课程文献中心 更多>>

关键词： Autophagy   Hematology   Metabolism   Mitochondria   Platelets  

摘要： Platelets play a dual role in hemostasis and inflammation-associated thrombosis and hemorrhage. While the mechanisms linking inflammation to platelet dysfunction remain poorly understood, our previous work demonstrated that TNFα alters mitochondrial mass, platelet activation, and autophagy-related pathways in megakaryocytes. Here, we hypothesized that TNFα impairs platelet function by disrupting autophagy, a process critical for mitochondrial health and cellular metabolism. Using human and murine models of TNFα-driven diseases, including myeloproliferative neoplasms and rheumatoid arthritis, we found that TNFα downregulates STX17, a key mediator of autophagosome-lysosome fusion. This disruption inhibited autophagy, leading to the accumulation of dysfunctional mitochondria and reduced mitochondrial respiration. These metabolic alterations compromised platelet-driven clot contraction, a process linked to thrombotic and hemorrhagic complications. Our findings reveal a mechanism by which TNFα disrupts hemostasis through autophagy inhibition, highlighting TNFα as a critical regulator of platelet metabolism and function. This study provides new insights into inflammation-associated pathologies and suggests autophagy-targeting strategies as potential therapeutic avenues to restore hemostatic balance.

关键词： Transceivers   Receivers   Signal integrity   Sensitivity   Frequency response   Encoding   Timing   Bit error rate   Transmitters   Complexity theory   Chiplet   parallel interface   pin efficiency   single-ended transceiver   simultaneous switching output noise (SSN)   skew   spatially correlated signaling (SCCS)  

摘要： This paper analyzes an effect of inter-wire skew on signal integrity in a multi-channel system and proposes circuit techniques to enhance signal integrity by using a spatially correlated coded signaling (SCCS). Through the in-depth analysis, the paper investigates a relation between skew and insertion loss (IL), and highlights an importance of wide-range inter-wire de-skewing (IWD). The proposed phase interpolator (PI)-based IWD technique adjusts the transition edges of receiver inputs to minimize skew caused by mismatch components, which increases timing jitter. The transceiver employs pseudo-differential signaling to verify the effect of the IWD in SCCS. The transmitter integrates a feed-forward equalizer (FFE) with a latch-based re-timer and a PI for each channel. Additionally, a 3-tap FFE at the transmitter and a continuous-time linear equalizer (CTLE) at the receiver are incorporated to compensate for channel ISI. Fabricated in 40-nm CMOS technology, the proposed 8-channel transceiver achieves an aggregate throughput of 112 Gb/s with a bit error rate (BER) below 10(-12). The transceiver occupies 0.382 mm(2) while achieving energy efficiencies of 0.77 pJ/bit/ch for the transmitter and 1.45 pJ/bit/ch for the receiver.

关键词： Extracellular vesicles   asthma   Th2 cells   eosinophils   IL-3   lung   allergic   type 2 inflammation   Th2   T helper 2   EV   extracellular vesicle   OVA   ovalbumin   HDM   house dust mite   SEC   size exclusion chromatography   EC50   half maximal effective concentration   TCR   T cell receptor   BALF   bronchoalveolar lavage fluid  

摘要： Background Extracellular vesicles (EVs) mediate intercellular communication during immune responses. EVs are abundant in respiratory biofluids, and the composition of EVs in the lung changes during inflammation. Objective We aimed to quantify the contribution of T cells to airway EVs in eosinophilic lung inflammation and ascertain their function during a type 2 inflammatory response. Methods Genetic membrane tagging was combined with single vesicle flow cytometry to quantify T cell EVs in the airways of mice challenged with ovalbumin or house dust mite. EVs were purified from mouse T helper type 2 (Th2) cell cultures and their functions on eosinophils assessed by flow cytometry and RNA sequencing. Th2 cell EVs were instilled into the lungs of mice to determine effects on lung eosinophilia. Finally, the function of an EV protein cargo was tested using inhibitors and blocking antibodies. Results T cell EVs are increased in the airways of mice after ovalbumin or house dust mite induced inflammation. EVs secreted by Th2 cells inhibit apoptosis and induce activating pathways in eosinophils in vitro. This effect depends on re-stimulation through the T cell receptor. Th2 cell EVs prolong eosinophilia in vivo during acute eosinophilic inflammation. Th2 cell EVs carry the cytokine IL-3 as a surface cargo, which inhibits apoptosis by activating Jak1/2-dependent pro-survival programs in eosinophils. Conclusion Th2 cell EVs promote eosinophil survival through the EV cargo IL-3, supporting a role for EVs as vehicles of cytokine-based communication in lung inflammation.

关键词： AML   NPM1   DNMT3A   mutation   HLA association study  

摘要： Introduction: Mutations in the nucleophosmin 1 gene (NPM1) are common and recurrent molecular abnormalities in acute myeloid leukemia (AML). NPM1 mutations are considered to be positive prognostic factors. The beneficial effect may be due to immune responses mediated by cytotoxic T cells targeting HLA-presented peptides derived from mutated NPM1 and thereby suppressing mutated NPM1-positive hematopoiesis. While the immunogenicity of these NPM1 peptides has not been demonstrated conclusively, certain HLA-types have been linked to a lower risk of NPM1-mutated AML. Method: In a comprehensive HLA association study at two-field resolution, we compared the proportions of HLA class I alleles between NPM1-mutated (n = 477) and/or DNMT3A-mutated (n = 216) patients with AML and a control group of healthy individuals (n = 51,890). Result: We found HLA-B*40:01 and HLA-C*03:04 to be significantly underrepresented in NPM1-mutated AML compared to the control group (4.0% vs. 10.2%, p < 0.001, and 8.2% vs, 15.9%, p < 0.001, respectively). This might suggest that neoepitopes presented by these HLA alleles trigger T-cell responses. Online epitope prediction tools predict that mutated NPM1-derived peptides bind strongly to B*40:01 and C*03:04. Discussion: Based on these findings, further studies should confirm the presence and functionality of neoepitope-specific T cells and characterize specific T-cell receptors (TCR). Sequence information might eventually be exploited in immunotherapeutic approaches to treat AML patients with TCR-engineered T cells or bispecific TCR T/NK cell engagers.

关键词： IL-33   immunotherapy   pancreatic ductal adenocarcinoma   prognosis   regulatory T cells   tumor microenvironment  

摘要： BACKGROUND:Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is constitutively expressed in barrier cells such as endothelial cells and fibroblasts. While the expression of IL-33 in regulatory T cells (Tregs) has been previously reported, its clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study aims to investigate the clinical relevance and biological role of IL-33+ Tregs in PDAC. METHODS:Infiltration of IL-33+ Tregs was assessed by immunohistochemistry in 215 patients from our institute. The correlation between IL-33+ Tregs and clinical characteristics was analyzed. Additionally, the functional status of cytotoxic T cells in relation to IL-33+ Treg infiltration was examined. The impact of IL-33+ Tregs on the tumor microenvironment (TME) was further evaluated both in silico and in vitro. RESULTS:IL-33+ Tregs infiltration was confirmed in PDAC tissues, and its abundance was positively associated with microvascular invasion, perineural invasion, and elevated serum CA19-9 levels. Patients with higher tumor-infiltrating IL-33+ Tregs demonstrated poorer overall survival (OS) and recurrence-free survival (RFS) compared to those with lower infiltration levels. Multivariate analysis confirmed IL-33+ Tregs as an independent prognostic factor for both OS and RFS, with improved survival prediction when combined with tumor differentiation. Subgroup analyses indicated that serum CA19-9 was not a useful risk stratification tool in patients with high IL-33+ Treg infiltration, and these patients showed limited survival benefit from adjuvant chemotherapy. Furthermore, increased IL-33+ Treg infiltration was associated with more pronounced immunosuppressive TME, marked by a reduction in cytotoxic phenotypes and an upregulation of exhausted markers on CD8+ T cells. CONCLUSION:Our findings identify IL-33+ Tregs as a novel subtype of Tregs, with strong prognostic value for survival risk stratification and therapeutic response prediction

摘要： Immune aplastic anemia (iAA) frequently results in transfusion dependence on platelets and packed red blood cells, increasing the risk for complications. The most common immune-mediated cause for platelet-transfusion refractoriness is alloimmunization with HLA antibody (Ab) to nonself class I antigens. The clinical impact of the HLA alloimmunization has not been well studied in patients with iAA. We investigated the clinical relevance of HLA alloimmunization in our large cohort of patients with iAA from 5 prospective trials and correlated with disease outcomes. Of 444 patients with severe AA treated with immunosuppressive therapy (IST), 99 (22%) had HLA alloimmunization. The presence of HLA Ab was associated with shorter overall survival, reduced responses to IST and higher risk of clonal evolution. Our data suggest that HLA alloimmunization is a marker of disease outcome. Furthermore, using single-cell RNA sequencing, we show enhanced activation of both complement-mediated pathways and the adaptive immune system in alloimmunized patients, indicating an interconnection between immune compartments.

关键词： 复发性流产   25羟维生素D   免疫细胞亚群   妊娠结局   辅助性T细胞   白细胞介素   肿瘤坏死因子-α   调控机制  

摘要： 目的 探讨原因不明复发性流产（URSA）患者25羟维生素D[25（OH）D]、免疫细胞亚群以及辅助性T细胞（Th）1、Th2的表达及意义。方法 选取307例URSA患者作为URSA组,按照是否维持妊娠分为非维持妊娠组127例和维持妊娠组180例;另选取同期正常妊娠女性307例作为对照组。比较各组25（OH）D、免疫细胞亚群及Th1、Th2表达,并采用Pearson相关性分析探讨URSA患者25（OH）D、免疫细胞亚群与Th1、Th2表达的相关性。结果 与对照组相比,URSA组25（OH）D、IL-10水平更低,CD3+、CD3+CD4+、CD3+CD8+、CD4+/CD8+、CD16+CD56+、CD19+、IL-2、TNF-α水平更高,差异均有统计学意义（P<0.001）。与维持妊娠组相比,非维持妊娠组25（OH）D、IL-10水平更低,CD3+、CD3+CD4+、CD3+CD8+、CD4+/CD8+、CD16+CD56+、CD19+、IL-2、TNF-α水平更高,差异均有统计学意义（P<0.001）。Pearson分析显示,URSA患者25（OH）D与IL-2、TNF-α呈显著负相关（P<0.05）,与IL-10呈显著正相关（P<0.05）;URSA患者CD3+、CD3+CD4+、CD3+CD8+、CD4+/CD8+、CD16+CD56+、CD19+与IL-2、TNF-α呈显著正相关（P<0.05）,与IL-10呈显著负相关（P<0.05）。结论 URSA患者25（OH）D、免疫细胞亚群以及Th1、Th2细胞因子表达存在异常,且不同妊娠结局的URSA患者25（OH）D、免疫细胞亚群以及Th1、Th2细胞因子表达也存在差异,其机制可能与调节Th1/Th2细胞因子平衡的表达有关。

关键词： colorectal cancer   Regnase-1   IL-17  

摘要： Regnase- 1 is a ribonuclease that regulates inflammation in immune cells by degrading cytokine mRNA. Regnase- 1 was identified as one of the frequently mutated genes in the inflamed colorectal epithelium of patients with ulcerative colitis;however, its significance in intestinal epithelial cells during the tumorigenic process remains unknown. Therefore, we developed an ApcMin/+ mouse model lacking Regnase- 1 in intestinal epithelia. Regnase- 1 deletion significantly enhanced colon tumor growth accompanied by elevated levels of extracellular signal- regulated kinase (ERK) phosphorylation in tumor tissues. Transcriptome analysis of the tumor tissues revealed that Nfkbiz, a mediator of the interleukin (IL)- 17 signaling pathway, was the primary degradative target of Regnase- 1 in enterocytes and that Regnase- 1 deficiency enhanced IL- 17 signaling. The treatment with antibiotics or IL- 17- neutralizing antibody canceled the proliferative effect of colon tumors due to Regnase- 1 deletion, suggesting the protective role of Regnase- 1 against colon tumor growth was dependent on IL- 17 signaling triggered by gut microbes. Analysis of the Nfkbiz knockout mouse model demonstrated that the treatment of dimethyl fumarate, a potential inhibitor of Regnase- 1 protein inactivaFurthermore, TCGA data analysis revealed that low Regnase- 1 expression in colorectal cancer tissue was related to poor prognosis. Therefore, Regnase- 1 represses colon tumor growth by regulating IL- 17 signaling via Nfkbiz mRNA degradation. Regnase- 1 could be a potential therapeutic target in colon tumors.

摘要： Plasmodium vivax (P. vivax) can lead to severe hematological complications, including anemia and thrombocytopenia, which may require hospitalization. This prospective observational study investigated the adaptive immune response in pediatric P. vivax malaria, focusing on sustained IFN-gamma production in CD4+ and CD8+ memory T cells as markers of immune protection. Conducted at the Dr. Heitor Vieira Dourado Tropical Medicine Foundation (FMT-HVD) in the Western Brazilian Amazon, peripheral blood mononuclear cells (PBMCs) were collected from 25 children aged 1-16 years at diagnosis (D0, acute phase) and 90 days post-treatment (D90, convalescent phase). PBMCs were stimulated ex vivo with the conserved P. vivax antigen, the 19 kDa fragment of the C-terminal region of merozoite surface protein-1 (PvMSP119), and intracellular production of IFN-gamma was quantified in memory T cells (CD3+CD4+CD45RO+ and CD3+CD8+CD45RO+ T cells) by flow cytometry. Individuals whose cells specifically produced IFN-gamma against PvMSP119 on both D0 and D90 were classified as responders, while those who responded in only one phase or in neither were classified as nonresponders. Responders, whose CD3+CD4+CD45RO+ T cells exhibited sustained IFN-gamma response against PvMSP119 demonstrated lower parasite density as well as improved normalization of hemoglobin levels and recovery of platelet counts. These results confirm the role of this response as acquisition of immunity. PvMSP119 antigen emerges as a promising marker of sustained immunity, though larger studies are required to evaluate its long-term impact on recovery and outcomes. These findings underscore the critical role of IFN-gamma-producing memory T cells in controlling parasitemia and mitigating anemia and thrombocytopenia in pediatric P. vivax malaria.

关键词： 金天格含药血清   类风湿关节炎   成纤维样滑膜细胞   迁移和侵袭   PI3K/Akt通路  

摘要： 探讨金天格含药血清对人类风湿关节炎成纤维样滑膜细胞（FLS）的作用及机制。制备SD大鼠空白血清，及金天格低、中、高剂量含药血清（JTG-CS）。超高效液相色谱-质谱联用技术检测血清内氨基酸成分和含量；肿瘤坏死因子α（TNF-α）刺激原代FLS细胞建立FLS炎症模型，CCK-8检测FLS细胞增殖，伤口愈合和Transwell试验分析FLS细胞的迁移和侵袭，Western blot分析相关蛋白的表达。JTG-CS能显著抑制FLS细胞的增殖和迁移，抑制FLS细胞的伤口愈合和侵袭能力，抑制黏附相关蛋白细胞间黏附分子-1（ICAM-1）、血管细胞黏附分子-1（VCAM-1）、基质金属蛋白酶（MMP）-2和MMP3的表达，降低炎性细胞因子TNF-α、白细胞介素（IL）-6和IL-1β的水平，抑制PI3K/Akt通路、NF-κB通路和JAK2/STAT3通路的激活。PI3K激动剂可逆转JTG-CS对FLS细胞炎性细胞因子和细胞侵袭的抑制作用。与空白大鼠血清相比，JTG-CS中46种氨基酸含量上升，20种氨基酸含量下降。JTG-CS通过抑制PI3K/Akt通路的激活，抑制TNF-α刺激的FLS细胞增殖、迁移、侵袭和炎症反应。