai, indicating the contribution of the grape-growing environment to grape skin mycobiota. Altogether, the current study demonstrated the contribution of the grape-growing environment to table grape skin mycobiota, and highlighted the importance of microbiota management in the production and consumption of table grapes. [ABSTRACT FROM AUTHOR]

The normal operation of various superconducting magnets is greatly influenced by the thermal stress of the insulating system, commonly made of epoxy resins with vacuum pressure impregnation (VPI) technology, throughout the curing and cooling processes. In this work, we developed a Fiber Bragg Grating (FBG) strain measurement method to monitor the real-time strain responses of an epoxy resin IR-3 and its glass fiber-reinforced composite during both curing and cooling processes. Then, we also monitored the same process of a Nb–Ti superconducting magnet coil prepared by VPI technology. With the help of FBG strain sensors, the residual strains of the coil at various positions and directions were investigated. The results show that the large residual strain occurred near the end of the coil in the axial direction. In addition, the interlaminar shear stress properties were measured at both room temperature and liquid nitrogen temperature. The strain characteristics of the epoxy resin IR-3 and the insulating system can provide useful guidance for the design and construction of high-field Nb–Ti superconducting magnets. [ABSTRACT FROM AUTHOR]

The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single- cell RNA sequencing of the LNs showed that anti-CD40L promotes a [Madcam1.sup.+] FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node address in (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79-anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79-anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance., Introduction Lymph nodes (LNs) are integral sites at which the alloimmune response is mounted following transplantation. Our group has shown that LNs also function as sites of immune regulation by [...]

Chronic allograft dysfunction (CAD) is the major cause of late graft loss in long-term renal transplantation. In our previous study, we found that epithelial–mesenchymal transition (EMT) is a significant event in the progression of renal allograft tubulointerstitial fibrosis, and impaired autophagic flux plays a critical role in renal allograft fibrosis. Everolimus (EVR) has been reported to be widely used to prevent the progression of organ fibrosis and graft rejection. However, the pharmacological mechanism of EVR in kidney transplantation remains to be determined. We used CAD rat model and the human kidney 2 (HK2) cell line treated with tumor necrosis factor-α (TNF-α) and EVR to examine the role of EVR on TNF-α-induced EMT and transplanted renal interstitial fibrosis. Here, we found that EVR could attenuate the progression of EMT and renal allograft interstitial fibrosis, and also activate autophagy in vivo. To explore the mechanism behind it, we detected the relationship among EVR, autophagy level, and TNF-α-induced EMT in HK2 cells. Our results showed that autophagy was upregulated upon mTOR pathway inhibition by EVR, which could significantly reduce expression of TNF-α-induced EMT. However, the inhibition of EVR on TNF-α-induced EMT was partly reversed following the addition of autophagy inhibitor chloroquine. In addition, we found that TNF-α activated EMT through protein kinase B (Akt) as well as nuclear factor kappa B (NF-κB) pathway according to the RNA sequencing, and EVR's effect on the EMT was only associated with IκB-α stabilization instead of the Akt pathway. Together, our findings suggest that EVR may retard impaired autophagic flux and block NF-κB pathway activation, and thereby prevent progression of TNF-α-induced EMT and renal allograft interstitial fibrosis. [ABSTRACT FROM AUTHOR]

Background: Nowadays, renal allograft survival is confined by the development of allograft fibrosis. Previous studies have reported interleukin-33 (IL-33) upregulated significantly in patients with chronic renal allograft dysfunction, and it could induce renal tubular epithelial to mesenchymal transition (EMT), which eventually contributed to renal allograft fibrosis. Our study intended to detect the underlying association between single nucleotide polymorphisms (SNPs) of IL-33 gene and renal allograft fibrosis in kidney transplant recipients.Methods: We collected blood samples from 200 renal transplant recipients for the identification of SNPs and transplanted kidney tissue samples for identifying differentially expressed genes (DEGs). Intersection of SNP-related genes and DEGs was conducted for further analysis. Relationships between these SNPs and renal allograft fibrosis were evaluated by the inheritance models. Immunohistochemical (IHC) staining and western blotting (WB) were used to detect the expression of IL-33 and the markers of EMT in human kidney tissues obtained from control and chronic renal allograft dysfunction (CAD) patients. In vitro, we detected the progressions of EMT-related markers and the levels of MAPK signaling pathway mediators after transfecting IL-33 mutant plasmids in HK2 cells.Results: Three intersected genes including IL-33 genes were significantly expressed. IL-33 expression was validated in kidney tissues by IHC and WB. Thirty-nine IL-33-related SNPs were identified in targeted sequencing, in which 26 tagger SNPs were found by linkage disequilibrium analysis for further analysis. General linear models indicated sirolimus administration significantly influenced renal allograft fibrosis (P < 0.05), adjustment of which was conducted in the following analysis. By multiple inheritance model analyses, SNP rs10975519 of IL-33 gene was found closely related to renal allograft fibrosis (P < 0.005). Furthermore, HK2 cells transfected with mutated plasmid of rs10975519 showed stronger mobility and migration ability. Moreover, IL-33 mutant plasmids could promote the IL-33-induced EMT through the sustained activation of p38 MAPK signaling pathway in HK2 cells.Conclusion: In our study, rs10975519 on the IL-33 gene was found to be statistically associated with the development of renal allograft fibrosis in kidney transplant recipients. This process may be related to the IL-33-induced EMT and sustained activation of p38 MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Iguratimod (IGU) can mitigate the symptoms of rheumatoid arthritis through its anti-inflammatory effects. The objective of this study was to investigate the clinical efficacy and safety of IGU in highly HLA-mismatched renal transplant recipients, in combination with standard immunosuppressive regimen. This pilot study was designed as an open-label, blank-control, randomized clinical trial on patients recruited from a single transplant center in China. Patients who met the inclusion criteria were randomized to the IGU (n=27) and blank control (n=27) groups. IGU was administrated with the conventional triple immunosuppressive protocol for 52 weeks after kidney transplantation. The incidence of biopsy-proven acute rejection rate was 14.8% (4/27) in the IGU group and 29.6% (8/27) in the control group, P = 0.19. The clinical rejection rate was also substantially reduced in the IGU group (3.7% vs. 18.5%, P = 0.08). De novo donor-specific antibody also showed a decline trend in the IGU group after 52 weeks. The graft function and incidence of adverse events were similar between the two groups. In addition, IGU intervention significantly decreased the number of NK cells throughout the follow-up. In conclusion, our study has shown the possibility that IGU could reduce the allograft rejection rate and de novo DSA with appreciable safety in combination with conventional immunosuppressants. Formal clinical trials were warranted based on current findings. [ABSTRACT FROM AUTHOR]

To resist large electromagnetic loads, the ITER correction coils (CCs) are protected by a 20-mm thickness 316LN austenitic stainless steel case. Due to the strict tolerance requirement of the case manufacture, tungsten inert gas (TIG) welding technology was used for subcase assembly welding, whereas laser beam welding (LBW) technology was applied to enclosure welding of the cases. The case shall be operated at 4.2 K and shall undergo considerably cyclic stress due to magnet electromagnetization as well as interaction with the toroidal field (TF) and poloidal field (PF). This article focuses on the assessment of the mechanical properties of the welding joints at cryogenic temperature. Results indicated that the values of the ultimate tensile strength of the TIG welding joint and the LBW welding joint were 1555 and 1522 MPa, respectively, which reach to 99.7 and 97.6% of that of the base material (BM). The elongation at the fracture of both the TIG and LBW weldments was larger than 35%. The plane strain fracture toughness KIc(J) of the TIG and the LBW weldments was 210 and 241 MPa·m1/2, respectively. The fractographic analysis indicated that the fracture surface was composed of fine equiaxed dimples, which indicated that both welding joints fractured in a ductile manner. The welding joints survived the minimum of 30 000 cycles fatigue test at stress level and load ratio specified by the ITER document. In addition, the fatigue crack growth rates of both welding joints were lower than that of the BM. All mechanical properties of both the welding joints satisfied the ITER specifications. [ABSTRACT FROM AUTHOR]

Background: Costimulatory blockade provides new therapeutic opportunities for ensuring the long-term survival of kidney grafts. The adoption of the novel immunosuppressant Belatacept has been limited, partly due to concerns regarding higher rates and grades of acute rejection in clinical trials. In this study, we hypothesized that a combined therapy, Belatacept combined with BTLA overexpression, may effectively attenuate acute rejection after kidney transplantation. Materials and Methods: The rat kidney transplantation model was used to investigate graft rejection in single and combined therapy. Graft function was analyzed by detecting serum creatinine. Pathological staining was used to observe histological changes in grafts. The expression of T cells was observed by immunohistochemistry and flow cytometry. In vitro , we constructed an antigen-stimulated immune response by mixed lymphocyte culture, treated with or without Belatacept and BTLA-overexpression adenovirus, to observe the proliferation of receptor cells and the expression of cytokines. In addition, western blot and qRT-PCR analyses were performed to evaluate the expression of CTLA-4 and BTLA at various time points during the immune response. Results: In rat models, combined therapy reduced the serum creatinine levels and prolonged graft survival compared to single therapy and control groups. Mixed acute rejection was shown in the allogeneic group and inhibited by combination treatment. Belatacept reduced the production of DSA and the deposition of C4d in grafts. Belatacept combined with BTLA overexpression downregulated the secretion of IL-2 and IFN-γ, as well as increasing IL-4 and IL-10 expression. We also found that Belatacept combined with BTLA overexpression inhibited the proliferation of spleen lymphocytes. The duration of the elevated expression levels of CTLA-4 and BTLA differentially affected the immune response. Conclusion: Belatacept combined with BTLA overexpression attenuated acute rejection after kidney transplantation and prolonged kidney graft survival, which suggests a new approach for the optimization of early immunosuppression after kidney transplantation. [ABSTRACT FROM AUTHOR]

The database of thermal expansion behavior of closed-cell polyurethane rigid foam at very low temperatures is required for designing and manufacturing thermal insulation components of various cryogenic systems. In the present work, thermal expansion behaviors of closed-cell polyurethane rigid foams with different densities were investigated in the 20 K–270 K temperature range by means of a high-resolution extensometer technique, which has been verified through comparison with standard values of an AISI 304 stainless steel rod. The comparison result demonstrates that the maximum deviation from the standard coefficient of thermal expansion of the AISI 304 in cryogenic temperatures is less than 6.6%. Testing results indicate that the cryogenic thermal expansions of closed-cell polyurethane rigid foams depend reversely on density. Moreover, the thermal expansion behavior of closed-celled polyurethane rigid foams exhibits difference from that of bulky amorphous isotropic polymers, which have been attributed to several factors such as enclosed air and cellular structure. [ABSTRACT FROM AUTHOR]

Allograft interstitial fibrosis was characterized by massive extracellular matrix deposition caused by activated fibroblasts and myofibroblasts. Epithelial‐mesenchymal transition (EMT) is recognized as an important source of myofibroblasts contributing to the pathogenesis of allograft interstitial fibrosis. Smad ubiquitination regulatory factor 1 (Smurf1) has been recently reported to be involved in the progression of EMT. Our study was to detect the effect of Bortezomib and Smurf1 in the EMT and allograft interstitial fibrosis. Biomarkers of EMT, as well as Smurf1, were examined in human proximal tubular epithelial cells (HK‐2) treated with tumour necrosis factor‐alpha (TNF‐α) in various doses or at various time points by Western Blotting or qRT‐PCR. We knockdown or overexpressed Smurf1 in HK‐2 cells. Furthermore, rat renal transplant model was established and intervened by Bortezomib. Allograft tissues from human and rats were also collected and prepared for HE, Masson's trichrome, immunohistochemical staining and western blotting assays. As a result, we found that TNF‐α significantly promoted the development of EMT in a time‐dependent and dose‐dependent manner through Smurf1/Akt/mTOR/P70S6K signalling pathway. More importantly, Bortezomib alleviated the progression of EMT and allograft interstitial fibrosis in vivo and in vitro by inhibiting the production of TNF‐α and expression of Smurf1. In conclusion, Smurf1 plays a critical role in the development of EMT induced by TNF‐α. Bortezomib can attenuate the Sumrf1‐mediated progression of EMT and renal allograft interstitial fibrosis, which could be suggested as a novel choice for the prevention and treatment of renal allograft interstitial fibrosis. [ABSTRACT FROM AUTHOR]