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Abstract Brain injury is the leading cause of mortality among patients who survive cardiac arrest (CA). Clinical studies have shown that the presence of post-CA hypoxic hepatitis or pre-CA liver disease is associated with increased mortality and inferior neurological recovery. In our in vivo global cerebral ischemia model, we observed a larger infarct area, elevated tissue injury scores, and increased intravascular CD45+ cell adhesion in reperfused brains with simultaneous hepatic ischemia than in those without it. In the ex vivo brain normothermic machine perfusion (NMP) model, we demonstrated that addition of a functioning liver to the brain NMP circuit significantly reduced post-CA brain injury, increased neuronal viability, and improved electrocortical activity. Furthermore, significant alterations were observed in both the transcriptome and metabolome in the presence or absence of hepatic ischemia. Our study highlights the crucial role of the liver in the pathogenesis of post-CA brain injury.

Abstract Orthopedic diseases, such as osteoarthritis and fractures, place a significant burden on individuals and healthcare systems worldwide. Extracellular vesicles (EVs), which are membrane‐derived particles, have emerged as a novel tool in the field of orthopedics. EVs play a crucial role in diagnosing, regenerating, and treating orthopedic diseases. In terms of diagnosis, EVs serve as potential biomarkers, carrying unique donor cell information and circulating effectively in bodily fluids. Specific biomolecules within EVs, including proteins, nucleic acids, and microRNAs, hold promise as biological markers for the early detection and monitoring of orthopedic diseases. EVs have shown significant potential in promoting bone and cartilage regeneration. They can enhance tissue regeneration by stimulating various stem cells to proliferate, migrate, and differentiate into mature chondrocytes and osteocytes. EVs can also target specific tissues, making them attractive candidates for drug delivery in orthopedic diseases. They can efficiently deliver therapeutic cargo, such as anti‐inflammatory agents and growth factors, to the affected sites, enhancing treatment efficacy while minimizing toxicity and adverse effects. In conclusion, EVs have significant potential in diagnosing, regenerating, and treating orthopedic diseases.

Myofibrillar protein–diacylglycerol emulsions containing catechin (MP-DAG-C) possess outstanding emulsifying property and oxidative stability. However, the effect of pH on MP-DAG-C emulsions should be revealed to provide possibilities for their application in practical meat products. Therefore, MP-DAG-C emulsions at different pH values were used in this study, in which lard, unpurified glycerolytic lard (UGL), and purified glycerolytic lard (PGL) were used as the oil phases. The results indicated that the emulsifying property of the UGL- and PGL-based emulsions increased compared to those of the lard-based emulsions (p < 0.05). The emulsifying activity and stability indices, absolute value of ζ-potential, and rheological characteristics increased with the increase in pH values (p < 0.05), with the droplets were smallest and distributed most uniformly at a pH of 6.5 compared to the other acidic environment (p < 0.05). The thiobarbituric acid substance and carbonyl content increased (p < 0.05), while the total sulfydryl content decreased (p < 0.05) during storage. However, there was no statistical difference between the oxidative stability of the MP-DAG-C emulsions with different pH values (p > 0.05). The results implied that the emulsifying property of MP-DAG-C emulsions increased with an increase in pH values. The oxidative stability of the MP-DAG-C emulsions at high pH values was improved by catechin.

Abstract As an important embodiment of a country's economic strength and national health, pharmaceutical manufacturing industry has made rapid development in China in recent years. But at the same time, the pharmaceutical manufacturing industry is facing many environmental problems, such as large pollution emissions, complex pollution components, controlling difficulties and so on. This paper measures the total factor productivity of pharmaceutical manufacturing industry (HTFP) by using data envelopment analysis with unexpected output, which is more accurate and effective than the traditional model. It also studies the effect of environmental regulation on the total factor productivity of pharmaceutical manufacturing industry (HTFP) by establishing panel data regression model and spatial econometric model based on 30 provinces in China from 2004 to 2019, which enriches the research results in the field of cleaning in pharmaceutical manufacturing industry. The conclusions are as follows: (1) Environmental regulation and total factor productivity of pharmaceutical manufacturing industry have significant spatial autocorrelation, showing "high-high" or "low-low" spatial aggregation characteristics; (2) Environmental regulation has a significant promoting effect on improving pharmaceutical manufacturing total factor productivity in local and surrounding areas, and there are differences in the impact of eastern, central and western regions; (3) Green technology, production technology and industrial structure play an important role in the impact of environmental regulation on pharmaceutical manufacturing total factor productivity, which provides theoretical guidance and policy recommendations for improving the level of total factor productivity of pharmaceutical manufacturing industry in the environmental aspect.

BackgroundClass I echocardiographic guidelines in primary mitral regurgitation (PMR) risks left ventricular ejection fraction (LVEF) 60%. There are no models predicting LVEF

The poor water solubility of myofibrillar proteins (MPs) limits their application in food industry, and is directly related to the molecular behavior associated with myosin assembly into filaments. This study aims to explore the effect of high-intensity ultrasound (HIU) combined with nonenzymatic glycation on the solubility, structural characteristics, and filament-forming behavior of MPs in low ionic strength media. The results showed that the HIU (200–400 W) application could promote the subsequent glycation reaction between MPs and dextran (DX) and interfere with the electrostatic balance between myosin rods, suppressing the formation of filamentous myosin polymers. Glycated MPs pretreated by 400 W HIU had the highest solubility, which corresponded to the smallest particle size, highest zeta potential, and optimum storage stability (P

Most existing recommendation models only consider single user–item interaction information, which leads to serious cold-start or data sparsity problems. In practical applications, a user’s behavior is multi-type, and different types of user behavior show different semantic information. To achieve more accurate recommendations, a major challenge comes from being able to handle heterogeneous behavior data from users more finely. To address this problem, this paper proposes a multi-behavior recommendation framework based on a graph neural network, which captures personalized semantics of specific behavior and thus distinguishes the importance of different behaviors for predicting the target behavior. Meanwhile, this model establishes dependency relationships among different types of interaction behaviors under the graph-based information transfer network, and the graph convolutional network is further used to capture the high-order complexity of interaction graphs. The experimental results of three benchmark datasets show that the proposed graph-based multi-behavior recommendation model displays significant improvements in recommendation accuracy compared to the baseline method.

Abstract Background Late blight seriously threatens potato cultivation worldwide. The severe and widespread damage caused by the fungal pathogen can lead to drastic decreases in potato yield. Although grafting technology has been widely used to improve crop resistance, the effects of grafting on potato late blight resistance as well as the associated molecular mechanisms remain unclear. Therefore, we performed RNA transcriptome sequencing analysis and the late blight resistance testing of the scion when the potato late blight-resistant variety Qingshu 9 and the susceptible variety Favorita were used as the rootstock and scion, respectively, and vice versa. The objective of this study was to evaluate the influence of the rootstock on scion disease resistance and to clarify the related molecular mechanisms. Results A Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the expression levels of genes related to plant–pathogen interactions, plant mitogen-activated protein kinase (MAPK) signaling pathways, and plant hormone signal transduction pathways were significantly up-regulated in the scion when Qingshu 9 was used as the rootstock. Some of these genes encoded calcium-dependent protein kinases (CDPKs), chitin elicitor receptor kinases (CERKs), LRR receptor serine/threonine protein kinases (LRR-LRKs), NPR family proteins in the salicylic acid synthesis pathway, and MAPKs which were potato late blight response proteins. When Favorita was used as the rootstock, only a few genes of late blight response genes were upregulated in the scion of Qingshu 9. Grafted plants using resistant variety as rootstocks inoculated with P. infestans spores showed significant reductions in lesion size while no significant difference in lesion size was observed when susceptible variety was used as the rootstock. We also showed that this induction of disease resistance in scions, especially scions derived from susceptible potato varieties was mediated by the up-regulation of expression of genes involved in plant disease resistance in scions. Conclusions Our results showed that potato grafting using late blight resistant varieties as rootstocks could render or enhance resistance to late blight in scions derived from susceptible varieties via up-regulating the expression of disease resistant genes in scions. The results provide the basis for exploring the molecular mechanism underlying the effects of rootstocks on scion disease resistance.

Background: Pulmonary arterial hypertension (PAH) is a severe and fatal clinical syndrome characterized by high blood pressure and vascular remodeling in the pulmonary arterioles, which is also a rapidly progressing disease of the lung vasculature with a poor prognosis. Although PAH medication made great advances in recent years, the efficacy and safety of the medication are unsatisfactory. Therefore, we aimed to update and expand previous studies to explore the efficacy and safety of PAH-targeted medications. Methods: Relevant articles were searched and selected from published or publicly available data in PubMed, Cochrane Library, CNKI, PsycInfo, and MEDLINE (from inception until October 1st, 2020). To assess the efficacy and safety of PAH therapies, five efficacy outcomes [6-minute walking distance (6MWD), mean pulmonary arterial pressure (mPAP), WHO functional class (WHO FC) improvement, clinical worsening, death] and two safety outcomes [adverse events (AEs), serious adverse events (SAEs)] were selected. And 6MWD was regarded as the primary efficacy outcome. Results: 50 trials included with 10 996participants were selected. In terms of efficacy, all targeted drugs were more effective than placebo. For 6MWD, Bosentan + Sildenafil, Sildenafil, Bosentan + Iloprost were better than others. Bosentan + Iloprost and Bosentan + Sildenafil were better for mPAP. Bosentan + Iloprost and Ambrisentan + Tadalafil were more effective in improving WHO FC. Bosentan + Tadalafil and Bosentan + Iloprost had the Ambrisentan probability to reduce the incidence of clinical worsening. It is demonstrated that Ambrisentan had clear benefits in reducing all-cause mortality. In terms of safety, no therapies had been shown to reduce the incidence of SAEs significantly, and Ambrisentan + Tadalafil significantly increased the incidence of AEs. Conclusions: Phosphodiesterase 5 inhibitor (PDE5i) + Endothelin Receptor Antagonists (ERA) seems to be better therapy for PAH. Prostacyclin analogs (ProsA) + ERA appear promising, though additional data is warranted. Registration PROSPERO CRD42020218818.

As China's strategic support belt, the green development of industry in the Yangtze River Economic Zone is of great significance to promote the construction of China's ecological civilization, build a modern industrial system and accelerate high-quality economic development. The study of green total factor productivity of industry in the Yangtze River Economic Zone has important theoretical and practical value for exploring the green development path of China's industry. This Paper takes the Yangtze River Economic Zone, a key strategic region in China, as the research object, selects the input and output data of industrial production from 2006 to 2018, based on DEA model. To construct an MML index considering expected and unexpected output, and to quantitatively analyze the changes of industrial GTFP in the Yangtze River Economic Zone. The results show that: (1) During the sample period, the industrial green total factor productivity in the Yangtze River Economic Zone shows the spatial characteristics of differential growth and the temporal characteristics of volatile growth. It shows the fluctuation characteristics of "N" shape. (2) According to the order of "upper, middle, and lower" reaches, the spatial pattern of industrial green total factor productivity is characterized by "lower ladder". But the difference between the upper and middle reaches is small. (3) Cities with higher green total factor productivity and lower green total factor productivity each form the characteristics of "club convergence" of spatial agglomeration. (4) Technological efficiency and technological progress efficiency have heterogeneous effects on different river basins in the upper, middle, and lower reaches, and technological progress efficiency is conducive to promoting the evolution of green total factor productivity to a high level. According to the above empirical results, this paper finally puts forward the policy recommendations to improve the industrial green total factor productivity of the Yangtze River Economic Zone and the policy recommendations to reduce the industrial differences between the Yangtze River Economic Zone.

The physicochemical properties of five vegetable oils (peanut, corn, rapeseed, sunflower seed, and soybean) and their impact on the development of heterocyclic aromatic amines (HAAs) in pan-fried bacon and in the remaining oil were investigated. Corn oil led to the lowest total free amino acids (FAAs) contents and glucose content of fried bacon (p < 0.05) and rapeseed oil led to the lowest creatine content of fried bacon (p < 0.05). Bacon fried in corn oil had the highest HAA contents (p < 0.05). The total HAA contents of the oils after frying were lowest in rapeseed and soybean oils (p < 0.05). The type of vegetable oil used affected the color of the fried bacon but not the flavor and taste (p < 0.05). To reduce the HAA concentrations of fried bacon, the type of vegetable oil should be considered.

Based on the experimental method of projectile penetration into the concrete target, different excitation by deceleration of polymer bonded explosives (PBXs) was achieved by controlling the length of steel pillars behind PBXs. A series of impact tests were conducted to study the mechanical response of PBXs with different initial densities under different excitation by deceleration. A physical model was developed to describe the viscoelastic-plastic deformation of PBXs. The plastic part was added on the basis of the viscoelastic statistical crack mechanical model (Visco-SCRAM) model, and the compaction behavior of charge in different environments was characterized based on the Heckel compaction equation. The model was implemented in LS-DYNA, and the simulation results were verified by the experiments. The dynamic mechanical behavior of PBXs under different excitation by deceleration was studied from the macroscopic and mesoscale aspects. The stress curves, strain curves, the density change and the interaction between particles in deceleration environment were predicted. After comparison and analysis, the dynamic response law of the charge in the penetrating process was obtained. Macroscopic responses along with mesoscale modeling results are significantly important to have a better understanding of deformation mechanisms of PBXs.

Abstract Background The potential benefits of long-acting injectable chemoprotection (LAI-C) against malaria have been recently recognized, prompting a call for suitable candidate drugs to help meet this need. On the basis of its known pharmacodynamic and pharmacokinetic profiles after oral dosing, ELQ-331, a prodrug of the parasite mitochondrial electron transport inhibitor ELQ-300, was selected for study of pharmacokinetics and efficacy as LAI-C in mice. Methods Four trials were conducted in which mice were injected with a single intramuscular dose of ELQ-331 or other ELQ-300 prodrugs in sesame oil with 1.2% benzyl alcohol; the ELQ-300 content of the doses ranged from 2.5 to 30 mg/kg. Initial blood stage challenges with Plasmodium yoelii were used to establish the model, but the definitive study measure of efficacy was outcome after sporozoite challenge with a luciferase-expressing P. yoelii, assessed by whole-body live animal imaging. Snapshot determinations of plasma ELQ-300 concentration ([ELQ-300]) were made after all prodrug injections; after the highest dose of ELQ-331 (equivalent to 30 mg/kg ELQ-300), both [ELQ-331] and [ELQ-300] were measured at a series of timepoints from 6 h to 5½ months after injection. Results A single intramuscular injection of ELQ-331 outperformed four other ELQ-300 prodrugs and, at a dose equivalent to 30 mg/kg ELQ-300, protected mice against challenge with P. yoelii sporozoites for at least 4½ months. Pharmacokinetic evaluation revealed rapid and essentially complete conversion of ELQ-331 to ELQ-300, a rapidly achieved (

Background: Akebia saponin D (ASD) has a variety of biological activities and great medicinal potential, but its oral bioavailability is so low as to limit its development. Its pharmacokinetic profiles and excretion and metabolism in vivo have not been fully elucidated. This study was an attempt in this area.Methods: A simple LC-MS/MS method to simultaneously quantify ASD and its metabolites M1∼M5 in rat plasma, feces, urine and bile was established with a negative ESI model using dexketoprofen as the internal standard. Meanwhile, the UPLC-HR/MS system was used to screen all possible metabolites in the urine, feces and bile of rats, as compared with blank samples collected before administration. Absolute quantitative analysis was for M0, M3, M4, and M5, while semi-quantitative analysis was for M1, M2, and Orbitrap data.Results: The AUC0-t values after intravenous administration of 10 mg/kg and intragastrical administration of 100 mg/kg ASD were 19.05 ± 8.64 and 0.047 ± 0.030 h*μg/ml respectively. The oral bioavailability was determined to be extremely low (0.025%) in rats. The exposure of M4 and M5 in the oral group was higher than that of M0 in the terminal phase of the plasma concentration time profile, and ASD was stable in the liver microsome incubation system of rats, but metabolism was relatively rapid during anaerobic incubation of intestinal contents of rats, suggesting that the low bioavailability of ASD might have been attributed to the poor gastrointestinal permeability and extensive pre-absorption degradation rather than to the potent first pass metabolism. This assertion was further verified by a series of intervention studies, where improvement of lipid solubility and intestinal permeability as well as inhibition of intestinal flora increased the relative bioavailability to different extents without being changed by P-gp inhibition. After intravenous administration, the cumulative excretion rates of ASD in the urine and bile were 14.79 ± 1.87%, and 21.76 ± 17.61% respectively, but only 0.011% in feces, suggesting that the urine and bile were the main excretion pathways and that there was a large amount of biotransformation in the gastrointestinal tract. Fifteen possible metabolites were observed in the urine, feces and bile. The main metabolites were ASD deglycosylation, demethylation, dehydroxylation, decarbonylation, decarboxylation, hydroxylation, hydroxymethylation, hydroxyethylation and hydrolysis.Conclusion: The pharmacokinetics, bioavailability, metabolism and excretion of ASD in rats were systematically evaluated for the first time in this study. It has been confirmed that the ultra-low oral bioavailability is due to poor gastrointestinal permeability, extensive pre-absorption degradation and biotransformation. ASD after iv administration is not only excreted by the urine and bile, but possibly undergoes complex metabolic elimination.

The outbreak of COVID-19, caused by the SARS-CoV-2 coronavirus, has been declared a pandemic by the World Health Organization (WHO) in March, 2020 and rapidly spread to over 210 countries and territories around the world. By December 24, there are over 77M cumulative confirmed cases with more than 1.72M deaths worldwide. To mathematically describe the dynamic of the COVID-19 pandemic, we propose a time-dependent SEIR model considering the incubation period. Furthermore, we take immunity, reinfection, and vaccination into account and propose the SEVIS model. Unlike the classic SIR based models with constant parameters, our dynamic models not only predicts the number of cases, but also monitors the trajectories of changing parameters, such as transmission rate, recovery rate, and the basic reproduction number. Tracking these parameters, we observe the significant decrease in the transmission rate in the U.S. after the authority announced a series of orders aiming to prevent the spread of the virus, such as closing non-essential businesses and lockdown restrictions. Months later, as restrictions being gradually lifted, we notice a new surge of infection emerges as the transmission rates show increasing trends in some states. Using our epidemiology models, people can track, timely monitor, and predict the COVID-19 pandemic with precision. To illustrate and validate our model, we use the national level data (the U.S.) and the state level data (New York and North Dakota), and the resulting relative prediction errors for the infected group and recovered group are mostly lower than 0.5%. We also simulate the long-term development of the pandemic based on our proposed models to explore when the crisis will end under certain conditions.

China's agricultural economy is developing rapidly, but the unbalanced regional development is still a key issue that needs to be discussed today. By studying the total factor productivity of green agriculture and its factors, this paper analyzes the regional differences in time and space changes between the eastern, central and western parts of China. In this paper, the total factor productivity of green agriculture is calculated and decomposed by Metafrontier Malmquist-Luenberger index based on directional distance function. The results are as follows: First, the total factor productivity level of green agriculture in China is increasing year by year, but the overall level is still at a low level and has greater volatility; Second, although the total factor productivity of green agriculture shows an upward trend, the three regions show a downward trend in turn, which has great differences; Third, there are obvious differences in technological efficiency, optimal production potential and technological gap between the eastern, central and western regions, and there are great differences in productivity among regions and provinces. Based on the results, this paper puts forward policy recommendations, according to the regional heterogeneity, from a number of angles to rely on the joint efforts of many parties to improve the level of total factor productivity of green agriculture.

Quinoline-based scaffolds have been the mainstay of antimalarial drugs, including many artemisinin combination therapies (ACTs), over the history of modern drug development. Although much progress has been made in the search for novel antimalarial scaffolds, it may be that quinolines will remain useful, especially if very potent compounds from this class are discovered. We report here the results of a structure-activity relationship (SAR) study assessing potential unsymmetrical bisquinoline antiplasmodial drug candidates using in vitro activity against intact parasites in cell culture. Many unsymmetrical bisquinolines were found to be highly potent against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. Further work to develop such compounds could focus on minimizing toxicities in order to find suitable candidates for clinical evaluation.

Combination antiretroviral therapy (cART) has extended the longevity of human immunodeficiency virus (HIV)-infected individuals. However, this has resulted in greater awareness of age-associated diseases such as chronic obstructive pulmonary disease (COPD). Accelerated cellular senescence may be responsible, but its magnitude as measured by leukocyte telomere length is unknown and its relationship to HIV-associated COPD has not yet been established. We measured absolute telomere length (aTL) in peripheral leukocytes from 231 HIV-infected adults. Comparisons were made to 691 HIV-uninfected individuals from a population-based sample. Subject quartiles of aTL were assessed for relationships with measures of HIV disease severity, airflow obstruction, and emphysema severity on computed tomographic (CT) imaging. Multivariable regression models identified factors associated with shortened aTL. Compared to HIV-uninfected subjects, the mean aTL in HIV-infected patients was markedly shorter by 27 kbp/genome (p

Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV(1) and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy "mid-life" volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy "mid-life" volunteers (p

OBJECTIVES: Existing studies have shown the benefits of second-generation antidiabetic medications in patients with type 2 diabetes (T2D). However, the medications' real-world utilization was not well understood. Our study assessed patient factors associated with the use of second-generation antidiabetic medications in a nationally representative sample of patients with T2D. STUDY DESIGN: This retrospective, cross-sectional analysis used the 2005 to 2018 National Health and Nutrition Examination Survey (NHANES) data. METHODS: Survey participants 18 years and older who had a diagnosis of T2D and had used antidiabetic medications in the past 30 days were included. The primary outcome was the prescription of any second-generation antidiabetic medication. Weighted stepwise multivariable logistic regression models were used to assess the associations between the use of second-generation antidiabetic medications and patients' characteristics. RESULTS: Among 4493 patients with T2D, 533 (weighted %, 13.67%) reported using at least 1 second-generation antidiabetic drug. In multivariable analyses, patients with incomes at least 400% of the federal poverty level (adjusted odds ratio [AOR], 2.30; 95% CI, 1.58-3.34), with higher hemoglobin A1c levels (AOR, 1.10; 95% CI, 1.02-1.18), and taking more medications (AOR, 1.14; 95% CI, 1.09-1.20) were more likely to use second-generation antidiabetic drugs compared with their counterparts. CONCLUSIONS: The uptake of second-generation antidiabetic medications was 14% among patients with T2D in the United States. Prescription benefit design that targets lower out-of-pocket payments for these newer drugs may improve patient access and clinical outcomes for patients with T2D. [ABSTRACT FROM AUTHOR]