Characteristics of the oral and gastric microbiome in patients with early-stage intramucosal esophageal squamous cell carcinoma.

BACKGROUND: Oral microbiome dysbacteriosis has been reported to be associated with the pathogenesis of advanced esophageal cancer. However, few studies investigated the potential role of oral and gastric microbiota in early-stage intramucosal esophageal squamous carcinoma (EIESC). METHOD: A total of 104 samples were collected from 31 patients with EIESC and 21 healthy controls. The compositions of oral and gastric microbiota were analyzed using 16 S rRNA V3-V4 amplicon sequencing. Linear discriminant analysis effect size (LEfSe) analysis was performed to assess taxonomic differences between groups. The correlation between oral microbiota and clinicopathological factors was evaluated using Spearman correlation analysis. Additionally, co-occurrence networks were established and random forest models were utilized to identify significant microbial biomarkers for distinguishing between the EIESC and control groups. RESULTS: A total of 292 oral genera and 223 species were identified in both EIESC and healthy controls. Six oral genera were remarkably enriched in EIESC groups, including the genera Porphyromonas, Shigella, Subdoligranulum, Leptotrichia, Paludibacter, and Odoribacter. LEfSe analysis identified genera Porphyromonas and Leptotrichia with LDA scores > 3. In the random forest model, Porphyromonas endodontalis ranked the top microbial biomarker to differentiate EIESC from controls. The elimination rate of Porphyromonas endodontalis from the oral cavity to the stomach was also dramatically decreased in the EIESC group than controls. In the microbial co-occurrence network, Porphyromonas endodontalis was positively correlated with Prevotella tannerae and Prevotella intermedia and was negatively correlated with Veillonella dispar. CONCLUSION: Our study potentially indicates that the dysbacteriosis of both the oral and gastric microbiome was associated with EIESC. Larger scale studies and experimental animal models are urgently needed to confirm the possible role of microbial dysbacteriosis in the pathogenesis of EIESC. (Chinese Clinical Trial Registry Center, ChiCTR2200063464, Registered 07 September 2022, https://www.chictr.org.cn/showproj.html?proj=178563).

AHNAK2 Regulates NF-κB/MMP-9 Signaling to Promote Pancreatic Cancer Progression.

Early metastasis of pancreatic cancer (PaC) is a major cause of its high mortality rate. Previous studies have shown that AHNAK2 is involved in the progression of some tumors and is predicted to be an independent prognostic factor for PaC; however, the specific mechanisms through which AHNAK2 regulates PaC remain unclear. In this study, we examined the role of AHNAK2 in PaC and its potential molecular mechanisms. AHNAK2 mRNA and protein expression in PaC tissues and cells were measured using qRT-PCR and western blot analysis. After AHNAK2 knockdown using small interfering RNA, PaC cells were subjected to CCK-8 scratch, and Transwell assays to assess cell proliferation, migration, and invasion, respectively. Furthermore, the validation of the mechanistic pathway was achieved by western blot analysis. AHNAK2 mRNA and protein levels were up-regulated in PaC and silencing AHNAK2 significantly inhibited the proliferation, migration, and invasion of PaC cells. Mechanistically, AHNAK2 knockdown decreased the expression of phosphorylated p65, phosphorylated IκBα, and matrix metalloproteinase-9 (MMP-9), suggesting that activation of the NF-κB/MMP-9 signaling pathway was inhibited. Importantly, activation of NF-κB reversed the effects of AHNAK2 knockdown. Our findings indicate that AHNAK2 promotes PaC progression through the NF-kB/MMP-9 pathway and provides a theoretical basis for targeting AHNAK2 for the treatment of PaC.

Alternation of the gut microbiota in irritable bowel syndrome: an integrated analysis based on multicenter amplicon sequencing data.

BACKGROUND: Gut dysbacteriosis has been reported as one of the etiologies for irritable bowel syndrome (IBS). However, the association between gut microbiota and IBS is still inconclusive. METHOD: A paired-sample study was designed by retrieving original multicenter 16 s-rRNA data of IBS patients and healthy controls from the GMrepo database. The propensity score matching (PSM) algorithm was applied to reduce confounding bias. The differential analysis of microbiota composition was performed at different taxonomic levels. The co-occurrence network was established. Subgroup analysis was performed to identify specific microbial compositions in different IBS subtypes. RESULTS: A total of 1522 amplicon samples were initially enrolled. After PSM, 708 individuals (354 IBS and 354 healthy controls) were eligible for further analysis. A total of 1,160 genera were identified. We identified significantly changed taxa in IBS groups (IBS-enriched: the families Enterobacteriaceae, Moraxellaceae and Sphingobacteriaceae; the genera Streptococcus, Bacillus, Enterocloster, Sphingobacterium, Holdemania and Acinetobacter. IBS-depleted: the phyla Firmicutes, Euryarchaeota, Cyanobacteria, Acidobacteria and Lentisphaerae; the families Bifidobacteriaceae, Ruminococcaceae, Methanobacteriaceae and the other 25 families; the genera Faecalibacterium, Bifidobacterium and other 68 genera). The co-occurrence network identified three hub genera and six hub species (including Faecalibacterium prausnitzii) that may be involved in IBS pathophysiology. Strong positive interactions were identified among the Bifidobacterium longum, Bifidobacterium breve and Bifidobacterium adolescentis in the Bifidobacterium community. CONCLUSION: This study provides quantitative analysis and visualization of the interaction between the gut microbiota and IBS. The identification of key species should be further validated to evaluate their causal relationships with the pathogenesis of IBS.

"M1/M2" Muscularis Macrophages Are Associated with Reduction of Interstitial Cells of Cajal and Glial Cells in Achalasia.

BACKGROUND AND AIMS: Several studies showed muscularis macrophages (MMφ) are associated with GI motility disorders. The purpose of this study was to preliminary explore the association between MMφ and achalasia. METHODS: Tissue samples of the lower esophageal sphincter (LES) high-pressure zone were obtained from 27 achalasia patients and 10 controls. Immunohistochemistry for MMφ, interstitial cells of Cajal (ICC), neuronal nitric oxide synthase (nNOS), and glial cells were conducted. Histological characteristics were compared between groups, and correlation analysis was performed. RESULTS: Fewer ICC was found in achalasia compared with controls (P = 0.018), and the level of M1 macrophages was higher than that in controls no matter in terms of the number or the proportion of M1(P = 0.026 for M1 and 0.037 for M1/MMφ). Statistical differences were found between two groups in terms of proportion of M2 and ratio of M1 to M2 (P = 0.048 for M2/ MMφ and < 0.001 for M1/M2). For the correlation analysis, significant correlations were detected between levels of nNOS, ICC, and glial cells in patients with achalasia (P = 0.026 for nNOS and ICC, 0.001 for nNOS and glial cells, 0.019 for ICC and glial cells). There were significant correlations between M2/MMφ and levels of ICC (P = 0.019), glial cells (P = 0.004), and nNOS (P = 0.135). CONCLUSION: Patients with achalasia had a higher level of M1/M2 ratio in LES and significant correlations were found between M2/MMφ and numbers of ICC and glial cells, which suggested that MMφ were probably associated with occurrence and development of achalasia.

α7 nicotinic acetylcholine receptor agonist GTS-21 attenuates DSS-induced intestinal colitis by improving intestinal mucosal barrier function.

BACKGROUND AND AIMS: Cholinergic output, which could modulate innate immune responses through stimulation of α7 nicotinic acetylcholine receptor (α7nAChR), might be a target to minimize tissue damage in autoimmune disease. GTS-21, a selective α7nAChR agonist, has previously demonstrated to inhibit synovium inflammation in rheumatoid arthritis. In this study, we investigated the effect of GTS-21 on dextran sulfate sodium (DSS)-induced colitis model and its potential mechanism. METHODS: Male BABL/c mice (n = 32) were randomly divided into four groups: normal control group, DSS-induced colitis group, GTS-21 treatment with or without α7nAChR antagonist α-BGT treatment group. Disease activity index (DAI), histological activity index (HAI) and colonic macroscopic damage were evaluated. Fluorescein isothiocyanate (FITC)-dextran assay was applied to measure intestinal permeability. The expressions of tight junction (TJ) proteins and NF-κB associated proteins were detected by Western blot. RESULTS: GTS-21 could decrease DAI scores, HAI scores, intestinal permeability and reduce the intestinal bacterial translocation in DSS-induced colitis group, whereas α7nAChR antagonist α-BGT could impair this protective influence. The expressions of TJ proteins were increased with administration of GTS-21 both in vivo and in vitro. Furthermore, GTS-21 also inhibited the NF-қB activation in intestinal epithelial cells and colitis model, while α-BGT reversed the inhibitory effect. CONCLUSION: The α7nAChR agonist GTS-21 attenuated DSS-induced colitis through increasing expressions of TJ proteins in colon tissues and improved intestinal barrier function, which might be due to  modulating NF-қB activation in intestinal epithelial cells.

A Prospective Trial to Access the Optimal Circumference of Resection in Antireflux Mucosectomy for Treatment-refractory GERD.

OBJECTIVE: There is still no gold standard regarding the optimal circumference of antireflux mucosectomy (ARMS) in patients with treatment-refractory gastroesophageal reflux disease (GERD). The aim of this study is to assess the safety and effectiveness of resection procedures when the circumferences are different. PATIENTS AND METHODS: Thirty-two patients with treatment-refractory GERD were allocated into group A (16 cases) and group B (16 cases) by randomization. In group A and group B, a 2/3 and 1/2 circumference, 1.5 cm wide mucosal resection of the gastric cardia was performed. Health-related quality of life (HRQOL), frequency scale for the symptoms of GERD (FSSG), DeMeester scores and acid exposure time (AET) were accessed at baseline and at 24 months after treatment. Physical component summaries (PCS), mental component summaries (MCS), and RE-specific summary (RES) scores were calculated. RESULTS: All patients had successful surgical procedures and no bleeding, perforation, or dysphagia occurred. The PCS, MCS, and RES scores of post-ARMS were higher than those of pre-ARMS in groups A and B, and the FSSG, DeMeester scores and AET decreased after ARMS in both groups, with differences that were statistically significant (P<0.05). The changes in PCS, MCS, RES, FSSG, DeMeester scores, and AET were greater in group A than in group B, with significant differences in PCS, MCS, RES, and FSSG scores (P<0.05), but no significant differences in, DeMeester scores and AET (P>0.05). CONCLUSION: ARMS is an effective treatment for treatment-refractory GERD. Moreover, we recommend the 2/3 circumference, 1.5 cm wide mucosal resection of the gastric cardia.

Combination of serological biomarkers and clinical features to predict mucosal healing in Crohn's disease: a multicenter cohort study.

PURPOSE: Mucosal healing (MH) has become the treatment goal of patients with Crohn's disease (CD). This study aims to develop a noninvasive and reliable clinical tool for individual evaluation of mucosal healing in patients with Crohn's disease. METHODS: A multicenter retrospective cohort was established. Clinical and serological variables were collected. Separate risk factors were incorporated into a binary logistic regression model. A primary model and a simple model were established, respectively. The model performance was evaluated with C-index, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy. Internal validation was performed in patients with small intestinal lesions. RESULTS: A total of 348 consecutive patients diagnosed with CD who underwent endoscopic examination and review after treatment from January 2010 to June 2021 were composed in the derivation cohort, and 112 patients with small intestinal lesions were included in the validation cohort. The following variables were independently associated with the MH and were subsequently included into the primary prediction model: PLR (platelet to lymphocyte ratio), CAR (C-reactive protein to albumin ratio), ESR (erythrocyte sedimentation rate), HBI (Harvey-Bradshaw Index) score and infliximab treatment. The simple model only included factors of PLR, CAR and ESR. The primary model performed better than the simple one in C-index (87.5% vs. 83.0%, p = 0.004). There was no statistical significance between these two models in sensitivity (70.43% vs. 62.61%, p = 0.467), specificity (87.12% vs. 80.69%, p = 0.448), PPV (72.97% vs. 61.54%, p = 0.292), NPV (85.65% vs. 81.39%, p = 0.614), and accuracy (81.61% vs. 74.71%, p = 0.303). The primary model had good calibration and high levels of explained variation and discrimination in validation cohort. CONCLUSIONS: This model can be used to predict MH in post-treatment patients with CD. It can also be used as an indication of endoscopic surveillance to evaluate mucosal healing in patients with CD after treatment.

Risk factors for the failure of endoscopic resection of gastric submucosal tumors: a long-term retrospective case-control study.

OBJECTIVE: Endoscopic resection (ER) is an effective treatment method for gastric submucosal tumors (G-SMTs), but endoscopic resection failure requires emergency surgery. The purpose of this study was to assess potential risk factors for endoscopic resection failure. METHODS: A total of 1041 patients with G-SMT undergoing endoscopic resection were enrolled. Twenty-five patients in whom endoscopic resection failed, requiring a transition to surgery midway through the operation, were included in the failed group, and 1016 patients who received successful endoscopic resection were included in the successful endoscopic resection group. Baseline and lesion characteristics were recorded, and the differences in tumor characteristics and risk factors for resection failure of G-SMT were analyzed. Sensitivity analysis was performed to detect the stability of the indicator. RESULTS: Of the 1041cases included, there were 25 cases (2.4%) of failed endoscopic resection. Binary logistic analysis showed that the independent risk factors included tumors originating from deep muscularis propria(OR = 14.42, 95% CI 4.47-46.52), size > 3 cm (OR = 7.75, 95% CI 2.64-22.70), exophytic growth pattern (OR = 4.98, 95% CI 1.62-15.29), endoscopist with less experience (OR = 5.99, 95% CI 1.07-12.19), and irregular borders (OR = 4.13, 95% CI 1.40-12.19). The stable risk factors were tumors size, tumor origin and growth pattern according to sensitivity analysis. CONCLUSIONS: Tumors originating from the deep muscularis propria, tumor size > 3 cm, endoscopists with less experience, an exophytic growth pattern, and irregular boundaries were found to be independent risk factors for endoscopic resection failure. To reduce the risk of endoscopic resection failure, physicians should carefully evaluate G-SMT characteristics preoperative.

Regio-, Diastereo-, and Enantioselective Decarboxylative Hydroaminoalkylation of Dienol Ethers Enabled by Dual Palladium/Photoredox Catalysis.

Intermolecular photocatalytic hydroaminoalkylation (HAA) of alkenes have emerged as a powerful method for the construction of alkyl amines. Although there are some studies aiming at stereoselective photocatalytic HAA reactions, the alkenes are limited to electrophilic alkenes. Herein, we report a highly regio-, diastereo-, and enantioselective HAA of electron-rich dienol ethers and α-amino radicals derived from α-amino acids using a unified photoredox and palladium catalytic system. This decarboxylative 1,2-Markovnikov addition enables the construction of vicinal amino tertiary ethers with high levels of regio- (up to >19 : 1 rr), diastereo- (up to >19 : 1 dr), and enantioselectivity control (up to >99 % ee). Mechanistic studies support a reversible hydropalladation as a key step.

Elevated Levels of IL-27 Are Associated with Disease Activity in Patients with Crohn's Disease.

Immune disorders play an important role in the pathogenesis of Crohn's disease (CD). Notably, the increased immune response of Th1 cells and related cytokines is associated with the onset of CD. IL-27 is a newly discovered IL-12-related cytokine, but its expression and clinical significance in CD patients are still controversial. This study is aimed at evaluating the serum levels of IL-27 in CD patients and analyzing their clinical significance. The results indicated that serum levels of IL-27 in CD patients were significantly higher than those in control subjects (median (interquartile range (IQR)): 110.0 (95.0, 145.0) vs. 85.0 (80.0, 95.0) pg/ml, P < 0.001). Furthermore, the IL-27 levels significantly increased in CD patients at the active stage compared with CD patients in remission (CDR) (127.5 (100.0, 150.0) vs. 90 (80.0, 110.0) pg/ml, P < 0.001). However, there was no difference in IL-27 levels between CDR and control subjects. The levels of IL-27 were positively correlated with Crohn's disease activity index (CDAI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin (FC), and Simple Endoscopic Score for Crohn's Disease (SES-CD) and negatively correlated with hemoglobin (Hb) and serum albumin (ALB). IL-27 combined with CRP favored the prediction of CD activity (area under the curve (AUC): 0.88). Additionally, the proportions of Th17 and Th1 cells in peripheral blood were higher in CD patients than in control subjects. Active CD patients exhibited significantly higher proportions of Th17 and Th1 cells than those in remission. Moreover, correlation analysis indicated that the serum levels of IL-27 were positively associated with the frequency of Th17 cells in CD patients (r = 0.519, P = 0.013) but not associated with the frequency of Th1 cells in CD patients. IL-27 is positively associated with multiple inflammation indicators and may exert a proinflammatory profile by regulating Th17 cell differentiation in the development of Crohn's disease. In the future, IL-27 combined with CRP is expected to become an important biological marker of CD activity.

XRCC1 Arg399Gln variation and leukemia susceptibility: evidence from 2,647 cases and 5,518 controls.

Previous reports implicate XRCC1 Arg399Gln polymorphism as a possible risk factor for several cancers. Increasing studies have been conducted on the association of XRCC1 Arg399Gln polymorphisms with susceptibility to leukemia. However, conflicting results have been generated. The goal of the present study was to derive a more precise estimation of the relationship. Meta-analyses assessing the association of XRCC1 Arg399Gln variation with leukemia were conducted, and subgroup analyses on ethnicity and clinical types were further performed. Eligible studies were identified for the period up to February 2013. Consequently, 16 publications including 17 case-control studies with 2,647 cases and 5,518 controls were selected for analysis. The overall data indicated a significant association of XRCC1 Arg399Gln polymorphism with leukemia risk (Gln/Gln versus Arg/Arg: OR = 1.37, 95% confidence interval (CI) = 1.08-1.74; dominant model: OR = 1.23, 95%CI = 1.03-1.46; recessive model: OR = 1.23, 95%CI = 1.06-1.44). In the subgroup analysis by ethnicity, Gln allele may increase leukemia susceptibility among Asians (Gln/Gln versus Arg/Arg: OR = 1.82, 95%CI = 1.19-2.78; dominant model: OR = 1.53, 95%CI = 1.00-2.33; recessive model: OR = 1.51, 95%CI = 1.11-2.06), but not Caucasians or mixed ethnicities. In the subgroup analysis by clinical types, increased risk was observed in acute lymphocytic leukemia (ALL) subgroup (Gln/Gln versus Arg/Arg: OR = 1.45, 95%CI = 1.09-1.93; recessive model: OR = 1.30, 95%CI = 1.00-1.69), but not in acute myeloid leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia subgroups, respectively. Collectively, the results of the present study suggest that XRCC1 Arg399Gln polymorphism might be a low-penetrant risk factor for leukemia, particularly among Asians. Homozygous Gln/Gln alleles might have a correlation with increased ALL susceptibility.

Catalyzing sustainable development: Exploring the interplay between access to clean water, sanitation, renewable energy and electricity services in shaping China's energy, economic growth, and environmental landscape.

The Sustainable Development Goals (SDGs) reflect the shift in global economic conversation toward inclusive growth. The growth can promote inclusivity and widespread sharing of its advancements by concentrating on four key dimensions. (a) Equality of opportunity, (b) sharing prosperity, (3) environmental sustainability/climate adaptation, and (4) macroeconomic stability. We used the Kao cointegration test to study how certain variables are connected over a long period. The relationship between CO2 and GDP per capita, renewable energy and tourism, improved water and sanitation, and access to power all have a positive feedback effect on each other. Based on FMOLS's findings, a 1 % increase in Inclusive growth leads to a 0.342 % (Model 1) and 0.258 % (Model 3) increase in CO2 emissions. An increase of 1 percent in energy consumption per person resulted in a rise of 1.343 % in CO2 emissions in Case 1, 0.524 % in Case 2, and 0.618 % in Case 3. Increasing the tourism sector's proportion of total exports by just one percent will reduce CO2 emissions by 0.221 % (case 1) and 0.234 % (case 3). Based on CCR findings, a 1 % improvement in inclusive growth leads to a 0.403.

CD274 (PD-L1) negatively regulates M1 macrophage polarization in ALI/ARDS.

Background: Acute lung injury (ALI)/severe acute respiratory distress syndrome (ARDS) is a serious clinical syndrome characterized by a high mortality rate. The pathophysiological mechanisms underlying ALI/ARDS remain incompletely understood. Considering the crucial role of immune infiltration and macrophage polarization in the pathogenesis of ALI/ARDS, this study aims to identify key genes associated with both ALI/ARDS and M1 macrophage polarization, employing a combination of bioinformatics and experimental approaches. The findings could potentially reveal novel biomarkers for the diagnosis and management of ALI/ARDS. Methods: Gene expression profiles relevant to ALI were retrieved from the GEO database to identify co-upregulated differentially expressed genes (DEGs). GO and KEGG analyses facilitated functional annotation and pathway elucidation. PPI networks were constructed to identify hub genes, and differences in immune cell infiltration were subsequently examined. The expression of hub genes in M1 versus M2 macrophages was evaluated using macrophage polarization datasets. The diagnostic utility of CD274 (PD-L1) for ARDS was assessed by receiver operating characteristic (ROC) analysis in a validation dataset. Experimental confirmation was conducted using two LPS-induced M1 macrophage models and an ALI mouse model. The role of CD274 (PD-L1) in M1 macrophage polarization and associated proinflammatory cytokine production was further investigated by siRNA-mediated silencing. Results: A total of 99 co-upregulated DEGs were identified in two ALI-linked datasets. Enrichment analysis revealed that these DEGs were mainly involved in immune-inflammatory pathways. The following top 10 hub genes were identified from the PPI network: IL-6, IL-1ß, CXCL10, CD274, CCL2, TLR2, CXCL1, CCL3, IFIT1, and IFIT3. Immune infiltration analysis revealed a significantly increased abundance of M1 and M2 macrophages in lung tissue from the ALI group compared to the control group. Subsequent analysis confirmed that CD274 (PD-L1), a key immunological checkpoint molecule, was highly expressed within M1 macrophages. ROC analysis validated CD274 (PD-L1) as a promising biomarker for the diagnosis of ARDS. Both in vitro and in vivo experiments supported the bioinformatics analysis and confirmed that the JAK-STAT3 pathway promotes CD274 (PD-L1) expression on M1 macrophages. Importantly, knockdown of CD274 (PD-L1) expression potentiated M1 macrophage polarization and enhanced proinflammatory cytokines production. Conclusion: This study demonstrates a significant correlation between CD274 (PD-L1) and M1 macrophages in ALI/ARDS. CD274 (PD-L1) functions as a negative regulator of M1 polarization and the secretion of proinflammatory cytokines in macrophages. These findings suggest potential new targets for the diagnosis and treatment of ALI/ARDS.

Bi2MoO6/MWCNTs-COOH/GCE electrochemical probe for ultrasensitively and selectively detecting antibiotic norfloxacin.

Antibiotics have emerged as a class of contaminants of concern globally, raising widespread worry and unease, primarily because of their inappropriately use and endless migration in food chains. Electrochemical ultrasensitive and selective determination of norfloxacin (NOR) using bismuth-based bimetallic salt bismuth molybdate (Bi2MoO6) and carboxylated multi-walled carbon nanotube (MWCNTs-COOH) hybrid electrode as sensing platforms is presented hereby. The electrocatalytic ability of the electrodes was verified to be enhanced by the synergy effect of both Bi2MoO6 and MWCNTs-COOH using cyclic voltammetry and electrochemical impedance spectroscopy. Linear scan voltammetry was applied to detect NOR. The oxidation peak current was linearly correlated with NOR concentration of 0.03-10 µM and the low limit detection of the optimized method was 6.7 nM (S/N = 3). In addition, it was verified that Bi2MoO6/MWCNTs-COOH/GCE probe had good stability, reproducibility, repeatability and selectivity. The spiked recovery method for NOR in milk and lake water samples showed recoveries of 94.8 - 96.9% and 90.2 - 98.3%, respectively, which can be used to determine NOR in real samples with high sensitivity. The preparation of Bi2MoO6/MWCNTs-COOH/GCE provides a new prototype for probing NOR detection at nanomolar concentration and safeguarding antibiotic contamination in environmental and food chains.

Visible-light induced metal-free intramolecular reductive cyclisations of ketones with alkynes and allenes.

A visible-light-induced, intramolecular, reductive cyclisation of ketones with an unsaturated hydrocarbon moiety was developed. In contrast to conventional protocols requiring resource precious or hazardous metal sources, this method enables facile access to ketyl radicals under metal-free and mild reaction conditions. By polarity-reversed, ketyl radical hydroalkoxylation of alkynes and allenes, a variety of five-membered (hetero-)cyclic products were generated in good yields with good to excellent stereoselectivities. The embedded homoallylic tertiary alcohol could be transformed into other useful functionalities, highlighting the synthetic utility of this reaction. This efficient and sustainable ketyl-alkyne/allene cross coupling also features broad functional group tolerance and scalability.

[Experimental study of subcutaneous adipose-derived stem cells inhibiting orthodontic root resorption].

Objective: To investigate the effect of human subcutaneous adipose-derived stem cells (hADSCs) local transplantation on orthodontically induced root resorption (OIRR) and provide theoretical and experimental basis for the clinical application of hADSCs to inhibit OIRR. Methods: Forty 8-week-old male Sprague Dawley rats were randomly divided into experimental group and control group, with 20 rats in each group, to establish the first molar mesial orthodontic tooth movement (OTM) model of rat right maxillary. The rats in the experimental group were injected with 25 µL of cell suspension containing 2.5×10 5 hADSCs on the 1st, 4th, 8th, and 12th day of modeling, while the rats in the control group were injected with 25 µL of PBS. The rat maxillary models were obtained before and after 7 and 14 days of force application, and 10 rats in each group were killed and sampled after 7 and 14 days of force application. The OTM distance was measured by stereomicroscope, the root morphology of the pressure side was observed by scanning electron microscope and the root resorption area ratio was measured. The root resorption and periodontal tissue remodeling of the pressure side were observed by HE staining and the root resorption index was calculated. The number of cementoclast and osteoclast in the periodontal tissue on the pressure side was counted by tartrate resistant acid phosphatase staining. Results: The TOM distance of both groups increased with the extension of the force application time, and there was no significant difference ( P<0.05). There was no significant difference in OTM distance between the experimental group and the control group after 7 and 14 days of force application ( P>0.05). Scanning electron microscope observation showed that small and shallow scattered resorption lacunae were observed on the root surface of the experimental group and the control group after 7 days of force application, and there was no significant difference in the root resorption area ratio between the two groups ( P>0.05); after 14 days of application, the root resorption lacunae deepened and became larger in both groups, and the root resorption area ratio in the experimental group was significantly lower than that in the control group ( P<0.05). The range and depth of root absorption in the experimental group were smaller and shallower than those in the control group, and the root absorption index in the experimental group was significantly lower than that in the control group after 14 days of force application ( P<0.05). The number of cementoclast in the experimental group was significantly lower than that in the control group after 7 and 14 days of force application ( P<0.05); the number of osteoclasts in the experimental group was significantly lower than that in the control group after 14 days of force application ( P<0.05). Conclusion: Local transplantation of hADSCs may reduce the area and depth of root resorption by reducing the number of cementoclasts and osteoclasts during OTM in rats, thereby inhibiting orthodontic-derived root resorption.

Development and validation of a risk model to predict the progression of ulcerative colitis patients to acute severe disease within one year.

BACKGROUND AND AIMS: Acute severe ulcerative colitis (ASUC) is strongly associated with poor prognosis. We aimed to establish and validate a model predicting ASUC occurrence within 1 year after ulcerative colitis(UC) diagnosis. METHODS: A cohort of UC patients diagnosed between 2018 and 2020 at Northern Jiangsu People's Hospital, who were followed up for one year, was used to develop a risk prediction model. An independent cohort from January to December 2021, monitored until December 2022 at the at the First Affiliated Hospital of Nanjing Medical University, was used for external validation. A multivariable logistic regression analysis was conducted to investigate the adjusted association between six risk factors and ASUC. Subsequently, a simplified model was developed by eliminating a relatively insignificant risk factor to create an easy-to-use index. RESULTS: The prediction model incorporates five parameters: disease extent, endoscopic appearance, histopathology, baseline response medication, and relapse frequency. It generates a nomogram in the end. The discriminant ability (c-index) was separately calculated as 0.982 and 0.925 in the development and validation cohorts. CONCLUSIONS: The risk prediction model for developing ASUC within one year demonstrated excellent reliability and validity, which could be a straightforward and clinically valuable tool for predicting ASUC occurrence within 1 year. CLINICAL TRIAL REGISTRATION: ChiCTR2300071794.

Bioinformatics and System Biology Approach to Identify the Influences of COVID-19 on Rheumatoid Arthritis.

Background: Severe coronavirus disease 2019 (COVID -19) has led to a rapid increase in mortality worldwide. Rheumatoid arthritis (RA) was a high-risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas the molecular mechanisms underlying RA and CVOID-19 are not well understood. The objectives of this study were to analyze potential molecular mechanisms and identify potential drugs for the treatment of COVID-19 and RA using bioinformatics and a systems biology approach. Methods: Two Differentially expressed genes (DEGs) sets extracted from GSE171110 and GSE1775544 datasets were intersected to generate common DEGs, which were used for functional enrichment, pathway analysis, and candidate drugs analysis. Results: A total of 103 common DEGs were identified in the two datasets between RA and COVID-19. A protein-protein interaction (PPI) was constructed using various combinatorial statistical methods and bioinformatics tools. Subsequently, hub genes and essential modules were identified from the PPI network. In addition, we performed functional analysis and pathway analysis under ontological conditions and found that there was common association between RA and progression of COVID-19 infection. Finally, transcription factor-gene interactions, protein-drug interactions, and DEGs-miRNAs coregulatory networks with common DEGs were also identified in the datasets. Conclusion: We successfully identified the top 10 hub genes that could serve as novel targeted therapy for COVID-19 and screened out some potential drugs useful for COVID-19 patients with RA.

Predicting Mucosal Healing in Crohn's Disease: A Nomogram Model Developed from a Retrospective Cohort.

Purpose: Mucosal healing (MH) has become a therapeutic end point for Crohn's disease (CD). The purpose of this study was to identify potential risk factors responsible for a lower probability of mucosal healing in CD. It also aimed to create and validate a noninvasive tool for predicting mucosal healing in CD to aid clinical decision-making. Patients and Methods: We established a derivation cohort diagnosed with CD, in which endoscopic examination was performed before and after treatment at the First Affiliated Hospital of Nanjing Medical University between January 2010 and June 2021. Patient data including demographic and clinical characteristics and treatment details were collected. The achievement of mucosal healing (without ulceration on endoscopic examination) after treatment was the endpoint observed during follow-up. We performed logistic regression analysis to identify factors associated with mucosal healing. These factors were used to develop a model (CD mucosal healing prediction nomogram) to predict mucosal healing in CD. External validation was performed using a new cohort of 60 patients from the Second Affiliated Hospital of Soochow University between January 2012 and June 2021. Results: A total of 331 patients were included in the derivation cohort. We found the following factors to be independently associated with mucosal healing after treatment: disease course <11 months, ulcer size <0.5 cm, Harvey-Bradshaw Index score <9, infliximab treatment, and non-exclusive use of 5-aminosalicylic acid. The model incorporating these factors achieved good discrimination, calibration, and clinical decision curve analysis results on internal validation (C-index: 0.788, 95% confidence interval [CI]: 0.74-0.84). The external validation cohort also demonstrated good discrimination (C-index: 0.785, 95% CI: 0.68-0.90) and calibration. Conclusion: The CD mucosal healing prediction nomogram model demonstrated good reliability and validated. It can potentially be developed into a simple and clinically useful tool for predicting mucosal healing in CD.

Aryl hydrocarbon receptor activation ameliorates experimental colitis by modulating the tolerogenic dendritic and regulatory T cell formation.

BACKGROUND: Intestinal immune dysfunction is involved in the onset of Crohn's disease (CD). Dendritic cells (DCs), antigen-presenting cells, play a key role in the maintenance of intestinal immune homeostasis. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor widely expressed in various immune cells, including DCs. Although AhR plays an important role in immune tolerance, its role in the DCs is unclear. The purpose of this study was to investigate whether the activation of AhR can induce tolerogenic DCs (tolDCs) and the differentiation of regulatory T (Treg) cells, as well as ameliorate experimental colitis. RESULTS: AhR activation in the DCs resulted in a lower expression of surface markers such as CD80, CD83, CD86, and pro-inflammatory cytokine production, and higher anti-inflammatory production (IL-1ß, IL-23, and IL-12) compared to the control DCs. The surface dendrites in DCs were significantly reduced following AhR activation by 6-formylindolo [3,2-b]carbazole (FICZ). Such DCs with FICZ-mediated activation of AhR, namely tolDCs, promoted Treg cell differentiation. Adoptive transfer of tolDCs to a TNBS-induced colitis mouse model significantly alleviated the severity of inflammation by improving the colon length and decreasing the disease activity index (DAI) and histopathological score. Moreover, the transferred tolDCs decreased the frequency of Th17 cells and increased the frequency of Treg cells in the spleen and mesenteric lymph nodes (MLNs) in murine colitis models. CONCLUSIONS: Activation of AhR in the DCs could induce tolDCs, and the transplantation of tolDCs may help in relieving intestinal inflammation and maintaining the Th17/Treg differentiation balance. Thus, our data suggest that AhR may be a potential therapeutic target for CD.