Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.

Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation.

Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs), in CD4+ T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE.

Targeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis.

Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.

Bone marrow CD8+ Trm cells induced by IL-15 and CD16+ monocytes contribute to HSPC destruction in human severe aplastic anemia.

Idiopathic severe aplastic anemia (SAA) is a disease of bone marrow failure caused by T-cell-induced destruction of hematopoietic stem and progenitor cells (HSPCs), however the mechanism remains unclear. We performed single-cell RNA sequencing of PBMCs and BMMCs from SAA patients and healthy donors and identified a CD8+ T cell subset with a tissue residency phenotype (Trm) in bone marrow that exhibit high IFN-γ and FasL expression and have a higher ability to induce apoptosis in HSPCs in vitro through FasL expression. CD8+ Trm cells were induced by IL-15 presented by IL-15Rα on monocytes, especially CD16+ monocytes, which were increased in SAA patients. CD16+ monocytes contributed to IL-15-induced CD38+CXCR6+ pre-Trm differentiation into CD8+ Trm cells, which can be inhibited by the CD38 inhibitor 78c. Our results demonstrate that IL-15-induced CD8+ Trm cells are pathogenic cells that mediate HSPC destruction in SAA patients and are therapeutic targets for future treatments.

Monitoring Hierarchical Assembly of Ring-in-Ring and Russian Doll Complexes Based on Carbon Nanoring by Förster Resonance Energy Transfer.

We presented the construction of the ring-in-ring and Russian doll complexes on the basis of triptycene-derived carbon nanoring (TP-[12]CPP), which not only acts as a host for pillar[5]arene (P5A) but also serves as an energy donor for building Förster resonance energy transfer (FRET) systems. We also demonstrated that their hierarchical assembly processes could be efficiently monitored in real time using FRET. NMR, UV-vis and fluorescence, and mass spectroscopy analyses confirmed the successful encapsulation of the guests P5A/P5A-An by TP-[12]CPP, facilitated by C-H···π and ···π interactions, resulting in the formation of a distinct ring-in-ring complex with a binding constant of Ka = 2.23 × 104 M-1. The encapsulated P5A/P5A-An can further reverse its role to be a host for binding energy acceptors to form Russian doll complexes, as evidenced by the occurrence of FRET and mass spectroscopy analyses. The apparent binding constant of the Russian doll complexes was up to 3.6 × 104 M-1, thereby suggesting an enhanced synergistic effect. Importantly, the Russian doll complexes exhibited both intriguing one-step and sequential FRET dependent on the subcomponent P5A/P5A-An during hierarchical assembly, reminiscent of the structure and energy transfer of the light-harvesting system presented in purple bacteria.

Lymphatic endothelial cell-mediated accumulation of CD177+Treg cells suppresses antitumor immunity in human esophageal squamous cell carcinoma.

Regulatory T (Treg) cells are critical in shaping an immunosuppressive microenvironment to favor tumor progression and resistance to therapies. However, the heterogeneity and function of Treg cells in esophageal squamous cell carcinoma (ESCC) remain underexplored. We identified CD177 as a tumor-infiltrating Treg cell marker in ESCC. Interestingly, expression levels of CD177 and PD-1 were mutually exclusive in tumor Treg cells. CD177+ Treg cells expressed high levels of IL35, in association with CD8+ T cell exhaustion, whereas PD-1+ Treg cells expressed high levels of IL10. Pan-cancer analysis revealed that CD177+ Treg cells display increased clonal expansion compared to PD-1+ and double-negative (DN) Treg cells, and CD177+ and PD-1+ Treg cells develop from the same DN Treg cell origin. Importantly, we found CD177+ Treg cell infiltration to be associated with poor overall survival and poor response to anti-PD-1 immunotherapy plus chemotherapy in ESCC patients. Finally, we found that lymphatic endothelial cells are associated with CD177+ Treg cell accumulation in ESCC tumors, which are also decreased after anti-PD-1 immunotherapy plus chemotherapy. Our work identifies CD177+ Treg cell as a tumor-specific Treg cell subset and highlights their potential value as a prognostic marker of survival and response to immunotherapy and a therapeutic target in ESCC.

Spatial transcriptomics reveals prognosis-associated cellular heterogeneity in the papillary thyroid carcinoma microenvironment.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common malignant endocrine tumour, and its incidence and prevalence are increasing considerably. Cellular heterogeneity in the tumour microenvironment is important for PTC prognosis. Spatial transcriptomics is a powerful technique for cellular heterogeneity study. METHODS: In conjunction with a clinical pathologist identification method, spatial transcriptomics was employed to characterise the spatial location and RNA profiles of PTC-associated cells within the tissue sections. The spatial RNA-clinical signature genes for each cell type were extracted and applied to outlining the distribution regions of specific cells on the entire section. The cellular heterogeneity of each cell type was further revealed by ContourPlot analysis, monocle analysis, trajectory analysis, ligand-receptor analysis and Gene Ontology enrichment analysis. RESULTS: The spatial distribution region of tumour cells, typical and atypical follicular cells (FCs and AFCs) and immune cells were accurately and comprehensively identified in all five PTC tissue sections. AFCs were identified as a transitional state between FCs and tumour cells, exhibiting a higher resemblance to the latter. Three tumour foci were shared among all patients out of the 13 observed. Notably, tumour foci No. 2 displayed elevated expression levels of genes associated with lower relapse-free survival in PTC patients. We discovered key ligand-receptor interactions, including LAMB3-ITGA2, FN1-ITGA3 and FN1-SDC4, involved in the transition of PTC cells from FCs to AFCs and eventually to tumour cells. High expression of these patterns correlated with reduced relapse-free survival. In the tumour immune microenvironment, reduced interaction between myeloid-derived TGFB1 and TGFBR1 in tumour focus No. 2 contributed to tumourigenesis and increased heterogeneity. The spatial RNA-clinical analysis method developed here revealed prognosis-associated cellular heterogeneity in the PTC microenvironment. CONCLUSIONS: The occurrence of tumour foci No. 2 and three enhanced ligand-receptor interactions in the AFC area/tumour foci reduced the relapse-free survival of PTC patients, potentially leading to improved prognostic strategies and targeted therapies for PTC patients.

Immunophenotyping with high-dimensional flow cytometry identifies Treg cell subsets associated with recurrence in papillary thyroid carcinoma.

The activation of Treg cell subsets is critical for the prognosis of tumor patients; however, their heterogeneity and disease association in papillary thyroid carcinoma (PTC) need further investigation. We performed high-dimensional flow cytometry for immunophenotyping on thyroid tissues and matched peripheral blood samples from patients with multinodular goiters or PTC. We analyzed CD4+ T cell and Treg cell phenotypes and compared the recurrence-free survival of PTC patients with different Treg cell subset characteristics using TCGA. Furthermore, PTC recurrent and non-recurrent group were compared by multiplex immunohistochemistry. High-dimensional flow cytometry and bioinformatics analysis revealed an enrichment of Tregs in tumors compared with multinodular goiters and peripheral blood specimens. Moreover, effector Tregs (e-Tregs) as well as FOXP3+ non-Tregs were enriched in tumor samples, and the expression of CD39, PD-1, and CD103 increased on tumor Tregs. TCGA data analysis showed that individuals with CD39hi PD-1loCD103loe-Treghi and CD39loPD-1loCD103hie-Treghi expression patterns had a high recurrence rate. According to the multiplex immunohistochemistry and analysis, compared with non-recurrent group, the proportion of high recurrence rate effector Treg clusters (CD39+PD-1-CD103- plus CD39-PD-1-CD103+) was increased in recurrent patients. Overall, our results highlight the potential of e-Treg subsets as future immunotherapy targets for PTC recurrence.

Highly Luminescent Chiral Carbon Nanohoops via Symmetry Breaking with a Triptycene Unit: Bright Circularly Polarized Luminescence and Size-Dependent Properties.

Chiral carbon nanohoops with both high fluorescence quantum yield and large luminescence dissymmetry factor are essential to the development of circularly polarized luminescence (CPL) materials. Herein, the rational design and synthesis of a series of highly fluorescent chiral carbon nanohoops TP-[8-13]CPPs via symmetry breaking with a chiral triptycene motif is reported. Theoretical calculations revealed that breaking the symmetry of nanohoops causes a unique size-dependent localization in the highest occupied molecular orbitals (HOMOs) and the lowest unoccupied molecular obtitals (LUMOs) as the increasing of sizes, which is sharply different from those of [n]cycloparaphenylenes. Photophysical investigations demonstrated that TP-[n]CPPs display size-dependent emissions with high fluorescence quantum yields up to 92.9% for TP-[13]CPP, which is the highest value among the reported chiral conjugated carbon nanohoops. The high fluorescence quantum yields are presumably attributed to both the unique acyclic, and radial conjugations and high radiative transition rates, which are further supported by theoretical investigations. Chiroptical studies revealed that chiral TP-[n]CPPs exhibit bright CPL with CPL brightness up to 100.5 M-1 cm-1 for TP-[11]CPP due to the high fluorescence quantum yield. Importantly, the investigations revealed the intrigued size-dependent properties of TP-[n]CPPs with regards to (chir)optical properties, which follow a nice linear relationship versus 1/n. Such a nice linear relationship is not observed in other reported conjugated nanohoops including CPPs.

Structurally Diverse Pyrene-decorated Planar Chiral [2,2]Paracyclophanes with Tunable Circularly Polarized Luminescence between Monomer and Excimer.

We reported the synthesis of a series of structurally diverse CPL-active molecules, in which pyrene units were installed to chiral pm/po-[2,2]PCP scaffolds either with or without a triple bond spacer for pm/po-PCP-P1 and pm/po-PCP-P2, respectively. The X-ray crystallographic analyses revealed that these pyrene-based [2,2]PCP derivatives exhibited diverse structures and crystal packings in the solid phases. The pyrene-based [2,2]PCP derivatives exhibit various (chir)optical properties in organic solutions, depending on their respective structures. In a mixture of dioxane and water, pm/po-PCP-P1 emit green excimer fluorescence, whereas pm/po-PCP-P2 emit blue one. The chiroptical investigation demonstrated that Rp-pm-PCP-P1 and Rp-pm-PCP-P2 exhibited completely opposite CD and CPL signals even they possess the same chiral Rp-[2,2]PCP core. The same argument also holds for other chiral pyrene-based [2,2]PCP derivatives. The theoretical calculation revealed that these unusual phenomena were attributed to different orientation between transition electric dipole moments and the magnetic dipole moments originating from the presence or absence of a triple bond spacer. These pyrene-based [2,2]PCP derivatives display various colours and fluorescence emissions in the solid state and PMMA films, possibly due to the different packings as observed in the crystal structure. Moreover, these compounds also can interact with perylene diimide through π-π interactions, leading to near-white fluorescence.

Sodium carboxymethylcellulose/MXene/zeolite imidazolium framework-67-derived 3D porous carbon aerogel for high-performance asymmetric supercapacitors.

Herein, we propose a carbon/TiO2/Co3O4 (CTC) composite carbon aerogel with a 3D porous conductive network structure derived from sodium carboxymethylcellulose (CMC)/Mxene (Ti3C2Tx)/zeolite imidazolium framework-67 (ZIF-67). Among them, CMC is used as the carbon skeleton, which can reduce the powdering caused by volume change and improve the cycle stability. Ti3C2Tx acts as the conductive agent and dispersant for ZIF-67, exposing more reactive sites while constructing fast conductive channels to enhance electrochemical performance. The microstructure of the CTC carbon aerogel is modulated by controlling the mass ratio of Ti3C2Tx to ZIF-67, and the carbon aerogel with a mass ratio of 2:3 (CTC-2:3) is experimentally demonstrated to have the best electrochemical performance. The CTC-2:3 electrode exhibits a high specific capacitance of 481.7 F g-1 at 1 A g-1 and possesses a rate performance of 78.9 % at 10 A g-1. The assembled asymmetric supercapacitor (ASC, CTC-2:3//Ti3C2Tx) delivers an energy density of 48.4 Wh kg-1 at a power density of 699.8 W kg-1. Moreover, the ASC device maintains 85.3 % initial capacitance and 99.1 % coulombic efficiency after 10,000 GCD cycles, indicating good cycling stability. This facile design pathway provides a new insight for the development of high-performance electrode materials.

Efficient manipulation of Förster resonance energy transfer through host-guest interaction enables tunable white-light emission and devices in heterotopic bisnanohoops.

In this study, we synthesized and reported the heterotopic bisnanohoops P5-[8,10]CPPs containing cycloparaphenylenes (CPPs) and a pillar[5]arene unit, which act not only as energy donors but also as a host for binding energy acceptors. We demonstrated that a series of elegant FRET systems could be constructed successfully through self-assembly between donors P5-[8,10]CPPs and acceptors with different emissions via host-guest interaction. These FRET systems further allow us to finely adjust the donors P5-[8,10]CPPs and acceptors (BODIPY-Br and Rh-Br) for achieving multiple color-tunable emissions, particularly white-light emission. More importantly, these host-guest complexes were successfully utilized in the fabrication of white-light fluorescent films and further integrated with a 365 nm LED lamp to create white LED devices. The findings highlight a new application of carbon nanorings in white-light emission materials, beyond the common recognition of π-conjugated molecules.

Shape-Persistent Triptycene-Derived Pillar[6]arenes: Synthesis, Host-Guest Complexation, and Enantioselective Recognitions of Chiral Ammonium Salts.

Construction of macrocyclic hosts with a novel structure and excellent property has emerged as an intriguing undertaking for the past few years. Here, we reported the synthesis of shape-persistent triptycene-derived pillar[6]arene (TP[6]). The single crystal structure analysis revealed that the macrocyclic molecule adopts a hexagonal structure, featuring a helical and electron-rich cavity capable of encapsulating electron-deficient guests. In order to obtain chiral TP[6] from an enantiomerically pure triptycene building block, an efficient resolution of chiral triptycene was successfully developed through introducing chiral auxiliaries into triptycene skeletons. The 1H NMR and isothermal titration calorimetry investigations demonstrated that chiral TP[6] exhibited enantioselectivity toward four pairs of chiral guests containing a trimethylamino group, implying a significant promising application in area of enantioselective recognition.

Single-cell and spatial transcriptome analysis reveals the cellular heterogeneity of liver metastatic colorectal cancer.

In this study, we comprehensively charted the cellular landscape of colorectal cancer (CRC) and well-matched liver metastatic CRC using single-cell and spatial transcriptome RNA sequencing. We generated 41,892 CD45- nonimmune cells and 196,473 CD45+ immune cells from 27 samples of six CRC patients, and found that CD8_CXCL13 and CD4_CXCL13 subsets increased significantly in liver metastatic samples that exhibited high proliferation ability and tumor-activating characterization, contributing to better prognosis of patients. Distinct fibroblast profiles were observed in primary and liver metastatic tumors. F3+ fibroblasts enriched in primary tumors contributed to worse overall survival by expressing protumor factors. However, MCAM+ fibroblasts enriched in liver metastatic tumors might promote generation of CD8_CXCL13 cells through Notch signaling. In summary, we extensively analyzed the transcriptional differences of cell atlas between primary and liver metastatic tumors of CRC by single-cell and spatial transcriptome RNA sequencing, providing different dimensions of the development of liver metastasis in CRC.

Evaluation of metoprolol standard dosing pathway in Chinese patients with acute coronary syndrome: a prospective multicenter single-arm interventional study.

OBJECTIVE: To evaluate the feasibility and tolerability of metoprolol standard dosing pathway (MSDP) in Chinese patients with acute coronary syndrome (ACS). METHODS: In this multicenter, prospective, open label, single-arm and interventional study that was conducted from February 2018 to April 2019 in fifteen Chinese hospitals. A total of 998 hospitalized patients aged ≥ 18 years and diagnosed with ACS were included. The MSDP was applied to all eligible ACS patients based on the standard treatment recommended by international guidelines. The primary endpoint was the percentage of patients achieving the target dose at discharge (V2). The secondary endpoints included the heart rate and blood pressure at V2 and four weeks after discharge (V4), and percentage of patients experiencing bradycardia (heart rate < 50 beats/min), hypotension (blood pressure < 90/60 mmHg) and transient cardiac dysfunction at V2 and V4. RESULTS: Of the 998 patients, 29.46% of patients achieved the target dose (≥ 95 mg/d) at V2. The total population was divided into two groups: target group (patients achieving the target dose at V2) and non-target group (patients not achieving the target dose at V2). There was significant difference in the reduction of heart rate from baseline to discharge in the two groups (-4.97 ± 11.90 beats/min vs. -2.70 ± 9.47 beats/min, P = 0.034). There was no significant difference in the proportion of bradycardia that occurred in the two groups at V2 (0 vs. 0, P = 1.000) and V4 (0.81% vs. 0.33%, P = 0.715). There was no significant difference in the proportion of hypotension between the two groups at V2 (0.004% vs. 0.004%, P = 1.000) and V4 (0 vs. 0.005%, P = 0.560). No transient cardiac dysfunction occurred in two groups during the study. A total of five adverse events (1.70%) and one serious adverse event (0.34%) were related to the pathway in target group. CONCLUSIONS: In Chinese ACS patients, the feasibility and tolerability of the MSDP have been proved to be acceptable.

Lemniscular carbon nanohoops with contiguous conjugation from planar chiral [2.2]paracyclophane: influence of the regioselective synthesis on topological chirality.

We report herein the regioselective synthesis of all-carbon lemniscular nanohoops bis-po-CC and bis-pm-TC by the rational control of ring closures at the different positions of planar chiral tetrasubstituted [2.2]paracyclophane. Topological analyses reveal that bis-pm-TC is topologically chiral while bis-po-CC is topologically achiral. X-ray crystal analysis demonstrates that bis-pm-TC adopts a lemniscular conformation with a contiguous conjugation. CD and CPL measurements further reveal that the chiroptical properties of bis-pm-TC are obviously different from those of bis-po-CC due to their different topological chiralities.

[2,2] Paracyclophanes-based double helicates for constructing artificial light-harvesting systems and white LED device.

The construction of efficient artificial light-harvesting systems (ALHSs) is of vital importance in utilizing solar energy. Herein, we report the non-covalent syntheses of double helicates PCP-TPy1/2 and Rp,Rp-PCP-TPy1/2 by metal-coordination interaction and their applications in ALHSs and white light-emitting diode (LED) device. All double helicates exhibit significant aggregation-induced emission in tetrahydrofuran/water (1:9, v/v) solvent. The aggregated double helicates can be used to construct one-step or sequential ALHSs with fluorescent dyes Eosin Y (EsY) and Nile red (NiR) with the energy transfer efficiency up to 89.3%. Impressively, the PMMA film of PCP-TPy1 shows white-light emission when doped 0.075% NiR, the solid of double helicates (Rp,Rp-) PCP-TPy2 can be used as the additive of a blue LED bulb to achieve white-light emission. In this work, we provided a general method for the preparation of novel double helicates and explored their applications in ALHSs and fluorescent materials, which will promote future construction and application of helicates as emissive devices.

Chiral Carbon Nanorings: Synthesis, Properties and Hierarchical Self-assembly of Chiral Ternary Complexes Featuring a Narcissistic Chiral Self-Recognition for Chiral Amines.

We report the synthesis and chiroptical properties of novel chiral carbon nanorings Sp-/Rp-[12]PCPP containing a planar chiral [2.2]PCP unit, and demonstrate that Sp-/Rp-[12]PCPP can not only host crown ether 18-Crown-6 to form ring-in-ring complexes with a binding constant 3.35×103  M-1 , but also accommodate the complexes of 18-Crown-6 and S/R-protonated amines to form homochiral S@Sp-/R@Rp- and heterochiral S@Rp-/R@Sp- ternary complexes, displaying significantly larger binding constants of up to 3.31×105  M-1 depending on the chiral guests. Importantly, homochiral S@Sp-/R@Rp- ternary complexes exhibit an enhanced CD signal, while the heterochiral S@Rp-/R@Sp- ones have a constant CD signal compared with the chiral carbon nanorings, respectively, which suggests that homochiral S@Sp-/R@Rp- ternary complexes display a highly narcissistic chiral self-recognition for S/R-protonated chiral amines, respectively. Finally, the chiral ternary complexes can be further applied to determine the ee values of chiral guests. The findings highlight a new application of carbon nanorings in supramolecular sensors, beyond the common recognition of π-conjugated molecules.

Single-Cell Analysis of Patients with Axial Spondyloarthritis After Anti-TNFα Treatment: Experimental Data and Review of the Literature.

Axial spondyloarthritis (Ax-SpA) is a chronic inflammatory disease that predominantly affects the axial joints and is most common in young men. However, the precise immune cell subset involved in Ax-SpA remains unclear. Our study characterized the periphery immune landscape of Ax-SpA patients before and after anti-TNFα treatment using single-cell transcriptomics and proteomics sequencing and elucidated the effects of anti-TNFα treatment at the single-cell level. First, we found that peripheral granulocytes and monocytes significantly increased in Ax-SpA patients. Second, we identified a more functional subtype of regulatory T cells, which was present in synovial fluid and increased in patients after treatment. Third, we identified a cluster of inflammatory monocyte subset with stronger inflammatory and chemotactic characteristics. A potential interaction between classical monocytes and granulocytes via the CXCL8/2-CXCR1/2 signaling pathway was observed, which decreased after treatment. Together, these results defined the complex expression profiles and advanced our understanding of the immune atlas in Ax-SpA patients before and after anti-TNFα treatment.

Single-cell profiling reveals pathogenic role and differentiation trajectory of granzyme K+CD8+ T cells in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune inflammatory disease mainly defined by T cell-dominated destruction of exocrine glands. Currently, CD8+ T cells are thought to be involved in the pathogenesis of pSS. However, the single-cell immune profiling of pSS and molecular signatures of pathogenic CD8+ T cells have not been well elucidated. Our multiomics investigation showed that both T cells and B cells, especially CD8+ T cells, were undergoing significant clonal expansion in pSS patients. TCR clonality analysis revealed that peripheral blood granzyme K+ (GZMK+) CXCR6+CD8+ T cells had higher a proportion of clones shared with CD69+CD103-CD8+ tissue-resident memory T (Trm) cells in labial glands in pSS. CD69+CD103-CD8+ Trm cells featured by high expression of GZMK were more active and cytotoxic in pSS compared with their CD103+ counterparts. Peripheral blood GZMK+CXCR6+CD8+ T cells with higher CD122 expression were increased and harbored a gene signature similar to Trm cells in pSS. Consistently, IL-15 was significantly elevated in pSS plasma and showed the capacity to promote differentiation of CD8+ T cells into GZMK+CXCR6+CD8+ T cells in a STAT5-dependent manner. In summary, we depicted the immune profile of pSS and further conducted comprehensive bioinformatics analysis and in vitro experimental investigations to characterize the pathogenic role and differentiation trajectory of CD8+ Trm cells in pSS.