Trojan Horse virus delivering CRISPR-AsCas12f1 controls plant bacterial wilt caused by Ralstonia solanacearum.

Plant bacterial wilt caused by Ralstonia solanacearum results in huge losses. Accordingly, developing an effective control method for this disease is urgently required. Filamentous phages, which do not lyse host bacteria and exert minimal burden, offer a potential biocontrol solution. A filamentous phage RSCq that infects R. solanacearum was isolated in this study through genome mining. We constructed engineered filamentous phages based on RSCq by employing our proposed approach with wide applicability to non-model phages, enabling the exogenous genes delivery into bacterial cells. CRISPR-AsCas12f1 is a miniature class 2 type V-F CRISPR-Cas system. A CRISPR-AsCas12f1-based gene editing system that targets the key virulence regulator gene hrpB was developed, generating the engineered phage RSCqCRISPR-Cas. Similar to the Greek soldiers in the Trojan Horse, our findings demonstrated that the engineered phage-delivered CRISPR-Cas system could disarm the key "weapon," hrpB, of R. solanacearum, in medium and plants. Remarkably, pretreatment with RSCqCRISPR-Cas significantly controlled tobacco bacterial wilt, highlighting the potential of engineered filamentous phages as promising biocontrol agents against plant bacterial diseases.IMPORTANCEBacterial disease, one of the major plant diseases, causes huge food and economic losses. Phage therapy, an environmentally friendly control strategy, has been frequently reported in plant bacterial disease control. However, host specificity, sensitivity to ultraviolet light and certain conditions, and bacterial resistance to phage impede the widespread application of phage therapy in crop production. Filamentous phages, which do not lyse host bacteria and exert minimal burden, offer a potential solution to overcome the limitations of lytic phage biocontrol. This study developed a genetic engineering approach with wide applicability to non-model filamentous phages and proved the application possibility of engineered phage-based gene delivery in plant bacterial disease biocontrol for the first.

Mechanism of Vaginal Epithelial Cell Pyroptosis Induced by the NLRP3 Inflammasome in Vulvovaginal Candidiasis.

PROBLEM: Vulvovaginal candidiasis (VVC) is a common mucosal fungal infection, and Candida albicans is the main causative agent. The NLRP3 inflammasome plays an important role in VVC, but the underlying mechanism is unknown. METHOD OF STUDY: Vaginal epithelial cells were divided into three groups: control, C. albicans strain SC5314 (wild-type, WT), and WT+ Matt Cooper Compound 950 (MCC950, a specific NLRP3 inhibitor). After human vaginal epithelial cells were pretreated with 1 µmol/L MCC950 for 2 h, C. albicans (MOI = 1) was cocultured with the human vaginal epithelial cells for 12 h. The cell supernatants were collected, LDH was detected, and the IL-1ß and IL-18 levels were determined by ELISA. The expression of the pyroptosis-related proteins NLRP3, Caspase-1 p20 and GSDMD was measured by Western blotting analysis. The protein expression of the pyroptosis-related N-terminus of GSDMD (GSDMD-N) was detected by immunofluorescence. RESULTS: In this study, we showed that the WT C. albicans strain induced pyroptosis in vaginal epithelial cells, as indicated by the LDH and proinflammatory cytokine levels and the upregulated levels of the pyroptosis-related proteins NLRP3, Caspase-1 p20, and GSDMD-N. MCC950 reversed the changes in the expression of these proteins and proinflammatory cytokines in vaginal epithelial cells. CONCLUSION: C. albicans activated the NLRP3 inflammasome to induce vaginal epithelial cell pyroptosis. MCC950 inhibited the NLRP3 inflammasome, reduced vaginal epithelial cell pyroptosis, and decreased the release of inflammatory cytokines.

Neurobehavioral toxicity induced by combined exposure of micro/nanoplastics and triphenyltin in marine medaka (Oryzias melastigma).

Microplastics/nanoplastics (MNPs) inevitably coexist with other pollutants in the natural environment, making it crucial to study the interactions between MNPs and other pollutants as well as their combined toxic effects. In this study, we investigated neurotoxicity in marine medaka (Oryzias melastigma) exposed to polystyrene micro/nanoplastics (PS-MNPs), triphenyltin (TPT), and PS-MNPs + TPT from physiological, behavioral, biochemical, and genetic perspectives. The results showed that marine medaka exposed to 200 ng/L TPT or 200 µg/L PS-NPs alone exhibited some degree of neurodevelopmental deficit, albeit with no significant behavioral abnormalities observed. However, in the PS-MP single exposure group, the average acceleration of short-term behavioral indices was significantly increased by 78.81%, indicating a highly stress-responsive locomotor pattern exhibited by marine medaka. After exposure to PS-MNPs + TPT, the swimming ability of marine medaka significantly decreased. In addition, PS-MNPs + TPT exposure disrupted normal neural excitability as well as activated detoxification processes in marine medaka larvae. Notably, changes in neural-related genes suggested that combined exposure to PS-MNPs and TPT significantly increased the neurotoxic effects observed with exposure to PS-MNPs or TPT alone. Furthermore, compared to the PS-MPs + TPT group, PS-NPs + TPT significantly inhibited swimming behavior and thus exacerbated the neurotoxicity. Interestingly, the neurotoxicity of PS-MPs was more pronounced than that of PS-NPs in the exposure group alone. However, the addition of TPT significantly enhanced the neurotoxicity of PS-NPs compared to PS-MPs + TPT. Overall, the study underscores the combined neurotoxic effects of MNPs and TPT, providing in-depth insights into the ecotoxicological implications of MNPs coexisting with pollutants and furnishing comprehensive data.

RGS19 activates the MYH9/ß-catenin/c-Myc positive feedback loop in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common fatal cancers worldwide, and the identification of novel treatment targets and prognostic biomarkers is urgently needed because of its unsatisfactory prognosis. Regulator of G-protein signaling 19 (RGS19) is a multifunctional protein that regulates the progression of various cancers. However, the specific function of RGS19 in HCC remains unclear. The expression of RGS19 was determined in clinical HCC samples. Functional and molecular biology experiments involving RGS19 were performed to explore the potential mechanisms of RGS19 in HCC. The results showed that the expression of RGS19 is upregulated in HCC tissues and is significantly associated with poor prognosis in HCC patients. RGS19 promotes the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, RGS19, via its RGS domain, stabilizes the MYH9 protein by directly inhibiting the interaction of MYH9 with STUB1, which has been identified as an E3 ligase of MYH9. Moreover, RGS19 activates ß-catenin/c-Myc signaling via MYH9, and RGS19 is also a transcriptional target gene of c-Myc. A positive feedback loop formed by RGS19, MYH9, and the ß-catenin/c-Myc axis was found in HCC. In conclusion, our research revealed that competition between RGS19 and STUB1 is a critical mechanism of MYH9 regulation and that the RGS19/MYH9/ß-catenin/c-Myc feedback loop may represent a promising strategy for HCC therapy.

Glymphatic dysfunction mediates the influence of choroid plexus enlargement on information processing speed in patients with white matter hyperintensities.

Glymphatic dysfunction has been correlated with cognitive decline, with a higher choroid plexus volume (CPV) being linked to a slower glymphatic clearance rate. Nevertheless, the interplay between CPV, glymphatic function, and cognitive impairment in white matter hyperintensities (WMHs) has not yet been investigated. In this study, we performed neuropsychological assessment, T1-weighted three-dimensional (3D-T1) images, and diffusion tensor imaging (DTI) in a cohort of 206 WMHs subjects and 43 healthy controls (HCs) to further explore the relationship. The DTI analysis along the perivascular space (DTI-ALPS) index, as a measure of glymphatic function, was calculated based on DTI. Severe WMHs performed significantly worse in information processing speed (IPS) than other three groups, as well as in executive function than HCs and mild WMHs. Additionally, severe WMHs demonstrated lower DTI-ALPS index and higher CPV than HCs and mild WMHs. Moderate WMHs displayed higher CPV than HCs and mild WMHs. Mini-Mental State Examination, IPS, and executive function correlated negatively with CPV but positively with DTI-ALPS index in WMHs patients. Glymphatic function partially mediated the association between CPV and IPS, indicating a potential mechanism for WMHs-related cognitive impairment. CPV may act as a valuable prognostic marker and glymphatic system as a promising therapeutic target for WMHs-related cognitive impairment.

Multimodal data-driven, vertical visualization prediction model for early prediction of atherosclerotic cardiovascular disease in patients with new-onset hypertension.

BACKGROUND: : Hypertension is an important contributing factor to atherosclerotic cardiovascular disease (ASCVD), and multiple risk factors, many of which are implicated in metabolic disorders, contribute to the cause of hypertension. Despite the promise of multimodal data-driven prediction model, no such prediction model was available to predict the risk of ASCVD in Chinese individuals with new-onset hypertension and no history of ASCVD. METHODS: : A total of 514 patients were randomly allocated to training and verification cohorts (ratio, 7 : 3). We employed Boruta feature selection and conducted multivariate Cox regression analyses to identify variables associated with ASCVD in these patients, which were subsequently utilized for constructing the predictive model. The performance of prediction model was assessed in terms of discriminatory power (C-index), calibration (calibration curves), and clinical utility [decision curve analysis (DCA)]. RESULTS: : This model was derived from four clinical variables: 24-h SBP coefficient of variation, 24-h DBP coefficient of variation, urea nitrogen and the triglyceride-glucose (TyG) index. Bootstrapping with 500 iterations was conducted to adjust the C-indexes were C-index = 0.731, 95% confidence interval (CI) 0.620-0.794 and C-index: 0.799, 95% CI 0.677-0.892 in the training and verification cohorts, respectively. Calibration plots with 500 bootstrapping iterations exhibited a strong correlation between the predicted and observed occurrences of ASCVD in both the training and verification cohorts. DCA analysis confirmed the clinical utility of this prediction model. The constructed nomogram demonstrated significant additional prognostic utility for ASCVD, as evidenced by improvements in the C-index, net reclassification improvement, integrated discrimination improvement, and DCA compared with the overall ASCVD risk assessment. CONCLUSION: The developed longitudinal prediction model based on multimodal data can effectively predict ASCVD risk in individuals with an initial diagnosis of hypertension. TRIAL REGISTRATION: : The trial was registered in the Chinese Clinical Trial Registry (ChiCTR2300074392).

Palmitic acid induces ß-cell ferroptosis by activating ceramide signaling pathway.

Individuals with type 2 diabetes mellitus frequently display heightened levels of palmitic acid (PA) in their serum, which may lead to ß-cell damage. The involvement of ferroptosis, a form of oxidative cell death in lipotoxic ß-cell injury remains uncertain. Here, we have shown that PA induces intracellular lipid peroxidation, increases intracellular Fe2+ content and decreases intracellular glutathione peroxidase 4 (GPX4) expression. Furthermore, PA causes distinct changes in pancreatic islets and INS-1 cells, such as mitochondrial atrophy and increased membrane density. Furthermore, the presence of the ferroptosis inhibitor has a significant mitigating effect on PA-induced ß-cell damage. Mechanistically, PA increased ceramide content and c-Jun N-terminal kinase (JNK) phosphorylation. The ceramide synthase inhibitor effectively attenuated PA-induced ß-cell damage and GPX4/Fe2+ abnormalities, while inhibiting JNK phosphorylation. Additionally, the JNK inhibitor SP600125 improved PA-induced cell damage. In conclusion, by promoting ceramide synthesis, PA inhibited GPX4 expression and increased intracellular Fe2+ to induce ß-cell ferroptosis. Moreover, JNK may be a downstream mechanism of ceramide-triggered lipotoxic ferroptosis in ß-cells.

Immunomodulation in Endometriosis: Investigating the interrelationship between VISTA expression and Escherichia.Shigella-Associated metabolites.

AIMS: Endometriosis is characterized by an abnormal immune microenvironment. Despite the extensive use of immune therapies, the application of immune checkpoint inhibitors in endometriosis lacks confidence due to the instability of preclinical research data. This study aims to elucidate the regulation of the immune inhibitory checkpoint VISTA and its effects on T cells from the perspective of microbiota and metabolism. MAIN METHODS: We divided endometriosis patients into high and low groups based on the expression levels of VISTA in lesion tissues. We collected peritoneal fluid samples from these two groups and performed 16 s RNA sequencing and metabolomics analysis to investigate microbial diversity and differential metabolites. Through combined analysis, we identified microbial-associated metabolites and validated their correlation with VISTA and CD8 + T cells using ELISA and immunofluorescence. In vitro experiments were conducted to confirm the regulatory relationship among these factors. KEY FINDINGS: Our findings revealed a distinct correlation between VISTA expression and the microbial colony Escherichia.Shigella. Moreover, we identified the metabolites LTD4-d5 and 2-n-Propylthiazolidine-4-carboxylic acid as being associated with both Escherichia.Shigella and VISTA expression. In vitro experiments confirmed the inhibitory effects of these metabolites on VISTA expression, while they demonstrated a positive regulation of CD8 + T cell infiltration into endometriotic lesions. SIGNIFICANCE: This study reveals the connection between microbial diversity, metabolites, and VISTA expression in the immune microenvironment of endometriosis, providing potential targets for therapeutic interventions.

Developing a High-Umami, Low-Salt Soy Sauce through Accelerated Moromi Fermentation with Corynebacterium and Lactiplantibacillus Strains.

The traditional fermentation process of soy sauce employs a hyperhaline model and has a long fermentation period. A hyperhaline model can improve fermentation speed, but easily leads to the contamination of miscellaneous bacteria and fermentation failure. In this study, after the conventional koji and moromi fermentation, the fermentation broth was pasteurized and diluted, and then inoculated with three selected microorganisms including Corynebacterium glutamicum, Corynebacterium ammoniagenes, and Lactiplantibacillus plantarum for secondary fermentation. During this ten-day fermentation, the pH, free amino acids, organic acids, nucleotide acids, fatty acids, and volatile compounds were analyzed. The fermentation group inoculated with C. glutamicum accumulated the high content of amino acid nitrogen of 0.92 g/100 mL and glutamic acid of 509.4 mg/100 mL. The C. ammoniagenes group and L. plantarum group were rich in nucleotide and organic acid, respectively. The fermentation group inoculated with three microorganisms exhibited the best sensory attributes, showing the potential to develop a suitable fermentation method. The brewing speed of the proposed process in this study was faster than that of the traditional method, and the umami substances could be significantly accumulated in this low-salt fermented model (7% w/v NaCl). This study provides a reference for the low-salt and rapid fermentation of seasoning.

Multimodal data integration for enhanced longitudinal prediction for cardiac and cerebrovascular events following initial diagnosis of obstructive sleep apnea syndrome.

Background: Obstructive sleep apnea syndrome (OSAS), a prevalent condition, often coexists with intricate metabolic issues and is frequently associated with negative cardiovascular outcomes. We developed a longitudinal prediction model integrating multimodal data for cardiovascular risk stratification of patients with an initial diagnosis of OSAS. Methods: We reviewed the data of patients with new-onset OSAS who underwent diagnostic polysomnography between 2018-19. Patients were treated using standard treatment regimens according to clinical practice guidelines. Results: Over a median follow-up of 32 months, 98/729 participants (13.4%) experienced our composite outcome. At a ratio of 7:3, cases were randomly divided into development (n = 510) and validation (n = 219) cohorts. A prediction nomogram was created using six clinical factors - sex, age, diabetes mellitus, history of coronary artery disease, triglyceride-glucose index, and apnea-hypopnea index. The prediction nomogram showed excellent discriminatory power, based on Harrell's C-index values of 0.826 (95% confidence interval (CI) = 0.779-0.873) for the development cohort and 0.877 (95% CI = 0.824-0.93) for the validation cohort. Moreover, comparing the predicted and observed major adverse cardiac and cerebrovascular events in both development and validation cohorts indicated that the prediction nomogram was well-calibrated. Decision curve analysis demonstrated the good clinical applicability of the prediction nomogram. Conclusions: Our findings demonstrated the construction of an innovative visualisation tool that utilises various types of data to predict poor outcomes in Chinese patients diagnosed with OSAS, providing accurate and personalised therapy. Registration: Chinese Clinical Trial Registry ChiCTR2300075727.

Decrypting the skeletal toxicity of vertebrates caused by environmental pollutants from an evolutionary perspective: From fish to mammals.

The rapid development of modern society has led to an increasing severity in the generation of new pollutants and the significant emission of old pollutants, exerting considerable pressure on the ecological environment and posing a serious threat to both biological survival and human health. The skeletal system, as a vital supportive structure and functional unit in organisms, is pivotal in maintaining body shape, safeguarding internal organs, storing minerals, and facilitating blood cell production. Although previous studies have uncovered the toxic effects of pollutants on vertebrate skeletal systems, there is a lack of comprehensive literature reviews in this field. Hence, this paper systematically summarizes the toxic effects and mechanisms of environmental pollutants on the skeletons of vertebrates based on the evolutionary context from fish to mammals. Our findings reveal that current research mainly focuses on fish and mammals, and the identified impact mechanisms mainly involve the regulation of bone signaling pathways, oxidative stress response, endocrine system disorders, and immune system dysfunction. This study aims to provide a comprehensive and systematic understanding of research on skeletal toxicity, while also promoting further research and development in related fields.

[Research progress in the regulation of autophagy and mitochondrial homeostasis by AMPK signaling channels].

AMP-activated protein kinase (AMPK) is a widely distributed and evolutionarily conserved serine/threonine protein kinase present in eukaryotic cells. In regulating cellular energy metabolism, AMPK plays an extremely important role as an energy metabolic kinase. When the body is in a low energy state, AMPK is activated in response to changes in intracellular adenine nucleotide levels and is bound to adenosine monophosphate (AMP) or adenosine diphosphate (ADP). Activated AMPK regulates various metabolic processes, including lipid and glucose metabolism and cellular autophagy. AMPK directly promotes autophagy by phosphorylating autophagy-related proteins in the mammalian target of rapamycin complex 1 (mTORC1), serine/threonine protein kinase-dysregulated 51-like kinase 1 (ULK1) and type III phosphatidylinositol 3-kinase-vacuolar protein-sorting 34 (PIK3C3-VPS34) complexes. AMPK also indirectly promotes autophagy by regulating the expression of downstream autophagy-related genes of transcription factors such as forkhead box O3 (FOXO3), lysosomal function transcription factor EB (TFEB) and bromodomain protein 4 (BRD4). AMPK also regulates mitochondrial autophagy, induces the division of damaged mitochondria and promotes the transfer of the autophagic response to damaged mitochondria. Another function of AMPK is to regulate mitochondrial health by stimulating mitochondrial biogenesis and participating in various aspects of mitochondrial homeostasis regulation. This review discusses the specific regulation of mitochondrial biology and internal environmental homeostasis by AMPK signaling channels as central to the cellular response to energy stress and regulation of mitochondria, highlighting the key role of AMPK in regulating cellular autophagy and mitochondrial autophagy, as well as advances in research on the regulation of mitochondrial homeostasis.

Extracellular vesicle dynamics in COPD: understanding the role of miR-422a, SPP1 and IL-17 A in smoking-related pathology.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) induced by smoking poses a significant global health challenge. Recent findings highlight the crucial role of extracellular vesicles (EVs) in mediating miRNA regulatory networks across various diseases. This study utilizes the GEO database to uncover distinct expression patterns of miRNAs and mRNAs, offering a comprehensive understanding of the pathogenesis of smoking-induced COPD. This study aims to investigate the mechanisms by which extracellular vesicles (EVs) mediate the molecular network of miR-422a-SPP1 to delay the onset of COPD caused by smoking. METHODS: The smoking-related miRNA chip GSE38974-GPL7723 was obtained from the GEO database, and candidate miRs were retrieved from the Vesiclepedia database. Downstream target genes of the candidate miRs were predicted using mRNA chip GSE38974-GPL4133, TargetScan, miRWalk, and RNA22 databases. This prediction was integrated with COPD-related genes from the GeneCards database, downstream target genes predicted by online databases, and key genes identified in the core module of WGCNA analysis to obtain candidate genes. The candidate genes were subjected to KEGG functional enrichment analysis using the "clusterProfiler" package in R language, and a protein interaction network was constructed. In vitro experiments involved overexpressing miRNA or extracting extracellular vesicles from bronchial epithelial cell-derived exosomes, co-culturing them with myofibroblasts to observe changes in the expression levels of the miR-422a-SPP1-IL-17 A regulatory network, and assessing protein levels of fibroblast differentiation-related factors α-SMA and collagen I using Western blot analysis. RESULTS: The differential gene analysis of chip GSE38974-GPL7723 and the retrieval results from the Vesiclepedia database identified candidate miRs, specifically miR-422a. Subsequently, an intersection was taken among the prediction results from TargetScan, miRWalk, and RNA22 databases, the COPD-related gene retrieval results from GeneCards database, the WGCNA analysis results of chip GSE38974-GPL4133, and the differential gene analysis results. This intersection, combined with KEGG functional enrichment analysis, and protein-protein interaction analysis, led to the final screening of the target gene SPP1 and its upstream regulatory gene miR-422a. KEGG functional enrichment analysis of mRNAs correlated with SPP1 revealed the IL-17 signaling pathway involved. In vitro experiments demonstrated that miR-422a inhibition targets suppressed the expression of SPP1 in myofibroblasts, inhibiting differentiation phenotype. Bronchial epithelial cells, under cigarette smoke extract (CSE) stress, could compensate for myofibroblast differentiation phenotype by altering the content of miR-422a in their Extracellular Vesicles (EVs). CONCLUSION: The differential gene analysis of Chip GSE38974-GPL7723 and the retrieval results from the Vesiclepedia database identified candidate miRs, specifically miR-422a. Further analysis involved the intersection of predictions from TargetScan, miRWalk, and RNA22 databases, gene search on COPD-related genes from the GeneCards database, WGCNA analysis from Chip GSE38974-GPL4133, and differential gene analysis, combined with KEGG functional enrichment analysis and protein interaction analysis. Ultimately, the target gene SPP1 and its upstream regulatory gene miR-422a were selected. KEGG functional enrichment analysis on mRNAs correlated with SPP1 revealed the involvement of the IL-17 signaling pathway. In vitro experiments showed that miR-422a targeted inhibition suppressed the expression of SPP1 in myofibroblast cells, inhibiting differentiation phenotype. Furthermore, bronchial epithelial cells could compensate for myofibroblast differentiation phenotype under cigarette smoke extract (CSE) stress by altering the miR-422a content in their extracellular vesicles (EVs).

Network pharmacology and molecular docking analysis on the mechanism of Tripterygium wilfordii Hook in the treatment of Sjögren syndrome.

Tripterygium wilfordii Hook. F (TWH) has significant anti-inflammatory and immunosuppressive effects, and is widely used in the inflammatory response mediated by autoimmune diseases. However, the multi-target mechanism of TWH action in Sjögren syndrome (SS) remains unclear. Therefore, the aim of this study was to explore the molecular mechanism of TWH in the treatment of SS using network pharmacology and molecular docking methods. TWH active components and target proteins were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. SS-related targets were obtained from the GeneCards database. After overlap, the therapeutic targets of TWH in the treatment of SS were screened. Protein-protein interaction and core target analysis were performed by STRING network platform and Cytoscape software. In addition, the affinity between TWH and the disease target was confirmed by molecular docking. Finally, the DAVID (visualization and integrated) database was used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of overlapping targets. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database shows that TWH contains 30 active components for the treatment of SS. Protein-protein interaction and core target analysis suggested that TNF, MMP9, TGFB1, AKT1, and BCL2 were the key targets of TWH in the treatment of SS. In addition, the molecular docking method confirmed that the bioactive molecules of TWH had a high affinity with the target of SS. Enrichment analysis showed that TWH active components were involved in multiple signaling pathways. Pathways in cancer, Lipid and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications is the main pathway. It is associated with a variety of biological processes such as inflammation, apoptosis, immune injury, and cancer. Based on data mining network pharmacology, and molecular docking method validation, TWH is likely to be a promising candidate for the treatment of SS drug, but still need to be further verified experiment.

Yu-Ping-Feng-San alleviates inflammation in atopic dermatitis mice by TLR4/MyD88/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Yu-Ping-Feng-San (YPF) is a traditional Chinese medicine formula that has therapeutic effects on allergic diseases such as allergic rhinitis and asthma. However, its potential efficacy and mechanism in the treatment of atopic dermatitis (AD) has not been extensively illustrated. AIM OF THE STUDY: The purpose of this study was to investigate the efficacy and possible mechanisms of YPF in AD pathogenesis. METHODS: Network pharmacology and GEO data mining were adopted to firstly identify the potential mechanisms of YPF on AD. Then DNCB induced-AD murine model was established to test the efficacy of YPF and verify its effects on inflammatory cytokines and NF-κB pathway. In addition, molecular docking was performed to detect the binding affinity of YPF's active components with NF-κB pathway related molecules. RESULTS: Network pharmacology and human data mining suggested that YPF may act on the NF-κB pathway in AD pathogenesis. With DNCB mice model, we found that YPF significantly improved AD symptoms, reduced SCORAD scores, and alleviated skin tissue inflammation in mice. At the same time, the expression of inflammatory cytokines, TNF-α, sPLA2-IIA and IL-6, was down-regulated. Moreover, YPF suppressed TLR4/MyD88/NF-κB pathway in situ in a dose-dependent manner. Molecular docking further confirmed that seven compounds in YPF had exceptional binding properties with TNF-α, IL-6 and TLR4. CONCLUSION: YPF may help the recovery of AD by inhibiting the TLR4/MyD88/NF-κB pathway, which provides novel insights for the treatment of AD by YPF.

Magnetron-Sputtered Lead Titanate Thin Films for Pyroelectric Applications: Part 2-Electrical Characteristics and Characterization Methods.

Pyroelectric materials are naturally electrically polarized and exhibits a built-in spontaneous polarization in their unit cell structure even in the absence of any externally applied electric field. These materials are regarded as one of the ideal detector elements for infrared applications because they have a fast response time and uniform sensitivity at room temperature across all wavelengths. Crystals of the perovskite lead titanate (PbTiO3) family show pyroelectric characteristics and undergo structural phase transitions. They have a high Curie temperature (the temperature at which the material changes from the ferroelectric (polar) to the paraelectric (nonpolar) phase), high pyroelectric coefficient, high spontaneous polarization, low dielectric constant, and constitute important component materials not only useful for infrared detection, but also with vast applications in electronic, optic, and MEMS devices. However, the preparation of large perfect and pure single crystals PbTiO3 is challenging. Additionally, difficulties arise in the application of such bulk crystals in terms of connection to processing circuits, large size, and high voltages required for their operation. In this part of the review paper, we explain the electrical behavior and characterization techniques commonly utilized to unravel the pyroelectric properties of lead titanate and its derivatives. Further, it explains how the material preparation techniques affect the electrical characteristics of resulting thin films. It also provides an in-depth discussion of the measurement of pyroelectric coefficients using different techniques.

Prednisone combined with Dihydroartemisinin attenuates systemic lupus erythematosus by regulating M1/M2 balance through the MAPK signaling pathway.

OBJECTIVE: Dihydroartemisinin (DHA) plays a very important role in various diseases. However, the precise involvement of DHA in systemic lupus erythematosus (SLE), relation to the equilibrium between M1 and M2 cells, remains uncertain. Therefore, we aimed to investigate the role of DHA in SLE and its effect on the M1/M2 cells balance. METHODS: SLE mice model was established by pristane induction. Flow cytometry was employed to measure the abundance of M1 and M2 cells within the peripheral blood of individuals diagnosed with SLE. The concentrations of various cytokines, namely TNF-α, IL-1ß, IL-4, IL-6, and IL-10, within the serum of SLE patients or SLE mice were assessed via ELISA. Immunofluorescence staining was utilized to detect the deposition of IgG and complement C3 in renal tissues of the mice. We conducted immunohistochemistry analysis to assess the expression levels of Collagen-I, a collagen protein, and α-SMA, a fibrosis marker protein, in the renal tissues of mice. Hematoxylin-eosin staining, Masson's trichrome staining, and Periodic acid Schiff staining were used to examine histological alterations. In this study, we employed qPCR and western blot techniques to assess the expression levels of key molecular markers, namely CD80 and CD86 for M1 cells, as well as CD206 and Arg-1 for M2 cells, within kidney tissue. Additionally, we investigated the involvement of the MAPK signaling pathway. The Venny 2.1 online software tool was employed to identify shared drug-disease targets, and subsequently, the Cytoscape 3.9.2 software was utilized to construct the "disease-target-ingredient" network diagram. Protein-protein interactions of the target proteins were analyzed using the String database, and the network proteins underwent enrichment analysis for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. RESULTS: The results showed that an increase in M1 cells and a decrease in M2 cells within the peripheral blood of individuals diagnosed with SLE. Further analysis revealed that prednisone (PDN) combined with DHA can alleviate kidney damage and regulate the balance of M1 and M2 cells in both glomerular mesangial cells (GMC) and kidney. The MAPK signaling pathway was found to be involved in SLE kidney damage and M1/M2 balance in the kidney. Furthermore, PDN and/or DHA were found to inhibit the MAPK signaling pathway in GMC and kidney. CONCLUSION: We demonstrated that PDN combined with DHA attenuates SLE by regulating M1/M2 balance through MAPK signaling pathway. These findings propose that the combination of PDN and DHA could serve as a promising therapeutic strategy for SLE, as it has the potential to mitigate kidney damage and reinstate the equilibrium of M1 and M2 cells.

Physics-driven structural docking and protein language models accelerate antibody screening and design for broad-spectrum antiviral therapy.

Therapeutic antibodies have become one of the most influential therapeutics in modern medicine to fight against infectious pathogens, cancer, and many other diseases. However, experimental screening for highly efficacious targeting antibodies is labor-intensive and of high cost, which is exacerbated by evolving antigen targets under selective pressure such as fast-mutating viral variants. As a proof-of-concept, we developed a machine learning-assisted antibody generation pipeline that greatly accelerates the screening and re-design of immunoglobulins G (IgGs) against a broad spectrum of SARS-CoV-2 coronavirus variant strains. These viruses infect human host cells via the viral spike protein binding to the host cell receptor angiotensin-converting enzyme 2 (ACE2). Using over 1300 IgG sequences derived from convalescent patient B cells that bind with spike's receptor binding domain (RBD), we first established protein structural docking models in assessing the RBD-IgG-ACE2 interaction interfaces and predicting the virus-neutralizing activity of each IgG with a confidence score. Additionally, employing Gaussian process regression (also known as Kriging) in a latent space of an antibody language model, we predicted the landscape of IgGs' activity profiles against individual coronaviral variants of concern. With functional analyses and experimental validations, we efficiently prioritized IgG candidates for neutralizing a broad spectrum of viral variants (wildtype, Delta, and Omicron) to prevent the infection of host cells in vitro and hACE2 transgenic mice in vivo. Furthermore, the computational analyses enabled rational redesigns of selective IgG clones with single amino acid substitutions at the RBD-binding interface to improve the IgG blockade efficacy for one of the severe, therapy-resistant strains - Delta (B.1.617). Our work expedites applications of artificial intelligence in antibody screening and re-design even in low-data regimes combining protein language models and Kriging for antibody sequence analysis, activity prediction, and efficacy improvement, in synergy with physics-driven protein docking models for antibody-antigen interface structure analyses and functional optimization.

Comparative efficacy of different repetitive transcranial magnetic stimulation protocols for lower extremity motor function in stroke patients: a network meta-analysis.

Background: Lower extremity motor dysfunction is one of the most severe consequences after stroke, restricting functional mobility and impairing daily activities. Growing evidence suggests that repetitive transcranial magnetic stimulation (rTMS) can improve stroke patients' lower extremity motor function. However, there is still controversy about the optimal rTMS protocol. Therefore, we compared and analyzed the effects of different rTMS protocols on lower extremity motor function in stroke patients using network meta-analysis (NMA). Methods: We systematically searched CNKI, WanFang, VIP, CBM, PubMed, Embase, Web of Science, and Cochrane Library databases (from origin to 31 December 2023). Randomized controlled trials (RCTs) or crossover RCTs on rTMS improving lower extremity motor function in stroke patients were included. Two authors independently completed article screening, data extraction, and quality assessment. RevMan (version 5.4) and Stata (version 17.0) were used to analyze the data. Results: A total of 38 studies with 2,022 patients were eligible for the NMA. The interventions included HFrTMS-M1, LFrTMS-M1, iTBS-Cerebellum, iTBS-M1, dTMS-M1, and Placebo. The results of NMA showed that LFrTMS-M1 ranked first in FMA-LE and speed, and HFrTMS-M1 ranked first in BBS, TUGT, and MEP amplitude. The subgroup analysis of FMA-LE showed that HFrTMS-M1 was the best stimulation protocol for post-stroke time > 1 month, and LFrTMS-M1 was the best stimulation protocol for post-stroke time ≤ 1 month. Conclusion: Considering the impact of the stroke phase on the lower extremity motor function, the current research evidence shows that HFrTMS-M1 may be the preferred stimulation protocol to improve the lower extremity motor function of patients for post-stroke time > 1 month, and LFrTMS-M1 for post-stroke time ≤ 1 month. However, the above conclusion needs further analysis and validation by more high-quality RCTs.Systematic Review Registration:www.crd.york.ac.uk/prospero/, identifier (CRD42023474215).

Cushing's Syndrome in Pregnancy Secondary to Adrenocortical Adenoma: A Case Series and Review.

PURPOSE: To present a case series of Cushing's syndrome (CS) during pregnancy caused by adrenocortical adenomas, highlighting clinical features, hormonal assessments and outcomes. METHODS: We describe five pregnant women with CS, detailing clinical presentations and laboratory findings. RESULTS: Common clinical features included a full moon face, buffalo back and severe hypertension. Elevated blood cortisol levels with circadian rhythm disruption and suppressed adrenocorticotrophic hormone (ACTH) levels were observed. Imaging revealed unilateral adrenal tumours. Two cases underwent laparoscopic adrenalectomies during the second trimester, while three had postpartum surgery. All required hormone replacement therapy, with postoperative pathological confirmation of adrenocortical adenomas. CONCLUSION: Diagnosis of CS during pregnancy is challenging due to overlapping features with normal pregnancy: elevated blood cortisol levels and abnormal diurnal rhythm of blood cortisol, suppressed aid diagnosis. Treatment should be individualised due to a lack of explicit optimum therapeutic approaches. Laparoscopic adrenalectomy may be an optimal choice, along with multidisciplinary management including hormone replacement therapy.