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1.
Ther Adv Cardiovasc Dis ; 13: 1753944719863641, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31364490

RESUMO

BACKGROUND: This analysis aimed to evaluate the impact of rivaroxaban exposure and patient characteristics on efficacy and safety outcomes in patients with acute coronary syndrome (ACS) and to determine whether therapeutic drug monitoring might provide additional information regarding rivaroxaban dose, beyond what patient characteristics provide. METHODS: A post hoc exposure-response analysis was conducted using data from the phase III ATLAS ACS 2 Thrombolysis in Myocardial Infarction (TIMI) 51 study, in which 15,526 randomized ACS patients received rivaroxaban (2.5 mg or 5 mg twice daily) or placebo for a mean of 13 months (maximum follow up: 31 months). A multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event clinical outcomes. RESULTS: For the incidence of myocardial infarction (MI), ischemic stroke, or nonhemorrhagic cardiovascular death, hazard ratios (HRs) for steady-state maximum plasma concentration (Cmax) in the 5th and 95th percentiles versus the median were statistically significant but close to 1 for both rivaroxaban doses. For TIMI major bleeding events, a statistically significant association was observed with Cmax [HR, 1.08; 95% CI, 1.06-1.11 (95th percentile versus median, 2.5 mg twice daily)], sex [HR, 0.56; 95% CI, 0.38-0.84 (female versus male)], and previous revascularization [HR, 0.62; 95% CI, 0.44-0.87 (no versus yes)]. CONCLUSIONS: The shallow slopes of the exposure-response relationships and the lack of a clear therapeutic window render it unlikely that therapeutic drug monitoring in patients with ACS would provide additional information regarding rivaroxaban dose beyond that provided by patient characteristics.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Modelos Biológicos , Rivaroxabana/administração & dosagem , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , Idoso , Isquemia Encefálica/mortalidade , Tomada de Decisão Clínica , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/farmacocinética , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Acidente Vascular Cerebral/mortalidade , Resultado do Tratamento
2.
BMC Vet Res ; 15(1): 272, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370843

RESUMO

BACKGROUND: Ceftiofur Sodium is widely used in China. Our aim was to determine Ceftiofur Sodium activity and optimize dosing regimens against the pathogen Haemophilus parasuis using an in vitro and ex vivo pharmacokinetics/pharmacodynamics modeling approach. By adopting these strategies, we wanted to extend the effective life of Ceftiofur Sodium in reduce drug-resistance in pigs. RESULTS: We established an H. parasuis infection model in pigs, and assessed the pharmacokinetics of Ceftiofur Sodium in both healthy and infected animals. After Ceftiofur Sodium (10 mg/kg, i.m.) administration to healthy and H. parasuis-infected pigs, plasma based desfuroylceftiofur (a metabolite of Ceftiofur Sodium) was measured by High Performance Liquid Chromatography. The pharmacokinetics of Ceftiofur Sodium (desfuroylceftiofur) was consistent with a two-compartment open model, with first-order absorption. We observed no significant differences (P > 0.05) in pharmacokinetic parameters between healthy and infected pigs. Pharmacodynamics data showed that Ceftiofur Sodium was highly inhibitory against H. parasuis, with MIC, MBC, and MPC values of 0.003125, 0.0125 and 0.032 µg/mL, respectively. Desfuroylceftiofur in plasma also had strong bactericidal activity. Almost all H. parasuis cultured in plasma medium of Ceftiofur Sodium-inoculated healthy pigs, at each time point, were killed within 24 h. A weaker antibacterial activity was measured in infected-pig plasma medium at 18, 24, 36, and 48 h, after Ceftiofur Sodium inoculation. Pharmacokinetic parameters were combined with ex vivo pharmacodynamic parameters, and the bacteriostatic effect (36.006 h), bactericidal effect (71.637 h) and clearance (90.619 h) within 24 h, were determined using the Hill equation. Dose-calculation equations revealed the optimal dose of Ceftiofur Sodium to be 0.599-1.507 mg/kg. CONCLUSIONS: There were no significant differences in Ceftiofur Sodium pharmacokinetic parameters between healthy and infected pigs, although pharmacokinetics/pharmacodynamics fitting curves showed obviously differences. The optimal dose of Ceftiofur Sodium was lower than recommended (3 mg/kg), which may provide improved treatments for Glässers disease, with lower drug-resistance possibility.


Assuntos
Cefalosporinas , Infecções por Haemophilus/veterinária , Modelos Biológicos , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefalosporinas/farmacocinética , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Infecções por Haemophilus/tratamento farmacológico , Infecções por Haemophilus/microbiologia , Haemophilus parasuis/efeitos dos fármacos , Suínos , Doenças dos Suínos/tratamento farmacológico , Doenças dos Suínos/microbiologia
3.
Phys Rev Lett ; 123(3): 038101, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31386470

RESUMO

Synthesis of biopolymers such as DNA, RNA, and proteins are biophysical processes aided by enzymes. The performance of these enzymes is usually characterized in terms of their average error rate and speed. However, because of thermal fluctuations in these single-molecule processes, both error and speed are inherently stochastic quantities. In this Letter, we study fluctuations of error and speed in biopolymer synthesis and show that they are in general correlated. This means that, under equal conditions, polymers that are synthesized faster due to a fluctuation tend to have either better or worse errors than the average. The error-correction mechanism implemented by the enzyme determines which of the two cases holds. For example, discrimination in the forward reaction rates tends to grant smaller errors to polymers with faster synthesis. The opposite occurs for discrimination in monomer rejection rates. Our results provide an experimentally feasible way to identify error-correction mechanisms by measuring the error-speed correlations.


Assuntos
Biopolímeros/biossíntese , Enzimas/química , Enzimas/metabolismo , Biopolímeros/química , DNA/biossíntese , DNA/química , Humanos , Modelos Biológicos , Modelos Químicos , RNA/biossíntese , RNA/química
4.
Am J Orthod Dentofacial Orthop ; 156(2): 210-219, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31375231

RESUMO

INTRODUCTION: More patients are choosing customized orthodontic appliances because of their excellent esthetics. It is essential that clinicians understand the biomechanics of the tooth movement tendency in customized lingual orthodontics. This study aimed to evaluate the tooth movement tendency during space closure in maxillary anterior teeth with the use of miniscrew anchorage in customized lingual orthodontics with various power arm locations. METHODS: Three-dimensional finite element models of the maxilla were created with miniscrews and power arms; the positions were varied to change the force directions. A retraction force (1.5 N) was applied from the top of the miniscrews to the selected points on the power arm, and the initial displacements of the reference nodes of the maxillary teeth were analyzed. RESULTS: After applying force in different directions, power arms located at the distal side of the canines led to larger initial lingual crown tipping and occlusal crown extrusion of the maxillary incisors compared with power arms located at the midpoint between the lateral incisors and canines, and caused a decreasing trend of the intercanine width. CONCLUSIONS: In customized lingual orthodontic treatment, power arms located at the distal side of the canines are unfavorable for anterior teeth torque control and intercanine width control. Power arms located at the midpoint between the lateral incisors and canines can get better torque control, but still cannot achieve excepted torque without extra torque control methods, no matter whether its force application point is higher than, lower than, or equal to the level of the top of the miniscrews.


Assuntos
Parafusos Ósseos , Análise de Elementos Finitos , Procedimentos de Ancoragem Ortodôntica/instrumentação , Procedimentos de Ancoragem Ortodôntica/métodos , Fechamento de Espaço Ortodôntico , Técnicas de Movimentação Dentária/instrumentação , Técnicas de Movimentação Dentária/métodos , Adulto , Fenômenos Biomecânicos , Simulação por Computador , Dente Canino/patologia , Humanos , Imagem Tridimensional/métodos , Incisivo/patologia , Maxila , Modelos Biológicos , Desenho de Aparelho Ortodôntico , Aparelhos Ortodônticos , Braquetes Ortodônticos , Fechamento de Espaço Ortodôntico/instrumentação , Fechamento de Espaço Ortodôntico/métodos , Fios Ortodônticos , Planejamento de Assistência ao Paciente , Estresse Mecânico , Coroa do Dente , Torque , Resultado do Tratamento
5.
Cell Physiol Biochem ; 53(2): 429-438, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424183

RESUMO

BACKGROUND/AIMS: Chronic kidney disease-mineral bone disorder is a major complication affecting the vast majority of chronic kidney disease patients. A hallmark of the disorder is an altered parathyroid gland biology resulting in secondary hyperparathyroidism. This condition is widely treated by calcimimetics like cinacalcet which act by allosteric activation of the calcium sensing receptor. METHODS: Here, we present a linear multi-compartment model based on physiological principles such as first-pass metabolism and protein binding, which captures all relevant pharmacokinetic parameters of cinacalcet. RESULTS: Due to the linear structure of the model, simulations are numerically stable and allow fast and accurate short or long-term predictions of cinacalcet concentrations in the body. CONCLUSION: The model compartments are physiological meaningful and can be easily adjusted to various conditions like impaired hepatic clearance or different drug administration regimens. Moreover, the model can be easily adapted to specific patient groups.


Assuntos
Calcimiméticos/farmacocinética , Cinacalcete/farmacocinética , Modelos Biológicos , Calcimiméticos/sangue , Calcimiméticos/metabolismo , Cinacalcete/sangue , Cinacalcete/metabolismo , Simulação por Computador , Humanos , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/etiologia , Hiperparatireoidismo Secundário/metabolismo , Fígado/metabolismo , Ligação Proteica , Insuficiência Renal Crônica/complicações
6.
An Acad Bras Cienc ; 91(supp 3): e20190097, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365607

RESUMO

Peugeot-ONF Forest Carbon Sink Project, located at Fazenda São Nicolau (FSN) in Cotriguaçu Municipality, is a public-private initiative and has been supported by several French and Brazilian institutions. Its Research Program includes studies aiming Biodiversity Conservation, Ecology, Carbon Dynamics, Silvicultural Techniques. FSN comprises a high richness of species with more than 20 new species of beetles (Histeridae, Scarabaeidae e Melolonthidae) described among them one endemic genus. A quick overview of the SuperFamily Scarabaeoidea within the FSN area registered 260 species which nearly 100 species might be new to Science. One new species of fish as well as research with amphibian toxins as tools to treat cancer and malaria are also done with material collected at the FSN. Ecology of the decomposer´s fauna at reforestation sites showed that after 10 years, such places were more similar to native forest sites than pastures or abandoned pastures. Finally large mammals studies indicated that many large mammals use FSN as a refuge. We stress the importance to keep the FSN natural habitats linked with the Juruena National Park. The FSN contour is under heavy deforestation which will increase the species loss and turn FSN in one of the few major natural vegetation fragments.


Assuntos
Biodiversidade , Conservação dos Recursos Naturais/métodos , Modelos Biológicos , Brasil , Setor Privado , Setor Público
7.
Medicine (Baltimore) ; 98(26): e16186, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261555

RESUMO

The prevalence of chronic kidney disease (CKD) in Taiwan is 11.9%, and the incidence and prevalence of end-stage renal disease (ESRD) is ranked first in the world. The severity of CKD progression to ESRD is dependent on glomerular filtration rate and proteinuria. However, the risk factors for ESRD also include diabetes, hypertension, hyperlipidemia, age, sex, and so on, and predicting CKD progression using few variables is insufficient. Currently, there are no models with high accuracy and high explanatory power that could predict the risk of progression to dialysis in CKD patients in Taiwan. Our aim was to establish an optimal prediction model for CKD progression in patientsThis study was a retrospective cohort study, which reviewed data from the "Public health insurance Pre-ESRD preventive program and patient health education program" that was implemented by the National Health Insurance Administration, Ministry of Health and Welfare. From 2006 to 2013, data of CKD patients from the Tri-Service General Hospital in Neihu District, Taipei City was examined. The data collected in this study included demographic variables, past medical history, and blood biochemical values. After exclusion of variables with >30% missing data, the remaining variables were interpolated using multiple imputations and inputted into the prediction model for analysis. The Cox proportion hazard model was used to investigate the influence of CKD risk factors on progression to dialysis. The strengths of various models were evaluated using likelihood ratios (LR), in order to identify a model which uses the least factors but has the strongest explanatory power.The study results included 1549 CKD patients, of whom 1017 eventually had dialysis. This study found that in the prediction model with the best explanatory power, the influencing factors and hazard ratios (HR) were: age 0.95 (0.91-0.99), creatinine 1.03 (1.02-1.05), urea nitrogen 1.18 (1.14-1.23), and comorbid systemic diabetes 1.65 (1.45-1.88).A prediction model was developed in this study, which could be used to carry out predictions based on blood biochemical values from patients, in order to accurately predict the risk of CKD progression to dialysis.


Assuntos
Insuficiência Renal Crônica/diagnóstico , Idoso , Biomarcadores/sangue , Comorbidade , Creatinina/sangue , Diabetes Mellitus/epidemiologia , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Modelos Estatísticos , Prognóstico , Diálise Renal , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taiwan
8.
Toxicol Lett ; 313: 196-204, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31278966

RESUMO

Fipronil is a chiral insecticide employed worldwide in crops, control of public hygiene and control of veterinary pests. Humans can be exposed to fipronil through occupational, food, and environmental contamination. Therefore, the risk assessment of fipronil in humans is important to protect human health. Fipronil sulfone is the major metabolite formed during fipronil metabolism by humans. Since the CYP450 enzymes are the main ones involved in drug metabolism, the evaluation of their inhibition by fipronil and its main metabolite is important to predict drug-pesticide interactions. The aim of this work was to investigate the inhibition effects of rac-fipronil, S-fipronil, R-fipronil and fipronil sulfone on the main human CYP450 isoforms. The results showed that CYP2D6 is the only CYP450 isoform inhibited by these xenobiotics. In addition, no enantioselective differences were observed in the inhibition of CYP450 isoforms by fipronil and its individuals' enantiomers. Rac-fipronil, S-fipronil and R-fipronil are moderate CYP2D6 inhibitors showing a competitive inhibition profile. On the other hand, the metabolite fipronil sulfone showed to be a strong inhibitor of CYP2D6 also by competitive inhibition. These results highlight the importance of metabolite evaluation on pesticide safety since the metabolism of fipronil into fipronil sulfone increases the risk of pesticide-drug interactions for drugs metabolized by CYP2D6.


Assuntos
Inibidores do Citocromo P-450 CYP2D6/toxicidade , Citocromo P-450 CYP2D6/metabolismo , Praguicidas/toxicidade , Pirazóis/toxicidade , Citocromo P-450 CYP2D6/química , Inibidores do Citocromo P-450 CYP2D6/química , Relação Dose-Resposta a Droga , Interações de Medicamentos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Biológicos , Praguicidas/química , Conformação Proteica , Pirazóis/química , Medição de Risco , Relação Estrutura-Atividade
9.
Expert Opin Drug Saf ; 18(8): 651-677, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31268355

RESUMO

INTRODUCTION: Historically, drug development and marketing failures have been experienced by pharma organizations largely from insufficient human-predictability of biological data. AREAS COVERED: Organs-on-chips (OOCs) are emerging, cutting edge microphysiology systems for in vitro production of microengineered three-dimensional, miniature organotypic constructs obtained by cultivating small amounts of human primary, or induced pluripotent stem, cells in native-like microhabitats. These preparations circumvent experimental limitations inherent to animal assays and two-dimensional monolayers, the mainstay core biological assays of traditional drug research. This report reviews the fundamental tenets, key components (chip plate, biomaterials, cell differentiation approaches, and monitoring sensors) and issues concerning OOC systems (engineered top-down and bottom-up strategies for tissue/organ assembly, public aids to OOC development, regulatory validation, advantages, limitations, prospective and perspective of OOCs, ethics). Examples of OOC platforms (cancer-, lung-, blood-brain barrier-, heart-, intestine-, kidney-, liver-, pharmacokinetics-, placenta and vessel-on-chip) and their importance for drug research and development are presented. EXPERT OPINION: OOC device-generated bioconstructs hold great promise as experimental human tissue and organ platforms for generating human-pertinent knowledge on drug candidates for clinical assessment and reducing reliance on animal models. MPS technologies currently enable ready-to-assemble tissue patches and, hopefully, in coming decades, full-size, patient-personalized organs for regenerative medical interventions.


Assuntos
Desenvolvimento de Medicamentos/métodos , Dispositivos Lab-On-A-Chip , Modelos Biológicos , Alternativas aos Testes com Animais , Animais , Humanos , Pesquisa Farmacêutica/métodos , Células-Tronco/citologia
10.
Eur Biophys J ; 48(6): 539-548, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31289882

RESUMO

In the context of decompression sickness, this paper presents analytical formulae and explanations for growth of a gas bubble in blood and other tissues in an unsteady diffusion field with a source or a sink. The formulae are valid for variable (through decompression) and constant (concerning diving stops/at sea level) ambient pressure. Under a linear decompression regime for ambient pressure, the gas bubble growth is proportional to ascent rate, tissue diffusivity and initial tissue tension and inversely proportional to surface tension, initial ambient pressure and the strength of the source/sink parameter [Formula: see text] which gives the conditions for bubble growth. We find that the growth process is noticeably affected by changing k-values within a specified range, with no significant effect on the value of the bubble radius when k is outside this range. We discuss the effect of the presence of multiple bubbles, and of repetitive diving. Of the three available models for bubble growth, the predicted time to completion is longest in the model by Srinivasan et al. (J Appl Physiol 86:732-741, 1999), where the bubble grows in a steady diffusion field, but shortest in the model we describe for k-values closest to the boundaries of the interval [Formula: see text]. This is because our model considers the effect of the presence of a source, increasing the bubble growth rate and not taken into account in our previous (2010) model predicting an intermediate timeframe for bubble growth. We believe our new model provides a more accurate and widely applicable description of bubble growth in decompression sickness than previous versions.


Assuntos
Gases/metabolismo , Modelos Biológicos , Pressão , Doença da Descompressão/metabolismo , Perfusão , Tensão Superficial
11.
Anim Genet ; 50(4): 347-357, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257665

RESUMO

Durability traits in Thoroughbred horses are heritable, economically valuable and may affect horse welfare. The aims of this study were to test the hypotheses that (i) durability traits are heritable and (ii) genetic data may be used to predict a horse's potential to have a racecourse start. Heritability for the phenotype 'number of 2- and 3-year-old starts' was estimated to be h m 2  = 0.11 ± 0.02 (n = 4499). A genome-wide association study identified SNP contributions to the trait. The neurotrimin (NTM), opioid-binding protein/cell adhesion molecule like (OPCML) and prolylcarboxypeptidase (PRCP) genes were identified as candidate genes associated with the trait. NTM functions in brain development and has been shown to have been selected during the domestication of the horse. PRCP is an established expression quantitative trait locus involved in the interaction between voluntary exercise and body composition in mice. We hypothesise that variation at these loci contributes to the motivation of the horse to exercise, which may influence its response to the demands of the training and racing environment. A random forest with mixed effects (RFME) model identified a set of SNPs that contributed to 24.7% of the heritable variation in the trait. In an independent validation set (n = 528 horses), the cohort with high genetic potential for a racecourse start had significantly fewer unraced horses (16% unraced) than did low (27% unraced) potential horses and had more favourable race outcomes among those that raced. Therefore, the information from SNPs included in the model may be used to predict horses with a greater chance of a racecourse start.


Assuntos
Cavalos/genética , Cavalos/fisiologia , Animais , Estudo de Associação Genômica Ampla , Modelos Biológicos , Fenótipo , Condicionamento Físico Animal , Polimorfismo de Nucleotídeo Único
12.
BMC Bioinformatics ; 20(1): 375, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272368

RESUMO

BACKGROUND: Cells operate in an uncertain environment, where critical cell decisions must be enacted in the presence of biochemical noise. Information theory can measure the extent to which such noise perturbs normal cellular function, in which cells must perceive environmental cues and relay signals accurately to make timely and informed decisions. Using multivariate response data can greatly improve estimates of the latent information content underlying important cell fates, like differentiation. RESULTS: We undertake an information theoretic analysis of two stochastic models concerning glioma differentiation therapy, an alternative cancer treatment modality whose underlying intracellular mechanisms remain poorly understood. Discernible changes in response dynamics, as captured by summary measures, were observed at low noise levels. Mitigating certain feedback mechanisms present in the signaling network improved information transmission overall, as did targeted subsampling and clustering of response dynamics. CONCLUSION: Computing the channel capacity of noisy signaling pathways present great probative value in uncovering the prevalent trends in noise-induced dynamics. Areas of high dynamical variation can provide concise snapshots of informative system behavior that may otherwise be overlooked. Through this approach, we can examine the delicate interplay between noise and information, from signal to response, through the observed behavior of relevant system components.


Assuntos
Glioma/tratamento farmacológico , Teoria da Informação , Diferenciação Celular/efeitos dos fármacos , Glioma/metabolismo , Humanos , Modelos Biológicos , Transdução de Sinais/efeitos dos fármacos , Processos Estocásticos
13.
J Chem Phys ; 151(3): 034109, 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31325941

RESUMO

The stochastic dynamics of biochemical networks are usually modeled with the chemical master equation (CME). The stationary distributions of CMEs are seldom solvable analytically, and numerical methods typically produce estimates with uncontrolled errors. Here, we introduce mathematical programming approaches that yield approximations of these distributions with computable error bounds which enable the verification of their accuracy. First, we use semidefinite programming to compute increasingly tighter upper and lower bounds on the moments of the stationary distributions for networks with rational propensities. Second, we use these moment bounds to formulate linear programs that yield convergent upper and lower bounds on the stationary distributions themselves, their marginals, and stationary averages. The bounds obtained also provide a computational test for the uniqueness of the distribution. In the unique case, the bounds form an approximation of the stationary distribution with a computable bound on its error. In the nonunique case, our approach yields converging approximations of the ergodic distributions. We illustrate our methodology through several biochemical examples taken from the literature: Schlögl's model for a chemical bifurcation, a two-dimensional toggle switch, a model for bursty gene expression, and a dimerization model with multiple stationary distributions.


Assuntos
Modelos Biológicos , Modelos Químicos , Biologia Celular , Computação Matemática , Processos Estocásticos
14.
Naturwissenschaften ; 106(7-8): 43, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263966

RESUMO

Dispersal, movement leading to gene flow, is a fundamental but costly life history trait. The use of indirect social information may help mitigate these costs, yet we often know little about the proximate sources of such information, and how dispersers and residents may differ in their information use. Terrestrial molluscs, which have a high cost of movement and obligatorily leave information potentially exploitable by conspecifics during movement (through mucus trails), are a good model to investigate links between dispersal costs and information use. We studied whether dispersers and residents differed in their trail-following propensity in the snail Cornu aspersum. Dispersers followed mucus trails more frequently than expected by chance, contrary to non-dispersers. Trail-following by dispersers may reduce dispersal costs by reducing energy expenditure and helping snails find existing habitat or resource patches. Finally, we point that ignoring the potential for collective dispersal provided by trail-following may hinder our understanding of the demographic and genetic consequences of dispersal.


Assuntos
Distribuição Animal/fisiologia , Modelos Biológicos , Caramujos/fisiologia , Animais , Muco/fisiologia
15.
Brain Nerve ; 71(8): 875-883, 2019 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-31346144

RESUMO

Parkinson's disease (PD), a common neurodegenerative disorder, is characterized by selective degeneration of dopaminergic neurons in the substantia nigra. There is no effective treatment to delay or halt the progression of PD. The establishment of disease models, based on human biology, is therefore important for developing effective disease-modifying therapies. The recent progress of human induced pluripotent stem cell-associated technologies provides an opportunity to understand disease etiology, discover new drugs, and develop novel therapeutic interventions.


Assuntos
Células-Tronco Pluripotentes Induzidas , Doença de Parkinson/patologia , Neurônios Dopaminérgicos/patologia , Humanos , Modelos Biológicos , Substância Negra/patologia
16.
J Agric Food Chem ; 67(31): 8617-8625, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31293160

RESUMO

Inhibiting starch digestion can effectively control postprandial blood sugar level. In this study, the in vitro digestion differences among the mixtures of five polyphenols (i.e., procyanidins [PAs], catechin [CA], tannic acid [TA], rutin [RU], and quercetin [QU]) and starch were analyzed through an in vitro simulation test of starch digestion. The interaction characteristics of these five polyphenols with α-amylase and α-glucosidase were investigated in terms of the inhibition effect, dynamics, fluorescence quenching, and circular dichroism (CD). The results revealed that the rapidly digestible starch (RDS) contents decreased, while the resistant starch (RS) contents increased. All five polyphenols inhibited the α-amylase activity through the noncompetitive approach but inhibited the α-glucosidase activity through the competitive approach. Five polyphenols combined with α-amylase spontaneously by using the hydrophobic effect. The interaction of PAs and QU with α-glucosidase were recognized as van der Waals forces and H bonding, whereas CA and TA interacted with α-glucosidase through the hydrophobic effect. All five polyphenols can cause conformational changes in enzymes.


Assuntos
Extratos Vegetais/química , Polifenóis/química , Amido/química , Animais , Digestão , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Cinética , Modelos Biológicos , Extratos Vegetais/metabolismo , Polifenóis/metabolismo , Amido/metabolismo , Suínos , Leveduras/enzimologia , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
17.
J Agric Food Chem ; 67(31): 8520-8526, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31310120

RESUMO

Reactive carbonyl species (RCS), such as acrolein (ACR), glyoxal (GO), and methylglyoxal (MGO), have received extensive attention recently as a result of their high activity and toxicity in vitro and in vivo. In the present study, propyl gallate (PG), a common food antioxidant, was found to effectively trap more ACR than butylated hydroxytoluene and butylated hydroxyanisole through the formation of mono-ACR adducts (PG-ACR) and di-ACR adducts (PG-2ACR). The two adducts were successfully purified, and their structures were elucidated on the basis of their high-resolution mass spectrometry and 1H, 13C, and two-dimensional nuclear magnetic resonance data. We further identified that PG-ACR had the ability to continue to trap GO and MGO to form PG-ACR-GO and PG-ACR-MGO, respectively, by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, we verified that PG could inhibit the production of ACR, GO, and MGO via trapping these RCS simultaneously to form the corresponding adducts in pound cakes using LC-MS/MS.


Assuntos
Acroleína/química , Antioxidantes/química , Galato de Propila/química , Culinária , Temperatura Alta , Espectroscopia de Ressonância Magnética , Modelos Biológicos , Estrutura Molecular , Espectrometria de Massas em Tandem
18.
Adv Exp Med Biol ; 1140: 45-68, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31317495

RESUMO

To initiate infection, non-enveloped viruses must recognize a target cell and penetrate the cell membrane by pore formation or membrane lysis. Rotaviruses are non-enveloped dsRNA viruses that infect the mature intestinal epithelium. They are major etiologic agents of diarrheal disease in human infants, as well as in young individuals of various avian and mammalian species. Rotavirus entry into the cell is a complex multistep process initiated by the interaction of the tip of the viral spike with glycan ligands at the cell surface, and driven by conformational changes of the proteins present in the outer protein capsid, the viral machinery for entry. This review feeds on the abundant structural information produced for rotavirus during the past 30 years and focuses on the structure and the dynamics of the rotavirus entry machinery. We survey the current models for rotavirus entry into cells.


Assuntos
Infecções por Rotavirus , Rotavirus , Internalização do Vírus , Animais , Membrana Celular/virologia , Humanos , Modelos Biológicos , Rotavirus/fisiologia , Infecções por Rotavirus/patologia , Infecções por Rotavirus/virologia
19.
Expert Opin Drug Metab Toxicol ; 15(8): 633-658, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31274340

RESUMO

Introduction: In quantitative modeling, the resolving of underpredictions and overpredictions of hepatic clearance (CLh) makes a top priority for pharmacokinetic modelers. Clearly, the 'protein-mediated hepatic uptake' is a violation of 'the free drug hypothesis', but the lack of its consideration in CLh-predictive approaches may be one of the reasons to explain the discrepancies between predicted and observed values. Areas covered: We first review the two 'albumin-facilitated hepatic uptake' models that were recently challenged to improve the in vitro-to-in vivo extrapolation (IVIVE) of CLh by reducing the underprediction bias, particularly in the absence of albumin (ALB) in vitro compared to the presence of ALB in vivo. Second, we identify three types of interactions related to the ALB-bound drug moiety (i.e., ALB-lipids, ALB-proteins, and ALB-ligand allosteric interactions) that may be behind the 'ALB-mediated hepatic uptake' mechanism(s) for highly bound drugs. Main keywords used in our search are IVIVE; albumin; allostery; protein-mediated uptake; hepatic clearance; polarized hepatocytes. Expert opinion: Understanding the implication of these interactions and the enzyme/transporter interplay for each drug would help selecting the appropriate IVIVE model. Therefore, we have proposed a tree of decision for guidance. The next step is to improve the 'ALB-facilitated hepatic uptake' models to cover the remaining uncertainties.


Assuntos
Albuminas/metabolismo , Hepatócitos/metabolismo , Modelos Biológicos , Transporte Biológico , Humanos , Lipídeos/química , Fígado/metabolismo , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Farmacocinética , Ligação Proteica , Proteínas/metabolismo
20.
J Cancer Res Clin Oncol ; 145(8): 1949-1976, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31292714

RESUMO

PURPOSE: Efflux transporters of the adenosine triphosphate-binding cassette (ABC)-superfamily play an important role in the development of multidrug resistance (multidrug resistant; MDR) in cancer. The overexpression of these transporters can directly contribute to the failure of chemotherapeutic drugs. Several in vitro and in vivo models exist to screen for the efficacy of chemotherapeutic drugs against MDR cancer, specifically facilitated by efflux transporters. RESULTS: This article reviews a range of efflux transporter-based MDR models used to test the efficacy of compounds to overcome MDR in cancer. These models are classified as either in vitro or in vivo and are further categorised as the most basic, conventional models or more complex and advanced systems. Each model's origin, advantages and limitations, as well as specific efflux transporter-based MDR applications are discussed. Accordingly, future modifications to existing models or new research approaches are suggested to develop prototypes that closely resemble the true nature of multidrug resistant cancer in the human body. CONCLUSIONS: It is evident from this review that a combination of both in vitro and in vivo preclinical models can provide a better understanding of cancer itself, than using a single model only. However, there is still a clear lack of progression of these models from basic research to high-throughput clinical practice.


Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Antineoplásicos/isolamento & purificação , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Modelos Biológicos , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Técnicas de Cultura/métodos , Técnicas de Apoio para a Decisão , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Especificidade de Órgãos , Seleção de Pacientes
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