The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

Background and Objectives: Psoriasis is a chronic inflammatory skin disease, which the mechanisms behind its initiation and development are related to many factors. DMSCs (dermal mesenchymal stem cells) represent an important member of the skin microenvironment and play an important role in the surrounding environment and in neighbouring cells, but they are also affected by the microenvironment. We studied the glucose metabolism of DMSCs in psoriasis patients and a control group to reveal the relationship among glucose metabolism, cell proliferation activity，and VEC (vascular endothelial cell) differentiation in vitro, we demonstrated the biological activity and molecular mechanisms of DMSCs in psoriasis. Methods: and Results: We found that the OCR of DMSCs in psoriatic lesions was higher than that in the control group, and mRNA of GLUT1 and HK2 were up-regulated compared with the control group. The proliferative activity of DMSCs in psoriasis was reduced at an early stage, and mRNA involved in proliferation, JUNB and FOS were expressed at lower levels than those in the control group. The number of blood vessels in psoriatic lesions was significantly higher than that in the control group (p＜0.05), which the mRNA of VEC differentiation, CXCL12, CXCR7, HEYL and RGS5 tended to be increased in psoriatic lesions compared to the control group, in addition to Notch3. Conclusions We speculated that DMSCs affected local psoriatic blood vessels through glucose metabolism, and the differentiation of VECs, which resulted in the pathophysiological process of psoriasis.

Objective To explore the value of new and fused conventional texture features extracted from mammograms using improved local ternary patterns (LTP) in predicting risk of breast cancer.Methods Mammograms were segmented.Based on improved LTP,the new and conventional texture features were extracted from segmented mammograms of bilateral breasts.Then the features of bilateral breasts were merged.The high dimensional characteristics were reduced with principal component analysis (PCA).Finally,the new texture features were classified with k-nearest neighbor (KNN),and the fusion features were clustered with logistic alternating decision tree (LADTree) algorithm.Results The area under ROC curve (AUC) of new texture features for predicting breast cancer was 0.732 4 ±0.042 8,and the sensitivity,specificity and prediction accuracy was 72.04％ (67/93),74.51％ (76/102) and 73.33％ (143/195),respectively.Furthermore,AUC of fusion features was 0.865 5± 0.014 8,the sensitivity,specificity and prediction accuracy was 84.95％ (79/93),88.23％ (90/102) and 86.67％ (169/195),respectively.Conclusion The new texture features based on improved LTP have high prediction accuracy for breast cancer,and the prediction efficacy can be improved after fusion with conventional features.

Cerebrospinal Fluid Leak ; surgery ; Endoscopy ; Humans ; Iatrogenic Disease ; Male ; Meningocele ; surgery ; Middle Aged ; Nose ; surgery

Objective To investigate the CT manifestations of gastric carcinoma invasion to lesser omentum and to assess the im-pact of lesser omentum on the spreading of gastric carcinoma.Methods We retrospectively reviewed CT findings in 48 patients with gastric carcinoma and lesser omentum involved for primary tumor and the lesser omentum abnormalities.The influence of lesser o-mentum on the extension of gastric carcinoma as well as the accompanied ascites were also analyzed.Results CT manifestations of lesser omentum involvement in gastric carcinoma included the following items:① direct infiltration (35.4%,1 7/48),which was mainly shown as increased density of fatty tissue and the development of mass within the lesser omentum,including spreading into the liver through the lesser omentum directly in two cases;② omental seeding (25.0%,12/48),including smudged appearance (1 1 cases)and omental caking (1 case);③ metastasis of lymph nodes (64.6%,31/48),including enlargement and increase of lymph nodes (27 cases)and cystic mass (4 cases).Ascites was found in 1 1 patients and fluid collection in the lesser sac was shown in 3 of these 1 1 patients.The lesser omentum forms the anterior wall of the lesser sac and separates the fluid collection in the lesser sac from the ascites in the greater peritoneal cavity.Ascites was associated with the omental seeding statistically.Conclusion CT scan is helpful for detecting lesser omentum invasion by gastric carcinoma.The imaging features consist of mass sign,enlargement of lymph nodes,smudged andcakingappearance,and so on.Lesser omentum may also play a certain role in both the extension of gastric carcinoma and the compartmentalization of ascites due to gastric carcinoma.

Objective To study the expressions of Notch receptors (Notch1 and 2) and target gene Hes-1 in bone marrow CD34+ cells from patients with psoriasis. Methods CD34+ cells were isolated from the bone marrow of 12 patients with psoriasis and 19 normal human controls. Western blot was conducted to detect the expressions of Notchl, Notch2 and Hes-1 proteins in CD34+ cells, with the house-keeping gene β-actin as an internal reference. Results In contrast with normal controls, a significant increment was observed in the expressions of Notch1 and Hes-1 proteins in psoriatic patients (0.9488 ± 0.3221 vs. 0.6693 ± 0.1465, 0.8579 ±0.3729 vs. 0.5728 ± 0.1787, both P ＜ 0.05). No significant difference was observed in the expression of Notch2 between psoriatic patients and normal controls (0.7568 ± 0.3461 vs. 0.8312 ± 0.2887, P ＞ 0.05).Conclusion The overexpression of Notch1 and Hes-1 may be associated with the low proliferation activity of psoriatic hematopoietic cells.

Objective To assess the preferential expressions of peripheral blood T cell receptor beta chain variable region (TRBV) subfamilies in patients with psoriasis vulgaris(PV), and to estimate their role in the pathogenesis of psoriasis. Methods Thirty-three upstream primers were designed to target the human functional TRBV genes, downstream primers to target the common T cell receptor beta constant (TRBC) gene,with T cell receptor alpha constant (TRAC) gene as the internal reference. Total RNA was extracted from the peripheral blood T cells of 10 health human controls and 10 patients with PV, and transcribed into cDNA.Then, TRBV genes were amplified by real-time fluorescence quantitative PCR (RFQ-PCR) and the fluorescence intensity of each samples was detected. The expression levels of TRBV genes in the control group were used to calculate the cut-off values (mean expression levels of TRBV subfamilies in the 10 normal controls + 3 standard deviations). When the expression level of a TRBV subfamily from patients with PV was equal to or higher than the cut-off value, it was considered as the preferentially expressed TRBV subfamily. Results The threshold cycle (Ct) value varied from 21 to 24 for TRAC gene. The difference in the Ct value between TRBV subfamily genes and TRAC gene in patients with PV was 2.98 for TRBV2 gene, 3.24 for TRBV5-7 gene, 2.52 for TRBV6-6/6-9 gene, 2.04 for TRBV 12 gene, 3.56 for TRBV 24 gene, and 4.12 for TRBV 29 gene, and the expression levels of these subfamily genes were significantly higher than those in the normal controls (all P ＜ 0.05). According to the above standard, TRBV6-6/6-9, TRBV12 and TRBV29 were considered to be preferentially expressed subfamilies. Conclusions There is a preferential expression of TRBV gene subfamilies in peripheral blood of patients with psoriasis vulgaris, which may play a vital role in the abnormal T cell-mediated immune responses in psoriasis.

OBJECTIVE: To investigate the methodology and efficacy of endoscopic sphenopalatine artery diathermy in management of refractory epistaxis. METHOD: Twenty patients with severe intractable posterior epistaxis, who had underwent various procedures like nasal packing, electro- or chemical cautery or others and still exacerbated, were subjected to this study. Under general anesthesia, according to the endoscopic anatomy of the sphenopalatine foramen, the sphenopalatine artery was identified under the posterior tip of the middle turbinate. After the pedicle of the artery was delineated, a bipolar cauterized the artery and transected it. RESULT: Twenty patients have been followed up for 5 to 20 months with an average of 10 months. No patients suffered recurrent epistaxis during the period. Only 1 patients in this series reported minor nasal adhesion. CONCLUSION Diathermy of sphenopalatine artery, as a purely endonasal procedure, is an effective and microinvasive means of achieving long-term control of refractory epistaxis. It has few complications associated with other forms of arterial ligation.
Adult ; Aged ; Diathermy ; methods ; Endoscopy ; Epistaxis ; surgery ; Female ; Humans ; Male ; Maxillary Artery ; surgery ; Middle Aged ; Treatment Outcome

BACKGROUND:It is discovered in our preliminary study that the activity of psoriatic bone marrow hematopoietic cells is abnormal.OBJECTIVE:To reveal level of stem cell factor(SCF) and granulocyte colony-stimulating factor(G-CSF) secreted by bone marrow stromal cells in psoriasis patients.DESIGN,TIME AND SETTING:This case-control observation experiment was performed at the Laboratory of Department of Dermatology,Taiyuan Central Hospital from October 2007 to August 2008.PARTICIPANTS:Twenty-four common-psoriasis outpatients were selected at the Department of Dermatology,Taiyuan Central Hospital,including 16 males and 8 females,aged 16-59 years old.Twenty controls were selected from Department of Hematology,Taiyuan Central Hospital,whose age and gender were matched with psoriasis patients.METHODS:Bone marrow mononuclear cells were isolated from psoriasis patients and controls using the density gradient centrifugation.Bone marrow stromal cells were cultured by the adherent method.When the cells were cultured for three passages and 72 hours,bone marrow stromal cells and supernatant liquid were collected.MAIN OUTCOME MEASURES:The phenotypes of cells were identified by flow cytometry and the level of SCF and G-CSF were detected by enzyme linked immunosorbent assay kit(ELISA).RESULTS:Flow cytometry assay showed that over 90% bone marrow stromal cells were positive for CD29,but negative for CD34,CD45 and HLA-DR.That is,the purity of bone marrow stromal cells was over 90%.The levels of SCF and G-CSF in psoriasis patients were significantly higher than that in controls(P

Objective:To investigate the influence of histamine on intedeukin(IL-2) production and proliferation of CD4+ T lymphocytes and CD8+ T lymphocytes.Methods:Density gradient centrifugalization and absorption technique were respecitively applied to detach peripheral blood mononuclear cells(PBMC) and peripheral blood lymphocytes(PBLC). CD4+ and CD8+ T lymphocytes divided with anti-CD4+ and anti-CD8+ antibody were cultured in vitro. IL-2 levels in supernatant were quantified by enzyme-linked immunosobent assay (ELBA), and proliferation index were measured by MTT methods. Results:IL-2 levels in supernatant and proliferation rate of CD4+ and CD8+ T lymphocytes treated with histamine were significantly lower than those of their corresponding un-stimulated controls(P