Opacimonas viscosa gen. nov., sp. nov., a novel bacterium isolated from phycosphere.

A novel strain of a member of the family Alteromonadaceae was isolated from the phycosphere of a diatom and designated as LMIT007T. LMIT007T could form milk-white, opaque, circular and smooth colonies on 2216E marine agar. LMIT007T cells were around 1.0-1.8 µm long, 0.8-1.8 µm wide, round or oval shaped and had polar flagella but were non-motile. Optimum conditions for growth were 25 °C, pH 7.0 and 6 % (w/v) NaCl. The results of 16S rRNA gene-based analysis indicated that LMIT007T had the highest similarity with the type strains Aestuaribacter halophilus JC2043T (95.95 %), Alteromonas lipolytica JW12T (95.60 %) and Alteromonas halophila KCTC 22164T (94.21 %). Furthermore, the results of phylogenetic analysis based on 16S rRNA gene sequences and of phylogenomic analysis indicated that LMIT007T could be clustered into the family Alteromonadaceae but formed a separate branch. The genome size of the strain was 2.95 Mbp and the DNA G+C content was 41.6 %. The average nucleotide identity (ANI) values of orthologous genes between LMIT007T and species of other closely related genera within the family Alteromonadaceae ranged from 66.9 to 69.2 %, and the average amino acid identity (AAI) values ranged from 60.0 to 65.7 %. The main respiratory quinone was ubiquinone-8. The major fatty acids were summed feature 3 (C16 : 1ω7c / C16 : 1ω6c) and C16 : 0. The polar lipid profile contain phosphatidylethanolamine, phosphatidylglycerol, aminolipid, two phospholipid and an unknown polar lipid. On the basis of the results of the polyphasic analysis, strain LMIT007T is suggested to represent a novel genus and species within the family Alteromonadaceae, for which the name Opacimonas viscosa gen. nov., sp. nov. is proposed. The type strain is LMIT007T (=MCCC 1K08161T=KCTC 92597T).

Using deep learning and explainable artificial intelligence to assess the severity of gastroesophageal reflux disease according to the Los Angeles Classification System.

OBJECTIVES: Gastroesophageal reflux disease (GERD) is a complex disease with a high worldwide prevalence. The Los Angeles classification (LA-grade) system is meaningful for assessing the endoscopic severity of GERD. Deep learning (DL) methods have been widely used in the field of endoscopy. However, few DL-assisted researches have concentrated on the diagnosis of GERD. This study is the first to develop a five-category classification DL model based on the LA-grade using explainable artificial intelligence (XAI). MATERIALS AND METHODS: A total of 2081 endoscopic images were used for the development of a DL model, and the classification accuracy of the models and endoscopists with different levels of experience was compared. RESULTS: Some mainstream DL models were utilized, of which DenseNet-121 outperformed. The area under the curve (AUC) of the DenseNet-121 was 0.968, and its classification accuracy (86.7%) was significantly higher than that of junior (71.5%) and experienced (77.4%) endoscopists. An XAI evaluation was also performed to explore the perception consistency between the DL model and endoscopists, which showed meaningful results for real-world applications. CONCLUSIONS: The DL model showed a potential in improving the accuracy of endoscopists in LA-grading of GERD, and it has noticeable clinical application prospects and is worthy of further promotion.

Patterns of Lymph Node Metastasis and Optimal Surgical Strategy in Small (≤20 mm) Gastroenteropancreatic Neuroendocrine Tumors.

Background: Regional lymph node metastasis (LNM) is crucial for planning additional lymphadenectomy, and is directly correlated with poor prognosis in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, the patterns of LNM for small (≤20 mm) GEP-NETs remain unclear. This population-based study aimed at evaluating LNM patterns and identifying optimal surgical strategies from the standpoint of lymph node dissemination. Methods: This retrospective cohort study retrieved data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database for 17,308 patients diagnosed as having localized well-differentiated GEP-NETs ≤ 20 mm between January 1, 2004, and December 31, 2017. The patterns of LNM were characterized in 6,622 patients who underwent extended resection for adequate lymph node harvest. Results: Of 6,622 patients with localized small GEP-NETs in the current study, 2,380 (36%) presented with LNM after regional lymphadenectomy. Nodal involvement was observed in approximately 7.4%, 49.1%, 13.6%, 53.7%, 13.8%, 7.8%, and 15.4% of gastric (g-), small intestinal (si-), appendiceal (a-), colonic (c-), rectal (r-), non-functional pancreatic (nfp-), and functional pancreatic (fp-) NETs ≤ 20 mm. Patients with younger age, larger tumor size, and muscularis invasion were more likely to present with LNM. Additional lymphadenectomy conferred a significant survival advantage in NETs (≤10 mm: HR, 0.47; 95% CI, 0.33-0.66; p < 0.001; 11-20 mm: HR, 0.54; 95% CI, 0.34-0.85; p = 0.008) and fp-NETs ≤ 20 mm (HR, 0.08; 95% CI, 0.02-0.36; p = 0.001), as well as g-NETs (HR, 0.39; 95% CI, 0.16-0.96; p = 0.041) and c-NETs of 11-20 mm (HR, 0.07; 95% CI, 0.01-0.48; p = 0.007). Survival benefits of additional lymphadenectomy were not found in a-NETs, r-NETs, and nfp-NETs with a small size. Conclusions: Given the increased risk for nodal metastasis, primary tumor resection with regional lymphadenectomy is a potential optimal surgical strategy for si-NETs and fp-NETs ≤ 20 mm, as well as g-NETs and c-NETs of 11-20 mm. Local resection is an appropriate and reliable surgical approach for a-NETs, r-NETs, and nfp-NETs ≤ 20 mm.

Comparison of the combined toxicity of polystyrene microplastics and different concentrations of cadmium in zebrafish.

Microplastic particles (MPs) are widely distributed in the environment. The high surface ratio of MPs make them effective transmission mediums for many toxic pollutants. The combined toxicity of MPs and heavy metals have received increasing attention in recent years. In this study, effects of MPs (100 µg/L) on the toxicity of low (15 µg/L) and high (150 µg/L) concentrations of cadmium (Cd) to zebrafish were evaluated based on a 10-day subacute exposure. The survival rate, growth, antioxidant capacity, reactive oxygen species (ROS) accumulation, histology and Cd biological enrichment in different tissues were investigated with the objective to understand the effect and mechanism of MPs on Cd toxicity to zebrafish. The results showed that the effect of MPs on Cd toxicity mainly depended on the concentration of Cd. MPs significantly enhanced the toxicity of low concentrations of Cd (LCd), including lower antioxidant enzyme activities, higher ROS levels, more severe tissue damage, inhibited growth rate and lower survival rate. However, the effects of MPs on the toxicity of high concentrations of Cd (HCd) were exactly opposite to LCd. Cd enrichment analysis showed that MPs could significantly increase LCd accumulation in intestine, gill, skin and muscle tissues, while decrease the enrichment of HCd in liver, intestine, gill and muscle tissues. Free Cd in the exposure water was significantly decreased by MPs in the HCd and MPs combined exposure group. These results suggest that effect of MPs on Cd toxicity to zebrafish depending on Cd concentration, MPs can increase the enrichment of LCd in zebrafish and enhance its toxicity, but can decrease the enrichment of HCd in zebrafish and attenuate its toxicity. The present study will broaden our understanding of the interaction between MPs and heavy metals.

A Comprehensive Prognostic Model for Colorectal Cancer Liver Metastasis Recurrence After Neoadjuvant Chemotherapy.

Background: For patients with colorectal cancer liver metastases (CRLMs), it is important to stratify patients according to the risk of recurrence. This study aimed to validate the predictive value of some clinical, imaging, and pathology biomarkers and develop an operational prognostic model for patients with CRLMs with neoadjuvant chemotherapy (NACT) before the liver resection. Methods: Patients with CRLMs accompanied with primary lesion and liver metastases lesion resection were enrolled into this study. A nomogram based on independent risk factors was identified by Kaplan-Meier analysis and multivariate Cox proportional hazard analysis. The predictive ability was evaluated by receiver operating characteristic (ROC) curves and decision curve analysis (DCA). Calibration plot were also used to explore the consistency between prediction and reality. Results: A total of 118 patients were enrolled into the study. Multivariable Cox analysis found that histopathological growth patterns (HGPs) [Hazard Rate (HR) = 2.130], radiology response (stable disease vs. partial response, HR = 2.207; progressive disease vs. partial response, HR = 3.824), lymph node status (HR = 1.442), and age (HR = 0.576) were independent risk factors for disease-free survival (DFS) (p < 0.05). Corresponding nomogram was constructed on the basis of the above factors, demonstrating that scores ranging from 5 to 11 presented better prognosis than the scores of 0-4 (median DFS = 14.3 vs. 4.9 months, p < 0.0001). The area under ROC curves of the model for 1-, 2-, and 3-year DFS were 0.754, 0.705, and 0.666, respectively, and DCA confirmed that the risk model showed more clinical benefits than clinical risk score. Calibration plot for the probability of DFS at 1 or 3 years verified an optimal agreement between prediction and actual observation. In the course of our research, compared with pure NACT, a higher proportion of desmoplastic HGP (dHGP) was detected in patients treated with NACT plus cetuximab (p = 0.030), and the use of cetuximab was an independent factor for decreased replacement HGP (rHGP) and increased dHGP (p = 0.049). Conclusion: Our model is concise, comprehensive, and high efficient, which may contribute to better predicting the prognosis of patients with CRLMs with NACT before the liver resection. In addition, we observed an unbalanced distribution of HGPs as well.

Efficacy and safety of leflunomide treatment in Takayasu arteritis: Case series from the East China cohort.

OBJECTIVE: To evaluate the efficacy and safety of leflunomide (LEF) as induction treatment in a series of Takayasu arteritis (TA) patients based on a Chinese cohort. METHOD: Fifty-six patients from the East China TA cohort treated with LEF for at least 3 months were enrolled in this study, including the naïve LEF treatment patients (n = 41) and the cyclophosphamide (CYC)-resistant LEF treatment patients (n = 15). Data in clinical features, NIH score and angiography were collected. Response to treatment was assessed by rates of complete remission (CR) and partial remission (PR) and response rate (RR) after 6 and 12 months of treatment. RESULTS: The total CR rate and RR were 67.86% and 83.93% after 6 months, and 55.36% and 69.64% after 12 months, respectively. ESR and CRP levels and NIH scores decreased significantly after 12 months of LEF treatment (P < 0.05). Patients of CYC-resistant switched to LEF and reached the CR of 60.00% (9/15) and RR of 86.67% (13/15) after 6 months, and 73.33% (11/15) and 80.00% (12/15) after 12 months, respectively, with decrease in NIH scores (all P < 0.05). After following up for 14.44 ± 6.86 months, 48 patients (85.71%) continued LEF treatment with good tolerance. One patient died from progression of TA after 2 months, 2 patients relapsed, and 3 patients with side effects were switched to other immunosuppressive agents. CONCLUSIONS: LEF led to a quick induction and sustained remission of TA, especially in refractory cases, and therefore, should be considered as an alternative treatment for TA.

Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs.

TLR7/9 signals are capable of mounting massive interferon (IFN) response in plasmacytoid dendritic cells (pDCs) immediately after viral infection, yet the involvement of epigenetic regulation in this process has not been documented. Here, we report that zinc finger CXXC family epigenetic regulator CXXC5 is highly expressed in pDCs, where it plays a crucial role in TLR7/9- and virus-induced IFN response. Notably, genetic ablation of CXXC5 resulted in aberrant methylation of the CpG-containing island (CGI) within the Irf7 gene and impaired IRF7 expression in steady-state pDCs. Mechanistically, CXXC5 is responsible for the recruitment of DNA demethylase Tet2 to maintain the hypomethylation of a subset of CGIs, a process coincident with active histone modifications and constitutive transcription of these CGI-containing genes. Consequently, CXXC5-deficient mice had compromised early IFN response and became highly vulnerable to infection by herpes simplex virus and vesicular stomatitis virus. Together, our results identify CXXC5 as a novel epigenetic regulator for pDC-mediated antiviral response.

MicroRNA-130b Ameliorates Murine Lupus Nephritis Through Targeting the Type I Interferon Pathway on Renal Mesangial Cells.

OBJECTIVE: Type I interferon (IFN) is a critical pathogenic factor during the progression of lupus nephritis (LN). Although microRNAs (miRNAs) have been shown to control the IFN response in immune cells in LN, the role of miRNAs in resident renal cells remains unclear. We undertook this study to investigate the role of microRNA-130b (miR-130b) in the IFN pathway in renal cells as well as its therapeutic effect in LN. METHODS: Kidney tissues from patients and (NZB × NZW)F1 lupus-prone mice were collected for detecting miR-130b levels. Primary renal mesangial cells (RMCs) were used to determine the role of miR-130b in the IFN pathway. We overexpressed miR-130b by administering miR-130b agomir in a mouse model of IFNα-accelerated LN to test its therapeutic efficacy. RESULTS: Down-regulated miR-130b expression was observed in kidney tissues from patients and lupus-prone mice. Further analysis showed that underexpression of miR-130b correlated negatively with abnormal activation of the IFN response in LN patients. In vitro, overexpressing miR-130b suppressed signaling downstream from the type I IFN pathway in RMCs by targeting IFN regulatory factor 1 (IRF-1). The opposite effect was observed when endogenous miR-130b expression was inhibited. The inverse correlation between IRF1 and miR-130b levels was detected in renal biopsy samples from LN patients. More importantly, in vivo administration of miR-130b agomir reduced IFNα-accelerated progression of LN, with decreased proteinuria, lower levels of immune complex deposition, and lack of glomerular lesions. CONCLUSION: MicroRNA-130b is a novel negative regulator of the type I IFN pathway in renal cells. Overexpression of miR-130b in vivo ameliorates IFNα-accelerated LN, providing potential novel strategies for therapeutic intervention in LN.

Dendritic Cells in Systemic Lupus Erythematosus: From Pathogenic Players to Therapeutic Tools.

System lupus erythematosus (SLE) is a multifactorial systemic autoimmune disease with a wide variety of presenting features. SLE is believed to result from dysregulated immune responses, loss of tolerance of CD4 T cells and B cells to ubiquitous self-antigens, and the subsequent production of anti-nuclear and other autoreactive antibodies. Recent research has associated lupus development with changes in the dendritic cell (DC) compartment, including altered DC subset frequency and localization, overactivation of mDCs and pDCs, and functional defects in DCs. Here we discuss the current knowledge on the role of DC dysfunction in SLE pathogenesis, with the focus on DCs as targets for interventional therapies.

Phenotypic and functional alterations of pDCs in lupus-prone mice.

Plasmacytoid dendritic cells (pDCs) were considered to be the major IFNα source in systemic lupus erythematosus (SLE) but their phenotype and function in different disease status have not been well studied. To study the function and phenotype of pDCs in lupus-prone mice we used 7 strains of lupus-prone mice including NZB/W F1, NZB, NZW, NZM2410, B6.NZM(Sle1/2/3), MRL/lpr and BXSB/Mp mice and C57BL/6 as control mice. Increased spleen pDC numbers were found in most lupus mice compared to C57BL/6 mice. The IFNα-producing ability of BM pDCs was similar between lupus and C57BL/6 mice, whereas pDCs from the spleens of NZB/W F1 and NZB mice produced more IFNα than pDCs from the spleens of C57BL/6 mice. Furthermore, spleen pDCs from MRL-lpr and NZM2410 mice showed increased responses to Tlr7 and Tlr9, respectively. As the disease progressed, IFN signature were evaluated in both BM and spleen pDC from lupus prone mice and the number of BM pDCs and their ability to produce IFNα gradually decreased in lupus-prone mice. In conclusion, pDC are activated alone with disease development and its phenotype and function differ among lupus-prone strains, and these differences may contribute to the development of lupus in these mice.

Deoxycytidine kinase promotes the migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a complex, multi-system disease whose primary site of inflammatory tissue damage is the joint. The increasing evidences indicate that activated RA fibroblast-like synoviocytes (FLS) play a critical role in the development of pannus by migrating into cartilage and bone. Furthermore FLS and T cells can activate each other in vitro and in vivo, which is crucial for the progress of RA. Deoxycytidine kinase (DCK) has been linked to peripheral T cell homeostatic proliferation and survival, which is very important for RA. Yet, the function of DCK in FLS is still unknown. Here, we present a story that DCK could regulate the migration and invasion of FLS through AKT pathway in RA patients. Moreover, DCK seems to be the upstream of AKT and FAK, and AKT inhibitor exerted the similar effect on FLS motility. In summary, our study characterized the new role of DCK in human primary FLS cells, and figured out the possible pathway DCK involved in, and these findings might propose DCK as a novel target for controlling joint destruction of RA.

Association of FcγRIIIa-158V/F with systemic lupus erythematosus in a Chinese population.

AIM: It has long been a controversy that polymorphisms in FcγRIIIa (CD16A) receptors are associated with systemic lupus erythematosus (SLE). We aimed to verify the association of FcγRIIIa polymorphisms with SLE in a large Chinese population. METHODS: We genotyped FcγRIIIa-158V/F (rs396991) using a pyro-sequencing assay (PSQ 96MA) in a total of 732 individuals with SLE (390 lupus nephritis and 342 non-lupus nephritis) and 886 controls. Meta-analysis was used to examine the association of the FcγRIIIa-F158 allele with SLE and lupus nephritis with RevMan 5. RESULTS: The allele frequencies of FcγRIIIa-F158 were significantly increased in SLE (OR 1.293, 95%CI 1.111-1.505, P = 0.0009). There was significant skewing in the distribution of FcγRIIIa genotypes between SLE patients and controls (P = 0.0026 for 158 F/F vs. 158F/V and 158V/V, OR 1.604, 95%CI 1.089-2.361). Serositis was more common in patients with the FcγRIIIa-F158 allele and FcγRIIIa-F/F genotype, and low complement was more common in patients with the FcγRIIIa-F/F genotype. There was no skewing in the distribution of FcγRIIIa genotypes in the lupus nephritis group. No association was found for the frequencies of the FcγRIIIa-F158 allele and 158F/F genotype compared with the V158 allele and F/V plus V/V genotypes, respectively, between lupus nephritis and SLE without nephritis patients in a meta-analysis of 11 Asian studies. CONCLUSION: Our results suggest that the low-binding allele FcγRIIIa-158F is one of the risk factors for SLE in the Chinese population.