Identification of Potential Biomarkers for Major Depressive Disorder: Based on Integrated Bioinformatics and Clinical Validation.

Major depressive disorder (MDD) is a severe mental illness characterized by a lack of objective biomarkers. Mounting evidence suggests there are extensive transcriptional molecular changes in the prefrontal cortex (PFC) of individuals with MDD. However, it remains unclear whether there are specific genes that are consistently altered and possess diagnostic power. In this study, we conducted a systematic search of PFC datasets of MDD patients from the Gene Expression Omnibus database. We calculated the differential expression of genes (DEGs) and identified robust DEGs using the RRA and MetaDE methods. Furthermore, we validated the consistently altered genes and assessed their diagnostic power through enzyme-linked immunosorbent assay experiments in our clinical blood cohort. Additionally, we evaluated the diagnostic power of hub DEGs in independent public blood datasets. We obtained eight PFC datasets, comprising 158 MDD patients and 263 healthy controls, and identified a total of 1468 unique DEGs. Through integrated analysis, we identified 290 robustly altered DEGs. Among these, seven hub DEGs (SLC1A3, PON2, AQP1, EFEMP1, GJA1, CENPD, HSD11B1) were significantly down-regulated at the protein level in our clinical blood cohort. Moreover, these hub DEGs exhibited a negative correlation with the Hamilton Depression Scale score (P < 0.05). Furthermore, these hub DEGs formed a panel with promising diagnostic power in three independent public blood datasets (average AUCs of 0.85) and our clinical blood cohort (AUC of 0.92). The biomarker panel composed of these genes demonstrated promising diagnostic efficacy for MDD and serves as a useful tool for its diagnosis.

Oral microbiota dysbiosis alters chronic restraint stress-induced depression-like behaviors by modulating host metabolism.

Studies have shown that the microbiota-gut-brain axis is highly correlated with the pathogenesis of depression in humans. However, whether independent oral microbiome that do not depend on gut microbes could affect the progression of depression in human beings remains unclear, neither does the presence and underlying mechanisms of the microbiota-oral-brain axis in the development of the condition. Hence this study that encompasses clinical and animal experiments aims at investigating the correlation between oral microbiota and the onset of depression via mediating the microbiota-oral-brain axis. We compared the oral microbial compositions and metabolomes of 87 patients with depressive symptoms versus 70 healthy controls. We found that the oral microbial and metabolic signatures were significantly different between the two groups. Significantly, germ-free (GF) mice transplanted with saliva from mice exposing to chronic restraint stress (CRS) displayed depression-like behavior and oral microbial dysbiosis. This was characterized by a significant differential abundance of bacterial species, including the enrichment of Pseudomonas, Pasteurellaceae, and Muribacter, as well as the depletion of Streptococcus. Metabolomic analysis showed the alternation of metabolites in the plasma of CRS-exposed GF mice, especially Eicosapentaenoic Acid. Furthermore, oral and gut barrier dysfunction caused by CRS-induced oral microbiota dysbiosis may be associated with increased blood-brain barrier permeability. Pseudomonas aeruginosa supplementation exacerbated depression-like behavior, while Eicosapentaenoic Acid treatment conferred protection against depression-like states in mice. These results suggest that oral microbiome and metabolic function dysbiosis may be relevant to the pathogenesis and pathophysiology of depression. The proposed microbiota-oral-brain axis provides a new way and targets for us to study the pathogenesis of depression.

Flavomycin restores colistin susceptibility in multidrug-resistant Gram-negative bacteria.

Polymyxin is used as a last resort antibiotics for infections caused by multi-drug resistant (MDR) Gram-negative bacteria and is often combined with other antibiotics to improve clinical effectiveness. However, the synergism of colistin and other antibiotics remains obscure. Here, we revealed a notable synergy between colistin and flavomycin, which was traditionally used as an animal growth promoter and has limited activity against Gram-negative bacteria, using checkerboard assay and time-kill curve analyses. The importance of membrane penetration induced by colistin was assessed by examining the intracellular accumulation of flavomycin and its antimicrobial impact on Escherichia coli (E. coli) strains with truncated lipopolysaccharides. Besides, a mutation in the flavomycin binding site was created to confirm its role in the observed synergy. This synergy is manifested as an augmented penetration of the E. coli outer membrane by colistin, leading to increased intracellular accumulation of flavomycin and enhanced cell killing thereafter. The observed synergy was dependent on the antimicrobial activity of flavomycin, as mutation of its binding site abolished the synergy. In vivo studies confirmed the efficacy of colistin combined with flavomycin against MDR E. coli infections. This study is the first to demonstrate the synergistic effect between colistin and flavomycin, shedding light on their respective roles in this synergism. Therefore, we propose flavomycin as an adjuvant to enhance the potency of colistin against MDR Gram-negative bacteria. IMPORTANCE: Colistin is a critical antibiotic in combating multi-drug resistant Gram-negative bacteria, but the emergence of mobilized colistin resistance (mcr) undermines its effectiveness. Previous studies have found that colistin can synergy with various drugs; however, its exact mechanisms with hydrophobic drugs are still unrevealed. Generally, the membrane destruction of colistin is thought to be the essential trigger for its interactions with its partner drugs. Here, we use clustered regularly interspaced palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) for specifically mutating the binding site of one hydrophobic drug (flavomycin) and show that antimicrobial activity of flavomycin is critical for the synergy. Our results first give the evidence that the synergy is set off by colistin's membrane destruction and operated the final antimicrobial function by its partner drugs.

Prevalence data for total corneal astigmatism in cataract patients.

PURPOSE: To report the prevalence data for total corneal astigmatism (TCA) in cataract patients. METHODS: The authors retrospectively collected and analyzed the preoperative biometric data of the patients who underwent cataract surgery in the Department of Ophthalmology, Peking University Third Hospital, from January 2019 to May 2023. RESULTS: The mean age of the 10817 patients was 71 ± 10 years; the male/female ratio was 4653/6164. The mean TCA obtained by the IOLMaster 700 (Carl Zeiss Meditec AG, Jena, Germany), the Abulafia-Koch (AK) formula, and the Barrett toric calculator was 1.11 ± 0.81 diopter (D), 1.13 ± 0.75 D, and 1.12 ± 0.74 D respectively, which was significantly greater than the mean standard keratometric (K) astigmatism (0.99 ± 0.75 D) obtained by IOLMaster 700. Against-the-rule (ATR) astigmatism was dominant in all the TCA measurements, and its proportion increased with age. TCA measurements by different methods exhibit high variability, with a total of 1574 (8.9%) data sets from 1016 (9.4%) patients showing a difference larger than 0.5 D in at least one pair of TCA measurements. CONCLUSION: The use of TCA rather than K astigmatism significantly influenced the choice of intraocular lenses (IOLs) as more patients would be candidates for toric IOLs. It was essential to carefully compare and select TCA obtained with multiple methods for optimal postoperative visual quality.

Zeb1-controlled metabolic plasticity enables remodeling of chromatin accessibility in the development of neuroendocrine prostate cancer.

Cell plasticity has been found to play a critical role in tumor progression and therapy resistance. However, our understanding of the characteristics and markers of plastic cellular states during cancer cell lineage transition remains limited. In this study, multi-omics analyses show that prostate cancer cells undergo an intermediate state marked by Zeb1 expression with epithelial-mesenchymal transition (EMT), stemness, and neuroendocrine features during the development of neuroendocrine prostate cancer (NEPC). Organoid-formation assays and in vivo lineage tracing experiments demonstrate that Zeb1+ epithelioid cells are putative cells of origin for NEPC. Mechanistically, Zeb1 transcriptionally regulates the expression of several key glycolytic enzymes, thereby predisposing tumor cells to utilize glycolysis for energy metabolism. During this process, lactate accumulation-mediated histone lactylation enhances chromatin accessibility and cellular plasticity including induction of neuro-gene expression, which promotes NEPC development. Collectively, Zeb1-driven metabolic rewiring enables the epigenetic reprogramming of prostate cancer cells to license the adeno-to-neuroendocrine lineage transition.

The relationship between anxiety symptoms and disturbances in biological rhythms in patients with depression.

BACKGROUND: Biological rhythms denote the cyclical patterns of life activities anchored to a 24-hour cycle. Research shows that depression exhibits disturbances in biological rhythms. Yet, the relationship between these biological rhythms and concomitant anxiety symptoms is insufficiently investigated in structured clinical assessments. METHODS: This multicenter study, carried out in four Chinese hospitals, comprehensively examined the relationship between anxiety and disruptions in biological rhythms among patients with depression. The study encompassed 218 patients diagnosed with depression and 205 matched healthy controls. The Chinese version of the Biological Rhythms Interview of Assessment in Neuropsychiatry was utilized to evaluate the participants' biological rhythms, focusing on four dimensions: sleep, activity, social, and diet. RESULTS: In patients with depression, there is a significant positive correlation between the severity of anxiety symptoms and the disturbances in biological rhythms. The severity of anxiety and depression, along with the quality of life, are independently associated with disruptions in biological rhythms. The mediation model reveals that anxiety symptoms mediate the relationship between depressive symptoms and biological rhythms. CONCLUSION: This research highlights the role of anxiety within the spectrum of depressive disorders and the associated disturbances in biological rhythms. Our findings shed light on potential pathways towards more targeted preventive strategies and therapeutic interventions for individuals battling depression and anxiety.

Integrated analysis of transcriptional changes in major depressive disorder: Insights from blood and anterior cingulate cortex.

Background: Major depressive disorder (MDD) was involved in widely transcriptional changes in central and peripheral tissues. While, previous studies focused on single tissues, making it difficult to represent systemic molecular changes throughout the body. Thus, there is an urgent need to explore the central and peripheral biomarkers with intrinsic correlation. Methods: We systematically retrieved gene expression profiles of blood and anterior cingulate cortex (ACC). 3 blood datatsets (84 MDD and 88 controls) and 6 ACC datasets (100 MDD and 100 controls) were obtained. Differential expression analysis, RobustRankAggreg (RRA) analysis, functional enrichment analysis, immune associated analysis and protein-protein interaction networks (PPI) were integrated. Furthermore, the key genes were validated in an independent ACC dataset (12 MDD and 15 controls) and a cohort with 120 MDD and 117 controls. Results: Differential expression analysis identified 2211 and 2021 differential expressed genes (DEGs) in blood and ACC, respectively. RRA identified 45 and 25 robust DEGs in blood and ACC based on DEGs, and all of them were closely associated with immune cells. Functional enrichment results showed both the robust DEGs in blood and ACC were enriched in humoral immune response. Furthermore, PPI identified 8 hub DEGs (CD79A, CD79B, CD19, MS4A1, PLP1, CLDN11, MOG, MAG) in blood and ACC. Independent ACC dataset showed the area under the curve (AUC) based on these hub DEGs was 0.77. Meanwhile, these hub DEGs were validated in the serum of MDD patients, and also showed a promising diagnostic power. Conclusions: The biomarker panel based on hub DEGs yield a promising diagnostic efficacy, and all of these hub DEGs were strongly correlated with immunity. Humoral immune response may be the key link between the brain and blood in MDD, and our results may provide further understanding for MDD.

Measuring job stress of dental workers in China during the COVID-19 pandemic: reliability and validity of the hospital consultants' job stress questionnaire.

BACKGROUND: The Hospital Consultants' Job Stress Questionnaire (HCJSQ) has been widely used to assess sources and levels of job stress. However, its reliability and validity among Chinese dental workers have not been extensively studied. The objective of this study was to assess the reliability and validity of the HCJSQ specifically in Chinese dental workers. METHODS: The HCJSQ was used to explore the sources and the global ratings of job stress among Chinese dental workers. To assess the reliability and validity of the HCJSQ, various statistical measures were employed, including Cronbach's alpha coefficient, Spearman-Brown coefficient, Spearman correlation coefficient, exploratory factor analysis, confirmatory factor analysis, convergent validity, and discriminant validity. RESULTS: Of the participants, 526 (17.4%) reported high levels of stress, while 1,246 (41.3%) and 1,248 (41.3%) reported moderate and low levels of stress, respectively. The Cronbach's alpha coefficient for the modified HCJSQ was 0.903, and the Spearman-Brown coefficient was 0.904. Spearman correlation coefficient between individuals' items and the total score ranged from 0.438 to 0.785 (p < 0.05). Exploratory factor analysis revealed that three factors accounted for 60.243% of the total variance. Confirmatory factor analysis demonstrated factor loadings between 0.624 and 0.834 on the specified items. The fit indices of the confirmatory factor analysis indicated good model fit, with a Root Mean Square Error of Approximation of 0.064, Normative Fit Index of 0.937, Comparative Fit Index of 0.952, Incremental Fit Index of 0.952, Tucker-Lewis index of 0.941, and Goodness of Fit Index of 0.944. Additionally, the convergent validity and discriminant validity showed a good fit for the three-factor model. CONCLUSION: The results of this study confirm that Chinese dental workers experience high levels of stress, and the three-factor model of the HCJSQ proves to be a suitable instrument for evaluating the sources and levels of job stress among Chinese dental workers. Therefore, it is imperative that relevant entities such as hospitals, medical associations, and government take appropriate measures to address the existing situation.

Dysregulated Glucuronidation of Bilirubin Exacerbates Liver Inflammation and Fibrosis in Schistosomiasis Japonica through the NF-κB Signaling Pathway.

Hepatic fibrosis is an important pathological manifestation of chronic schistosome infection. Patients with advanced schistosomiasis show varying degrees of abnormalities in liver fibrosis indicators and bilirubin metabolism. However, the relationship between hepatic fibrosis in schistosomiasis and dysregulated bilirubin metabolism remains unclear. In this study, we observed a positive correlation between total bilirubin levels and the levels of ALT, AST, LN, and CIV in patients with advanced schistosomiasis. Additionally, we established mouse models at different time points following S. japonicum infection. As the infection time increased, liver fibrosis escalated, while liver UGT1A1 consistently exhibited a low expression, indicating impaired glucuronidation of bilirubin metabolism in mice. In vitro experiments suggested that SEA may be a key inhibitor of hepatic UGT1A1 expression after schistosome infection. Furthermore, a high concentration of bilirubin activated the NF-κB signaling pathway in L-O2 cells in vitro. These findings suggested that the dysregulated glucuronidation of bilirubin caused by S. japonicum infection may play a significant role in schistosomiasis liver fibrosis through the NF-κB signaling pathway.

Alterations of the gut microbiota in patients with schizophrenia.

Introduction: Schizophrenia is a complex psychiatric disorder, of which molecular pathogenesis remains largely unknown. Accumulating evidence suggest that gut microbiota may affect brain function via the complex gut-brain axis, which may be a potential contributor to schizophrenia. However, the alteration of gut microbiota showed high heterogeneity across different studies. Therefore, this study aims to identify the consistently altered gut microbial taxa associated with schizophrenia. Methods: We conducted a systematic search and synthesis of the up-to-date human gut microbiome studies on schizophrenia, and performed vote counting analyses to identify consistently changed microbiota. Further, we investigated the effects of potential confounders on the alteration of gut microbiota. Results: We obtained 30 available clinical studies, and found that there was no strong evidence to support significant differences in α-diversity and ß-diversity between schizophrenic patients and healthy controls. Among 428 differential gut microbial taxa collected from original studies, we found that 8 gut microbial taxa were consistently up-regulated in schizophrenic patients, including Proteobacteria, Gammaproteobacteria, Lactobacillaceae, Enterobacteriaceae, Lactobacillus, Succinivibrio, Prevotella and Acidaminococcus. While 5 taxa were consistently down-regulated in schizophrenia, including Fusicatenibacter, Faecalibacterium, Roseburia, Coprococcus and Anaerostipes. Discussion: These findings suggested that gut microbial changes in patients with schizophrenia were characterized by the depletion of anti-inflammatory butyrate-producing genera, and the enrichment of certain opportunistic bacteria genera and probiotics. This study contributes to further understanding the role of gut microbiota in schizophrenia, and developing microbiota-based diagnosis and therapy for schizophrenia.

Profiling Intact Glycosphingolipids with Automated Structural Annotation and Quantitation from Human Samples with Nanoflow Liquid Chromatography Mass Spectrometry.

Sphingolipids are an essential subset of bioactive lipids found in most eukaryotic cells that contribute to membrane biophysical properties and are involved in cellular differentiation, recognition, and mediating interactions. The described nanoHPLC-ESI-Q/ToF methodology utilizes known biosynthetic pathways, accurate mass detection, optimized collision-induced disassociation, and a robust nanoflow chromatographic separation for the analysis of intact sphingolipids found in human tissue, cells, and serum. The methodology was developed and validated with an emphasis on addressing the common issues experienced in profiling these amphipathic lipids, which are part of the glycocalyx and lipidome. The high sensitivity obtained using nanorange flow rates with robust chromatographic reproducibility over a wide range of concentrations and injection volumes results in confident identifications for profiling these low-abundant biomolecules.

Potential AhR-independent mechanisms of 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibition of human glioblastoma A172 cells migration.

The toxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is generally believed to be mediated by aryl hydrocarbon receptor (AhR), but some evidence suggests that the effects of TCDD can also be produced through AhR-independent mechanisms. In previous experiments, we found that mainly AhR-dependent mechanism was involved in the migration inhibition of glioblastoma U87 cells by TCDD. Due to the heterogeneity of glioblastomas, not all tumor cells have significant AhR expression. The effects and mechanisms of TCDD on the migration of glioblastomas with low AhR expression are still unclear. We employed a glioblastoma cell line A172 with low AhR expression as a model, using wound healing and Transwell® assay to detect the effect of TCDD on cell migration. We found that TCDD can inhibit the migration of A172 cells without activating AhR signaling pathway. Further, after being pre-treated with AhR antagonist CH223191, the inhibition of TCDD on A172 cells migration was not changed, indicating that the effect of TCDD on A172 cells is not dependent on AhR activation. By transcriptome sequencing analysis, we propose dysregulation of the expression of certain migration-related genes, such as IL6, IL1B, CXCL8, FOS, SYK, and PTGS2 involved in cytokines, MAPK, NF-κB, and IL-17 signaling pathways, as potential AhR-independent mechanisms that mediate the inhibition of TCDD migration in A172 cells.

Emergence of tet(X4)-positive Enterobacterales in retail eggs and the widespread of IncFIA(HI1)-HI1A-HI1B(R27) plasmids carrying tet(X4).

The proliferation of antimicrobial-resistant microbes and resistance genes in various foods poses a serious hazard to public health. The plasmid-mediated tigecycline resistance gene tet(X4) has been detected in Enterobacterales from various niches but has not yet been reported in eggs. This study aimed to investigate the occurrence and characteristics of tigecycline-resistant strains from retail eggs. A total of 144 eggs were purchased from farmers' markets in Guangdong province, China, and eggshell (n = 144) and egg content (n = 96) samples were used to screen for tigecycline-resistant strains. Eight Escherichia coli strains (two ST195, one ST48, ST8165, ST752, ST93, ST189, and ST224) and one Klebsiella pneumoniae strain (ST252) recovered from eight (5.56 %, 8/144) egg samples (eggshells, n = 6; egg content, n = 2) were positive for tet(X4). Notably, the two E. coli ST195 strains were closely (15-54 SNPs) related to all the tet(X4)-positive E. coli ST195 from various origins (food animals, foods, migratory birds, human, and environment) deposited in GenBank. The E. coli ST224 showed a close phylogenetic relationship (9-12 SNPs) with two tet(X4)-positive E. coli strains from chicken feces and retail chicken in Guangdong province. The hybrid plasmid IncFIA(HI1)-HI1A-HI1B(R27) constitutes the predominant tet(X4) vector both herein (7/9, 77.78 %) and in the GenBank database (32/160, 20 %). The tet(X4)-positive IncFIA(HI1)-HI1A-HI1B(R27) plasmids, sharing highly similar structures, have been widely disseminated across China. However, the IncFIA(HI1)-HI1A-HI1B(R27) plasmids exhibit poor stability and low conjugation frequency. The contamination of tet(X4)-positive bacteria internally and externally in retail eggs poses a prospective food safety threat. More attention should be paid to the spread of the tet(X4) gene via epidemic clone E. coli ST195 and the plasmid IncFIA(HI1)-HI1A-HI1B(R27).

Emergence of plasmid-mediated high-level tigecycline resistance gene tet(X4) in Enterobacterales from retail aquatic products.

The spread of antimicrobial-resistant microbes and genes in various foods poses a significant threat to public health. Of particular global concern is the plasmid-mediated tigecycline resistance gene tet(X4), which, while identified in various sources, has not hitherto been reported in aquatic products. This study aimed to investigate the occurrence and characterization of tigecycline-resistant strains from aquatic products. A total of 73 nonrepetitive seafood samples were purchased from 26 farmers' markets to detect tigecycline-resistant strains. Of these, nine Escherichia coli strains (comprising two ST58, one ST195, ST10, ST48, ST88, ST877, ST1244, ST14462) and one Citrobacter meridianamericanus, recovered from nine (12.33 %, 9/73) seafood samples (fish, n = 7; shrimp, clam and crab, n = 1 respectively), were positive for the tet(X4). Notably, phylogenetic analysis showed that E. coli ST195, a common ST carrying tet(X4), has a close phylogenetic relationship (23∼48 SNPs) with 32 tet(X4)-harboring E. coli ST195 isolates (isolated from pigs, animal foods, vegetable, and humans) deposited in NCBI database. Additionally, E. coli ST58 was closely (2 SNPs) related to one tet(X4)-positive E. coli strain from retail vegetables documented in the NCBI database. Whole genome sequencing and bioinformatic analysis revealed that tet(X4) genes were located on IncX1 (7 E. coli) or hybrid plasmid IncFIA(HI1)/IncHI1B(R27)/IncHI1A (2 E.coli and one C. meridianamericanus). These plasmids displayed high homology with those of plasmids from other sources deposited in GenBank database. These findings underscore the role of epidemic clones and plasmids in driving the dissemination of tet(X4) gene within Enterobacterales of aquatic products origin. To the best of our knowledge, this is the first report of tet(X4)-positive Enterobacterales from aquatic products. The pervasive propagation of tet(X4) gene facilitated by epidemic plasmids and clones across food animals, food products, humans, and the environment presents a serious threat to public health.

Ocular Biometry Features and Their Relationship with Anterior and Posterior Segment Lengths among a Myopia Population in Northern China.

Objectives: The study aims to explore the ocular biometry of a myopic population in Northern China, focusing specifically on anterior and posterior segment lengths. Methods: This is a cross-sectional study. The medical records of 3458 myopic patients who underwent refractive surgery were evaluated. Axial length (AL), anterior chamber depth (ACD), lens thickness (LT) and other biometric parameters were measured using the IOL Master 700. The study determined the anterior segment length (ASL = ACD + LT), the posterior segment length (PSL = AL - ASL) and the ratio of ASL to PSL (ASL/PSL). Results: This study included 3458 eyes from 3458 myopic patients (1171 men and 2287 women). The mean age was 27.38 ± 6.88, ranging from 16 to 48 years old. The mean ASL was 7.35 ± 0.27 mm, and the mean PSL was 18.39 ± 1.18 mm. The ASL and PSL trends demonstrate an age-related increase for both genders, with notable gender-specific variations. Across most age groups, males typically exhibited higher ASLs and PSLs than females, with the exception of the 35-40 and 40-45 age groups. The ASL and PSL consistently increased with a rising AL. The AL strongly correlates with the PSL and negatively correlates with the ASL/PSL ratio. The ACD and LT moderately correlate with the ASL, but an increased LT does not imply a longer posterior segment. The CCT and SE show little correlation with axial eye parameters. Conclusions: Among Chinese myopic patients, a longer ASL and PSL were correlated with older age and the male gender. The AL strongly correlates positively with the PSL and negatively correlates with the ASL/PSL ratio. An elongation of the posterior segment may primarily account for an eyeball's lengthening.

Salivary microbiota and metabolic phenotype of patients with recurrent aphthous ulcers.

OBJECTIVES: Recurrent aphthous ulcer (RAU) is a prevalent oral mucosal disease, affecting around 20% of the global population. It can greatly impair the quality of life for affected individuals. However, the exact etiology of RAU remains unknown. SUBJECTS AND METHODS: 16S rRNA sequencing (16S rRNA-seq) and non-targeted liquid chromatography-mass spectrometry (LC-MS) were employed to investigate the salivary microbiota and metabolic phenotype between RAU patients (N = 61) and healthy controls (HCs) (N = 105). RESULTS: Findings from 16S rRNA -seq indicated reduced oral microbial diversity in RAU patients compared to HCs, but increased interactions. Clinical variables did not show any significant association with the overall diversity of oral microbiota in RAU patients. However, significant correlations were observed between specific microorganisms and clinical variables. LC-MS results revealed dysregulation of amino acid, lipid, nucleotide, and caffeine metabolism in RAU patients. Furthermore, correlation analysis of 16S rRNA-seq and LC-MS data revealed a significant association between salivary microbiota and metabolites in RAU patients. CONCLUSIONS: Our study revealed notable differences in salivary microbiota and metabolic profiles between RAU patients and HCs, indicating a strong link between oral microbiota dysbiosis, metabolic disturbances, and the onset and progression of RAU.

Interpretable Detection of Diabetic Retinopathy, Retinal Vein Occlusion, Age-Related Macular Degeneration, and Other Fundus Conditions.

Diabetic retinopathy (DR), retinal vein occlusion (RVO), and age-related macular degeneration (AMD) pose significant global health challenges, often resulting in vision impairment and blindness. Automatic detection of these conditions is crucial, particularly in underserved rural areas with limited access to ophthalmic services. Despite remarkable advancements in artificial intelligence, especially convolutional neural networks (CNNs), their complexity can make interpretation difficult. In this study, we curated a dataset consisting of 15,089 color fundus photographs (CFPs) obtained from 8110 patients who underwent fundus fluorescein angiography (FFA) examination. The primary objective was to construct integrated models that merge CNNs with an attention mechanism. These models were designed for a hierarchical multilabel classification task, focusing on the detection of DR, RVO, AMD, and other fundus conditions. Furthermore, our approach extended to the detailed classification of DR, RVO, and AMD according to their respective subclasses. We employed a methodology that entails the translation of diagnostic information obtained from FFA results into CFPs. Our investigation focused on evaluating the models' ability to achieve precise diagnoses solely based on CFPs. Remarkably, our models showcased improvements across diverse fundus conditions, with the ConvNeXt-base + attention model standing out for its exceptional performance. The ConvNeXt-base + attention model achieved remarkable metrics, including an area under the receiver operating characteristic curve (AUC) of 0.943, a referable F1 score of 0.870, and a Cohen's kappa of 0.778 for DR detection. For RVO, it attained an AUC of 0.960, a referable F1 score of 0.854, and a Cohen's kappa of 0.819. Furthermore, in AMD detection, the model achieved an AUC of 0.959, an F1 score of 0.727, and a Cohen's kappa of 0.686. Impressively, the model demonstrated proficiency in subclassifying RVO and AMD, showcasing commendable sensitivity and specificity. Moreover, our models enhanced interpretability by visualizing attention weights on fundus images, aiding in the identification of disease findings. These outcomes underscore the substantial impact of our models in advancing the detection of DR, RVO, and AMD, offering the potential for improved patient outcomes and positively influencing the healthcare landscape.

Chronic restraint stress promotes oral squamous cell carcinoma development by inhibiting ALDH3A1 via stress response hormone.

BACKGROUND: Chronic restraint stress (CRS) has iteratively been reported to be possibly implicated in the development of numerous cancer types. However, its role in oral squamous cell carcinoma (OSCC) has not been well elucidated. Here we intended to evaluate the role and mechanism. METHODS: The effects of CRS were investigated in xenograft models of OSCC by using transcriptome sequencing, LC-MS, ELISA and RT-PCR. Moreover, the role of CRS and ALDH3A1 on OSCC cells was researched by using Trans-well, flow cytometry, western blotting, immunofluorescence, ATP activity and OCR assay. Furthermore, immunohistochemical staining was employed to observe the cell proliferation and invasion of OSCC in xenotransplantation models. RESULTS: CRS promoted the progression of OSCC in xenograft models, stimulated the secretion of norepinephrine and the expression of ADRB2, but decreased the expression of ALDH3A1. Moreover, CRS changed energy metabolism and increased mitochondrial metabolism markers. However, ALDH3A1 overexpression suppressed proliferation, EMT and mitochondrial metabolism of OSCC cells. CONCLUSION: Inhibition of ALDH3A1 expression plays a pivotal role in CRS promoting tumorigenic potential of OSCC cells, and the regulatory of ALDH3A1 on mitochondrial metabolism may be involved in this process.

PPARß/δ-ANGPTL4 axis mediates the promotion of mono-2-ethylhexyl phthalic acid on MYCN-amplified neuroblastoma development.

Di-2-ethylhexyl phthalic acid (DEHP) is one of the most widely used plasticizers in the industry, which can improve the flexibility and durability of plastics. It is prone to migrate from various daily plastic products through wear and leaching into the surrounding environment and decompose into the more toxic metabolite mono-2-ethylhexyl phthalic acid (MEHP) after entering the human body. However, the impacts and mechanisms of MEHP on neuroblastoma are unclear. We exposed MYCN-amplified neuroblastoma SK-N-BE(2)C cells to an environmentally related concentration of MEHP and found that MEHP increased the proliferation and migration ability of tumor cells. The peroxisome proliferator-activated receptor (PPAR) ß/δ pathway was identified as a pivotal signaling pathway in neuroblastoma, mediating the effects of MEHP through transcriptional sequencing analysis. Because MEHP can bind to the PPARß/δ protein and initiate the expression of the downstream gene angiopoietin-like 4 (ANGPTL4), the PPARß/δ-specific agonist GW501516 and antagonist GSK3787, the recombinant human ANGPTL4 protein, and the knockdown of gene expression confirmed the regulation of the PPARß/δ-ANGPTL4 axis on the malignant phenotype of neuroblastoma. Based on the critical role of PPARß/δ and ANGPTL4 in the metabolic process, a non-targeted metabolomics analysis revealed that MEHP altered multiple metabolic pathways, particularly lipid metabolites involving fatty acyls, glycerophospholipids, and sterol lipids, which may also be potential factors promoting tumor progression. We have demonstrated for the first time that MEHP can target binding to PPARß/δ and affect the progression of neuroblastoma by activating the PPARß/δ-ANGPTL4 axis. This mechanism confirms the health risks of plasticizers as tumor promoters and provides new data support for targeted prevention and treatment of neuroblastoma.

Plasmid-mediated colistin-resistance genes: mcr.

Colistin is regarded as a last-line drug against serious infections caused by multidrug-resistant Gram-negative bacterial pathogens. Therefore, the emergence of mobile colistin resistance (mcr) genes has attracted global concern and led to policy changes for the use of colistin in food animals across many countries. Currently, the distribution, function, mechanism of action, transmission vehicles, origin of mcr, and new treatment strategies against MCR-producing pathogens have been extensively studied. Here we review the prevalence, structure and function of mcr, the fitness cost and persistence of mcr-carrying plasmids, the impact of MCR on host immune response, as well as the control strategies to combat mcr-mediated colistin resistance.