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1.
J Hazard Mater ; : 121556, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711724

RESUMO

The widespread contamination and high poisonousness have created significant concerns and thus demands for facile, rapid and selective monitoring of trace Hg2+. Inspired from the unique aggregation-induced emission (AIE) feature, in the current study, novel tetraphenylethylene (TPE) derivatives are prepared containing sulfonic groups for water solubility modulation and carboxyl dithioacetals for Hg2+ sensing. The TPE derivatives are grafted on electrospun fiber as test papers to initiate the AIE activities, while the Hg2+-specific cleavage of dithioacetal groups leads to the release of TPE derivatives and fluorescence turn-off. The decrease in the fluorescence intensities of fibrous mats could be fitted with Hg2+ levels for quantitative analysis, and the fibrous mats turn from green to bluish-green and then to blue in the presence of different Hg2+ levels. The limit of detection (LOD) reaches as low as 20 nM Hg2+, satisfying the threshold detection in drinking water, and the Hg2+ sensing indicates negligible interference from other metal ions and pH variations. The detected Hg2+ levels in lake water are consistent with the added amount with a recovery rate of over 98 %. It demonstrates a feasible strategy to integrate Hg2+-cleavable AIE probes on fibrous strips for real-time, highly specific and naked-eye detection of trace Hg2+.

2.
J Med Chem ; 62(21): 9931-9946, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31638797

RESUMO

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

3.
Nanoscale ; 11(38): 17831-17840, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31552986

RESUMO

The rapid and sensitive identification of bacteria has long been a major challenge in quality control, environmental monitoring and food safety. In the current study, the "motion-capture-lighting" strategy is proposed via integration of motion-enhanced capture of bacteria and capture-induced fluorescence turn-on of micromotors. Compared with the commonly used microtubes and microparticles, micromotors of flexible fiber rods could offer multiple interactions with the bacterial surface with less steric hindrance. Janus fiber rods (JFRs) are prepared by cryocutting of aligned fibers prepared by side-by-side electrospinning. Catalase is grafted on one side of JFRs to produce oxygen bubbles for propulsion of Janus micromotors (JMs), and mannose is conjugated on the other side for specific recognition of FimH proteins from fimbriae on the bacterial surface. The biphasic Janus structure of JFRs and the separate grafting of catalase and mannose on the opposite sides of JMs are confirmed after fluorescent labelling. JMs with aspect ratios of 0.5, 1, 2 and 4 are fabricated, and the aspect ratios of JMs show significant effects on the tracking trajectories and motion speed. JMs with the aspect ratio of 2 exhibit significantly higher magnitudes of mean square displacement (MSD) with a directional motion trajectory, leading to higher bacterial capture and larger fluorescence intensity changes. The bacteria capture leads to lighting up of JMs due to the aggregation-induced emission (AIE) effect of tetraphenylethene (TPE) derivatives. Under an ultraviolet lamp, the fluorescence color of JM suspensions turns from blue to bluish-green and to green after incubation with E. coli of 102 and 105 CFU mL-1, respectively. The fluorescence intensities of JM suspensions could be fitted to an equation versus bacterial concentrations, and the limit of detection (LOD) was around 45 CFU mL-1 within 1 min. Thus, this study demonstrates a motion-capture-lighting strategy for visual, rapid and real-time detection of bacteria without complicated sample pretreatment, expensive apparatus, and trained operators.

4.
Radiat Res ; 192(4): 399-409, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31373872

RESUMO

In a large-scale radiological incident, rapid and high-throughput biodosimetry would be needed. Gene expression-based biodosimetry is a promising approach to determine the dose received after radiation exposure. We previously identified 35 candidate genes as biodosimetry markers based on a systematic review. The goal of the current study was to establish and validate a specific gene expression-based radiological biodosimetry using a panel of highly radioresponsive genes in human peripheral blood for improving the accuracy of dose estimation. Human peripheral blood samples from 30 adult donors were irradiated to 0, 0.5, 1, 2, 3, 4, 6 and 8 Gy with 60Co γ rays at a dose rate of 1 Gy/min. We examined the expression patterns of candidate genes using real-time polymerase chain reaction (qRT-PCR) at 6, 12, 24 and 48 h postirradiation. Stepwise regression analysis was employed to develop the gene expression-based dosimetry models at each time point. Samples from another 10 healthy donors (blind samples) and four total-body irradiated (TBI) patients were used to validate the radiation dosimetry models. We observed significant linear dose-response relationships of CDKN1A, BAX, MDM2, XPC, PCNA, FDXR, GDF-15, DDB2, TNFRSF10B, PHPT1, ASTN2, RPS27L, BBC3, TNFSF4, POLH, CCNG1, PPM1D and GADD45A in human peripheral blood at the various time points. However, the expression levels of these genes were affected by inter-individual variations and gender. We found that the gender-dependent regression models could explain 0.85 of variance at 24 h postirradiation and could also accurately estimate the absorbed radiation doses with dose range of 0-5 Gy, in human peripheral blood samples irradiated ex vivo and from TBI patients, respectively. This study demonstrates that developing gender-specific biodosimetry based on a panel of highly radioresponsive genes may help advance the application of gene expression signature for dose estimation in the event of a radiological accident or in clinical treatment.

5.
BMC Cardiovasc Disord ; 19(1): 144, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200660

RESUMO

BACKGROUND: Using the current meta-analysis as well as systematic review, to determine the curative effect of Nicorandil in comparison of no Nicorandil after elective percutaneous coronary intervention(PCI) on patients. METHODS: Published literatures were identified via a computerized literature search of CENTRAL, PubMed, Cochrane, Embase Databases of Systematic Reviews. A set of randomized trials evaluating Nicorandil in comparison of no Nicorandil administered following PCI in patients harboring coronary artery disease were included. Outcomes were revealed based on the following parameters: peak creatine kinase-MB (CK-MB) value, left ventricular ejection fraction (LVEF), peak troponin I (cTnI), and major adverse cardiovascular events (MACEs) per randomized patients. RESULTS: We included a total of 14 RCTs involving 1864 subjects in the present review. According to this meta-analysis, LVEF was significantly improved in Nicorandil group; the peak CK-MB level and the incidence of adverse cardiovascular events were remarkably lower in Nicorandil group. Nicorandil and no Nicorandil administered group appeared to be equivalent with regards to cTnI. CONCLUSIONS: Nicorandil is effective for patients undergoing elective PCI with coronary artery disease in terms of reducing the incidence of adverse cardiovascular events as well as improving heart function. Nicorandil may exert potential role as a valid and adjunctive therapy accompanied with PCI.

6.
Nanotechnology ; 30(37): 375301, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31195376

RESUMO

Electrospinning is becoming an efficient method to produce fibers in the submicron range, but the bending instability of conventional electrospinning system (CES) brings limitations in the distinctive deposition of electrospun fibers. Herein, we proposed a strategy to update the electrospinning system through establishment of a uniform electric field, realizing 3D printing of electrospun fibers with well-controlled, low-cost, and template-free manners. The uniform field electrospinning (UFES) apparatus is configured by inserting the electrospinning nozzle into the center of an aided metal plate. The electric field simulation of UFES indicates a uniform distribution between the aided metal plate and the collector, while a diverging and weaker electric field is produced by CES. The collector of UFES is mounted on a translation stage, which moves along x and y axes under computer control. The distinctive deposition of electrospun fibers produces fibrous mats with rectangular patterns of different grid sizes, and butterfly and TaiJi figures with high resolutions are directly written by UFES. The layer-by-layer deposition of electrospun fibers under UFES produces microscale Mongolian yurts with distinct hollow structure. Fibrous blocks with an average width of 120 µm and height of 630 µm were printed by UFES from conductive polymer composites and constructed into strain sensors. The electric current strength of fibrous microblocks changes sharply in response to the finger bending and release, indicating the capability to monitor human motions. Thus, this study demonstrates that the UFES becomes an easy-handling strategy for 3D printing of electrospun fibers to create complex geometries.

7.
J Med Chem ; 62(7): 3228-3250, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30893553

RESUMO

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

8.
Sensors (Basel) ; 19(2)2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30650645

RESUMO

Building damage accounts for a high percentage of post-natural disaster assessment. Extracting buildings from optical remote sensing images is of great significance for natural disaster reduction and assessment. Traditional methods mainly are semi-automatic methods which require human-computer interaction or rely on purely human interpretation. In this paper, inspired by the recently developed deep learning techniques, we propose an improved Mask Region Convolutional Neural Network (Mask R-CNN) method that can detect the rotated bounding boxes of buildings and segment them from very complex backgrounds, simultaneously. The proposed method has two major improvements, making it very suitable to perform building extraction task. Firstly, instead of predicting horizontal rectangle bounding boxes of objects like many other detectors do, we intend to obtain the minimum enclosing rectangles of buildings by adding a new term: the principal directions of the rectangles θ. Secondly, a new layer by integrating advantages of both atrous convolution and inception block is designed and inserted into the segmentation branch of the Mask R-CNN to make the branch to learn more representative features. We test the proposed method on a newly collected large Google Earth remote sensing dataset with diverse buildings and very complex backgrounds. Experiments demonstrate that it can obtain promising results.

9.
Bioorg Med Chem Lett ; 28(18): 3080-3084, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30097367

RESUMO

Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2,3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight.

10.
Opt Express ; 26(16): 20929-20943, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30119400

RESUMO

We investigate the topological phase transition between Type-I and Type-II Weyl points (WPs) in a composite three-dimensional lattice composed of a two-dimensional brick-wall waveguide array and a synthetic frequency dimension created by dynamic modulation. By imposing different modulation amplitudes and phases in the two sublattices, we can break either parity or time-reversal symmetry and realize the phase transition between Type-I and Type-II WPs. As the array is truncated to have two edges, two Fermi-arc surface states will emerge, which propagate in opposite directions for Type-I WPs while in same directions for Type-II WPs, accompanied by bidirectional and unidirectional frequency shifts for the optical modes. Particularly at the phase transition point, we find that one of two bands becomes flat with a vanished group velocity along frequency axis in the vicinity of WPs. The study paves a way towards realizing different topological phases in the same photonic structure, which offers new opportunities to control wave transportation both in spatial and frequency domains.

11.
Mutat Res ; 832-833: 29-34, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30057018

RESUMO

Baseline nucleoplasmic bridges (NPB) vary widely in the general population from different regions in the same country or from different countries. The baseline NPB level in the normal Chinese population and the factors affecting the baseline and radiation-induced NPB levels have not been explored yet. The cytokinesis-block micronucleus cytome assay was conducted on the peripheral blood samples of 121 healthy individuals for the baseline NPB and 52 healthy individuals for the 2 Gy γ-ray-induced NPB level. The effects of age and gender on the baseline NPB and 2 Gy γ-ray-induced NPB level were evaluated. The overall baseline NPB in the peripheral blood lymphocytes of 121 healthy adults from the general population in China was 0.46 ±â€¯0.20 per 1000 binucleated (BN) cells. The overall baseline NPB in males (0.56 ±â€¯0.15 per 1000 BN cells) was higher than that in females (0.36 ±â€¯0.22 per 1000 BN cells, P < 0.05). The effect of age on the baseline NPB was not significant, except for females in the 40-year age group. The overall 2 Gy γ-ray-induced NPB frequency for male donors was lower than that for female donors (P < 0.01). No evident trend of the radiation-induced NPB level with increasing age was observed for both genders. For the baseline micronucleus (MN) and radiation-induced MN levels, the effects of gender and age were confirmed. Therefore, the gender of donors affects the baseline and radiation-induced levels of NPB and MN. In addition, the effect of the age of the donors on the baseline and radiation-induced NPB levels showed no clear pattern and needed to be further investigated.

12.
Radiat Environ Biophys ; 57(3): 215-222, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29774413

RESUMO

Chromosome damage is related to DNA damage and erroneous repair. It can cause cell dysfunction and ultimately induce carcinogenesis. Histone acetylation is crucial for regulating chromatin structure and DNA damage repair. Ionizing radiation (IR) can alter histone acetylation. However, variations in histone acetylation in response to IR exposure and the relationship between histone acetylation and IR-induced chromosome damage remains unclear. Hence, this study investigated the variation in the total acetylation levels of H3 and H4 in human lymphocytes exposed to 0-2 Gy 60Co γ-rays. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, was added to modify the histone acetylation state of irradiated cells. Then, the total acetylation level, enzyme activity, dicentric plus centric rings (dic + r) frequencies, and micronucleus (MN) frequencies of the treated cells were analyzed. Results indicated that the acetylation levels of H3 and H4 significantly decreased at 1 and 24 h, respectively, after radiation exposure. The acetylation levels of H3 and H4 in irradiated groups treated with SAHA were significantly higher than those in irradiated groups that were not treated with SAHA. SAHA treatment inhibited HDAC activity in cells exposed to 0-1 Gy 60Co γ-rays. SAHA treatment significantly decreased dic + r/cell and MN/cell in cells exposed to 0.5 or 1.0 Gy 60Co γ-rays relative to that in cells that did not receive SAHA treatment. In conclusion, histone acetylation is significantly affected by IR and is involved in chromosome damage induced by 60Co γ-radiation.


Assuntos
Cromossomos Humanos/genética , Radioisótopos de Cobalto/efeitos adversos , Raios gama/efeitos adversos , Histonas/metabolismo , Linfócitos/efeitos da radiação , Acetilação/efeitos dos fármacos , Acetilação/efeitos da radiação , Linhagem Celular , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Vorinostat
13.
Nanoscale Res Lett ; 13(1): 108, 2018 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-29675565

RESUMO

Oil wettability in the water-oil-rock systems is very sensitive to the evolution of surface charges on the rock surfaces induced by the adsorption of ions and other chemical agents in water flooding. Through a set of large-scale molecular dynamics simulations, we reveal the effects of surface charge on the oil contact angles in an ideal water-decane-silicon dioxide system. The results show that the contact angles of oil nano-droplets have a great dependence on the surface charges. As the surface charge density exceeds a critical value of 0.992 e/nm2, the contact angle reaches up to 78.8° and the water-wet state is very apparent. The variation of contact angles can be confirmed from the number density distributions of oil molecules. With increasing the surface charge density, the adsorption of oil molecules weakens and the contact areas between nano-droplets and silicon dioxide surface are reduced. In addition, the number density distributions, RDF distributions, and molecular orientations indicate that the oil molecules are adsorbed on the silicon dioxide surface layer-by-layer with an orientation parallel to the surface. However, the layered structure of oil molecules near the silicon dioxide surface becomes more and more obscure at higher surface charge densities.

14.
Opt Express ; 26(3): 2817-2828, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29401817

RESUMO

We theoretically investigate the Goos-Hänchen (GH) shifts of optical beam in a defective photonic crystal composed of dielectric multilayers and graphene. The system is non-Hermitian and possesses exceptional points (EPs) as the scattering matrix becomes defective at the zero points of reflection. The reflective wave at EPs experiences an abrupt phase change and there the eigenvalues of scattering matrix coalesce. The GH shifts are extremely large near EPs in parametric space composed of dielectric refractive index and incident angle. The positive and negative maxima of GH shifts could be as high as 103 times of the incident wavelength. The direction of GH shifts switches at EPs and the EPs position can be readily controlled by the chemical potential of graphene. Moreover, the GH shifts should remarkably change as the incident waves impinge on the structure from opposite directions. The study of GH shifts in the graphene incorporated multilayers may find great applications in highly sensitive sensors.

15.
J Med Chem ; 60(12): 5193-5208, 2017 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-28541707

RESUMO

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.


Assuntos
Artrite Experimental/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Relação Estrutura-Atividade , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Células CACO-2/efeitos dos fármacos , Células CACO-2/imunologia , Cães , Canal de Potássio ERG1/metabolismo , Inibidores Enzimáticos/química , Feminino , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Coelhos
16.
Mol Med Rep ; 15(6): 3599-3606, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28440431

RESUMO

The identification of rapid, sensitive and high­throughput biomarkers is imperative in order to identify individuals harmed by radiation accidents, and accurately evaluate the absorbed doses of radiation. DNA microarrays have previously been used to evaluate the alterations in growth/differentiation factor 15 (GDF15) gene expression in AHH­1 human lymphoblastoid cells, following exposure to γ­rays. The present study aimed to characterize the relationship between the dose of ionizing radiation and the produced effects in GDF­15 gene expression in AHH­1 cells and human peripheral blood lymphocytes (HPBLs). GDF­15 mRNA and protein expression levels following exposure to γ­rays and neutron radiation were assessed by reverse transcription­quantitative polymerase chain reaction and western blot analysis in AHH­1 cells. In addition, alterations in GDF­15 gene expression in HPBLs following ex vivo irradiation were evaluated. The present results demonstrated that GDF­15 mRNA and protein expression levels in AHH­1 cells were significantly upregulated following exposure to γ­ray doses ranging between 1 and 10 Gy, regardless of the dose rate. A total of 48 h following exposure to neutron radiation, a dose­response relationship was identified in AHH­1 cells at γ­ray doses between 0.4 and 1.6 Gy. GDF­15 mRNA levels in HPBLs were significantly upregulated following exposure to γ­ray doses between 1 and 8 Gy, within 4­48 h following irradiation. These results suggested that significant time­ and dose­dependent alterations in GDF­15 mRNA and protein expression occur in AHH­1 cells and HPBLs in the early phases following exposure to ionizing radiation. In conclusion, alterations in GDF­15 gene expression may have potential as a biomarker to evaluate radiation exposure.


Assuntos
Regulação da Expressão Gênica/efeitos da radiação , Fator 15 de Diferenciação de Crescimento/genética , Linfócitos/metabolismo , Linfócitos/efeitos da radiação , Radiação Ionizante , Adulto , Linhagem Celular Tumoral , Relação Dose-Resposta à Radiação , Raios gama , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Masculino , Nêutrons , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
Opt Express ; 25(7): 7203-7212, 2017 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-28380845

RESUMO

We investigate the optical exceptional points (EPs) in the graphene incorporated multilayer metamaterial manifesting Fano resonance. The system is non-Hermitian and possesses EPs where both the eigenvalues and eigenvectors of the Hamiltonian coalesce. In the aid of Fano resonance, the reflection may reach minimum approaching to zero, resulting in the degeneration of both eigenvalues and eigenvectors and thus the emergence of EPs. The transmission and reflection of light through the metamaterial change sharply by varying slightly the incident wavelength and chemical potential of graphene in the parameter space when encircling the EPs. In addition, the unidirectional invisibility can be achieved at EPs. The study paves a way to precisely controlling the transmission and reflection through metamaterials and may find applications in optoelectronic switches, modulators, absorbers, and optical sensors.

18.
Nanoscale ; 9(15): 4950-4962, 2017 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-28382363

RESUMO

The spatial arrangement of cardiac myocytes (CMs) and other non-myocytes scaffolds, closely resembling native tissue, is essential to control the CM morphology and function for cardiac tissue regeneration. In the current study, micropatterned fibrous scaffolds were developed to establish a CM co-culture system with cardiac fibroblasts (CFs) and endothelial cells (ECs) as a potential in vitro drug screening model. To pursue a biomimetic approach to influence CM behaviors, strip, oval and wave-patterned mats were constructed by deposition of electrospun fibers on lithographic collectors, followed by precise stacking for cell co-cultures. CMs, CFs, and ECs were located on the patterned scaffolds with controlled cellular distribution in the respective regions and no across condition was found. Compared with those after strip and oval-patterned co-culture, CMs co-cultured on wave-patterned scaffolds displayed significantly greater cell viabilities, larger cell elongation ratios, stronger expressions of cardiac-specific Troponin I, connexin 43 and sarcomeric α-actinin and higher beating rates during 15 days of incubation. The responses of co-cultured CMs to quinidine, erythromycin and sotalol show good correlations with clinical observations in the beating rate and the prolongation of the contraction and relaxation time. The in vivo safety data reflected well with the concentrations for 50% of maximal effect (EC50) after drug treatment on co-cultured CMs, which was determined from the changes in the corrected field potential duration (FPDc) against the drug concentrations. During 15 days of patterned co-culture, the interbeat intervals and fluctuations of the CMs indicated quick changes in response to haloperidol treatment and sufficient restoration of the original beating profiles after drug removal. This study demonstrates the capabilities of micropatterned co-culture of CMs to establish the cardiac function as a reproducible and reliable platform for screening cardiac side effects of drugs.


Assuntos
Técnicas de Cocultura , Células Endoteliais/citologia , Fibroblastos/citologia , Miócitos Cardíacos/citologia , Animais , Cardiotoxicidade , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Ratos Sprague-Dawley , Engenharia Tecidual
19.
Sensors (Basel) ; 16(11)2016 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-27879661

RESUMO

This study explores the ability of WorldView-2 (WV-2) imagery for bamboo mapping in a mountainous region in Sichuan Province, China. A large area of this place is covered by shadows in the image, and only a few sampled points derived were useful. In order to identify bamboos based on sparse training data, the sample size was expanded according to the reflectance of multispectral bands selected using the principal component analysis (PCA). Then, class separability based on the training data was calculated using a feature space optimization method to select the features for classification. Four regular object-based classification methods were applied based on both sets of training data. The results show that the k-nearest neighbor (k-NN) method produced the greatest accuracy. A geostatistically-weighted k-NN classifier, accounting for the spatial correlation between classes, was then applied to further increase the accuracy. It achieved 82.65% and 93.10% of the producer's and user's accuracies respectively for the bamboo class. The canopy densities were estimated to explain the result. This study demonstrates that the WV-2 image can be used to identify small patches of understory bamboos given limited known samples, and the resulting bamboo distribution facilitates the assessments of the habitats of giant pandas.


Assuntos
Conservação dos Recursos Naturais/métodos , Ecossistema , Animais , China , Ursidae
20.
J Med Chem ; 59(19): 9173-9200, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27583770

RESUMO

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.


Assuntos
Carbazóis/química , Carbazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Carbazóis/farmacocinética , Cristalografia por Raios X , Feminino , Humanos , Isomerismo , Macaca fascicularis , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Relação Estrutura-Atividade
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