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1.
J Chem Phys ; 151(12): 125101, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31575173

RESUMO

Gene regulation is one of the most important fundamental biological processes in living cells. It involves multiple protein molecules that locate specific sites on DNA and assemble gene initiation or gene repression multimolecular complexes. While the protein search dynamics for DNA targets has been intensively investigated, the role of intermolecular interactions during the genetic activation or repression remains not well quantified. Here, we present a simple one-dimensional model of target search for two interacting molecules that can reversibly form a dimer molecular complex, which also participates in the search process. In addition, the proteins have finite residence times on specific target sites, and the gene is activated or repressed when both proteins are simultaneously present at the target. The model is analyzed using first-passage analytical calculations and Monte Carlo computer simulations. It is shown that the search dynamics exhibit a complex behavior depending on the strength of intermolecular interactions and on the target residence times. We also found that the search time shows a nonmonotonic behavior as a function of the dissociation rate for the molecular complex. Physical-chemical arguments to explain these observations are presented. Our theoretical approach highlights the importance of molecular interactions in the complex process of gene activation/repression by multiple transcription factor proteins.


Assuntos
DNA/química , Modelos Químicos , Simulação por Computador , DNA/genética , DNA/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Cinética , Método de Monte Carlo , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
2.
J Chem Phys ; 151(12): 124905, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31575216

RESUMO

The von Willebrand Factor (vWF) is a large blood glycoprotein that aids in hemostasis. Within each vWF monomer, the A2 domain hosts a cleavage site for enzyme ADAMTS13, which regulates the size of vWF multimers. This cleavage site can only be exposed when an A2 domain unfolds, and the unfolding reaction energy landscape is highly sensitive to the force conditions on the domain. Based on previous optical tweezer experimental results, we advance here a new activated A2 monomer model (AA2MM) for coarse-grained modeling of vWF that accurately represents the force-based probabilistic change between the unfolded/refolded states. A system of springs is employed to mimic the complex mechanical response of vWF monomers subject to pulling forces. AA2MM was validated by comparing monomer scale simulation results to data from prior pulling experiments on vWF monomer fragments. The model was further validated by comparing multimer scale Brownian dynamics simulation results to experiments using microfluidic chamber microscopy to visualize tethered vWF proteins subject to flow. The A2 domain unfolding reaction was studied in bulk flow simulations (pure shear and elongation flow), giving evidence that elongational flow drives the vWF size regulation process in blood. The mechanoreactive, coarse-grained AA2MM accurately describes the complex mechanical coupling between human blood flow conditions and vWF protein reactivity.


Assuntos
Modelos Químicos , Fator de von Willebrand/química , Proteína ADAMTS13/sangue , Proteína ADAMTS13/química , Fenômenos Biomecânicos , Simulação por Computador , Humanos , Domínios Proteicos , Desdobramento de Proteína
3.
Am J Orthod Dentofacial Orthop ; 156(3): 326-336, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31474262

RESUMO

INTRODUCTION: Orthodontic mini-implants aid in the correction of distocclusions via direct anchorage (pull from mini-implant to teeth) and indirect anchorage (teeth pulled against other teeth anchored by the mini-implant). The aim of this study was to compare stress levels on the periodontal ligament (PDL) of maxillary buccal teeth in direct and indirect distalization against orthodontic mini-implants and accounting for individual variation in maxillary anatomy and biomechanical characteristics of the compact bone. METHODS: A 3D model of the maxilla containing the different components (teeth, PDL, trabecular and cortical bones) was generated from a computed tomographic scan. Cortical bone was divided into several areas according to previously defined zones. Bone stiffness and thickness data, obtained from 11 and 12 cadavers, respectively, were incorporated into the initial model to simulate the individual cortical bone variation at the different locations. Subsequently, a finite element analysis was used to simulate the distalization modalities. RESULTS: Stresses at the buccal, palatal, mesial, and distal surfaces were significantly different between adjacent teeth under stiffness but not thickness variation. In both distalization modalities, low or no significant correlations were found between stress values and corresponding cortical bone thicknesses. High significant and inverted correlations were observed at the first molar between stress amounts and cortical bone stiffness (direct modality: -0.68 < r < -0.72; indirect modality: -0.80 < r < -0.82; P <0.05). CONCLUSIONS: With the use of a novel finite element approach that integrated human data on variations in bone properties, findings suggested that cortical bone stiffness may influence tooth movement more than bone thickness. Significant clinical implications could be related to these findings.


Assuntos
Análise do Estresse Dentário/métodos , Análise de Elementos Finitos , Técnicas de Movimentação Dentária/métodos , Fenômenos Biomecânicos , Parafusos Ósseos , Simulação por Computador , Implantes Dentários , Humanos , Imagem Tridimensional/métodos , Maxila/anatomia & histologia , Maxila/diagnóstico por imagem , Modelos Anatômicos , Dente Molar , Procedimentos de Ancoragem Ortodôntica/instrumentação , Procedimentos de Ancoragem Ortodôntica/métodos , Desenho de Aparelho Ortodôntico , Ligamento Periodontal , Estresse Mecânico , Técnicas de Movimentação Dentária/instrumentação , Torção Mecânica
4.
Phys Chem Chem Phys ; 21(37): 20727-20742, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31509121

RESUMO

The left-handed polyproline II (PPII) type helical structures are thought to play a very important role in many essential biological processes, particularly in recognition mechanisms. However, reliable characterisation of PPII conformation in solution can be experimentally challenging. Computational simulation of these structures offers an attractive alternative, but the accuracy of the results is dependent on the accuracy of the force field employed. In this report, we present the results of simulation of the structural and dynamical properties of a proline-rich viral fusion peptide for which a solution NMR study reported a substantial stretch of PPII conformation in the central region. The suggested mode of action of the p15 fusion peptide depended on the exposure of the flanking N-terminal hydrophobic residues to solvent thereby facilitating their interaction with the target membrane. Our simulations with a set of four force field and water model combinations consisting of (AMBER ff99SB*-ILDNP + TIP3P), (OPLS-AA + SPC/E), (AMBER ff03ws + TIP4P/2005 water with scaled protein-water interactions) and (CHARMM36m + TIP3P) showed a general agreement with the NMR results for all the four force field and water model combinations. The central region encompassing positions 9-15 showed a large PPII propensity, reduced flexibility and lower conformational entropy. The PPII conformations were stable and satisfied the Burgi-Dunitz criteria without the participation of any significant water bridging interaction. However, comparison of the experimentally observed chemical shifts with the distribution of shifts predicted from the simulated ensembles showed a much better agreement for the CHARMM36m + TIP3P and AMBER ff03ws + TIP4P/2005 combinations. The models based on these two force fields also generated conformations which were in much better agreement with the NMR model than the much more compact structures predicted by the AMBER ff99SB*-ILDNP and OPLS-AA force fields and predicted a substantially larger solvent accessible surface area in accordance with the suggested mechanism of action of the peptide.


Assuntos
Modelos Moleculares , Prolina/química , Proteínas Recombinantes de Fusão/química , Simulação por Computador , Espectroscopia de Ressonância Magnética , Conformação Molecular , Água/química
5.
Stud Health Technol Inform ; 264: 1939-1940, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438417

RESUMO

In recent years, health care organizations, in particular emergency department (ED), have come under increasing pressure to provide quality care. In this context, human resources are a central aspect: a good utilization of health worker could improve quality of care. In this paper, a simulation model is proposed. The model represents an ED coupled with an optimization method to optimize the allocation of medical and para-medical human resources in the hospital center of Troyes. We aim to improve the quality of services offered to patients through the minimization of Average Waiting Time (AWT) and Average Inpatient Stay (AS). The proposed approach has proved to be effective to reduce AWT and AS by 12 minutes and 21 minutes respectively.


Assuntos
Serviço Hospitalar de Emergência , Simulação por Computador , Humanos , Tempo de Internação
6.
Gene ; 717: 144047, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31421190

RESUMO

BACKGROUND: Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways play important roles in the formation of the blood vascular system and nervous system across animal phyla. We have earlier reported VEGF and FGF from Hydra vulgaris Ind-Pune, a cnidarian with a defined body axis, an organized nervous system and a remarkable ability of regeneration. We have now identified three more components of VEGF and FGF signaling pathways from hydra. These include FGF-1, FGF receptor 1 (FGFR-1) and VEGF receptor 2 (VEGFR-2) with a view to deciphering their possible roles in regeneration. METHODS: In silico analysis of proteins was performed using Clustal omega, Swiss model, MEGA 7.0, etc. Gene expression was studied by whole mount in situ hybridization. VEGF and FGF signaling was inhibited using specific pharmacological inhibitors and their effects on head regeneration were studied. RESULTS: Expression patterns of the genes indicate a possible interaction between FGF-1 and FGFR-1 and also VEGF and VEGFR-2. Upon treatment of decapitated hydra with pharmacological inhibitor of FGFR-1 or VEGFR-2 for 48 h, head regeneration was delayed in treated as compared to untreated, control regenerates. When we studied the expression of head specific genes HyBra1 and HyKs1 and tentacle specific gene HyAlx in control and treated regenerates using whole mount in situ hybridization, expression of all the three genes was found to be adversely affected in treated regenerates. CONCLUSIONS: The results suggest that VEGF and FGF signaling play important roles in regeneration of hypostome and tentacles in hydra.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Cabeça/fisiologia , Hydra/fisiologia , Regeneração/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Simulação por Computador , Fator 1 de Crescimento de Fibroblastos/química , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Hydra/efeitos dos fármacos , Indóis/farmacologia , Domínios Proteicos , Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Regeneração/efeitos dos fármacos , Transdução de Sinais , Homologia Estrutural de Proteína , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
7.
J Agric Food Chem ; 67(33): 9210-9219, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31390203

RESUMO

The insecticidal and antifeedant activities of five 7-chloro-4-(1H-1,2,3-triazol-1-yl)quinoline derivatives were evaluated against the maize armyworm, Spodoptera frugiperda (J.E. Smith). These hybrids were prepared through a copper-catalyzed azide alkyne cycloaddition (CuAAC, known as a click reaction) and displayed larvicidal properties with LD50 values below 3 mg/g insect, and triazolyl-quinoline hybrid 6 showed an LD50 of 0.65 mg/g insect, making it 2-fold less potent than methomyl, which was used as a reference insecticide (LD50 = 0.34 mg/g insect). Compound 4 was the most active antifeedant derivative (CE50 = 162.1 µg/mL) with a good antifeedant index (56-79%) at concentrations of 250-1000 µg/mL. Additionally, triazolyl-quinoline hybrids 4-8 exhibited weak inhibitory activity against commercial acetylcholinesterase from Electrophorus electricus (electric-eel AChE) (IC50 = 27.7 µg/mL) as well as low anti-ChE activity on S. frugiperda larvae homogenate (IC50 = 68.4 µg/mL). Finally, molecular docking simulations suggested that hybrid 7 binds to the catalytic active site (CAS) of this enzyme and around the rim of the enzyme cavity, acting as a mixed (competitive and noncompetitive) inhibitor like methomyl. Triazolyl-quinolines 4-6 and 8 inhibit AChE by binding over the perimeter of the enzyme cavity, functioning as noncompetitive inhibitors. The results described in this work can help to identify lead triazole structures from click chemistry for the development of insecticide and deterrent products against S. frugiperda and related insect pests.


Assuntos
Inseticidas/síntese química , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Spodoptera/efeitos dos fármacos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Química Click , Simulação por Computador , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Inseticidas/química , Larva/enzimologia , Larva/crescimento & desenvolvimento , Simulação de Acoplamento Molecular , Doenças das Plantas/parasitologia , Spodoptera/enzimologia , Spodoptera/crescimento & desenvolvimento , Zea mays/parasitologia
8.
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
9.
Zoology (Jena) ; 135: 125678, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31383297

RESUMO

In a majority of ray-finned fishes (Actinopterygii), effective acquisition of food resources is predicated on rapid jaw adduction. Although the musculoskeletal architecture of the feeding system has been the subject of comparative research for many decades, individual contributions of the major adductor divisions to closing dynamics have not been elucidated. While it is understood that the dorsal divisions that arise from the head and insert on the posterior of the lower jaw are major contributors to closing dynamics, the contribution of the ventral components of the adductor system has been largely overlooked. In many ray-finned fishes, the ventral component is comprised of a single division, the Aω, that originates on an intersegmental aponeurosis of the facialis divisions and inserts on the medial face of the dentary, anterior to the Meckelian tendon. This configuration resembles a sling applied at two offset points of attachment on a third-order lever. The goal of this study was to elucidate the contributions of the Aω to jaw adduction by modeling jaw closing in the deep-sea viperfish Chauliodus sloani. To do this, we simulated adduction with a revised computational model that incorporates the geometry of the Aω. By comparing results between simulations that included and excluded Aω input, we show that the Aω adds substantially to lower-jaw adduction dynamics in C. sloani by acting as a steering motor and displacing the line of action of the dorsal facialis adductor muscles and increasing the mechanical advantage and input moment arms of the jaw lever system. We also explored the effect of the Aω on muscle dynamics and found that overall facialis muscle shortening velocities are higher and normalized force production is lower in simulations including the Aω. The net effect of these changes in muscle dynamics results in similar magnitudes of peak power in the facialis divisions between simulations, however, peak power is achieved earlier in adduction Modifications of muscle mechanics and posture result in significant increases in closing performance, including static bite force, angular velocity, and adduction time. We compare this configuration to a similar design in crocodilians and suggest that the Aω configuration and similar sling configurations across the vertebrate tree of life indicate the importance of this musculoskeletal design in feeding.


Assuntos
Simulação por Computador , Peixes/fisiologia , Músculo Esquelético/fisiologia , Animais , Comportamento Alimentar/fisiologia , Peixes/anatomia & histologia , Arcada Osseodentária/anatomia & histologia , Músculo Esquelético/anatomia & histologia
10.
An Acad Bras Cienc ; 91(3): e20180040, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31411253

RESUMO

We introduce a new class of continuous distributions called the generalized odd Lindley-G family. Four special models of the new family are provided. Some explicit expressions for the quantile and generating functions, ordinary and incomplete moments, order statistics and Rényi and Shannon entropies are derived. The maximum likelihood method is used for estimating the model parameters. The flexibility of the generated family is illustrated by means of two applications to real data sets.


Assuntos
Tábuas de Vida , Modelos Estatísticos , Distribuições Estatísticas , Simulação por Computador , Entropia , Funções Verossimilhança
11.
Vet Parasitol ; 272: 44-52, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31395204

RESUMO

In the present study, a quantitative proteomic approach to study changes in saliva proteins associated with canine leishmaniosis (CanL) was performed. For this, canine salivary proteins were analysed and compared between dogs before (T0) and after (T1) experimental infection with Leishmania infantum by high-throughput label-based quantitative LC-MS/MS proteomic approach and bioinformatic analysis of the in silico inferred interactome protein network was created from the initial list of differential proteins. More than 2000 proteins were identified, and of the 90 differentially expressed proteins between T0 and T1, 12 were down-regulated with log2 fold change lower than -0.5849, and 19 were up-regulated with log2 fold change greater than 0.5849. This study provides evidence of changes in salivary proteome that can occur in canine leishmaniosis and revealed biological pathways in saliva modulated in canine leishmaniosis with potential for further targeted research.


Assuntos
Doenças do Cão/fisiopatologia , Leishmaniose/veterinária , Saliva , Proteínas e Peptídeos Salivares/genética , Proteínas e Peptídeos Salivares/metabolismo , Animais , Cromatografia Líquida , Simulação por Computador , Cães , Regulação da Expressão Gênica , Leishmaniose/fisiopatologia , Proteoma/genética , Proteoma/metabolismo , Proteômica , Saliva/química , Saliva/metabolismo , Espectrometria de Massas em Tandem
12.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 36(4): 633-642, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31441265

RESUMO

The deoxyribonucleic acid (DNA) molecule damage simulations with an atom level geometric model use the traversal algorithm that has the disadvantages of quite time-consuming, slow convergence and high-performance computer requirement. Therefore, this work presents a density-based spatial clustering of applications with noise (DBSCAN) clustering algorithm based on the spatial distributions of energy depositions and hydroxyl radicals (·OH). The algorithm with probability and statistics can quickly get the DNA strand break yields and help to study the variation pattern of the clustered DNA damage. Firstly, we simulated the transportation of protons and secondary particles through the nucleus, as well as the ionization and excitation of water molecules by using Geant4-DNA that is the Monte Carlo simulation toolkit for radiobiology, and got the distributions of energy depositions and hydroxyl radicals. Then we used the damage probability functions to get the spatial distribution dataset of DNA damage points in a simplified geometric model. The DBSCAN clustering algorithm based on damage points density was used to determine the single-strand break (SSB) yield and double-strand break (DSB) yield. Finally, we analyzed the DNA strand break yield variation trend with particle linear energy transfer (LET) and summarized the variation pattern of damage clusters. The simulation results show that the new algorithm has a faster simulation speed than the traversal algorithm and a good precision result. The simulation results have consistency when compared to other experiments and simulations. This work achieves more precise information on clustered DNA damage induced by proton radiation at the molecular level with high speed, so that it provides an essential and powerful research method for the study of radiation biological damage mechanism.


Assuntos
Algoritmos , Dano ao DNA , DNA/efeitos da radiação , Transferência Linear de Energia , Simulação por Computador , Método de Monte Carlo , Prótons
13.
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
14.
Soft Matter ; 15(33): 6630-6641, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31403143

RESUMO

The mechanics of blister delamination and growth plays a major role in a diversity of areas including medicine (skin pathology and mechanics of cell membranes), materials (adhesive and fracture) or soft robotics (actuation and morphing). The behavior of a blister in this context is typically difficult to grasp as it arises from the interplay of two highly nonlinear and time-dependent processes: membrane attachment and decohesion from a substrate. In the present work, we device a simplified approach, based on experimental systems, to predict the deformation path of a blister under various conditions. For this, we consider the problem of a growing blister made of a rubber-like membrane adhered on a rigid substrate, and develop a theoretical and experimental framework to study its stability and growth. We start by constructing a theoretical model of viscoelastic blister growth which we later validate with an experimental setup. We show that blister growth is controlled by the competition between two instabilities: one inherent to the rubber, and a second one pertaining to the adhesion with the substrate. Using these concepts, we show that a "targeted" stable blister shape can be achieved by controlling two parameters: the thickness of the film and the inflation rate.


Assuntos
Simulação por Computador , Membranas Artificiais , Modelos Teóricos , Adsorção , Elasticidade , Cinética , Propriedades de Superfície , Termodinâmica , Viscosidade
15.
Phys Chem Chem Phys ; 21(35): 18850-18865, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31432055

RESUMO

Proton detected solid-state NMR under fast magic-angle-spinning (MAS) conditions is currently redefining the applications of solid-state NMR, in particular in structural biology. Understanding the contributions to the spectral linewidth is thereby of paramount importance. When disregarding the sample-dependent inhomogeneous contributions, the NMR proton linewidth is defined by homogeneous broadening, which has incoherent and coherent contributions. Understanding and disentangling these different contributions in multi-spin systems like proteins is still an open issue. The coherent contribution is mainly caused by the dipolar interaction under MAS and is determined by the molecular structure and the proton chemical shifts. Numerical simulation approaches based on numerically exact direct integration of the Liouville-von Neumann equation can give valuable information about the lineshape, but are limited to small spin systems (<12 spins). We present an alternative simulation method for the coherent contributions based on the rapid and partially analytic calculation of the second moments of large spin systems. We first validate the method on a simple system by predicting the 19F linewidth in CaF2 under MAS. We compare simulation results to experimental data for microcrystalline ubiquitin (deuterated 100% back-exchanged at 110 kHz and fully-protonated at 125 kHz). Our results quantitatively explain the observed linewidth per-residue basis for the vast majority of residues.


Assuntos
Simulação por Computador , Modelos Químicos , Proteínas/química , Ressonância Magnética Nuclear Biomolecular , Prótons
16.
Phys Chem Chem Phys ; 21(35): 19192-19200, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31436279

RESUMO

Despite advances, tuberculosis remains a significant infectious disease, whose mortality presents alarming numbers. Although it can be cured, the number of cases of antimicrobial resistant strains is increasing, requiring the use of less efficient second-line drugs. Capreomycin and streptomycin are part of this group, being antibiotics whose mechanism of action is the inhibition of protein synthesis when interacting with the tuberculosis bacterial ribosome. Their binding mechanisms are distinct: capreomycin is able to bind to both ribosomal (30S and 50S) subunits, whereas streptomycin binds only to the smaller one (30S). In this context, the biochemical characterization of these binding sites for a proper understanding of their complex interactions is of crucial importance to increase their efficacy. Through crystallographic data and computer simulations, in this work we calculated the interaction binding energies of capreomycin and streptomycin in complex with the tuberculosis bacterial ribosome subunits, by using density functional theory (DFT) within the molecular fractionation with conjugated caps (MFCC) approach. For capreomycin in the 30S (50S) subunit, we investigated the binding energies of 44 (30) residues presented within a pocket radius of 14 Å (30 Å). Regarding streptomycin, 60 nucleotide (25 amino acid) residues distributed up to 12.5 Å (15 Å) away from the drug in the 30S subunit (S12 protein) were taken into account. We also identify the contributions of hydrogen bonds and hydrophobic interactions in the drug-receptor complex, and the regions of the drugs that most contributed to the anchorages of them in their binding sites, as well as identify residues that are most associated with mutations.


Assuntos
Antibacterianos/química , Capreomicina/química , Metabolismo Energético , Mycobacterium tuberculosis/metabolismo , Subunidades Ribossômicas/química , Subunidades Ribossômicas/metabolismo , Estreptomicina/química , Antibacterianos/metabolismo , Antibacterianos/uso terapêutico , Capreomicina/metabolismo , Capreomicina/uso terapêutico , Simulação por Computador , Cristalização , Humanos , Mutação , Mycobacterium tuberculosis/química , Receptores de Droga/genética , Receptores de Droga/metabolismo , Estreptomicina/metabolismo , Estreptomicina/uso terapêutico , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
17.
Pharm Res ; 36(10): 146, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396727

RESUMO

PURPOSE: CTB-001, a recently developed generic version of bivalirudin, an FDA-approved anticoagulant used for prophylaxis and treatment of cardiovascular diseases, has shown good efficacy and safety in clinical trials. We characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of CTB-001 by modeling and simulation analysis. METHODS: PK/PD data were collected from a randomized, double-blind, placebo-controlled, single-dose, dose-escalation phase 1 study conducted in 24 healthy Korean male subjects. PK/PD analysis was conducted sequentially by nonlinear mixed-effects modeling implemented in NONMEM®. Monte-Carlo simulations were conducted for PK, activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT). RESULTS: The CTB-101 PK was best described by a three-compartment linear model with a saturable binding peripheral compartment. All PD endpoints showed dose-response relationship, and their changes over time paralleled those of CTB-101 concentrations. A simple maximum effect model best described the aPTT, PT in INR, PT in seconds, and TT, whereas an inhibitory simple maximum effect model best described PT in percentages. The maximum duration of effect of CTB-001 on aPTT prolongation was 52.1 s. CONCLUSIONS: The modeling and simulation analysis well-characterized the PK and PD of CTB-001 in healthy Koreans, which will be valuable for identifying optimal dosing regimens of CBT-001.


Assuntos
Anticoagulantes/farmacologia , Hirudinas/farmacologia , Modelos Biológicos , Fragmentos de Peptídeos/farmacologia , Adulto , Anticoagulantes/farmacocinética , Simulação por Computador , Relação Dose-Resposta a Droga , Método Duplo-Cego , Medicamentos Genéricos , Hirudinas/farmacocinética , Humanos , Masculino , Método de Monte Carlo , Fragmentos de Peptídeos/farmacocinética , Tempo de Protrombina , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Resultado do Tratamento , Adulto Jovem
18.
Genet Sel Evol ; 51(1): 34, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262251

RESUMO

BACKGROUND: Milk quality in dairy cattle is routinely assessed via analysis of mid-infrared (MIR) spectra; this approach can also be used to predict the milk's cheese-making properties (CMP) and composition. When this method of high-throughput phenotyping is combined with efficient imputations of whole-genome sequence data from cows' genotyping data, it provides a unique and powerful framework with which to carry out genomic analyses. The goal of this study was to use this approach to identify genes and gene networks associated with milk CMP and composition in the Montbéliarde breed. RESULTS: Milk cheese yields, coagulation traits, milk pH and contents of proteins, fatty acids, minerals, citrate, and lactose were predicted from MIR spectra. Thirty-six phenotypes from primiparous Montbéliarde cows (1,442,371 test-day records from 189,817 cows) were adjusted for non-genetic effects and averaged per cow. 50 K genotypes, which were available for a subset of 19,586 cows, were imputed at the sequence level using Run6 of the 1000 Bull Genomes Project (comprising 2333 animals). The individual effects of 8.5 million variants were evaluated in a genome-wide association study (GWAS) which led to the detection of 59 QTL regions, most of which had highly significant effects on CMP and milk composition. The results of the GWAS were further subjected to an association weight matrix and the partial correlation and information theory approach and we identified a set of 736 co-associated genes. Among these, the well-known caseins, PAEP and DGAT1, together with dozens of other genes such as SLC37A1, ALPL, MGST1, SEL1L3, GPT, BRI3BP, SCD, GPAT4, FASN, and ANKH, explained from 12 to 30% of the phenotypic variance of CMP traits. We were further able to identify metabolic pathways (e.g., phosphate and phospholipid metabolism and inorganic anion transport) and key regulator genes, such as PPARA, ASXL3, and bta-mir-200c that are functionally linked to milk composition. CONCLUSIONS: By using an approach that integrated GWAS with network and pathway analyses at the whole-genome sequence level, we propose candidate variants that explain a substantial proportion of the phenotypic variance of CMP traits and could thus be included in genomic evaluation models to improve milk CMP in Montbéliarde cows.


Assuntos
Bovinos/genética , Queijo , Estudo de Associação Genômica Ampla/veterinária , Leite/química , Animais , Simulação por Computador , Conjuntos de Dados como Assunto , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Masculino , Locos de Características Quantitativas , Sequenciamento Completo do Genoma/veterinária
19.
JAMA ; 322(1): 81, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31265091
20.
JAMA ; 322(1): 81, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31265092
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