High-density, highly sensitive sensor array of spiky carbon nanospheres for strain field mapping.

While accurate mapping of strain distribution is crucial for assessing stress concentration and estimating fatigue life in engineering applications, conventional strain sensor arrays face a great challenge in balancing sensitivity and sensing density for effective strain mapping. In this study, we present a Fowler-Nordheim tunneling effect of monodispersed spiky carbon nanosphere array on polydimethylsiloxane as strain sensor arrays to achieve a sensitivity up to 70,000, a sensing density of 100 pixel cm-2, and logarithmic linearity over 99% within a wide strain range of 0% to 60%. The highly ordered assembly of spiky carbon nanospheres in each unit also ensures high inter-unit consistency (standard deviation ≤3.82%). Furthermore, this sensor array can conformally cover diverse surfaces, enabling accurate acquisition of strain distributions. The sensing array offers a convenient approach for mapping strain fields in various applications such as flexible electronics, soft robotics, biomechanics, and structure health monitoring.

Excessive ER-phagy mediated by FAM134B contributes to trophoblast cell mitochondrial dysfunction in preeclampsia.

Autophagy dysregulation and Ca 2+-induced mitochondrial dysfunction in trophoblast cells are proposed to contribute to preeclampsia (PE) development. FAM134B is identified as a receptor associated with endoplasmic reticulum autophagy (ER-phagy). In this study, the placentas of normal pregnant women and PE patients are collected and analyzed by immunohistochemistry, quantitative real-time PCR, and western blot analysis. The effects of ER-phagy are investigated in HTR8/SVneo cells. Significantly increased levels of FAM134B, inositol-1,4,5-triphosphate receptor type 1 (IP3R), calnexin, cleaved caspase 3 and cytochrome C are detected in the PE placenta and sodium nitroprusside (SNP)-treated HTR-8/SVneo cells. Overexpression of FAM134B in HTR-8/SVneo cells results in increased apoptosis, impaired invasion capacity, and diminished mitochondrial function, while an autophagy inhibitor improves mitochondrial performance. Excessive ER-phagy is also associated with an increased concentration of gamma linolenic acid. Our findings suggest that FAM134B contributes to trophoblast apoptosis by mediating ER-mitochondria Ca 2+ transfer through mitochondria-associated endoplasmic reticulum membranes (MAMs) and subsequent mitochondrial function, further enhancing our understanding of PE etiology.

Epidemiological characteristics of tuberculosis incidence and its macro-influence factors in Chinese mainland during 2014-2021.

BACKGROUND: Tuberculosis (TB) remains a pressing public health issue, posing a significant threat to individuals' well-being and lives. This study delves into the TB incidence in Chinese mainland during 2014-2021, aiming to gain deeper insights into their epidemiological characteristics and explore macro-level factors to enhance control and prevention. METHODS: TB incidence data in Chinese mainland from 2014 to 2021 were sourced from the National Notifiable Disease Reporting System (NNDRS). A two-stage distributed lag nonlinear model (DLNM) was constructed to evaluate the lag and non-linearity of daily average temperature (℃, Atemp), average relative humidity (%, ARH), average wind speed (m/s, AWS), sunshine duration (h, SD) and precipitation (mm, PRE) on the TB incidence. A spatial panel data model was used to assess the impact of demographic, medical and health resource, and economic factors on TB incidence. RESULTS: A total of 6,587,439 TB cases were reported in Chinese mainland during 2014-2021, with an average annual incidence rate of 59.17/100,000. The TB incidence decreased from 67.05/100,000 in 2014 to 46.40/100,000 in 2021, notably declining from 2018 to 2021 (APC = -8.87%, 95% CI: -11.97, -6.85%). TB incidence rates were higher among males, farmers, and individuals aged 65 years and older. Spatiotemporal analysis revealed a significant cluster in Xinjiang, Qinghai, and Xizang from March 2017 to June 2019 (RR = 3.94, P < 0.001). From 2014 to 2021, the proportion of etiologically confirmed cases increased from 31.31% to 56.98%, and the time interval from TB onset to diagnosis shortened from 26 days (IQR: 10-56 days) to 19 days (IQR: 7-44 days). Specific meteorological conditions, including low temperature (< 16.69℃), high relative humidity (> 71.73%), low sunshine duration (< 6.18 h) increased the risk of TB incidence, while extreme low wind speed (< 2.79 m/s) decreased the risk. The spatial Durbin model showed positive associations between TB incidence rates and sex ratio (ß = 1.98), number of beds in medical and health institutions per 10,000 population (ß = 0.90), and total health expenses (ß = 0.55). There were negative associations between TB incidence rates and population (ß = -1.14), population density (ß = -0.19), urbanization rate (ß = -0.62), number of medical and health institutions (ß = -0.23), and number of health technicians per 10,000 population (ß = -0.70). CONCLUSIONS: Significant progress has been made in TB control and prevention in China, but challenges persist among some populations and areas. Varied relationships were observed between TB incidence and factors from meteorological, demographic, medical and health resource, and economic aspects. These findings underscore the importance of ongoing efforts to strengthen TB control and implement digital/intelligent surveillance for early risk detection and comprehensive interventions.

Correlation study of serum lipid levels and lipid metabolism-related genes in cervical cancer.

Objective: Lipid metabolism plays an important role in cancer. The aim of this study was to investigate the relationship between lipid metabolism and the development of cervical cancer, and to explore the prognostic significance of lipid metabolism-related genes in patients with cervical cancer. Methods: Initially, we retrospectively collected data from 1589 cervical cancer patients treated at the Affiliated Hospital of Qingdao University, with 1589 healthy individuals from the physical examination center serving as the control group. The correlation between their serum lipid levels and cervical cancer was analyzed. Subsequently, leveraging public databases, we conducted comprehensive studies on lipid metabolism-related genes. Additionally, we analyzed RNA expression profiling and clinical information sourced from TCGA and GTEx databases. Finally, we established a prognostic model integrating 9 genes associated with lipid metabolism and generated a nomogram model using R. GO and KEGG were performed to explore the functions and pathways of lipid metabolism-related genes. Results: Our findings revealed that patients with cervical cancer exhibited dyslipidemia, characterized by elevated levels of TC, TG, and LDL-C, alongside reduced HDL-C levels compared to controls (P<0.05). Interestingly, compared with early-stage patients, advanced patients had lower HDL-C level and higher LDL-C level. Regression analysis further highlighted high TC, TG, and LDL-C as significant risk factors for cervical cancer. Then a total of 188 lipid metabolism-related genes were identified and a prognostic signature based on 9 genes was established and validated. The results of the GO and KEGG functional analysis indicated that the lipid metabolism-related genes are primarily concentrated on pathways associated with fatty acid metabolism. Conclusion: Our study underscores the varying degrees of dyslipidemia observed in patients with cervical cancer, emphasizing the relevance of serum lipids in disease development. Our prognostic riskScore model predicted the overall survival time of patients based on 9 genes associated with lipid metabolism. These 9 genes may be tumor biomarkers and new targets for the treatment of cervical cancer.

Present status of scheduled vaccinations and vaccination-related bleeding in Chinese children with haemophilia.

AIM: Many countries have detailed recommendations for haemophilia patients to reduce the risk of vaccination-related bleeding. However, data from developing countries are lacking. We investigated scheduled vaccinations and vaccination-related bleeding complications in Chinese children with haemophilia and analysed issues related to vaccinations. METHODS: Children with haemophilia in the PUMCH Haemophilia Treatment Centre were contacted via telephone. We distributed a vaccination questionnaire to their parents. The severity of haemophilia, coagulation factor infusions before vaccination, injection mode, and vaccination-related complications were analysed. RESULTS: A total of 440 valid questionnaires were received from 27 of 34 provinces in China. 31.3% (138/440) of the children with haemophilia did not receive all of their vaccinations. Among the children who received vaccinations, 48.1% (197/409) experienced bleeding complications. In patients with severe haemophilia, those on regular prophylaxis had a lower incidence of local hematoma compared to those on intermittent or no prophylaxis (14.3% vs. 26.5% vs. 39.7%, P < 0.05). The incidence of local hematomas was lower by subcutaneous (SQ) injections than by intramuscular injections (24.6% vs. 35.3%, P < 0.05). CONCLUSION: The vaccination rate is quite insufficient in Chinese children with haemophilia. Missed vaccinations are related to vaccination-related bleeding complications. Prophylaxis before vaccination and SQ injections would help reduce bleeding complications.

Protonation of an Imine-linked Covalent Organic Framework for Efficient H2O2 Photosynthesis under Visible Light up to 700 nm.

Covalent organic frameworks (COFs) are promising photocatalysts for H2O2 production from water via oxygen reduction reactions (ORR). The design of COFs for efficient H2O2 production indubitably hinges on an in-depth understanding of their ORR mechanisms. In this work, taking an imine-linked COF as an example, we demonstrate that protonation of the functional units such as imine, amine, and triazine, is a highly efficient strategy to upgrade the activity levels for H2O2 synthesis. The protonation not only extends the light absorption of the COF but also provides proton sources that directly participate in H2O2 generation. Notably, the protonation simplifies the reaction pathways of ORR to H2O2, i.e. from an indirect superoxide radical ([[EQUATION]]) mediated route to a direct one-step two-electron route. Theoretical calculations confirm that the protonation favors H2O2 synthesis due to easy access of protons near the reaction sites that removes the energy barrier for generating *OOH intermediate. These findings not only extend the mechanistic insight into H2O2 photosynthesis but also provide a rational guideline for the design and upgradation of efficient COFs.

Copper-Catalyzed Decarboxylation Cross-Coupling Cascade Reaction for Synthesis of Fused Dihydro-benzoxazinones.

A protocol for a tandem copper-catalyzed intermolecular decarboxylation cross-coupling cascade between o-bromobenzoic acids and proline or piperic acid has been disclosed. The developed protocol allows access to a variety of synthetically useful fused benzoxazinones scaffolds with high efficiency and good functional group compatibility. A mechanistically sequential approach for the decarboxylation and dehydration coupling process was presented.

Study on the correlation of supplementation with L-citrulline on the gastrointestinal flora and semen antifreeze performance of ram.

Introduction: Cryopreservation of semen can give full play to the reproductive advantages of male animals. However, in actual production, due to the poor frost resistance of sheep semen and the low conception rate, the promotion of sheep frozen semen is greatly hindered. Therefore, it is urgent to improve the frost resistance of semen to improve the quality of frozen semen. At present, most studies on improving the quality of frozen semen are based on the improvement of semen dilutions, and few studies on improving the freezing resistance of ram semen by feeding functional amino acids. Methods: Therefore, 24 Turpan black rams were divided into high antifreeze group (HF) and a low antifreeze group (LF) Each of these groups was further randomly divided into control and experimental subgroups. The control subgroup was fed a basal diet, while the experimental subgroup received an additional 12 g/d of L-Cit supplementation based on the control group for a duration of 90 days. Results: The results showed that Following L-Cit supplementation, the experimental group demonstrated significantly elevated sperm density and VSL (Velocity of straight line), T-AOC, GSH-Px, and NO levels in fresh semen compared to the control group (P < 0.01). After thawing, the experimental group exhibited significantly higher levels of T-AOC, GSH-Px, and NO compared to the control group (P < 0.01). Additionally, the HFT group, after thawing frozen semen, displayed significantly higher HK1 protein expression compared to the control group. The number of spermatogonia, spermatocytes, and sperm cells in the HFT group was significantly higher than that in the HFC group. Moreover, 16S rRNA sequence analysis showed that Candidatus_Saccharimonas, Staphylococcus, Weissella, succinivbrionaceae_UcG_002, and Quinella were significantly enriched in the rumen of the HFT group, while Ureaplasma was significantly enriched in the HFC group. In the duodenum, Clostridiales_bacterium_Firm_14, Butyrivibrio, and Prevotellaceae_NK3831_group were significantly enriched in the HFT group, whereas Desulfovibrio and Quinella were significantly enriched in the HFC group. Discussion: Under the conditions employed in this study, L-Cit supplementation was found to enhance the intestinal flora composition in rams, thereby improving semen quality, enhancing the antifreeze performance of semen, and promoting the development of testicular spermatogenic cells.

Evaluation method for the color preference of lighting traditional Chinese paintings in museum based on light source spectral analysis.

To evaluate the lighting color preference on traditional Chinese paintings based on the spectral power distributions (SPDs) of light sources, an experiment to examine the color preference of 40 representative SPDs illuminating two typical traditional Chinese paintings was performed in a 1:1 simulated exhibition hall. By decomposing the data, the influence trend from the different narrowband spectra on the color preference was obtained, and two key spectra with a significant influence on the color preference were determined (WLP = 425 nm with FWHM = 20 nm and WLP = 525 nm with FWHM = 30 nm). With an evaluation model using the relative spectral areas of S425 and S525, the calculation of the lighting color preference for traditional Chinese painting illumination based on SPD was achieved. Our results could provide a mathematical tool for the comparison and selection of light sources for the illumination of traditional Chinese paintings and the development and design of specific light sources.

Sensitive and visual detection of SARS-CoV-2 using RPA-Cas12a one-step assay with ssDNA-modified crRNA.

BACKGROUND: CRISPR-Cas12a based one-step assays are widely used for nucleic acid detection, particularly for pathogen detection. However, the detection capability of the one-step assay is reduced because the Cas12a protein competes with the isothermal amplification enzymes for the target DNA and cleaves it. Therefore, the key to improving the sensitivity of the one-step assay is to address the imbalance between isothermal amplification and CRISPR detection. In previous study, we developed a Cas12a one-step assay using single-stranded DNA (ssDNA)-modified crRNA (mD-crRNA) and applied this method for the detection of pathogenic DNA. RESULTS: Here, we utilized mD-crRNA to establish a sensitive one-step assay that enables the visual detection of SARS-CoV-2 under ultraviolet light, achieving a detection limit of 5 aM without cross-reactivity. The sensitivity of mD-crRNA in the one-step assay was 100-fold higher than that of wild-type crRNA. Mechanistic studies revealed that the addition of ssDNA at the 3' end of mD-crRNA attenuates the binding affinity between the Cas12a-mD-crRNA complex and the target DNA. Consequently, this reduction in binding affinity decreases the cis-cleavage activity of Cas12a, mitigating its cleavage of the target DNA in the one-step assay. As a result, there is an augmentation in the amplification and accumulation of target DNA, thereby enhancing detection sensitivity. In the clinical testing of 40 SARS-CoV-2 RNA samples, the concordance between the results of the one-step assay and known qPCR results was 97.5 %. SIGNIFICANCE: The one-step assay using mD-crRNA proves to be highly sensitive and specificity and visually effective for the detection of SARS-CoV-2. Our study delves into the application of the mD-crRNA-mediated one-step assay in nucleic acid detection and its associated reaction mechanism. This holds great significance in addressing the inherent incompatibility issues between isothermal amplification and CRISPR detection.

Identification of hub genes and therapeutic siRNAs to develop novel adjunctive therapy for Duchenne muscular dystrophy.

OBJECTIVE: Duchenne muscular dystrophy (DMD) is a devastating X-linked neuromuscular disorder caused by various defects in the dystrophin gene and still no universal therapy. This study aims to identify the hub genes unrelated to excessive immune response but responsible for DMD progression and explore therapeutic siRNAs, thereby providing a novel treatment. METHODS: Top ten hub genes for DMD were identified from GSE38417 dataset by using GEO2R and PPI networks based on Cytoscape analysis. The hub genes unrelated to excessive immune response were identified by GeneCards, and their expression was further verified in mdx and C57 mice at 2 and 4 months (M) by (RT-q) PCR and western blotting. Therapeutic siRNAs were deemed as those that could normalize the expression of the validated hub genes in transfected C2C12 cells. RESULTS: 855 up-regulated and 324 down-regulated DEGs were screened from GSE38417 dataset. Five of the top 10 hub genes were considered as the candidate genes unrelated to excessive immune response, and three of these candidates were consistently and significantly up-regulated in mdx mice at 2 M and 4 M when compared with age-matched C57 mice, including Col1a2, Fbn1 and Fn1. Furthermore, the three validated up-regulated candidate genes can be significantly down-regulated by three rational designed siRNA (p < 0.0001), respectively. CONCLUSION: COL1A2, FBN1 and FN1 may be novel biomarkers for DMD, and the siRNAs designed in our study were help to develop adjunctive therapy for Duchenne muscular dystrophy.

Predicting prostate cancer recurrence: Introducing PCRPS, an advanced online web server.

Background: Prostate cancer (PCa) is one of the leading causes of cancer death in men. About 30% of PCa will develop a biochemical recurrence (BCR) following initial treatment, which significantly contributes to prostate cancer-related deaths. In clinical practice, accurate prediction of PCa recurrence is crucial for making informed treatment decisions. However, the development of reliable models and biomarkers for predicting PCa recurrence remains a challenge. In this study, the aim is to establish an effective and reliable tool for predicting the recurrence of PCa. Methods: We systematically screened and analyzed potential datasets to predict PCa recurrence. Through quality control analysis, low-quality datasets were removed. Using meta-analysis, differential expression analysis, and feature selection, we identified key genes associated with recurrence. We also evaluated 22 previously published signatures for PCa recurrence prediction. To assess prediction performance, we employed nine machine learning algorithms. We compared the predictive capabilities of models constructed using clinical variables, expression data, and their combinations. Subsequently, we implemented these machine learning models into a user-friendly web server freely accessible to all researchers. Results: Based on transcriptomic data derived from eight multicenter studies consisting of 733 PCa patients, we screened 23 highly influential genes for predicting prostate cancer recurrence. These genes were used to construct the Prostate Cancer Recurrence Prediction Signature (PCRPS). By comparing with 22 published signatures and four important clinicopathological features, the PCRPS exhibited a robust and significantly improved predictive capability. Among the tested algorithms, Random Forest demonstrated the highest AUC value of 0.72 in predicting PCa recurrence in the testing dataset. To facilitate access and usage of these machine learning models by all researchers and clinicians, we also developed an online web server (https://urology1926.shinyapps.io/PCRPS/) where the PCRPS model can be freely utilized. The tool can also be used to (1) predict the PCa recurrence by clinical information or expression data with high accuracy. (2) provide the possibility of PCa recurrence by nine machine learning algorithms. Furthermore, using the PCRPS scores, we predicted the sensitivity of 22 drugs from GDSC2 and 95 drugs from CTRP2 to the samples. These predictions provide valuable insights into potential drug sensitivities related to the PCRPS score groups. Conclusion: Overall, our study provides an attractive tool to further guide the clinical management and individualized treatment for PCa.

Lanthanide metal-organic framework-based surface molecularly imprinted polymers ratiometric fluorescence probe for visual detection of perfluorooctanoic acid with a smartphone-assisted portable device.

Perfluorooctanoic acid (PFOA) poses a threat to the environment and human health due to its persistence, bioaccumulation, and reproductive toxicity. Herein, a lanthanide metal-organic framework (Ln-MOF)-based surface molecularly imprinted polymers (SMIPs) ratiometric fluorescence probe (Eu/Tb-MOF@MIPs) and a smartphone-assisted portable device were developed for the detection of PFOA with high selectivity in real water samples. The integration of Eu/Tb MOFs as carriers not only had highly stable multiple emission signals but also prevented deformation of the imprinting cavity of MIPs. Meanwhile, the MIPs layer preserved the fluorescence of Ln-MOF and provided selective cavities for improved specificity. Molecular dynamics (MD) was employed to simulate the polymerization process of MIPs, revealing that the formation of multiple recognition sites was attributed to the establishment of hydrogen bonds between functional monomers and templates. The probe showed a good linear relationship with PFOA concentration in the range of 0.02-2.8 µM, by giving the limit of detection (LOD) of 0.98 nM. Additionally, The red-green-blue (RGB) values analysis based on the smartphone-assisted portable device demonstrated a linear relationship of 0.1-2.8 µM PFOA with the LOD of 3.26 nM. The developed probe and portable device sensing platform exhibit substantial potential for on-site detecting PFOA in practical applications and provide a reliable strategy for the intelligent identification of important targets in water environmental samples.

Microbiota characterization of the green mussel Perna viridis at the tissue scale and its relationship with the environment.

Research on the microbiota associated with marine invertebrates is important for understanding host physiology and the relationship between the host and the environment. In this study, the microbiota of the green mussel Perna viridis was characterized at the tissue scale using 16S rRNA gene high-throughput sequencing and compared with the microbiota of the surrounding environment. Different mussel tissues were sampled, along with two environmental samples (the mussel's attachment substratum and seawater). The results showed that the phyla Proteobacteria, Bacteroidetes, and Spirochaetae were dominant in mussel tissues. The bacterial community composition at the family level varied among the tissues of P. viridis. Although the microbiota of P. viridis clearly differed from that of the surrounding seawater, the composition and diversity of the microbial community of the foot and outer shell surface were similar to those of the substratum, indicating their close relationship with the substratum. KEGG prediction analysis indicated that the bacteria harbored by P. viridis were enriched in the degradation of aromatic compounds, osmoregulation, and carbohydrate oxidation and fermentation, processes that may be important in P. viridis physiology. Our study provides new insights into the tissue-scale characteristics of mussel microbiomes and the intricate connection between mussels and their environment.

Residential mobility and liver cancer risk: findings from a prospective cohort study in Chinese women.

BACKGROUND: Residential mobility is believed to influence the occurrence and development of cancer; however, the results are inconclusive. Furthermore, limited studies have been conducted on Asian populations. This study aimed to evaluate the relationship between residential mobility and liver cancer risk among Chinese women. METHODS: We enrolled 72,818 women from urban Shanghai between 1996 and 2000, and then followed them until the end of 2016. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the association between residential mobility and liver cancer risk. A linear trend test was conducted by ranking variables. A sensitivity analysis was also conducted, excluding participants with follow-up times of less than 2 years, to prevent potential bias. RESULTS: During the 1,269,765 person-years of follow-up, liver cancer was newly diagnosed in 259 patients. Domestic migration (HR = 1.47, 95% CI, 1.44-1.50), especially immigration to Shanghai (HR = 1.47, 95% CI, 1.44-1.50) was associated with an increased risk of liver cancer. In addition, migration frequency, age at initial migration and first immigration to Shanghai had linear trends with an increased liver cancer risk (Ptrend <0.001). The results were similar when excluding participants with less than two years of follow-up. CONCLUSIONS: The possible association between residential mobility and a higher risk of liver cancer in women could suggest the need for effective interventions to reduce adverse environmental exposures and enhance people's health.

Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol.

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

Psoralen and Isopsoralen, Two Estrogen-Like Natural Products from Psoraleae Fructus, Induced Cholestasis via Activation of ERK1/2.

With the increasing use of oral contraceptives and estrogen replacement therapy, the incidence of estrogen-induced cholestasis (EC) has tended to rise. Psoralen (P) and isopsoralen (IP) are the major bioactive components in Psoraleae Fructus, and their estrogen-like activities have already been recognized. Recent studies have also reported that ERK1/2 plays a critical role in EC in mice. This study aimed to investigate whether P and IP induce EC and reveal specific mechanisms. It was found that P and IP increased the expression of esr1, cyp19a1b and the levels of E2 and VTG at 80 µM in zebrafish larvae. Exemestane (Exe), an aromatase antagonist, blocked estrogen-like activities of P and IP. At the same time, P and IP induced cholestatic hepatotoxicity in zebrafish larvae with increasing liver fluorescence areas and bile flow inhibition rates. Further mechanistic analysis revealed that P and IP significantly decreased the expression of bile acids (BAs) synthesis genes cyp7a1 and cyp8b1, BAs transport genes abcb11b and slc10a1, and BAs receptor genes nr1h4 and nr0b2a. In addition, P and IP caused EC by increasing the level of phosphorylation of ERK1/2. The ERK1/2 antagonists GDC0994 and Exe both showed significant rescue effects in terms of cholestatic liver injury. In conclusion, we comprehensively studied the specific mechanisms of P- and IP-induced EC and speculated that ERK1/2 may represent an important therapeutic target for EC induced by phytoestrogens.

LncRNA NEAT1 promotes MPP+ induced injury of PC12 cells and accelerates the progression of Parkinson's disease in mice through FUS mediated inhibition of PI3K/AKT/mTOR signalling pathway.

Long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) is involved in the progression of Parkinson's disease (PD), but the specific regulatory role needs further exploration. This study showed that the expression of NEAT1 was upregulated in the cerebrospinal fluid (CSF) and peripheral blood of patients with different stages of PD. 1-Methyl-4-phenylpyridine (MPP)-treated PC 12 cells were transfected with si-NEAT1, and MPP treatment promoted cell apoptosis, oxidative stress and inflammatory factor secretion. Si-NEAT1 reversed the effects of MPP. NEAT1 silencing eliminated the effect of MPP on the protein expression levels of LC3-II and p62/SQSTM1. By using an online bioinformatics database, Fused in Sarcoma (FUS) was confirmed to be an RNA binding protein of NEAT1, and it was highly expressed in the CSF and peripheral blood of patients with PD. Si-FUS was transfected into MPP-treated PC 12 cells to detect cell apoptosis, oxidative stress, inflammatory factor secretion and autophagy, and the results were the same as those of transfection of si-NEAT1. Furthermore, MPP treatment reduced the phosphorylation levels of PI3K, Akt and mTOR, whereas si-FUS reversed the effects of MPP. In vivo, compared with the model group, the PD mice showed reduced NEAT1 and FUS expression levels and activated PI3K pathway after being injected with si-NEAT1. The brain tissue of NEAT1-silenced PD mice had decreased inflammatory infiltration and apoptosis and increased neurological scores. In conclusion, NEAT1 is involved in PD progression through FUS-mediated inhibition of the PI3K/AKT/mTOR signalling pathway.

Disturbed flow in the juxta-anastomotic area of an arteriovenous fistula correlates with endothelial loss, acute thrombus formation, and neointimal hyperplasia.

Clinical failure of arteriovenous neointimal hyperplasia (NIH) fistulae (AVF) is frequently due to juxta-anastomotic NIH (JANIH). Although the mouse AVF model recapitulates human AVF maturation, previous studies focused on the outflow vein distal to the anastomosis. We hypothesized that the juxta-anastomotic area (JAA) has increased NIH compared with the outflow vein. AVF was created in C57BL/6 mice without or with chronic kidney disease (CKD). Temporal and spatial changes of the JAA were examined using histology and immunofluorescence. Computational techniques were used to model the AVF. RNA-seq and bioinformatic analyses were performed to compare the JAA with the outflow vein. The jugular vein to carotid artery AVF model was created in Wistar rats. The neointima in the JAA shows increased volume compared with the outflow vein. Computational modeling shows an increased volume of disturbed flow at the JAA compared with the outflow vein. Endothelial cells are immediately lost from the wall contralateral to the fistula exit, followed by thrombus formation and JANIH. Gene Ontology (GO) enrichment analysis of the 1,862 differentially expressed genes (DEG) between the JANIH and the outflow vein identified 525 overexpressed genes. The rat jugular vein to carotid artery AVF showed changes similar to the mouse AVF. Disturbed flow through the JAA correlates with rapid endothelial cell loss, thrombus formation, and JANIH; late endothelialization of the JAA channel correlates with late AVF patency. Early thrombus formation in the JAA may influence the later development of JANIH.NEW & NOTEWORTHY Disturbed flow and focal endothelial cell loss in the juxta-anastomotic area of the mouse AVF colocalizes with acute thrombus formation followed by late neointimal hyperplasia. Differential flow patterns between the juxta-anastomotic area and the outflow vein correlate with differential expression of genes regulating coagulation, proliferation, collagen metabolism, and the immune response. The rat jugular vein to carotid artery AVF model shows changes similar to the mouse AVF model.

Osteoporosis: Emerging targets on the classical signaling pathways of bone formation.

Osteoporosis is a multifaceted skeletal disorder characterized by reduced bone mass and structural deterioration, posing a significant public health challenge, particularly in the elderly population. Treatment strategies for osteoporosis primarily focus on inhibiting bone resorption and promoting bone formation. However, the effectiveness and limitations of current therapeutic approaches underscore the need for innovative methods. This review explores emerging molecular targets within crucial signaling pathways, including wingless/integrated (WNT), bone morphogenetic protein (BMP), hedgehog (HH), and Notch signaling pathway, to understand their roles in osteogenesis regulation. The identification of crosstalk targets between these pathways further enhances our comprehension of the intricate bone metabolism cycle. In summary, unraveling the molecular complexity of osteoporosis provides insights into potential therapeutic targets beyond conventional methods, offering a promising avenue for the development of new anabolic drugs.