A New Ferroptosis-Related Long Non-Coding RNA Risk Model Predicts the Prognosis of Patients With Papillary Thyroid Cancer.

Background: Ferroptosis is a novel form of regulated cell death that involves in cancer progression. However, the role of ferroptosis-related long non-coding RNAs (lncRNAs) in papillary thyroid cancer (PTC) remains to be elucidated. The purpose of this paper was to clarify the prognostic value of ferroptosis-related lncRNAs in PTC. Methods: The transcriptome data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. The correlation between ferroptosis-related genes (FRGs) and lncRNA was determined using Pearson correlation analysis. Multivariate Cox regression model (P < 0.01) was performed to establish a ferroptosis-related lncRNAs risk model. Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, risk curve and nomograms were then performed to assess the accuracy and clinical applicability of prognostic models. The correlations between the prognosis model and clinicopathological variables, immune and m6A were analyzed. Finally, in vitro assays were performed to verify the role of LINC00900, LINC01614 and PARAL1 on the proliferation, migration and invasion in TPC-1 and BCPAP cells, as well as the relationship between three lncRNAs and ferroptosis. Results: A five-ferroptosis-related lncRNAs (PARAL1, LINC00900, DPH6-DT, LINC01614, LPP-AS2) risk model was constructed. Based on the risk score, samples were divided into the high- and low-risk groups. Patients in the low-risk group had better prognosis than those in high-risk group. Compared to traditional clinicopathological features, risk score was more accurate in predicting prognosis in patients with PTC. Additionally, the difference of immune cell, function and checkpoints was observed between two groups. Moreover, experiments showed that LINC00900 promoted the proliferation, migration and invasion in TPC-1 and BCPAP cells, while LINC01614 and PARAL1 revealed opposite effects, all of which were related to ferroptosis. Conclusions: In summary, we identified a five-ferroptosis-related lncRNAs risk model to predict the prognosis of PTC. Furthermore, our study also revealed that LINC00900 functioned as a tumor suppressor lncRNA, LINC01614 and PARAL1 as an oncogenic lncRNA in PTC.

Integrated Assays of Genome-Wide Association Study, Multi-Omics Co-Localization, and Machine Learning Associated Calcium Signaling Genes with Oilseed Rape Resistance to Sclerotinia sclerotiorum.

Sclerotinia sclerotiorum (Ss) is one of the most devastating fungal pathogens, causing huge yield loss in multiple economically important crops including oilseed rape. Plant resistance to Ss pertains to quantitative disease resistance (QDR) controlled by multiple minor genes. Genome-wide identification of genes involved in QDR to Ss is yet to be conducted. In this study, we integrated several assays including genome-wide association study (GWAS), multi-omics co-localization, and machine learning prediction to identify, on a genome-wide scale, genes involved in the oilseed rape QDR to Ss. Employing GWAS and multi-omics co-localization, we identified seven resistance-associated loci (RALs) associated with oilseed rape resistance to Ss. Furthermore, we developed a machine learning algorithm and named it Integrative Multi-Omics Analysis and Machine Learning for Target Gene Prediction (iMAP), which integrates multi-omics data to rapidly predict disease resistance-related genes within a broad chromosomal region. Through iMAP based on the identified RALs, we revealed multiple calcium signaling genes related to the QDR to Ss. Population-level analysis of selective sweeps and haplotypes of variants confirmed the positive selection of the predicted calcium signaling genes during evolution. Overall, this study has developed an algorithm that integrates multi-omics data and machine learning methods, providing a powerful tool for predicting target genes associated with specific traits. Furthermore, it makes a basis for further understanding the role and mechanisms of calcium signaling genes in the QDR to Ss.

Successfully saving a child with destuctive iliac artery damage by hybrid surgery.

Non-iatrogenic trauma of the iliac artery is rarely reported but is always life-threatening. In this report, we describe the case of a child with complete transection and partial disappearance of the iliac artery caused by bicycle handlebar impalement. He experienced catastrophic hemorrhage, malignant arrhythmia, and difficulty in exploring transected vessel stumps. Aggressive infusion, blood transfusion in time, and pediatric vascular characteristics help delay the deterioration during anesthesia induction. Eventually he was successfully rescued by performing interventional balloon occlusion and open revascularization after more than 7 h post-trauma. A series of interventions and precautionary methods may benefit such severely injured patients; thus, these methods should be highlighted.

Randomized Double-Blind Study of the Effect of Injectate Temperature on Intrathecal Bupivacaine Dose Requirement in Spinal Anesthesia for Cesarean Delivery.

BACKGROUND: Increasing the temperature of intrathecal local anesthetics has been shown to increase the speed of onset and block height of spinal anesthesia. However, how this influences dose requirement has not been fully quantified. The aim of this study was to determine and compare the effective dose for anesthesia for cesarean delivery in 50% of patients (ED50) of intrathecal bupivacaine given at temperatures of 37 °C (body temperature) or 24 °C (room temperature). METHODS: Eighty healthy parturients having elective cesarean delivery under combined spinal-epidural anesthesia were randomly assigned to receive intrathecal hyperbaric bupivacaine stored at 37 °C (body temperature group) or 24 °C (room temperature group). The first subject in each group received a bupivacaine dose of 10 mg. The dose for each subsequent subject in each group was varied with an increment or decrement of 1 mg based on the response (effective or noneffective) of the previous subject. Patients for whom the dose was noneffective received epidural supplementation after data collection with lidocaine 2% as required until anesthesia was sufficient for surgery. Values for ED50 were calculated using modified up-down sequential analysis with probit analysis applied as a backup sensitivity analysis. These values were compared and the relative mean potency was calculated. RESULTS: The ED50 (mean [95% confidence interval, CI]) of intrathecal hyperbaric bupivacaine was lower in the body temperature group (6.7 [5.7-7.6] mg) compared with the room temperature group (8.1 [7.7-8.6] mg) (P < .05). The relative potency ratio for intrathecal bupivacaine for the room temperature group versus the body temperature group was 0.84 (95% CI, 0.77-0.93). CONCLUSIONS: Warming hyperbaric bupivacaine to body temperature reduced the dose requirement for spinal anesthesia for cesarean delivery by approximately 16% (95% CI, 7%-23%).

Glutamate Receptor-like (GLR) Family in Brassica napus: Genome-Wide Identification and Functional Analysis in Resistance to Sclerotinia sclerotiorum.

Plant glutamate receptor-like channels (GLRs) are homologs of animal ionotropic glutamate receptors. GLRs are critical in various plant biological functions, yet their genomic features and functions in disease resistance remain largely unknown in many crop species. Here, we report the results on a thorough genome-wide study of the GLR family in oilseed rape (Brassica napus) and their role in resistance to the fungal pathogen Sclerotinia sclerotiorum. A total of 61 GLRs were identified in oilseed rape. They comprised three groups, as in Arabidopsis thaliana. Detailed computational analyses, including prediction of domain and motifs, cellular localization, cis-acting elements, PTM sites, and amino acid ligands and their binding pockets in BnGLR proteins, unveiled a set of group-specific characteristics of the BnGLR family, which included chromosomal distribution, motif composition, intron number and size, and methylation sites. Functional dissection employing virus-induced gene silencing of BnGLRs in oilseed rape and Arabidopsis mutants of BnGLR homologs demonstrated that BnGLR35/AtGLR2.5 positively, while BnGLR12/AtGLR1.2 and BnGLR53/AtGLR3.2 negatively, regulated plant resistance to S. sclerotiorum, indicating that GLR genes were differentially involved in this resistance. Our findings reveal the complex involvement of GLRs in B. napus resistance to S. sclerotiorum and provide clues for further functional characterization of BnGLRs.

The mediatory role of water quality on the association between extreme precipitation events and infectious diarrhea in the Yangtze River Basin, China.

Extreme precipitation is exacerbating the burden of infectious diarrhea in the context of climate change, it is necessary to identify the critical and easy-to-intervene intermediate factors for public health strategies. Water quality may be the most important mediator, while relevant empirical evidence is limited. This study aimed to examine the role of water quality in the process of infectious diarrhea caused by extreme precipitation. Weekly infectious diarrhea cases, meteorological factors and water quality data in Yangtze River Basin in China between October 29, 2007 to February 19, 2017 were obtained. Two-stage statistical models were used to estimate city-specific extreme precipitation, water quality and infectious diarrhea relationships that were pooled to derive regional estimates. A causal mediation analysis was used to assess the mediation effect of water quality. In Yangtze River Basin, extreme precipitation events had a significant impact on infectious diarrhea (Incidence Rate Ratios [IRR]: 1.027, 95% Confidence Interval [CI]: 1.013∼1.041). After extreme precipitation events, the dissolved oxygen (DO) in surface water decreased (-0.123 mg/L, 95%CI: -0.159 mg/L∼-0.086 mg/L), while the un-ionized ammonia (NH(3)-N) increased (0.004 mg/L, 95%CI: 0.001 mg/L∼0.006 mg/L). The combined overall effect of DO and NH(3)-N on infectious diarrhea showed that both low and high concentrations were associated with an increased risk of infectious diarrhea. The causal mediation analysis showed that the mediation proportion of the two water quality indexes (DO and NH(3)-N) is 70.54% (P < 0.001). To reduce the health effects of extreme precipitation, in contrast to current population-oriented health strategies, those that take into account more direct and easy-to-intervene water quality indicators should be encouraged by future policies.

Synergistic impact of 25-hydroxyvitamin D concentrations and physical activity on delaying aging.

OBJECTIVE: Our study aims to examine the independent and combined associations of serum 25-hydroxyvitamin D [25(OH)D] concentrations and physical activity (PA) status with phenotypic age (PhenoAge). METHOD: The analysis included 18,738 participants from the NHANES 2007-2010 & 2015-2018. Phenotypic Age Acceleration (PhenoAgeAccel) was calculated as the residuals from regressing PhenoAge on chronological age. Weighted multivariable logistic regression models were used to analysis the relationship between 25(OH)D and PA with PhenoAgeAccel. Population attributable fraction (PAF) was used to estimate the proportion of PhenoAgeAccel which could be avoided if exposure were eliminated. RESULTS: The multivariate-adjusted OR (95%CI) for PhenoAgeAccel with high 25(OH)D and adequate PA were 0.657 (0.549,0.787) (p < 0.001) for all, 0.663 (0.538,0.818) (p < 0.001) for participants whose age ≤65years old. Furthermore, there was multiplicative interaction between 25(OH)D and PA in age ≤65 years old group (0.729 (0.542,0.979), p = 0.036). High 25(OH)D level and adequate PA reduced the risk of PhenoAgeAccel by 14.3 % and 14.2 %, respectively. Notably, 30.7 % decrease was attributable to both high 25(OH)D level and engaging in adequate PA concurrently. Combining 25(OH)D above 80.4 nmol/l with PA decreased PhenoAge by 1.291 years (p < 0.001). CONCLUSION: Higher 25(OH)D level was associated with lower risk of biological ageing. Combining 25(OH)D and PA demonstrated enhanced protective effects, especially in middle or young adults. These findings underscore the importance of outdoor PA in slowing down the aging process.

Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial.

OBJECTIVE: To determine whether a single low dose of esketamine administered after childbirth reduces postpartum depression in mothers with prenatal depression. DESIGN: Randomised, double blind, placebo controlled trial with two parallel arms. SETTING: Five tertiary care hospitals in China, 19 June 2020 to 3 August 2022. PARTICIPANTS: 364 mothers aged ≥18 years who had at least mild prenatal depression as indicated by Edinburgh postnatal depression scale scores of ≥10 (range 0-30, with higher scores indicating worse depression) and who were admitted to hospital for delivery. INTERVENTIONS: Participants were randomly assigned 1:1 to receive either 0.2 mg/kg esketamine or placebo infused intravenously over 40 minutes after childbirth once the umbilical cord had been clamped. MAIN OUTCOME MEASURES: The primary outcome was prevalence of a major depressive episode at 42 days post partum, diagnosed using the mini-international neuropsychiatric interview. Secondary outcomes included the Edinburgh postnatal depression scale score at seven and 42 days post partum and the 17 item Hamilton depression rating scale score at 42 days post partum (range 0-52, with higher scores indicating worse depression). Adverse events were monitored until 24 hours after childbirth. RESULTS: A total of 364 mothers (mean age 31.8 (standard deviation 4.1) years) were enrolled and randomised. At 42 days post partum, a major depressive episode was observed in 6.7% (12/180) of participants in the esketamine group compared with 25.4% (46/181) in the placebo group (relative risk 0.26, 95% confidence interval (CI) 0.14 to 0.48; P<0.001). Edinburgh postnatal depression scale scores were lower in the esketamine group at seven days (median difference -3, 95% CI -4 to -2; P<0.001) and 42 days (-3, -4 to -2; P<0.001). Hamilton depression rating scale scores at 42 days post partum were also lower in the esketamine group (-4, -6 to -3; P<0.001). The overall incidence of neuropsychiatric adverse events was higher in the esketamine group (45.1% (82/182) v 22.0% (40/182); P<0.001); however, symptoms lasted less than a day and none required drug treatment. CONCLUSIONS: For mothers with prenatal depression, a single low dose of esketamine after childbirth decreases major depressive episodes at 42 days post partum by about three quarters. Neuropsychiatric symptoms were more frequent but transient and did not require drug intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT04414943.

Inhibiting the Aggregation of Aß by Natural Product Molecules.

The abnormal aggregation of Aß has been considered one of the primary causative factors for Alzheimer's disease. Diverse molecular entities have been developed to mitigate the formation of toxic Aß aggregates within the brain by inhibiting Aß aggregation. Recognizing that many FDA-approved drugs are derived from natural products, we present a summary of recent discoveries involving natural product molecules with inhibitory effects on Aß aggregation. By consolidating these findings, our review offers researchers a concise overview of the latest advancements in natural product-based interventions for Alzheimer's disease.

High-throughput sequencing-based analysis of the composition and diversity of the endophyte community in roots of Stellera chamaejasme.

Stellera chamaejasme (S. chamaejasme) is an important medicinal plant with heat-clearing, detoxifying, swelling and anti-inflammatory effects. At the same time, it is also one of the iconic plants of natural grassland degradation in northwest China, playing a key role in the invasion process. Plant endophytes live in healthy plant tissues and can synthesize substances needed for plant growth, induce disease resistance in host plants, and enhance plant resistance to environmental stress. Therefore, studying the root endophytes of S. chamaejasme is of great significance for mining beneficial microbial resources and biological prevention and control of S. chamaejasme. This study used Illumina MiSeq high-throughput sequencing technology to analyze the composition and diversity of endophytes in the roots of S. chamaejasme in different alpine grasslands (BGC, NMC and XGYZ) in Tibet. Research results show that the main phylum of endophytic fungi in the roots of S. chamaejasme in different regions is Ascomycota, and the main phyla of endophytic bacteria are Actinobacteria, Proteobacteria and Firmicutes (Bacteroidota). Overall, the endophyte diversity of the NMC samples was significantly higher than that of the other two sample sites. Principal coordinate analysis (PCoA) and permutational multivariate analysis of variance (PERMANOVA) results showed significant differences in the composition of endophytic bacterial and fungal communities among BGC, NMC and XGYZ samples. Co-occurrence network analysis of endophytes showed that there were positive correlations between fungi and some negative correlations between bacteria, and the co-occurrence network of bacteria was more complex than that of fungi. In short, this study provides a vital reference for further exploring and utilizing the endophyte resources of S. chamaejasme and an in-depth understanding of the ecological functions of S. chamaejasme endophytes.

Greater upper limb muscle mass associated with reduced cardiovascular mortality compared with other muscle groups in diabetics.

OBJECTIVES: Although muscle mass and its distribution have been shown to affect prognosis, the association between regional muscle mass and cardiovascular mortality risk in diabetic patients remains unclear. METHODS: This prospective cohort study analyzed data from 2166 individuals with diabetes who participated in the National Health and Nutrition Survey conducted in the United States between 2003 to 2006 and 2011 to 2018, linked to the National Death Index. Weighted Kaplan-Meier analysis and multivariable Cox proportional hazards models were used to explore the association between different regional lean mass and cardiovascular mortality. RESULTS: The weighted Kaplan-Meier analysis revealed statistically significant differences in survival probabilities across lean upper limbs, lean lower limbs, lean gynoid, and lean trunk mass levels in diabetic participants (P < 0.05). In the multivariate adjusted Cox proportional hazards models, higher levels of upper limb lean mass were found to be associated with decreased cardiovascular mortality (hazard ratio, 0.589; 95% confidence interval, 0.332-0.976; P = 0.041). Notably, this correlation was more significant in men (hazard ratio, 0.378; 95% confidence interval, 0.171-0.834; P = 0.016), which was indicated by the results of the Cox regression and nonlinear regression analysis. CONCLUSIONS: Higher upper limb lean mass is associated with lower cardiovascular mortality compared with other regional lean mass in patients with diabetes, especially for men. Further research is needed to elucidate the mechanisms involved in muscle metabolic differentiation.

Effect of Remimazolam Supplementation on Propofol Requirements During Hysteroscopy: A Double-Blind, Dose-Response Study.

BACKGROUND: Propofol is commonly used for procedural sedation but may increase side effects in a dose-dependent manner. Remimazolam, an ultrashort-acting benzodiazepine, has been approved for procedural sedation but may delay awakening. This study tested the hypothesis that remimazolam as a supplement reduces effect-site propofol concentration (Ceprop) required to suppress response to cervical dilation in patients undergoing hysteroscopy. METHODS: One hundred and fifty patients who were scheduled for hysteroscopy were randomized to receive 0, 0.05, 0.1, 0.15, or 0.2 mg·kg-1 intravenous remimazolam, followed by a bolus of sufentanil 0.15 µg⋅kg-1, and a target-controlled propofol infusion. The initial target Ceprop was 3.5 µg·mL-1 and was increased or decreased in subsequent patients by steps of 0.5 µg·mL-1 according to whether there was loss of response to cervical dilation in the previous patient. We used up-down sequential analysis to determine values of Ceprop that suppressed response to cervical dilation in 50% of patients (EC50). RESULTS: The EC50 of propofol for suppressing response to cervical dilation was lower in patients given 0.1 mg·kg-1 (2.08 [95% confidence interval, CI, 1.88-2.28] µg·mL-1), 0.15 mg⋅kg-1 (1.83 [1.56-2.10] µg·mL-1), and 0.2 mg⋅kg-1 (1.43 [1.27-1.58] µg·mL-1) remimazolam than those given 0 mg⋅kg-1 (3.67 [3.49-3.86] µg·mL-1) or 0.05 mg⋅kg-1 (3.47 [3.28-3.67] µg·mL-1) remimazolam (all were P < .005). Remimazolam at doses of 0.1, 0.15, and 0.2 mg·kg-1 decreased EC50 of propofol by 43.3% (95% CI, 41.3%-45.5%), 50.3% (48.0%-52.8%), and 61.2% (58.7%-63.8%), respectively, from baseline (remimazolam 0 mg⋅kg-1). Propofol consumption was lower in patients given 0.1 mg⋅kg-1 (4.15 [3.51-5.44] mg·kg-1), 0.15 mg⋅kg-1 (3.54 [3.16-4.46] mg·kg-1), and 0.2 mg⋅kg-1 (2.74 [1.73-4.01] mg·kg-1) remimazolam than those given 0 mg⋅kg-1 (6.09 [4.99-7.35] mg·kg-1) remimazolam (all were P < .005). Time to anesthesia emergence did not differ significantly among the 5 groups. CONCLUSIONS: For women undergoing hysteroscopic procedures, remimazolam at doses from 0.1 to 0.2 mg·kg-1 reduced the EC50 of propofol inhibiting response to cervical dilation and the total propofol requirement. Whether the combination could improve perioperative outcomes deserves further investigation.

Net greenhouse gas balance in U.S. croplands: How can soils be part of the climate solution?

Agricultural soils play a dual role in regulating the Earth's climate by releasing or sequestering carbon dioxide (CO2 ) in soil organic carbon (SOC) and emitting non-CO2 greenhouse gases (GHGs) such as nitrous oxide (N2 O) and methane (CH4 ). To understand how agricultural soils can play a role in climate solutions requires a comprehensive assessment of net soil GHG balance (i.e., sum of SOC-sequestered CO2 and non-CO2 GHG emissions) and the underlying controls. Herein, we used a model-data integration approach to understand and quantify how natural and anthropogenic factors have affected the magnitude and spatiotemporal variations of the net soil GHG balance in U.S. croplands during 1960-2018. Specifically, we used the dynamic land ecosystem model for regional simulations and used field observations of SOC sequestration rates and N2 O and CH4 emissions to calibrate, validate, and corroborate model simulations. Results show that U.S. agricultural soils sequestered 13.2 ± 1.16 $$ 13.2\pm 1.16 $$ Tg CO2 -C year-1 in SOC (at a depth of 3.5 m) during 1960-2018 and emitted 0.39 ± 0.02 $$ 0.39\pm 0.02 $$ Tg N2 O-N year-1 and 0.21 ± 0.01 $$ 0.21\pm 0.01 $$ Tg CH4 -C year-1 , respectively. Based on the GWP100 metric (global warming potential on a 100-year time horizon), the estimated national net GHG emission rate from agricultural soils was 122.3 ± 11.46 $$ 122.3\pm 11.46 $$ Tg CO2 -eq year-1 , with the largest contribution from N2 O emissions. The sequestered SOC offset ~28% of the climate-warming effects resulting from non-CO2 GHG emissions, and this offsetting effect increased over time. Increased nitrogen fertilizer use was the dominant factor contributing to the increase in net GHG emissions during 1960-2018, explaining ~47% of total changes. In contrast, reduced cropland area, the adoption of agricultural conservation practices (e.g., reduced tillage), and rising atmospheric CO2 levels attenuated net GHG emissions from U.S. croplands. Improving management practices to mitigate N2 O emissions represents the biggest opportunity for achieving net-zero emissions in U.S. croplands. Our study highlights the importance of concurrently quantifying SOC-sequestered CO2 and non-CO2 GHG emissions for developing effective agricultural climate change mitigation measures.

Neuron-derived exosomes mediate sevoflurane-induced neurotoxicity in neonatal mice via transferring lncRNA Gas5 and promoting M1 polarization of microglia.

Sevoflurane exposure during rapid brain development induces neuronal apoptosis and causes memory and cognitive deficits in neonatal mice. Exosomes that transfer genetic materials including long non-coding RNAs (lncRNAs) between cells play a critical role in intercellular communication. However, the lncRNAs found in exosomes derived from neurons treated with sevoflurane and their potential role in promoting neurotoxicity remain unknown. In this study, we investigated the role of cross-talk of newborn mouse neurons with microglial cells in sevoflurane-induced neurotoxicity. Mouse hippocampal neuronal HT22 cells were exposed to sevoflurane, and then co-cultured with BV2 microglial cells. We showed that sevoflurane treatment markedly increased the expression of the lncRNA growth arrest-specific 5 (Gas5) in neuron-derived extracellular vesicles, which inhibited neuronal proliferation and induced neuronal apoptosis by promoting M1 polarization of microglia and the release of inflammatory cytokines. We further revealed that the exosomal lncRNA Gas5 significantly upregulated Foxo3 as a competitive endogenous RNA of miR-212-3p in BV2 cells, and activated the NF-κB pathway to promote M1 microglial polarization and the secretion of inflammatory cytokines, thereby exacerbating neuronal damage. In neonatal mice, intracranial injection of the exosomes derived from sevoflurane-treated neurons into the bilateral hippocampi significantly increased the proportion of M1 microglia, inhibited neuronal proliferation and promoted apoptosis, ultimately leading to neurotoxicity. Similar results were observed in vitro in BV2 cells treated with the CM from HT22 cells after sevoflurane exposure. We conclude that sevoflurane induces the transfer of lncRNA Gas5-containing exosomes from neurons, which in turn regulates the M1 polarization of microglia and contributes to neurotoxicity. Thus, modulating the expression of lncRNA Gas5 or the secretion of exosomes could be a strategy for addressing sevoflurane-induced neurotoxicity.

Mechanism of Qizhu Kang'ai Prescription for Inhibiting Proliferation of Hepatocellular Carcinoma by Regulating Tumor Metabolic Reprogramming via PCK1/Akt/p21 Signal Axis / 中国实验方剂学杂志

ObjectiveTo study the effect of Qizhu Kang'ai prescription （QZAP） on the gluconeogenesis enzyme phosphoenolpyruvate carboxykinase 1 （PCK1） in the liver of mouse model of liver cancer induced by diethylnitrosamine （DEN） combined with carbon tetrachloride （CCl4） and Huh7 cells of human liver cancer， so as to explore the mechanism on regulating metabolic reprogramming and inhibiting cell proliferation of liver cancer cells. MethodDEN combined with CCl4 was used to construct a mouse model of liver cancer via intraperitoneal injection. A normal group， a model group， and a QZAP group were set up， in which QZAP （3.51 g·kg-1） or an equal volume of normal saline was administered daily by gavage， respectively. Serum and liver samples were collected after eight weeks of intervention. Serum alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， γ-glutamyltransferase （γ-GT）， and alpha-fetoprotein （AFP） in mice were detected to evaluate liver function changes of mice in each group. Hematoxylin-eosin （HE） staining and Sirius red staining were used to observe pathological changes in liver tissue. In the cell experiment， Huh7 cells were divided into blank group， QZAP low， medium， and high dose groups and/or PCK1 inhibitor （SKF-34288 hydrochloride） group， and Sorafenib group. The corresponding drug-containing serum and drug treatment were given， respectively. Cell counting kit-8 （CCK-8） method， colony formation experiment， Edu fluorescent labeling detection， intracellular adenosine triphosphate （ATP） content detection， and cell cycle flow cytometry detection were used to evaluate the proliferation ability， energy metabolism changes， and change in the cell cycle of Huh7 cells in each group. Western blot was used to detect the protein expression levels of PCK1， serine/threonine kinase （Akt）， phosphorylated Akt （p-Akt）， and cell cycle-dependent protein kinase inhibitor 1A （p21）. ResultCompared with the model group， the pathological changes such as cell atypia， necrosis， and collagen fiber deposition in liver cancer tissue of mice in the QZAP group were alleviated， and the number of liver tumors was reduced （P<0.01）. The serum ALT， AST， γ-GT， and AFP levels were reduced （P<0.01）. At the cell level， compared with the blank group， low， medium， and high-dose groups of QZAP-containing serum and the Sorafenib group could significantly reduce the survival rate of Huh7 cells （P<0.01） and the number of positive cells with Edu labeling （P<0.01） and inhibit clonal proliferation ability （P<0.01）. The QZAP groups could also reduce the intracellular ATP content （P<0.05） and increase the distribution ratio of the G0/G1 phase of the cell cycle （P<0.05） in a dose-dependent manner. Compared with the model group and blank group， PCK1 and p21 protein levels of mouse liver cancer tissue and Huh7 cells in the QZAP groups were significantly reduced （P<0.05，P<0.01）， and the p-Akt protein level was significantly increased （P<0.01）. Compared with the blank group， the ATP content and cell survival rate of Huh7 cells in the SKF-34288 hydrochloride group were significantly increased （P<0.05）， but there was no statistical difference in the ratio of Edu-positive cells and the proportion of G0/G1 phase distribution. Compared with the SKF-34288 hydrochloride group， the QZAP combined with the SKF-34288 hydrochloride group significantly reduced the ATP content， cell survival rate， and Edu-positive cell ratio of Huh7 cells （P<0.05） and significantly increased the G0/G1 phase distribution proportion （P<0.05）. ConclusionQZAP may induce the metabolic reprogramming of liver cancer cells by activating PCK1 to promote Akt/p21-mediated tumor suppression， thereby exerting an anti-hepatocellular carcinoma proliferation mechanism.

Management of Male Infertility with Coexisting Sexual Dysfunction: A Consensus Statement and Clinical Recommendations from the Asia-Pacific Society of Sexual Medicine (APSSM) and the Asian Society of Men's Health and Aging (ASMHA).

Male infertility (MI) and male sexual dysfunction (MSD) can often coexist together due to various interplay factors such as psychosexual, sociocultural and relationship dynamics. The presence of each form of MSD can adversely impact male reproduction and treatment strategies will need to be individualized based on patients' factors, local expertise, and geographical socioeconomic status. The Asia Pacific Society of Sexual Medicine (APSSM) and the Asian Society of Men's Health and Aging (ASMHA) aim to provide a consensus statement and practical set of clinical recommendations based on current evidence to guide clinicians in the management of MI and MSD within the Asia-Pacific (AP) region. A comprehensive, narrative review of the literature was performed to identify the various forms of MSD and their association with MI. MEDLINE and EMBASE databases were searched for the following English language articles under the following terms: "low libido", "erectile dysfunction", "ejaculatory dysfunction", "premature ejaculation", "retrograde ejaculation", "delayed ejaculation", "anejaculation", and "orgasmic dysfunction" between January 2001 to June 2022 with emphasis on published guidelines endorsed by various organizations. This APSSM consensus committee panel evaluated and provided evidence-based recommendations on MI and clinically relevant MSD areas using a modified Delphi method by the panel and specific emphasis on locoregional socio-economic-cultural issues relevant to the AP region. While variations exist in treatment strategies for managing MI and MSD due to geographical expertise, locoregional resources, and sociocultural factors, the panel agreed that comprehensive fertility evaluation with a multidisciplinary management approach to each MSD domain is recommended. It is important to address individual MI issues with an emphasis on improving spermatogenesis and facilitating reproductive avenues while at the same time, managing various MSD conditions with evidence-based treatments. All therapeutic options should be discussed and implemented based on the patient's individual needs, beliefs and preferences while incorporating locoregional expertise and available resources.

RALF22 promotes plant immunity and amplifies the Pep3 immune signal.

Rapid alkalinization factors (RALFs) in plants have been reported to dampen pathogen-associated molecular pattern (PAMP)-triggered immunity via suppressing PAMP-induced complex formation between the pattern recognition receptor (PRR) and its co-receptor BAK1. However, the direct and positive role of RALFs in plant immunity remains largely unknown. Herein, we report the direct and positive roles of a typical RALF, RALF22, in plant immunity. RALF22 alone directly elicited a variety of typical immune responses and triggered resistance against the devastating necrotrophic fungal pathogen Sclerotinia sclerotiorum in a FERONIA (FER)-dependent manner. LORELEI (LRE)-like glycosylphosphatidylinositol (GPI)-anchored protein 1 (LLG1) and NADPH oxidase RBOHD were required for RALF22-elicited reactive oxygen species (ROS) generation. The mutation of cysteines conserved in the C terminus of RALFs abolished, while the constitutive formation of two disulfide bridges between these cysteines promoted the RALF22-elicited ROS production and resistance against S. sclerotiorum, demonstrating the requirement of these cysteines in the functions of RALF22 in plant immunity. Furthermore, RALF22 amplified the Pep3-induced immune signal by dramatically increasing the abundance of PROPEP3 transcript and protein. Supply with RALF22 induced resistance against S. sclerotiorum in Brassica crop plants. Collectively, our results reveal that RALF22 triggers immune responses and augments the Pep3-induced immune signal in a FER-dependent manner, and exhibits the potential to be exploited as an immune elicitor in crop protection.

The optimal oxytocin infusion rate for preventing uterine atony during cesarean delivery in elderly parturients with prior history of cesarean delivery.

Background: An estimate of 90% effective dose (ED90) of oxytocin infusion has already been proved effective in non-laboring parturients. However, the requirements of oxytocin for elderly parturients with prior history of cesarean delivery (CD) may be higher. The aim of this study was to find the optimum oxytocin infusion rate for preventing uterine atony during CD in elderly parturients with prior history of CD. Method: We performed a randomized, double-blinded study in 120 healthy elderly parturients with prior history of CD scheduled for elective CD under combined spinal-epidural (CSE) anesthesia. Participants were treated with oxytocin infusion randomly at the rates of 0, 4, 8, 12, 16, or 20 IU h-1 after the delivery of infants. Following oxytocin administration, a blinded obstetrician evaluated the uterine tone (UT), verbally describing it using numerical scales (0-10: 0, no UT; 10, optimal UT) as either adequate or inadequate at the time intervals of 3, 6, and 9 min. Maternal adverse effects, requirements for additional uterotonic agents, delivery-placenta delivery time (PD), and estimated blood loss (EBL) were recorded. Results: The 50% effective dose (ED50) and 90% effective dose (ED90) of oxytocin infusion were 14.6 IU h-1 (95% confidence interval 12.0-18.4 IU h-1) and 27.7 IU h-1 (95% confidence interval 22.5-39.4 IU h-1), respectively. As the rate of infusion was increased in parturients, the rescue oxytocin dose and delivery-PD time were decreased. Parturients who received 0 IU h-1 oxytocin at 3, 6, and 9 min obtained lower UT scores than those who received 16 and 20 IU h-1 oxytocin (p < 0.05, respectively). No significant differences were observed among groups in EBL and maternal adverse effects. Conclusion: The infusion rate of oxytocin at 14.57 and 27.74 IU h-1 produces adequate UT in 50% and 90% of elderly parturients with prior history of CD, respectively. An oxytocin infusion rate of 27.7 IU h-1 is suggested to be the optimal dose for preventing uterine atony during CD in elderly parturients with prior history of cesarean delivery. Clinical Trial Registration: [https://www.chictr.org.cn/bin/project/edit?pid=62489], Identifier: [ChiCTR2000038891].

Comparison of Dural Puncture Epidural, Epidural and Combined Spinal-Epidural Anesthesia for Cesarean Delivery: A Randomized Controlled Trial.

Purpose: Catheter-based techniques such as combined spinal-epidural (CSE) anesthesia which are sometimes indicated for obstetric anesthesia have a complex mechanism of action. The application of the dural puncture epidural (DPE) anesthesia for cesarean section (CS) has not been well investigated. The present study compared the relatively novel DPE technique with epidural (EA) and CSE anesthesia. Patients and Methods: We randomly assigned 150 parturients who underwent elective CS to receive DPE, EA or CSE anesthesia. The primary outcome was the onset of sensory anesthesia to the T5 dermatome assessed using the Cox proportional hazards model. Secondary outcomes included median time to sensory block, quality of block, patient and surgeon satisfaction, APGAR scores and other side effects. Results: For DPE anesthesia versus EA anesthesia, the onset of anesthesia was faster (hazard ratio 2.47 [95% CI 1.56 to 3.90], adjusted P < 0.001) and the median time to surgical level was shorter (16 [IQR 14-18] min versus 19 [15.5-21] min, adjusted P < 0.001); the incidence of intraoperative pain was lower (7/48 versus 17/47, adjusted P = 0.046) and the median patient satisfaction score was higher (9 [IQR 9-10] versus 8 [8-9.5], adjusted P = 0.004). In the CSE group, the onset of anesthesia was faster than in the other two but the incidence of hypotension was higher (P < 0.001) and the phenylephrine requirement was greater (P < 0.001). Conclusion: DPE anesthesia had a faster onset and better quality of block than EA anesthesia and provided less influence to maternal hemodynamic parameters than CSE anesthesia for CS. These results suggest that the dural puncture plays a significant role in enhancing the effectiveness of epidural top-ups during CSE anesthesia and indicates enlightenment that contributes to the satisfaction of anesthetic effect in DPE technique labor analgesia transferred to CS.