Mechanosensitive (MS) channels are universal cellular membrane pores. Bacterial MS channels, as typified by MS channel of small conductance (MscS) from Escherichia coli (EcMscS), release osmolytes under hypoosmotic conditions. MS channels are known to be ion selective to different extents, but the underlying mechanism remains poorly understood. Here we identify an anion-selective MscS channel from Thermoanaerobacter tengcongensis (TtMscS). The structure of TtMscS closely resembles that of EcMscS, but it lacks the large cytoplasmic equatorial portals found in EcMscS. In contrast, the cytoplasmic pore formed by the C-terminal β-barrel of TtMscS is larger than that of EcMscS and has a strikingly different pattern of electrostatic surface potential. Swapping the β-barrel region between TtMscS and EcMscS partially switches the ion selectivity. Our study defines the role of the β-barrel in the ion selection of an anion-selective MscS channel and provides a structural basis for understanding the ion selectivity of MscS channels.crystal structure | anion selection | cytoplasmic region | electrophysiology | single channel recording

Objective: This study aimed to compare the diagnostic performance of 68 Ga-FAPI-04 and 18 F-FDG PET/CT in the patients with various oncological and non-oncological lesions.Patients and Methods: A total of 123 patients underwent contemporaneous 68 Ga-FAPI-04 and 18 F-FDG PET/CT were included in this prospective study. The maximum standard uptake value (SUVmax) was measured to compare oncological and non-oncological lesion uptake. The sensitivity, speci city, predictive values and accuracy of 18 F-FDG and 68 Ga-FAPI-04 PET/CT for detecting primary, metastatic, and non-oncological lesions were calculated and compared to evaluate the diagnostic e cacy.Results: The study subjects consisted of 123 patients (69 men and 54 women; mean age: 56.11±11.94). A total of 84 patients with 88 solid primary malignant tumors, 58 patients with 376 nodal metastases, 43 patients with 406 distant metastases, 8 patients with hematological neoplasms and 52 patients with 145 non-oncological lesions and benign tumors were detected. 68 Ga-FAPI-04 PET/CT demonstrated a signi cantly higher uptake and detection rate for the primary (SUVmax: 10.98±5.83 vs. 8.36±6.43, p 0.001; X 2 =0.538, p=0.021), nodal (SUVmax: 10.50±5.98 vs. 8.20±6.29, p=0.011; X 2 =2.067, p 0.001) and distant metastatic lesions (SUVmax: 6.74±4.83 vs. 9.64±6.45; p 0.001; X 2 =4.897, p 0.001) of solid tumor than did 18 F-FDG PET/CT. 68 Ga-FAPI-04 PET/CT demonstrated a lower activity (SUVmax: 6.84±4.67 vs. 13.09±7.29, p 0.001) and detection rate (X 2 =5.166, p 0.001) for multiple myeloma and lymphoma compared to 18 F-FDG PET/CT. 68 Ga-FAPI-04 and 18 F-FDG PET/CT PET/CT demonstrated a comparative diagnostic e cacy (SUVmax: 6.40±3.95 vs. 5.74±15.78, p = 0.729; X 2 = 9.460, p = 0.007) for nononcological lesion and benign tumor detection.Conclusions: Except for myeloma and lymphoma, 68 Ga-FAPI-04 PET/CT showed a superior diagnostic e cacy for detecting various primary and metastatic lesions than 18 F-FDG PET/CT. A comparative diagnostic utility for nononcological lesion detection was obtained with both tracers. 68 Ga-FAPI-04 could be used as a broad-spectrum tumor and in ammatory imaging agent in the clinical especially for various solid tumors and non-oncological lesions.

Background: Glucocorticoids (GCs) show powerful treatment effect on rheumatoid arthritis (RA). However, the clinical application is limited by their nonspecific distribution after systemic administration, serious adverse reactions during long-term administration. To achieve better treatment, reduce side effect, we here established a biomimetic exosome (Exo) encapsulating dexamethasone sodium phosphate (Dex) nanoparticle (Exo/Dex), whose surface was modified with folic acid (FA)-polyethylene glycol (PEG)-cholesterol (Chol) compound to attain FPC-Exo/Dex active targeting drug delivery system. Results: The size of FPC-Exo/Dex was 128.43 ± 16.27 nm, with a polydispersity index (PDI) of 0.36 ± 0.05, and the Zeta potential was − 22.73 ± 0.91 mV. The encapsulation efficiency (EE) of the preparation was 10.26 ± 0.73%, with drug loading efficiency (DLE) of 18.81 ± 2.05%. In vitro study showed this system displayed enhanced endocytosis and excellent anti-inflammation effect against RAW264.7 cells by suppressing pro-inflammatory cytokines and increasing anti-inflammatory cytokine. Further biodistribution study showed the fluorescence intensity of FPC-Exo/Dex was stronger than other Dex formulations in joints, suggesting its enhanced accumulation to inflammation sites. In vivo biodistribution experiment displayed FPC-Exo/Dex could preserve the bone and cartilage of CIA mice better and significantly reduce inflamed joints. Next in vivo safety evaluation demonstrated this biomimetic drug delivery system had no obvious hepatotoxicity and exhibited desirable biocompatibility. Conclusion: The present study provides a promising strategy for using exosome as nanocarrier to enhance the therapeutic effect of GCs against RA.