A cellulose synthesis inhibitor affects cellulose synthase complex secretion and cortical microtubule dynamics.

P4B (2-phenyl-1-[4-(6-(piperidin-1-yl) pyridazin-3-yl) piperazin-1-yl] butan-1-one) is a novel cellulose biosynthesis inhibitor (CBI) discovered in a screen for molecules to identify inhibitors of Arabidopsis (Arabidopsis thaliana) seedling growth. Growth and cellulose synthesis inhibition by P4B were greatly reduced in a novel mutant for the cellulose synthase catalytic subunit gene CESA3 (cesa3pbr1). Cross-tolerance to P4B was also observed for isoxaben-resistant (ixr) cesa3 mutants ixr1-1 and ixr1-2. P4B has an original mode of action as compared with most other CBIs. Indeed, short-term treatments with P4B did not affect the velocity of cellulose synthase complexes (CSCs) but led to a decrease in CSC density in the plasma membrane without affecting their accumulation in microtubule-associated compartments. This was observed in the wild type but not in a cesa3pbr1 background. This reduced density correlated with a reduced delivery rate of CSCs to the plasma membrane but also with changes in cortical microtubule dynamics and orientation. At longer timescales, however, the responses to P4B treatments resembled those to other CBIs, including the inhibition of CSC motility, reduced growth anisotropy, interference with the assembly of an extensible wall, pectin demethylesterification, and ectopic lignin and callose accumulation. Together, the data suggest that P4B either directly targets CESA3 or affects another cellular function related to CSC plasma membrane delivery and/or microtubule dynamics that is bypassed specifically by mutations in CESA3.

Tongue coating-dependent superior temporal sulcus remodeling in amnestic mild cognitive impairment.

Tongue coating affects cognition, and cognitive decline at early stage also showed relations to functional and structural remodeling of superior temporal sulcus (STS) in amnestic mild cognitive impairment (aMCI). The potential correlation between disparate cognitive manifestations in aMCI patients with different tongue coatings, and corresponding mechanisms of STS remodeling remains uncharted. In this case-control study, aMCI patients were divided into thin coating (n = 18) and thick coating (n = 21) groups. All participants underwent neuropsychological evaluations and multimodal magnetic resonance imaging. Group comparisons were conducted in clinical assessments and neuroimaging measures of banks of the STS (bankssts). Generalized linear models were constructed to explore relationships between neuroimaging measures and cognition. aMCI patients in the thick coating group exhibited significantly poorer immediate and delayed recall and slower information processing speed (IPS) (P < 0.05), and decreased functional connectivity (FC) of bilateral bankssts with frontoparietal cortices (P < 0.05, AlphaSim corrected) compared to the thin coating group. It was found notable correlations between cognition encompassing recall and IPS, and FC of bilateral bankssts with frontoparietal cortices (P < 0.05, Bonferroni's correction), as well as interaction effects of group × regional homogeneity (ReHo) of right bankssts on the first immediate recall (P < 0.05, Bonferroni's correction). aMCI patients with thick coating exhibited poor cognitive performance, which might be attributed to decreased FC seeding from bankssts. Our findings strengthen the understanding of brain reorganization of STS via which tongue coating status impacts cognition in patients with aMCI.

Unmet rehabilitation needs in the first 6 months post-injury in a trauma centre population with moderate-to-severe traumatic injuries.

OBJECTIVE: To describe the needs for subacute inpatient rehabilitation and community-based healthcare services, rehabilitation, and social support in patients with moderate-to-severe traumatic injury in the first 6 months post-injury. Further, to explore associations between sociodemographic and clinical characteristics and unmet needs. DESIGN: Multicentre prospective cohort study. SUBJECTS: Of 601 persons (75% males), mean (standard deviation) age 47 (21) years, admitted to trauma centres in 2020 with moderate-to-severe injury, 501 patients responded at the 6-month follow-up and thus were included in the analyses. METHODS: Sociodemographic and injury-related characteristics were recorded at inclusion. Estimation of needs was assessed with the Rehabilitation Complexity Scale Extended-Trauma and the Needs and Provision Complexity Scale on hospital discharge. Provision of services was recorded 6 months post-injury. Multivariable logistic regressions explored associations between baseline variables and unmet inpatient rehabilitation and community-based service needs. RESULTS: In total, 20% exhibited unmet needs for subacute inpatient rehabilitation, compared with 60% for community-based services. Predictors for unmet community-based service needs included residing in less central areas, profound injury severity, severe head injury, and rehabilitation referral before returning home. CONCLUSION: Inadequate provision of healthcare and rehabilitation services, particularly in the municipalities, resulted in substantial unmet needs in the first 6 months following injury.

Predicting multifaceted risks using machine learning in atrial fibrillation: insights from GLORIA-AF study.

Aims: Patients with atrial fibrillation (AF) have a higher risk of ischaemic stroke and death. While anticoagulants are effective at reducing these risks, they increase the risk of bleeding. Current clinical risk scores only perform modestly in predicting adverse outcomes, especially for the outcome of death. We aimed to test the multi-label gradient boosting decision tree (ML-GBDT) model in predicting risks for adverse outcomes in a prospective global AF registry. Methods and results: We studied patients from phase II/III of the Global Registry on Long-Term Oral Anti-Thrombotic Treatment in Patients with Atrial Fibrillation registry between 2011 and 2020. The outcomes were all-cause death, ischaemic stroke, and major bleeding within 1 year following the AF. We trained the ML-GBDT model and compared its discrimination with the clinical scores in predicting patient outcomes. A total of 25 656 patients were included [mean age 70.3 years (SD 10.3); 44.8% female]. Within 1 year after AF, ischaemic stroke occurred in 215 (0.8%), major bleeding in 405 (1.6%), and death in 897 (3.5%) patients. Our model achieved an optimized area under the curve in predicting death (0.785, 95% CI: 0.757-0.813) compared with the Charlson Comorbidity Index (0.747, P = 0.007), ischaemic stroke (0.691, 0.626-0.756) compared with CHA2DS2-VASc (0.613, P = 0.028), and major bleeding (0.698, 0.651-0.745) as opposed to HAS-BLED (0.607, P = 0.002), with improvement in net reclassification index (10.0, 12.5, and 23.6%, respectively). Conclusion: The ML-GBDT model outperformed clinical risk scores in predicting the risks in patients with AF. This approach could be used as a single multifaceted holistic tool to optimize patient risk assessment and mitigate adverse outcomes when managing AF.

MOICS, a novel classier deciphering immune heterogeneity and aid precise management of clear cell renal cell carcinoma at multiomics level.

Recent studies have indicated that the tumor immune microenvironment plays a pivotal role in the initiation and progression of clear cell renal cell carcinoma (ccRCC). However, the characteristics and heterogeneity of tumor immunity in ccRCC, particularly at the multiomics level, remain poorly understood. We analyzed immune multiomics datasets to perform a consensus cluster analysis and validate the clustering results across multiple internal and external ccRCC datasets; and identified two distinctive immune phenotypes of ccRCC, which we named multiomics immune-based cancer subtype 1 (MOICS1) and subtype 2 (MOICS2). The former, MOICS1, is characterized by an immune-hot phenotype with poor clinical outcomes, marked by significant proliferation of CD4+ and CD8+ T cells, fibroblasts, and high levels of immune inhibitory signatures; the latter, MOICS2, exhibits an immune-cold phenotype with favorable clinical characteristics, characterized by robust immune activity and high infiltration of endothelial cells and immune stimulatory signatures. Besides, a significant negative correlation between immune infiltration and angiogenesis were identified. We further explored the mechanisms underlying these differences, revealing that negatively regulated endopeptidase activity, activated cornification, and neutrophil degranulation may promote an immune-deficient phenotype, whereas enhanced monocyte recruitment could ameliorate this deficiency. Additionally, significant differences were observed in the genomic landscapes between the subtypes: MOICS1 exhibited mutations in TTN, BAP1, SETD2, MTOR, MUC16, CSMD3, and AKAP9, while MOICS2 was characterized by notable alterations in the TGF-ß pathway. Overall, our work demonstrates that multi-immune omics remodeling analysis enhances the understanding of the immune heterogeneity in ccRCC and supports precise patient management.

A molecule-imprinted electrochemiluminescence sensor based on CdS@MWCNTs for ultrasensitive detection of fenpropathrin.

A molecularly-imprinted electrochemiluminescence sensor was constructed for the determination of fenpropathrin (FPT) by molecular imprinting technology. In this sensing platform, the introduction of CdS@MWCNTs significantly enhanced the initial ECL signal of the luminol-O2 system. Specifically, MWCNTs was used as a carrier to adsorb more CdS, in which CdS acted as a co-reaction promoter for luminescence. Molecularly imprinted polymer (MIP) containing specific recognition sites of FPT was used as the material for selective recognition. With increasing amount of FPT the ECL signal decreased. Under the optimum conditions, the ECL response was linearly related to the logarithm of FPT concentration. The developed ECL sensor allowed for sensitive determination of FPT and exhibited a wide linear range from 1.0 × 10- 10 mol L- 1 to 1.0 × 10- 6 mol L- 1. The limit of detection was 3.3 × 10- 11 mol L- 1 (S/N = 3). It can be used for the detection of FPT in vegetable samples.

Clinical significance of RNA methylation in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a primary liver malignancy with high mortality rates and poor prognosis. Recent advances in high-throughput sequencing and bioinformatic technologies have greatly enhanced the understanding of the genetic and epigenetic changes in liver cancer. Among these changes, RNA methylation, the most prevalent internal RNA modification, has emerged as a significant contributor of the development and progression of HCC. Growing evidence has reported significantly abnormal levels of RNA methylation and dysregulation of RNA-methylation-related enzymes in HCC tissues and cell lines. These alterations in RNA methylation play a crucial role in the regulation of various genes and signaling pathways involved in HCC, thereby promoting tumor progression. Understanding the pathogenesis of RNA methylation in HCC would help in developing prognostic biomarkers and targeted therapies for HCC. Targeting RNA-methylation-related molecules has shown promising potential in the management of HCC, in terms of developing novel prognostic biomarkers and therapies for HCC. Exploring the clinical application of targeted RNA methylation may provide new insights and approaches for the management of HCC. Further research in this field is warranted to fully understand the functional roles and underlying mechanisms of RNA methylation in HCC. In this review, we described the multifaceted functional roles and potential mechanisms of RNA methylation in HCC. Moreover, the prospects of clinical application of targeted RNA methylation for HCC management are discussed, which may provide the basis for subsequent in-depth research on RNA methylation in HCC.

Protective Effects of Lycium ruthenicum Murray against Acute Alcoholic Liver Disease in Mice via the Nrf2/HO-1/NF-κB Signaling Pathway.

Acute alcoholic liver disease (ALD) resulting from short-term heavy alcohol consumption has become a global health concern. Moreover, anthocyanins have attracted much attention for their ability to prevent oxidation and inflammation. The present work evaluates the protective effects of Lycium ruthenicum Murray (LRM) against ALD and explores the possible underlying mechanism involved. The total anthocyanin content in LRM was 43.64 ± 9.28 Pt g/100 g dry weight. Mice were orally administered 50, 125, or 375 mg LRM/kg body weight (BW) for 21 days. On days 18-21, mice were orally administered 15 mL of ethanol/kg BW. Markers of liver damage, oxidative stress, and inflammation were examined. Furthermore, the modulatory effect of LRM on Nrf2/HO-1/NF-κB pathway molecules was evaluated through quantitative reverse transcription polymerase chain reaction (RT‒qPCR) and immunohistochemistry analyses. The difference between the groups indicated that LRM improved liver histopathology and the liver index, decreased aspartate transaminase, alanine transaminase, malondialdehyde, reactive oxygen species, IL-6, TNF-α, and IL-1ß expression, but elevated superoxide dismutase, catalase, and glutathione-s-transferase levels. Moreover, LRM upregulated Nrf2 and Ho-1 but downregulated Nf-κb and Tnf-α genes at the transcript level. In summary, LRM alleviated ethanol-induced ALD in mice by reducing oxidative damage and associated inflammatory responses. LRM protects against ALD by reducing damage factors and enhancing defense factors, especially via the Nrf2/HO-1/NF-κB pathway. Thus, LRM has application potential in ALD prophylaxis and treatment.

The interaction between intratumoral bacteria and metabolic distortion in hepatocellular carcinoma.

BACKGROUND: Intratumoral bacteria might play essential roles in tumorigenesis in different cancer types. However, its features and potential roles in hepatocellular carcinoma (HCC) are largely unknown. METHODS: In this study, we assessed bacterial RNA by 16S rRNA fluorescence in situ hybridization and detected bacterial lipopolysaccharide (LPS) via immunohistochemistry. Hepa1-6 cells were used to establish orthotopic HCC models in mice. 2bRAD sequencing for microbiome was performed to determine the intratumoral bacterial characteristics, and liquid chromatography-mass spectrometry was conducted to explore the metabolic profile. The potential association between different intratumoral microbiota and metabolites were evaluated. RESULTS: We detected bacterial 16S rRNA and LPS in HCC tissues from the patients with HCC. In HCC mouse model, we found that the intratumor bacteria in HCC tissues were significantly different to adjacent nontumor tissues. Furthermore, we observed different metabolites in HCC tissues and adjacent nontumor tissues, such as N-acetyl-D-glucosamine and a-lactose. Our results showed that several bacteria were significantly associated with metabolites, such as Pseudomonas koreensis, which was positively correlated with N-acetyl-D-glucosamine and negatively correlated with citrulline. CONCLUSIONS: This study confirmed the close association between different bacteria and metabolites, which might provide novel opportunities for developing new biomarkers and therapeutic targets for HCC.

Apoptosis and turnover disruption of olfactory sensory neurons in eosinophilic chronic rhinosinusitis.

Olfactory dysfunction (OD) is one of the important and difficult-to-treat symptoms of eosinophilic chronic rhinosinusitis (CRS), which is typically associated with type 2 inflammation where eosinophils (EOSs) function as both effectors and initiators. Eosinophilic infiltration in the olfactory mucosa (OM) is associated with severe OD, mucosal erosion, and more loss of olfactory sensory neurons (OSNs). Active EOS-derived cytokines, chemokines, and eosinophil granule proteins may lead to aggravation of inflammation, tissue damage, and impairment of the survival and regeneration of OSNs. Recent studies show that EOSs can lead to apoptosis of OSNs through axonal and neural body damage, turnover disorder of OSNs through the loss of immature OSNs and globose basal cells (GBCs), changed proliferative activity of horizontal basal cells (HBCs), and dysfunction of OSNs through the breakdown of neuroepithelial integrity and alteration of ion concentration in OSNs and mucin. In this review, we outline the current progress on the role of EOSs on OD in patients with eosinophilic CRS and the mechanism of EOS-associated injury of the OM and OSNs in experimental animal models with sinonasal inflammation. Further investigations on the molecular mechanisms of tissue eosinophilia-induced injury of OSNs are warranted to obtain new therapeutic targets and achieve better restoration of olfactory function.

Anthocyanins from Lycium ruthenicum Murray Mitigate Cadmium-Induced Oxidative Stress and Testicular Toxicity by Activating the Keap1/Nrf2 Signaling Pathway.

Cadmium (Cd) is a hazardous heavy metal environmental pollutant that has carcinogenic, teratogenic, and mutagenic properties. Excessive exposure to Cd can induce oxidative stress, which greatly harms the male reproductive system. Anthocyanins have remarkable antioxidative, anti-inflammatory, and anti-stress properties. In this study, we investigated the effects of anthocyanins and the underlying mechanisms through which anthocyanins mitigate Cd-induced reproductive damage. We isolated and purified Lycium ruthenicum Murray anthocyanin extract (LAE) and performed UHPLC-MS/MS to identify 30 different anthocyanins. We established an ICR mouse Cd injury model by administering 5 mg/kg/day CdCl2 for 28 consecutive days. LAE at 500 mg/kg/day effectively ameliorated testicular damage and preserved spermatogenesis. The mice in the LAE-treated group had elevated testosterone and inhibin B levels. Additionally, the treatment restored the activity of antioxidant enzymes, including T-SOD, CAT, and GR, and substantially increased the levels of the non-enzymatic antioxidant GSH. Research findings indicate that LAE can activate the SIRT1/Nrf2/Keap1 antioxidant pathway. This activation is achieved through the upregulation of both the SIRT1 gene and protein levels, leading to the deacetylation of Nrf2. Moreover, LAE reduces the expression of Keap1, alleviating its inhibitory effect on Nrf2. This, in turn, facilitates the uncoupling process, promoting the translocation of Nrf2 to the nucleus, where it governs downstream expression, including that of HO-1 and GPX1. LAE effectively mitigated toxicity to the reproductive system associated with exposure to the heavy metal Cd by alleviating oxidative stress in the testes.

Medication self-management capacity among older adults living in low-income housing communities.

BACKGROUND: Medication self-management capacity (MMC) is essential to safe and independent living. There is a need to understand the challenges low-income older adults face during the routine use of medications to promote safe medication use and healthy aging in place. OBJECTIVE: To assess the cognitive and physical deficiencies in MMC and the impact of using pharmaceutical aids/services on MMC among low-income older adults. METHODS: This was a cross-sectional study of 107 older residents of 5 low-income housing buildings in Richmond, VA. The Medication Management Instrument for Deficiencies in the Elderly was used to measure MMC during individual in-person interviews. Participants were asked whether they used any medication aids, including medication lists, organizers, or reminders, or pharmacy services such as specialized medication packaging, medication synchronization, prescription home delivery, or mail order services. Multiple regression modeling was used to assess the relationship between MMC and the use of pharmaceutical aids/services. RESULTS: Eighty-nine percent of participants were African American with a mean (standard deviation [±SD]) age of 68.5 (7.2) years. The mean deficit in MMC was 3 (±2.0). The most challenging skill was naming all the medications (69.2%), followed by stating their indications (46.7%) and knowing how or when all of the medications should be taken (38.3%). Seventy-nine percent used at least 1 pharmaceutical aid/service; using 1 pharmaceutical aid/service was significantly associated with better MMC (P = .0285). Low educational level and health literacy were associated with deficits in MMC (P < .05). CONCLUSION: Many older adults residing in low-income housing had impaired capacity to manage their medications independently. Inadequate medication knowledge affected their cognitive ability to manage medications. Using a pharmaceutical aid/service was associated with better MMC. Greater attention to developing medication self-management skills for older adults with low health literacy and adverse social determinants of health is needed.

Circuit-based neuromodulation enhances delayed recall in amnestic mild cognitive impairment.

BACKGROUND: This study aimed to investigate the efficacy of circuits-based paired associative stimulation (PAS) in adults with amnestic mild cognitive impairment (aMCI). METHODS: We conducted a parallel-group, randomised, controlled clinical trial. Initially, a cohort of healthy subjects was recruited to establish the cortical-hippocampal circuits by tracking white matter fibre connections using diffusion tensor imaging. Subsequently, patients diagnosed with aMCI, matched for age and education, were randomly allocated in a 1:1 ratio to undergo a 2-week intervention, either circuit-based PAS or sham PAS. Additionally, we explored the relationship between changes in cognitive performance and the functional connectivity (FC) of cortical-hippocampal circuits. RESULTS: FCs between hippocampus and precuneus and between hippocampus and superior frontal gyrus (orbital part) were most closely associated with the Auditory Verbal Learning Test (AVLT)_N5 score in 42 aMCI patients, thus designated as target circuits. The AVLT_N5 score improved from 2.43 (1.43) to 5.29 (1.98) in the circuit-based PAS group, compared with 2.52 (1.44) to 3.86 (2.39) in the sham PAS group (p=0.003; Cohen's d=0.97). A significant decrease was noted in FC between the left hippocampus and left precuneus in the circuit-based PAS group from baseline to postintervention (p=0.013). Using a generalised linear model, significant group×FC interaction effects for the improvements in AVLT_N5 scores were found within the circuit-based PAS group (B=3.4, p=0.017). CONCLUSIONS: Circuit-based PAS effectively enhances long-term delayed recall in adults diagnosed with aMCI, which includes individuals aged 50-80 years. This enhancement is potentially linked to the decreased functional connectivity between the left hippocampus and left precuneus. TRIAL REGISTRATION NUMBER: ChiCTR2100053315; Chinese Clinical Trial Registry.

Tryptophan metabolism in digestive system tumors: unraveling the pathways and implications.

Tryptophan (Trp) metabolism plays a crucial role in influencing the development of digestive system tumors. Dysregulation of Trp and its metabolites has been identified in various digestive system cancers, including esophageal, gastric, liver, colorectal, and pancreatic cancers. Aberrantly expressed Trp metabolites are associated with diverse clinical features in digestive system tumors. Moreover, the levels of these metabolites can serve as prognostic indicators and predictors of recurrence risk in patients with digestive system tumors. Trp metabolites exert their influence on tumor growth and metastasis through multiple mechanisms, including immune evasion, angiogenesis promotion, and drug resistance enhancement. Suppressing the expression of key enzymes in Trp metabolism can reduce the accumulation of these metabolites, effectively impacting their role in the promotion of tumor progression and metastasis. Strategies targeting Trp metabolism through specific enzyme inhibitors or tailored drugs exhibit considerable promise in enhancing therapeutic outcomes for digestive system tumors. In addition, integrating these approaches with immunotherapy holds the potential to further enhance treatment efficacy.

Ultrasensitive solid-state electrochemiluminescence sensor based on lotus root shaped carbon fiber, CdSe QDs and Fe3O4 synergically amplify Ru(bpy)32+ luminophore signal for detection of cyfluthrin.

An efficient and innovative electrochemiluminescence (ECL) sensor was developed for trace detection of cyfluthrin. The sensor utilized materials such as lotus root shaped carbon fiber (Co CNFs), cadmium selenide quantum dots (CdSe QDs), and Fe3O4 to amplify Ru(bpy)32+ signals. Co CNFs, with its large specific surface area and porosity, served the purpose of not only enhancing the stability of the sensor by fixing CdSe QDs and Ru(bpy)32+ on the Co CNFs/GCE, but also facilitating electron transfer. CdSe QDs was involved in the luminescence reaction and collaborated with Ru(bpy)32+ to enhance the sensor's sensitivity, while Fe3O4 promoted electron transfer in the system due to its large surface area. The solid-state ECL sensor achieved satisfactory signal under the synergistic action of these components. The ECL signal of the sensor was quenched by cyfluthrin, and a favorable linear relationship was observed between the sensor and cyfluthrin in the concentration range 1 × 10-12 to 1 × 10-6 M. The detection limit of the sensor was 3.3 × 10-13 M (S/N = 3). The utilization of lotus root shaped carbon fiber, CdSe QDs, and Fe3O4 in the Ru(bpy)32+ system demonstrated a synergistic effect for cyfluthrin detection, presenting a new approach for the rapid determination analysis of pesticide residues in foods.

Association between body stature with ocular biometrics and refraction among Chinese preschoolers.

PURPOSE: To evaluate the association of body stature with ocular biometrics and refraction in preschool children. METHODS: A cross-sectional, school-based study was conducted in Shenzhen, China. Preschool children aged 3 to 6 from 10 randomly-selected kindergartens were recruited. Ocular biometric parameters, including axial length (AL), anterior chamber depth (ACD), vitreous chamber depth (VCD), corneal radius curvature (CR), axial length to corneal radius ratio (AL-to-CR ratio) and lens thickness (LT) were measured using non-contact partial-coherence laser interferometry. Cycloplegic refractions were obtained by a desktop autorefractor. Body height and weight were measured using standard procedures. The association between body stature and ocular biometrics were analyzed with univariable and multivariable regression model. RESULTS: A total of 373 preschoolers were included. AL, ACD, VCD, CR, and AL-to-CR ratio, were positively associated with height and weight (p < 0.05), whereas LT was negatively associated with height and weight (p < 0.01). No association was observed between stature and central cornea thickness and refraction. After adjusted for age and gender in a multivariable regression model, AL had positive associations with height (p < 0.01) and weight (p < 0.01). However, refraction had no significant association with stature parameters. CONCLUSION: Taller and heavier preschoolers had eyes with longer AL, deeper vitreous chamber, and flatter cornea. The significant associations between body stature and ocular biometric parameters reveal the driving influence of body development on the growth of eyeballs in preschoolers.

Diabetes Promotes Myocardial Fibrosis via AMPK/EZH2/PPAR-γ Signaling Pathway.

Background: Diabetes-induced cardiac fibrosis is one of the main mechanisms of diabetic cardiomyopathy. As a common histone methyltransferase, enhancer of zeste homolog 2 (EZH2) has been implicated in fibrosis progression in multiple organs. However, the mechanism of EZH2 in diabetic myocardial fibrosis has not been clarified. Methods: In the current study, rat and mouse diabetic model were established, the left ventricular function of rat and mouse were evaluated by echocardiography and the fibrosis of rat ventricle was evaluated by Masson staining. Primary rat ventricular fibroblasts were cultured and stimulated with high glucose (HG) in vitro. The expression of histone H3 lysine 27 (H3K27) trimethylation, EZH2, and myocardial fibrosis proteins were assayed. Results: In STZ-induced diabetic ventricular tissues and HG-induced primary ventricular fibroblasts in vitro, H3K27 trimethylation was increased and the phosphorylation of EZH2 was reduced. Inhibition of EZH2 with GSK126 suppressed the activation, differentiation, and migration of cardiac fibroblasts as well as the overexpression of the fibrotic proteins induced by HG. Mechanical study demonstrated that HG reduced phosphorylation of EZH2 on Thr311 by inactivating AMP-activated protein kinase (AMPK), which transcriptionally inhibited peroxisome proliferator-activated receptor γ (PPAR-γ) expression to promote the fibroblasts activation and differentiation. Conclusion: Our data revealed an AMPK/EZH2/PPAR-γ signal pathway is involved in HG-induced cardiac fibrosis.

Metagenomic survey of viral diversity obtained from feces of piglets with diarrhea.

Pigs are natural host to various zoonotic pathogens including viruses. In this study, we analyzed the viral communities in the feces of 89 piglets with diarrhea under one month old which were collected from six farms in Jiangsu Province of the Eastern China, using the unbiased virus metagenomic method. A total of 89 libraries were constructed, and 46937894 unique sequence reads were generated by Illumina sequencing. Overall, the family Picornaviridae accounted for the majority of the total reads of putative mammalian viruses. Ten novel virus genomes from different family members were discovered, including Parvoviridae (n = 2), Picobirnaviridae (n = 4) and CRESS DNA viruses (n = 4). A large number of phages were identified, which mainly belonged to the order Caudovirales and the family Microviridae. Moreover, some identified viruses were closely related to viruses found in non-porcine hosts, highlighting the potential for cross-species virus dissemination. This study increased our understanding of the fecal virus communities of diarrhea piglets and provided valuable information for virus monitoring and preventing.

Machine learning for differentiating between pancreatobiliary-type and intestinal-type periampullary carcinomas based on CT imaging and clinical findings.

PURPOSE: To develop a diagnostic model for distinguishing pancreatobiliary-type and intestinal-type periampullary adenocarcinomas using preoperative contrast-enhanced computed tomography (CT) findings combined with clinical characteristics. METHODS: This retrospective study included 140 patients with periampullary adenocarcinoma who underwent preoperative enhanced CT, including pancreaticobiliary (N = 100) and intestinal (N = 40) types. They were randomly assigned to the training or internal validation set in an 8:2 ratio. Additionally, an independent external cohort of 28 patients was enrolled. Various CT features of the periampullary region were evaluated and data from clinical and laboratory tests were collected. Five machine learning classifiers were developed to identify the histologic type of periampullary adenocarcinoma, including logistic regression, random forest, multi-layer perceptron, light gradient boosting, and eXtreme gradient boosting (XGBoost). RESULTS: All machine learning classifiers except multi-layer perceptron used achieved good performance in distinguishing pancreatobiliary-type and intestinal-type adenocarcinomas, with the area under the curve (AUC) ranging from 0.75 to 0.98. The AUC values of the XGBoost classifier in the training set, internal validation set and external validation set are 0.98, 0.89 and 0.84 respectively. The enhancement degree of tumor, the growth pattern of tumor, and carbohydrate antigen 19-9 were the most important factors in the model. CONCLUSION: Machine learning models combining CT with clinical features can serve as a noninvasive tool to differentiate the histological subtypes of periampullary adenocarcinoma, in particular using the XGBoost classifier.

The Clinical Significance and the Potential Regulatory Mechanism of the LncRNA OIP5-AS1 in Paediatric Severe Community-Acquired Pneumonia Blood Through the MiR-150-5p/PDCD4 Axis.

BACKGROUND: This study aimed to elucidate the clinical significance and regulatory mechanism of the long non-coding RNA OIP5-AS1 in severe community-acquired pneumonia (SCAP) among paediatric patients. METHODS: qRT-PCR was used to assess the mRNA levels of OIP5-AS1. ROC curve analysis was used to assess the diagnostic significance of OIP5-AS1. Short-term prognostic significance was evaluated through Kaplan-Meier survival. An in vitro cell model was developed using LPS-induced MRC-5 cells. CCK-8, flow cytometry, and ELISA were conducted to measure cell viability, apoptosis, and inflammatory factor levels. The association between miR-150-5p and PDCD4 was confirmed through DLR assays. RESULTS: Elevated OIP5-AS1 were observed in paediatric patients with SCAP, which enabled effective differentiation from healthy individuals. High expression of OIP5-AS1 correlated with reduced survival rates. OIP5-AS1 knockdown attenuated cell viability suppression and the promotion of apoptosis and inflammatory factors induced by LPS. However, this attenuation was reversed by reduced levels of miR-150-5p. miR-150-5p was identified as a target of PDCD4 and OIP5-AS1. CONCLUSION: Increased OIP5-AS1 levels show potential as a valuable diagnostic and prognostic biomarker for paediatric patients with SCAP. This study illustrates its role in regulating cell viability, apoptosis, and the inflammatory response via the miR-150-5p/PDCD4 axis, acting as a ceRNA.