Integrated analysis of metabolome, transcriptome, and bioclimatic factors of Acer truncatum seeds reveals key candidate genes related to unsaturated fatty acid biosynthesis, and potentially optimal production area.

BACKGROUND: Lipids found in plant seeds are essential for controlling seed dormancy, dispersal, and defenses against biotic and abiotic stress. Additionally, these lipids provide nutrition and energy and are therefore important to the human diet as edible oils. Acer truncatum, which belongs to the Aceaceae family, is widely cultivated around the world for its ornamental value. Further because its seed oil is rich in unsaturated fatty acids (UFAs)- i.e. α-linolenic acid (ALA) and nervonic acid (NA)- and because it has been validated as a new food resource in China, the importance of A. truncatum has greatly risen. However, it remains unknown how UFAs are biosynthesized during the growth season, to what extent environmental factors impact their content, and what areas are potentially optimal for their production. RESULTS: In this study, transcriptome and metabolome of A. truncatum seeds at three representative developmental stages was used to find the accumulation patterns of all major FAs. Cumulatively, 966 metabolites and 87,343 unigenes were detected; the differential expressed unigenes and metabolites were compared between stages as follows: stage 1 vs. 2, stage 1 vs. 3, and stage 2 vs. 3 seeds, respectively. Moreover, 13 fatty acid desaturases (FADs) and 20 ß-ketoacyl-CoA synthases (KCSs) were identified, among which the expression level of FAD3 (Cluster-7222.41455) and KCS20 (Cluster-7222.40643) were consistent with the metabolic results of ALA and NA, respectively. Upon analysis of the geographical origin-affected diversity from 17 various locations, we found significant variation in phenotypes and UFA content. Notably, in this study we found that 7 bioclimatic variables showed considerable influence on FAs contents in A. truncatum seeds oil, suggesting their significance as critical environmental parameters. Ultimately, we developed a model for potentially ecological suitable regions in China. CONCLUSION: This study provides a comprehensive understanding of the relationship between metabolome and transcriptome in A. truncatum at various developmental stages of seeds and a new strategy to enhance seed FA content, especially ALA and NA. This is particularly significant in meeting the increasing demands for high-quality edible oil for human consumption. The study offers a scientific basis for A. truncatum's novel utilization as a woody vegetable oil rather than an ornamental plant, potentially expanding its cultivation worldwide.

Olaparib and niraparib as maintenance therapy in patients with newly diagnosed and platinum-sensitive recurrent ovarian cancer: A single-center study in China.

BACKGROUND: Poly adenosine-diphosphate-ribose polymerase (PARP) inhibitors (PARPi) have been approved to act as first-line maintenance (FL-M) therapy and as platinum-sensitive recurrent maintenance (PSR-M) therapy for ovarian cancer in China for >5 years. Herein, we have analyzed the clinical-application characteristics of olaparib and niraparib in ovarian cancer-maintenance therapy in a real-world setting to strengthen our understanding and promote their rational usage. METHODS: A retrospective chart review identified patients with newly diagnosed or platinum-sensitive recurrent ovarian cancer, who received olaparib or niraparib as maintenance therapy at Sichuan Cancer Hospital between August 1, 2018, and December 31, 2021. Patient medical records were reviewed. We grouped and analyzed patients based on the type of PARPi they used (the olaparib group and the niraparib group) and the line of PARPi maintenance therapy (the FL-M setting and the PSR-M setting). The primary endpoint was the 24-month progression-free survival (PFS) rate. RESULTS: In total, 131 patients (olaparib: n = 67, 51.1%; niraparib: n = 64, 48.9%) were enrolled. Breast cancer susceptibility genes (BRCA) mutations (BRCAm) were significantly less common in the niraparib group than in the olaparib group [9.4% (6/64) vs. 62.7% (42/67), P <0.001], especially in the FL-M setting [10.4% (5/48) vs. 91.4% (32/35), P <0.001]. The 24-month PFS rates in the FL-M and PSR-M settings were 60.4% and 45.7%, respectively. In patients with BRCAm, the 24-month PFS rates in the FL-M and PSR-M settings were 62.2% and 72.7%, respectively. CONCLUSIONS: Olaparib and niraparib were effective in patients with ovarian cancer without any new safety signals except for skin pigmentation. In patients with BRCAm, the 24-month PFS of the PARPi used in the PSR-M setting was even higher than that used in the FL-M setting.

Comparative epidemiology of outbreaks caused by SARS-CoV-2 Delta and Omicron variants in China.

From 2020 to December 2022, China implemented strict measures to contain the spread of severe acute respiratory syndrome coronavirus 2. However, despite these efforts, sustained outbreaks of the Omicron variants occurred in 2022. We extracted COVID-19 case numbers from May 2021 to October 2022 to identify outbreaks of the Delta and Omicron variants in all provinces of mainland China. We found that omicron outbreaks were more frequent (4.3 vs. 1.6 outbreaks per month) and longer-lasting (mean duration: 13 vs. 4 weeks per outbreak) than Delta outbreaks, resulting in a total of 865,100 cases, of which 85% were asymptomatic. Despite the average Government Response Index being 12% higher (95% confidence interval (CI): 9%, 15%) in Omicron outbreaks, the average daily effective reproduction number (Rt) was 0.45 higher (95% CI: 0.38, 0.52, p < 0.001) than in Delta outbreaks. Omicron outbreaks were suppressed in 32 days on average (95% CI: 26, 39), which was substantially longer than Delta outbreaks (14 days; 95% CI: 11, 19; p = 0.004). We concluded that control measures effective against Delta could not contain Omicron outbreaks in China. This highlights the need for continuous evaluation of new variants' epidemiology to inform COVID-19 response decisions.

Preoperative evaluation and a nomogram prediction model for pelvic lymph node metastasis in endometrial cancer.

OBJECTIVE: The primary objective of this study is to explore the preoperative risk factors of pelvic lymph node metastasis (PLNM) in endometrial cancer patients, and construct a nomogram prediction model. MATERIALS AND METHODS: We retrospectively collected various preoperative clinical characteristics of patients and analyzed their relationship with PLNM. Logistic regression analysis was used to screen for independent risk factors for PLNM of endometrial cancer. A nomogram prediction model was constructed, the receiver operating characteristic (ROC), calibration curve and decision curve analysis (DCA) were constructed and used to assess discrimination, calibration, and net benefit. RESULTS: Out of the 276 patients, 74 (26.81%) with postoperative pathological confirmation of PLNM. Multivariate logistic regressive analysis demonstrated that preoperative depth of myometrial invasion (DIM) ≥50% determined by Magnetic Resonance Imaging (MRI) (p = 0.003), carbohydrate antigen 125 (CA125) (p = 0.030), carbohydrate antigen 19-9 (CA 19-9) (p = 0.044), and platelet/lymphocyte ratio (PLR) (p = 0.025) could serve as independent risk factors for PLNM. A risk factors-based nomogram prediction model was constructed, which showed good discrimination (AUC = 0.841, p < 0.001) and good efficacy (C-index = 0.842) and good calibration (mean absolute error = 0.046). DCA showed that the model can provide clinical benefits. CONCLUSIONS: Preoperative DIM ≥50% determined by MRI, serum CA 19-9, CA125 and PLR could be utilized to predict PLNM in endometrial cancer patients. This nomogram prediction model can provide preoperative help for evaluation and identification of patients with endometrial cancer, and provide a theoretical basis for clinical intervention.

The functional significance of circRNA/miRNA/mRNA interactions as a regulatory network in lung cancer biology.

Lung cancer, the leading cause of cancer-related deaths, presents significant challenges to patients due to its poor prognosis. Recent research has increasingly implicated circular RNAs in the development and progression of lung cancer. These circular RNAs have been found to impact various aspects of tumor behavior, including proliferation, metastasis, cell cycle regulation, apoptosis, cancer stem cells, therapy response, and the tumor microenvironment. One of the key mechanisms by which circular RNAs exert their influence is through their ability to act as miRNA sponges, sequestering microRNAs and preventing them from targeting other RNA molecules. Accumulating evidence suggests that circular RNAs can function as competing endogenous RNAs, affecting the expression of target mRNAs by sequestering microRNAs. Dysregulation of competing endogenous RNAs networks involving circular RNAs, microRNAs, and mRNAs leads to the aberrant expression of oncogenes and tumor suppressors involved in lung cancer pathogenesis. Understanding the dynamic interplay and molecular mechanisms among circular RNAs, microRNAs, and mRNAs holds great promise for advancing early diagnosis, personalized therapeutic interventions, and improved patient outcomes in lung cancer. Therefore, this study aims to provide an in-depth exploration of the executive roles of circular RNAs/microRNAs/ mRNAs interactions in lung cancer pathogenesis and their potential utility for diagnosing lung cancer, predicting patient prognosis, and guiding targeted therapies. By offering a comprehensive overview of the dysregulation of the axes as driving factors in lung cancer, we aim to pave the way for their translation into clinical practice in the future.

Fluorescent sensor based on bismuth metal-organic frameworks (Bi-MOFs) mimic enzyme for H2O2 detection in real samples and distinction of phenylenediamine isomers.

Although peroxidase-like nano-enzymes have been widely utilized in biosensors, nano-enzyme based biosensors are seldom used for both quantitative analysis of H2O2 and differentiation of isomers of organic compounds simultaneously. In this study, a dual-functional mimetic enzyme-based fluorescent sensor was constructed using metal-organic frameworks (Bi-MOFs) with exceptional oxidase activity and fluorescence properties. This mimetic enzyme sensor facilitated quantitative analysis of H2O2 and accurate discrimination of phenylenediamine isomers. The sensor exhibited a wide linear range (0.5-400 µM) and low detection limit (0.16 µM) for the detection of H2O2. Moreover, the sensor can also be used for the discrimination of phenylenediamine isomers, in which the presence of o-phenylenediamine (OPD) leads to the appearance of a new fluorescence emission peak at 555 nm, while the presence of p-phenylenediamine (PPD) significantly quenched its fluorescence due to the internal filtration effect. The proposed strategy exhibited a commendable capability in distinguishing phenylenediamine isomers, thereby paving the way for novel applications of MOFs in the field of environmental science.

A dual-functional fluorescence probe CDs@ZIF-90 for highly specific detection of Al3+ and Hg2+ in environmental water samples.

In recent years, the escalating water pollution has resulted in serious harm to human health and ecological environment due to the excessive discharge of toxic metal ions such as Al3+ and Hg2+. Therefore, it is crucial to develop a simple, efficient, and rapid detection method for monitoring the levels of the metal ions in water environment to ensure public health and ecological safety. In this study, carbon dots (CDs) containing heteroatom Si were successfully synthesized by the solvothermal method. Subsequently, a novel dual-functional fluorescent sensor (CDs@ZIF-90) was constructed by integrating CDs with zeolitic imidazolate framework-90 (ZIF-90). The fluorescent composite CDs@ZIF-90 showed outstanding optical properties and excellent structural and luminescence stability in aqueous medium. Particularly, its fluorescence at 453 nm can be remarkably enhanced by Al3+ and quenched upon exposure to Hg2+. As a result, the CDs@ZIF-90 was applied in sensitive and selective determination of Al3+ and Hg2+ ions with wide linear ranges (1-200 µM and 0.05-240 µM) and low detection limits (0.81 µM and 19.6 nM). Moreover, a convenient and rapid fluorescence test strip was also successfully prepared for visual detection of Al3+ and Hg2+ ions. This work is the first try to use the CDs@ZIF-90 fluorescence sensing material for highly sensitive and selective determination of Al3+ and Hg2+ based on "turn-on" and "turn-off" dual modes, respectively and it provides a new idea for monitoring quality of drinking water and environmental water. It is of great significance for human health and environmental protection.

The effect of nurse assisted colonoscopy on adenoma detection rates: A meta-analysis of randomized controlled trials.

BACKGROUND: Adenoma's detection rates have been reported to vary with the participation status of endoscopic nurses during colonoscopy. This meta-analysis was conducted to determine whether the participation of endoscopy nurses during colonoscopy contributed to the improved detection rate of polyps and adenomas. METHODS: We retrieved English original research from PubMed, Embase, Web of Science, and Cochrane library databases and Chinese original research from the CNKI Data database. We searched for randomized controlled trials (RCTs) comparing the effect of participation of endoscopy nurses during colonoscopy of colorectal polyps and adenomas on polyp detection rates to that of nonparticipation. RevMan5.4 software was used to perform the meta-analysis. RESULTS: This meta-analysis included 11 randomized controlled trials involving 8278 patients. The results showed no significant difference between colonoscopies performed by nurses and endoscopists, but colonoscopies performed by two nurses significantly improved the detection rate of polyps and adenomas. In the random effects model, there was a significant difference in PDR between the single-observation and dual-observation groups (RR, 1.27; 95%CI, 1.05, 1.54; Z = 2.51; P = 0.01). The ADR difference between the single observation group and the double observation group was statistically significant (RR, 1.15; 95%CI, 1.05, 1.26; Z = 2.91; P = 0.004). CONCLUSION: Endoscopy nurses' participation in colonoscopy can improve the detection rate of polyps and adenomas, However, more research is needed to confirm the results.

WTAP Mediates NUPR1 Regulation of LCN2 Through m6A Modification to Influence Ferroptosis, Thereby Promoting Breast Cancer Proliferation, Migration and Invasion.

Ferroptosis is involved in various pathophysiological diseases, including triple-negative breast cancer (TNBC). Targeting ferroptosis is considered as a novel anti-TNBC strategy. Nevertheless, the regulatory mechanism of ferroptosis during TNBC progression is unclear. Here, the role of WTAP in ferroptosis during TNBC progression  was investigated. The clinicopathological significance of WTAP, NUPR1 and LCN2 was analyzed by Kaplan-Meier method. Cell viability was assessed using MTT assay. Transwell assay was employed to analyze cell migration and invasion. GSH/GSSG and Fe2+ levels in TNBC cells were analyzed using kits. m6A level was examined using m6A dot blot assay. NUPR1 mRNA stability was analyzed using RNA degradation assay. RIP was performed to analyze the interaction between eIF3a and NURP1. Herein, our results revealed that WTAP, NUPR1 and LCN2 expressions were significantly elevated in TNBC. NUPR1 silencing inhibited TNBC cell proliferation, migration and invasion by inducing ferroptosis. NUPR1 positively regulated LCN2 expression in TNBC cells, and LCN2 knockdown induced ferroptosis to suppress TNBC cell malignant behaviors. Our molecular study further revealed that WTAP promoted NUPR1 expression in an m6A-EIF3A mediated manner. And, as expected, WTAP knockdown promoted ferroptosis to suppress TNBC cell malignant behaviors, which were abrogated by NUPR1 overexpression. WTAP upregulated LCN2 by regulation of NUPR1 m6A modification, thereby suppressing ferroptosis to contribute to accelerate TNBC progression. Our study revealed the cancer-promoting effect of WTAP, NUPR1 and LCN2 in TNBC and clarified the relevant mechanism, providing a theoretical basis for developing novel diagnostic and therapeutic strategies for TNBC.

Oxidative stress is the pivot for PM2.5-induced lung injury.

Fine particulate matter (PM2.5) is a primary air pollutant recognized worldwide as a serious threat to public health. PM2.5, which has a diameter of less than 2.5 µm, is known to cause various diseases, including cardiovascular, respiratory, metabolic, and neurological diseases. Studies have shown that the respiratory system is particularly susceptible to PM2.5 as it is the first line of defense against external pollutants. PM2.5 can cause oxidative stress, which is triggered by the catalyzation of biochemical reactions, the activation of oxidases and metabolic enzymes, and mitochondrial dysfunction, all of which can lead to lung injury and aggravate various respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, and cancer. Oxidative stress plays a crucial role in the harmful effects and mechanisms of PM2.5 on the respiratory system by activating several detrimental pathways related to inflammation and cellular damage. However, experimental studies have shown that antioxidative therapy methods can effectively cure PM2.5-induced lung injury. This review aims to clarify how PM2.5 induces oxidative stress and the mechanisms by which it is involved in the aggravation of various lung diseases. Additionally, we have listed antioxidant treatments to protect against PM2.5-induced lung injury.

Molecular characteristics of circulating B cells and kidney cells at the single-cell level in special types of primary membranous nephropathy.

Background: Although primary membranous nephropathy (pMN) associated with podocyte autoantibodies (POS) is becoming well-known, the molecular characteristics of the specific type of pMN that is negative for podocyte autoantibodies (NEG) is still unclear. Methods: We performed single-cell transcriptome sequencing and single-cell B cell receptor sequencing on circulating CD19+ cells and kidney cells of a NEG paediatric patient with pMN. The single-cell datasets of POS patients and healthy control individuals were included for integrative analysis. Results: The gene expression characteristics and clonal expansion of naïve and memory B cells in the NEG patient changed significantly. We found that a group of CD38+ naïve B cells expanded in the NEG patient, which had the functional characteristics of cell activation. In addition, the conversion between immunoglobulin M (IgM)/IgD and IgG1 in the NEG patient was increased. Parietal epithelial cells (PECs) and podocytes shared similar signature genes (WT1, CLIC5), and new candidate marker genes for PECs, such as NID2, CAV1 and THY1, might contribute to the definition of cell subsets. PECs might have undergone significant changes in the disease, mainly manifested by changes in the expression of CCN2, PLAAT4 and SEPTIN2. The scores of gene sets related to extracellular matrix, cell adhesion and calcium channel in podocytes of the NEG patient was significantly increased. The gene expression of sodium transporter in a group of proximal tubule cells in the disease was significantly increased, especially SLC5A12, which might be related to the oedema of patients. Conclusions: Our research demonstrated the cell type-specific molecular features in the circulation and kidney of the NEG pMN patient.

Clinical characteristics, treatments, and outcomes of interferon-beta-induced thrombotic microangiopathy: a literature-based retrospective analysis.

Background: Thrombotic microangiopathy (TMA) is a rare side effect of interferon-beta (IFN-ß) therapy. The clinical characteristics of IFN-ß-induced TMA are unknown. Objectives: To explore the clinical characteristics of IFN-ß-induced TMA and provide reference for the prevention of TMA. Design: Articles on IFN-ß-induced TMA were collected by searching the literature in relevant Chinese and English databases from inception to 31 July 2023. Methods: Data in the articles were extracted and analyzed retrospectively. Results: Forty-seven patients, with a median age of 41 years (range 22, 66), were included in the analysis. The median time to the diagnosis of IFN-ß-induced TMA was 8 years (range 0.1-30) after administration. The main clinical symptoms were neurological symptoms (51.1%), hypertension (78.7%), dyspnea (19.1%), edema (19.1%), asthenia/fatigue (19.1%), and digestive symptoms (17.0%). Most patients presented with hemolytic anemia (76.6%), thrombocytopenia (63.8%), and acute kidney injury (70.2%). All patients stopped IFN-ß and received plasma exchange therapy (53.2%), systemic steroids (46.8%), antihypertensive therapy (46.8%), eculizumab (12.8%), and rituximab (12.8%). Kidney damage was not completely reversible; 40.4% of patients achieved renal function and hematology remission, 27.7% developed chronic kidney disease, 25.5% developed end-stage renal disease, and 2.1% died. Conclusion: IFN-ß-induced TMA is a rare but serious complication that can be life-threatening. It may occur after many years of IFN-ß therapy, and patients taking IFN-ß should be monitored for symptoms such as headache and hypertension.

Cell-type-specific molecular characterization of cells from circulation and kidney in IgA nephropathy with nephrotic syndrome.

Nephrotic syndrome (NS) is a relatively rare and serious presentation of IgA nephropathy (IgAN) (NS-IgAN). Previous research has suggested that the pathogenesis of NS-IgAN may involve circulating immune imbalance and kidney injury; however, this has yet to be fully elucidated. To investigate the cellular and molecular status of NS-IgAN, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) and kidney cells from pediatric patients diagnosed with NS-IgAN by renal biopsy. Consistently, the proportion of intermediate monocytes (IMs) in NS-IgAN patients was higher than in healthy controls. Furthermore, flow cytometry confirmed that IMs were significantly increased in pediatric patients with NS. The characteristic expression of VSIG4 and MHC class II molecules and an increase in oxidative phosphorylation may be important features of IMs in NS-IgAN. Notably, we found that the expression level of CCR2 was significantly increased in the CMs, IMs, and NCMs of patients with NS-IgAN. This may be related to kidney injury. Regulatory T cells (Tregs) are classified into two subsets of cells: Treg1 (CCR7 high, TCF7 high, and HLA-DR low) and Treg2 (CCR7 low, TCF7 low, and HLA-DR high). We found that the levels of Treg2 cells expressed significant levels of CCR4 and GATA3, which may be related to the recovery of kidney injury. The state of NS in patients was closely related to podocyte injury. The expression levels of CCL2, PRSS23, and genes related to epithelial-mesenchymal transition were significantly increased in podocytes from NS-IgAN patients. These represent key features of podocyte injury. Our analysis suggests that PTGDS is significantly downregulated following injury and may represent a new marker for podocytes. In this study, we systematically analyzed molecular events in the circulatory system and kidney tissue of pediatric patients with NS-IgAN, which provides new insights for targeted therapy in the future.

Simulation and optimisation of magnetic and experimental study of magnetic field coupling constructed wetland.

This study developed a novel constructed wetland (CW) coupled with a magnetic field for treating domestic wastewater, and the magnetic field distribution was solved and optimised by the finite element method. Herein, we investigated the effects of optimising magnetic field optimisation and studied its impact on CW treatment performance and the responses of a microbial community. The optimisation results showed that the average magnetic field strength of the CW unit increases from 3 to 8 mT, and the proportion of areas with magnetic field strength greater than 5 mT also increases from 30% to 74%. The water quality analysis results showed that the removal of chemical oxygen demand (COD) and NH4+-N (p < 0.01) was significantly increased by the magnetic field (average 3 mT), increasing by 12.2% and 8.49%, respectively. Moreover, the removal of COD and NH4+-N (p < 0.01) was more significantly increased by M-VFCW(O) (average 8 mT), increasing by 15.58% and 49.1%, respectively. The magnetic field application shifted significantly the abundance of dominant bacteria in CWs. Relative abundance of dominant bacteria such as Proteobacteria (63.3%), Firmicutes (4.72%) and Actinobacteria (2.11%) that played an important role in organics removal and nitrification and denitrification-related bacteria such as Nitrospirae (1.48%) and Planctomycetes (9.58%) significantly promoted in M-VFCW(O). These results suggest that introducing a magnetic field into CWs may improve organics and nitrogen removal via the biological process, and the optimisation of the magnetic field was significant in enhancing the performance of VFCWs.

Histology, physiology, and transcriptomic and metabolomic profiling reveal the developmental dynamics of annual shoots in tree peonies (Paeonia suffruticosa Andr.).

The development of tree peony annual shoots is characterized by "withering", which is related to whether there are bud points in the leaf axillaries of annual shoots. However, the mechanism of "withering" in tree peony is still unclear. In this study, Paeonia ostii 'Fengdan' and P. suffruticosa 'Luoyanghong' were used to investigate dynamic changes of annual shoots through anatomy, physiology, transcriptome, and metabolome. The results demonstrated that the developmental dynamics of annual shoots of the two cultivars were comparable. The withering degree of P. suffruticosa 'Luoyanghong' was higher than that of P. ostii 'Fengdan', and their upper internodes of annual flowering shoots had a lower degree of lignin deposition, cellulose, C/N ratio, showing no obvious sclerenchyma, than the bottom ones and the whole internodes of vegetative shoot, which resulted in the "withering" of upper internodes. A total of 36 phytohormone metabolites were detected, of which 33 and 31 were detected in P. ostii 'Fengdan' and P. suffruticosa 'Luoyanghong', respectively. In addition, 302 and 240 differentially expressed genes related to lignin biosynthesis, carbon and nitrogen metabolism, plant hormone signal transduction, and zeatin biosynthesis were screened from the two cultivars. Furtherly, 36 structural genes and 40 transcription factors associated with the development of annual shoots were highly co-expressed, and eight hub genes involved in this developmental process were identified. Consequently, this study explained the developmental dynamic on the varied annual shoots through multi-omics, providing a theoretical foundation for germplasm innovation and the mechanized harvesting of tree peony annual shoots.

Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's disease.

Human glutaminyl cyclase (hQC) is drawing considerable attention and emerging as a potential druggable target for Alzheimer's disease (AD) due to its close involvement in the pathology of AD via the post-translational pyroglutamate modification of amyloid-ß. A recent phase 2a study has shown promising early evidence of efficacy for AD with a competitive benzimidazole-based QC inhibitor, PQ912, which also demonstrated favorable safety profiles. This finding has sparked new hope for the treatment of AD. In this review, we briefly summarize the discovery and evolution of hQC inhibitors, with a particular interest in classic Zinc binding group (ZBG)-containing chemicals reported in recent years. Additionally, we highlight several high-potency inhibitors and discuss new trends and challenges in the development of QC inhibitors as an alternative and promising disease-modifying therapy for AD.

Combined genome-wide association studies and expression quantitative trait locus analysis uncovers a genetic regulatory network of floral organ number in a tree peony (Paeonia suffruticosa Andrews) breeding population.

Great progress has been made in our understanding of floral organ identity determination and its regulatory network in many species; however, the quantitative genetic basis of floral organ number variation is far less well understood for species-specific traits from the perspective of population variation. Here, using a tree peony (Paeonia suffruticosa Andrews, Paeoniaceae) cultivar population as a model, the phenotypic polymorphism and genetic variation based on genome-wide association studies (GWAS) and expression quantitative trait locus (eQTL) analysis were analyzed. Based on 24 phenotypic traits of 271 representative cultivars, the transcript profiles of 119 cultivars were obtained, which indicated abundant genetic variation in tree peony. In total, 86 GWAS-related cis-eQTLs and 3188 trans-eQTL gene pairs were found to be associated with the numbers of petals, stamens, and carpels. In addition, 19 floral organ number-related hub genes with 121 cis-eQTLs were obtained by weighted gene co-expression network analysis, among which five hub genes belonging to the ABCE genes of the MADS-box family and their spatial-temporal co-expression and regulatory network were constructed. These results not only help our understanding of the genetic basis of floral organ number variation during domestication, but also pave the way to studying the quantitative genetics and evolution of flower organ number and their regulatory network within populations.

Initial treatment with a single capsule containing half-dose quadruple therapy vs standard-dose dual therapy in hypertensive patients (QUADUAL): Study protocol for a randomized, blinded, crossover trial.

BACKGROUND: Combined antihypertensive therapy has obvious advantages over single drug therapy. Hypertension guidelines fully affirm the efficacy of dual combination in initial antihypertensive therapy. Recent studies have also pointed out that the quadruple combination of very low-dose antihypertensive drugs is superior to single drugs. However, whether low-dose quadruple therapy is better than dual combination is unknown. OBJECTIVE: To evaluate and compare the efficacy and safety of half-dose quadruple therapy vs standard-dose dual therapy in the initial treatment of hypertensive patients with systolic/diastolic blood pressure 140-179/90-109 mm Hg. METHODS: A randomized double-blind crossover clinical trial will be conducted to compare the efficacy and safety of low-dose quadruple antihypertensives (irbesartan 75 mg + metoprolol 23.75 mg + amlodipine 2.5 mg + indapamide 1.25 mg) with standard-dose dual antihypertensives (irbesartan 150 mg + amlodipine 5 mg) in the initial treatment of patients with mild to moderate hypertension (140-179/90-109 mm Hg). Ninety patients are required and will be recruited and randomly assigned in a 1:1 ratio to 2 crossover groups. Two groups will receive a different combination therapy for 4 weeks, then switch to the other combination therapy for 4 weeks, with a 2-week wash-out. The patients will be followed up for 4 weeks to compare the antihypertensive effects and related adverse effects of the 2 antihypertensive combination treatments. CONCLUSIONS: We present the rationale for the design of the QUADUAL trial. The trial started in July 2022 and is expected to be completed by August 2023. The study aims to evaluate if an initial treatment regimen of quadruple combination of half-dose blood pressure medications will result in greater reduction in blood pressure and fewer side effects compared to standard dose dual therapy. REGISTRATION: www. CLINICALTRIALS: gov (NCT05377203).

Daphnetin ameliorates PM2.5-induced airway inflammation by inhibiting NLRP3 inflammasome-mediated pyroptosis in CS-exposed mice.

Epidemiologic studies have shown that fine particulate matter 2.5 (PM2.5) exaggerates airway inflammation associated with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Daphnetin (Daph) is a natural compound with a variety of biological activities. At present, there are limited data on whether Daph can protect against cigarette smoke (CS)-induced chronic obstructive pulmonary disease (COPD) and PM2.5-CS-induced AECOPD. Therefore, this study systematically evaluated the effects of Daph on CS-induced COPD and PM2.5-CS-induced AECOPD and determined its mechanism of action. First, in vitro studies showed that PM2.5 exacerbated cytotoxicity and NLRP3 inflammasome-mediated pyroptosis induced by low-dose cigarette smoke extracts (CSE). However, the effect was reversed by si-NLRP3 and MCC950. Similar results were obtained in PM2.5-CS-induced AECOPD mice. The results of the mechanistic studies suggested that blocking NLRP3 abolished PM2.5 combined with cigarette induced cytotoxicity, lung damage, NLRP3 inflammasome activation and pyroptosis in vitro and in vivo. Second, Daph suppressed the expression of NLRP3 inflammasome and pyroptosis in BEAS-2B cells. Third, Daph significantly protected against CS-induced COPD and PM2.5-CS-induced AECOPD by inhibiting the NLRP3 inflammasome and pyroptosis in mice. Our findings identified the NLRP3 inflammasome as a critical contributor to PM2.5-CS-induced airway inflammation, and Daph as a negative regulator of NLRP3-mediated pyroptosis, which has implications for the pathophysiology of AECOPD.