KLHL21 suppresses gastric tumourigenesis via maintaining STAT3 signalling equilibrium in stomach homoeostasis.

OBJECTIVE: Precancerous metaplasia transition to dysplasia poses a risk for subsequent intestinal-type gastric adenocarcinoma. However, the molecular basis underlying the transformation from metaplastic to cancerous cells remains poorly understood. DESIGN: An integrated analysis of genes associated with metaplasia, dysplasia was conducted, verified and characterised in the gastric tissues of patients by single-cell RNA sequencing and immunostaining. Multiple mouse models, including homozygous conditional knockout Klhl21-floxed mice, were generated to investigate the role of Klhl21 deletion in stemness, DNA damage and tumour formation. Mass-spectrometry-based proteomics and ribosome sequencing were used to elucidate the underlying molecular mechanisms. RESULTS: Kelch-like protein 21 (KLHL21) expression progressively decreased in metaplasia, dysplasia and cancer. Genetic deletion of Klhl21 enhances the rapid proliferation of Mist1+ cells and their descendant cells. Klhl21 loss during metaplasia facilitates the recruitment of damaged cells into the cell cycle via STAT3 signalling. Increased STAT3 activity was confirmed in cancer cells lacking KLHL21, boosting self-renewal and tumourigenicity. Mechanistically, the loss of KLHL21 promotes PIK3CB mRNA translation by stabilising the PABPC1-eIF4G complex, subsequently causing STAT3 activation. Pharmacological STAT3 inhibition by TTI-101 elicited anticancer effects, effectively impeding the transition from metaplasia to dysplasia. In patients with gastric cancer, low levels of KLHL21 had a shorter survival rate and a worse response to adjuvant chemotherapy. CONCLUSIONS: Our findings highlighted that KLHL21 loss triggers STAT3 reactivation through PABPC1-mediated PIK3CB translational activation, and targeting STAT3 can reverse preneoplastic metaplasia in KLHL21-deficient stomachs.

Safety and efficacy of COVID-19 vaccination in the Chinese population with pulmonary lymphangioleiomyomatosis: a single-center retrospective study.

BACKGROUND: The safety and efficacy of vaccination against coronavirus disease 2019 (COVID-19) in patients with lymphangioleiomyomatosis (LAM) is still unclear. This study investigates COVID-19 vaccine hesitancy, vaccine safety and efficacy, and COVID-19 symptoms in LAM patients. RESULTS: In total, 181 LAM patients and 143 healthy individuals responded to the questionnaire. The vaccination rate of LAM patients was 77.34%, and 15.7% of vaccinated LAM patients experienced adverse events. Vaccination decreased the risk of LAM patients developing anorexia [OR: 0.17, 95% CI: (0.07, 0.43)], myalgia [OR: 0.34, 95% CI: (0.13, 0.84)], and ageusia [OR: 0.34, 95% CI: (0.14, 0.84)]. In LAM patients, a use of mTOR inhibitors reduced the risk of developing symptoms during COVID-19, including fatigue [OR: 0.18, 95% CI: (0.03, 0.95)], anorexia [OR: 0.30, 95% CI: (0.09, 0.96)], and ageusia [OR: 0.20, 95% CI: (0.06, 0.67)]. CONCLUSIONS: Vaccination rates in the LAM population were lower than those in the general population, as 22.7% (41/181) of LAM patients had hesitations regarding the COVID-19 vaccine. However, the safety of COVID-19 vaccination in the LAM cohort was comparable to the healthy population, and COVID-19 vaccination decreased the incidence of COVID-19 symptoms in LAM patients. In addition, mTOR inhibitors seem not to determine a greater risk of complications in patients with LAM during COVID-19.

The wheat powdery mildew resistance gene Pm4 also confers resistance to wheat blast.

Wheat blast, caused by the fungus Magnaporthe oryzae, threatens global cereal production since its emergence in Brazil in 1985 and recently spread to Bangladesh and Zambia. Here we demonstrate that the AVR-Rmg8 effector, common in wheat-infecting isolates, is recognized by the gene Pm4, previously shown to confer resistance to specific races of Blumeria graminis f. sp. tritici, the cause of powdery mildew of wheat. We show that Pm4 alleles differ in their recognition of different AVR-Rmg8 alleles, and some confer resistance only in seedling leaves but not spikes, making it important to select for those alleles that function in both tissues. This study has identified a gene recognizing an important virulence factor present in wheat blast isolates in Bangladesh and Zambia and represents an important first step towards developing durably resistant wheat cultivars for these regions.

Harnessing landrace diversity empowers wheat breeding.

Harnessing genetic diversity in major staple crops through the development of new breeding capabilities is essential to ensure food security1. Here we examined the genetic and phenotypic diversity of the A.E. Watkins landrace collection2 of bread wheat (Triticum aestivum), a major global cereal, through whole-genome re-sequencing (827 Watkins landraces and 208 modern cultivars) and in-depth field evaluation spanning a decade. We discovered that modern cultivars are derived from just two of the seven ancestral groups of wheat and maintain very long-range haplotype integrity. The remaining five groups represent untapped genetic sources, providing access to landrace-specific alleles and haplotypes for breeding. Linkage disequilibrium (LD) based haplotypes and association genetics analyses link Watkins genomes to the thousands of high-resolution quantitative trait loci (QTL), and significant marker-trait associations identified. Using these structured germplasm, genotyping and informatics resources, we revealed many Watkins-unique beneficial haplotypes that can confer superior traits in modern wheat. Furthermore, we assessed the phenotypic effects of 44,338 Watkins-unique haplotypes, introgressed from 143 prioritised QTL in the context of modern cultivars, bridging the gap between landrace diversity and current breeding. This study establishes a framework for systematically utilising genetic diversity in crop improvement to achieve sustainable food security.

Immune profiling of mouse lung adenocarcinoma paraffin tissues using multiplex immunofluorescence panel: a pilot study.

BACKGROUND: Immune profiling has become an important tool for identifying predictive, prognostic and response biomarkers for immune checkpoint inhibitors from tumor microenvironment (TME). We aimed to build a multiplex immunofluorescence (mIF) panel to apply to formalin-fixed and paraffin-embedded tissues in mice tumors and to explore the programmed cell death protein 1/ programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. RESULTS: An automated eight-color mIF panel was evaluated to study the TME using seven antibodies, including cytokeratin 19, CD3e, CD8a, CD4, PD-1, PD-L1, F4-80 and DAPI, then was applied in six mice lung adenocarcinoma samples. Cell phenotypes were quantified by software to explore the co-localization and spatial distribution between immune cells within the TME. This mice panel was successfully optimized and applied to a small cohort of mice lung adenocarcinoma cases. Image analysis showed a sparse degree of immune cell expression pattern in this cohort. From the spatial analysis we found that T cells and macrophages expressing PD-L1 were close to the malignant cells and other immune cells. CONCLUSIONS: Comprehensive immune profiling using mIF in translational studies improves our ability to correlate the PD-1/PD-L1 axis and spatial distribution of lymphocytes and macrophages in mouse lung cancer cells to provide new cues for immunotherapy, that can be translated to human tumors for cancer intervention.

Correlation of TyG-BMI and TyG-WC with severity and short-term outcome in new-onset acute ischemic stroke.

Objectives: To research the connection between the indexes of the indexes of triglyceride-glucose (TyG) combined with obesity indices and the initial neurological severity and short-term outcome of new-onset acute ischemic stroke. Methods: Data of patients with acute ischemic stroke admitted to the Stroke Ward of the Affiliated Hospital of Beihua University from November 2021 to October 2023, were collected. The two indexes were calculated by combining TyG and obesity indices: TyG-body mass index (TyG-BMI) and TyG-waist circumference (TyG-WC). The National Institute of Health Stroke Scale (NIHSS) was used to assess and group patients with neurological deficits within 24 hours of admission: mild stroke (NIHSS ≤5) and moderate-severe stroke (NIHSS >5). Short-term prognosis was evaluated using the modified Rankin Scale (mRS) at discharge or 14 days after onset of the disease and grouped: good outcome (mRS ≤2) and poor outcome (mRS >2). According to the quartiles of TyG-BMI and TyG-WC, the patients were placed into four groups: Q1, Q2, Q3 and Q4. Multi-factor logistic regression analysis was utilized to evaluate the correlation of TyG-BMI and TyG-WC with the severity and short-term outcome. Results: The study included 456 patients. After adjusting for multiple variables, the results showed that compared with the quartile 1, patients in quartile 4 of TyG-BMI had a reduced risk of moderate-severe stroke [Q4: OR: 0.407, 95%CI (0.185-0.894), P = 0.025]; Patients in quartiles 2, 3 and 4 of TyG-BMI had sequentially lower risk of short-term adverse outcomes [Q2: OR: 0.394, 95%CI (0.215-0.722), P = 0.003; Q3: OR: 0.324, 95%CI (0.163-0.642), P = 0.001; Q4: OR: 0.158, 95%CI (0.027-0.349), P <0.001]; Patients in quartiles 3 and 4 of TyG-WC had sequentially lower risk of moderate-severe stroke [Q3: OR: 0.355, 95%CI (0.173-0.728), P = 0.005; Q4: OR: 0.140, 95%CI (0.056-0.351), P <0.001]; Patients in quartiles 3 and 4 of TyG-WC had sequentially lower risk of short-term adverse outcomes [Q3: OR: 0.350, 95%CI (0.175-0.700), P = 0.003; Q4: OR: 0.178, 95%CI (0.071-0.451), P <0.001]. Conclusions: TyG-WC and TyG-BMI were correlated with the severity and short-term outcome of new-onset acute ischemic stroke. As TyG-WC and TyG-BMI increased, stroke severity decreased and short-term outcome was better.

Homochiral Tetraphenylethene-Based Metal-Organic Frameworks with Circularly Polarized Luminescence for Enantioselective Recognition.

A pair of water-stable and highly porous homochiral fluorescent silver-organic framework enantiomers, namely, R-Ag-BPA-TPyPE (R-1) and S-Ag-BPA-TPyPE (S-1), had been prepared as enantioselective fluorescence sensors. Combining homochiral 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (BPA) with an AIE-based ligand tetrakis[4-(pyridin-4-yl)phenyl]ethene (TPyPE) in complexes R-1 and S-1 made them possess favorable circularly polarized luminescence (CPL) properties, and their CPL spectra were almost mirror images of each other. The luminescence dissymmetry factors (glum) are ±2.2 × 10-3 for R-1 and S-1, and the absolute fluorescence quantum yields (ΦFs) are 32.0% for R-1 and S-1, respectively. Complex R-1 could enantioselectively recognize two enantiomers of amino acids in water or DMF with high Stern-Volmer constants of 236-573 M-1 and enantioselectivity ratios of 1.40-1.78.

Prediction of clinical risk assessment and survival in chronic obstructive pulmonary disease with pulmonary hypertension.

BACKGROUND: Patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) have an increased risk of disease exacerbation and decreased survival. We aimed to develop and validate a non-invasive nomogram for predicting COPD associated with severe PH and a prognostic nomogram for patients with COPD and concurrent PH (COPD-PH). METHODS: This study included 535 patients with COPD-PH from six hospitals. A multivariate logistic regression analysis was used to analyse the risk factors for severe PH in patients with COPD and a multivariate Cox regression was used for the prognostic factors of COPD-PH. Performance was assessed using calibration, the area under the receiver operating characteristic curve and decision analysis curves. Kaplan-Meier curves were used for a survival analysis. The nomograms were developed as online network software. RESULTS: Tricuspid regurgitation velocity, right ventricular diameter, N-terminal pro-brain natriuretic peptide (NT-proBNP), the red blood cell count, New York Heart Association functional class and sex were non-invasive independent variables of severe PH in patients with COPD. These variables were used to construct a risk assessment nomogram with good discrimination. NT-proBNP, mean pulmonary arterial pressure, partial pressure of arterial oxygen, the platelet count and albumin were independent prognostic factors for COPD-PH and were used to create a predictive nomogram of overall survival rates. CONCLUSIONS: The proposed nomograms based on a large sample size of patients with COPD-PH could be used as non-invasive clinical tools to enhance the risk assessment of severe PH in patients with COPD and for the prognosis of COPD-PH. Additionally, the online network has the potential to provide artificial intelligence-assisted diagnosis and treatment. HIGHLIGHTS: A multicentre study with a large sample of chronic obstructive pulmonary disease (COPD) patients diagnosed with PH through right heart catheterisation. A non-invasive online clinical tool for assessing severe pulmonary hypertension (PH) in COPD. The first risk assessment tool was established for Chinese patients with COPD-PH.

Metabolomic and transcriptomic analyses highlight metabolic regulatory networks of Salvia miltiorrhiza in response to replant disease.

BACKGROUND: Salvia miltiorrhiza, a well-known traditional Chinese medicine, frequently suffers from replant diseases that adversely affect its quality and yield. To elucidate S. miltiorrhiza's metabolic adaptations to replant disease, we analyzed its metabolome and transcriptome, comparing normal and replant diseased plants for the first time. RESULTS: We identified 1,269 metabolites, 257 of which were differentially accumulated metabolites, and identified 217 differentially expressed genes. Integrated transcriptomic and metabolomic analyses revealed a significant up-regulation and co-expression of metabolites and genes associated with plant hormone signal transduction and flavonoid biosynthesis pathways in replant diseases. Within plant hormone signal transduction pathway, plants afflicted with replant disease markedly accumulated indole-3-acetic acid and abscisic acid, correlating with high expression of their biosynthesis-related genes (SmAmidase, SmALDH, SmNCED, and SmAAOX3). Simultaneously, changes in hormone concentrations activated plant hormone signal transduction pathways. Moreover, under replant disease, metabolites in the local flavonoid metabolite biosynthetic pathway were significantly accumulated, consistent with the up-regulated gene (SmHTC1 and SmHTC2). The qRT-PCR analysis largely aligned with the transcriptomic results, confirming the trends in gene expression. Moreover, we identified 10 transcription factors co-expressed with differentially accumulated metabolites. CONCLUSIONS: Overall, we revealed the key genes and metabolites of S. miltiorrhiza under replant disease, establishing a robust foundation for future inquiries into the molecular responses to combat replant stress.

Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke.

BACKGROUND: Treatment of acute stroke, before a distinction can be made between ischemic and hemorrhagic types, is challenging. Whether very early blood-pressure control in the ambulance improves outcomes among patients with undifferentiated acute stroke is uncertain. METHODS: We randomly assigned patients with suspected acute stroke that caused a motor deficit and with elevated systolic blood pressure (≥150 mm Hg), who were assessed in the ambulance within 2 hours after the onset of symptoms, to receive immediate treatment to lower the systolic blood pressure (target range, 130 to 140 mm Hg) (intervention group) or usual blood-pressure management (usual-care group). The primary efficacy outcome was functional status as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days after randomization. The primary safety outcome was any serious adverse event. RESULTS: A total of 2404 patients (mean age, 70 years) in China underwent randomization and provided consent for the trial: 1205 in the intervention group and 1199 in the usual-care group. The median time between symptom onset and randomization was 61 minutes (interquartile range, 41 to 93), and the mean blood pressure at randomization was 178/98 mm Hg. Stroke was subsequently confirmed by imaging in 2240 patients, of whom 1041 (46.5%) had a hemorrhagic stroke. At the time of patients' arrival at the hospital, the mean systolic blood pressure in the intervention group was 159 mm Hg, as compared with 170 mm Hg in the usual-care group. Overall, there was no difference in functional outcome between the two groups (common odds ratio, 1.00; 95% confidence interval [CI], 0.87 to 1.15), and the incidence of serious adverse events was similar in the two groups. Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common odds ratio, 0.75; 95% CI, 0.60 to 0.92) but an increase among patients with cerebral ischemia (common odds ratio, 1.30; 95% CI, 1.06 to 1.60). CONCLUSIONS: In this trial, prehospital blood-pressure reduction did not improve functional outcomes in a cohort of patients with undifferentiated acute stroke, of whom 46.5% subsequently received a diagnosis of hemorrhagic stroke. (Funded by the National Health and Medical Research Council of Australia and others; INTERACT4 ClinicalTrials.gov number, NCT03790800; Chinese Trial Registry number, ChiCTR1900020534.).

Analyzing greenhouse gas emissions and influencing factors of 247 actual wastewater treatment plants in China using emission factor and operational data integrated methods (ODIM).

In response to China's policies on pollution control and carbon emission (CE) reductions, more stringent regulations have been implemented to evaluate CE in wastewater treatment facilities. In this study, we have analyzed CE from China's wastewater treatment plants (WWTPs) and influencing factor. Emission factor (EF) and operational data integrated methods (ODIM) were utilized to measure emissions, using data collected from 247 WWTPs over a 1-year period across seven regions in China. The average CE intensity was 0.45 kgCO2-eq/m3, affected by region, season, influent water quality, treatment processes, effluent discharge standards, and facilities. The scale effect was obvious only in the range of 2 × 105 m3/day. Underground WWTPs exhibited significantly higher CE compared to aboveground WWTPs. In summary, the assessment of CE in 247 actual WWTPs not only identifies emission reduction potential but also provides a scientific basis for formulating targeted emission reduction measures.

Comprehensive analysis of the mitochondrial genome of Rehmannia glutinosa: insights into repeat-mediated recombinations and RNA editing-induced stop codon acquisition.

Rehmannia glutinosa is an economically significant medicinal plant. Yet, the structure and sequence of its mitochondrial genome has not been published, which plays a crucial role in evolutionary analysis and regulating respiratory-related macromolecule synthesis. In this study, the R. glutinosa mitogenome was sequenced employing a combination of Illumina short reads and Nanopore long reads, with subsequent assembly using a hybrid strategy. We found that the predominant configuration of the R. glutinosa mitogenome comprises two circular chromosomes. The primary structure of the mitogenome encompasses two mitochondrial chromosomes corresponding to the two major configurations, Mac1-1 and Mac1-2. The R. glutinosa mitogenome encoded an angiosperm-typical set of 24 core genes, nine variable genes, three rRNA genes, and 15 tRNA genes. A phylogenetic analysis using the 16 shared protein-coding genes (PCG) yielded a tree consistent with the phylogeny of Lamiales species and two outgroup taxa. Mapping RNA-seq data to the coding sequences (CDS) of the PCGs revealed 507 C-to-U RNA editing sites across 31 PCGs of the R. glutinosa mitogenome. Furthermore, one start codon (nad4L) and two stop codons (rpl10 and atp6) were identified as products of RNA editing events in the R. glutinosa mitogenome.

Associations of cold-inducible RNA-binding protein with bacterial load, proinflammatory cytokines and mortality from pneumonia.

Cold-inducible RNA-binding protein (CIRP) is a damage-associated molecular pattern that plays a critical role in triggering inflammatory responses. It remains unknown whether CIRP is strongly associated with bacterial load, inflammatory response, and mortality in sepsis model. Pneumonia was induced in specific pathogen-free 8-9-week old male rats by injecting bacteria via puncture of the tracheal cartilage. The expressions of CIRP and proinflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1ß] in lung tissues, alveolar macrophages (AMs), plasma, and bronchoalveolar lavage fluid (BALF) were determined by reverse transcription-polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The numbers of bacteria recovered from the lungs were correlated with the bacterial loads injected and mortality. The expressions of CIRP increased sharply as the bacterial loads increased in the lung tissues and AMs. The amounts of TNF-α, IL-6 and IL-1ß proteins synthesized were dependent on the bacterial load in the lung tissues. Releases of CIRP, TNF-α, IL-6, and IL-1ß increased with the bacterial load in the blood plasma. The proteins confirmed similar patterns in the BALF. CIRP was strongly associated with the releases of TNF-α, IL-6, and IL-1ß in the lung tissues, blood plasma, and BALF, and showed a close correlation with mortality. CIRP demonstrated a strong association with bacterial load, which is new evidence, and close correlations with proinflammatory cytokines and mortality of pneumonia in rats, suggesting that it might be an interesting pneumonic biomarker for monitoring host response and predicting mortality, and a promising target for immunotherapy.

Single-cell and spatial transcriptome sequencing uncover a platinum-resistant cluster overexpressed TACSTD2 in high-grade serous ovarian cancer.

Purpose: Platinum-based chemotherapy is effective but limited by resistance in high-grade serous ovarian cancer (HGSOC). Single-cell RNA sequencing (scRNA-seq) can reveal tumour cell heterogeneity and subclonal differentiation. We aimed to analyze resistance mechanisms and potential targets in HGSOC using scRNA-seq. Methods: We performed 10× genomics scRNA-seq sequencing on tumour tissues from 3 platinum-sensitive and 3 platinum-resistant HGSOC patients. We analyzed cell subcluster communication networks and spatial distribution using cellchat. We performed RNA-seq analysis on TACSTD2, a representative resistance gene in the E0 subcluster, to explore its molecular mechanism. Results: Epithelial cells, characterized by distinct chemotherapy resistance traits and highest gene copy number variations, revealed a specific cisplatin-resistant cluster (E0) associated with poor prognosis. E0 exhibited malignant features related to resistance, fostering growth through communication with fibroblasts and endothelial cells. Spatially, E0 promoted fibroblasts to protect tumour cells and impede immune cells infiltration. Furthermore, TACSTD2 was identified as a representative gene of the E0 subcluster, elucidating its role in platinum resistance through the Rap1/PI3K/AKT pathway. Conclusions: Our study reveals a platinum-resistant epithelial cell subcluster E0 and its association with TACSTD2 in HGSOC, uncovers new insights and evidence for the platinum resistance mechanism, and provides new ideas and targets for the development of therapeutic strategies against TACSTD2+ epithelial cancer cells.

Genome-wide view and characterization of natural antisense transcripts in Cannabis Sativa L.

Natural Antisense Transcripts (NATs) are a kind of complex regulatory RNAs that play crucial roles in gene expression and regulation. However, the NATs in Cannabis Sativa L., a widely economic and medicinal plant rich in cannabinoids remain unknown. In this study, we comprehensively predicted C. sativa NATs genome-wide using strand-specific RNA sequencing (ssRNA-Seq) data, and validated the expression profiles by strand-specific quantitative reverse transcription PCR (ssRT-qPCR). Consequently, a total of 307 NATs were predicted in C. sativa, including 104 cis- and 203 trans- NATs. Functional enrichment analysis demonstrated the potential involvement of the C. sativa NATs in DNA polymerase activity, RNA-DNA hybrid ribonuclease activity, and nucleic acid binding. Finally, 18 cis- and 376 trans- NAT-ST pairs were predicted to produce 621 cis- and 5,679 trans- small interfering RNA (nat-siRNAs), respectively. These nat-siRNAs were potentially involved in the biosynthesis of cannabinoids and cellulose. All these results will shed light on the regulation of NATs and nat-siRNAs in C. sativa.

Generation of an induced pluripotent stem cell line (SJTUGHi003-A) from a patient with Sorsby fundus dystrophy carrying c.484G>A mutation in TIMP3 gene.

Sorsby fundus dystrophy (SFD) is a rare autosomal dominant disorder with macular dystrophy and severe visual loss. Mutations in TIMP3 gene has been related to SFD with mechanisms unclear. We have successfully reprogrammed the peripheral blood mononuclear cells (PBMCs) from an SFD patient carrying c.484G>A mutation in TIMP3 gene to induced pluripotent stem cells (iPSCs) and characterized their pluripotency and genetic stability. This line may serve as a useful tool to explore the role of TIMP3 in SFD pathogenesis.

Identification and characterization of the WOX Gene Family revealed two WUS Clade Members associated with embryo development in Cunninghamia lanceolata.

The WUSCHEL-related homeobox (WOX) gene family is vital for plant development and stress response. In this study, we conducted a comprehensive analysis of WOX genes in Cunninghamia lanceolata (C. lanceolata) and subsequently explored the potential roles of two ClWOX genes within the WUS clade. In total, six ClWOX genes were identified through a full-length transcriptome analysis. These genes, exhibiting conserved structural and functional motifs, were assigned to the ancient clade and Modern/WUS clade, respectively, through a phylogenetic analysis. Our expression analysis indicated that these ClWOX genes were highly expressed in the middle and late developmental stages of zygotic embryos in C. lanceolata. Moreover, only ClWOX5 and ClWOX6 within the Modern/WUS clade exhibited transcriptional activity, and their expressions were also induced in response to auxin and wounding. Overexpression of ClWOX5 and ClWOX6 in Arabidopsis caused a partially sterile phenotype, resulting in a very low seed setting rate. Transcriptomic analysis revealed that expressions of many embryo-defective (EMB) genes, phytohormone-related genes, and transcription factors (TFs) were dramatically altered in ClWOX5 and ClWOX6 transgenic plants, which suggested that ClWOX5 and ClWOX6 may play specific important roles in embryo development via complex gene networks. In addition, overexpression of ClWOX5 and ClWOX6 in leaf segments promoted shoot regeneration in tobacco, indicating that ClWOX5 and ClWOX6 can promote plant regeneration and could be used to improve genetic transformation. In conclusion, these results help to elucidate the function of the WOX gene and provide a valuable basis for future studies of the developmental regulation and applications of WOX genes in C. lanceolata.

Association between exposure to multiple metals and stress urinary incontinence in women: a mixture approach.

There is limited evidence linking exposure to heavy metals, especially mixed metals, to stress urinary incontinence (SUI). This study aimed to explore the relationship between multiple metals exposure and SUI in women. The data were derived from the National Health and Nutrition Examination Survey (NHANES), 2007-2020. In the study, a total of 13 metals were analyzed in blood and urine. In addition, 5155 adult women were included, of whom 2123 (41.2%) suffered from SUI. The logistic regression model and restricted cubic spline (RCS) were conducted to assess the association of single metal exposure with SUI risk. The Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) were used to estimate the combined effect of multiple metals exposure on SUI. First, we observed that blood Pb, Hg and urinary Pb, Cd were positively related to SUI risk, whereas urinary W was inversely related by multivariate logistic regression (all p-FDR < 0.05). Additionally, a significant non-linear relationship between blood Hg and SUI risk was observed by RCS analysis. In the co-exposure models, WQS model showed that exposure to metal mixtures in blood [OR (95%CI) = 1.18 (1.06, 1.31)] and urine [OR (95%CI) = 1.18 (1.03, 1.34)] was positively associated with SUI risk, which was consistent with the results of BKMR model. A potential interaction was identified between Hg and Cd in urine. Hg and Cd were the main contributors to the combined effects. In summary, our study indicates that exposure to heavy metal mixtures may increase SUI risk in women.

A Study on the Effects of Esketamine Combined with Comprehensive Nursing Intervention on Postoperative Pain, Postpartum Depression, and Quality of Life in Women Undergoing Cesarean Section.

Objective: The objective of this study was to investigate and analyze the effects of esketamine combined with comprehensive nursing intervention on postoperative pain, postpartum depression, and quality of life in women undergoing cesarean section. Methods: This study included 140 parturients who underwent cesarean section in The Second Hospital of Dalian Medical University (from May 2021 to May 2022). The participants were divided into two groups: the control group and the study group, based on random allocation. The control group received traditional treatment and routine nursing care, while the study group received esketamine combined with comprehensive nursing intervention. Postoperative pain, postpartum depression, and quality of life were assessed using the Visual Analog Scale (VAS), Edinburgh Postnatal Depression Scale (EPDS), and SF-36 questionnaire, respectively. Results: The two groups had no significant differences in baseline data (P > .05). The postoperative VAS scores of the study group (1.86 ± 0.65) were lower than those of the control group (3.04 ± 0.79) (P < .05). The postoperative EPDS scores of the study group (5.23 ± 1.07) were lower than those of the control group (8.11 ± 1.84) (P < .05). The postoperative physiological recovery of the study group was superior to that of the control group (P < .05). The postoperative SF-36 scores of the study group were higher than those of the control group (P < .05). Practical Implications: The combined use of esketamine and comprehensive nursing in cesarean sections offers practical benefits for patient care. Notably, it leads to reduced postoperative pain, as indicated by lower VAS scores, promising improved satisfaction for parturients. The intervention also demonstrates a positive impact on postpartum mental health, with lower EPDS scores suggesting potential benefits in alleviating depression. Moreover, the observed accelerated physiological recovery in the study group, along with shorter hospital stays, signifies efficiency gains in healthcare delivery. This not only optimizes resource utilization but also contributes to an enhanced overall recovery experience for women undergoing cesarean sections. Conclusion: The application of esketamine combined with comprehensive nursing intervention after cesarean section has a positive impact on the pain relief, postpartum depression, and quality of life of parturients. This study provides new insights and guidance for clinical practice, potentially enhancing the postoperative experience of women undergoing cesarean section. These findings furnish healthcare professionals with valuable insights and guidance, fostering a nuanced and improved standard of care in obstetric practices.

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis.

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-ß-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.