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Gangliosides play an imperative role in cell signaling, neuronal recovery, apoptosis, and other physiological processes. For example, GM3 can regulate hypothalamic leptin resistance and control energy homeostasis, GD3 can mediate cell proliferation and differentiation and induce apoptosis, and GQ1b can stimulate neurogenesis. Therefore, the present study sought to establish and optimize the targeted analysis method for ganglioside subclasses and their molecular species using hydrophilic interaction liquid chromatography–triple quadrupole–MS/MS (HILIC-QQQ-MS/MS). Additionally, the fragmentation pattern of different ganglioside subclasses and their retention time patterns were analyzed, providing more accurate qualitative results. The limit of quantitation (LOQ) was as low as 10−4 ng. Moreover, the molecular species of gangliosides in the liver, cortex, and hypothalamus of C57BL/6 mice were analyzed using the established method. A total of 23 ganglioside subclasses with 164 molecular species, including 40 O-acetylated ganglioside molecular species and 28 NeuGc ganglioside molecular species, were identified using the semi-quantitative analysis method of an external standard curve corrected by an internal standard. In addition to NeuGc gangliosides, the contents of ganglioside subclasses were more abundant in the mouse brain than those in the mouse liver; especially, the contents of unsaturated gangliosides in the hypothalamus were much higher than those in the liver. Among them, O-acetylated gangliosides were detected only in the cortex and hypothalamus at a concentration of up to 100 μg/mg protein (40 molecular species). Overall, the proposed method expanded the detectable number of ganglioside subclasses and molecular species in biological samples and provided more opportunities for further study of the biological functions of gangliosides. [ABSTRACT FROM AUTHOR]

Purpose: Ulcerative colitis (UC) is a serious health problem with increasing morbidity and prevalence worldwide. The pathogenesis of UC is complex, currently believed to be influenced by genetic factors, dysregulation of the host immune system, imbalance in the intestinal microbiota, and environmental factors. Currently, UC is typically managed using aminosalicylates, immunosuppressants, and biologics as adjunctive therapies, with the risk of relapse and development of drug resistance upon discontinuation. Therefore, further research into the pathogenesis of UC and exploration of potential treatment strategies are necessary to improve the quality of life for affected patients. According to previous studies, Lactobacillus paracasei Jlus66 (Jlus66) reduced inflammation and may help prevent or treat UC. Methods: We used dextran sulfate sodium (DSS) to induce a mouse model of UC to assess the effect of Jlus66 on the progression of colitis. During the experiment, we monitored mouse body weight, food and water consumption, as well as rectal bleeding. Hematoxylin-eosin staining was performed to assess intestinal pathological damage. Protein imprinting and immunohistochemical methods were used to evaluate the protein levels of nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and tight junction (TJ) proteins in intestinal tissues. Fecal microbiota was analyzed based on partial 16S rRNA gene sequencing. Results: Jlus66 supplementation reduced the degree of colon tissue damage, such as colon shortening, fecal occult blood, colon epithelial damage, and weight loss. Supplementation with Jlus66 reduced DSS-induced upregulation of cytokine levels such as TNF-α, IL-1β, and IL-6 (p < 0.05). The NF-κB pathway and MAPK pathway were inhibited, and the expression of TJ proteins (ZO-1, Occludin, and Claudin-3) was upregulated. 16S rRNA sequencing of mouse cecal contents showed that Jlus66 effectively regulated the structure of the intestinal biota. Conclusion: In conclusion, these data indicate that Jlus66 can alter the intestinal biota and slow the progression of UC, providing new insights into potential therapeutic strategies for UC. [ABSTRACT FROM AUTHOR]

Our study was designed to investigate the original spectrum of feline respiratory tract infection and to provide a scientific basis for the clinical diagnosis and treatment of feline respiratory infections and for precise prevention and control measures. A total of 400 cats with upper respiratory tract infections from animal hospitals in 12 provinces in China were examined from November 2022 to October 2023 to investigate the epidemiology of feline calicivirus (FCV), feline herpes virus type 1 (FHV-1), influenza A virus (IAV), Mycoplasma felis, Chlamydia felis, and Bordetella bronchiseptica through loop-mediated isothermal amplification (LAMP) with microfluidic chip detection. The results showed that 396 of the 400 samples tested were positive for at least one of these pathogens, with an overall detection rate of 99.00%. The detection rates were as follows: FCV, 36.00% (144/400); M. felis, 34.00% (136/400); FHV-1, 21.50% (86/400); C. felis, 15.75% (63/400); B. b, 13.00% (52/400); IAV, 4.50% (18/400). There were no statistically significant differences in the detection rates of respiratory pathogens between different sexes, ages, seasons, breeds, or regions (P > 0.05). There were 88 mixed infections, giving a total mixed infection rate of 22.00% (88/400). It is worth noting that the detection rate of FCV at different ages and of FHV-1 in different sexes showed significant differences (P < 0.05). The highest rate of FCV infection was found in animals that were 1 to 2 years old, and the rate of FHV-1 infection in male cats was higher than that in female cats. The results showed that the spectrum of feline respiratory pathogens is complex, with diverse epidemiological characteristics and mixed infections, and some differences among different respiratory pathogens were found with regard to the sex, age, and breed of the cat. Studies should be continued to provide a scientific basis for precise prevention and control of feline respiratory diseases. [ABSTRACT FROM AUTHOR]

The electrochemical reaction in silicon (Si) electrode, accompanying with tremendous volume expansion, causes rapid capacity fade of Li-ion batteries. The Li-ion concentration gradient and structural distribution uniformity influence the inhomogeneous expansion, and the kinetic mechanism of lithiation and interfacial morphology evolvement remains debated. The present study focuses on the dynamics of Li-Si interdiffusion at Si/Li interfaces with various Si-facet orientations and phases using a machine-learning potential. We find that the Si flux from bulk Si to Li-Si interface regions controls the length of Li-Si interdiffusion region. The lithiation length in different Si/Li interface systems exhibits the order of amorphous-Si > crystalline-Si(110) > crystalline-Si(100) > crystalline-Si(111), which agrees with the experimental trend. Our atomic simulations further reveal that the key factor determining the Li-Si interdiffusion is the difference of on-site Si atomic energies between the bulk Si and the Li-Si interface regions. We propose that the large interdiffusion extent is due to a low thermodynamics barrier. Our findings provide insights for the development of high-performance Si anode materials. [ABSTRACT FROM AUTHOR]

A localized parameter system is constructed for the Taihu Lake Basin based on the shared socioeconomic pathways (SSPs) to predict the rural population and economy including ANPSP from 2020 to 2050. The results show that: (1) Under the five paths of SSP1–SSP5, the population will continue to decrease, and the scenarios from large to small are SSP3 > SSP1 > SSP2 > SSP4 > SSP5. Agricultural GDP continues to rise under the SSP1, SSP4 and SSP5, and rises first and then slowly declines under the SSP2 and SSP3. (2) The ANPSP caused by living and production will show a downward trend. The scenarios with the highest and lowest rural life pollution are SSP3 and SSP5, and the scenarios with the highest and lowest agricultural production pollution are SSP5 and SSP1, respectively. The total pollution will be reduced, however the reduction rate will gradually slow down, and the pollution caused by rural production and life is difficult to completely avoid. (3) The total nitrogen (TN) and total phosphorus (TP) pollution showed a similar trend. Both types of pollutants are mainly from agricultural production activities, however the proportion of rural domestic pollution is gradually increasing. Agricultural production has a greater impact on TP, while rural life contributes more to TN than TP. (4) SSP1 is the only path that can prevent ANPSP and achieve agricultural economic growth. On the contrary, SSP3 leads to the increase of ANPSP and the decrease of agricultural GDP, which brings the double pressure of economic growth and environmental protection. [ABSTRACT FROM AUTHOR]

The aim of this study was to design a tulobuterol (TUL) patch with good penetration behavior and mechanical properties. Particular attention was paid to the effect of transdermal permeation enhancers on the release process of metal ligand-based acrylic pressure-sensitive adhesive (AA-NAT/Fe3+). The type and dosage of the enhancers were screened by in vitro transdermal penetration in rat skin. The optimized formulation was evaluated in a pharmacokinetic study in rats. Furthermore, the molecular mechanism by which Azone (AZ) improves the release rate of TUL from AA-NAT/Fe3+ was investigated by FT-IR, shear strength test, rheological study, and molecular simulation. As a result, the optimized formula using AA-NAT/Fe3+ showed better mechanical properties compared to commercial products. Meanwhile, the AUC0-t and Cmax of the optimized patch were 1045 ± 89 ng/mL·h and 106.8 ± 28.5 ng/mL, respectively, which were not significantly different from those of the commercial product. In addition, AZ increased the mobility of the pressure-sensitive adhesive (PSA) rather than decreasing the drug-PSA interaction, which was the main factor in enhancing TUL release from the patch. In conclusion, a TUL transdermal drug delivery patch was successfully developed using metal-coordinated PSA, and a reference was provided for the design of metal-coordinated acrylic PSA for transdermal patch delivery applications. [ABSTRACT FROM AUTHOR]

Piezoelectric actuators are a class of actuators that precisely transfer input electric energy into displacement, force, or movement outputs efficiently via inverse piezoelectric effect-based electromechanical coupling. Various types of piezoelectric actuators have sprung up and gained widespread use in various applications in terms of compelling attributes, such as high precision, flexibility of stoke, immunity to electromagnetic interference, and structural scalability. This paper systematically reviews the piezoelectric materials, operating principles, representative schemes, characteristics, and potential applications of each mainstream type of piezoelectric actuator. Herein, we intend to provide a more scientific and nuanced perspective to classify piezoelectric actuators into direct and indirect categories with several subcategories. In addition, this review outlines the pros and cons and the future development trends for all kinds of piezoelectric actuators by exploring the relations and mechanisms behind them. The rich content and detailed comparison can help build an in-depth and holistic understanding of piezoelectric actuators and pave the way for future research and the selection of practical applications. [ABSTRACT FROM AUTHOR]

Superconducting topological metals (SCTMs) have recently emerged as a promising platform of topological superconductivity (TSC) and Majorana zero modes for quantum computation. Despite their importance in both fundamental research and applications, SCTMs are very rare in nature. Here, we propose a strategy to design SCTMs by intercalating the superconducting units into the topological insulators. A program that characterizes the superconducting BdG Chern number of 2D BdG Hamiltonian from ab initio calculations is also developed. Following this strategy, PdBi2Te5 and PdBi2Te4 are found to be experimentally synthesizable and ideal SCTMs. Chiral TSC could be realized in such SCTMs by incorporating topological surface states with Zeeman effect, which can be realized by an external magnetic field or in proximity to ferromagnetic insulator. Our strategy provides a new method for identifying the SCTMs and TSC candidates, and the program makes it possible to design and modulate the TSC candidates from ab initio calculations. [ABSTRACT FROM AUTHOR]

Aim: To apply model-informed drug development (MIDD) approach to support the decision making in drug development and accelerate the clinical development of janagliflozin, an orally selective SGLT2 inhibitor. Method: We previously developed a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model of janagliflozin based on preclinical data to optimize dose design in the first-in-human (FIH) study. In the current study, we used clinical PK/PD data of the FIH study to validate the model and then simulate the PK/PD profiles of multiple ascending dosing (MAD) study in healthy subjects. Besides, we developed a population PK/PD model of janagliflozin to predict steady-state urinary glucose excretion (UGE [UGE,ss]) in healthy subjects in the Phase 1 stage. This model was subsequently used to simulate the UGE, ss in patients with type 2 diabetes mellitus (T2DM) based on a unified PD target (ΔUGEc) across healthy subjects and patients with T2DM. This unified PD target was estimated from our previous work of model-based meta-analysis (MBMA) for the same class of drugs. The model-simulated UGE,ss in patients with T2DM was validated by data from the clinical Phase 1e study. Finally, at the end of the Phase 1 study, we simulated the 24-week hemoglobin A1c (HbA1c) level in patients with T2DM of janagliflozin based on the quantitative UGE/FPG/HbA1c relationship informed by our previous MBMA study for the same class of drugs. Results: The pharmacologically active dose (PAD) levels of multiple ascending dosing (MAD) study were estimated to be 25, 50,100 mg once daily (QD) for 14 days based on the effective PD target of approximately 50 g daily UGE in healthy subjects. Besides, our previous MBMA analysis for the same class of drugs has provided a unified effective PD target of ΔUGEc approximately 0.5–0.6 g/(mg/dL) in both healthy subjects and patients with T2DM. In this study, the model-simulated steady-state ΔUGEc (ΔUGEc,ss) of janagliflozin in patients with T2DM were 0.52, 0.61 and 0.66 g/(mg/dL) for 25, 50, 100 mg QD dose levels. Finally, we estimated that HbA1c at 24 weeks would decrease 0.78 and 0.93 from baseline for the 25 and 50 mg QD dose groups. Conclusions: The application of MIDD strategy adequately supported the decision making at each stage of janagliflozin development process. A waiver of Phase 2 study was successfully approved for janagliflozin based on these model-informed results and suggestions. This MIDD strategy of janagliflozin could be further utilized to support the clinical development of other SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

Objective: To compare the performance of the EAONO/JOS, STAMCO, and ChOLE Cholesteatoma Staging Systems in prognostic evaluation of children acquired middle ear cholesteatoma after primary surgery and identify the other factors that could predict cholesteatoma recidivism. And the correlation between the staging and the recidivism of cholesteatoma after grouping according to operation was evaluated. Methods: A total of 123 ears of 118 patients that underwent surgery for primary cholesteatoma from November 2008 to May 2020 were included in this retrospective study, and then classified and staged according to the EAONO/JOS, STAMCO, and ChOLE cholesteatoma staging system, respectively. Each indicator involved in the system above was analyzed separately to evaluate its prognostic value for cholesteatoma recidivism. Results: The type of surgical procedure performed (P = 0.020) was shown to be associated with cholesteatoma recidivism. Cholesteatoma location the supratubal recess (S1) (P = 0.026, HR = 3.614, 95% CI 1.137, 7.945), and the sinus tympani (S2) (P = 0.004, HR = 4.208, 95% CI 1.574, 11.250) were shown to be significantly associated with disease recidivism. When focusing on the CWU operation group, ossicular chain status in STAMCO stage (P = 0.043) and in the ChOLE stage (P = 0.018) were significantly associated with cholesteatoma recidivism. The results had shown no association between the three stages and cholesteatoma recidivism in the CWD and endoscopic surgery groups. Conclusions: Based on our study, the EAONO/JOS, STAMCO, and ChOLE Classifications have limited value in predicting cholesteatoma recidivism, in acquired middle ear cholesteatoma in children. Adding the pathological status of the ossicular chain may be useful for predicting the recidivism of cholesteatoma. Additional validation studies are entailed to definitively assess the clinical utility of these classifications. [ABSTRACT FROM AUTHOR]

Concentrations, composition profiles, sources, and health risks of 16 USEPA priority polycyclic aromatic hydrocarbons (PAHs) in urban soils from 23 cities across China based on metadata collected from previous studies between 2005 and 2021 were investigated. ΣPAH concentrations in urban soils from 23 cities across China ranged from 0.1231 to 17.2000 mg/kg (mean = 2.7171 ± 3.8276 mg/kg). Overall PAH contamination in urban soils across China was moderate compared to that in global cities. Based on energy consumption and climate conditions, the spatial distributions of mean ΣPAH concentrations in Northeast China were highest, followed by those in North China, West China, East China, and South China. Individual PAH composition profiles decreased in the order: 4-ring PAHs (41.36%) > 5-ring PAHs (21.77%) > 3-ring PAHs (18.53%) > 6-ring PAHs (14.00%) > 2-ring PAHs (2.27%). Diagnostic ratios and positive matrix factorization (PMF) revealed that PAHs in urban soils were mainly derived from fossil fuel combustion (from coal, natural gas, and biomass), especially in North, Northeast, and East China, with smaller contributions from petrogenic sources. Health risk assessment results suggest that although there are potential cancer risks from PAHs, risks were acceptable. Toxic equivalent concentration (TEQ) and the corresponding oral cancer slope factor (CFS0) contributed most to the uncertainty of total risks. This study will help develop strategies to reduce PAH risk management in urban soils in China. [ABSTRACT FROM AUTHOR]

Characteristics, profile composition, ecological and human health risk of polycyclic aromatic hydrocarbons in surface dust collected from Shenyang city, China, were investigated. Concentrations of 16 USEPA priority PAHs ranged between 371.57 and 3300.04 μg/kg (mean 1244.76 ± 715.25 μg/kg). Fluoranthene was the most abundant individual PAHs, followed by pyrene, and high molecular weight PAHs, more than three times of low molecular weight PAHs, were the predominant components. Profiles of PAHs showed that 4-ring PAHs were dominant, followed by 3-ring and 5-ring PAHs, and indicated that combustion sources accounted for the most PAHs. Results of diagnostic ratios and positive matrix factorization all suggested that pyrogenic sources were the most important source of PAHs in urban dust, followed by natural gas combustion and petrogenic sources, and traffic emissions would play an increasingly critical role with the increasing of vehicles. Health risk assessment suggested children were the most vulnerable to PAHs compared to adolescents and adults. Ingestion was the most important exposure pathway. The total lifetime cancer risk of 43.33% of sampling sites was higher than 10–6, but the TLCR at all sites was much lower than the highest acceptable risk established by USEPA (10–4). [ABSTRACT FROM AUTHOR]

Inspired by the single-atom catalysts (SACs) concept, we rationally design a series of Pt single atom catalysts embedded in different transition metal nanoclusters through first-principles calculations. In these so-called "crown-jewel" (CJ) structures, Pt atoms (jewels) occupy the vertex sites of the metal nanocluster (crown) surface. We investigated the thermal stability and oxygen reduction reaction (ORR) catalytic activity of these catalysts. The results reveal that CJ-structured PtCu nanoclusters are stable and possess a comparable or even better ORR activity compared to Pt catalyst, making it a promising candidate for low-cost ORR catalysts. The effect of cluster size on the adsorption strength of ORR intermediates and catalytic property has also been studied. Furthermore, the overall ORR catalytic activity trend of these SACs is explained based on analysis of their electronic properties. A descriptor Ψ was established to provide further insight into the correlation between the electronic structure and catalytic activity, which provides a design strategy for new ORR catalysts. More importantly, we reveal that this electronic descriptor can be extended to predict other CJ-structured nanoclusters. [ABSTRACT FROM AUTHOR]

The N-nitrosamine (NA) concentrations and types in raw chicken and duck meats of different parts and seasons were estimated by headspace solid-phase micro-extraction with gas chromatography-mass spectrometry (HS–SPME–GC–MS). The exposure level and hazard quotient of each detected volatile N-nitrosamine (VNA) were conducted. The selected chicken and duck samples were contaminated by VNAs to some extent. The major types and contents of VNAs in different parts of chicken and duck meats varied seasonally. For chicken samples, the order of the total VNA concentrations was as follows: autumn > spring > winter > summer. For duck samples, the order was changed as follows: winter > autumn > summer > spring (thigh samples) and autumn > spring > winter > summer (breast samples). The estimated exposure levels for adults caused by duck consumption were slightly higher than those by chickens, which was consistent with the tendency in 2–3 years old children. According to the linear regression correlation between the 10% benchmark dose limit (BMDL10) and subtriplicate of median lethal dose (LD50), BMDL10 values of each VNA were calculated. Due to this hypothesis, the risk assessments of each detected VNA and total VNAs posed by consuming chicken and duck meats in Tianjin, China were of low concern. [ABSTRACT FROM AUTHOR]

Syntactic foams with high strength and light weight are essential for aerospace and deep sea explorations. In this study, high-performance carbon fiber/hollow glass microspheres/epoxy syntactic foams were prepared, and the reinforcing mechanism of carbon fiber is discussed. The syntactic foam with 3 wt% short carbon fiber achieves a uniaxial compressive strength of 141.7 MPa, which is among the highest values reported in the literature. The thermal conductivity of syntactic foam increased by 66.7% with the addition of 3 wt% short carbon fibers, which helped to control the cracking issue caused by the inner temperature surge during the curing process. Further stress characterizations using fiber Bragg gratings (FBGs) confirmed that carbon fiber can relieve the evolution of thermal stress and reduce the residual thermal stress. [ABSTRACT FROM AUTHOR]

The rate of early misdiagnosis in patients with nodular fasciitis of the ear is high. To provide a basis for clinical diagnosis and treatment, we aimed to summarise the clinical manifestations, imaging results, pathological findings, treatment strategies, and postoperative follow-up results for three cases of paediatric nodular fasciitis (two girls, one boy) treated in the Department of Otorhinolaryngology, Head and Neck Surgery, at Beijing Children's Hospital of Capital Medical University from 2018 to 2020. The average age at diagnosis was 24 months. Lesions occurred in the left ear in two cases and right ear in one case. All patients had a history of biopsy before surgery. Rapid growth was observed following biopsy in two patients, and anti-inflammatory treatment was ineffective in all three cases. Fluorescence in situ hybridisation analysis of ubiquitin-specific peptidase 6 (USP6) was performed in two of the three cases, with positive results. The lesions exhibited hypo-intensity or iso-intensity on T1-weighted magnetic resonance imaging (MRI) and heterogeneous hyper-intensity on T2-weighted MRI. "Fascial tail" signs were observed on imaging in all cases. Surgical resection was performed in all cases. Intact ear appearance was observed at follow-up, and there were no cases of recurrence. Conclusion: Combining clinical features with imaging findings may improve the accuracy of preoperative diagnosis in patients with nodular fasciitis. In addition to pathological findings, genetic testing for USP6 may aid in diagnosis. The final diagnosis should be based on comprehensive assessment. Complete surgical resection can prevent recurrence. What is Known: • Paediatric NF around the ear is rare and is easily misdiagnosed as other inflammatory masses that have a higher incidence in children. • Most previous reports of NF were case reports. What is New: • Combining clinical and imaging findings with genetic testing for USP6 rearrangement may improve the accuracy of preoperative diagnosis in patients with NF. Nonetheless, the final diagnosis should be based on comprehensive assessment. • The present paper is significant in that it represents the only report of three cases of ear NF in children with a complete medical history and prognosis. [ABSTRACT FROM AUTHOR]

In this paper, a new variational Gaussian regression filter (VGRF) is proposed by constructing the linear parametric Gaussian regression (LPGR) process including variational parameters. Through modeling the measurement likelihood by LPGR to implement the Bayesian update, the nonlinear measurement function will not be directly involved in the state estimation. The complex Monte Carlo computation used in traditional methods is also avoided well. Hence, in PVFF, the inference of state posteriori and variational parameters can be achieved tractably and simply by using variational Bayesian inference approach. Secondly, a filtering evidence lower bound (F-ELBO) is proposed as a quantitative evaluation rule of different filters. Compared with traditional methods, the higher estimation accuracy of VGRF can be explained by the F-ELBO. Thirdly, a relationship between F-ELBO and the monitored ELBO (M-ELBO) is found, i.e., F-ELBO is always larger than M-ELBO. Based on this finding, the accuracy performance improvement of VGRF can be theoretically explained. Finally, three numerical examples are employed to illustrate the effectiveness of VGRF. [ABSTRACT FROM AUTHOR]

Aims: Chloroquine (CQ) has been repurposed to treat coronavirus disease 2019 (COVID-19). Understanding the pharmacokinetics (PK) in COVID-19 patients is essential to study its exposure–efficacy/safety relationship and provide a basis for a possible dosing regimen optimization. Subject and methods: In this study, we used a population-based meta-analysis approach to develop a population PK model to characterize the CQ PK in COVID-19 patients. An open-label, single-center study (ethical review approval number: PJ-NBEY-KY-2020-063-01) was conducted to assess the safety, efficacy, and pharmacokinetics of CQ in patients with COVID-19. The sparse PK data from 50 COVID-19 patients, receiving 500 mg CQ phosphate twice daily for 7 days, were combined with additional CQ PK data from 18 publications. Results: A two-compartment model with first-order oral absorption and first-order elimination and an absorption lag best described the data. Absorption rate (ka) was estimated to be 0.559 h−1, and a lag time of absorption (ALAG) was estimated to be 0.149 h. Apparent clearance (CL/F) and apparent central volume of distribution (V2/F) was 33.3 l/h and 3630 l. Apparent distribution clearance (Q/F) and volume of distribution of peripheral compartment (Q3/F) were 58.7 l/h and 5120 l. The simulated CQ concentration under five dosing regimens of CQ phosphate were within the safety margin (400 ng/ml). Conclusion: Model-based simulation using PK parameters from the COVID-19 patients shows that the concentrations under the currently recommended dosing regimen are below the safety margin for side-effects, which suggests that these dosing regimens are generally safe. The derived population PK model should allow for the assessment of pharmacokinetics–pharmacodynamics (PK-PD) relationships for CQ when given alone or in combination with other agents to treat COVID-19. [ABSTRACT FROM AUTHOR]

The study intends to investigate the regulation of syndecan-1 in human uterine leiomyoma cells. Human syndecan-1 levels were detected by Western blot in uterus leimyoma's tissue. The efficacy of syndecan-1 silencing on the cell proliferation, metalloproteinases and extracellular matrix were determined through Cell Counting Kit (CCK8) assay and Western blot assay, respectively. We compared the respective and combined effect of mifepristone and syndecan-1 on cell proliferation and the expression of metalloproteinases and extracellular matrix (ECM) in human uterine leiomyoma cells. The inhibitory effects of Syndecan-1 silencing on proliferation, ECM and Matrix Metalloproteinase (MMP) were observed in human uterine leiomyoma cells. Furthermore, syndecan-1 inhibition enhanced the effects of mifepristone against uterine leiomyoma cell proliferation. The expression of MMPs and ECM components in human uterine leiomyoma cells was decreased dramatically after syndecan-1 silencing, which was promoted after mifepristone treatment. Altogether, syndecan-1 silencing enhanced the efficacy of mifepristone on the uterine leiomyoma cell proliferation and ECM formation. Therefore, targeting syndecan-1 represents a novel therapeutic strategy to treat uterine leiomyoma. [ABSTRACT FROM AUTHOR]

This paper proposes a quantitative method to optimize the existing river monitoring network based on a modified approaching degree model, T test, and Euclidean distance. In this study, the Liaohe River located in Liaoning province, China, was taken as a research object. Samples were collected from 8 sampling sites throughout the monitoring network, and water quality parameters were analyzed every 2 months from January 2009 to December 2010. The results show that the average concentrations of the ammonia nitrogen (NH4+-N) and chemical oxygen demand (COD) were beyond grade III of the Environmental Quality Standards for Surface Water of China (GB3838-2002), and they were the main water quality parameters. After optimization, the number of monitoring sections along the Liaohe River was reduced to five from the original eight, thus saving 37.5% of the monitoring cost; meanwhile, there is no significant difference between the un-optimized and optimized monitoring networks, and the optimized monitoring network remains to be able to perform as good as the original one. In addition, the total data attainment rate was improved greatly, and the duplicate setting degree of monitoring points decreased significantly compared with other optimal methods. The optimized monitoring network proves to be more efficient, reasonable, and economically feasible, so this quantitative method can help optimize the changing orderly river monitoring networks. [ABSTRACT FROM AUTHOR]

To evaluate the effects of selenium (Se) and vitamin E (Vit E) on female sika deer. This study was conducted using a 3 × 2 + 1 factorial experiment. Depending on treatment design, the deer were fed with the basal diet supplemented with 0.2, 0.3, and 0.4 mg of selenium as well as 100 and 200 IU of vitamin E per kg of dry matter (DM). Accordingly, six groups named G1 to G6 are involved in this study. In addition, group G0 was available in the study, in which the deer were fed with only basal diet. The results show that the final body weight (BW), average daily gain (ADG), and apparent digestibility of crude protein, ether extract, and neutral detergent fiber of the deer in G1 to G6 increased as the selenium level increased from 0.2 to 0.3 mg per kg of DM (P < 0.05). Higher IgG content of the deer was observed with the intake of selenium and vitamin E (P < 0.05). The total content of protein of the deer in G3 was higher than that in G0 (P < 0.05), and the activity of glutathione peroxidase increased following the increase in the supplementation levels of selenium and vitamin E (P < 0.05). Furthermore, selenium had significant effects on the concentration of T4 and T3 (P < 0.05). The optimum levels of selenium and vitamin E for 1-year-old female sika deer were 0.3 mg and 100 IU per kg of dietary DM, respectively. [ABSTRACT FROM AUTHOR]

Electron-beam irradiation has demonstrated the promising results for tuning the exothermic behavior of polyacrylonitrile (PAN) fibers, and the stabilization time can be shortened accordingly. However, the mechanical properties, especially the tensile strength, of carbon fibers based on irradiated PAN fibers are usually lower than those of standard carbon fibers. In this study, PAN fibers irradiated with an electron beam to 1200 kGy are continuously stabilized and carbonized to produce carbon fibers (i-CFs). The mechanical properties of the i-CFs are optimized by controlling the density of the stabilized fibers, and the best performing i-CF achieves a tensile strength of 2.27 GPa and a modulus of 174 GPa. The structure and properties of the carbon fibers and the precursor fibers are investigated to determine the origin of the low tensile properties of the i-CFs. The results show that the graphite crystalline structures are comparable between the CFs and the i-CFs. However, two distinct peaks at 2020 and 1668 cm−1 emerge in the FT-IR spectra of PAN fibers after irradiation that correspond to the C=C=N (ketenimine) and C=N–N=C conjugation groups. These cross-linking structures may disrupt the cyclization reaction and hinder the formation of the aromatic structure of PAN during stabilization, which bring about defects in the resultant carbon fibers. [ABSTRACT FROM AUTHOR]

Carbon nanofibrous nonwoven mats (CNFMs) prepared via electrospinning offer excellent electrical and structural properties and have been used as frameworks for electrodes in electrochemical energy storage devices. However, lack of mechanical strength hinders the broad applications of CNFMs in flexible electronics or industry use. In this work, a rapid stabilization method is developed to prepare high-strength and flexible CNFMs. Studies of the effects of stabilization time on the structures of the stabilized polyacrylonitrile (PAN) nanofibers and the subsequent carbon nanofibers reveal that there is an optimal stabilization time for making high-strength CNFMs. Long stabilization time results in excessive oxidation of the stabilized PAN nanofibers and unwanted defects in the carbon nanofibers. Short stabilization time results in carbon nanofibers with less crystalline structures due to insufficient formation of the thermally stable ladder-like structure. Robust and flexible CNFM with the highest tensile strength of 192.7 MPa is obtained using an optimized total stabilization time of 40 min. To demonstrate the application of the flexible CNFMs, they are fabricated as an electrode framework to load TiO2 nanoparticles without use of organic binders. Lithium ion half-cell based on this electrode demonstrates superior rate cycling performance owning to the porous structure and highly conductive fibrous carbon network of CNFM. [ABSTRACT FROM AUTHOR]

Wood is still a widely used raw material in many fields and is surface-modified for diverse applications. Though a few studies reported the anti-fungal effect derived from enhanced hydrophobicity of wood surface, no report about the influence of superhydrophobic surface upon fungi is known and the comparison of anti-fungal effects between hydrophobicity and superhydrophobicity on wood surface has not been demonstrated. We herein addressed these aspects regarding the anti-fungal properties of both hydrophobic and superhydrophobic wood. Hydrophobic and superhydrophobic beech and pine, representing hard- and softwood were fabricated, using environmentally friendly organic materials (cellulose and glycerol). Cellulose stearoyl ester was used for dip-coating (1st layer) the wood, leading to a hydrophobic surface and glycerol stearoyl ester was used for brush-coating (2nd layer) the wood, leading to a hierarchical superhydrophobic surface. Results showed that hydrophobic and superhydrophobic woods exhibited better anti-fungal properties comparing with non-treated wood. Furthermore, differential anti-fungal effects of hydrophobic and superhydrophobic wood were observed: superhydrophobic wood could thoroughly prevent fungal attachment to treated wood, while fungi could still be found inside hydrophobic wood after anti-fungal test. [ABSTRACT FROM AUTHOR]

Enterotoxigenic Escherichia coli (ETEC) is a significant cause of infectious diarrhea in animals. In this study, yeast surface display technology was employed to investigate the effects of ETEC enterotoxin fusion protein on the intestinal flora and mucosal immunity of rats. ETEC estA, estB, and eltAB (heat-labile and heat-stable toxins) were expressed on the surface of yeast. Rats were divided into normal saline, yeast and display yeast groups. Fecal and jejunal content samples were collected on the 7th, 14th, and 21st days. Rats were then fed ETEC for 3 days before again collecting these samples. Levels of SIgA, IL-2, IL-4, IFN-γ, and microbial population density and diversity were documented by ELISA, T-RFLP and real-time PCR. The results demonstrated that estA, estB, and eltAB fusion proteins were expressed on the surface of yeast. Following ETEC challenge, levels of SIgA, IL-2, IL-4, IFN-γ, and, the numbers and variety of intestinal microbes were significantly increased in rats receiving display yeast and yeast. These factors were significantly decreased in rats given normal saline and yeast. Our results indicate that display yeast and yeast can increase the number and diversity of intestinal microbes in rats and improve intestinal immune function. After ETEC challenge, the display yeast can better maintain the balance of intestinal bacteria and mucosal immunity. [ABSTRACT FROM AUTHOR]

This paper focuses on designing Gaussian sum approximation filter for both accurately and rapidly estimating the state of a class of nonlinear dynamic time-delay systems. Firstly, a novel nonaugmented Gaussian filter (GF) is derived, whose superiority in computation efficiency is theoretically analyzed as compared to the standard augmented GF. Secondly, a nonaugmented Gaussian sum filter (GSF) is proposed to accurately capture the state estimates by a weight sum of the above-proposed GF. In GSF, each GF component is independent from the others and can be performed in a parallel manner so that GSF is conducive to high-performance computing across many compute nodes. Finally, the performance of the proposed GSF is demonstrated by a vehicle suspension system with time delay, where the GSF achieves higher accuracy than the single GF and is computationally much more efficient than the particle filter with the almost same accuracy. [ABSTRACT FROM AUTHOR]

Autophagy, the process by which proteins and organelles are sequestered in double-membrane structures called autophagosomes and delivered to lysosomes for degradation, is critical in diseases such as cancer and neurodegeneration. Much of our understanding of this process has emerged from analysis of bulk cytoplasmic autophagy, but our understanding of how specific cargo, including organelles, proteins or intracellular pathogens, are targeted for selective autophagy is limited. Here we use quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins in human cells, including cargo receptors. Like known cargo receptors, nuclear receptor coactivator 4 (NCOA4) was highly enriched in autophagosomes, and associated with ATG8 proteins that recruit cargo-receptor complexes into autophagosomes. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species but is degraded via autophagy to release iron through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin led to decreased bioavailable intracellular iron. This work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy), which is critical for iron homeostasis, and provides a resource for further dissection of autophagosomal cargo-receptor connectivity. [ABSTRACT FROM AUTHOR]

Nanocrystalline (NC) copper was fabricated by severe plastic deformation of coarse-grained copper at a high strain rate under explosive loading. The feasibility of grain refinement under different explosive loading and the influence of overall temperature rise on grain refinement under impact compression were studied in this paper. The calculation model for the macroscopic temperature rise was established according to the adiabatic shock compression theory. The calculation model for coarse-grained copper was established by the Voronoi method and the microscopic temperature rise resulted from severe plastic deformation of grains was calculated by ANSYS/ls-dyna finite element software. The results show that it is feasible to fabricate NC copper by explosively dynamic deformation of coarse-grained copper and the average grain size of the NC copper can be controlled between 200∼400 nm. The whole temperature rise would increase with the increasing explosive thickness. Ammonium nitrate fuel oil explosive was adopted and five different thicknesses of the explosive, which are 20 mm, 25 mm, 30 mm, 35 mm, 45 mm, respectively, with the same diameter using 20 mm to the fly plate were adopted. The maximum macro and micro temperature rise is up to 532.4 K, 143.4 K, respectively, which has no great effect on grain refinement due to the whole temperature rise that is lower than grain growth temperature according to the high pressure melting theory. [ABSTRACT FROM AUTHOR]

Cancer cells have metabolic dependencies that distinguish them from their normal counterparts. Among these dependencies is an increased use of the amino acid glutamine to fuel anabolic processes. Indeed, the spectrum of glutamine-dependent tumours and the mechanisms whereby glutamine supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumour growth. Whereas most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derived glutamate into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP+ ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumours. [ABSTRACT FROM AUTHOR]

The interactions of toxic metals with essential metals may result in disturbances in the homeostasis of essential elements. However, there are few reports about toxic effect of arsenic (As) on the levels of essential trace elements in the central nervous system. To investigate whether subchronic exposure to As disturbs levels of main essential trace elements in the brain of mice and whether the gender difference in the response to As are altered, the concentrations of As, Iron (Fe), copper (Cu), selenium (Se), zinc (Zn) and Chromium (Cr) in the cerebrum and cerebellum of mice exposed to As subchronically were examined by inductively coupled plasma-mass spectrometry (ICP-MS). The gender difference in the changed levels of these essential trace elements was also statistically analyzed. The concentration of As was significantly higher in the cerebrum or cerebellum of mice exposed to As than that in control group ( P < 0.05). It indicates that As can accumulate in brain of mice after subchronic exposure. The concentrations of Fe, Se and Cr in the cerebrum or cerebellum were significantly lower in mice exposed to As than those in control group ( P < 0.05). On the contrary, the concentration of Cu in the cerebrum or cerebellum was significantly higher in mice exposed to As ( P < 0.05). Our results indicate that subchronic exposure to As may decrease the levels of Fe, Se and Cr or increase the level of Cu in the brain of mice. Moreover, the significant gender difference was found relative to the effect of As on concentration of Se in cerebrum and concentrations of Cu and Se in cerebellum of mice. Therefore, more experiments are required to further understand mechanisms whereby As interacts with essential elements in brain and induces the gender difference. [ABSTRACT FROM AUTHOR]

Chondrocytes from the lateral trochlear ridge of the distal femur taken from 1-day-old piglets were cultured in medium supplemented with 0, 7.8, 15.6, 31.2, and 62.5 μmol/L copper. Insulin-like growth factor-1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) levels in culture medium were determined by radioimmunoassay. DNA synthesis in chondrocytes was measured by tritiated thymidine (H-TdR) incorporation. Proliferation-promoting activity and incorporation of H-TdR in chondrocytes were increased in all culture media supplemented with copper and 15% fetal calf serum (FCS). The contents of IGF-1 and IGFBP-3 were also enhanced significantly in culture media containing 15% FCS and supplemented with copper at 15.6, 31.2, and 62.5 μmol/L. The optimal copper concentration for promoting chondrocyte proliferation and autocrine secretion of IGF-1 and IGFBP-3 was 31.2 μmol/L. [ABSTRACT FROM AUTHOR]

This experiment was conducted to measure the effect of copper supplementation on TGF-β gene expression in chondrocytes of newborn pigs. Chondrocytes were cultured in media containing 15% fetal calf serum supplemented with 0, 15.6, 31.2, and 62.5 μmol/L copper in 90-mm culture plate. Total RNA was isolated from chondrocytes, and TGF-β cDNA was synthesized, amplified, and sequenced. The expression level of TGF-β was examined by reverse transcription polymerase chain reaction. The results showed that the sequence of the cloned TGF-β gene was 99.4% identical to that in GenBank. The expression of TGF-β increased in culture media added with final concentration of 15.6, 31.2, and 62.5 μmol/L copper. In this study, the optimal copper concentration and optimal culture time for the highest level of TGF-β expression were 31.2 μmol/L and 48 h, respectively. [ABSTRACT FROM AUTHOR]

This experiment was conducted to examine the effect of dietary copper supplementation on somatostatin (SS) and growth hormone-releasing hormone (GHRH) mRNA expression levels in the hypothalami of growing pigs. A total of 45 crossbred pigs were randomly assigned to three groups of 15 pigs each; five replicates of three animals comprised each group. Pigs were allocated to diets that contained 5 mg/kg copper (control), 125 mg/kg copper sulfate, or 125 mg/kg copper methionine. At the end of the experiment, five pigs were selected at random from each group and slaughtered, and hypothalami were collected for determination of SS and GHRH mRNA expression levels. The results showed that the SS expression levels were lower and the GHRH levels were higher in pigs fed the diets with 125 mg/kg copper methionine ( P < 0.05) and 125 mg/kg copper sulfate ( P < 0.05), respectively, than in pigs fed the diet with 5 mg/kg copper. Furthermore, the relationship between SS mRNA and GHRH mRNA abundance had a significantly negative correlation ( P < 0.05). The data indicated that high dietary copper could enhance GHRH mRNA expression levels and suppress SS mRNA expression levels in the hypothalami of pigs. High lever dietary copper (125 mg/kg copper sulfate or 125 mg/kg copper methionine) increased pigs' growth performance and feed efficiency but had no significant effect on daily feed intake; 125 mg/kg copper sulfate or 125 mg/kg copper methionine at the same lever had no difference on growth promoting in pigs. [ABSTRACT FROM AUTHOR]

The main objective of this article is to demonstrate the utility of stratal slice images for exploring the sequence stratigraphy and sedimentology of complex depositional systems. The Dongying Depression is underlain by a productive, petroleum-prone, non-marine Cenozoic stratigraphic section. Here, we have integrated the recent 3D seismic profiles and borehole data to map sediment dispersal characteristics of the second member of the Shahejie Formation in the central-north Dongying Depression, located in the Bohai Bay Basin, China. We have documented the following key points: (i) the main strata under study were divided into two long-term sequence cycles (LSC1-2) with 14 middle-term sequence cycles (MSC1-14); (ii) five microfacies, distributary channel, inter-channel, mouth bar, underwater distributary channel, and tributary bay, were identified from well-based analysis of sedimentary facies; (iii) the mouth bar was generated at the center of the study area during the deposit stage of MSC6-7; (iv) the channel was distributed along the EW direction. The seismic sedimentological study on the second member of the Shahejie Formation in this study area highlights the distribution of the most important potential reservoirs. [ABSTRACT FROM AUTHOR]

Oncogenic KRAS is the key driver of pancreatic ductal adenocarcinoma (PDAC). We previously described a role for KRAS in PDAC tumor maintenance through rewiring of cellular metabolism to support proliferation. Understanding the details of this metabolic reprogramming in human PDAC may provide novel therapeutic opportunities. Here we show that the dependence on oncogenic KRAS correlates with specific metabolic profiles that involve maintenance of nucleotide pools as key mediators of KRAS-dependence. KRAS promotes these effects by activating a MAPK-dependent signaling pathway leading to MYC upregulation and transcription of the non-oxidative pentose phosphate pathway (PPP) gene RPIA, which results in nucleotide biosynthesis. The use of MEK inhibitors recapitulates the KRAS-dependence pattern and the expected metabolic changes. Antagonizing the PPP or pyrimidine biosynthesis inhibits the growth of KRAS-resistant cells. Together, these data reveal differential metabolic rewiring between KRAS-resistant and sensitive cells, and demonstrate that targeting nucleotide metabolism can overcome resistance to KRAS/MEK inhibition. Pancreatic ductal adenocarcinoma (PDAC) cells display varying degrees of reliance on oncogenic KRAS. Here the authors show that KRAS-resistant PDAC cells maintain nucleotides synthesis through a KRAS-independent upregulation of the non-oxidative pentose phosphate pathway gene RPIA and that targeting nucleotide metabolism restore sensitivity to KRAS pathway inhibition. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma is a notoriously difficult-to-treat cancer and patients are in need of novel therapies. We have shown previously that these tumours have altered metabolic requirements, making them highly reliant on a number of adaptations including a non-canonical glutamine (Gln) metabolic pathway and that inhibition of downstream components of Gln metabolism leads to a decrease in tumour growth. Here we test whether recently developed inhibitors of glutaminase (GLS), which mediates an early step in Gln metabolism, represent a viable therapeutic strategy. We show that despite marked early effects on in vitro proliferation caused by GLS inhibition, pancreatic cancer cells have adaptive metabolic networks that sustain proliferation in vitro and in vivo. We use an integrated metabolomic and proteomic platform to understand this adaptive response and thereby design rational combinatorial approaches. We demonstrate that pancreatic cancer metabolism is adaptive and that targeting Gln metabolism in combination with these adaptive responses may yield clinical benefits for patients. [ABSTRACT FROM AUTHOR]

Cell membrane proteins are believed to play a critical role in the pathogenesis of autoimmune diseases. However, few membrane autoantigens have been linked with Behçet's disease. Here, a cell-chip was performed to identify autoantibody target cells, and the suspected autoantigens were detected using immunoblotting. The amino acid sequences of the detected proteins were determined using LC-MALDI-TOF/TOF. Putative proteins were recombinantly expressed and purified, and a corresponding ELISA was developed and clinically validated using real clinical samples. It was found that a 36-kDa membrane protein - annexin A2 - was detected in approximately one-third of the patients' blood circulation. The immunohistochemistry results showed that annexin A2 was highly expressed in vascular endothelial cells. Moreover, vascular involvement was significantly higher in the anti-annexin A2 antibody-positive group versus the anti-annexin A2 antibody-negative group among all the clinical samples analyzed, indicating that annexin A2 is a novel endothelial cell membrane antigen involved in Behçet's disease. [ABSTRACT FROM AUTHOR]

A correction to the article "Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway" that was published in the 2013 issue is presented.