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Abstract Pelton turbines functioning in sandy river environments often encounter difficulties due to the swift movement of sediment particles, leading to erosion and damage to overflow components. These challenges can result in operational instability, particularly noticeable in large turbines. Pressure pulsation is crucial for turbine stability, and alterations in overflow component profiles caused by sediment erosion can worsen pressure pulsations. This study utilizes numerical simulations to analyze turbine pressure pulsations based on surface profile changes of runner buckets after 2 and 4 years of sediment erosion in a single 500 MW large‐scale Pelton turbine. Our findings reveal that erosion leads to a gradual decrease in pressure pulsation along the bucket's splitting edge from the notch to the root. After 4 years of erosion and wear, the relative pressure pulsation amplitude in the root region increased by more than 530%. Additionally, changes occur in the thickness of the water film in the erosion area on the working surface, disrupting the flow pattern and generating more vortices. This occurrence intensifies the relative pressure pulsation amplitude and reduces bucket stability. The study findings highlight the significant impact of sediment erosion on Pelton turbine pressure pulsation, posing a considerable risk to the unit's operational stability and safety.

Abstract Tobacco smoke exposure has been demonstrated to impede bone remodeling and diminish bone density, yet research regarding its correlation with parathyroid hormone (PTH) remains limited. This study aims to investigate the relationship between tobacco smoke exposure and serum PTH levels in adults aged 20 years and older. This study included 7,641 participants from two cycles of the National Health and Nutrition Examination Survey (NHANES, United States, 2003- 2006). Reflect tobacco smoke exposure through serum cotinine levels, and use an adjusted weighted multivariate linear regression model to test the independent linear relationship between serum cotinine and PTH. Stratified analysis was conducted to validate the sensitivity of the conclusions. Smooth curve fitting and threshold effect analysis were performed to assess the non-linear relationship. After comprehensive adjustment using weighted multivariate regression analysis, a negative correlation was found between serum cotinine and PTH levels. The interaction p-values in subgroup analyses were all greater than 0.05. Moreover, smooth curve fitting indicated a non-linear relationship between serum cotinine and PTH, with a turning point observed. Our research indicates that tobacco smoke exposure is negatively correlated and independent of serum parathyroid hormone levels, indicating that long-term tobacco smoke exposure may lead to parathyroid dysfunction in adults.

Abstract Drug resistance after long‐term use of Tyrosine kinase inhibitors (TKIs) has become an obstacle for prolonging the survival time of patients with clear cell renal cell carcinoma (ccRCC). Here, genome‐wide CRISPR‐based screening to reveal that HDAC8 is involved in decreasing the sensitivity of ccRCC cells to sunitinib is applied. Mechanically, HDAC8 deacetylated ETS1 at the K245 site to promote the interaction between ETS1 and HIF‐2α and enhance the transcriptional activity of the ETS1/HIF‐2α complex. However, the antitumor effect of inhibiting HDAC8 on sensitized TKI is not very satisfactory. Subsequently, inhibition of HDAC8 increased the expression of NEK1, and up‐regulated NEK1 phosphorylated ETS1 at the T241 site to promote the interaction between ETS1 and HIF‐2α by impeded acetylation at ETS1‐K245 site is showed. Moreover, TKI treatment increased the expression of HDAC8 by inhibiting STAT3 phosphorylation in ccRCC cells is also found. These 2 findings highlight a potential mechanism of acquired resistance to TKIs and HDAC8 inhibitors in ccRCC. Finally, HDAC8‐in‐PROTACs to optimize the effects of HDAC8 inhibitors through degrading HDAC8 and overcoming the resistance of ccRCC to TKIs are synthesized. Collectively, the results revealed HDAC8 as a potential therapeutic candidate for resistance to ccRCC‐targeted therapies.

Lung cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, leading to a dysfunctional CFTR protein. Gene therapy offers promise for the treatment of lung CF. However, the development and clinical application of CF gene therapy have long been hampered by the absence of safe and highly efficient delivery vectors. In this work, a novel polymer-based gene replacement treatment approach was developed. A series of poly (β-amino esters) (PAEs) with various topological structures and chemical compositions were screened to create non-viral therapeutic systems for CFTR restoration in lung CF disease. A nanoparticle, formed by the selected highly branched PAE (HPAE) with a CpG-depleted CFTR plasmid, demonstrated CFTR gene expression and biocompatibility in lung epithelial cells, outperforming leading commercial gene transfection reagents such as Lipofectamine 3000 and Xfect. The newly developed gene therapy system successfully restored functional CFTR protein production in lung CF epithelial monolayers. This therapeutic approach holds great potential for use as an efficient and safe non-viral treatment for CF patients.

Abstract Acute asthma exacerbation refers to the progressive deterioration of asthma symptoms that is always triggered by virus infection represented by respiratory syncytial virus (RSV). After RSV infection, exaggerated Th2‐mediated pulmonary inflammation is the critical pathological response of asthmatic patients with acute exacerbation. Significantly, airway epithelial cells, being the primary targets of RSV infection, play a crucial role in controlling the pulmonary inflammatory response by releasing airway epithelial cell‐derived exosomes (AEC‐Exos), which potentially influence the development of asthma. However, the specific role of AEC‐Exos in acute asthma exacerbation after RSV infection remains obscure. The purpose of this study was to determine the distinct function of AEC‐Exos in exacerbating acute asthma following RSV infection. Blockade of exosomes by GW reduce the enhanced pulmonary inflammation significantly. Specifically, the enhanced Th2 inflammation was induced by AEC‐Exos thorough transportation of hsa‐miR‐155‐5p–Sirtuin 1 (SIRT1) pathway during acute asthma exacerbation. Targeted inhibition of hsa‐miR‐155‐5p blocks the exaggerated Th2 inflammation effectively in mice with acute asthma exacerbation. In summary, our study showed that during acute asthma exacerbation after RSV infection, AEC‐Exos promote the enhanced Th2 inflammation through transportation of increased hsa‐miR‐155‐5p, which was mediated partly through SIRT1‐mediated pathway. hsa‐miR‐155‐5p is a potential biomarker for early prediction of acute asthma exacerbation.

BackgroundFerroptosis has been proven to contribute to the progression of myocardial ischemia/reperfusion (I/R) injury and can be inhibited or promoted by ATF3. Short-chain fatty acids (SCFAs) have shown benefits in various cardiovascular diseases with anti-inflammatory and antioxidant effects. However, the impact of SCFAs on ferroptosis in ischemic-stimulated cardiomyocytes remains unknown. This study aimed to investigate the effect of SCFAs on cardiomyocyte ferroptosis, the expression of ATF3, and its potential upstream regulators.Methods and resultsThe expression of ATF3, ferroptosis pathway geneset (FPG), and geneset of potential regulators for ATF3 (GPRA, predicted by the PROMO database) was explored in the public human myocardial infarction single-cell RNA-seq (sma) dataset. Cardiomyocyte data was extracted from the dataset and re-clustered to explore the FPG, ATF3, and GPRA expression patterns in cardiomyocyte subclusters. A dose-dependent toxic experiment was run to detect the suitable dose for SCFA treatment. The erastin-induced ferroptosis model and hypoxia-reoxygenation (H/R) model (10 h of hypoxia followed by 6 h of reoxygenation) were adopted to assess the effect of SCFAs via the CCK8 assay. Gene expression was examined via RT-PCR and western blot. Ferroptosis markers, including lipid peroxides and Fe2+, were detected using the liperfluo and ferroOrange probes, respectively. In the sma dataset, upregulated ferroptosis pathway genes were mainly found in the infarction-stimulated cardiac cells (border zone and fibrotic zone), particularly the cardiomyocytes and adipocytes. The ATF3 and some of its potential transcription factors (VDR, EGR3, PAX5, and SP1) can be regulated by SCFA. SCFA can attenuate erastin-induced lipid peroxidation in cardiomyocytes. SCFA treatment can also reverse erastin-induced Fe2+ increase but may strengthen the Fe2+ in the H/R model. We also precisely defined a ferroptosis subcluster of cardiomyocytes (CM09) that highly expressed FPG, ATF3, and GPRA.ConclusionThe ATF3 and the ferroptosis pathway are elevated in cardiomyocytes of injury-related cardiac regions (border zone, ischemic zone, and fibrotic zone). SCFA can attenuate cardiomyocyte ferroptosis and regulate the expression of ATF3. Our study offers novel insights into the potential targets of SCFAs in the cardiovascular system.

ObjectiveTo examine the correlation between SIRI and the probability of cardiovascular mortality as well as all-cause mortality in individuals with chronic kidney disease.MethodsA cohort of 3,262 participants from the US National Health and Nutrition Examination Survey (NHANES) database were included in the study. We categorized participants into five groups based on the stage of chronic kidney disease. A weighted Cox regression model was applied to assess the relationship between SIRI and mortality. Subgroup analyses, Kaplan–Meier survival curves, and ROC curves were conducted. Additionally, restricted cubic spline analysis was employed to elucidate the detailed association between SIRI and hazard ratio (HR).ResultsThis study included a cohort of 3,262 individuals, of whom 1,535 were male (weighted proportion: 42%), and 2,216 were aged 60 or above (weighted proportion: 59%). Following adjustments for covariates like age, sex, race, and education, elevated SIRI remained a significant independent risk factor for cardiovascular mortality (HR=2.50, 95%CI: 1.62-3.84, p1.2 identified as an independent risk factor for cardiovascular mortality in CKD patients.ConclusionHeightened SIRI independently poses a risk for both all-cause and cardiovascular mortality in chronic kidney disease patients, with potentially heightened significance in the early stages (Stage I to Stage III) of chronic kidney disease.

Abstract The data regarding the prognosis of cutaneous Kaposi sarcoma (KS) was limited. The current study aimed to explore the risk factors and develop a predictive model for the prognosis of cutaneous KS patients. Data were extracted from Surveillance, Epidemiology, and End Results database from 2000 to 2018 and randomly divided into training and validation cohort. The Kaplan–Meier analysis, cumulative incidence function based on the competing risk model and Fine–Gray multivariable regression model was used to identify the prognostic factors and then construct a 5-, 10-, and 15-year KS-specific death (KSSD) nomogram for patients. The concordance index (C-index), area under the curve (AUC) of operating characteristics and calibration plots were used to evaluate the performance of the model. The clinical utility of the model was measured by decision curve analysis (DCA). In 2257 cutaneous KS patients identified from database, the overall median survival time was about 13 years. Radiotherapy (p = 0.013) and surgery (p

Abstract In cold regions, the freezing of pore water in rock affects the mechanical behavior of the rock. This paper studied the ice content of frozen sandstone at different temperatures and its effects on the mechanical properties of sandstone. First, the progressive freezing treatment (from 25.0 to − 30.0 °C) and in-situ nuclear magnetic resonance test were conducted to study the evolution of the ice content of sandstone with temperature. This evolution was quantitatively described by the frozen ratio defined as the percentage of the mass of ice and the total mass of water. Then, the mechanical properties of frozen sandstone at different temperatures (25.0 °C, 0.0 °C, − 5.0 °C, − 10.0 °C, − 20.0 °C and − 30.0 °C, respectively) were tested, such as P-wave velocity, uniaxial compressive strength (UCS), peak strain and elastic modulus. Finally, the effects of the frozen ratio on these properties were discussed. The results show that the pore water in sandstone shows three stages as the temperature decreases: stable liquid (from 25.0 to 0.0 °C), sharp phase transition (from 0.0 to − 2.5 °C) and slow phase transition (from − 2.5 to − 30.0 °C). Especially, the capillary and bulk water in sandstone is almost completely frozen in the sharp phase transition stage. As the temperature decreases, the frozen ratio first remains constant, then increases rapidly and finally increases slowly. Moreover, as the frozen ratio increases, the P-wave velocity, UCS and peak strain increase while the elastic modulus decreases. Interestingly, the compressive failure mode of sandstone changes from brittle to ductile as the frozen ratio increases.

Abstract Myocardial infarction (MI) is a major cause of mortality worldwide. The major limitation of regenerative therapy for MI is poor cardiac retention of therapeutics, which results from an inefficient vascular network and poor targeting ability. In this study, a two‐layer intrinsically magnetic epicardial patch (MagPatch) prepared by 3D printing with biocompatible materials like poly (glycerol sebacate) (PGS) is designed, poly (ε‐caprolactone) (PCL), and NdFeB. The two‐layer structure ensured that the MagPatch multifariously utilized the magnetic force for rapid vascular reconstruction and targeted drug delivery. MagPatch accumulates superparamagnetic iron oxide (SPION)‐labelled endothelial cells, instantly forming a ready‐implanted organization, and rapidly reconstructs a vascular network anastomosed with the host. In addition, the prefabricated vascular network within the MagPatch allowed for the efficient accumulation of SPION‐labelled therapeutics, amplifying the therapeutic effects of cardiac repair. This study defined an extendable therapeutic platform for vascularization‐based targeted drug delivery that is expected to assist in the progress of regenerative therapies in clinical applications.

Recessive dystrophic epidermolysis bullosa (RDEB) is an autosomal monogenic skin disease caused by mutations in COL7A1 gene and lack of functional type VII collagen (C7). Currently, there is no cure for RDEB, and most of the gene therapies under development have been designed as ex vivo strategies because of the shortage of efficient and safe carriers for gene delivery. Herein, we designed, synthesized, and screened a new group of highly branched poly(β amino ester)s (HPAEs) as non-viral carriers for the delivery of plasmids encoding dual single-guide RNA (sgRNA)-guided CRISPR-Cas9 machinery to delete COL7A1 exon 80 containing the c.6527dupC mutation. The selected HPAEs (named PTTA-DATOD) showed robust transfection efficiency, comparable with or surpassing that of leading commercial gene transfection reagents such as Lipofectamine 3000, Xfect, and jetPEI, while maintaining negligible cytotoxicity. Furthermore, CRISPR-Cas9 plasmids delivered by PTTA-DATOD achieved efficient targeted deletion and restored bulk C7 production in RDEB patient keratinocyte polyclones. The non-viral CRISPR-Cas9-based COL7A1 exon deletion approach developed here has great potential to be used as a topical treatment for RDEB patients with mutations in COL7A1 exon 80. Besides, this therapeutic strategy can easily be adapted for mutations in other COL7A1 exons, other epidermolysis bullosa subtypes, and other genetic diseases.

Abstract The neuroendocrine peptide somatostatin (SST) has long been thought of as influencing the deposition of the amyloid β peptide (Aβ) in Alzheimer’s disease (AD). Missing have been in vivo data in a relevant Aβ amyloidosis model. Here we crossed App NL-F/NL-F mice with Sst-deficient mice to assess if and how the presence of Sst influences pathological hallmarks of Aβ amyloidosis. We found that Sst had no influence on whole brain neprilysin transcript, protein or activity levels, an observation that cannot be accounted for by a compensatory upregulation of the Sst paralog, cortistatin (Cort), that we observed in 15-month-old Sst-deficient mice. Sst-deficiency led to a subtle but significant increase in the density of cortical Aβ amyloid plaques. Follow-on western blot analyses of whole brain extracts indicated that Sst interferes with early steps of Aβ assembly that manifest in the appearance of SDS-stable smears of 55–150 kDa in Sst null brain samples. As expected, no effect of Sst on tau steady-state levels or its phosphorylation were observed. Results from this study are easier reconciled with an emerging body of data that point toward Sst affecting Aβ amyloid plaque formation through direct interference with Aβ aggregation rather than through its effects on neprilysin expression.

AIM: To compare the differences in choroidal structure between hyperopic amblyopia and normal children of the same age by the enhanced depth imaging optical coherence tomography(EDI-OCT)technique.METHODS: There were 35 cases in 50 eyes of children with hyperopic amblyopia visiting our hospital in January 2021 to December 2021 selected in the amblyopic group, and 30 cases in 51 eyes of healthy children who matched general data in the same period were selected in the control group. EDI-OCT examination was performed to measure the choroidal thickness(CT). After image processing, the total choroidal area(TCA), luminal area(LA), stromal area(SA)and choroidal vascularity index(CVI)were obtained.RESULTS: TCA(except inferior quadrant), SA(except inferior quadrant of the outer ring), LA and CT(except inferior and temporal quadrant )in the amblyopic group of each area were significantly larger than that in the control group(P0.05). There was no significant difference in CT for all degrees of hyperopic amblyopia, with the exception of the nasal quadrant(P>0.05).CONCLUSION: Hyperopic amblyopia is accompanied with abnormal choroidal structure. As the degree of hyperopia increases, TCA, LA and SA exhibit increasing trends. The changes in choroidal structure are presumed to be related to hyperopic amblyopia.

DAPB, a new molecule including danshensu, borneol, and a mother nucleus of ACEI (Angiotensin-converting enzyme inhibitors), is being developed as an antihypertensive candidate compound. A rapid, accurate, and sensitive ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method was established and validated for the determination of DAPB in rat plasma. Chromatographic separation was performed on an Agilent SB-C18 column after protein precipitation by acetonitrile with a mobile phase consisting of acetonitrile and deionized water with 0.02% formic acid and 5 mM NH4F (v/v) at a flow rate of 0.2 mL/min. Quantification was performed using electrospray positive ionization mass spectrometry in the multiple reaction monitoring (MRM) mode. The method was linear over the range of 2–1000 ng/mL. The intra- and inter-day precision was within 12%, with accuracies less than 7%. Stability was within the acceptable limits under various storage and processing conditions. No apparent matrix effect was detected. The validated method was applied to the pre-clinical pharmacokinetic study of DAPB after oral administration of 30 mg/kg and intravenous administration of 6 mg/kg in rats.

BackgroundIPF is an undetermined, progressive lung disease. Necroptosis is a type of programmed apoptosis, which involved in the pathogenesis of lung diseases like COPD and ARDS. However, necroptosis in IPF have not been adequately studied. This study aimed to investigate the necroptosis in IPF and the relationship between necroptosis and immune infiltration, to construct a prognostic prediction model of IPF based on necroptosis-related genes.MethodsGSE110147 was downloaded from the GEO database and utilized to analyze the expression of necroptosis-related differentially expressed genes (NRDEGs). Then NRDEGs were used to construct protein-protein interaction (PPI) networks in the STRING database, and Cytoscape software was used to identify and visualize hub genes. Necroptosis-related prognosticgenes were explored in GSE70866, and a prognostic prediction model was constructed. The ImmuCellAI algorithm was utilized to analyze the landscape of immune infiltration in GSE110147. The single-cell RNA sequencing dataset GSE122960 was used to explore the association between necroptosis and type II alveolar epithelial cells (AT II) in IPF. The GSE213001 and GSE93606 were used for external validation. The expression of prognostic genes was quantified using RT-qPCRin the IPF A549 cell model, and was further verified by western blotting in the bleomycin-induced pulmonary fibrosis mouse model.ResultsIt was observed that necroptosis-related signaling pathways were abundantly enriched in IPF. 29 NRDEGs were screened, of which 12 showed consistent expression trends in GSE213001. Spearman correlation analysis showed that the expression of NRDEGs was positively correlated with the infiltration of proinflammatory immune cells, and negatively correlated with the infiltration of anti-inflammatory immune cells. NRDEGs, including MLKL, were highly expressed in AT II of fibrotic lung tissue. A necroptosis-related prediction model was constructed based on 4 NRDEGsby the cox stepwise regression. In the validation dataset GSE93606, the prognostic prediction model showed good applicability. The verification results of RT-qPCR and western blotting showed the reliability of most of the conclusions.ConclusionsThis study revealed that necroptosis existed in IPF and might occur in AT II. Necroptosis was associated with immune infiltration, suggesting that necroptosis of AT II might involve in IPF by activating immune infiltration and immune response.

In this work, spherical Al-Mg-Zr alloy with intensive heat release were characterized and compared to neat Al powders. The morphology, element distribution and thermal performance were characterized by TEM, SEM, Mapping and TG-DSC. The laser-induced ignition and combustion characteristics of Al-Mg-Zr alloy powders were performed by microscopic high-speed video-recording. The effect of Al-Mg-Zr on the combustion process of HTPB-based solid propellants were carried out as well. It was observed that, the energy release process of Al-Mg-Zr is accompanied by the phenomena of gas emission and microexplosion, which is useful for improving the combustion efficiency of the alloy and reducing the combustion product particles of solid propellants. The findings in this work validate the potential of Al-Mg-Zr as an additional fuel for high aluminum content solid propellants.

Cardiovascular diseases such as myocardial infarction (MI) are among the major causes of death worldwide. Although intramyocardial injection of hydrogels can effectively enhance the ventricular wall, this approach is limited because of its restriction to the poor vascularization in the infarcted myocardium. Here, we reported a new type of hydrogel composed of alginate (ALG) and hyaluronic acid (HA) with lyophilized platelet-rich fibrin (Ly-PRF) for releasing abundant growth factors to realize their respective functions. The results of in vitro studies demonstrated favorable mechanical property and release ability of ALG-HA with Ly-PRF. When injected into the infarcted myocardium, this composite hydrogel preserved heart function and the Ly-PRF within the hydrogel promoted angiogenesis and increased vascular density in both infarcted and border zone, which rescued the ischemic myocardium. These beneficial effects were also accompanied by macrophage polarization and regulation of myocardial fibrosis. Moreover, the autologous origin of Ly-PRF with ALG-HA hydrogel offers myriad advantages including safety profile, easiness to obtain and cost-effectiveness. Overall, this study demonstrated the versatile therapeutic effects of a novel composite hydrogel ALG-HA with Ly-PRF, which optimizes a promising vascularized substitution strategy for improving cardiac function after MI.

Abstract Lung cancer is the leading cause of cancer‐related death worldwide due to diagnosis in the advanced stage and drug resistance in the subsequent treatments. Development of novel diagnostic and therapeutic methods is urged to improve the disease outcome. Exosomes are nano‐sized vehicles which transport different types of biomolecules intercellularly, including DNA, RNA and proteins, and are implicated in cross‐talk between cells and their surrounding microenvironment. Tumor‐derived exosomes (TEXs) have been revealed to strongly influence the tumor microenvironment, antitumor immunoregulatory activities, tumor progression and metastasis. Potential of TEXs as biomarkers for lung cancer diagnosis, prognosis and treatment prediction is supported by numerous studies. Moreover, exosomes have been proposed to be promising drug carriers. Here, we review the mechanisms of exosomal formation and uptake, the functions of exosomes in carcinogenesis, and potential clinical utility of exosomes as biomarkers, tumor vaccine and drug delivery vehicles in the diagnosis and therapeutics of lung cancer.

Abstract Background Excessive autophagic activity in alveolar epithelial cells is one of the main causes of acute lung injury (ALI), but the underlying molecular mechanism has not been fully elucidated. Previous studies have shown that microRNAs (miRs) are involved in regulating autophagy in several diseases. This study aimed to determine the role of miR-223 in excessive autophagic activity in alveolar epithelial cells and the underlying mechanism to identify a novel therapeutic targets for the development of new drugs to treat acute respiratory distress syndrome (ARDS). Methods A549 cells were treated with lipopolysaccharide (LPS) to establish an ALI in vitro model. The expression of miR-223 and its role of miR-223 in regulating oxidative stress and autophagy in the LPS-treated A549 cells, were examined using RT-PCR, flow cytometry and ELISA. A luciferase reporter assay was performed to verify the interaction between miR-223 and the high-mobility group box 2 (HMGB2) protein. Results The results showed that the LPS treatment downregulated miR-223 expression in alveolar epithelial cells. We further proved that miR-223 directly targeted the 3-untranslated region of the HMGB2 gene and the downregulation of miR-223 increased HMGB2 protein level, which activated the JNK signalling pathway and thus induced oxidative stress and autophagy in LPS-treated alveolar epithelial cells. Knockdown of HMGB2 protein deactivated the JNK signalling pathway and inhibited autophagy and oxidative stress in alveolar epithelial cells. Conclusions The results of this study suggest that miR-223 regulates oxidative stress and autophagy in alveolar epithelial cells by targeting HMGB2 via the JNK signalling pathway.

Background: A new form of cell death, copper-dependent cell death (termed cuproptosis), was illustrated in a recent scientific study. However, the biological function or prognostic value of cuproptosis regulators in bladder cancer (BLCA) remains unknown.Materials and Methods: Sequencing data obtained from BLCA samples in TCGA and GEO databases were preprocessed for analysis. Biological function and immune cell infiltration levels evaluated by gene set variation analysis (GSVA) were employed to calculate enrichment scores. Iteration least absolute shrinkage and selection operator (LASSO) and COX regression model were employed to select feature genes and construct a novel cuproptosis-related (CR) score signature. The genomics of drug sensitivity in cancer (GDSC) and tumor immune dysfunction and exclusion (TIDE) analysis were used to predict the chemotherapy and immunotherapy efficacy for BLCA patients. The relative expression of the genes involved in the signature was also verified by real-time quantitative PCR (qRT-PCR) in cell lines and tissues.Results: Expression abundance and the prognostic value of cuproptosis regulators proved that cuproptosis might play a vital part in the carcinogenesis of BLCA. GSVA revealed that cuproptosis regulators might be associated with metabolism and metastasis-related pathways such as TGF-β, protein secretion, oxidative Phosphorylation, MYC targets, MTORC1, and adipogenesis pathways. CR scores could predict the prognosis and evaluate the chemotherapy and immunotherapy efficacies of BLCA. CR scores were positively correlated with EMT, MYC, MTORC1, HEDGEHOG, and E2F signaling pathways; meanwhile, they were negatively correlated with several immune cell infiltration levels such as CD8+ T cells, γδT cells, and activated dendritic cells. Several GEO datasets were used to validate the power of prognostic prediction, and a nomogram was also established for clinical use. The expressions of DDX10, RBM34, and RPL17 were significantly higher in BLCA cell lines and tissues in comparison with those in the corresponding normal controls.Conclusion: Cuproptosis might play an essential role in the progression of BLCA. CR scores could be helpful in the investigation of prognostic prediction and therapeutic efficacy and could make contributions to further studies in BLCA.

BackgroundBreast malignant adenomyoepithelioma (MAME) after breast augmentation has never been reported.Case summaryWe reported a case of a 55-year-old woman who was diagnosed with breast MAME 16 years after breast augmentation. Breast augmentation was performed on the patient with two 200 ml round textured prostheses in the subpectoral plane through axillary incisions in 2004. However, a breast ultrasound in 2020 revealed a suspicious malignant lump in the right breast, which was finally confirmed as MAME by pathology. Skin-sparing modified radical mastectomy and immediate breast reconstruction with expander implantation were performed. Subsequently, the patient received three cycles of chemotherapy with the regimen of anthracycline and cyclophosphamide. In the following nearly 2 years of follow-up, no tumor recurrence and metastasis were found, and the overall treatment was satisfactory for the patient.ConclusionHere, we present a unique case in which a patient was diagnosed with breast MAME after breast augmentation. Skin-sparing modified radical mastectomy and immediate breast reconstruction with expander implantation are feasible approaches that yield at least short-term oncological safety and acceptable aesthetic results. However, whether there is a potential relationship between MAME and breast implants remains to be further explored. Meanwhile, due to the rarity of breast MAME, more authoritative strategies considering both oncological safety and aesthetics to seek better long-term therapeutic effects are needed.

IntroductionSpinal cord injury (SCI) is a severe disease of the central nervous system with a very high disability rate that seriously affects the daily life of patients. Acupuncture is one of the rehabilitation therapies that has shown significant efficacy in treating post-SCI complications such as motor disorders, neuropathic pain, and neurogenic bladder. Current studies have focused on the effectiveness and mechanisms of acupuncture for SCI, but no studies are available to analyze the bibliometrics of publications related to this area.MethodsPublications related to acupuncture for SCI were retrieved from the Web of Science Core Collection for quantitative and qualitative analyses. The quantitative analysis was unfolded in the following six main areas: annual publications, countries, institutions, authors, sources, and keywords. The qualitative analysis section screened out publications with high annual citation rates and categorized them according to the study content.ResultsThere were 213 relevant publications, more than half of which were journal articles. The number of publications showed a fluctuating upward trend. China and the United States were hub countries for related publications and had extensive cooperation with other countries. The most relevant author was Yuanshan Zeng from Sun Yat-sen University, China. The efficacy and mechanism of acupuncture for neuropathic pain after SCI was the first research hotspot in this field, and electroacupuncture was the most widely used technique. In the past 5 years, the mechanism of acupuncture to improve the local microenvironment of SCI and promote nerve regeneration had become a new research trend. At the same time, acupuncture had been gradually applied to various complications after SCI and in veterinary medicine.ConclusionThe findings suggest that research on acupuncture for SCI is still flourishing, and more research on electroacupuncture for promoting nerve repair and regeneration after SCI will be available in the future.

Hypertension is the main risk factor of cardiovascular and cerebrovascular diseases. In this paper, a novel compound known as 221s (2,9), which includes tanshinol, borneol and a mother nucleus of ACEI, was synthesized by condensation esterification, deprotection, amidation, deprotection, and amidation, with borneol as the initial raw material, using the strategy of combinatorial molecular chemistry. The structure of the compound was confirmed by 1H NMR, 13C NMR, and high-resolution mass spectrometry, with a purity of more than 99.5%. The compound 221s (2,9) can significantly reduce the systolic and diastolic blood pressure of SHR rats by about 50 mmHg and 35 mmHg after 4 weeks of administration. The antihypertensive effect of 221s (2,9) is equivalent to that of captopril. The use of 221s (2,9) can reduce the content of Ren, Ang II and ACE in the serum of SHR rats, inhibit the RAAS and enhance the vascular endothelial function by upregulating the level of NO. Pathological studies in this area have shown that high dosage of 221s (2,9) can notably protect myocardial fibrosis in rats and reduce the degeneration and necrosis of myocardial fibers, inflammatory cell infiltration, and proliferation of fibrous tissue in the heart of rat. Therefore, the existing work provided a foundation for preclinical research and follow-up clinical research of 221s (2,9) as a new drug.

The unique properties of self-healing materials hold great potential in the field of biomedical engineering. Here, the authors designed a series of biodegradable and biocompatible self-healing elastomers with tunable mechanical properties, and apply them to various disease models in vivo, including aortic aneurism, bone fracture and nerve amputation.

BackgroundOvertreatment of papillary thyroid microcarcinoma (PTMC) has become a common concern. This study aimed to compare clinicopathological features between PTMC and papillary thyroid carcinoma (PTC) and to explore whether surgery can confer significant survival benefits in all patients with PTC or PTMC.MethodsData of 145,951 patients with PTC registered in Surveillance, Epidemiology, and End Results (SEER) database and 8,751 patients with PTC in our institution were retrospectively collected. Patients with tumors less than 10 mm in diameter were classified as PTMC cohort and the rest as PTC cohort. Clinicopathological features between PTMC and PTC were compared on the basis of SEER cohort and validated with institutional data. Survival analysis was conducted to explore the effect of surgery on the prognosis of patients. To minimize potential confounders and selection bias, we performed propensity score matching (PSM) analysis to match more comparable cohorts.ResultsCompared with PTC, PTMC exhibited the following characteristics: more common in women and whites, older age at diagnosis, lower proportion of follicular variants, intraglandular dissemination, extraglandular and capsular invasion, higher proportion of multifocality, fewer lymph node and distant metastases, and higher cancer-specific survival (CSS) and overall survival (OS) (all p-value < 0.05). Regarding treatment, patients with PTMC received a lower proportion of radiotherapy, chemotherapy, and total thyroidectomy but a higher proportion of lobectomy and/or isthmectomy. There was no significant difference in CSS for patients with PTMC at stage T1N0M0 with or without surgery (P = 0.36).ConclusionGenerally, PTMC showed higher biological indolence than PTC, which meant a higher survival rate for patients in both OS and CSS. For patients with PTMC at staged T1N0M0, active surveillance (AS) may be a potentially feasible management strategy. However, the maintenance of good medical compliance and the management of psychological burden cannot be ignored for patients included in AS.

BackgroundPathological complete response (pCR) is considered a surrogate for favorable survival in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NACT), which is the goal of NACT. This study aimed to develop and validate a nomogram for predicting the pCR probability of BC patients after NACT based on the clinicopathological features.MethodsA retrospective analysis of 527 BC patients treated with NACT between January 2018 and December 2021 from two institutions was conducted. Univariate and multivariate logistic regression analyses were performed to select the most useful predictors from the training cohort (n = 225), and then a nomogram model was developed. The performance of the nomogram was evaluated with respect to its discrimination, calibration, and clinical usefulness. Internal validation and external validation were performed in an independent validation cohort of 96 and 205 consecutive BC patients, respectively.ResultsAmong the 18 clinicopathological features, five variables were selected to develop the prediction model, including age, American Joint Committee on Cancer (AJCC) T stage, Ki67 index before NACT, human epidermal growth factor receptor 2 (HER2), and hormone receptor (HR) status. The model showed good discrimination with an area under the receiver operating characteristic curve (AUC) of 0.825 (95% CI, 0.772 to 0.878) in the training cohort, and 0.755 (95% CI, 0.658 to 0.851) and 0.79 (95% CI, 0.724 to 0.856) in the internal and external validation cohorts, respectively. The calibration curve presented good agreement between prediction by nomogram and actual observation, and decision curve analysis (DCA) indicated that the nomogram had good net benefits in clinical scenarios.ConclusionThis study constructed a validated nomogram based on age, AJCC T stage, Ki67 index before NACT, HER2, and HR status, which could be non-invasively applied to personalize the prediction of pCR in BC patients treated with NACT.

Abstract Fibrotic diseases remain a substantial health burden with few therapeutic approaches. A hallmark of fibrosis is the aberrant activation and accumulation of myofibroblasts, which is caused by excessive profibrotic cytokines. Conventional anticytokine therapies fail to undergo clinical trials, as simply blocking a single or several antifibrotic cytokines cannot abrogate the profibrotic microenvironment. Here, biomimetic nanoparticles based on autologous skin fibroblasts are customized as decoys to neutralize multiple fibroblast‐targeted cytokines. By fusing the skin fibroblast membrane onto poly(lactic‐co‐glycolic) acid cores, these nanoparticles, termed fibroblast membrane‐camouflaged nanoparticles (FNPs), are shown to effectively scavenge various profibrotic cytokines, including transforming growth factor‐β, interleukin (IL)‐11, IL‐13, and IL‐17, thereby modulating the profibrotic microenvironment. FNPs are sequentially prepared into multiple formulations for different administration routines. As a proof‐of‐concept, in three independent animal models with various organ fibrosis (lung fibrosis, liver fibrosis, and heart fibrosis), FNPs effectively reduce the accumulation of myofibroblasts, and the formation of fibrotic tissue, concomitantly restoring organ function and indicating that FNPs are a potential broad‐spectrum therapy for fibrosis management.

DNA damage response (DDR) pathways play a crucial role in lung cancer. In this retrospective analysis, we aimed to develop a prognostic model and molecular subtype based on the expression profiles of DDR-related genes in early-stage lung adenocarcinoma (LUAD). A total of 1,785 lung adenocarcinoma samples from one RNA-seq dataset of The Cancer Genome Atlas (TCGA) and six microarray datasets of Gene Expression Omnibus (GEO) were included in the analysis. In the TCGA dataset, a DNA damage response gene (DRG)–based signature consisting of 16 genes was constructed to predict the clinical outcomes of LUAD patients. Patients in the low-DRG score group had better outcomes and lower genomic instability. Then, the same 16 genes were used to develop DRG-based molecular subtypes in the TCGA dataset to stratify early-stage LUAD into two subtypes (DRG1 and DRG2) which had significant differences in clinical outcomes. The Kappa test showed good consistency between molecular subtype and DRG (K = 0.61, p < 0.001). The DRG subtypes were significantly associated with prognosis in the six GEO datasets (pooled estimates of hazard ratio, OS: 0.48 (0.41–0.57), p < 0.01; DFS: 0.50 (0.41–0.62), p < 0.01). Furthermore, patients in the DRG2 group benefited more from adjuvant therapy than standard-of-care, which was not observed in the DRG1 group. In summary, we constructed a DRG-based molecular subtype that had the potential to predict the prognosis of early-stage LUAD and guide the selection of adjuvant therapy for early-stage LUAD patients.

Abstract Background In the long-term use of multiple medications for elderly patients diagnosed with chronic diseases, medication problems are prominent, which seriously reduces their quality of life. The burden of medications of patients critically affects their medication beliefs, behaviors and disease outcomes. It may be a solution to stress the burden of medications of patients. Its medication issues develops a novel perspective. The present study aimed to exploit the Chinese version of Living with Medicines Questionnaire-3(C-LMQ-3) to quantify the medicines burden of elderly patients diagnosed with chronic diseases in China, and evaluate the relevant demographic characteristics of sub-populations with high medicines burden. Methods The survey was distributed to elderly patients aged ≥ 60 years with chronic disease by using ≥ 5 medicines, C-LMQ-3 scores and domain scores were compared by the characteristics of elderly patients by employing descriptive statistics and performing statistical tests. Results On the whole, 430 responses were analyzed, and the participants were aged between 60 and 91 years, with the average age of 73.57 years (SD: 7.87). Most of the responses were female (61.7 %) with middle school education (38.5 %). Moreover, 54.1 % of the participants lived with spouse only, 16.2 % had both spouse and children, and 10.0 % lived alone. As indicated from regression analysis, higher C-LMQ-3 scores were associated with those who were with low education level, 60–69 years-old, using ≥ 11 medicines, using medicines ≥ 3 times a day, income per month (RMB) ≤ 3000, and who having higher monthly self-paid medication (RMB) ≥ 300 (p

The problem of vision-based fixed-wing UAV formation control under communication limitations and the presence of measurement errors was investigated. In the first part of this paper, the single UAV motion model and the process of estimating the neighboring UAV states using the Extended Kalman Filter are introduced. The second part describes how we designed a sliding mode controller considering the sensor measurement errors and discusses the sufficient conditions for the stability and formation system in the presence of state transfer time delays in the formation. The main motivation of this paper was to develop a hierarchical, globally stable sliding mode controller that could enable the considered vision-based multiple fixed-wing UAVs to achieve and maintain formation in the presence of measurement errors. To this end, the selected problem was first transformed into a state-tracking problem for UAVs in the neighborhood, and then the stability criterion was established using the Lyapunov stability theory. Finally, the effectiveness of the proposed control method was illustrated using three numerical arithmetic examples.

Highly branched poly(β-amino ester) (HPAE) has become one of the most promising non-viral gene delivery vector candidates. When compared to other gene delivery vectors, HPAE has a broad molecular weight distribution (MWD). Despite significant efforts to optimize HPAE targeting enhanced gene delivery, the effect of different molecular weight (MW) components on transfection has rarely been studied. In this work, a new structural optimization strategy was proposed targeting enhanced HPAE gene transfection. A series of HPAE with different MW components was obtained through a stepwise precipitation approach and applied to plasmid DNA delivery. It was demonstrated that the removal of small MW components from the original HPAE structure could significantly enhance its transfection performance (e.g., GFP expression increased 7 folds at w/w of 10/1). The universality of this strategy was proven by extending it to varying HPAE systems with different MWs and different branching degrees, where the transfection performance exhibited an even magnitude enhancement after removing small MW portions. This work opened a new avenue for developing high-efficiency HPAE gene delivery vectors and provided new insights into the understanding of the HPAE structure–property relationship, which would facilitate the translation of HPAEs in gene therapy clinical applications.

ObjectiveTo further supplement the previous research on the relationship between neutrophil–lymphocyte ratio (NLR) and all-cause and cardiovascular mortality, and construct clinical models to predict mortality.MethodsA total number of 2,827 observers were included from the National Health and Nutrition Examination Survey (NHANES) database in our research. NLR was calculated from complete blood count. According to the quartile of baseline NLR, those observers were divided into four groups. A multivariate weighted Cox regression model was used to analyze the association of NLR with mortality. We constructed simple clinical prognosis models by nomograms. Kaplan–Meier survival curves were used to depict cause-specific mortality. Restricted cubic spline regression was used to make explicit relationships between NLR and mortality.ResultsThis study recruited 2,827 subjects aged ≥ 18 years from 2005 to 2014. The average age of these observers was 51.55 ± 17.62, and 57.69% were male. NLR is still an independent predictor, adjusted for age, gender, race, drinking, smoking, dyslipidemia, and other laboratory covariates. The area under the receiver operating characteristic curves (AUCs) of NLR for predicting all-cause mortality and cardiovascular mortality were 0.632(95% CI [0599, 0.664]) and 0.653(95% CI [0.581, 0.725]), respectively, which were superior to C-reactive protein (AUCs: 0.609 and 0.533) and WBC (AUCs: 0.522 and 0.513). The calibration and discrimination of the nomograms were validated by calibration plots and concordance index (C-index), and the C-indexes (95% CIs) of nomograms for all-cause and cardiovascular mortality were 0.839[0.819,0.859] and 0.877[0.844,0.910], respectively. The restricted cubic spline showed a non-linear relationship between NLR and mortality. NLR > 2.053 might be a risk factor for mortality.ConclusionThere is a non-linear relationship between NLR and mortality. NLR is an independent factor related to mortality, and NLR > 2.053 will be a risk factor for prognosis. NLR and nomogram should be promoted to medical use for practicality and convenience.

BackgroundUrinary retention is one of the most frequent complications of spinal cord injuries (SCI) and negatively impacts patient satisfaction and quality of life. Acupuncture as an integral part of traditional Chinese medicine (TCM) has recently drawn widespread attention for its potential in the management of urinary retention. However, there are many different styles of acupuncture-related techniques, and the optimal choice of acupuncture for urinary retention after SCI is still unclear. Hence, this study uses a Bayesian network meta-analysis (NMA) to compare the efficacy of different types of acupuncture therapies using both direct and indirect evidence.MethodsRandomized controlled trials of acupuncture-related techniques for treating urinary retention after SCI were retrieved from the following electronic databases: Pubmed, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), the Chinese Biomedical Literature Service System (SinoMed), the Wan-Fang database, and the Chinese Scientific Journals Database (VIP). The retrieval time was from inception to November 2020. Clinical effective rate (CER) was the primary outcome indicator and residual urine volume (RUV) was the secondary outcome indicator. A Bayesian NMA was performed using the Markov chain Monte Carlo method in R software (version 3.6.1) interfacing with JAGS software (version 4.3.0). The node-splitting method was used to identify inconsistencies. In addition, a comparative adjusted funnel plot was used to assess publication bias.ResultsA total of 26 randomized controlled trials involving 1,652 patients were included. Bayesian NMA showed that electroacupuncture combined with moxibustion ranks first in both CER and RUV. In addition, in terms of cumulative probability, electro-acupuncture combined with moxibustion ranked first in CER. The results of the node splitting method revealed that direct and indirect evidence were consistent (P > 0.05). In addition, publication bias was detected.ConclusionA Bayesian NMA that combined direct and indirect comparisons showed that electro-acupuncture combined with moxibustion had a better effect on urinary retention due to SCI. However, it still needs a large sample size and high-quality randomized controlled trials to verify this finding.Systematic Review Registration:https://inplasy.com/, identifier: INPLASY2021110005.

BackgroundParathyroid carcinoma (PC) is a rare but often lethal malignancy for which staging system, prognostic indicators, and treatment guidelines are still not established. We aimed to explore the prognostic parameters and construct a nomogram for cancer-specific survival (CSS) of PC.MethodsA retrospective analysis of 604 PC patients in the SEER database from 2001 through 2018 was performed. All the cases were randomly assigned to the training cohort (n = 424) or the validation cohort (n = 180) at a ratio of 7:3. The Kaplan–Meier method and Cox regression model were applied to estimate the CSS and risk factors, and a nomogram was constructed. The predictive accuracy and discriminative ability of the nomogram in CSS were assessed by concordance index (C-index), the area under the curve (AUC) of receiver operating characteristics (ROC), and the calibration curve.ResultsAge at diagnosis > 70 years [hazard ratio (HR): 3.55, 95% CI: 1.07–11.78, p = 0.039] and tumor size > 35 mm (HR 4.22, 95% CI: 1.67–10.68, p = 0.002) were associated with worse CSS. Compared with distant metastasis, localized (HR 0.17, 95% CI: 0.06–0.47, p = 0.001) and regional lesions (HR 0.22, 95% CI: 0.07–0.66, p = 0.007) showed an improved CSS rate. Parathyroidectomy was the recommended treatment (p = 0.02). The C-index of the nomogram was 0.826, and the AUC for 5-, 10-, and 15-year CSS was 83.7%, 79.7%, and 80.7%, respectively. The calibration curve presented good agreement between prediction by nomogram and actual observation.ConclusionAge at diagnosis > 70 years, tumor size > 35 mm, and distant metastasis were independent risk factors for PC-specific mortality. Parathyroidectomy was currently the most recommended treatment for PC. This nomogram provided individualized assessment and reliable prognostic prediction for patients with PC.

This study uses Internet of Things technology to build a smart system for ideological and political education in order to remove several flaws in present ideological and political teaching. Furthermore, to achieve intelligent monitoring of the ideological and political classroom, this research uses a technique based on IGHT edge feature matching and the ideological and political classroom monitoring image monitoring calculation formula to compute the image light reflection angle. In addition, this paper adopts the method of adaptively obtaining segmentation threshold (OTSU algorithm) to binarize the differenced image. After constructing the smart teaching system, this paper conducts a systematic evaluation based on the simulation experiment. The research results show that the ideological and political teaching system based on the Internet of Things technology proposed in this paper has a good simulation teaching effect, and the system can be used in the follow-up ideological and political teaching to improve the teaching effect.

It is widely anticipated that a reduction of brain levels of the cellular prion protein (PrPC) can prolong survival in a group of neurodegenerative diseases known as prion diseases. To date, efforts to decrease steady-state PrPC levels by targeting this protein directly with small molecule drug-like compounds have largely been unsuccessful. Recently, we reported Na,K-ATPases to reside in immediate proximity to PrPC in the brain, unlocking an opportunity for an indirect PrPC targeting approach that capitalizes on the availability of potent cardiac glycosides (CGs). Here, we report that exposure of human co-cultures of neurons and astrocytes to non-toxic nanomolar levels of CGs causes profound reductions in PrPC levels. The mechanism of action underpinning this outcome relies primarily on a subset of CGs engaging the ATP1A1 isoform, one of three α subunits of Na,K-ATPases expressed in brain cells. Upon CG docking to ATP1A1, the ligand receptor complex, and PrPC along with it, is internalized by the cell. Subsequently, PrPC is channeled to the lysosomal compartment where it is digested in a manner that can be rescued by silencing the cysteine protease cathepsin B. These data signify that the repurposing of CGs may be beneficial for the treatment of prion disorders.

Stroke is one of the leading causes of death and disability worldwide. Evidence shows that ischemic stroke (IS) accounts for nearly 80 percent of all strokes and that the etiology, risk factors, and prognosis of this disease differ by gender. Female patients may bear a greater burden than male patients. The immune system may play an important role in the pathophysiology of females with IS. Therefore, it is critical to investigate the key biomarkers and immune infiltration of female IS patients to develop effective treatment methods. Herein, we used weighted gene co-expression network analysis (WGCNA) to determine the key modules and core genes in female IS patients using the GSE22255, GSE37587, and GSE16561 datasets from the GEO database. Subsequently, we performed functional enrichment analysis and built a protein-protein interaction (PPI) network. Ten genes were selected as the true central genes for further investigation. After that, we explored the specific molecular and biological functions of these hub genes to gain a better understanding of the underlying pathogenesis of female IS patients. Moreover, the “Cell type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT)” was used to examine the distribution pattern of immune subtypes in female patients with IS and normal controls, revealing a new potential target for clinical treatment of the disease.

As a comprehensive analysis of all metabolites in a biological system, metabolomics is being widely applied in various clinical/health areas for disease prediction, diagnosis, and prognosis. However, challenges remain in dealing with the metabolomic complexity, massive data, metabolite identification, intra- and inter-individual variation, and reproducibility, which largely limit its widespread implementation. This study provided a comprehensive workflow for clinical metabolomics, including sample collection and preparation, mass spectrometry (MS) data acquisition, and data processing and analysis. Sample collection from multiple clinical sites was strictly carried out with standardized operation procedures (SOP). During data acquisition, three types of quality control (QC) samples were set for respective MS platforms (GC-MS, LC-MS polar, and LC-MS lipid) to assess the MS performance, facilitate metabolite identification, and eliminate contamination. Compounds annotation and identification were implemented with commercial software and in-house-developed PAppLineTM and UlibMS library. The batch effects were removed using a deep learning model method (NormAE). Potential biomarkers identification was performed with tree-based modeling algorithms including random forest, AdaBoost, and XGBoost. The modeling performance was evaluated using the F1 score based on a 10-times repeated trial for each. Finally, a sub-cohort case study validated the reliability of the entire workflow.

Many polymeric gene delivery nano-vectors with hyperbranched structures have been demonstrated to be superior to their linear counterparts. The higher delivery efficacy is commonly attributed to the abundant terminal groups of branched polymers, which play critical roles in cargo entrapment, material-cell interaction, and endosome escape. Hyperbranched poly(β-amino ester)s (HPAEs) have developed as a class of safe and efficient gene delivery vectors. Although numerous research has been conducted to optimise the HPAE structure for gene delivery, the effect of the secondary amine residue on its backbone monomer, which is considered the non-ideal termination, has never been optimised. In this work, the effect of the non-ideal termination was carefully evaluated. Moreover, a series of HPAEs with only ideal terminations were synthesised by adjusting the backbone synthesis strategy to further explore the merits of hyperbranched structures. The HPAE obtained from modified synthesis methods exhibited more than twice the amounts of the ideal terminal groups compared to the conventional ones, determined by NMR. Their transfection performance enhanced significantly, where the optimal HPAE candidates developed in this study outperformed leading commercial benchmarks for DNA delivery, including Lipofectamine 3000, jetPEI, and jetOPTIMUS.

Summary: Solar heat storage technology is urgently needed to harness intermittent solar energy to directly drive widespread heat-related applications. However, achieving high-efficiency solar heat storage remains elusive due to the loss of heat to the surroundings, especially through radiative processes. Here, we present a bioinspired light-adaptive shutter (LAS) with a multi-layer architecture that autonomously switches between open and closed states according to solar illumination fluctuations because of a photothermal-expansion mismatch effect. As a result, in a LAS-integrated solar heat storage system, the LAS governs the incident and dissipated radiation, suppresses the radiative heat dissipation by 20 times, and achieves high-efficiency solar heat storage with a near-zero net radiative heat dissipation. Furthermore, a LAS is demonstrated to enhance the temperature by >20°C in a 3-day field test. Given excellent responsiveness, scalable manufacturing, and feasibility under wide operating conditions, the LAS provides a promising radiation management strategy for high-efficiency solar heat storage.

Abstract Aims Galectin‐3 (Gal‐3) is implicated in the pathogenesis of heart failure and is also influenced by ageing. This study aims to determine the extent to which Gal‐3 levels estimate odds of myocardial dysfunction in ageing cohorts, ‘upstream’ prior to clinical disease. Methods and results Four hundred seventy‐five asymptomatic subjects underwent simultaneous assessments of cardiovascular structure and function, with measurements of circulating Gal‐3. Myocardial dysfunction was defined as impaired myocardial relaxation (ratio of peak velocity flow in early diastole E (m/s) to peak velocity flow in late diastole by atrial contraction A (m/s)

Piperine amino acid derivatives containing phenolic hydroxyl groups were synthesized using piperine as the raw material by amide hydrolysis, amidation, ester hydrolysis, and deacetalization. The obtained products were characterized by mass spectrometry and nuclear magnetic resonance. The antioxidant activity of the piperine derivatives was evaluated by the DPPH and ABTS scavenging rates and the total antioxidant capacity. The results showed that the piperine amino acid (4a–4d) had relatively weak radical-scavenging ability, while the piperine amino acid derivatives (5a–5d) containing phenolic hydroxyl groups had significant radical-scavenging effects. In addition, the total reducing ability of 5a–5d was better than that of piperine. The study also found that piperine derivatives containing phenolic hydroxyl groups played an important role in inhibiting oxidative damage in DNA and erythrocytes.

Piperine was used in this study in its raw form, and different steps, such as amide hydrolysis and amidation, were used to synthesize piperine derivatives containing a phenolic hydroxyl group. DPPH and ABTS free radical scavenging assays were used to assess piperine derivative antioxidant activities. We constructed an AAPH oxidative stress erythrocyte model to study the effect of piperine derivatives on the hemolysis rate of oxidatively damaged erythrocytes as well as the hemoglobin oxidation rate. This AAPH model was also used to determine piperine derivative effects on antioxidant enzyme activity and malondialdehyde (MDA) content. Results showed that spectroscopic methods could synthesize and identify piperine derivatives containing phenolic hydroxyl groups (H-1∼H-3). Moreover, DPPH and ABTS assay results showed that piperine derivative free radical clearance rates were higher compared with the parent compound. Additionally, piperine derivatives (H-1∼H-3) were found to provide protection to AAPH oxidatively damaged erythrocytes in their ability to inhibit AAPH-induced erythrocyte lysis, while hemoglobin oxidation was higher compared with the parent compound. Piperine derivatives may protect intracellular glutathione peroxidase (GSH-Px) antioxidant enzyme system activities, safeguarding against oxidative damage. This study synthesized novel piperine derivatives for use as potential antioxidant agent candidates.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare autosomal inherited skin disorder caused by mutations in the COL7A1 gene that encodes type VII collagen (C7). The development of an efficient gene replacement strategy for RDEB is mainly hindered by the lack of vectors able to encapsulate and transfect the large cDNA size of this gene. To address this problem, our group has opted to use polymeric-based non-viral delivery systems and minicircle DNA. With this approach, safety is improved by avoiding the usage of viruses, the absence of bacterial backbone, and the replacement of the control viral cytomegalovirus (CMV) promoter of the gene with human promoters. All the promoters showed impressive C7 expression in RDEB skin cells, with eukaryotic translation elongation factor 1 α (EF1α) promoter producing higher C7 expression levels than CMV following minicircle induction, and COL7A1 tissue-specific promoter (C7P) generating C7 levels similar to normal human epidermal keratinocytes. The improved system developed here has a high potential for use as a non-viral topical treatment to restore C7 in RDEB patients efficiently and safely, and to be adapted to other genetic conditions.

Objective(s): The main objective of this study was to investigate the variations of β-endorphin (β-EP), vasoactive intestinal peptide (VIP), serotonin (5-HT) and norepinephrine (NE) of immune thrombocytopenia (ITP) mice as well as the regulatory mechanism of prednison. Materials and Methods: Sixty BALB/c mice were randomly divided into control group, model group and prednison intervention group. ITP mice model was duplicated by injecting with glycoprotein-antiplatelet serum (GP-APS) except in control group. After ITP disease model was successful established, prednison was used in prednison intervention group. The β-EP, VIP, 5-HT and NE contents of ITP mice were detected by enzyme linked immunosorbent assay (ELISA). Results:Compared with the values in control group, the detection values of VIP and 5-HT in model group declined, while the detection values of β-EP and NE increased. Compared with prednison intervention group, the detection values of VIP and 5-HT in model group increased, while the detection values of β-EP and NE showed no significant change. Conclusion: In this study, the β-EP, VIP, 5-HT and NE contents in ITP mice injected with GP-APS were changed by prednison. It shows that prednison as the first-line therapy for ITP with effective hemostasis function is likely to increasing the contents of VIP and 5-HT. These results suggest the therapeutic value of prednison for the treatment of ITP.

Research on language change has been complicated and hindered by the problem of obtaining quality data. In many cases, the large volume of time required to collect recorded speech at different intervals, as necessary in lifespan studies, is prohibitive. Researchers further risk having participants drop out, leading to a limited pool of data. One way to avoid this is to use recordings available in the public domain that have been recorded for other purposes. The BBC broadcaster Sir David Attenborough is one of the few people who have had occasion to be recorded regularly over a great span of their lives. In this study, a selection of clips from wildlife documentaries that he has narrated furnishes the data for a glimpse into the possibilities of language change in adulthood. Received Pronunciation, the accent that Attenborough commands, is in the spotlight in this study. Two features of speech, namely, the presence and degree of t-glottalisation and the TRAP/STRUT vowel distinction, are examined in Attenborough’s speech against a background of known changes in the general usage of Received Pronunciation. The aim of the study is thus to see if language change occurs within the speech of an adult individual, particularly one whose speech is almost iconic. His narration from the 1960s is compared with narrations from the 1980s and 2000s in a dataset spanning nearly 60 years with the aim of discerning any trajectories of change. Some patterns in his formant values for several vowels across the three year groups are also discussed to provide an idea of what sort of changes can occur in the course of nearly 60 years. The study ultimately finds limited change in level of t-glottaling and only a slight movement of his TRAP/STRUT vowels towards each other between the narrations of the 1960s and the 1980s, with no perceptible change thereafter. The changes in community use of Received Pronunciation seem to affect him little. In terms of the overall vowel space, the trend seems to be towards a centering of most of the vowels, particularly the front vowels. Some plausible explanations for the limited amount of change are discussed in the article, which include Attenborough being seen as a steward of the accent as well as its utility to him in his position as a renowned broadcaster. The article also brings up the need for more research into the interface of gerontology and sociolinguistics, as the quite pronounced centering of the vowels may suggest natural age-related pronunciation effects.

Ageing-related alterations in cardiovascular structure and function are commonly associated with chronic inflammation. A potential blood-based biomarker indicative of a chronic inflammatory state is N-Terminal Pro C-Type Natriuretic Peptide (NTproCNP). We aim to investigate associations between NTproCNP and ageing-related impairments in cardiovascular function. Community-based participants underwent same-day assessment of cardiovascular function and circulating profiles of plasma NTproCNP. Associations between cardiovascular and biomarker profiles were studied in adjusted models including standard covariates. We studied 93 participants (mean age 73 ± 5.3 years, 36 women), of whom 55 (59%) had impaired myocardial relaxation (ratio of peak velocity flow in early diastole E (m/s) to peak velocity flow in late diastole by atrial contraction A (m/s)