Discovery of Orally Active Phenylquinoline-Based Soluble Epoxide Hydrolase Inhibitors with Anti-Inflammatory and Analgesic Activity.

Currently, there are no specific drugs for treating acute pancreatitis. Soluble epoxide hydrolase (sEH) inhibitors show promise, but face challenges like low blood drug concentrations and potential adverse effects on CYP enzymes and the human ether-a-go-go-related gene (hERG). In this study, an approach involving scaffold hopping and structure-activity guided optimization was employed to design a series of phenylquinoline-based sEH inhibitors. Among these compounds, DJ-53 exhibited potent in vitro and in vivo effects in alleviating pain and reducing inflammation. The in vivo mechanism of action involved inhibiting sEH enzyme activity, thereby increasing levels of anti-inflammatory epoxyeicosatrienoic acids (EETs) and decreasing levels of proinflammatory dihydroxyeicosatrienoic acids (DHETs). Importantly, DJ-53 showed exceptional oral bioavailability and pharmacokinetics, while avoiding inhibition of CYP enzymes or the hERG channel. These results highlight DJ-53's potential as a new lead compound for anti-inflammatory and analgesic applications and provide a safe and effective scaffold for developing sEH inhibitors.

Machine learning-based phenogroups and prediction model in patients with functional gastrointestinal disorders to reveal distinct disease subsets associated with gas production.

Background and Objectives: Symptom-based subtyping for functional gastrointestinal disorders (FGIDs) has limited value in identifying underlying mechanisms and guiding therapeutic strategies. Small intestinal dysbiosis is implicated in the development of FGIDs. We tested if machine learning (ML) algorithms utilizing both gastrointestinal (GI) symptom characteristics and lactulose breath tests could provide distinct clusters. Materials and Methods: This was a prospective cohort study. We performed lactulose hydrogen methane breath tests and hydrogen sulfide breath tests in 508 patients with GI symptoms. An unsupervised ML algorithm was used to categorize subjects by integrating GI symptoms and breath gas characteristics. Generalized Estimating Equation (GEE) models were used to examine the longitudinal associations between cluster patterns and breath gas time profiles. An ML-based prediction model for identifying excessive gas production in FGIDs patients was developed and internal validation was performed. Results: FGIDs were confirmed in 300 patients. K-means clustering identified 4 distinct clusters. Cluster 2, 3, and 4 showed enrichments for abdominal distention and diarrhea with a high proportion of excessive gas production, whereas Cluster 1 was characterized by moderate lower abdominal discomforts with the most psychological complaints and the lowest proportion of excessive gas production. GEE models showed that breath gas concentrations varied among different clusters over time. We further sought to develop an ML-based prediction model to determine excessive gas production. The model exhibited good predictive capabilities. Conclusion: ML-based phenogroups and prediction model approaches could provide distinct FGIDs subsets and efficiently determine FGIDs subsets with greater gas production, thereby facilitating clinical decision-making and guiding treatment.

High internal phase emulsion stabilized by soy protein isolate-Rutin complex: Rheological properties, bioaccessibility and in vitro release kinetics.

High internal phase emulsions (HIPEs) are promising carrier materials for encapsulating and delivering hydrophobic bioactive compounds. By strategically adjusting the composition, particle size, or charge of HIPEs, it is possible to enhance both their stability and the bioaccessibility of hydrophobic polyphenols encapsulated within them. In this study, different soy protein isolate (SPI)-rutin (SPI-R) complexes (formed under various preheating temperatures) were used to stabilize HIPEs, while the particle size, and charge of HIPEs was further adjusted through different homogenization rates. The results demonstrated that an optimal preheating temperature of 70 °C for the complex and a homogenization rate of 15,000 rpm for HIPEs enhanced the stability of the entire emulsion system by producing more uniform and smaller droplet distribution with improved rheological properties. Furthermore, in vitro digestion experiments showed that HIPEs stabilized by the SPI-R complexes (HSR) at optimal homogenization rate had better loading efficiency (98.68 %) and bioaccessibility compared to other groups. Additionally, fitting results from release kinetics confirmed that rutin encapsulated by HSR could achieve sustained release effect. Overall, these findings suggest that HSR has great potential as an effective vehicle for delivering hydrophobic bioactive compounds like rutin within the food industry.

Etamsylate-loaded hydrogel composed of carboxymethyl chitosan and oxidized tannic acid for improved wound healing.

Proper wound dressing is essential to facilitate skin wound healing, stop bleeding, and prevent infections. Herein, carboxymethyl chitosan (CMC) was crosslinked with oxidized tannic acid (OTA) to form an adhesive and self-healing OTA/CMC hydrogel, and etamsylate was loaded to enhance the hemostatic effect of the hydrogel dressing. The resultant OTA/CMC/E hydrogel exhibited a spectrum of noteworthy attributes including excellent cell compatibility, high antioxidant activity, effective anti-bacterium, and excellent hemorrhage control. Functionally, it mitigated intracellular ROS levels, hindered the proliferation of Staphylococcus aureus, while also significantly reducing hemostasis duration and total blood loss. In vivo full-thickness skin incision results showed that the OTA/CMC/E hydrogel could efficiently accelerate in vivo wound closure and healing, promising as an advanced wound healing material.

Mitochondria-related HSDL2 is a potential biomarker in temporal lobe epilepsy by modulating astrocytic lipid metabolism.

Temporal lobe epilepsy (TLE) is the most prevalent type of focal epilepsy in adults. While comprehensive bioinformatics analyses have facilitated the identification of novel biomarkers in animal models, similar efforts are limited for TLE patients. In the current study, a comprehensive analysis using human transcriptomics datasets GSE205661, GSE190451, and GSE186334 was conducted to reveal differentially expressed genes related to mitochondria (Mito-DEGs). Protein-protein interaction (PPI) network and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were performed to identify hub genes. Additional GSE127871 and GSE255223 were utilized to establish the association with hippocampal sclerosis (HS) and seizure frequency, respectively. Single-cell RNA analysis, functional investigation, and clinical verification were conducted. Herein, we reported that the Mito-DEGs in human TLE were significantly enriched in metabolic processes. Through PPI and LASSO analysis, HSDL2 was identified as the hub gene, of which diagnostic potential was further confirmed using independent datasets, animal models, and clinical validation. Subsequent single-cell and functional analyses revealed that HSDL2 expression was enriched and upregulated in response to excessive lipid accumulation in astrocytes. Additionally, the diagnostic efficiency of blood HSDL2 was verified in Qilu cohort. Together, our findings highlight the translational potential of HSDL2 as a biomarker and provide a novel therapeutic perspective for human TLE.

Isoliensinine activated the Nrf2/GPX4 pathway to inhibit glutamate-induced ferroptosis in HT-22 cells.

Isoliensinine (ISO), a natural compound, is a bibenzyl isoquinoline alkaloid monomer in lotus seed, which has strong antioxidant and free radical scavenging activities. The oxidative toxicity caused by glutamic acid overdose is one of the important mechanisms of nerve cell injury, and the oxidative toxicity caused by glutamic acid is related to ferroptosis. This study aims to establish a glutamate-induced injury model of mouse hippocampal neurons HT-22 cells, and investigate the protective effect of ISO on the neurotoxicity of glutamate-induced HT-22 cells. The results showed that ISO inhibited glutamate-induced ferroptosis of neuronal cells through nuclear factor E2-related factor 2/glutathione peroxidase 4 (Nrf2/GPX4) signaling pathway. Pretreatment of HT-22 cells with ISO significantly reduced glutamate-induced cell death. Ferroptosis inhibitors have the same effect. ISO inhibited the decrease of mitochondrial membrane potential detection and the increase of iron content induced by glutamate, the increase of malondialdehyde and reactive oxygen species in cytoplasm and lipid, and protected the activities of GPx and superoxide dismutase enzymes. In addition, WB showed that glutamic acid could induce the upregulated expression of long-chain esteryl coA synthase 4 (ACSL4) protein and the downregulated expression of SLC7A11 and GPX4 protein in HT-22 cells, while ISO could prevent the abnormal expression of these proteins induced by glutamic acid. The nuclear translocation of Nrf2 in HT-22 cells was increased, and the expression of downstream heme oxygenase-1 protein was upregulated. In summary, ISO protects HT-22 cells from glutamate-induced ferroptosis through a novel mechanism of the Nrf2/GPX4 signaling pathway.

Effect of stakeholder pressure on environmental performance: Do virtual CSR, green credit, environmental and social reputation matter?

In today's globalized and interconnected world, businesses operate within an interconnected network with various stakeholders. Among these stakeholders, the pressure from consumers, investors, regulators, and communities for corporations to adopt environmentally responsible practices has intensified significantly. Therefore, this study investigates the relationship between stakeholder pressure and environmental performance (EP) in Pakistan's manufacturing sector while examining the potential moderating roles of environmental reputation, social reputation, virtual CSR, and green credit. Data was gathered by convenience sampling and a cross-sectional research approach. A structural questionnaire was given to 376 employees of manufacturing firms that are listed on the Pakistan Stock Exchange (PSE). The research hypotheses were tested using PLS-SEM techniques, which examined the interactions between these variables. The results reveal that stakeholder pressure significantly influences the environmental performance of manufacturing firms. Environmental reputation and virtual CSR negatively moderate the relationship between stakeholder pressure and EP. Moreover, social reputation and green credit positively moderate the relationship between stakeholder pressure and EP. These results contribute to the existing literature by shedding light on how stakeholder pressure influences firms' environmental behavior. Practical implications include integrating virtual CSR strategies, securing green financing options, and building strong environmental and social reputations to effectively respond to stakeholder demands and improve environmental performance.

Asymptomatic Purely Intracranial Vagal Schwannoma: Clinical Case Report and Literature Review.

Vagus nerve schwannoma is an infrequently occurring schwannoma, in which a distinct subtype exists wherein the tumor is confined to the cerebellomedullary cistern without invading the jugular foramen. This unique tumor is called purely intracranial vagal schwannoma. In this case report, we present a case of purely intracranial vagal schwannoma in its asymptomatic early phase, incidentally discovered during surgery performed on a patient with hemifacial spasm. Because of the small size of the tumor, we definitively recognized that it originated from the second rootlet on the caudal side. The tumor was totally resected uneventfully and a favorable prognosis was achieved. Furthermore, we conducted a comprehensive literature review to summarize the classification, origin, and surgical complications associated with this rare tumor type. Based on our literature review, we propose that: 1) the origin of tumor is related to the time of onset of symptoms, 2) nearly all purely intracranial vagal schwannomas can be entirely resected and favorable prognosis can be achieved, and 3) surgeons should be aware of potential cardiovascular complications during surgical procedures.

Sorbitol mediates age-dependent changes in apple plant growth strategy through gibberellin signaling.

Plants experience various age-dependent changes during juvenile to adult vegetative phase. However, the regulatory mechanisms orchestrating the changes remain largely unknown in apple (Malus domestica). This study showed that tissue-cultured apple plants at juvenile, transition, and adult phase exhibit age-dependent changes in their plant growth, photosynthetic performance, hormone levels, and carbon distribution. Moreover, this study identified an age-dependent gene, sorbitol dehydrogenase (MdSDH1), a key enzyme for sorbitol catabolism, highly expressed in the juvenile phase in apple. Silencing MdSDH1 in apple significantly decreased the plant growth and GA3 levels. However, exogenous GA3 rescued the reduced plant growth phenotype of TRV-MdSDH1. Biochemical analysis revealed that MdSPL1 interacts with MdWRKY24 and synergistically enhance the repression of MdSPL1 and MdWRKY24 on MdSDH1, thereby promoting sorbitol accumulation during vegetative phase change. Exogenous sorbitol application indicated that sorbitol promotes the transcription of MdSPL1 and MdWRKY24. Notably, MdSPL1-MdWRKY24 module functions as key repressor to regulate GA-responsive gene, Gibberellic Acid-Stimulated Arabidopsis (MdGASA1) expression, thereby leading to a shift from the quick to the slow-growth strategy. These results reveal the pivotal role of sorbitol in controlling apple plant growth, thereby improving our understanding of vegetative phase change in apple.

Treatment of tetracycline in an aqueous solution with an iron-biochar/periodate system: Influencing factors and mechanisms.

In this study, a potassium ferrate (K2FeO4)-modified biochar (Fe-BC) was prepared and characterized. Afterwards, Fe-BC was applied to activated periodate (PI) to degrade tetracycline (TC), an antibiotic widely used in animal farming. The degradation effects of different systems on TC were compared and the influencing factors were investigated. In addition, several reactive oxygen species (ROS) generated by the Fe-BC/PI system were identified, and TC degradation pathways were analyzed. Moreover, the reuse performance of Fe-BC was evaluated. The results exhibited that the Fe-BC/PI system could remove almost 100% of TC under optimal conditions of [BC] = 1.09 g/L, initial [PI] = 3.29 g/L, and initial [TC] = 20.3 mg/L. Cl-, HCO3-, NO3-, and humic acid inhibited TC degradation to varying degrees in the Fe-BC/PI system due to their quenching effects on ROS. TC was degraded into intermediates and even water and carbon dioxide by the synergistic effect of ROS generated and Fe on the BC surface. Fe-BC was reused four times, and the removal rate of TC was still maintained above 80%, indicating the stable nature of Fe-BC.

Screening of broad-host expression promoters for shuttle expression vectors in non-conventional yeasts and bacteria.

BACKGROUND: Non-conventional yeasts and bacteria gain significance in synthetic biology for their unique metabolic capabilities in converting low-cost renewable feedstocks into valuable products. Improving metabolic pathways and increasing bioproduct yields remain dependent on the strategically use of various promoters in these microbes. The development of broad-spectrum promoter libraries with varying strengths for different hosts is attractive for biosynthetic engineers. RESULTS: In this study, five Yarrowia lipolytica constitutive promoters (yl.hp4d, yl.FBA1in, yl.TEF1, yl.TDH1, yl.EXP1) and five Kluyveromyces marxianus constitutive promoters (km.PDC1, km.FBA1, km.TEF1, km.TDH3, km.ENO1) were selected to construct promoter-reporter vectors, utilizing α-amylase and red fluorescent protein (RFP) as reporter genes. The promoters' strengths were systematically characterized across Y. lipolytica, K. marxianus, Pichia pastoris, Escherichia coli, and Corynebacterium glutamicum. We discovered that five K. marxianus promoters can all express genes in Y. lipolytica and that five Y. lipolytica promoters can all express genes in K. marxianus with variable expression strengths. Significantly, the yl.TEF1 and km.TEF1 yeast promoters exhibited their adaptability in P. pastoris, E. coli, and C. glutamicum. In yeast P. pastoris, the yl.TEF1 promoter exhibited substantial expression of both amylase and RFP. In bacteria E. coli and C. glutamicum, the eukaryotic km.TEF1 promoter demonstrated robust expression of RFP. Significantly, in E. coli, The RFP expression strength of the km.TEF1 promoter reached ∼20% of the T7 promoter. CONCLUSION: Non-conventional yeast promoters with diverse and cross-domain applicability have great potential for developing innovative and dynamic regulated systems that can effectively manage carbon flux and enhance target bioproduct synthesis across diverse microbial hosts.

The WUSCHEL-related homeobox transcription factor CsWOX3 negatively regulates fruit spine morphogenesis in cucumber (Cucumis sativus L.).

Cucumber (Cucumis sativus L.) is a widely cultivated crop with rich germplasm resources, holding significant nutritional value. It also serves as an important model for studying epidermal cell fate and sex determination. Cucumbers are covered with multicellular and unbranched trichomes, including a specific type called spines found on the surface of the fruit. The presence and density of these fruit spines determine the visual quality of cucumber fruits. However, the key regulatory genes and mechanisms underlying cucumber fruit spine development remain poorly understood. In this study, we identified a WUSCHEL-related homeobox (WOX) family gene CsWOX3, which functioned as a typical transcriptional repressor and played a negative role in fruit spine development. Spatial-temporal expression analysis revealed that CsWOX3 exhibited a relatively high expression level in the cucumber female floral organs, particularly in the fruit exocarp. Knockout of CsWOX3 using CRISPR/Cas9 resulted in a significant 2-to-3-fold increase in the diameter of fruit spines base, while overexpression led to a 17% decrease in the diameter compared to the wild-type. A SQUAMOSA PROMOTER BINDING PROTEIN-LIKE transcription factor CsSPL15 could directly bind and activate the expression of CsWOX3, thereby suppressing the expression of downstream auxin-related genes, such as CsARF18. Additionally, the RING-finger type E3 ubiquitin ligase CsMIEL1-like interacted with the HD domain of CsWOX3, which might result in the ubiquitination and subsequent alteration in protein stability of CsWOX3. Collectively, our study uncovered a WOX transcription factor CsWOX3 and elucidated its expression pattern and biological function. This discovery enhances our comprehension of the molecular mechanism governing cucumber fruit spine morphogenesis.

Benchmarking Algorithms for Gene Set Scoring of Single-cell ATAC-seq Data.

Gene set scoring (GSS) has been routinely conducted for gene expression analysis of bulk or single-cell RNA sequencing (RNA-seq) data, which helps to decipher single-cell heterogeneity and cell type-specific variability by incorporating prior knowledge from functional gene sets. Single-cell assay for transposase accessible chromatin using sequencing (scATAC-seq) is a powerful technique for interrogating single-cell chromatin-based gene regulation, and genes or gene sets with dynamic regulatory potentials can be regarded as cell type-specific markers as if in single-cell RNA-seq (scRNA-seq). However, there are few GSS tools specifically designed for scATAC-seq, and the applicability and performance of RNA-seq GSS tools on scATAC-seq data remain to be investigated. Here, we systematically benchmarked ten GSS tools, including four bulk RNA-seq tools, five scRNA-seq tools, and one scATAC-seq method. First, using matched scATAC-seq and scRNA-seq datasets, we found that the performance of GSS tools on scATAC-seq data was comparable to that on scRNA-seq, suggesting their applicability to scATAC-seq. Then, the performance of different GSS tools was extensively evaluated using up to ten scATAC-seq datasets. Moreover, we evaluated the impact of gene activity conversion, dropout imputation, and gene set collections on the results of GSS. Results show that dropout imputation can significantly promote the performance of almost all GSS tools, while the impact of gene activity conversion methods or gene set collections on GSS performance is more dependent on GSS tools or datasets. Finally, we provided practical guidelines for choosing appropriate preprocessing methods and GSS tools in different application scenarios.

Dihydroisotanshinone I regulates ferroptosis via PI3K/AKT pathway to enhance cisplatin sensitivity in lung adenocarcinoma.

OBJECTIVES: Dihydroisotanshinone I (DT) is a kind of diterpenoid compound extracted from the dried roots of Salvia miltiorrhiza Bunge, and exhibits multiple biological activities including anti-tumor activity. Cisplatin is one of the first-line drugs for the treatment of lung adenocarcinoma (LAUD), but the drug resistance and toxicity limit its efficacy. DT is known to induce apoptosis and ferroptosis, but it is unclear whether DT can inhibit the cisplatin-resistant LAUD cells and reverse the drug resistance in LAUD. Therefore, our study intends to establish the cisplatin-resistant human LAUD cells (A549/DDP), and figure out the influence and related mechanisms of DT reversing cisplatin resistance in A549/DDP cells, so as to provide a theoretical basis for the DT as a new natural candidate for the treatment of LAUD. METHODS: The establishment of A549/DDP was the continuous stimulation by exposing A549 to gradient concentrations of Cisplatin. The cell viability of A549 and A549/DDP was detected by CCK-8 kit, and the IC50 value was calculated. The morphological changes of A549 and A549/DDP cells were observed by an inverted microscope. The contents of malondialdehyde (MDA) and glutathione (GSH) in A549/DDP cells after drug treatment were detected by related kits. The levels of Fe2+, cytosolic reactive oxygen species (ROS), and lipid reactive oxygen species (lipid ROS) were detected by a fluorescence microplate reader or fluorescence cell imager according to the related fluorescent probe kit instructions. Western blot was used to detect the expressions of PI3K, phospho-PI3K, AKT, phospho-AKT, MDM2, p53, GPX4, and SLC7A11 in A549/DDP after different drug treatments. KEY FINDINGS: Our study demonstrated that the inhibitory effect of DT on A549 and A549/DDP cells was time-dependent and concentration-dependent, and DT and DDP had a synergistic effect on inhibiting the proliferation of A549/DDP cells. Furthermore, DT mainly induced ferroptosis in A549/DDP cells and synergized with cisplatin to promote ferroptosis in A549/DDP cells. The result of KEGG pathway analysis, molecular docking and western blot showed that DT could enhance the cisplatin sensitivity of A549/DDP by inhibiting PI3K/MDM2/P53 signaling pathway. CONCLUSIONS: Consequently, we concluded that DT promotes ferroptosis in cisplatin-resistant LAUD A549/DDP cells. Additionally, DT reverses cisplatin resistance by promoting ferroptosis via PI3K/MDM2/P53 pathway in A549/DDP cells.

Examining the influence of technological self-efficacy, perceived trust, security, and electronic word of mouth on ICT usage in the education sector.

The context of education has changed due to revolutionary developments in the information communication technology (ICT) industry in the post-COVID era. Innovative learning methods were introduced in the education sector to promote quality education. The students find it more convenient to use ICT tools to integrate their knowledge-seeking. China has recently paid more attention to developing and adopting electronic infrastructure. The study assesses the effect of technology self-efficacy (TSE) on ICT acceptance and implementation in China's education sector. It also analyzed the role of perceived trust, perceived security, and electronic word of mouth (eWOM) in integrating digital information sharing and interaction tools. Data is collected from 382 business students at Chinese universities. The results revealed that perceived trust mediates the relationship between TSE and the actual use of ICT tools, intention to use ICT tools for information, and intention to use ICT tools for interaction. Further, perceived security and eWOM significantly moderate the relationship between TSE and perceived trust. The findings indicate that it is essential to offer assistance and instruction to students in the educational sector so they can use ICT technology more frequently. It is also crucial for organizations to establish a supportive culture and provide the necessary technological resources to facilitate the use of ICT.

Plasma lipidomics profiling in predicting the chemo-immunotherapy response in advanced non-small cell lung cancer.

Background: Advanced non-small cell lung cancer (NSCLC) presents significant treatment challenges, with chemo-immunotherapy emerging as a promising approach. This study explores the potential of lipidomic biomarkers to predict responses to chemo-immunotherapy in advanced non-small cell lung cancer (NSCLC) patients. Methods: A prospective analysis was conducted on 68 NSCLC patients undergoing chemo-immunotherapy, divided into disease control (DC) and progressive disease (PD) groups based on treatment response. Pre-treatment serum samples were subjected to lipidomic profiling using liquid chromatography-mass spectrometry (LC-MS). Key predictive lipids (biomarkers) were identified through projection to latent structures discriminant analysis. A biomarker combined model and a clinical combined model were developed to enhance the prediction accuracy. The predictive performances of the clinical combined model in different histological subtypes were also performed. Results: Six lipids were identified as the key lipids. The expression levels of PC(16:0/18:2), PC(16:0/18:1), PC(16:0/18:0), CE(20:1), and PC(14:0/18:1) were significantly up-regulated. While the expression level of TAG56:7-FA18:2 was significantly down-regulated. The biomarker combined model demonstrated a receiver operating characteristic (ROC) curve of 0.85 (95% CI: 0.75-0.95) in differentiating the PD from the DC. The clinical combined model exhibited an AUC of 0.87 (95% CI: 0.79-0.96) in differentiating the PD from the DC. The clinical combined model demonstrated good discriminability in DC and PD patients in different histological subtypes with the AUC of 0.78 (95% CI: 0.62-0.96), 0.79 (95% CI: 0.64-0.94), and 0.86 (95% CI: 0.52-1.00) in squamous cell carcinoma, large cell carcinoma, and adenocarcinoma subtype, respectively. Pathway analysis revealed the metabolisms of linoleic acid, alpha-linolenic acid, glycerolipid, arachidonic acid, glycerophospholipid, and steroid were implicated in the chemo-immunotherapy response in advanced NSCLC. Conclusion: Lipidomic profiling presents a highly accurate method for predicting responses to chemo-immunotherapy in patients with advanced NSCLC, offering a potential avenue for personalized treatment strategies.

Association of COPD with adverse outcomes in heart failure patients with preserved ejection fraction.

We performed a systematic review and meta-analysis to detect the impact of chronic obstructive pulmonary disease (COPD) on the prognosis of heart failure patients with preserved ejection fraction (HFpEF). We systematically screened eligible literature from three electronic databases, PubMed, EMBASE and Cochrane Library, up to April 2023. Two researchers participated in data collection independently. Risk ratios (RRs) from included studies with 95% confidence intervals (CIs) were pooled in the Review Manager version 5.40 software using a random-effects model for analysis. A total of 11 studies (3 post hoc analyses of RCTs and 8 observational studies) with 18 602 participants were included in this meta-analysis. After pooling all the data from eligible studies, our results indicated that COPD was associated with an increased risk of hospitalization (RR = 1.66, 95% CI, 1.47-1.87, P < 0.00001), mortality (RR = 1.62, 95% CI, 1.34-1.95, P < 0.00001), and the composition of hospitalization or mortality (RR = 1.84, 95% CI, 1.35-2.51, P < 0.001) in patients with HFpEF. In a subgroup analysis, the risks of cardiovascular-related mortality (RR = 1.59, 95% CI, 1.30-1.93, P < 0.00001) and post-discharge mortality risk (RR = 2.57, 1.34-4.93, P < 0.01) were increased in HFpEF patients comorbid with COPD, and these associations were also detected in HF-caused hospitalization (RR = 1.64, 95% CI, 1.44-1.87, P < 0.00001). Evidence from existing studies supported that COPD was an independent prognostic risk factor for patients with HFpEF. Developing rapid clinical diagnostic indicators and early use of novel drugs such as SGLT-2 and ARNI may improve the prognosis of this population, deserving further study.

Direct Construction of 1,4-Dihydropyridazines and Pyrazoles via Annulation of Alkyl 2-Aroyl-1-chlorocyclopropanecarboxylates.

An efficient and chemodivergent synthesis of highly functionalized 1,4-dihydropyridazines and pyrazoles has been accomplished via base-promoted annulation between hydrazones and alkyl 2-aroyl-1-chlorocyclopropanecarboxylates, respectively. This transition-metal-free domino reaction proceeded rapidly under mild basic conditions, affording potentially bioactive 1,4-dihydropyridazine and pyrazole derivatives in moderate yields. The conversion of 1,4-dihydropyridazine to pyrazole was confirmed by adjusting the quantity of the base.

The protective effect of erythropoietin and its novel derived peptides in peripheral nerve injury.

Peripheral nerve injury seriously endangers human life and health, but there is no clinical drug for the treatment of peripheral nerve injury, so it is imperative to develop drugs to promote the repair of peripheral nerve injury. Erythropoietin (EPO) not only has the traditional role of promoting erythropoiesis, but also has a tissue-protective effect. Over the past few decades, researchers have confirmed that EPO has neuroprotective effects. However, side effects caused by long-term use of EPO limited its clinical application. Therefore, EPO derivatives with low side effects have been explored. Among them, ARA290 has shown significant protective effects on the nervous system, but the biggest disadvantage of ARA290, its short half-life, limits its application. To address the short half-life issue, the researchers modified ARA290 with thioether cyclization to generate a thioether cyclized helical B peptide (CHBP). ARA290 and CHBP have promising applications as peptide drugs. The neuroprotective effects they exhibit have attracted continuous exploration of their mechanisms of action. This article will review the research on the role of EPO, ARA290 and CHBP in the nervous system around this developmental process, and provide a certain reference for the subsequent research.

An optimized filter design approach for enhancing imaging quality in industrial linear accelerator.

BACKGROUND: The polychromatic X-rays generated by a linear accelerator (Linac) often result in noticeable hardening artifacts in images, posing a significant challenge to accurate defect identification. To address this issue, a simple yet effective approach is to introduce filters at the radiation source outlet. However, current methods are often empirical, lacking scientifically sound metrics. OBJECTIVE: This study introduces an innovative filter design method that optimizes filter performance by balancing the impact of ray intensity and energy on image quality. MATERIALS AND METHODS: Firstly, different spectra under various materials and thicknesses of filters were obtained using GEometry ANd Tracking (Geant4) simulation. Subsequently, these spectra and their corresponding incident photon counts were used as input sources to generate different reconstructed images. By comprehensively comparing the intensity differences and noise in images of defective and non-defective regions, along with considering hardening indicators, the optimal filter was determined. RESULTS: The optimized filter was applied to a Linac-based X-ray computed tomography (CT) detection system designed for identifying defects in graphite materials within high-temperature gas-cooled reactor (HTR), with defect dimensions of 2 mm. After adding the filter, the hardening effect reduced by 22%, and the Defect Contrast Index (DCI) reached 3.226. CONCLUSION: The filter designed based on the parameters of Average Difference (AD) and Defect Contrast Index (DCI) can effectively improve the quality of defect images.