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1.
Clin Pharmacol Ther ; 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31925955

RESUMO

Machine learning (ML), a field of data science with over 50 years of history, has gained momentum in the past decade due to the intersection of powerful computing tools and the increased availability of large data sets. Herein, we provide an overview of a sample of ML algorithms and describe areas where ML has been used to support drug development and regulatory submissions to US FDA, as well as to facilitate review and research.

2.
Theranostics ; 10(2): 725-740, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31903147

RESUMO

Chitin-derived hydrogels are commonly used in bone regeneration because of their high cell compatibility; however, their poor mechanical properties and little knowledge of the interaction between the materials and host cells have limited their practical application. Methods: To evaluate osteoinductivity and enhance the mechanical properties of a newly synthesized thermosensitive hydroxypropyl chitin hydrogel (HPCH), a mesenchymal stem cell (MSC)-encapsulated HPCH was infused into a three-dimensional-printed poly (ε-caprolactone) (PCL)/ nano-hydroxyapatite (nHA) scaffold to form a hybrid scaffold. The mechanical properties and cell compatibility of the scaffold were tested. The interaction between macrophages and scaffold for angiogenesis and osteogenesis were explored in vitro and in vivo. Results: The hybrid scaffold showed improved mechanical properties and high cell viability. When MSCs were encapsulated in HPCH, osteo-differentiation was promoted properly via endochondral ossification. The co-culture experiments showed that the hybrid scaffold facilitated growth factor secretion from macrophages, thus promoting vascularization and osteoinduction. The Transwell culture proved that MSCs modulated the inflammatory response of HPCH. Additionally, subcutaneous implantation of MSC-encapsulated HPCH confirmed M2 activation. In situ evaluation of calvarial defects confirmed that the repair was optimal in the MSC-loaded HPCH + PCL/nHA group. Conclusions: PCL/nHA + HPCH hybrid scaffolds effectively promoted vascularization and osteoinduction via osteogenesis promotion and immunomodulation, which suggests promising applications for bone regeneration.

3.
Hepatology ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31899548

RESUMO

Several major factors limit our understanding of hepatocellular carcinoma (HCC). First, human HCCs are infrequently biopsied for diagnosis and thus are not often biologically interrogated. Second, HCC initiation and progression are strongly influenced by the cirrhotic microenvironment, and the exact contributions of intrinsic and extrinsic tumor factors are unclear. A powerful approach to examine the personalized biology of liver cancers and the influence of host tissues is with patient derived xenograft (PDX) models. In Asia, HCCs from hepatitis B virus patients have been efficiently converted into PDXs, but few parallel efforts from the west have been reported. In a large-scale analysis, we implanted 93 HCCs and 8 cholangiocarcinomas (CCAs) to systematically analyze host factors and to define an optimized platform for PDX development from both surgical and biopsy samples. NSG mice that had undergone partial hepatectomy (PHx) represented the best combination of engraftability, growth, and passagability, but overall rates were low and indicative of a unique intrinsic biology for HCCs in the US. PDX models preserved the histology and genetic features of parental tumors, and ultimately, 8 new models were usable for pre-clinical studies. Intriguingly, HCC PDXs were differentially sensitive to regorafenib and sorafenib and CCA PDXs were also highly sensitive to regorafenib. PDX models functionalize early and advanced stage HCCs and revealed unique biological features of liver cancers from the US.

4.
Chem Res Toxicol ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31878777

RESUMO

Dioxins, mostly through activation of aryl hydrocarbon receptor (AhR), are potent toxic substances widely distributed in the environment, while moderated suppression of AhR also exhibits anti-tumor effects. Therefore, the proper modulation of AhR activity may counteract AhR-mediated toxicities and certain diseases. In this investigation, we identified several novel AhR moderate agonists and antagonists using chemical biology approaches. The mechanisms and mode of interactions with AhR by these hits were also revealed using both experimental and computational studies. The newly identified AhR moderate agonists and antagonists were predicted to bind to AhR and modulate AhR signaling. The structure-activity relationships of moderate agonists and antagonists and their unique binding features with AhR have created a solid framework for further optimization of the next generation of AhR modulators.

5.
Bioresour Technol ; 296: 122306, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31677402

RESUMO

Fe3O4 supported on water hyacinth biochar (Fe3O4/WHB) was successfully used in anaerobic degradation of 2,4,6-trichlorophenol and coal gasification wastewater (CGW). Chemical oxygen demand removal efficiency and methane production were significantly improved to 98.9% and 2.0 L with Fe3O4/WHB assisted. Fe3O4/WHB facilitated the conversion of CO2 to methane and reduce H2 production. A higher coenzyme F420 concentration of 1.32 µmol/(g-mixed liquor volatile suspended solids) was found with the presence of Fe3O4/WHB, which might result in a faster conversion of acetate to methane. More interspecific signal molecules, lower diffusible signal factor, and higher mean particle size indicated that Fe3O4/WHB accelerated the sludge granulation process. Microbial community analysis revealed that enriched bacteria Geobacter along with archaea Methanothrix and Methanosarcina may be involved in direct interspecies electron transfer by Fe3O4/WHB stimulation, enhancing the performance of 2,4,6-trichlorophenol fermentation. It is shown that use of Fe3O4/WHB is feasible for enhanced CGW treatment.


Assuntos
Eichhornia , Águas Residuárias , Anaerobiose , Reatores Biológicos , Carvão Vegetal , Clorofenóis , Carvão Mineral , Elétrons , Metano , Esgotos , Eliminação de Resíduos Líquidos
6.
Drug Metab Dispos ; 48(1): 31-40, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31699809

RESUMO

Human liver microsomes (HLM) and human liver S9 fractions (HLS9) are commonly used to study drug metabolism in vitro. However, a quantitative comparison of HLM and HLS9 proteomes is lacking, resulting in the arbitrary selection of one hepatic preparation over another and in difficulties with data interpretation. In this study, we applied a label-free global absolute quantitative proteomics method to the analysis of HLS9 and the corresponding HLM prepared from 102 individual human livers. A total of 3137 proteins were absolutely quantified, and 3087 of those were determined in both HLM and HLS9. Protein concentrations were highly correlated between the two hepatic preparations (R = 0.87, P < 0.0001). We reported the concentrations of 98 drug-metabolizing enzymes (DMEs) and 51 transporters, and demonstrated significant differences between their abundances in HLM and HLS9. We also revealed the protein-protein correlations among these DMEs and transporters and the sex effect on the HLM and HLS9 proteomes. Additionally, HLM and HLS9 displayed distinct expression patterns for protein markers of cytosol and various cellular organelles. Moreover, we evaluated the interindividual variability of three housekeeping proteins, and identified five proteins with low variation across individuals that have the potential to serve as new internal controls for western blot experiments. In summary, these results will lead to better understanding of data obtained from HLM and HLS9 and assist in in vitro-in vivo extrapolations. Knowing the differences between HLM and HLS9 also allows us to make better-informed decisions when choosing between these two hepatic preparations for in vitro drug metabolism studies. SIGNIFICANCE STATEMENT: This investigation revealed significant differences in protein concentrations of drug-metabolizing enzymes and transporters between human liver microsomes and S9 fractions. We also determined the protein-protein correlations among the drug-metabolizing enzymes and transporters and the sex effect on the proteomes of these two hepatic preparations. The results will help interpret data obtained from these two preparations and allow us to make more informed decisions when choosing between human liver microsomes and S9 fractions for in vitro drug metabolism studies.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31804938

RESUMO

Light field cameras (LFCs) have received increasing attention due to their wide-spread applications. However, current LFCs suffer from the well-known spatio-angular trade-off, which is considered an inherent and fundamental limit for LFC designs. In this paper, by doing a detailed optical analysis of the sampling process in an LFC, we show that the effective resolution is generally higher than the number of micro-lenses. This contribution makes it theoretically possible to super-resolve a light field. Further optical analysis proves the "2D predictable series" nature of the 4D light field, which provides new insights for analyzing light field using series processing techniques. To model this nature, a specifically designed epipolar plane image (EPI) based CNN-LSTM network is proposed to super-resolve a light field in the spatial and angular dimensions simultaneously. Rather than leveraging semantic information, our network focuses on extracting geometric continuity in the EPI domain. This gives our method an improved generalization ability and makes it applicable to a wide range of previously unseen scenes. Experiments on both synthetic and real light fields demonstrate the improvements over state-of-the-arts, especially in large disparity areas.

8.
Drug Metab Dispos ; 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31871135

RESUMO

Carboxylesterase 1 (CES1) is the most abundant drug-metabolizing enzyme in human livers, comprising approximately 1% of the entire liver proteome. CES1 is responsible for 80-95% of total hydrolytic activity in the liver and plays a crucial role in the metabolism of a wide range of drugs (especially ester-prodrugs), pesticides, environmental pollutants, and endogenous compounds. Expression and activity of CES1 vary markedly among individuals, which is a major contributing factor to interindividual variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by CES1. Both genetic and non-genetic factors contribute to CES1 variability. Here, we discuss genetic polymorphisms, including single-nucleotide polymorphisms (SNPs) and copy number variants, and non-genetic contributors, such as developmental status, genders, and drug-drug interactions, that could influence CES1 functionality and the PK and PD of CES1 substrates. Currently, the loss-of-function SNP G143E (rs71647871) is the only clinically significant CES1 variant identified to date, and alcohol is the only potent CES1 inhibitor that could alter the therapeutic outcomes of CES1 substrate medications. However, G143E and alcohol can only explain a small portion of the interindividual variability in the CES1 function. A better understanding of the regulation of CES1 expression and activity and identification of biomarkers for CES1 function in vivo could lead to the development of a precision pharmacotherapy strategy to improve the efficacy and safety of many CES1 substrate drugs. SIGNIFICANCE STATEMENT: Carboxylesterase 1 (CES1) is a major phase I drug-metabolizing enzyme responsible for 80-95% of total hydrolytic activity in human livers. CES1 plays a crucial role in metabolizing a wide range of drugs, pesticides, environmental pollutants, and endogenous compounds. The clinical relevance of CES1 has been well demonstrated in various clinical trials with methylphenidate, oseltamivir, and clopidogrel. Here, we discuss genetic polymorphisms and non-genetic contributors that influence CES1 functionality and the PK and PD of drugs metabolized by CES1.

9.
ACS Nano ; 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31869202

RESUMO

Nanoparticle structural parameters, such as size, surface chemistry, and shape, are well-recognized parameters that affect biological activities of nanoparticles. However, whether the core material of a nanoparticle also plays a role remains unknown. To answer this long-standing question, we synthesized and investigated a comprehensive library of 36 nanoparticles with all combinations of three types of core materials (Au, Pt, and Pd), two sizes (6 and 26 nm), and each conjugated with one of six surface ligands of different hydrophobicity. Using this systematic approach, we were able to identify cellular perturbation specifically attributed to core, size, or surface ligand. We discovered that core materials exhibited a comparable regulatory ability as surface ligand on cellular ROS generation and cytotoxicity. Pt nanoparticles were much more hydrophilic and showed much less cell uptake compared to Au and Pd nanoparticles with identical size, shape, and surface ligands. Furthermore, diverse core materials also regulated levels of cellular redox activities, resulting in different cytotoxicity. Specifically, Pd nanoparticles significantly reduced cellular H2O2 and promoted cell survival, while Au nanoparticles with identical size, shape, and surface ligand induced higher cellular oxidative stress and cytotoxicity. Our results demonstrate that nanoparticle core material is as important as other structural parameters in nanoparticle-cell interactions, making it also a necessary consideration when designing nanomedicines.

10.
Am J Bot ; 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31879950

RESUMO

PREMISE: Outcomes of species interactions, especially mutualisms, are notoriously dependent on environmental context, and environments are changing rapidly. Studies have investigated how mutualisms respond to or ameliorate anthropogenic environmental changes, but most have focused on nutrient pollution or climate change and tested stressors one at a time. Relatively little is known about how mutualisms may be altered by or buffer the effects of multiple chemical contaminants, which differ fundamentally from nutrient or climate stressors and are especially widespread in aquatic habitats. METHODS: We investigated the impacts of two contaminants on interactions between the duckweed Lemna minor and its microbiome. Sodium chloride (salt) and benzotriazole (a corrosion inhibitor) often co-occur in runoff to water bodies where duckweeds reside. We tested three L. minor genotypes with and without the culturable portion of their microbiome across field-realistic gradients of salt (3 levels) and benzotriazole (4 levels) in a fully factorial experiment (24 treatments, tested on each genotype) and measured plant and microbial growth. RESULTS: Stressors had conditional effects. Salt decreased both plant and microbial growth and decreased plant survival more as benzotriazole concentrations increased. In contrast, benzotriazole did not affect microbial abundance and even benefited plants when salt and microbes were absent, perhaps due to biotransformation into growth-promoting compounds. Microbes did not ameliorate duckweed stressors; microbial inoculation increased plant growth, but not at high salt concentrations. CONCLUSIONS: Our results suggest that multiple stressors matter when predicting responses of mutualisms to global change and that beneficial microbes may not always buffer hosts against stress.

11.
Math Biosci Eng ; 16(6): 7384-7404, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31698618

RESUMO

The Hi-C experiment can capture the genome-wide spatial proximities of the DNA, based on which it is possible to computationally reconstruct the three-dimensional (3D) structures of chromosomes. The transcripts of the long non-coding RNA (lncRNA) Xist spread throughout the entire X-chromosome and alter the 3D structure of the X-chromosome, which also inactivates one copy of the two X-chromosomes in a cell. The Hi-C experiments are expensive and time-consuming to conduct, but the Hi-C data of the active and inactive X-chromosomes are available. However, the Hi-C data of the X-chromosome during the process of X-chromosome inactivation (XCI) are not available. Therefore, the 3D structure of the X-chromosome during the process of X-chromosome inactivation (XCI) remains to be unknown. We have developed a new approach to reconstruct the 3D structure of the X-chromosome during XCI, in which the chain of DNA beads representing a chromosome is stored and simulated inside a 3D cubic lattice. A 2D Gaussian function is used to model the zero values in the 2D Hi-C contact matrices. By applying simulated annealing and Metropolis-Hastings simulations, we first generated the 3D structures of the X-chromosome before and after XCI. Then, we used Xist localization intensities on the X-chromosome (RAP data) to model the traveling speeds or acceleration between all bead pairs during the process of XCI. The 3D structures of the X-chromosome at 3 hours, 6 hours, and 24 hours after the start of the Xist expression, which initiates the XCI process, have been reconstructed. The source code and the reconstructed 3D structures of the X-chromosome can be downloaded from http://dna.cs.miami.edu/3D-XCI/.

12.
Small ; : e1904369, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31769618

RESUMO

2D transition metal dichalcogenides (TMDs) based photodetectors have shown great potential for the next generation optoelectronics. However, most of the reported MoS2 photodetectors function under the photogating effect originated from the charge-trap mechanism, which is difficult for quantitative control. Such devices generally suffer from a poor compromise between response speed and responsivity (R) and large dark current. Here, a dual-gated (DG) MoS2 phototransistor operating based on the interface coupling effect (ICE) is demonstrated. By simultaneously applying a negative top-gate voltage (VTG ) and positive back-gate voltage (VBG ) to the MoS2 channel, the photogenerated holes can be effectively trapped in the depleted region under TG. An ultrahigh R of ≈105 A W-1 and detectivity (D*) of ≈1014 Jones are achieved in several devices with different thickness under Pin of 53 µW cm-2 at VTG = -5 V. Moreover, the response time of the DG phototransistor can also be modulated based on the ICE. Based on these systematic measurements of MoS2 DG phototransistors, the results show that the ICE plays an important role in the modulation of photoelectric performances. The results also pave the way for the future optoelectrical application of 2D TMDs materials and prompt for further investigation in the DG structured phototransistors.

13.
Mol Cell Biochem ; 2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31732832

RESUMO

Sepsis-associated acute kidney injury (AKI) is a life threatening condition with high morbidity and mortality. The pathogenesis of AKI is associated with apoptosis. In this study, we investigated the effects of ligustrazine (LGZ) on experimental sepsis-associated AKI in mice. Sepsis-associated AKI was induced in a mice model using cecal ligation and puncture (CLP) method. Mice were administered LGZ (10, 30, and 60 mg/kg) via tail vein injection 0.5 h before CLP surgery. Mice survival was evaluated. Renal water content was detected. Urine samples were collected for ELISA of Kim1. Kidneys were collected for nucleic acid analysis and histological examination. Pathological assessment was used to determine the effect of LGZ on sepsis-associated AKI. Caspase-3 expression in kidney was assessed by immunohistochemistry. Renal NMDAR1 level was also determined. Treatment of LGZ improved mice survival rate; the effect was significant when administered at a high LGZ dose (60 mg/kg). Renal water content of mice undergoing CLP was significantly reduced by LGZ treatment. Both middle-dose and high-dose LGZ treatments reduced urine Kim1 level in sepsis-associated AKI mice. The severity of AKI in septic mice was reduced by middle-dose and high-dose LGZ administration. Immunohistochemical analysis revealed decreased caspase-3 and NMDAR1 levels in the kidney following middle-dose and high-dose LGZ treatments. RT-PCR assay showed a significant reduction in NMDAR1 mRNA expression in the kidney of middle-dose and high-dose LGZ-treated mice. LGZ exhibited protective effects against sepsis-associated AKI in mice, possibly via downregulation of renal NMDAR1 expression and its anti-apoptotic action by inhibiting caspase-3.

14.
Am J Perinatol ; 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31739366

RESUMO

OBJECTIVE: Aim of this study was to identify risk factors for adverse neonatal outcomes in neonates born to mothers with noninfectious intrapartum hyperthermia. STUDY DESIGN: A retrospective study was conducted of 460 singleton deliveries diagnosed with noninfectious intrapartum hyperthermia. Logistic regression was used to estimate the association between ante- and intrapartum risk factors and neonatal outcomes. RESULTS: The 460 singleton pregnant women were 19 to 43 years of age. They developed an intrapartum temperature of ≥37.5°C somewhere between 340/7 to 414/7 weeks' gestation; 437 (95%) were nulliparous. Meconium-stained amniotic fluid was associated with positive pressure ventilation or intubation ventilation (odds ratio [OR] = 5.940, 95% confidence interval [CI]: 2.038-17.318), birth depression (OR = 6.288, 95% CI: 2.273-17.399), and wet lung (OR = 2.747, 95% CI: 1.322-5.709). Induction of labor with artificial rupture of membranes (AROM; OR = 2.632, 95% CI: 1.325-5.228) was associated with neonatal infections. Maternal temperature ≥ 38°C was associated with neonate's artery blood gas pH < 7.3 (OR = 2.366, 95%CI: 1.067-5.246) and wet lung (OR = 2.909, 95% CI: 1.515-5.586). Maternal elevated C-reactive protein (CRP) was associated with neonatal infections (OR = 1.993, 95% CI: 1.260-3.154) and wet lung (OR = 2.600, 95% CI: 1.306-5.178). CONCLUSION: Meconium-stained amniotic fluid, induction of labor, maternal temperature ≥ 38°C, and elevated CRP during labor were risk factors for adverse neonatal outcomes.

15.
J Surg Res ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31767276

RESUMO

BACKGROUND: Current treatments of lipopolysaccharide (LPS)-induced acute lung injury (ALI) are unsatisfactory due to the insufficient understanding of the pathogenesis of LPS-induced ALI. The NLRP3 inflammasome is an essential part of the innate protection system and is involved in LPS-induced ALI; however, comprehensive understanding of molecular pathogenesis of the disease is lacking. Our study explored the effect of heme oxygenase-1 (HO-1) on NLRP3 inflammasomes in vitro. METHODS: Alveolar macrophages (NR8383) were preincubated with high-mobility group box-1 (HMGB1) or HO-1 CRISPR plasmids before LPS stimulation. Then, we detected the effect of HO-1 on NLRP3 inflammasomes. RESULTS: Our study demonstrates that the activation of HO-1 represses the level of NLRP3 inflammasomes and the subsequent increases of the level of IL-1ß. Moreover, NLRP3 inflammasome activation was sensitive to the HMGB1 activity, and HO-1 was able to reduce the amount of HMGB1 released. Furthermore, downregulation of NLRP3 inflammasomes was related to NADPH quinone oxidoreductase 1 (an HO-1-related gene). CONCLUSIONS: Our study clarifies the constrained coordination of the HO-1 signal in the HMGB1-mediated activation of NLRP3 inflammasomes in NR8383 alveolar macrophages after LPS stimulation.

16.
J Phys Chem Lett ; 10(21): 6800-6806, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31618041

RESUMO

The adsorption and assembly of sub-monolayered bowl-shaped corannulene (COR) on Cu(111) and Ag(111) are investigated by scanning tunneling microscopy (STM). Three COR configurations, namely, up, down, and tilted ones, are formed on Cu(111), as unraveled by high-resolution STM images. It is also experimentally revealed that monodispersed, hexagonal, and evenly spaced stripe patterns develop on both Cu(111) and Ag(111). A quantitative evaluation of the long-range intermolecular interaction on Cu(111) mediated by electrostatic repulsion and surface-state mediation is presented. At 0.05 monolayer (ML), the long-range monodispersed pattern is mainly induced by electrostatic interaction. At 0.24 and 0.47 ML, however, surface-state mediation plays a dominant role, and the electrostatic interaction is leveled due to the identical static environment for each molecule.

17.
J Autoimmun ; 104: 102333, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31564474

RESUMO

During host immune response, an initial and sufficient activation is required to avoid infection and cancer, yet an excessive activation bears the risk of autoimmune reactivity and disease development. This fastidious balance of the immune system is regulated by co-stimulatory and co-inhibitory molecules, also known as immune checkpoints. Both excessive co-stimulation and insufficient co-inhibition can induce the activation and proliferation of autoreactive cells that may lead to the development of autoimmune diseases. During the last decade, a growing number of new immune checkpoint receptors and ligands have been discovered, providing an attractive approach to investigate their implication in the pathogenesis of autoimmune diseases and their potential role as targets for effective therapeutic interventions. In this review, we focus on the roles and underlying mechanisms of co-stimulatory and co-inhibitory receptors and other molecules that function as immune checkpoints in autoimmune diseases such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, Sjögren's syndrome, type I diabetes and inflammatory bowel disease. We also summarize previous and current clinical trials targeting these checkpoint pathways in autoimmune diseases and discuss further therapeutic implications and possible risks and challenges.

18.
Water Sci Technol ; 80(4): 634-643, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31661442

RESUMO

The effects of nitrite and nitrate on the integration of ammonium oxidization and sulfate reduction were investigated in a self-designed reactor with an effective volume of 5 L. An experimental study indicated that the ammonium oxidization and sulfate reduction efficiencies were increased in the presence of nitrite and nitrate. Studies showed that a decreasing proportion of N/S in the presence of NO2- at 30 mg·L-1 would lead to high removal efficiencies of NH4+-N and SO42--S of up to 78.13% and 46.72%, respectively. On the other hand, NO3- was produced at approximately 26.89 mg·L-1. Proteobacteria, Chloroflexi, Bacteroidetes, Chlorobi, Acidobacteria, Planctomycetes and Nitrospirae were detected in the anaerobic cycle growth reactor. Proteobacteria was identified as the dominant functional bacteria removing nitrogen in the reactor. The nitritation reaction could promote the sulfate-reducing ammonium oxidation (SRAO) process. NH4+ was converted to NO2 and other intermediates, for which the electron acceptor was SO42-. These results showed that nitrogen was converted by the nitrification process, the denitrification process, and the traditional anammox process simultaneously with the SRAO process. The sulfur-based autotrophic denitration and denitrification in the reactor were caused by the influent nitrite and nitrate.


Assuntos
Compostos de Amônio , Nitritos , Reatores Biológicos , Nitratos , Nitrogênio , Oxirredução , Sulfatos
19.
Artigo em Inglês | MEDLINE | ID: mdl-31652029

RESUMO

The use of computational models in drug development has grown during the past decade. These model-informed drug development (MIDD) approaches can inform a variety of drug development and regulatory decisions. When used for regulatory decision making, it is important to establish that the model is credible for its intended use. Currently, there is no consensus on how to establish and assess model credibility, including the selection of appropriate verification and validation activities. In this article, we apply a risk-informed credibility assessment framework to physiologically-based pharmacokinetic modeling and simulation and hypothesize this evidentiary framework may also be useful for evaluating other MIDD approaches. We seek to stimulate a scientific discussion around this framework as a potential starting point for uniform assessment of model credibility across MIDD. Ultimately, an overarching framework may help to standardize regulatory evaluation across therapeutic products (i.e., drugs and medical devices).

20.
Dose Response ; 17(3): 1559325819877271, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31579126

RESUMO

The purpose of this study is to investigate the effects of melatonin on the radiosensitivity of HeLa cells. Concentration from 10 to 1000 µM of melatonin was used on HeLa cells before X-rays irradiation (IR). The cellular inactivation effect was analyzed by clonogenic assay, and cell growth was measured by MTT assay at various concentrations. Ten micrometer melatonin promoted the cell-killing effects of IR, while 1000-µM melatonin prevented IR-induced cellular inactivation. Further analysis revealed that 1000-µM melatonin protected the cells from IR-induced reactive oxygen species damage, as the oxidative stress measured by fluorescent microscopy and fluorescence-activated cell sorting using 2,7-dichlorofluorescein diacetate staining. This is further confirmed by melatonin receptor agonist, which has no antioxidant capacity. A 10-µM melatonin, on the contrary, enhanced the cell-killing effects of IR by activating c-Jun NH2-terminal kinase (JNK) signaling. c-Jun NH2-terminal kinase signaling activation was indicated by Western blot of phosphorylated JNK. We used JNK inhibitor to further confirm the involvement of JNK signaling in the cell-killing enhancement of 10-µM melatonin administration. Our results suggest the importance of dose-dependent effects in melatonin application for radiotherapy.

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