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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： 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： 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。

关键词： Th1 cell responses   complement   complosome   C5aR2   prostaglandin   prostacyclin   IL-1β   Crohn’s disease   rheumatoid arthritis   cryopyrin-associated periodic fever syndrome   CAPS  

摘要： T helper 1 (Th1) cell initiation pathways are well characterized;however, those regulating their contraction are less understood. Here, we define a CD4+ T cell-autonomous pathway in which complement C5 orchestrated a shift from prostaglandin E2 (PGE2) dominance to enhanced prostacyclin (PGI2) production via activation of C5a receptor 2 (C5aR2). This pivot in lipid mediators induced autocrine signaling through the PGI2 receptor and expression of the interleukin-1 (IL-1) decoy IL-1 receptor type 2 (IL-1R2), which sequestered Th1 cell-driving intrinsic IL-1 beta, facilitating Th1 cell contraction. Disruption of this C5aR2-PGI2-R axis was a hallmark of pathologically persistent Th1 cell activity in inflammatory conditions, including cryopyrin-associated periodic syndromes (CAPS), Crohn's disease, and rheumatoid arthritis. Rebalancing this axis through selective PGE2 synthase inhibition rectified the hyperactive Th1 cell phenotype in vitro in T cells from individuals with CAPS. Therefore, complement is a key controller of prostanoid metabolism, and the latter is an intrinsic-and potentially druggable-checkpoint for the cessation of Th1 cell effector responses.

摘要： Although multiple single-cell RNA sequencing (scRNA-seq) based studies have explored rheumatoid arthritis (RA), most have focused on synovial tissue, limiting the ability to perform paired pre- and post-treatment comparisons and to elucidate dynamic changes. Moreover, the single-cell impact of TNF-alpha and JAK inhibitors on RA remains poorly understood, hindering effects toward precision medicine for RA. Here, we present a comprehensive scRNA-seq analysis of synovial fluid samples of RA patients treated with tofacitinib or adalimumab, both pre- and post-treatment. Following stringent quality control, we analyzed 100,387 high-quality cells, providing an in-depth characterization of cell composition, molecular signaling pathways, and functional properties. This rich dataset offers a valuable resource to address diverse research questions, from uncovering the mechanisms of action of TNF-alpha and JAK inhibitors, to identifying novel therapeutic targets for RA, and advancing our understanding of the pathogenesis of inflammatory diseases.

关键词： PIEZO1   Psoriasis   IL-17   NF-kB   Inflammation   Keratinocyte   Th17 cells  

摘要： Background Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferative keratinocytes and an altered immune response. PIEZO1, a mechanically activated ion channel, has been implicated in various cellular processes, but its role in psoriasis pathogenesis remains unclear. Methods We examined PIEZO1 expression in skin samples from psoriatic patients and healthy individuals using western blot, immunohistochemistry, and mRNA expression analyses. Subsequently, we employed PIEZO1 knock-out (KO) mice to establish imiquimod (IMQ)-induced psoriasiform models for in vivo experiments. Additionally, we conducted in vitro experiments with PIEZO1-silenced human keratinocytes (HaCaT cells) to investigate the impact on keratinocyte function and the expression of inflammatory cytokines. Results PIEZO1 expression was significantly upregulated in the basal layer of psoriatic lesions compared to healthy controls. In vivo, PIEZO1 KO mice showed attenuated psoriasis-like symptoms, reduced keratinocyte proliferation, inflammatory cell infiltration, and less Th17 cells compared to wild-type mice. Loss of PIEZO1 in vitro inhibited keratinocyte proliferation and migration, while inducing apoptosis. Transcriptome sequencing and subsequent analyses revealed that PIEZO1 knockdown modulates the NF-kB signaling pathway and associated inflammatory genes. The in vitro activation of NF-kB signaling was diminished by PIEZO1 silencing in keratinocytes, resulting in decreased inflammatory cytokine and chemokine expression. Furthermore, PIEZO1 facilitated keratinocyte-mediated CD4 + T cell differentiation into Th17 cells, a key pathogenic factor in psoriasis. Conclusion This study highlights the critical role of PIEZO1 in psoriatic skin inflammation and suggests that PIEZO1 may serve as a novel therapeutic target for psoriasis treatment. Our findings reveal that PIEZO1 modulates keratinocyte proliferation, immune cell infiltration, and T cell differentiation through the NF-kB sig