A Role for Human Renal Tubular Epithelial Cells in Direct Allo-Recognition by CD4+ T-Cells and the Effect of Ischemia-Reperfusion

Direct allorecognition is the earliest and most potent immune response against a kidney allograft. Currently, it is thought that passenger donor professional antigen-presenting cells (APCs) are responsible. Further, many studies support that graft ischemia-reperfusion injury increases the probability of acute rejection. We evaluated the possible role of primary human proximal renal tubular epithelial cells (RPTECs) in direct allorecognition by CD4+ T-cells and the effect of anoxia-reoxygenation. In cell culture, we detected that RPTECs express all the required molecules for CD4+ T-cell activation (HLA-DR, CD80, and ICAM-1). Anoxia-reoxygenation decreased HLA-DR and CD80 but increased ICAM-1. Following this, RPTECs were co-cultured with alloreactive CD4+ T-cells. In T-cells, zeta chain phosphorylation and c-Myc increased, indicating activation of T-cell receptor and co-stimulation signal transduction pathways, respectively. T-cell proliferation assessed with bromodeoxyuridine assay and with the marker Ki-67 increased. Previous culture of RPTECs under anoxia raised all the above parameters in T-cells. FOXP3 remained unaffected in all cases, signifying that proliferating T-cells were not differentiated towards a regulatory phenotype. Our results support that direct allorecognition may be mediated by RPTECs even in the absence of donor-derived professional APCs. Also, ischemia-reperfusion injury of the graft may enhance the above capacity of RPTECs, increasing the possibility of acute rejection.     

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.     

Decreased CD10-positive granulocytes for the differential diagnosis of myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are highly heterogeneous myeloid neoplasms, and a large number of patients are difficult to diagnose and classify by blood and bone marrow examination. As a surface marker of granulocyte, studies have shown CD10 can be used to define the degree of granulocyte maturation in MDS patients. However, whether it can be used for differential diagnosis of MDS and other hematological diseases remains inconclusive. To explore the value of CD10 for differential diagnosis of MDS, 60 newly diagnosed MDS, 20 aplastic anemia (AA) patients, and 35 iron-deficient anemia (IDA) patients were selected for this study. Bone marrow (BM) specimens were processed for surface marker analysis and labeled with pre-conjugated monoclonal antibodies. Stained cells were detected by flow cytometry. Our results indicated that CD10-positive granulocytes were significantly decreased in BM of MDS patients than AA and IDA patients, and the level of CD10-positive mature granulocytes was not associated with the clinical stages of malignancy. Receiver operating characteristic (ROC) areas under the curve (AUC) of CD10-positive granulocytes was 0.86 and 0.85, respectively, in MDS patients than the IDA group and AA group with good specificity and sensitivity. Further, CD10-positive granulocytes were increased after effective treatment. In conclusion, we found the decrease in CD10-positive granulocytes has a differential diagnostic value of MDS.     

5754-H34铝合金板材生产工艺研究

研究了不同冷变形程度，退火温度对5754铝合金冷轧板材的组织和力学性能的影响，确定了5754合金H34状态板材的生产工艺参数，即冷变形程度25%-45￥，稳定化退火温度120-160℃，保温时间3-6h，在工业生产条件下，其产品的技术指标达到了用户要求。     

一种以太网兼容的综合话音/数据传输协议

本文提出一种与现有以太网兼容的综合话音/数据协议.描述了协议模型及实现方法.并用PASCAL语言在IBM-PC机上模拟研究了该协议的性能.模拟结果表明,该协议能满足话音的实时要求,性能良好,且数据传输性能没有明显下降.协议克服了以太网传输话音延迟不确定的缺点.     

SAPO-34/SiO_2催化甲醇制烯烃

采用水热法合成了SAPO-34分子筛,并用X射线粉末衍射仪和扫描电子显微镜对SAPO-34分子筛的结构进行了表征,同时探讨了黏合剂种类、甲醇分压、催化剂粒径和硅源等对SAPO-34分子筛催化甲醇制烯烃(MTO)反应性能的影响。实验结果表明,在MTO反应中,三烯(乙烯、丙烯和丁烯)选择性在反应初期存在明显的诱导期;以S iO2为黏合剂合成的SAPO-34/S iO2催化剂不但可缩短MTO反应的诱导期,三烯选择性也较未添加黏合剂或以A l2O3为黏合剂时高1~2个百分点;且当催化剂活性明显下降时,三烯选择性下降的幅度较小。催化剂粒径、甲醇分压及硅源对催化剂的诱导期也有明显的作用。在甲醇分压低于19kPa、催化剂粒径0.25~0.38mm、S iO2为黏合剂、硅酸四乙酯为硅源时,SAPO-34/S iO2催化剂的MTO性能明显提高。     

34CrMoV结构钢动态再结晶行为研究

应用Gleeble-1500热模拟实验机进行等温压缩试验,研究了变形工艺参数对34CrMoV结构钢动态再结晶行为的影响.结果表明,其流变应力随变形温度升高而降低,随应变速率提高而增大;随着应变速率的降低,应变量的增加和变形温度的升高,动态再结晶速度加快且奥氏体晶粒得到细化.     

Characterization of Urine Stem Cell-Derived Extracellular Vesicles Reveals B Cell Stimulating Cargo

Elucidation of the biological functions of extracellular vesicles (EVs) and their potential roles in physiological and pathological processes is an expanding field of research. In this study, we characterized USC–derived EVs and studied their capacity to modulate the human immune response in vitro. We found that the USC–derived EVs are a heterogeneous population, ranging in size from that of micro–vesicles (150 nm–1 μm) down to that of exosomes (60–150 nm). Regarding their immunomodulatory functions, we found that upon isolation, the EVs (60–150 nm) induced B cell proliferation and IgM antibody secretion. Analysis of the EV contents unexpectedly revealed the presence of BAFF, APRIL, IL–6, and CD40L, all known to play a central role in B cell stimulation, differentiation, and humoral immunity. In regard to their effect on T cell functions, they resembled the function of mesenchymal stem cell (MSC)–derived EVs previously described, suppressing T cell response to activation. The finding that USC–derived EVs transport a potent bioactive cargo opens the door to a novel therapeutic avenue for boosting B cell responses in immunodeficiency or cancer.     

Dysregulated CD38 Expression on Peripheral Blood Immune Cell Subsets in SLE

Given its uniformly high expression on plasma cells, CD38 has been considered as a therapeutic target in patients with systemic lupus erythematosus (SLE). Herein, we investigate the distribution of CD38 expression by peripheral blood leukocyte lineages to evaluate the potential therapeutic effect of CD38-targeting antibodies on these immune cell subsets and to delineate the use of CD38 as a biomarker in SLE. We analyzed the expression of CD38 on peripheral blood leukocyte subsets by flow and mass cytometry in two different cohorts, comprising a total of 56 SLE patients. The CD38 expression levels were subsequently correlated across immune cell lineages and subsets, and with clinical and serologic disease parameters of SLE. Compared to healthy controls (HC), CD38 expression levels in SLE were significantly increased on circulating plasmacytoid dendritic cells, CD14⁺⁺CD16⁺ monocytes, CD56⁺ CD16^dim natural killer cells, marginal zone-like IgD⁺CD27⁺ B cells, and on CD4⁺ and CD8⁺ memory T cells. Correlation analyses revealed coordinated CD38 expression between individual innate and memory T cell subsets in SLE but not HC. However, CD38 expression levels were heterogeneous across patients, and no correlation was found between CD38 expression on immune cell subsets and the disease activity index SLEDAI-2K or established serologic and immunological markers of disease activity. In conclusion, we identified widespread changes in CD38 expression on SLE immune cells that highly correlated over different leukocyte subsets within individual patients, but was heterogenous within the population of SLE patients, regardless of disease severity or clinical manifestations. As anti-CD38 treatment is being investigated in SLE, our results may have important implications for the personalized targeting of pathogenic leukocytes by anti-CD38 monoclonal antibodies.     

Identification of Cyclophilin A as a Potential Anticancer Target of Novel Nargenicin A1 Analog in AGS Gastric Cancer Cells

We recently discovered a novel nargenicin A1 analog, 23-demethyl 8,13-deoxynargenicin (compound 9), with potential anti-cancer and anti-angiogenic activities against human gastric adenocarcinoma (AGS) cells. To identify the key molecular targets of compound 9, that are responsible for its biological activities, the changes in proteome expression in AGS cells following compound 9 treatment were analyzed using two-dimensional gel electrophoresis (2-DE), followed by MALDI/TOF/MS. Analyses using chemical proteomics and western blotting revealed that compound 9 treatment significantly suppressed the expression of cyclophilin A (CypA), a member of the immunophilin family. Furthermore, compound 9 downregulated CD147-mediated mitogen-activated protein kinase (MAPK) signaling pathway, including c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) by inhibiting the expression of CD147, the cellular receptor of CypA. Notably, the responses of AGS cells to CypA knockdown were significantly correlated with the anticancer and antiangiogenic effects of compound 9. CypA siRNAs reduced the expression of CD147 and phosphorylation of JNK and ERK1/2. In addition, the suppressive effects of CypA siRNAs on proliferation, migration, invasion, and angiogenesis induction of AGS cells were associated with G2/M cell cycle arrest, caspase-mediated apoptosis, inhibition of MMP-9 and MMP-2 expression, inactivation of PI3K/AKT/mTOR pathway, and inhibition of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression. The specific interaction between compound 9 and CypA was also confirmed using the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA) approaches. Moreover, in silico docking analysis revealed that the structure of compound 9 was a good fit for the cyclosporin A binding cavity of CypA. Collectively, these findings provide a novel molecular basis for compound 9-mediated suppression of gastric cancer progression through the targeting of CypA.