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Patients with rheumatoid arthritis (RA) have a much higher incidence of cardiac dysfunction, which contributes to the high mortality rate of RA despite anti-arthritic drug therapy. In this study, we investigated dynamic changes in cardiac function in classic animal models of RA and examined the potential effectors of RA-induced heart failure (HF). Collagen-induced arthritis (CIA) models were established in rats and mice. The cardiac function of CIA animals was dynamically monitored using echocardiography and haemodynamics. We showed that cardiac diastolic and systolic dysfunction occurred in CIA animals and persisted after joint inflammation and that serum proinflammatory cytokine (IL-1ß, TNF-α) levels were decreased. We did not find evidence of atherosclerosis (AS) in arthritic animals even though cardiomyopathy was significant. We observed that an impaired cardiac ß1AR-excitation contraction coupling signal was accompanied by sustained increases in blood epinephrine levels in CIA rats. Furthermore, serum epinephrine concentrations were positively correlated with the heart failure biomarker NT-proBNP in RA patients (r2 = +0.53, P < 0.0001). In CIA mice, treatment with the nonselective ßAR blocker carvedilol (2.5 mg·kg-1·d-1, for 4 weeks) or the specific GRK2 inhibitor paroxetine (2.5 mg·kg-1·d-1, for 4 weeks) effectively rescued heart function. We conclude that chronic and persistent ß-adrenergic stress in CIA animals is a significant contributor to cardiomyopathy, which may be a potential target for protecting RA patients against HF.
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Artritis Experimental , Artritis Reumatoide , Cardiomiopatías , Insuficiencia Cardíaca , Humanos , Ratones , Ratas , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/inducido químicamente , Roedores , Adrenérgicos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Citocinas , Insuficiencia Cardíaca/tratamiento farmacológico , Epinefrina/efectos adversosRESUMEN
To investigate the therapeutic effect and primary pharmacological mechanism of Ziyuglycoside I (Ziyu I) on collagen-induced arthritis (CIA) mice. CIA mice were treated with 5, 10, or 20 mg/kg of Ziyu I or 2 mg/kg of methotrexate (MTX), and clinical manifestations, as well as pathological changes, were observed. T cell viability and subset type were determined, and serum levels of transforming growth factor-beta (TGF-ß) and interleukin-17 (IL-17) were detected. The mRNA expression of retinoid-related orphan receptor-γt (RORγt) and transcription factor forkhead box protein 3 (Foxp3) in mouse spleen lymphocytes was ascertained by the real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). Molecular docking was used to detect whether there was a molecular interaction between Ziyu I and protein kinase B (Akt). The activation of mechanistic target of rapamycin (mTOR) in T cells was verified by Western blotting or immunofluorescence. Ziyu I treatment effectively alleviated arthritis symptoms of CIA mice, including body weight, global score, arthritis index, and a number of swollen joints. Similarly, pathological changes of joints and spleens in arthritic mice were improved. The thymic index, T cell activity, and RORγt production of Ziyu I-treated mice were significantly reduced. Notably, through molecular docking, western blotting, and immunofluorescence data analysis, it was found that Ziyu I could interact directly with Akt to reduce downstream mTOR activation and inhibit helper T cell 17 (Th17) differentiation, thereby regulating Th17/regulatory T cell (Treg) balance and improving arthritis symptoms. Ziyu I effectively improves arthritic symptoms in CIA mice by inhibiting mTOR activation, thereby affecting Th17 differentiation and regulating Th17/Treg balance.
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Artritis Experimental , Ratones , Animales , Artritis Experimental/metabolismo , Linfocitos T Reguladores/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Simulación del Acoplamiento Molecular , Serina-Treonina Quinasas TOR/metabolismo , Células Th17/metabolismoRESUMEN
BACKGROUND: This study investigated the effect of surfactants on wheat straw biodegradation and the growth-associated generation of exo- and endo-phenolic compounds (EPC and IPC) and antioxidant activity expression by liquid-cultured Inonotus obliquus, an edible and medicinal mushroom, also known as a white rot fungus. Changes in the chemical composition and multiscale structure of wheat straw, in the production and activity of EPC and IPC and in individual flavonoids were analyzed. RESULTS: Fungal pretreatment decreased significantly the contents of all lignocellulose components, increased and enlarged substrate porosity and caused changes in the structure of wheat straw with the aid of Triton X-100. A gradual increase in EPC and IPC production was observed up to 6.4- and 1.5-fold for 9 days. The EPC obtained on day 9 showed the highest antioxidant activity (IC50 of 30.96 mg L-1 ) against 2,2-diphenyl-1-picrylhydrazyl radicals. High-performance liquid chromatographic results indicated the presence of high amounts of epicatechin-3-gallate (ECG; (374.9 mg g-1 ) and epigallocatechin-3-gallate (EGCG; 447.2 mg g-1 ) in the EPC; other polyphenols were also enhanced but to a lesser extent. Surfactant supplementation was effective in enhancing flavonoid production and in increasing antioxidant activity in EPC. CONCLUSIONS: The results indicated enhanced accumulation of phenolic compounds, particularly ECG and EGCG in Inonotus obliquus via biodegradation and bioconversion of lignocellulose residues. They also indicated enhancement in the production of several flavonoids and also an increase in antioxidant activity in the product by a surfactant-treated process, which may be a useful way of exploiting underused lignocellulosic residues to various high-added-value functional ingredients. © 2020 Society of Chemical Industry.
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Antioxidantes/metabolismo , Inonotus/metabolismo , Fenoles/metabolismo , Triticum/microbiología , Antioxidantes/química , Biodegradación Ambiental , Biotransformación , Fermentación , Lignina/química , Lignina/metabolismo , Fenoles/química , Tallos de la Planta/metabolismo , Tallos de la Planta/microbiología , Tensoactivos/química , Triticum/metabolismo , Residuos/análisisRESUMEN
BACKGROUND: Accurate network models of species interaction could be used to predict population dynamics and be applied to manage real world ecosystems. Most relevant models are nonlinear, however, and data available from real world ecosystems are too noisy and sparsely sampled for common inference approaches. Here we improved the inference of generalized Lotka-Volterra (gLV) ecological networks by using a new optimization algorithm to constrain parameter signs with prior knowledge and a perturbation-based ensemble method. RESULTS: We applied the new inference to long-term species abundance data from the freshwater fish community in the Illinois River, United States. We constructed an ensemble of 668 gLV models that explained 79% of the data on average. The models indicated (at a 70% level of confidence) a strong positive interaction from emerald shiner (Notropis atherinoides) to channel catfish (Ictalurus punctatus), which we could validate using data from a nearby observation site, and predicted that the relative abundances of most fish species will continue to fluctuate temporally and concordantly in the near future. The network shows that the invasive silver carp (Hypophthalmichthys molitrix) has much stronger impacts on native predators than on prey, supporting the notion that the invader perturbs the native food chain by replacing the diets of predators. CONCLUSIONS: Ensemble approaches constrained by prior knowledge can improve inference and produce networks from noisy and sparsely sampled time series data to fill knowledge gaps on real world ecosystems. Such network models could aid efforts to conserve ecosystems such as the Illinois River, which is threatened by the invasion of the silver carp.
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Ecosistema , Ríos , Animales , Ecología , Cadena Alimentaria , Dinámica Poblacional , Estados UnidosRESUMEN
Regional change in the variability and magnitude of flooding could be a major consequence of future global climate change. Extreme floods have the capacity to rapidly transform landscapes and expose landscape vulnerabilities through highly variable spatial patterns of inundation, erosion, and deposition. We use the historic activation of the Birds Point-New Madrid Floodway during the Mississippi and Ohio River Flooding of 2011 as a scientifically unique stress experiment to analyze indicators of floodplain vulnerability. We use pre- and postflood airborne Light Detection and Ranging data sets to locate erosional and depositional hotspots over the 540 km(2) agricultural Floodway. While riparian vegetation between the river and the main levee breach likely prevented widespread deposition, localized scour and deposition occurred near the levee breaches. Eroded gullies nearly 1 km in length were observed at a low ridge of a relict meander scar of the Mississippi River. Our flow modeling and spatial mapping analysis attributes this vulnerability to a combination of erodible soils, flow acceleration associated with legacy fluvial landforms, and a lack of woody vegetation to anchor soil and enhance flow resistance. Results from this study could guide future mitigation and adaptation measures in cases of extreme flooding.
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Inundaciones , Sedimentos Geológicos/análisis , Modelos Teóricos , Ríos , Animales , Estados UnidosRESUMEN
Hyperplasia and migration of fibroblast-like synoviocytes (FLSs) are the key drivers in the pathogenesis of rheumatoid arthritis (RA) and joint destruction. Abundant Yes-associated protein (YAP), which is a powerful transcription co-activator for proliferative genes, was observed in the nucleus of inflammatory FLSs with unknown upstream mechanisms. Using Gene Expression Omnibus database analysis, it was found that Salvador homolog-1 (SAV1), the pivotal negative regulator of the Hippo-YAP pathway, was slightly downregulated in RA synovium. However, SAV1 protein expression is extremely reduced. Subsequently, it was revealed that SAV1 is phosphorylated, ubiquitinated, and degraded by interacting with an important serine-threonine kinase, G protein-coupled receptor (GPCR) kinase 2 (GRK2), which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E2 (PGE2) in RA. This process further contributes to the decreased phosphorylation, nuclear translocation, and transcriptional potency of YAP, and leads to aberrant FLSs proliferation. Genetic depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and migration. Similarly, paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical manifestations. Collectively, these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA.
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Sepsis-induced myocardial dysfunction (SIMD) is a severe complication in sepsis, manifested as myocardial systolic dysfunction, which is associated with poor prognosis and higher mortality. Mitophagy, a self-protective mechanism maintaining cellular homeostasis, plays an indispensable role in cardioprotection. This study aimed to unveil the cardioprotective effects of Baricitinib on LPS-induced myocardial dysfunction and its effect on mitophagy. Herein, we demonstrated that LPS induced severe myocardial dysfunction and initiated mitophagy in septic mice hearts. Despite the initiation of mitophagy, a significant number of apoptotic cells and damaged mitochondria persisted in the myocardium, and myocardial energy metabolism remained impaired, indicating that the limited mitophagy was insufficient to mitigate LPS-induced damage. The JAK2-AKT-mTOR signaling pathway is activated in LPS-induced cardiomyocytes and in the hearts of septic mice. Baricitinib administration remarkably improved cardiac function, suppressed systemic inflammatory response, attenuated histopathological changes, inhibited cardiac cell apoptosis and alleviated myocardial damage in septic mice. Furthermore, Baricitinib treatment significantly enhanced PINK1-Parkin-mediated mitophagy, increased autophagosomes, decreased impaired mitochondria, and restored myocardial energy metabolism. Mechanically, the limited mitophagy in septic myocardium was associated with increased p-ULK1 (Ser757), which was regulated by p-mTOR. Baricitinib reduced p-ULK1 (Ser757) and enhanced mitophagy by inhibiting the JAK2-AKT-mTOR signaling pathway. Inhibition of mitophagy with Mdivi-1 reversed the cardiac protective and anti-inflammatory effects of Baricitinib in septic mice. These findings suggest that Baricitinib attenuates SIMD by enhancing mitophagy in cardiomyocytes via the JAK2-AKT-mTOR signaling pathway, providing a novel mechanistic and therapeutic insight into the SIMD.
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Janus Quinasa 2 , Mitofagia , Miocitos Cardíacos , Sepsis , Transducción de Señal , Animales , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Mitofagia/efectos de los fármacos , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Ratones , Masculino , Janus Quinasa 2/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Apoptosis/efectos de los fármacos , Lipopolisacáridos , Serina-Treonina Quinasas TOR/metabolismo , Cardiotónicos/farmacologíaRESUMEN
Motor oil is one of the most common pollutants in stormwater runoff in freshwater ecosystems. It can form aggregates with solids (creating oil particle aggregates, OPAs) which complicates the understanding of the fate and transport of motor oil, particularly in cold freshwater, conditions that have not been studied extensively. Laboratory and numerical experiments were conducted with kaolinite clay and three types of motor oil in both cold and warm freshwater, in which: (1) the interaction of clay particles with motor oil was experimentally investigated, in response to changes in oil viscosity, water temperature, and mixing intensity; (2) variability in particle size distribution of the formed OPAs was measured; and (3) a mechanistic OPA formation model was applied and results were compared with experimental data. The results showed that kaolinite clay and motor oil formed mostly droplet-type OPAs, lower-viscosity oil tended to form a wider size range of OPAs, and higher mixing intensity and higher water temperature produced larger numbers of smaller OPAs. Although there was a reasonably good match between the experimental data and the modeling results, more research is needed to further improve the modeling framework.
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Caolín , Petróleo , Arcilla , Ecosistema , Agua , Agua DulceRESUMEN
The installation of green infrastructure (GI) is an effective approach to manage urban stormwater and combined sewer overflow (CSO) by restoring pre-development conditions in urban areas. Research on simulation-optimization techniques to aid with GI planning decision-making is expanding. However, due to high computational expense, the simulation-optimization methods are often based on design storm events, and it is unclear how much different rainfall scenarios (i.e., design storm events vs. long-term historical rainfall data) impact the optimal siting of GI. The Parallel Pareto Archived Dynamically Dimensioned Search (ParaPADDS) algorithm in a novel simulation-optimization tool OSTRICH-SWMM was used to leverage distributed computing resources. A case study was conducted to optimally site rainwater harvesting cisterns within 897 potential subcatchments throughout the City of Buffalo, New York. Seven design storm events with different return periods and rainfall durations and a one-month historical rainfall time series were considered. The results showed that the optimal solutions of siting cisterns using event-based scenarios, though less computationally expensive, may not perform well under continuous rainfall scenarios, suggesting design rainfall scenarios should be carefully considered for optimizing GI planning. The impact of rainfall scenarios was particularly significant in the middle region of the Pareto front of multi-objective optimization. Utilizing high-performance parallel computing, OSTRICH-SWMM is a promising tool to optimize GI at large spatial and temporal scales.
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Algoritmos , Lluvia , Ciudades , Simulación por Computador , New YorkRESUMEN
T helper type 17 (Th17) cell which is induced by interleukine-6 (IL-6)-signal transducers and activators of transcription 3 (STAT3) signaling is a central pro-inflammatory T cell subtype in rheumatoid arthritis (RA) and could be significantly reduced by paeoniflorin-6'-O-benzene sulfonate (CP-25) treatment with unclear mechanisms. This study was aimed to found out the mechanism of CP-25 in hampering Th17 cells differentiation in arthritic animals thus explore more therapeutic targets for RA. In mice with collagen-induced arthritis (CIA), both circulating and splenic Th17 subsets were expanded with increased STAT3 phosphorylation and decreased Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1)-ß-arrestin2 (arrb2)-STAT3 interaction in CD4+ helper T (Th) cells. Either CP-25 or paroxetine (PAR), an established G protein coupled receptor kinase 2 (GRK2) inhibitor treatment effectively relieved the joints inflammation of CIA mice with substantially reduced Th17 cell population through inhibiting STAT3 and restoring the SHP1-arrb2-STAT3 complex. Knockout of arrb2 exacerbated the clinical manifestations of collagen antibody-induced arthritis with upregulated Th17 cells. In vitro studies revealed that depletion of arrb2 or inhibition of SHP1 promoted Th17 cell differentiation. Moreover, stimulation of adenosine A3 receptor (A3AR) simultaneously promoted Th17 cell differentiation via accelerating abbr2-A3AR binding, which could be prevented through inhibiting GRK2 phosphorylation by CP-25 or PAR, or genetically reducing GRK2. This work has demonstrated that CP-25 or PAR treatment recovers the SHP1-arrb2-STAT3 complex which prevents STAT3 activation in Th cells through reducing arrb2 recruitment to A3AR by inhibiting GRK2 phosphorylation, leading to the reduction in Th17 cell differentiation and arthritis attenuation.
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Artritis Experimental , Artritis Reumatoide , Ratones , Animales , Artritis Experimental/tratamiento farmacológico , Quinasa 2 del Receptor Acoplado a Proteína-G/metabolismo , Ratones Noqueados , Células Th17 , Artritis Reumatoide/tratamiento farmacológico , Diferenciación CelularRESUMEN
Tree-based machine learning models based on environmental features offer low-cost and timely solutions for predicting microbial fecal contamination in beach water to inform the public of the health risk. However, many of these models are black boxes that are difficult for humans to understand, which may cause severe consequences such as unexplained decisions and failure in accountability. To develop interpretable predictive models for beach water quality, we evaluate five tree-based models, namely classification tree, random forest, CatBoost, XGBoost, and LightGBM, and employ a state-of-the-art explanation method SHAP to explain the models. When tested on the Escherichia coli (E. coli) concentration data collected from three beach sites along Lake Erie shores, LightGBM, followed by XGBoost, achieves the highest averaged precision and recall scores. For all three sites, both models suggest lake turbidity as the most important predictor, and elucidate the crucial role of accurate local data of wave height and rainfall in the model development. Local SHAP values further reveal the robustness of the importance of lake turbidity as its SHAP value increases nearly monotonically with its value and is minimally affected by other environmental factors. Moreover, we found an intriguing interaction between lake turbidity and day-of-year. This work suggests that the combination of LightGBM and SHAP has a promising potential to develop interpretable models for predicting microbial water quality in freshwater lakes.
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Playas , Calidad del Agua , Monitoreo del Ambiente , Escherichia coli , Heces/microbiología , Lagos , Microbiología del AguaRESUMEN
Hydraulic fracturing or fracking has led to a rapid growth of oil and gas production in the United States, but the impact of fracking on public health is an important but underresearched topic. We designed a methodology to study spatiotemporal correlations between the risk of fracking and stroke mortality. An annualized loss expectancy (ALE) model is applied to quantify the risk of fracking. The geographically and temporally weighted regression (GTWR) model is used to analyze spatiotemporal correlations of stroke mortality, fracking ALE, and nine other socioeconomic- and health-related factors. The analysis shows that fracking ALE is moderately correlated with stroke mortality at ages over 65 in most states of fracking, in addition to cardiovascular disease and drug overdose being positively correlated with stroke mortality. Furthermore, the correlations between fracking ALE and stroke mortality in men appear to be higher than in women near the Marcellus Shale, including Ohio, Pennsylvania, West Virginia, and Virginia, while stroke mortality among women is concentrated in the Great Plains, including Montana, Wyoming, New Mexico, and Oklahoma. Lastly, within two kilometers of the fracking mining activity, the level of benzene in the air was found to be significantly correlated with the fracking activity in Colorado.
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Fracking Hidráulico , Accidente Cerebrovascular , Femenino , Humanos , Masculino , Minería , Gas Natural , Pennsylvania , Análisis Espacio-Temporal , Accidente Cerebrovascular/epidemiología , Estados Unidos/epidemiologíaRESUMEN
G protein-coupled receptor kinase type 2 (GRK2) and ß-arrestin2 are representative proteins that regulate the transduction and trafficking of G protein-coupled receptor (GPCR) signaling. The kinase GRK2 and the multifunctional scaffolding protein ß-arrestin2 are key integrated signaling nodes in various biological processes, and both of them regulate cell proliferation and promote cell invasion and migration. GRK2/ß-arrestin2 play multiple roles in the pathological mechanisms of a wide range of diseases including heart failure, cancer, and inflammatory diseases. This review summarizes the roles of GRK2/ß-arrestin2 in immune cell function and focuses on the pathological implications of GRK2/ß-arrestin2 in various inflammatory diseases.
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Quinasa 2 del Receptor Acoplado a Proteína-G , Transducción de Señal , Quinasa 2 del Receptor Acoplado a Proteína-G/metabolismo , Humanos , Inflamación , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/fisiología , beta-Arrestina 1/metabolismo , Arrestina beta 2/metabolismo , beta-Arrestinas/metabolismoRESUMEN
Human G protein-coupled receptor 56 (GPR56) is encoded by gene ADGRG1 from chromosome 16q21 and is homologously encoded in mice, at chromosome 8. Both 687 and 693 splice forms are present in humans and mice. GPR56 has a 381 amino acid-long N-terminal extracellular segment and a GPCR proteolysis site upstream from the first transmembrane domain. GPR56 is mainly expressed in the heart, brain, thyroid, platelets, and peripheral blood mononuclear cells. Accumulating evidence indicates that GPR56 promotes the formation of myelin sheaths and the development of oligodendrocytes in the cerebral cortex of the central nervous system. Moreover, GPR56 contributes to the development and differentiation of hematopoietic stem cells, induces adipogenesis, and regulates the function of immune cells. The lack of GPR56 leads to nervous system dysfunction, platelet disorders, and infertility. Abnormal expression of GPR56 is related to the malignant transformation and tumor metastasis of several cancers including melanoma, neuroglioma, and gastrointestinal cancer. Metabolic disorders and cardiovascular diseases are also associated with dysregulation of GPR56 expression, and GPR56 is involved in the pharmacological resistance to some antidepressant and cancer drug treatments. In this review, the molecular structure, expression profile, and signal transduction of GPR56 are introduced, and physiological and pathological functions of GRP56 are comprehensively summarized. Attributing to its significant biological functions and its long N-terminal extracellular region that interacts with multiple ligands, GPR56 is becoming an attractive therapeutic target in treating neurological and hematopoietic diseases.
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Leucocitos Mononucleares , Melanoma , Aminoácidos , Animales , Humanos , Ratones , Receptores Acoplados a Proteínas G/metabolismo , Transducción de SeñalRESUMEN
ETHNOBOTANICAL RELEVANCE: With most of the anti-rheumatic drugs having severe adverse drug reactions and poor tolerance, the active components from natural herbs provides a repository for novel, safe, and effective drug development. Sanguisorba officinalis L. exhibits definite anti-inflammatory capacity, however, whether it has anti-rheumatic effects has not been revealed. AIM OF THE STUDY: In the present study, the effect of Ziyuglycoside I (Ziyu I), one of the most important active components in Sanguisorba officinalis L., was investigated in treating collagen-induced arthritis (CIA), illuminating its potential pharmacological mechanisms. MATERIAL AND METHODS: CIA mice were treated with 5, 10, or 20 mg/kg of Ziyu I or 2 mg/kg of MTX, and clinical manifestations as well as pathological changes were observed. T and B cell viability was determined using cell counting kit-8, plasma autoantibodies and cytokines were tested with ELISA, T and B cell subsets were identified by flow cytometry, Blimp1 expression was detected by RT-qPCR and in situ immunofluorescence. The expression of activation-induced cytidine deaminase (AID) was detected by immunohistochemistry. ERK activation in B cells was verified through western blotting and immunofluorescence. Meanwhile, bioinformatics retrieval and molecular docking/molecular dynamics were used to predict the relationship between Blimp1, ERK and Ziyu I with the pharmacokinetics and toxicity of Ziyu I being evaluated in the ADMETlab Web platform. RESULTS: Ziyu I treatment effectively alleviated the joint inflammatory manifestation including arthritis index, global scores, swollen joint count and body weight of CIA mice. It improved the pathological changes of joint and spleen of arthritic mice, especially in germinal center formation. Ziyu I displayed a moderate regulatory effect on T cell activation, the percentage of total T and helper T cells, and tumor necrosis factor-α, but transforming growth factor-ß was not restored. Increased spleen index, B cell viability and plasma auto-antibody production in CIA mice were significantly reduced by Ziyu I therapy. Of note, we found that Ziyu I administration substantially inhibited the excessive expansion of plasma cells in spleen through preventing the expression of B lymphocyte induced maturation protein 1 (Blimp1) and AID in B cells. Ziyu I was predicted in silico to directly interact with ERK2, and reduce ERK2 activation, contributing to the depressed expression of Blimp1. Moreover, Ziyu I was predicted to have a favorable pharmacokinetic profile and low toxicity. CONCLUSION: Ziyu I effectively ameliorates CIA in mice by inhibiting plasma cell generation through prevention of ERK2-mediated Blimp1 expression in B cells. Therefore, Ziyu I is a promising candidate for anti-arthritic drug development.
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Artritis Experimental , Saponinas , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Citocinas/metabolismo , Ratones , Simulación del Acoplamiento Molecular , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Saponinas/farmacologíaRESUMEN
Population growth and urbanization have led to the increasing presence of treated wastewater effluents in downstream drinking water sources. Drinking water sources influenced by organic matter from upstream wastewater treatment plant (WWTP) effluents are thought prone to the formation of haloacetonitriles (HANs), a group of nitrogenous disinfection by-products (DBPs) that can exhibit higher toxicity than currently regulated carbonaceous DBPs. We develop a framework for studying the HAN formation potential (HAN-FP) considering the WWTP and non-WWTP related sources of HAN precursors, and apply this framework to a representative WWTP-impacted river, the Illinois River, USA. A spatiotemporally-resolved river hydrodynamic and water quality model is developed using HEC-RAS to quantify the contribution of WWTP versus non-WWTP sources of HAN-FP precursors. Results show that non-WWTP sources of HAN-FP are considerable, accounting for up to 78% of HAN-FP concentration. Moreover, the contribution of the two sources varies due to streamflow discharge variability. During lower flows, the contribution of WWTPs drives the high concentration of HAN-FP and during higher flows, the contribution of non-WWTP sources becomes dominant. As a result, a high risk of HAN-FP may exist persistently (HAN-FP concentration is always larger than 9.7 µg/L in this study), not only during low flows but also during high flows due to both wastewater- and non-wastewater-derived HAN-FP sources.
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Contaminantes Químicos del Agua , Purificación del Agua , Desinfección , Ríos , Aguas Residuales , Contaminantes Químicos del Agua/análisisRESUMEN
Microbial pollution of beach water can expose swimmers to harmful pathogens. Predictive modeling provides an alternative method for beach management that addresses several limitations associated with traditional culture-based methods of assessing water quality. Widely-used machine learning methods often suffer from high variability in performance from one year or beach to another. Therefore, the best machine learning method varies between beaches and years, making method selection difficult. This study proposes an ensemble machine learning approach referred to as model stacking that has a two-layered learning structure, where the outputs of five widely-used individual machine learning models (multiple linear regression, partial least square, sparse partial least square, random forest, and Bayesian network) are taken as input features for another model that produces the final prediction. Applying this approach to three beaches along eastern Lake Erie, New York, USA, we show that generally the model stacking approach was able to generate reliably good predictions compared to all of the five base models. The accuracy rankings of the stacking model consistently stayed 1st or 2nd every year, with yearly-average accuracy of 78%, 81%, and 82.3% at the three studied beaches, respectively. This study highlights the value of the model stacking approach in predicting beach water quality and solving other pressing environmental problems.
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To understand the heterogeneous behavior of oil-particle aggregates (OPAs) in the riverine environment as well as the uncertainties caused by the coupling effects between their stochastic formation and transportation processes, this study employed the coagulation conceptual formula and random-walk particle tracking model. Through careful inspection using the classic Rouse-Vanoni diagram and existing laboratory observations, a vertical diffusivity scheme and the packing coefficient for an oil-sediment interaction model were determined. The density variations and deposition patterns of hypothetically fully developed OPAs as well as the impact of oil-sediment interactions on the longitudinal distribution of deposited OPAs were then investigated. The results indicate that the formation process of OPAs has a significant effect on their longitudinal deposition. The range of potentially trapped OPAs varied from several to hundreds of times the range of cases that exclude oil-sediment interactions. The deposition diagram proposed in this study visualizes the relationship between the configuration and deposition pattern of OPAs and can assist in determining the most unfavorable scenarios for oil-spill countermeasures. Further refinement and calibration of the model are necessary in the future to provide guidelines for oil spill responses and recovery in riverine environments.
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This study proposes an innovative strategy of lignocellulose biodegradation by Inonotus obliquus under solid-state fermentation in extracting Eucommia ulmoides trans-1,4-polyisoprene (EUG) and producing reducing sugars efficiently. EUG and sugars were obtained through the white rot fungal pretreatment of E. ulmoides leaves, ultrasound-assisted solvent extraction, and enzymatic saccharification. After mere 2-day fermentation, the loss of lignin, cellulose, and hemicelluloses of the leaves achieved 7.11%, 3.47%, and 6.44%, respectively due to the high activity levels of manganese peroxidase (MnP, 973 IU g-1) and lignin peroxidase (LiP, 1341 IU g-1) produced by the fungus. The breakdown of fibrous networks brought higher yields of EUG and reducing sugars. The highest extraction yield of EUG was 4.86% from the 2-day fermented leaves, 31.4% greater than that from the control (3.69%). Meanwhile, the leaf residues after EUG extraction released 97.8 mg g-1 reducing sugars with enzymatic saccharification, 77.5% greater than that from the control (55.1 mg g-1). The results demonstrated that I. obliquus could use E. ulmoides leaves as substrate to produce high-activity-level ligninolytic enzymes in a very short time and the lignocellulose selective degradation of E. ulmoides leaves enhanced the yields of EUG and reducing sugars.
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Enzimas/metabolismo , Eucommiaceae/química , Hemiterpenos/aislamiento & purificación , Inonotus/metabolismo , Látex/aislamiento & purificación , Lignina/metabolismo , Hojas de la Planta/químicaRESUMEN
We used a numerical model to analyze the impact of combined sewer overflows (CSOs) in the hydrodynamics and water quality of the Chicago Area Waterway System (CAWS). We coupled the Environmental Fluid Dynamics Code (EFDC) with the Water Quality Analysis Simulation Program (WASP) to perform three-dimensional simulations of the hydrodynamics and water quality in CAWS. The analysis was performed for two different storms: (i) May 6, 2009 representing a 6-hour duration 4-month return period, and (ii) September 12, 2008 representing a 48-hour duration 100-year return period. Results from the simulations show distinct differences between the two storms. During the May 2009 storm there was only one major CSO pumping event with negligible impact on the water quality of CAWS. During the September 2008 storm there were several CSOs that impacted the hydrodynamics and water quality of CAWS. In particular, CSOs during the September 2008 event induced a reversal flow in CAWS, with a plume of constituents that traveled in the opposite direction as water does under normal conditions. However, the simulation results show that CSOs events in CAWS take place during periods of high rainfall, thus the discharge of CSOs is significantly diluted along the CAWS. As a result, the concentrations of organic matter and inorganic nutrients observed at the downstream boundary in CAWS were significantly lower than those recorded at the CSOs outfalls and are within the limits established in the regulation for regular effluents. These results suggest that even during storms events with significant CSOs into the CAWS there is a significant dilution that reduce the impact in the water quality at the system boundaries.