The level of partial pressure of carbon dioxide affects organ perfusion in respiratory failure patients undergoing pressure support ventilation with venovenous extracorporeal membrane oxygenation: a prospective study.

BACKGROUND: We evaluated the influence of different partial carbon dioxide pressure (PaCO2) levels on organ perfusion in patients with respiratory failure receiving pressure-support ventilation with veno-venous extracorporeal membrane oxygenation (V-V ECMO). METHODS: In this twelve patients prospective study, ECMO gas-flow was decreased from baseline (PaCO2 < 40 mmHg) until PaCO2 increased by 5-10 mmHg (High-CO2 phase). Resistance indices of gut, spleen, and snuffbox artery, the peripheral perfusion index (PPI), and heart rate variability were measured at baseline and High-CO2 phase. RESULTS: When PaCO2 increased from 36 (36-37) mmHg at baseline to 42 (41-43) mmHg in the High-CO2 phase (p < 0.001), PPI decreased significantly (p = 0.026). The snuffbox artery (p = 0.022), superior mesenteric artery (p = 0.042), and spleen (p = 0.012) resistance indices increased significantly. The root mean square of successive differences (RMSSD) decreased from 19.5(18.1-22.7) to 15.9(14.4-18.6) ms (p = 0.034), and the ratio of low-frequency to high-frequency components(LF/HF) increased from 0.47 ± 0.23 to 0.70 ± 0.38 (p = 0.013). CONCLUSIONS: High PaCO2 might cause decreased peripheral tissue and visceral organ perfusion through autonomic nervous system in patients with respiratory failure undergoing PSV with V-V ECMO.

A transcriptional cascade involving BBX22 and HY5 finely regulates both plant height and fruit pigmentation in citrus.

Dwarfing is a pivotal agronomic trait affecting both yield and quality. Citrus species exhibit substantial variation in plant height, among which internode length is a core element. However, the molecular mechanism governing internode elongation remains unclear. Here, we unveiled that the transcriptional cascade consisting of B-BOX DOMAIN PROTEIN 22 (BBX22) and ELONGATED HYPOCOTYL 5 (HY5) finely tunes plant height and internode elongation in citrus. Loss-of-function mutations of BBX22 in an early-flowering citrus (Citrus hindsii "SJG") promoted internode elongation and reduced pigment accumulation, whereas ectopic expression of BBX22 in SJG, sweet orange (C. sinensis), pomelo (C. maxima) or heterologous expression of BBX22 in tomato (Solanum lycopersicum) significantly decreased internode length. Furthermore, exogenous application of gibberellin A3 (GA3) rescued the shortened internode and dwarf phenotype caused by BBX22 overexpression. Additional experiments revealed that BBX22 played a dual role in regulation internode elongation and pigmentation in citrus. On the one hand, it directly bound to and activated the expression of HY5, GA metabolism gene (GA2 OXIDASE 8, GA2ox8), carotenoid biosynthesis gene (PHYTOENE SYNTHASE 1, PSY1) and anthocyanin regulatory gene (Ruby1, a MYB DOMAIN PROTEIN). On the other hand, it acted as a cofactor of HY5, enhancing the ability of HY5 to regulate target genes expression. Together, our results reveal the critical role of the transcriptional cascade consisting of BBX22 and HY5 in controlling internode elongation and pigment accumulation in citrus. Unraveling the crosstalk regulatory mechanism between internode elongation and fruit pigmentation provides key genes for breeding of novel types with both dwarf and health-beneficial fortification in citrus.

[Diagnostic Efficacy of Platelet-Related Parameters on Anxiety and Depression in Patients Undergoing Peritoneal Dialysis].

Objective To analyze the correlations between platelet-related parameters and the incidence of anxiety and depression in the patients undergoing peritoneal dialysis(PD),and evaluate the efficacy of the parameters in the diagnosis of anxiety and depression in PD patients. Methods A total of 245 patients undergoing PD in the First Affiliated Hospital of Hebei North University from September 2022 to February 2023 were enrolled.The generalized anxiety scale(GAD-7) and the patient health questionnaire(PHQ-9) were used to evaluate the anxiety and depression of the patients,respectively.The personal information and biochemical indicators of the patients were collected,and the platelet count(PLT),mean platelet volume(MPV),and platelet distribution width(PDW) were measured.Logistic regression was adopted to analyze the relationships of platelet-related parameters with anxiety and depression in PD patients. Results Among the 245 patients undergoing PD,the incidences of anxiety and depression were 15.9% and 38.0%,respectively.There were differences in the dialysis period(Z=-2.358,P=0.018;Z=-3.079,P=0.002),MPV(Z=-4.953,P<0.001;Z=-7.878,P<0.001),and PDW(Z=-4.587,P<0.001;Z=-7.367,P<0.001) between the anxiety group and the non-anxiety group as well as between the depression group and the non-depression group.The correlation analysis showed that MPV(r=0.358,P<0.001;r=0.489,P<0.001) and PDW(r=0.340,P<0.001;r=0.447,P<0.001) were positively correlated with anxiety and depression in the patients undergoing PD.The Logistic regression model showed that MPV(P=0.022,P=0.011),PDW(P=0.041,P=0.018),and dialysis period(P=0.011,P=0.030) were independent risk factors for the anxiety and depressive state in PD patients.The areas under the receiver operating characteristic curve of MPV in the diagnosis of anxiety and depression in PD patients were 0.750 and 0.800,respectively,and those of PDW were 0.732 and 0.780,respectively. Conclusion MPV and PDW have high efficacy in the diagnosis of anxiety and depression associated with PD and can be used as objective indicators to evaluate the anxiety and depression in the patients undergoing PD.

Value of DUSP6 in peripheral blood mononuclear cells in predicting adverse cardiovascular events after peritoneal dialysis in diabetic nephropathy. / å¤–å‘¨è¡€å•ä¸ªæ ¸ç»†èƒžä¸­DUSP6é¢„è­¦ç³–å°¿ç— è‚¾ç— è ¹è†œé€æžåŽä¸è‰¯å¿ƒè¡€ç®¡äº‹ä»¶çš„ä»·å€¼.

OBJECTIVES: Adverse cardiovascular events are the leading cause of death in peritoneal dialysis patients. Identifying indicators that can predict adverse cardiovascular events in these patients is crucial for prognosis. This study aims to assess the value of dual-specificity phosphatase 6 (DUSP6) in peripheral blood mononuclear cells as a predictor of adverse cardiovascular events after peritoneal dialysis in diabetic nephropathy patients. METHODS: A total of 124 diabetic nephropathy patients underwent peritoneal dialysis treatment at the Department of Nephrology of the First Affiliated Hospital of Hebei North University from June to September 2022 were selected as study subjects. The levels of DUSP6 in peripheral blood mononuclear cells were determined using Western blotting. Patients were categorized into high-level and low-level DUSP6 groups based on the median DUSP6 level. Differences in body mass index, serum albumin, high-sensitivity C-reactive protein, and dialysis duration were compared between the 2 groups. Pearson, Spearman, and multiple linear regression analyses were performed to examine factors related to DUSP6. Patients were followed up to monitor the occurrence of adverse cardiovascular events, and risk factors for adverse cardiovascular events after peritoneal dialysis were analyzed using Kaplan-Meier and Cox regression. RESULTS: By the end of the follow-up, 33 (26.61%) patients had experienced at least one adverse cardiovascular event. The high-level DUSP6 group had higher body mass index, longer dialysis duration, and higher high-sensitivity C-reactive protein, but lower serum albumin levels compared to the low-level DUSP6 group (all P<0.05). DUSP6 was negatively correlated with serum albumin levels (r=-0.271, P=0.002) and positively correlated with dialysis duration (rs=0.406, P<0.001) and high-sensitivity C-reactive protein (rs=0.367, P<0.001). Multiple linear regression analysis revealed that dialysis duration and high-sensitivity C-reactive protein were independently correlated with DUSP6 levels (both P<0.05). The cumulative incidence of adverse cardiovascular events was higher in the high-level DUSP6 group than in the low-level DUSP6 group (46.67% vs 7.81%, P<0.001). Cox regression analysis indicated that low serum albumin levels (HR=0.836, 95% CI 0.778 to 0.899), high high-sensitivity C-reactive protein (HR=1.409, 95% CI 1.208 to 1.644), and high DUSP6 (HR=6.631, 95% CI 2.352 to 18.693) were independent risk factors for adverse cardiovascular events in peritoneal dialysis patients. CONCLUSIONS: Dialysis duration and high-sensitivity C-reactive protein are independently associated with DUSP6 levels in peripheral blood mononuclear cells of diabetic nephropathy patients undergoing peritoneal dialysis. High DUSP6 levels indicate a higher risk of adverse cardiovascular events.

Visual and Rapid Detection of Nerve Agent Mimics in Gas and Solution Phase by a Simple Fluorescent Probe.

Chemical nerve agents are highly toxic organophosphorus compounds that are easy to obtain and can be utilized by terrorists to threaten homeland security and human safety. Those organophosphorus nerve agents contain nucleophilic ability that can react with acetylcholinesterase leading to muscular paralysis and human death. Therefore, there is great importance to explore a reliable and simple method to detect chemical nerve agents. Herein, the o-phenylenediamine-linked dansyl chloride as a colorimetric and fluorescent probe has been prepared to detect specific chemical nerve agent stimulants in the solution and vapor phase. The o-phenylenediamine unit serves as a detection site that can react with diethyl chlorophosphate (DCP) in a rapid response within 2 min. A satisfied relationship line was obtained between fluorescent intensity and the concentration of DCP in the range of 0-90 µM. In the optimized conditions, we conducted the fluorescent titration to measure the limits of detection (0.082 µM) with the fluorescent enhancement up to 18-fold. Fluorescence titration and NMR studies were also conducted to explore the detection mechanism, indicating that the formation of phosphate ester causes the intensity of fluorescent change during the PET process. Finally, probe 1 coated with the paper test is utilized to detect DCP vapor and solution by the naked eye. We expect that this probe may give some admiration to design the small molecule organic probe and applied in the selectivity detection of chemical nerve agents.

Evolution-guided multiomics provide insights into the strengthening of bioactive flavone biosynthesis in medicinal pummelo.

Pummelo (Citrus maxima or Citrus grandis) is a basic species and an important type for breeding in Citrus. Pummelo is used not only for fresh consumption but also for medicinal purposes. However, the molecular basis of medicinal traits is unclear. Here, compared with wild citrus species/Citrus-related genera, the content of 43 bioactive metabolites and their derivatives increased in the pummelo. Furthermore, we assembled the genome sequence of a variety for medicinal purposes with a long history, Citrus maxima 'Huazhouyou-tomentosa' (HZY-T), at the chromosome level with a genome size of 349.07 Mb. Comparative genomics showed that the expanded gene family in the pummelo genome was enriched in flavonoids-, terpenoid-, and phenylpropanoid biosynthesis. Using the metabolome and transcriptome of six developmental stages of HZY-T and Citrus maxima 'Huazhouyou-smooth' (HZY-S) fruit peel, we generated the regulatory networks of bioactive metabolites and their derivatives. We identified a novel MYB transcription factor, CmtMYB108, as an important regulator of flavone pathways. Both mutations and expression of CmtMYB108, which targets the genes PAL (phenylalanine ammonia-lyase) and FNS (flavone synthase), displayed differential expression between Citrus-related genera, wild citrus species and pummelo species. This study provides insights into the evolution-associated changes in bioactive metabolism during the origin process of pummelo.

Meerwein Arylation of Aryl(alkyl)idenemalononitriles and Diazonium Salts for the Synthesis of 2-(Aryl(alkyl)/arylmethylene)malononitrile Derivatives.

A metal-free Meerwein arylation reaction from aryl(alkyl)idenemalononitriles and diazonium salts for the synthesis of 2-(aryl(alkyl)/arylmethylene)malononitrile derivatives under mild conditions was well developed. Different from the general addition reactions between alkenes and diazonium salts, this study performed the traditional coupling reaction for the formation of C(sp2)-C(sp2) bond arylation products. The radical reaction mechanism was well verified in the control experiments. The other advantages of the approach are broad-scope substrates and good group tolerance. Moreover, the obtained products can be readily converted into high-value asymmetric ketones and hydrogenation reactions.

Electrochemical Radical Reaction Construction of C-C Bonds: Access to 1,4-Dicarbonyl Compounds from Enol Acetates and 1,3-Diketones.

As important substrates for the construction of heterocycles, a simple and efficient approach for synthesis of 1,4-diones is highly desirable. In this work, novel and efficient electrochemical radical reactions of enol acetates and 1,3-diketones have been developed to successfully achieve 1,4-diketones under catalyst-free and oxidant-free conditions. The wide range of substrates, good group tolerance, and simple operation process make the approach have important practical value. Moreover, the obtained 1,4-diketones can be easily further transformed to pyrrole and furan derivatives.

Copper(I)-Catalyzed Radical Carbamylation/Cyclization of 2-Aryl-N-methacryloylindoles with Substituted Formamides to Assemble Amidated Indolo[2,1-a]isoquinolin-6(5H)-ones.

An efficient synthesis of amidated indolo[2,1-a]isoquinolin-6(5H)-ones has been achieved via copper(I)-catalyzed radical carbamylation/cyclization of 2-aryl-N-methacryloylindoles with substituted formamides. In this reaction, an isoquinoline ring was constructed by carbamylation of a carbon-carbon double bond in 2-arylindoles. This strategy successfully introduces the substituted amide group into the indolo[2,1-a]isoquinoline skeleton and has advantages such as wide substituent scope, mild reaction conditions, high regioselectivity, and good to excellent yields.

Spectrally tunable humic acid-based carbon dots: a simple platform for metronidazole and ornidazole sensing in multiple real samples.

Humic acid-based carbon dots (HACDs) have excellent properties and are widely used in environmental detection, bioimaging, and optoelectronic materials. Herein, we investigated the structure-activity relationship between the morphology and optical properties of HACDs, and reported on a novel strategy for metronidazole (MNZ) and ornidazole (ONZ) sensing in multiple real samples. It was found that the average particle size decreased from 3.28 to 2.44 nm, optimal emission wavelength was blue-shifted from 500 to 440 nm, and the quantum yield (QY) improved from 5 to 23% with the temperature increasing from 110 to 400 °C. Under the oxidation of hydrogen peroxide (H2O2) and potassium permanganate (KMnO4), the UV-vis spectra of HACD aqueous solution showed time-dependent behavior, and the fluorescence emission of HACDs achieved spectrally tunable multi-color luminescence in the temporal dimension. The surface of HACDs contained a large number of hydroxyl (-OH) and carboxyl (-COOH) fluorophores, resulting in excellent pH sensing. Meanwhile, the synthesized HACDs revealed sensitive response to MNZ and ONZ with the limit of detection (LOD) of 60 nM and 50 nM in aqueous solutions, which had also been successfully applied in various actual samples such as lake water, honey, eggs, and milk with satisfactory results because of the inner filter effect (IFE). Our research is advantageous to enhance the potential applications of HACDs in advanced analytical systems.

Preparation of Tetrandrine Nanocrystals by Microfluidic Method and Its In Vitro and In Vivo Evaluation.

The anti-hepatocellular carcinoma effects of TET are acknowledged, but its application is hindered by its poor water solubility and low bioavailability. Conventional methods for nanocrystal preparation are laborious and lack control. To address these limitations, we propose employing the microfluidic method in the preparation of TET nanocrystals, aiming to enhance the aforementioned constraints. The objectives of this study were to prepare TET nanocrystals (TET-NC@GL) using a Y-microfluidic method with glycyrrhetinic acid (GL) as a stabilizer. The optimal preparation prescription was determined through a single-factor test and Box-Behnken response surface method. Additionally, the nanocrystals prepared with the commonly used stabilizer polyvinylpyrrolidone K30 (PVPK30), known as TET-NC@PVPK30, were characterized and evaluated for their toxicity to HepG2 cells. Hybridized nanocrystals (TET-HNC@GL and TET-HNC@PVPK30) were synthesized using a water-soluble aggregation-induced emission (AIE) fluorescent probe (TVP). Qualitative and quantitative cellular uptake experiments were conducted using these hybridized nanocrystals. Conducting in vivo pharmacokinetic assays evaluates the relative bioavailability of nanocrystals. The results indicated that TET-NC@GL, optimized using the response surface method, had a particle size of 136.47 ± 3.31 nm and a PDI of 0.219 ± 0.002. The administration of TET-NC@GL significantly enhanced the cell inhibition rate compared to the TET group and the TET-NC@PVPK30 group (P < 0.01). Moreover, the qualitative and quantitative cellular uptake results revealed a significant enhancement in cellular uptake in the TET-HNC@GL administration group compared to the TET-HNC@PVPK30 group (P < 0.01). In vivo pharmacokinetic results showed that the bioavailability of TET-NC@GL group was 3.5 times higher than that of the TET group. The results demonstrate the successful preparation of TET-NC@GL nanocrystals.

Reversible Ratiometric Electrochemiluminescence Biosensor Based on DNAzyme Regulated Resonance Energy Transfer for Myocardial miRNA Detection.

Myocardial miRNAs in peripheral blood are closely related to the pathogenic process of myocardial infarction. Rapid identification and accurate quantification of myocardial miRNAs are of great significance to clinical interventions for treating cardiovascular lesions. Therefore, a ratiometric electrochemiluminescence (ECL) biosensor integrating DNAzyme with a resonance energy transfer (RET) system was designed to detect myocardial miRNA. The dual-signal system was composed of rA marked substrate strand functionalized CdTe quantum dots (QDs) as reductive-oxidative (R-O) emitters and Cy5-labeled strand-functionalized Ru(bpy)32+-filled silica nanoparticles (RuSi NPs) as oxidative-reductive (O-R) emitters. In the presence of target miRNA, DNAzyme was activated to cut substrate strands on the CdTe QDs and release triggers for opening hairpin probes. Then, the Cy5 molecule-labeled hairpin DNA on the RuSi NPs was opened to introduce Cy5 molecules and RuSi NPs into the system. The R-O ECL was quenched by ECL-RET between CdTe QDs and Cy5 molecules and the O-R ECL was introduced by the RuSi NPs. In this way, based on the simultaneous changing of the ECL signal, the dual-potential dynamic signal ratiometric ECL sensing platform was developed. By measuring the ratio of O-R ECL signal to R-O ECL signal, the concentration of miRNA-499 was accurately quantified in the range of 10 fM to 10 nM, and the detection limit was as low as 2.44 fM (S/N = 3). This DNAzyme guided dual-potential ratiometric ECL method provides a sensitive and reliable method for myocardial miRNA detection, and it has great potential in clinical diagnosis and treatment.

A Multitargeted Electrochemiluminescent Biosensor Coupling DNAzyme with Cascading Amplification for Analyzing Myocardial miRNAs.

Several circulating miRNAs are associated with the pathogenic process of acute myocardial infarction (AMI). Thus, analyzing myocardial miRNAs in the circulatory system is important for the diagnosis and treatment of AMI, especially for early-stage diagnosis. Based on the characteristics of myocardial miRNAs, an ultrasensitive and multitargeted electrochemiluminescence (ECL) sensing platform was developed with a versatile probe that can couple DNAzyme with hybridization chain reaction amplification. The target miRNA and auxiliary chains form a circular unit that shears the versatile probe hairpin, and the products subsequently trigger cascading amplification; a long strand of dsDNA is then generated with many C-rich sequences that can undergo in situ reductions to generate ECL luminophore silver clusters. Using this strategy, three myocardial miRNAs are successfully detected with a detection limit as low as 29.6 aM (S/N = 3). Notably, our method can detect myocardial miRNA groups composed of multiple related circulating miRNAs with high selectivity over interfering miRNAs in blood. This is extremely important for solving the problem of diverse and low abundance of infarct-associated miRNAs. Our strategy pioneers a new idea of miRNA detection, and given its versatility and sensitivity, it is promising for the diagnosis of multigene-regulated cardiovascular diseases.

Implications of gender-based variabilities in bone mineral density and hemoglobin levels.

BACKGROUND: Studies reported that there is a relationship between volumetric bone mineral density (vBMD) and hemoglobin (HGB) in sickle cell anemia, chronic obstructive pulmonary disease, inflammatory bowel disease, and chronic kidney disease, it is not clear whether this association exists in normal populations or different genders. In order to further clarify the relationship between vBMD and HGB, and provide the basis for the diagnosis of related diseases, this study was conducted in the physical examination population. METHODS: A cross-sectional study was conducted on a health check-up population from Wannan area of China from January to December 2018. The study involved 1238 individuals aged 23 to 85 years. Linear regression analysis and smooth curve were applied to determine the relationship of HGB and vBMD. RESULTS: The average level of vBMD in the population was 130.11 ± 79.51 mg/cm3, after adjusting for age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), triglycerides (TG), glucose (GLU), high-density lipoprotein (HDL) and low-density lipoprotein (LDL). A U-shape relationship was established between vBMD and HGB, the cut off value of HGB was 130 g/L. After gender stratification, the results showed a U-shaped curve relationship between vBMD and HGB in male group, and a linear relationship between vBMD and HGB in female group. The vBMD decreased with HGB when HGB < 120 g/L, and increased when HGB ≥ 120 g/L in male group. CONCLUSION: The relationship between vBMD and HGB in the male physical examination population presents a U-shaped curve.

Optimal timing of coronary angiograms for patients with chronic kidney disease: association between the duration of kidney dysfunction and SYNTAX scores.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased risk of the progression of coronary artery disease (CAD). However, there are few data on the relationship between CAD severity and the duration of CKD. This study assessed the predictive value of the duration of kidney dysfunction in CKD patients with CAD severity. METHODS: In 145 patients (63.4% male, n = 92; mean age, 68.8 ± 12.8 years) with CKD, severity of CAD was assessed by coronary angiography and quantified by SYNTAX scores, and duration of kidney dysfunction was either assessed by checking historical biochemical parameters of individuals or was based on enquiries. RESULTS: Patients with high SYNTAX scores (≥ 22) had a greater prevalence of cardiovascular risk factors including age, gender, history of heart failure and smoking. In CKD patients, SYNTAX scores were positively correlated to duration of CKD and serum uric acid (UA), and negatively correlated to high-density lipoprotein-cholesterol (HDL-C) and ApoA1 levels. Univariate binary logistic regression and multivariate logistic analyses showed that SYNTAX scores correlated significantly with CKD duration, UA, and HDL-C. Receiver-operating characteristic analysis was used to explore a time point when coronary angiography application was economical and effective and yielded a Youden index of 6.5 years. CONCLUSIONS: Together, our results demonstrated that the duration of kidney dysfunction was an independent correlate of the severity of CAD in patients with CKD. Our findings suggest that coronary angiography should be considered for CKD patients with renal insufficiency having lasted for more than 6.5 years.

Porous Liquid: A Stable ZIF-8 Colloid in Ionic Liquid with Permanent Porosity.

We reported an example of metal-organic framework (MOF)-based porous liquid by dispersing ZIF-8 ({Zn(mim)2}, mim = 2-methylimidazole) nanocrystallites in ionic liquid (IL) of [Bpy][NTf2] ( N-butyl pyridinium bis(trifluoromethyl sulfonyl)imide). Two essential challenges, stable colloid formation and porosity retention, have been overcome to prepare MOF-based porous liquid. Preventing ZIF-8 nanocrystals from aggregation before dispersing is vital to form a stable ZIF-8 colloid in IL via enhancing the interaction between ZIF-8 and IL. The resultant ZIF-8-[Bpy][NTf2] colloid is able to be stable over months without precipitating. [Bpy][NTf2] with larger ion sizes cannot occupy pores in ZIF-8, leaving the ZIF-8 cage empty for enabling access by guest molecules. The porosity of this porous liquid system was verified by positron (e+) annihilation lifetime spectroscopy and I2 adsorption in ZIF-8 in the colloid. MOF-based porous liquids could provide a new material platform for liquid-bed-based gas separations.

Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model.

Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid Emax equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an Emax equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.

SIMPLIFIED IMMUNE-DYSREGULATION INDEX: A NOVEL MARKER PREDICTS 28-DAY MORTALITY OF INTENSIVE CARE PATIENTS WITH SEPSIS.

ABSTRACT: Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. There is currently no simple immune-imbalance-driven indicator for patients with sepsis. Methods: This study was conducted in Peking Union Medical College Hospital. Patients with sepsis were identified according to Sepsis 3.0 after reviewing patient data from May 2018 through October 2022. Least absolute shrinkage and selection operator logistic regression was used for features selection. Receiver operating characteristic curves for 28-day mortality were used to compare the predictive performance of level of interleukin 6 (IL-6) and lymphocyte count (LY#) with that of the combined ratio, namely, the IL-6/LY# ratio. A Cox hazard model was also used to test the predictive performance of IL-6/LY# versus several other measurements. The dynamic trend of IL-6/LY# based on day 1 IL-6/LY# level was analyzed. Results: The mortality rate was 24.5% (220/898) in the study cohort. The LY#, IL-6 level, blood platelet count, Sequential Organ Failure Assessment score, Acute Physiology and Chronic Health Evaluation II score, heart rate, age and Fi o2 level were identified as key factors for predicting 28-day mortality. IL-6/LY# was identified as a core indicator according to Least absolute shrinkage and selection operator logistic regression analysis. IL-6/LY# was significantly higher in nonsurvivors than in survivors (348 [154.6-1371.7] vs. 42.3 [15.4-117.1]). IL-6/LY# yielded a higher area under the curve (0.852 [95% CI = 0.820-0.879]) than the level of IL-6 (0.776 [95% CI = 0.738-0.809]) and LY# (0.719 [95% CI = 0.677-0.755]) separately. Survival analysis of mortality risk versus the IL-6/LY# ratio suggested that IL-6/LY# was significantly more predictive of patient risk than the Sequential Organ Failure Assessment score or the other factors ( P = 1.5 × 10 -33 ). In trend analysis, as the trend of D1-D3-D7 IL-6/LY# decreases, the morality rate is lower than increase or fluctuate group (42.1% vs. 58.3%, 37.9% vs. 43.8%, 37.5% vs. 38.5% in high, moderate, and low D1 IL-6/LY# group separately). Conclusion: IL-6/LY# examined on first day in intensive care unit can be used as an immune-imbalance alert to identify sepsis patients with higher risk of 28-day mortality. Decreasing trend of IL-6/LY# suggests a lower 28-day mortality rate of sepsis patients.

Comprehensive analysis of the differential expression of mRNAs, lncRNAs, and miRNAs in Zi goose testis with high and low sperm mobility.

Sperm mobility (SM) is an objective index for measuring sperm motility; however, the mechanisms underlying its regulation in geese remain unclear. The present study sought to elucidate the genetic mechanism underlying SM traits in Zi geese (Anser cygnoides L.). To this end, three successive experiments were performed. In Experiment I, SM was determined in 40 ganders; the 3 ganders with the highest mobility and three with the lowest mobility were assigned to the high and low sperm mobility rank (SMR) groups, respectively. In Experiment II, the differences in fertility between the two SMR groups were assessed within two breeding flocks comprising the selected six ganders from Experiment I and 30 females (each flock had 3 ganders and 15 females). In Experiment III, the testes of the 6 ganders were harvested for histological observation and whole-transcriptome sequencing. Results revealed better fertility, well-developed seminiferous tubules, and abundant mature sperm in the high-SMR-flock compared to those of the low-SMR-flock (89 vs. 81%) (P < 0.05). Differential expression (DE) analysis identified 76 mRNAs, 344 lncRNAs, and 17 miRNAs between the SMR groups, with LOC106049708, XPNPEP3, GNB3, ADCY8, PRKAG3, oha-miR-182-5p, and ocu-miR-10b-5p identified as key mRNAs and miRNAs contributing to SM. Enrichment analysis implicated these DE RNAs in pathways related to ATP binding, cell metabolism, apelin signaling, Wnt signaling, and Adherens junctions. Additionally, competing endogenous RNA (ceRNA) networks comprising 9 DE mRNAs, 17 DE miRNAs, and 169 DE lncRNAs were constructed. Two ceRNA network pathways (LOC106049708-oha-miR-182-5p-MSTRG.2479.6 and PRKAG3-ocu-miR-10b-5p-MSTRG.9047.14) were identified as key regulators of SM in geese. These findings offer crucial insights into the identification of key genes and ceRNA pathways influencing sperm mobility in geese.