The Probability Density Function Related to Shallow Cumulus Entrainment Rate and Its Influencing Factors in a Large-Eddy Simulation

The process of entrainment-mixing between cumulus clouds and the ambient air is important for the development of cumulus clouds.Accurately obtaining the entrainment rate(λ)is particularly important for its parameterization within the overall cumulus parameterization scheme.In this study,an improved bulk-plume method is proposed by solving the equations of two conserved variables simultaneously to calculateλof cumulus clouds in a large-eddy simulation.The results demonstrate that the improved bulk-plume method is more reliable than the traditional bulk-plume method,becauseλ,as calculated from the improved method,falls within the range ofλvalues obtained from the traditional method using different conserved variables.The probability density functions ofλfor all data,different times,and different heights can be well-fitted by a log-normal distribution,which supports the assumed stochastic entrainment process in previous studies.Further analysis demonstrate that the relationship betweenλand the vertical velocity is better than other thermodynamic/dynamical properties;thus,the vertical velocity is recommended as the primary influencing factor for the parameterization ofλin the future.The results of this study enhance the theoretical understanding ofλand its influencing factors and shed new light on the development ofλparameterization.

Functional assessment and influencing factors after staged functional training in patients with ankle fractures

BACKGROUND The recovery of limb function after ankle fracture surgery is a gradual process.The main purpose of implementing early functional exercise,joint mobility,muscle contraction function,passive ankle flexion and extension exercises,or physical factor therapy techniques is to achieve the rapid recovery of normal physiological limb function.However,currently the most effective rehabilitation training method is staged limb functional exercise,which promotes rapid recovery of limb function while preventing adverse consequences caused by overwork or insufficient training.Staged limb functional exercise divides the rehabilitation process into multiple stages,each of which has specific training objectives and contents.This method helps patients gradually restore limb function.Nevertheless,some patients still exhibit poor limb function after standardized exercise.Therefore,a functional evaluation should be performed to analyze the impact of staged functional training after ankle fracture surgery.AIM To perform a functional evaluation and determine the influencing factors of staged functional training in patients with ankle fracture.METHODS A retrospective study enrolled 150 patients who underwent surgical treatment for ankle fracture from May 2020 to May 2022 at our hospital.Univariate and multivariate linear regression analyses were performed on general data,functional exercise compliance scale for orthopedic patients,Social Support Rating Scale(SSRS),American Orthopedic Foot and Ankle Score(AOFAS)Ankle-Hindfoot Score,and pain factors[serum bradykinin(BK),prostaglandin E2(PGE2),5-hydroxytryptamine(5-HT)].RESULTS Based on the AOFAS Ankle-Hindfoot Scale,the cases were divided into the excellent function(n=111)and ordinary function(n=39)groups.Univariate analysis revealed that monthly family income,education level,diabetes mellitus,functional exercise compliance scale of orthopedic patients score,SSRS,BK,PGE2,and 5-HT significantly influenced limb function after ankle fracture(P<0.05);Multiple linear regression analysis showed that the functional exercise compliance scale score,SSRS,BK,PGE2,and 5-HT were independent risk factors affecting functional performance after staged functional exercise(P<0.05).CONCLUSION Exercise compliance,SSRS,and pain level are the independent risk factors affecting functional performance after staged functional training following ankle surgery.Clinical nursing care after ankle surgery should include analgesic and health education measures to ensure optimal recovery of limb function.

Relationship between postoperative rehabilitation style, gastrointestinal function, and inflammatory factor levels in children with intussusception

BACKGROUND Intussusception occurs in children and progresses rapidly.If not treated in time,it may lead to secondary complications such as intestinal perforation,which affect the quality of life and health of children.Surgery is the most common clinical treatment and has a good effect.However,the postoperative prognosis of children with intussusception has a correlation with the postoperative rehabilitation method.Therefore,in this study,we explored the relationship between postopera-tive rehabilitation,gastrointestinal function,and the expression of inflammatory factors in children with intussusception.The medical records of 18 children who were admitted to our hospital for intussusception surgery between October 2022 and May 2024 were retrospectively reviewed.The patients were divided into the routine nursing group(n=6)and rehabilitation training group(n=12)according to the postoperative rehabilitation method.The general data,gastrointestinal function,and inflammatory factor levels of the two groups were statistically analyzed.Pearson correlation analysis of gastrointestinal function,inflammatory factors,and postoperative rehabil-itation was performed.RESULTS We found no significant intergroup differences in sex,age,or disease course(P>0.05).The times to first defecation,bowel sound recovery,and anal exhaust were shorter and inflammatory factor levels were lower in the rehabilitation training group than in the routine nursing group(P<0.05).Pearson correlation analysis showed that gastrin and motilin levels were positively correlated with postoperative rehabilitation(P<0.05).Interleukin(IL)-2,IL-4,IL-6,IL-10,high-sensitivity C-reactive protein,and tumor necrosis factor-αlevels were negatively correlated with postoperative rehabilitation(P<0.05).Gastrointestinal function was positively correlated(P<0.05),and levels of inflammatory factors were negatively correlated with postoperative recovery time(P<0.05).CONCLUSION We found a positive correlation between gastrointestinal function and postoperative rehabilitation training,and a negative correlation between inflammatory factor levels and rehabilitation training in children with intussus-ception.

Risk Factors of the Progression of Renal Function Deterioration Among Patients with Diabetic Nephropathy

Objective:To explore the risk factors for the progression of renal function deterioration in patients with diabetic nephropathy(DN).Methods:The clinical data and biochemical indexes of 100 diabetic patients admitted to our hospital from October 2021 to October 2022 were retrospectively analyzed.The patients were divided into a DN group,which consisted of 55 cases,and a nondiabetic nephropathy group(NDN),which consisted of 45 cases.The urinary microalbumin to creatinine ratio,the clinical data(gender,age,duration of the disease,and BMI),and the biochemical indexes(triglycerides[TG],low-density lipoprotein cholesterol[LDL-C],high-density lipoprotein cholesterol[HDL-C],total cholesterol[TC],glycated hemoglobin A1c[HbA1c],systolic blood pressure[SBP],diastolic blood pressure[DBP])of the two groups were compared.Subsequently,the risk factors related to the progression of renal function deterioration in DN were analyzed through multifactorial logistic regression analysis.Results:No statistically significant difference was observed in the comparison of gender,age,BMI,LDL-C,and DBP between the two groups(P>0.05).The DN group demonstrated a longer disease duration and higher SBP,TC,HDL-C,HbA1c,and TG compared to the NDN group(P<0.05).Through multifactorial logistic regression analysis,it was found that the duration of the disease,the TC,the HDL-C,the HbA1c,the TG,and the SBP were independent risk factors of the deterioration of renal function in DN patients.Conclusion:Other than conventional indicators,TC,HDL-C,HbA1c,TG,and SBP are also crucial indicators in determining the progression of renal function deterioration in DN patients.

Efficacy and Impact on Inflammatory Factors and Lung Function in Pediatric Bronchial Asthma Treated with Modified Dingchuan Decoction

Objective:To study the efficacy of treating pediatric bronchial asthma with a modified Dingchuan Decoction and its effect on inflammatory factors and lung function levels.Methods:Sixty cases of bronchial asthma admitted to the hospital between January and December 2023 were divided into two groups using a computerized randomization method.One group of 30 cases received basic treatment with a salmeterol ticarcoson powder inhaler(control group),while the observation group received the same treatment plus a modified Dingchuan Decoction.The disappearance time of symptoms,levels of inflammatory factors,lung function indexes,and clinical efficacy were compared between the two groups.Results:The disappearance time of symptoms in the observation group was shorter than that in the control group.The levels of inflammatory factors after treatment were lower,and lung function indexes were higher in the observation group compared to the control group.Additionally,the total effective rate of treatment in the observation group was higher than that in the control group(P<0.05).Conclusion:In the clinical treatment of pediatric bronchial asthma,supplementing conventional Western medicine with a modified Dingchuan Decoction is effective,as it actively reduces inflammatory factor levels and improves lung function.

The Expression Characteristics and Potential Functions of Heat Shock Factors in Diatom Phaeodactylum tricornutum

Heat shock transcription factor(HSF)are essential regulators of heat shock protein(HSP)gene expression in plants and algae,contributing to their resilience against biotic and abiotic stresses.However,the localization,structure,phylogenetic relationship,and characteristics of PtHSF genes in microalgae,especially in diatom Phaeodactylum tricornutum,remain largely unexplored.This study presents a comprehensive analysis of the PtHSF gene family in P.tricornutum.A genome-wide analysis identified 68 PtHSF genes,which were classified into two distinct subfamilies:traditional and untraditional.Motif and structure analyses revealed evidence of multiple duplication events within the PtHSF gene family.Expression profiling revealed diurnal patterns,with 34 genes being downregulated during the light period and upregulated during the dark period,while 19 genes exhibited the opposite pattern.These findings suggest that PtHSF genes may have specialized functions during the diurnal cycle and play a crucial role in maintaining cellular homeostasis in response to various stresses.Notably,PtHSF16,30,and 43 genes exhibited higher expression levels,suggesting their potential importance.This study provides a valuable foundation for future investigations into the specific functions of HSFs under different stress conditions and their regulatory mechanisms in P.tricornutum and other microalgae.

Structural failure analysis with CMS-based ground motion selection using innovative cost function and weight factors

The selection and scaling of ground motion records is considered a primary and essential task in performing structural analysis and design.Conventional methods involve using ground motion models and a conditional spectrum to select ground motion records based on the target spectrum.This research demonstrates the influence of adopting different weighted factors for various period ranges during matching selected ground motions with the target hazard spectrum.The event data from the Next Generation Attenuation West 2(NGA-West 2)database is used as the basis for ground motion selection,and hazard de-aggregation is conducted to estimate the event parameters of interest,which are then used to construct the target intensity measure(IM).The target IMs are then used to select ground motion records with different weighted vector-valued objective functions.The weights are altered to account for the relative importance of IM in accordance with the structural analysis application of steel moment resisting frame(SMRF)buildings.Instead of an ordinary objective function for the matching spectrum,a novel model is introduced and compared with the conventional cost function.The results indicate that when applying the new cost function for ground motion selection,it places higher demands on structures compared to the conventional cost function.Moreover,submitting more weights to the first-mode period of structures increases engineering demand parameters.Findings demonstrate that weight factors allocated to different period ranges can successfully account for period elongation and higher mode effects.

Prevalence and risk factors for impaired renal function among Asian patients with nonalcoholic fatty liver disease

Background:Nonalcoholic fatty liver disease(NAFLD)is associated with impaired renal function,and both diseases often occur alongside other metabolic disorders.However,the prevalence and risk factors for impaired renal function in patients with NAFLD remain unclear.The objective of this study was to identify the prevalence and risk factors for renal impairment in NAFLD patients.Methods:All adults aged 18-70 years with ultrasound-diagnosed NAFLD and transient elastography examination from eight Asian centers were enrolled in this prospective study.Liver fibrosis and cirrhosis were assessed by FibroScan-aspartate aminotransferase(FAST),Agile 3+and Agile 4 scores.Impaired renal function and chronic kidney disease(CKD)were defined by an estimated glomerular filtration rate(eGFR)with value of<90 mL/min/1.73 m^(2) and<60 mL/min/1.73 m^(2),respectively,as estimated by the CKD-Epidemiology Collaboration(CKD-EPI)equation.Results:Among 529 included NAFLD patients,the prevalence rates of impaired renal function and CKD were 37.4%and 4.9%,respectively.In multivariate analysis,a moderate-high risk of advanced liver fibrosis and cirrhosis according to Agile 3+and Agile 4 scores were independent risk factors for CKD(P<0.05).Furthermore,increased fasting plasma glucose(FPG)and blood pressure were significantly associated with impaired renal function after controlling for the other components of metabolic syndrome(P<0.05).Compared with patients with normoglycemia,those with prediabetes[FPG≥5.6 mmol/L or hemoglobin A1c(HbA1c)≥5.7%]were more likely to have impaired renal function(P<0.05).Conclusions:Agile 3+and Agile 4 are reliable for identifying NAFLD patients with high risk of CKD.Early glycemic control in the prediabetic stage might have a potential renoprotective role in these patients.

Prognostic factors associated with gastrointestinal dysfunction after gastrointestinal tumor surgery:A meta-analysis

BACKGROUND Explore the risk factors of gastrointestinal dysfunction after gastrointestinal tumor surgery and to provide evidence for the prevention and intervention of gastrointestinal dysfunction in patients with gastrointestinal tumor surgery.AIM To investigate the potential risk factors for gastrointestinal dysfunction following gastrointestinal tumor surgery and to present information supporting the prevention and management of gastrointestinal dysfunction in surgery patients.METHODS Systematically searched the relevant literature from PubMed,Web of Science,Cochrane Library,Embase,CNKI,China Biomedical Database,Wanfang Database,and Weipu Chinese Journal Database self-established until October 1,2022.Review Manager 5.3 software was used for meta-analysis after two researchers independently screened literature,extracted data,and evaluated the risk of bias in the included studies.RESULTS A total of 23 pieces of literature were included,the quality of which was medium or above,and the total sample size was 43878.The results of meta-analysis showed that the patients were male(OR=1.58,95%CI:1.25-2.01,P=0.002)and≥60 years old(OR=2.60,95%CI:1.76-2.87,P<0.001),physical index≥25.3 kg/m2(OR=1.6,95%CI:1.00-1.12,P=0.040),smoking history(OR=1.89,95%CI:1.31-2.73,P<0.001),chronic obstructive pulmonary disease(OR=1.49,95%CI:1.22-1.83,P<0.001),enterostomy(OR=1.47,95%CI:1.26-1.70,P<0.001),history of abdominal surgery(OR=2.90,95%CI:1.67-5.03,P<0.001),surgical site(OR=1.2,95%CI:1.40-2.62,P<0.001),operation method(OR=1.68,95%CI:1.08-2.62,P=0.020),operation duration(OR=2.65,95%CI:1.92-3.67,P<0.001),abdominal adhesion grade(OR=2.52,95%CI:1.90-3.56,P<0.001),postoperative opioid history(OR=5.35,95%CI:3.29-8.71,P<0.001),tumor TNM staging(OR=2.58,95%CI:1.84-3.62,P<0.001),postoperative blood transfusion(OR=2.92,95%CI:0.88-9.73,P=0.010)is a risk factor for postoperative gastrointestinal dysfunction in patients with gastrointestinal tumors.CONCLUSION There are many factors affecting gastrointestinal dysfunction in gastrointestinal patients after surgery.Clinical staff should identify relevant risk factors early and implement targeted intervention measures on the basis of personalized assessment to improve the clinical prognosis of patients.

Semaphorin 7A impairs barrier function in cultured human corneal epithelial cells in a manner dependent on nuclear factor-kappa B

●AIM:To evaluate the role of semaphorin 7A(Sema7A)and its associated regulatory mechanisms in modulating the barrier function of cultured human corneal epithelial cells(HCEs).●METHODS:Barrier models of HCEs were treated with recombinant human Sema7A at concentrations of 0,125,250,or 500 ng/mL for 24,48,or 72h in vitro.Transepithelial electrical resistance(TEER)as well as Dextran-fluorescein isothiocyanate(FITC)permeability assays were conducted to assess barrier function.To quantify tight junctions(TJs)such as occludin and zonula occludens-1(ZO-1)at the mRNA level,reverse transcriptionpolymerase chain reaction(RT-PCR)analysis was performed.Immunoblotting was used to examine the activity of the nuclear factor-kappa B(NF-κB)signaling pathway and the production of TJs proteins.Immunofluorescence analyses were employed to localize the TJs.Enzyme-linked immunosorbent assay(ELISA)and RT-PCR were utilized to observe changes in interleukin(IL)-1βlevels.To investigate the role of NF-κB signaling activation and IL^(-1)βin Sema7A’s anti-barrier mechanism,we employed 0.1μmol/L IκB kinase 2(IKK2)inhibitor IV or 500 ng/mL IL^(-1)receptor(IL-1R)antagonist.●RESULTS:Treatment with Sema7A resulted in decreased TEER and increased permeability of Dextran-FITC in HCEs through down-regulating mRNA and protein levels of TJs in a time-and dose-dependent manner,as well as altering the localization of TJs.Furthermore,Sema7A stimulated the activation of inhibitor of kappa B alpha(IκBα)and expression of IL-1β.The anti-barrier function of Sema7A was significantly suppressed by treatment with IKK2 inhibitor IV or IL-1R antagonists.●CONCLUSION:Sema7A disrupts barrier function through its influence on NF-κB-mediated expression of TJ proteins,as well as the expression of IL-1β.These findings suggest that Sema7A could be a potential therapeutic target for the diseases in corneal epithelium.

Interleukin-1 receptor associated kinase 2 is a functional downstream regulator of complement factor D that controls mitochondrial fitness in diabetic cardiomyopathy

Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in the pathogenesis of the disease and its progression towards heart failure,including endothelial dysfunction,autonomic neuropathy,metabolic alterations,oxidative stress,and alterations in ion homeostasis,especially calcium transients[1].In Military Medical Research,Jiang et al.[2]sought to determine the functional role of complement factor D(Adipsin)in the pathophysiology of diabetic cardiomyopathy.

Analysis of Cardiac Functional Status and Factors Influencing Adverse Pregnancy Outcomes in Pregnant Women with Combined Heart Disease

Objective:To investigate the cardiac function of pregnant women with complicated heart disease during pregnancy and the factors influencing the adverse pregnancy outcome.Methods:A total of 162 cases of pregnant women with complicated heart disease admitted to the Beijing Anzhen Hospital from October 2021 to December 2023 were selected to compare the occurrence of adverse pregnancy outcomes in pregnant women with complicated heart disease at different levels of cardiac function and to analyze the single and multi factors leading to adverse pregnancy outcomes in pregnant women with complicated heart disease.Results:Among 162 pregnant women with combined heart disease in pregnancy,the highest percentage of heart disease type was congenital heart disease(80/49.38%),and the lowest percentage was other(9/5.56%);the overall incidence of adverse pregnancy outcomes in pregnant women with combined heart disease in pregnancy with cardiac function grades of 3–4 cardiac function(30/68.18%)was higher than that in pregnant women with combined heart disease in cardiac function grades of 1–2(40/33.90%)(P=0.000);age,marital status,hypertension,and past history of all pregnant women were not statistically significant(P>0.05);gestational age,type of heart disease,and cardiac function grading were statistically significant(P<0.05),and these factors were all independent risk factors for adverse pregnancy resolution in pregnant women with combined heart disease(P<0.05).Conclusion:The overall incidence of adverse pregnancy outcomes was higher in pregnant women with heart disease than in those with heart disease grades 1–2,and the number of pregnancies,the type of heart disease,and heart function grades were all independent risk factors for adverse pregnancy outcomes in pregnant women with heart disease.

Genome-wide analysis of nuclear factor Y genes and functional investigation of watermelon ClNF-YB9 during seed development

The nuclear factor Y(NF-Y) gene family is a class of transcription factors that are widely distributed in eukaryotes and are involved in various biological processes. However, the NF-Y gene family members in watermelon, a valued and nutritious fruit, remain largely unknown and their functions have not been characterized. In the present study, 22 ClNF-Y genes in watermelon, 29 CsNF-Y genes in cucumber, and 24CmNF-Y genes in melon were identified based on the whole-genome investigation and their protein properties, gene location, gene structure, motif composition, conserved domain, and evolutionary relationship were investigated. ClNF-YB9 from watermelon and its homologs in cucumber and melon were expressed specifically in seeds. Its expression remained low in the early stages of watermelon seed development,increased at 20 days after pollination(DAP), and peaked at 45–50 DAP. Moreover, the knockout mutant Clnf-yb9 exhibited abnormal leafy cotyledon phenotype, implying its critical role during seed formation.Finally, protein interaction assays showed that ClNF-YB9 interacts with all ClNF-YCs and the ClNF-YB9-YC4 heterodimer was able to recruit a ClNF-YA7 subunit to assemble a complete NF-Y complex, which may function in seed development. This study revealed the structure and evolutionary relationships of the NF-Y gene family in Cucurbitaceae and the novel function of ClNF-YB9 in regulating seed development in watermelon.

Combining stochastic density functional theory with deep potential molecular dynamics to study warm dense matter

In traditional finite-temperature Kohn–Sham density functional theory(KSDFT),the partial occupation of a large number of high-energy KS eigenstates restricts the use of first-principles molecular dynamics methods at extremely high temperatures.However,stochastic density functional theory(SDFT)can overcome this limitation.Recently,SDFT and the related mixed stochastic–deterministic density functional theory,based on a plane-wave basis set,have been implemented in the first-principles electronic structure software ABACUS[Q.Liu and M.Chen,Phys.Rev.B 106,125132(2022)].In this study,we combine SDFT with the Born–Oppenheimer molecular dynamics method to investigate systems with temperatures ranging from a few tens of eV to 1000 eV.Importantly,we train machine-learning-based interatomic models using the SDFT data and employ these deep potential models to simulate large-scale systems with long trajectories.Subsequently,we compute and analyze the structural properties,dynamic properties,and transport coefficients of warm dense matter.

Significant risk factors for intensive care unit-acquired weakness:A processing strategy based on repeated machine learning

BACKGROUND Intensive care unit-acquired weakness(ICU-AW)is a common complication that significantly impacts the patient's recovery process,even leading to adverse outcomes.Currently,there is a lack of effective preventive measures.AIM To identify significant risk factors for ICU-AW through iterative machine learning techniques and offer recommendations for its prevention and treatment.METHODS Patients were categorized into ICU-AW and non-ICU-AW groups on the 14th day post-ICU admission.Relevant data from the initial 14 d of ICU stay,such as age,comorbidities,sedative dosage,vasopressor dosage,duration of mechanical ventilation,length of ICU stay,and rehabilitation therapy,were gathered.The relationships between these variables and ICU-AW were examined.Utilizing iterative machine learning techniques,a multilayer perceptron neural network model was developed,and its predictive performance for ICU-AW was assessed using the receiver operating characteristic curve.RESULTS Within the ICU-AW group,age,duration of mechanical ventilation,lorazepam dosage,adrenaline dosage,and length of ICU stay were significantly higher than in the non-ICU-AW group.Additionally,sepsis,multiple organ dysfunction syndrome,hypoalbuminemia,acute heart failure,respiratory failure,acute kidney injury,anemia,stress-related gastrointestinal bleeding,shock,hypertension,coronary artery disease,malignant tumors,and rehabilitation therapy ratios were significantly higher in the ICU-AW group,demonstrating statistical significance.The most influential factors contributing to ICU-AW were identified as the length of ICU stay(100.0%)and the duration of mechanical ventilation(54.9%).The neural network model predicted ICU-AW with an area under the curve of 0.941,sensitivity of 92.2%,and specificity of 82.7%.CONCLUSION The main factors influencing ICU-AW are the length of ICU stay and the duration of mechanical ventilation.A primary preventive strategy,when feasible,involves minimizing both ICU stay and mechanical ventilation duration.

Tailoring MXene Thickness and Functionalization for Enhanced Room‑Temperature Trace NO_(2) Sensing

In this study,precise control over the thickness and termination of Ti3C2TX MXene flakes is achieved to enhance their electrical properties,environmental stability,and gas-sensing performance.Utilizing a hybrid method involving high-pressure processing,stirring,and immiscible solutions,sub-100 nm MXene flake thickness is achieved within the MXene film on the Si-wafer.Functionalization control is achieved by defunctionalizing MXene at 650℃ under vacuum and H2 gas in a CVD furnace,followed by refunctionalization with iodine and bromine vaporization from a bubbler attached to the CVD.Notably,the introduction of iodine,which has a larger atomic size,lower electronegativity,reduce shielding effect,and lower hydrophilicity(contact angle:99°),profoundly affecting MXene.It improves the surface area(36.2 cm^(2) g^(-1)),oxidation stability in aqueous/ambient environments(21 days/80 days),and film conductivity(749 S m^(-1)).Additionally,it significantly enhances the gas-sensing performance,including the sensitivity(0.1119Ωppm^(-1)),response(0.2% and 23%to 50 ppb and 200 ppm NO_(2)),and response/recovery times(90/100 s).The reduced shielding effect of the–I-terminals and the metallic characteristics of MXene enhance the selectivity of I-MXene toward NO2.This approach paves the way for the development of stable and high-performance gas-sensing two-dimensional materials with promising prospects for future studies.

Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease

BACKGROUND Alcohol-associated liver disease(ALD)is a leading cause of liver-related morbidity and mortality,but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis.Peroxisome proliferator activated receptor(PPAR)α and δ play a key role in lipid metabolism and intestinal barrier homeostasis,which are major contributors to the pathological progression of ALD.Meanwhile,elafibranor(EFN),which is a dual PPARαand PPARδagonist,has reached a phase III clinical trial for the treatment of metabolic dysfunctionassociated steatotic liver disease and primary biliary cholangitis.However,the benefits of EFN for ALD treatment is unknown.AIM To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model.METHODS ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol(EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly(1 mL/kg)for 8 weeks.EFN(3 and 10 mg/kg/day)was orally administered during the experimental period.Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis,fibrosis,and intestinal barrier integrity.The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays.RESULTS The hepatic steatosis,apoptosis,and fibrosis in the ALD mice model were significantly attenuated by EFN treatment.EFN promoted lipolysis and β-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells,primarily through PPARαactivation.Moreover,EFN inhibited the Kupffer cell-mediated inflammatory response,with blunted hepatic exposure to lipopolysaccharide(LPS)and toll like receptor 4(TLR4)/nuclear factor kappa B(NF-κB)signaling.EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses.The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation.CONCLUSION EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis,enhancing hepatocyte autophagic and antioxidant capacities,and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.

Are TrkB receptor agonists the right tool to fulfill the promises for a therapeutic value of the brain-derived neurotrophic factor?

Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor.Therefore,while,based on the current knowledge,the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reve rse the disease pathology per se,promoting brainderived neurotrophic factor/tro pomyosin receptor kinase B signaling still has a very high therapeutic relevance.

Interaction between systemic iron parameters and left ventricular structure and function in the preserved ejection fraction population:a two-sample bidirectional Mendelian randomization study

BACKGROUND Left ventricular(LV)remodeling and diastolic function in people with heart failure(HF)are correlated with iron status;however,the causality is uncertain.This Mendelian randomization(MR)study investigated the bidirectional causal relationship between systemic iron parameters and LV structure and function in a preserved ejection fraction population.METHODS Transferrin saturation(TSAT),total iron binding capacity(TIBC),and serum iron and ferritin levels were extracted as instrumental variables for iron parameters from meta-analyses of public genome-wide association studies.Individuals without myocardial infarction history,HF,or LV ejection fraction(LVEF)<50%(n=16,923)in the UK Biobank Cardiovascular Magnetic Resonance Imaging Study constituted the outcome dataset.The dataset included LV end-diastolic volume,LV endsystolic volume,LV mass(LVM),and LVM-to-end-diastolic volume ratio(LVMVR).We used a two-sample bidirectional MR study with inverse variance weighting(IVW)as the primary analysis method and estimation methods using different algorithms to improve the robustness of the results.RESULTS In the IVW analysis,one standard deviation(SD)increased in TSAT significantly correlated with decreased LVMVR(β=-0.1365;95%confidence interval[CI]:-0.2092 to-0.0638;P=0.0002)after Bonferroni adjustment.Conversely,no significant relationships were observed between other iron and LV parameters.After Bonferroni correction,reverse MR analysis showed that one SD increase in LVEF significantly correlated with decreased TSAT(β=-0.0699;95%CI:-0.1087 to-0.0311;P=0.0004).No heterogeneity or pleiotropic effects evidence was observed in the analysis.CONCLUSIONS We demonstrated a causal relationship between TSAT and LV remodeling and function in a preserved ejection fraction population.

Multiple pretreatments can effectively improve the functionality of mesenchymal stem cells

In this editorial,we offer our perspective on the groundbreaking study entitled“Hypoxia and inflammatory factor preconditioning enhances the immunosup-pressive properties of human umbilical cord mesenchymal stem cells”,recently published in World Journal of Stem Cells.Despite over three decades of research on the clinical application of mesenchymal stem cells(MSCs),only a few therapeutic products have made it to clinical use,due to multiple preclinical and clinical challenges yet to be addressed.The study proved the hypoxia and inflammatory factor preconditioning led to higher immunosuppressive effects of MSCs without damaging their biological characteristics,which revealed the combination of inflammatory factors and hypoxic preconditioning offers a promising approach to enhance the function of MSCs.As we delve deeper into the intricacies of pretreat-ment methodologies,we anticipate a transformative shift in the landscape of MSC-based therapies,ultimately contributing to improved patient outcomes and advancing the field as a whole.