Elevated CO2 concentration increases maize growth under water deficit or soil salinity but with a higher risk of hydraulic failure.

Climate change presents a challenge for plants to acclimate their water relations under changing environmental conditions, and may increase the risks of hydraulic failure under stress. In this study, maize plants were acclimated to two different CO2 concentrations ([CO2]; 400 ppm and 700 ppm) while under either water stress (WS) or soil salinity (SS) treatments, and their growth and hydraulic traits were examined in detail. Both WS and SS inhibited growth and had significant impacts on hydraulic traits. In particular, the water potential at 50% loss of stem hydraulic conductance (P50) decreased by 1 MPa in both treatments at 400 ppm. When subjected to elevated [CO2], the plants under both WS and SS showed improved growth by 7-23%. Elevated [CO2] also significantly increased xylem vulnerability (measured as loss of conductivity with decreasing xylem pressure), resulting in smaller hydraulic safety margins. According to the plant desiccation model, the critical desiccation degree (time×vapor pressure deficit) that the plants could tolerate under drought was reduced by 43-64% under elevated [CO2]. In addition, sensitivity analysis showed that P50 was the most important trait in determining the critical desiccation degree. Thus, our results demonstrated that whilst elevated [CO2] benefited plant growth under WS or SS, it also interfered with hydraulic acclimation, thereby potentially placing the plants at a higher risk of hydraulic failure and increased mortality.

Irisin alters D-galactose-induced apoptosis by increasing caveolin-1 expression in C2C12 myoblasts and skeletal muscle fibroblasts.

Muscle atrophy and skeletal muscle fibrosis are significant pathological manifestations of primary sarcopenia. The regulation of C2C12 myoblast and skeletal muscle fibroblast apoptosis is associated with these pathological changes. Previous studies have indicated that irisin, the cleaved form of fibronectin type III domain-containing protein 5 (FNDC5), can alleviate primary sarcopenia. However, the mechanisms of the effect of irisin in age-related apoptosis remain unknown. Our present research aimed to explore the effect of irisin and the underlying mechanism of D-galactose (D-gal)-induced apoptosis in skeletal muscle fibroblasts and C2C12 myoblasts. We found the opposite effects of D-gal on C2C12 myoblasts and fibroblasts. We also found that irisin suppressed C2C12 cell apoptosis and promoted fibroblast apoptosis. Mechanistically, irisin altered D-gal-induced apoptosis by increasing caveolin-1 expression. Taken together, these findings further demonstrated that irisin is a potential agent that can treat aged-relative muscle atrophy and fibrosis.

A meta-analysis highlights the cross-resistance of plants to drought and salt stresses from physiological, biochemical, and growth levels.

In nature, drought and salt stresses often occur simultaneously and affect plant growth at multiple levels. However, the mechanisms underlying plant responses to drought and salt stresses and their interactions are still not fully understood. We performed a meta-analysis to compare the effects of drought, salt, and combined stresses on plant physiological, biochemical, morphological and growth traits, analyze the different responses of C3 and C4 plants, as well as halophytes and non-halophytes, and identify the interactive effects on plants. There were numerous similarities in plant responses to drought, salt, and combined stresses. C4 plants had a more effective antioxidant defense system, and could better maintain above-ground growth. Halophytes could better maintain photosynthetic rate (Pn) and relative water content (RWC), and reduce growth as an adaptation strategy. The responses of most traits (Pn, RWC, chlorophyll content, soluble sugar content, H2O2 content, plant dry weight, etc.) to combined stress were less-than-additive, indicating cross-resistance rather than cross-sensitivity of plants to drought and salt stresses. These results are important to improve our understanding of drought and salt cross-resistance mechanisms and further induce resistance or screen-resistant varieties under stress combination.

A novel derivative synchronous fluorescence method for the rapid, non-destructive and intuitive differentiation of denitrifying bacteria.

It is challenging to differentiate bacteria residing in the same habitat by direct observation. This difficulty impedes the harvest, application and manipulation of functional bacteria in environmental engineering. In this study, we developed a novel method for rapid differentiation of living denitrifying bacteria based on derivative synchronous fluorescence spectroscopy, as exemplified by three heterotrophic nitrification-aerobic denitrification bacteria having the maximum nitrogen removal efficiencies greater than 90%. The intact bacteria and their living surroundings can be analyzed as an integrated target, which eliminates the need for the complex pre-processing of samples. Under the optimal synchronous scanning parameter (Δλ = 40 nm), each bacterium possesses a unique fluorescence spectral structure and the derivative synchronous fluorescence technique can significantly improve the spectral resolution compared to other conventional fluorescence methods, which enables the rapid differentiation of different bacteria through derivative synchronous fluorescence spectra as fast as 2 min per spectrum. Additionally, the derivative synchronous fluorescence technique can extract the spectral signals contributed by bacterial extracellular substances produced in the biological nitrogen removal process. Moreover, the results obtained from our method can reflect the real-time denitrification properties of bacteria in the biological nitrogen removal process of wastewater. All these merits highlight derivative synchronous fluorescence spectroscopy as a promising analytic method in the environmental field.

Anlotinib plus icotinib as a potential treatment option for EGFR-mutated advanced non-squamous non-small cell lung cancer with concurrent mutations: final analysis of the prospective phase 2, multicenter ALTER-L004 study.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and concurrent mutations have a poor prognosis. This study aimed to examine anlotinib plus icotinib as a first-line treatment option for advanced NSCLC carrying EGFR mutation with or without concurrent mutations. METHODS: This phase 2, single-arm, multicenter trial (ClinicalTrials.gov NCT03736837) was performed at five hospitals in China from December 2018 to November 2020. Non-squamous NSCLC cases with EGFR-sensitizing mutations were treated with anlotinib and icotinib. The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. RESULTS: Sixty participants were enrolled, including 31 (52%) and 29 (48%) with concurrent mutations and pathogenic concurrent mutations, respectively. The median follow-up was 26.9 (range, 15.0-38.9) months. ORR and DCR were 68.5% and 98.2%, respectively. Median PFS was 15.1 (95%CI: 12.6-17.6) months which met the primary endpoint, median DoR was 13.5 (95%CI: 10.0-17.1) months, and median OS was 30.0 (95%CI: 25.5-34.5) months. Median PFS and OS in patients with pathogenic concurrent mutations were 15.6 (95%CI: 12.5-18.7) months and not reached (95%CI: 17.46 months to not reached), respectively. All patients experienced TRAEs, including 26 (43%) and 1 (1.7%) who had grade ≥ 3 and serious treatment-related adverse events (TRAEs). CONCLUSIONS: Anlotinib combined with icotinib was effective and well-tolerated as a first-line treatment option for EGFR mutation-positive advanced NSCLC with or without concurrent mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03736837.

The Clinical Relevance and Functional Implications of Thymosin Beta-10 in Glioma.

Glioma is a highly aggressive form of brain cancer characterized by limited treatment options and poor patient prognosis. In this study, we aimed to elucidate the oncogenic role of thymosin beta-10 (TMSB10) in glioma through comprehensive analyses of patient data from the TCGA and GTEx databases. Our investigation encompassed several key aspects, including the analysis of patients' clinical characteristics, survival analysis, in vitro and in vivo functional experiments, and the exploration of correlations between TMSB10 expression and immune cell infiltration. Our findings revealed a significant upregulation of TMSB10 expression in glioma tissues compared to normal brain tissues, with higher expression levels observed in tumors of advanced histological grades. Moreover, we observed positive correlations between TMSB10 expression and patient age, while no significant association with gender was detected. Additionally, TMSB10 exhibited marked elevation in gliomas with wild-type IDH and noncodeletion of 1p/19q. Survival analysis indicated that high TMSB10 expression was significantly associated with worse overall survival, disease-specific survival, and progression-free survival in glioma patients. Functionally, knockdown of TMSB10 in glioma cells resulted in reduced cellular growth rates and impaired tumor growth in xenograft models. Furthermore, our study revealed intriguing correlations between TMSB10 expression and immune cell infiltration within the tumor microenvironment. Specifically, TMSB10 showed negative associations with plasmacytoid dendritic cells (pDC) and γδ T cells (Tgd), while displaying positive correlations with neutrophils and macrophages. These findings collectively provide valuable insights into the oncogenic properties of TMSB10 in glioma, suggesting its potential as a therapeutic target and a biomarker for patient stratification.

Model-assisted analysis for tuning anthocyanin composition in grape berries.

Anthocyanin composition is responsible for the red colour of grape berries and wines, and contributes to their organoleptic quality. However, anthocyanin biosynthesis is under genetic, developmental and environmental regulation, making its targeted fine-tuning challenging. We constructed a mechanistic model to simulate the dynamics of anthocyanin composition throughout grape ripening in Vitis vinifera, employing a consensus anthocyanin biosynthesis pathway. The model was calibrated and validated using six datasets from eight cultivars and 37 growth conditions. Tuning the transformation and degradation parameters allowed us to accurately simulate the accumulation process of each individual anthocyanin under different environmental conditions. The model parameters were robust across environments for each genotype. The coefficients of determination (R2) for the simulated versus observed values for the six datasets ranged from 0.92 to 0.99, while the relative root mean square errors (RRMSEs) were between 16.8 and 42.1 %. The leave-one-out cross-validation for three datasets showed R2 values of 0.99, 0.96 and 0.91, and RRMSE values of 28.8, 32.9 and 26.4 %, respectively, suggesting a high prediction quality of the model. Model analysis showed that the anthocyanin profiles of diverse genotypes are relatively stable in response to parameter perturbations. Virtual experiments further suggested that targeted anthocyanin profiles may be reached by manipulating a minimum of three parameters, in a genotype-dependent manner. This model presents a promising methodology for characterizing the temporal progression of anthocyanin composition, while also offering a logical foundation for bioengineering endeavours focused on precisely adjusting the anthocyanin composition of grapes.

Clinical outcome analysis of modified B-Lynch sutures in the fundus uteri and part of the corpus uteri for the prevention of intraoperative haemorrhage during caesarean delivery in women with twin pregnancy: a retrospective study.

OBJECTIVE: To explore the efficacy of modified B-Lynch sutures in the fundus uteri and part of the corpus uteri for the prevention of intraoperative haemorrhage during caesarean delivery in women with twin pregnancy. METHODS: This retrospective analysis covers the clinical data of 40 women with postpartum haemorrhage caused by uterine inertia during caesarean section in women with twin pregnancy in our hospital from January 2018 to May 2022. These women were divided into the group with modified B-Lynch sutures at the fundus and part of the corpus uteri (Group A, 20 patients) and the group with classic B-Lynch sutures (Group B, 20 patients) according to the treatment received. The treatment effect and safety of the two uterine compression sutures were compared. RESULTS: In this study, no statistically significant differences were found in the outcomes of haemostasis or intraoperative and 24-h postoperative blood loss between the two uterine compression suture groups (P > 0.05). Compared to Group B, Group A showed a significantly reduced operative time, postoperative hospital stay, puerperal morbidity rate, pain score and duration of lochia. CONCLUSION: Modified B-Lynch sutures at the fundus and part of the corpus uteri can achieve a haemostatic effect similar to that of the classic B-Lynch suture, while it allows for a shortened operative time and reduced postoperative complications. Modified B-Lynch sutures can serve as a safe, rapid and effective haemostatic method for the prevention and treatment of postpartum haemorrhage during caesarean section in women with twin pregnancy, showing certain validity for promotion in clinics.

Clinical outcome analysis of intramural myoma greater than 8 cm in diameter removed during caesarean section: a retrospective study.

OBJECTIVE: To explore the safety and efficiency of endometrial myomectomy (EM) and Serosal myomectomy (SM) for the removal of intramural myoma greater than 8 cm in diameter during cesarean section. METHODS: Retrospective analysis and follow-up were used, and 190 cases of pregnancy complicated with uterine myoma from Jan. 2017 to May 2022 in Ningbo Women's and Children's Hospital were collected, 130 cases of caesarean myomectomy as study group, 64 cases of EM as study group A, 66 cases of SM as study group B, 33 cases with uterine fibroids removed before suturing the uterine incision as study group B1, 33 cases with uterine incision sutured followed by removal of fibroids as study group B2, 60 cases of Caesarean section alone as control group. To compare perioperative conditions between and within groups. RESULTS: ① Operation time, postoperative exhaust time, pre- and post-operative haemoglobin drop, intraoperative blood loss were all more than those of the control group in the study group (68.65 ± 11.87 vs 56.17 ± 9.18 min, 21.04 ± 4.98 vs 17.03 ± 1.3 h, 1.27 ± 0.59 vs 1.09 ± 0.43 g/dl, 613 ± 221 vs 532 ± 156 ml, P < 0.001, P < 0.001, P = 0.025, P = 0.011). ② For type III and V fibroids, the time of myoma removal, postoperative exhaust and pre- and post-operative haemoglobin drop and intraoperative blood loss in study group A were less than those in study group B (18.02 ± 3.89 vs 20.19 ± 5.32 min, 18.83 ± 2.57 vs 23.93 ± 6.84 h, 600 ± 194 vs 730 ± 277 ml, 1.20 ± 0.57 vs 1.59 ± 0.70 g/dl, P = 0.036, P < 0.001, P = 0.014, P = 0.008); For type IV uterine fibroids, only postoperative exhaust time was less in Study Group A than in Study Group B (19.27 ± 2.2 vs 21.35 ± 3.23 h, P = 0.016). ③ Time of myoma removed was less in study group B1 than in study group B2 (18.24 ± 4.53 vs 20.7 ± 4.59 min, P = 0.033). CONCLUSION: It is safe and feasible to remove interstitial myomas larger than 8 cm in diameter during caesarean section. EM has the advantage of shorter operation time and less intraoperative bleeding, SM, in a way that the myoma is removed before suturing the uterine incision, can shorten the myomectomy time. It can benefit the patients more.

Predictive Value of EGFR Mutation Status for First-Line Tyrosine Kinase Inhibitor Treatment in Patients with Advanced Lung Cancer.

Objective: This study aims to investigate and analyze the correlation between EGFR-TKI first-line therapy and EGFR mutation status in patients with advanced lung cancer. Methods: We selected 60 patients with advanced lung cancer and EGFR mutations (diagnosed as stage IIIb or IV) from our hospital between January 2019 and November 2022. Each patient underwent an EGFR mutation test and was categorized into two groups based on their mutation status: 28 patients with exon 21 mutations and 32 with exon 19 deletions. After three months of therapy, we assessed treatment efficacy and adverse reactions. Results: Our data revealed that in the EGFR exon 21 mutation group, the objective response rate (ORR) and disease control rate (DCR) were 57.14% and 60.71%, respectively. In the EGFR exon 19 deletion group, the ORR and DCR were 68.75% and 84.38%, respectively. There were significant differences in DCR and ORR between the two EGFR mutation states, with statistical significance (P < .05). The progression-free survival (PFS) in the EGFR exon 21 mutant group was 8.4 months after third-generation EGFR-TKI treatment, while the EGFR exon 19 deletion group had a PFS of 12.7 months after the same treatment, with a statistically significant difference (P < .05). Cox regression analysis showed that female patients with no smoking history and an adenocarcinoma pathological type had significantly better PFS after treatment compared to male patients with a smoking history and squamous cell carcinoma type, with statistical significance (P < .05). Age and clinical stage did not significantly impact PFS after third-generation EGFR-TKI treatment (P > .05). Adverse reaction incidences, such as nausea, fatigue, diarrhea, vomiting, and rash, did not significantly differ in either the EGFR exon 21 mutation group or the EGFR exon 19 deletion group (P > .05). Conclusion: The status of EGFR mutations serves as a predictive factor for PFS, DCR, and ORR in lung cancer patients undergoing EGFR-TKI first-line therapy. This status can be a valuable predictive indicator of lung cancer treatment efficacy, with potential applications in clinical practice.

Population pharmacokinetics and enterohepatic recirculation of hyzetimibe and its main metabolite in Chinese healthy subjects.

AIMS: Hyzetimibe (HS-25), a new drug approved for hypercholesterolaemia, exhibits obvious enterohepatic recirculation (EHC) after oral administration. Up to now, little is known about the kinetics of HS-25. Therefore, we performed this population pharmacokinetic (PopPK) analysis aiming to describe the PK behaviour of HS-25 and its main metabolite (M1), and to identify significant covariates contributing to the variability. METHODS: The plasma concentration data used for modelling were obtained from an open-label, single-dose, randomized, 2-period crossover bioequivalence study. PopPK modelling was performed with NONMEM 7.4.1 using nonlinear mixed effect modelling approach. Goodness of fit plots, bootstrap and visual predictive check were used for model internal validation. Data from another study were used for external validation. RESULTS: Data from 16 male and 8 female subjects were used in the PopPK analysis. HS-25 and M1 concentrations in the modelling cohort were well described by a 1-compartment model incorporating first-pass metabolism and a gallbladder compartment, accounting for the EHC process. The release kinetic of gall was mimicked by a first-order constant plus a switch on/off effect. Body weight was identified as a significant covariate effecting on the clearance and apparent distribution volume of HS-25, as well as kmg , the transfer rate from metabolite compartment to gallbladder compartment. Internal and external validation demonstrated an acceptable predictive ability of the final model. CONCLUSION: We present the first PopPK model describing HS-25 and M1 concentrations simultaneously, with the EHC process considered. The modelling and simulation results could provide reference for the clinical use of HS-25.

The clinical evaluation of IIA balloon occlusion in caesarean delivery for patients with PAS: a retrospective study.

OBJECTIVE: The aim of this study is the clinical evaluation of IIA balloon occlusion in the caesarean delivery in patients with a diagnosis of placenta accreta spectrum. BACKGROUND: High incidence of cesarean section leads to the increasing incidence of placenta accreta spectrum (PAS), which contributes to serious consequences such as severe obstetric postpartum hemorrhage or even maternal mortality. METHODS: Fifty-eight patients with a diagnosis of PAS were retrospectively reviewed. The balloon group consisted of 23 patients, who underwent a caesarean delivery with internal iliac artery occlusion. 35 patients were in the control group, who had a standard caesarean delivery. The primary outcomes were estimated blood loss (EBL). The secondary outcomes were cesarean hysterectomy, blood transferring volume, operating time, intraoperative hemostatic approaches, surgical complications, balloon catheter-related complications, length of maternal stay, cost of hospitalization, and neonatal outcomes. RESULTS: No difference was observed in estimated blood loss (EBL), blood transferring percentages and volume, additional measures to secure hemostasis, surgical complications, hospital stay postoperatively and newborn outcomes. More than 40% of the balloon group underwent hysterectomy because of uncontrollable postpartum bleeding (10 [43.48%] vs. 11 [31.43%], P=0.350). Complications related to occlusion of IIA did not occur. The duration of the surgery of the balloon group was significantly longer than that of the control group (123.52 min±74.76 versus 89.17±48.68, P=0.038), and the total hospitalization cost was also significantly higher than that of the control group (45116.67±9358.67 yuan versus 30615.41±11587.44 yuan, P=0.000). CONCLUSION: It does not permit to draw final conclusions for us on the effectiveness of the balloons IIA given the heterogeneity of selection of cases undergoing the procedures in the retrospective design. However, it is possible that IIA balloon occlusion may contribute to limiting intraoperative blood loss in more severe cases, particularly those undergoing peripartum hysterectomy.

Simulation of febuxostat pharmacokinetics in healthy subjects and patients with impaired kidney function using physiologically based pharmacokinetic modeling.

Febuxostat is recommended by the American College of Rheumatology Gout Management Guidelines as a first-line therapy for lowering the level of urate in patients with gout. At present, this drug is being prescribed mainly based on the clinical experience of doctors. The potential effects of clinical and demographic variables on the bioavailability and therapeutic effectiveness of febuxostat are not being considered. In this study a physiologically based pharmacokinetic (PBPK) model of febuxostat was developed, thereby providing a theoretical basis for the individualized dosing of this drug in gout patients. The plasma concentration-time profiles corresponding to healthy subjects and gout patients with normal kidney function were simulated and validated; then, the model was used to predict the pharmacokinetic (PK) data of the drug in gout patients suffering from varying degrees of impaired kidney function. The error values (the predicted value/observed value) were used to validate the simulated PK parameters predicted by the PBPK model, including the area under the plasma concentration-time curve, the maximum plasma concentration, and time to maximum plasma concentration. Considering that to all error fold changes were smaller than 2, the PBPK model was. In subjects suffering from mild kidney impairment, moderate kidney impairment, severe kidney impairment, and endstage kidney disease (ESRD), the predicted AUC0-24h values increased by 1.62, 1.74, 2.27, and 2.65-fold, respectively, compared to gout patients with normal kidney function. Overall, the results showed that the PBPK model constructed in this study predict the pharmacokinetic changes in gout patients suffering from varying degrees of impaired kidney function.

Menopausal hormone therapy and women's health: An umbrella review.

BACKGROUND: There remains uncertainty about the impact of menopausal hormone therapy (MHT) on women's health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes. METHODS AND FINDINGS: We searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p < 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412). CONCLUSIONS: MHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.

Modelling predicts tomatoes can be bigger and sweeter if biophysical factors and transmembrane transports are fine-tuned during fruit development.

The trade-off between yield and quality, a major problem for the production of fleshy fruits, involves fruit expansive growth and sugar metabolism. Here we developed an integrative model by coupling a biophysical model of fleshy fruit growth processes, including water and carbon fluxes and organ expansion, with an enzyme-based kinetic model of sugar metabolism to better understand the interactions between these two processes. The integrative model was initially tested on tomato fruit, a model system for fleshy fruit. The integrative model closely simulated the biomass and major carbon metabolites of tomato fruit developing under optimal or stress conditions. The model also performed robustly when simulating the fruit size and sugar concentrations of different tomato genotypes including wild species. The validated model was used to explore ways of uncoupling the size-sweetness trade-off in fruit. Model-based virtual experiments suggested that larger sweeter tomatoes could be obtained by simultaneously manipulating certain biophysical factors and transmembrane transports. The integrative fleshy fruit model provides a promising tool to facilitate the targeted bioengineering and breeding of tomatoes and other fruits.

Identification of the antidepressive properties of C1, a specific inhibitor of Skp2, in mice.

We have reported that SMIP004, an inhibitor of S-phase kinase-associated protein 2 (Skp2), displays antidepressant-like activities in stress-naïve and chronically stressed mice. Here, we investigated the antidepressant-like effect of C1, another inhibitor of Skp2, in mouse models following acute or chronic drug administration at different doses and treatment times by using the tail suspension test (TST), forced swimming test (FST), and social interaction test (SIT). The time- and dose-dependent results showed that the antidepressant-like effect of C1 occurred 8 days after the drug treatment, and C1 produced antidepressant-like activities at the dose of 5 and 10 but not 1 mg/kg in male or female mice. C1 administration (5 mg/kg) also induced antidepressant-like effects in stress-naïve mice in a three-times administration mode within 24 h (24, 5, and 1 h before the test) but not in an acute administration mode (1 h before the test). The C1 and fluoxetine co-administration produced additive effect on depression-like behaviors in stress-naïve mice. The antidepressant-like effect of C1 was not associated with the change in locomotor activity, as no increased locomotor activity was observed in different treatment modes. Furthermore, the long-term C1 treatment (5 mg/kg) was found to ameliorate the depression-like behaviors in chronic social defeat stress-exposed mice, suggesting that C1 can produce antidepressant-like actions in stress conditions. Since C1 is a specific inhibitor of Skp2, our results demonstrate that inhibition of Skp2 might be a potential strategy for the treatment of depression, and Skp2 may be potential target for the development of novel antidepressants.

Effect of sarcolipin-mediated cell transdifferentiation in sarcopenia-associated skeletal muscle fibrosis.

Fibrosis is a key pathological event during muscle aging that accelerates the development of sarcopenia. We show that sarcolipin (SLN) is highly expressed during aging, promotes intracellular calcium overload and participates in impaired myogenic differentiation. d-Galactose (D-gal) was used to induce senescence in C2C12 myoblasts. Conventional AAV-mediated SLN knockdown cells were used to study the role of SLN in muscle physiology and pathophysiology. C2C12 cells were treated with D-gal, which promoted fibrosis and SLN upregulation. The expression of TGF-ß1 and α-SMA, which participate in myogenic transdifferentiation, were also elevated. C2C12 cells with reduced sarcolipin expression produced decreased amounts of collagen. Our study identified an unrecognized role of SLN in regulating myogenic transdifferentiation during aging-associated skeletal muscle cell fibrosis. Targeting SLN may be a novel therapeutic strategy to relieve sarcopenia-associated muscle fibrosis.

Development of LC-MS/MS determination method and backpropagation artificial neural networks pharmacokinetic model of febuxostat in healthy subjects.

WHAT IS KNOWN AND OBJECTIVE: Febuxostat is a well-known drug for treating hyperuricemia and gout. The published methods for determination of febuxostat in human plasma might be unsuitable for high-throughput determination and widespread application. We need to develop a highly selective, sensitive and rapid liquid chromatography-tandem mass spectrometry method. METHODS: The chromatographic separation was achieved on a Hypersil Gold-C18 (2.1 mm × 100 mm, 1.9 µm) column with mobile phase A (Water containing 0.1% formic acid) and mobile phase B (acetonitrile containing 0.1% formic acid). Multiple reaction monitoring (MRM) mode was used for quantification using target ions at m/z 315.3 â†’ m/z 271.3 for febuxostat and m/z 324.3 â†’ m/z 280.3 for Febuxostat-d9 (IS). A backpropagation artificial neural network (BPANN) pharmacokinetic model was constructed by the data of bioequivalence study. RESULTS AND DISCUSSION: After the LC-MS/MS method validated, it was successfully applied to the bioequivalence study of 30 human volunteers under fed condition. The predicted concentrations generated by BPANN model had a high correlation coefficient with experimental values. WHAT IS NEW AND CONCLUSION: A sensitive LC-MS/MS method had been developed and validated for determination of febuxostat in healthy subjects under fed condition, and a BPANN model was developed that can be used to predict the plasma concentration of febuxostat.

A new simple method for quantification of cilostazol and its active metabolite in human plasma by LC-MS/MS: Application to pharmacokinetics of cilostazol associated with CYP genotypes in healthy Chinese population.

A simple, sensitive, and fully automated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of cilostazol (CIL) and its active metabolite, 3,4-dehydro cilostazol (CIL-M), in human plasma. Plasma samples were processed by protein precipitation in 2 mL 96-deep-well plates, and all liquid transfer steps were performed through robotic liquid handling workstation, enabling the whole procedure fast, compared to the reported methods. Separation of analytes was successfully achieved on a UPLC BEH C18 column (2.1 × 100 mm, 1.7 µm) with mobile phase A (5 mM ammonium formate containing 0.1% formic acid) and mobile phase B (methanol) at a flow rate of 0.30 mL min-1 . The total run time was 3.5 min per sample. Mass spectrometric detection was conducted by electrospray ion source in positive ion multiple reaction monitoring mode. Calibration curves were linear over the concentration range of 1.0-800 ng·mL-1 for CIL and 0.05-400 ng·mL-1 for CIL-M. The coefficient of variation for the assay's precision was 12.3%, and the accuracy was 88.8-99.8%. It was fully validated and successfully applied to assess the influence of CYP genotypes on the pharmacokinetics of CIL after oral administration of 50 mg tablet formulations of CIL to healthy Chinese volunteers. The results suggest that, in Chinese population, the genotype of CYP3A5 affects the plasma exposure of CIL.

Soluble epoxide hydrolase inhibitor protects against blood-brain barrier dysfunction in a mouse model of type 2 diabetes via the AMPK/HO-1 pathway.

Diabetes mellitus is a metabolic disorder that can lead to blood-brain barrier (BBB) disruption and cognitive decline. However, the mechanisms of BBB breakdown in diabetes are still unclear. Soluble epoxide hydrolase (sEH) is an enzyme that degrades epoxyeicosatrienoic acids (EETs), which have multiple protective effects on vascular structure and functions. In the current study, we showed increased vascular permeability of the BBB, which was accompanied by upregulation of sEH and downregulation of 14,15-EET. Moreover, the sEH inhibitor t-AUCB restored diabetic BBB integrity in vivo, and 14,15-EET prevented ROS accumulation and MEC injury in vitro. t-AUCB or 14,15-EET treatment provoked AMPK/HO-1 activation under diabetic conditions in vivo and in vitro. Thus, we suggest that decreased EET degradation by sEH inhibition might be a potential therapeutic approach to attenuate the progression of BBB injury in diabetic mice via AMPK/HO-1 pathway activation.