A novel multimodal aptasensor for Patulin detection in fruit products based on high-performance RuMOF@hydrogel and versatile pericarp-derived carbonized polymer dots.

Patulin (PAT) is a widespread fruit toxin. Trace-level PAT exposure can cause serious harm to human health. Herein, a multimodal PAT aptasensor was designed based on Ru(bpy)32+-based metal organic framework composited hydrogel (RuMOF@hydrogel) and versatile banana peel-derived carbonized polymer dots (BPPDs). RuMOF@hydrogel modified magnetic-electrode exhibited excellent anodic and cathodic electrochemiluminescence (ECL) emission and stability. Meanwhile, the BPPDs could enhance anodic ECL of RuMOF@hydrogel, and also show excellent fluorescence (FL) and photothermal (PT) properties. With the aid of PAT-triggered hybridization chain reaction and magnetic separation, ECL, FL, and PT responses could be recorded concurrently. The detection limit can reach as low as 0.25 fg mL-1. The ratiometric ECL quantitation ensured the sensitivity and accuracy of this assay. And visual FL and portable PT modes contributed to the utility. Furthermore, this aptasensor demonstrated better performances than HPLC in fruit products and the protocol can be extended to determine various contaminants in foods.

Potential therapeutic targets for pelvic organ prolapse: insights from key genes related to blood vessel development.

Objective: Pelvic organ prolapse (POP) is a disease in which pelvic floor support structures are dysfunctional due to disruption of the extracellular matrix (ECM). The vascular system is essential for maintaining ECM homeostasis. Therefore, this study explored the potential mechanism of blood vessel development-related genes (BVDRGs) in POP. Methods: POP-related datasets and BVDRGs were included in this study. Differentially expressed genes (DEGs) between the POP and control groups were first identified in the GSE12852 and GSE208271 datasets, and DE-BVDRGs were identified by determining the intersection of these DEGs and BVDRGs. Subsequently, the feature genes were evaluated by machine learning. Feature genes with consistent expression trends in the GSE12852 and GSE208271 datasets were considered key genes. Afterward, the overall diagnostic efficacy of key genes in POP was evaluated through receiver operating characteristic (ROC) curve analysis. Based on the key genes, enrichment analysis, immune infiltration analysis and regulatory network construction were performed to elucidate the molecular mechanisms underlying the functions of the key genes in POP. Results: A total of 888 DEGs1 and 643 DEGs2 were identified in the GSE12852 and GSE208271 datasets, and 26 candidate genes and 4 DE-BVDRGs were identified. Furthermore, Hyaluronan synthase 2 (HAS2), Matrix metalloproteinase 19 (MMP19) and Plexin Domain Containing 1 (PLXDC1) were identified as key genes in POP and had promising value for diagnosing POP (AUC > 0.8). Additional research revealed that the key genes were predominantly implicated in immune cell activation, chemotaxis, and cytokine release via the chemokine signaling pathway, the Nod-like receptor signaling pathway, and the Toll-like receptor signaling pathway. Analysis of immune cell infiltration confirmed a decrease in the proportion of plasma cells in POP, and MMP19 expression showed a significant negative correlation with plasma cell numbers. In addition, regulatory network analysis revealed that MALAT1 (a lncRNA) targeted hsa-miR-503-5p, hsa-miR-23a-3p and hsa-miR-129-5p to simultaneously regulate three key genes. Conclusion: We identified three key BVDRGs (HAS2, MMP19 and PLXDC1) related to the ECM in POP, providing markers for diagnostic studies and investigations of the molecular mechanism of POP.

LRRK2-Associated Parkinsonism With and Without In Vivo Evidence of Alpha-Synuclein Aggregates.

Background: Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates. Methods: Data were from the Parkinson's Progression Markers Initiative, a multicenter prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient- reported outcome assessments were administered. Biomarkers included dopamine transporter SPECT scan, CSF amyloid-beta1-42, total tau, phospho-tau181, urine bis(monoacylglycerol)phosphate levels, and serum neurofilament light chain. Linear mixed effects models examined differences in trajectory in CSF negative and positive groups. Results: 148 LRRK2-parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay were included. At baseline, the negative group were older than the positive group (median [interquartile range] 69.1 [65.2-72.3] vs 61.5 [55.6-66.9] years, p<0.001) and a greater proportion were female (28 (61%) vs 43 (42%), p=0.035). Despite being older, the negative group had similar duration since diagnosis, and similar motor rating scale (16 [11-23] vs 16 [10-22], p=0.480) though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared to 75 (77%) of the positive group. Lowest putamen dopamine transporter binding expected for age and sex was greater in the negative vs positive groups (0.36 [0.29-0.45] vs 0.26 [0.22-0.37], p<0.001). Serum neurofilament light chain was higher in the negative group compared to the positive group (17.10 [13.60-22.10] vs 10.50 [8.43-14.70]; age-adjusted p-value=0.013). In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (p=0.037), but no other differences in trajectory were found. Conclusion: Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline may have more significant cognitive dysfunction. The underlying biology in LRRK2-parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation.

Association between organophosphorus insecticides exposure and osteoarthritis in patients with arteriosclerotic cardiovascular disease.

BACKGROUND: Organic phosphorus insecticides (OPPs) are a class of environmental pollutants widely used worldwide with potential human health risks. We aimed to assess the association between exposure to OPPs and osteoarthritis (OA) particularly in participants with atherosclerotic cardiovascular disease (ASCVD). METHODS: Participants' information was obtained from data in the National Health and Nutrition Examination (NHANES). Weighted logistic regression models were utilized to detect associations between OPPs metabolites and OA. Restricted cubic spline plots (RCS) were drawn to visualize the dose-response relationship between each metabolite and OA prevalence. Weighted quantile sum (WQS) regression and Bayesian kernel-machine regression (BKMR), were applied to investigate the joint effect of mixtures of OPPs on OA. RESULTS: A total of 6871 samples were included in our study, no significant associations between OPPs exposure and OA incidence were found in whole population. However, in a subset of 475 individuals with ASCVD, significant associations between DMP (odds ratio [OR] as a continuous variable = 1.22, 95% confidence interval [CI]: 1.07,1.28), DEP ((odds ratio [OR] of the highest tertile compared to the lowest = 2.43, 95% confidence interval [CI]: 1.21,4.86), and OA were observed. DMP and DEP showed an increasing dose-response relationship to the prevalence of OA, while DMTP, DETP, DMDTP and DEDTP showed a nonlinear relationship. Multi-contamination modeling revealed a 1.34-fold (95% confidence intervals:0.80, 2.26) higher prevalence of OA in participants with high co-exposure to OPPs compared to those with low co-exposure, with a preponderant weighting (0.87) for the dimethyl dialkyl phosphate metabolites (DMAPs). The BKMR also showed that co-exposure of mixed OPPs was associated with an increased prevalence of OA, with DMP showing a significant dose-response relationship. CONCLUSION: High levels of urine dialkyl phosphate metabolites (DAP) of multiple OPPs are associated with an increased prevalence of OA in patients with ASCVD, suggesting the need to prevent exposure to OPPs in ASCVD patients to avoid triggering OA and further avoid the occurrence of cardiovascular events caused by OA.

Exploring the Targets and Molecular Mechanisms of Thalidomide in the Treatment of Ulcerative Colitis: Network Pharmacology and Experimental Validation.

BACKGROUND: Ulcerative colitis (UC) is a chronic, nonspecific, inflammatory disease of the intestine with an unknown cause. Thalidomide (THA) has been shown to be an effective drug for the treatment of UC. However, the molecular targets and mechanism of action of THA for the treatment of UC are not yet clear. OBJECTIVES: Combining network pharmacology with in vitro experiments, this study aimed to investigate the potential targets and molecular mechanisms of THA for the treatment of UC. METHODS: Firstly, relevant targets of THA against UC were obtained from public databases. Then, the top 10 hub targets and key molecular mechanisms of THA for UC were screened based on the network pharmacology approach and bioinformatics method. Finally, an in vitro cellular inflammation model was constructed using lipopolysaccharide (LPS) induced intestinal epithelial cells (NCM460) to validate the top 10 hub targets and key signaling pathways. RESULTS: A total of 121 relevant targets of THA against UC were obtained, of which the top 10 hub targets were SRC, LCK, MAPK1, HSP90AA1, EGFR, HRAS, JAK2, RAC1, STAT1, and MAP2K1. The PI3K-Akt pathway was significantly associated with THA treatment of UC. In vitro experiments revealed that THA treatment reversed the expression of HSP90AA1, EGFR, STAT1, and JAK2 differential genes. THA was able to up- regulate the mRNA expression of pro-inflammatory factor IL-10 and decrease the mRNA levels of anti-inflammatory factors IL-6, IL-1ß, and TNF-α. Furthermore, THA also exerted anti-inflammatory effects by inhibiting the activation of the PI3K/Akt pathway. CONCLUSION: THA may play a therapeutic role in UC by inhibiting the PI3K-Akt pathway. HSP90AA1, EGFR, STAT1, and JAK2 may be the most relevant potential therapeutic targets for THA in the treatment of UC.

Transcutaneous Auricular Vagal Nerve Stimulation Is Effective for the Treatment of Functional Dyspepsia: A Multicenter, Randomized Controlled Study.

INTRODUCTION: Vagal nerve stimulation (VNS) can be used to modulate gastrointestinal motility, inflammation, and nociception. However, it remains unclear whether VNS is effective in adult patients with functional dyspepsia (FD). We investigated the effectiveness of transcutaneous auricular VNS (taVNS) in patients with FD. METHODS: Consecutive patients with FD meeting Rome IV criteria with modified FD Symptom Diary score ≥10 were enrolled. Patients were randomly allocated to 10-Hz taVNS (V10 group), 25-Hz taVNS (V25 group), or sham group, with 30 minutes of treatment twice a day for 4 weeks. The primary outcome was the response rate at week 4, defined as the proportion of patients whose modified FD Symptom Diary score was reduced ≥5 when compared with the baseline. Secondary outcomes included adequate relief rate and adverse events. RESULTS: A total of 300 patients were randomized to V10 (n = 101), V25 (n = 99), and sham groups (n = 100). After 4 weeks of treatment, V10 and V25 groups had a higher response rate (81.2% vs 75.9% vs 47%, both P < 0.001) and adequate relief rate (85.1% vs 80.8% vs 67%, both P < 0.05) compared with the sham group. There was no significant difference between V10 and V25 in response rate and adequate relief rate (both P > 0.05). The efficacy of taVNS (both 10 and 25 Hz) lasted at week 8 and week 12 during follow-up period. Adverse events were all mild and comparable among the 3 groups (1%-3%). DISCUSSION: Our study firstly showed that 4-week taVNS (both 10 and 25 Hz) was effective and safe for the treatment of adult FD ( clinicaltrials.gov number: NCT04668534).

Rapid screening of electrochemically active bacteria based on a biocathode-functional bipolar electrode-electrochemiluminescence platform.

A functional bipolar electrode-electrochemiluminescence (BPE-ECL) platform based on biocathode reducing oxygen was constructed for detecting electrochemically active bacteria (EAB) in this paper. Firstly, thiolated trimethylated chitosan quaternary ammonium salt (TMC-SH) layer was assembled on the gold-plated cathode of BPE. TMC-SH contains quaternary ammonium salt branch chain, which can inhibit the growth of microorganisms on the surface or in the surrounding environment while absorbing bacteria. Then, the peristaltic pump was used to flow all of the samples through the cathode, and the EAB was electrostatically adsorbed on the electrode surface. Finally, applying a constant potential to the BPE, bacteria can catalyze electrochemical reduction of O2, and decrease the overpotential of O2 reduction at the cathode, which in turn generates an ECL reporting intensity change at the anode. In this way, live and dead bacteria can be distinguished, and the influence of complex food substrates on detection can be greatly reduced.

Double bipolar electrode electrochemiluminescence color switch for food-borne pathogens detection.

Color-switch electrochemiluminescence (ECL) sensing platform based on a dual-bipolar electrode (D-BPE) is reported in this work. The D-BPE was composed of a cathode filled with buffer and two anodes filled with [Ru(bpy)3]2+-TPrA and luminol-H2O2 solutions, respectively. Both anodes were modified with capture DNA and served as ECL reporting platforms. After introducing ferrocene-labeled aptamer (Fc-aptamer) on both anodes, the ECL emission signal of the [Ru(bpy)3]2+ was difficult to be observed (anode 1), while luminol emitted a strong and visible ECL signal (anode 2). Ferrocene (Fc) did not only prevent the oxidation of [Ru(bpy)3]2+ due to its lower oxidation potential, its oxidation product Fc+ also quenched the [Ru(bpy)3]2+ ECL through efficient energy transfer. For luminol, Fc+ catalyzes the accelerated formation of the excited-state of the luminol anion radical, which leads to the enhancement of the luminol ECL. In the presence of food-borne pathogens, the aptamer was assembled with them, leading to the leaving of Fc from the surface of the D-BPE anodes. The ECL intensity of [Ru(bpy)3]2+ was enlarged, meanwhile, the blue emission signal of luminol became weakened. By self-calibrating the ratio of the two signals, 1-106 CFU mL-1 food-borne pathogenic bacteria can be sensitively detected with a detection limit of 1 CFU mL-1. Ingeniously, the color-switch biosensor can be used to detect S. aureus, E. coli and S. typhimurium by assembling the corresponding aptamers onto the D-BPE anodes.

Disrupted resting-state functional connectivity of the thalamus in patients with coronary heart disease.

Background: Although homeostasis of the cardiovascular system is regulated by the cerebral cortex via the autonomic nervous system, the role of abnormal brain functional connectivity (FC) networks in patients with cardiac dysfunction remains unclear. Here, we report thalamus-based FC alterations and their relationship with clinical characteristics in patients with coronary heart disease (CHD). Methods: We employed resting-state functional magnetic resonance imaging (rs-fMRI) to acquire imaging data in twenty-six patients with CHD alongside sixteen healthy controls (HCs). Next, we performed a thalamus-based FC analysis to profile abnormal FC patterns in the whole brain. Subsequently, the mean time series of the brain regions that survived in the FC analysis were used to determine correlations with clinical parameters in patients with CHD. Results: We found no statistically significant differences in demographic and clinical data between patients with CHD and HCs. Patients with CHD showed decreased FC patterns between bilateral thalami and left hemisphere, encompassing supplementary motor area, superior frontal gyrus, superior parietal gyrus, inferior parietal gyrus, middle cingulate cortex, lingual gyrus and calcarine sulcus. Conclusions: These findings not only have implications in clarifying the relationship between cerebral functional imbalance and cardiovascular system, but also provide valuable insights to guide future evaluation and management of cardiac autonomic regulation via the brain-heart axis.

Biocathodes reducing oxygen in BPE-ECL system for rapid screening of E. coli O157:H7.

After discovery of electron transfer from bacteria, most bacteria known to be electrochemically active are utilized as a self-regenerable catalyst at the anode of microbial fuel cells (MFCs). However, the reverse phenomenon, cathodic catalysts is not so widely researched. This present study demonstrated that E. coli O157:H7 was electrochemically active, and it was able to catalyze oxygen reduction at the cathode of bipolar electrode (BPE). Applying a constant potential to the BPE, E. coli O157:H7 can catalyze electrochemical reduction of O2, decrease the overpotential of O2 reduction at the cathode, which in turn generates an electrochemiluminescence (ECL) reporting intensity change at the anode. Significantly, a majority of food matrix does not exhibit catalytic activity for electrochemical reduction of O2. Meanwhile, due to the physically separation of two poles of closed BPE, complex food matrix at the cathode does not interfere with the ECL reaction at the anode. Therefore, the effect of food matrix is negligible when measuring E. coli O157:H7 levels in food. A low detection limit of 10 CFU mL-1 E. coli O157:H7 could be identified within 1 h. Thus, biocathodes reducing oxygen in BPE-ECL system has shown excellent characteristics in the field of rapid detection of electroactive bacteria in food.