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1.
Plant Cell ; 32(1): 166-185, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31690653

RESUMO

Multiple long-distance signals have been identified for pathogen-induced systemic acquired resistance, but mobile signals for symbiont-induced systemic resistance (ISR) are less well understood. We used ISR-positive and -negative mutants of maize (Zea mays) and the beneficial fungus Trichoderma virens and identified 12-oxo-phytodienoic acid (12-OPDA) and α-ketol of octadecadienoic acid (KODA) as important ISR signals. We show that a maize 13-lipoxygenase mutant, lox10, colonized by the wild-type T. virens (TvWT) lacked ISR response against Colletotrichum graminicola but instead displayed induced systemic susceptibility. Oxylipin profiling of xylem sap from T. virens-treated plants revealed that 12-OPDA and KODA levels correlated with ISR. Transfusing sap supplemented with 12-OPDA or KODA increased receiver plant resistance in a dose-dependent manner, with 12-OPDA restoring ISR of lox10 plants treated with TvWT or T. virens Δsm1, a mutant unable to induce ISR. Unexpectedly, jasmonic acid (JA) was not involved, as the JA-deficient opr7 opr8 mutant plants retained the capacity for T. virens-induced ISR. Transcriptome analysis of TvWT-treated maize B73 revealed upregulation of 12-OPDA biosynthesis and OPDA-responsive genes but downregulation of JA biosynthesis and JA response genes. We propose a model that differential regulation of 12-OPDA and JA in response to T. virens colonization results in ISR induction.

2.
Clin Pharmacol Ther ; 107(1): 102-111, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31709525

RESUMO

This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and Drug Administration-sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model-based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31738948

RESUMO

PURPOSE: The cone-beam computed tomography (CBCT)-guided small animal radiation research platform (SARRP) has provided unique opportunities to test radiobiologic hypotheses. However, CBCT is less adept to localize soft tissue targets growing in a low imaging contrast environment. Three-dimensional bioluminescence tomography (BLT) provides strong image contrast and thus offers an attractive solution. We introduced a novel and efficient BLT-guided conformal radiation therapy and demonstrated it in an orthotopic glioblastoma (GBM) model. METHODS AND MATERIALS: A multispectral BLT system was integrated with SARRP for radiation therapy (RT) guidance. GBM growth curve was first established by contrast CBCT/magnetic resonance imaging (MRI) to derive equivalent sphere as approximated gross target volume (aGTV). For BLT, mice were subject to multispectral bioluminescence imaging, followed by SARRP CBCT imaging and optical reconstruction. The CBCT image was acquired to generate anatomic mesh for the reconstruction and RT planning. To ensure high accuracy of the BLT-reconstructed center of mass (CoM) for target localization, we optimized the optical absorption coefficients µa by minimizing the distance between the CoMs of BLT reconstruction and contrast CBCT/MRI-delineated GBM volume. The aGTV combined with the uncertainties of BLT CoM localization and target volume determination was used to generate estimated target volume (ETV). For conformal irradiation procedure, the GBM was first localized by the predetermined ETV centered at BLT-reconstructed CoM, followed by SARRP radiation. The irradiation accuracy was qualitatively confirmed by pathologic staining. RESULTS: Deviation between CoMs of BLT reconstruction and contrast CBCT/MRI-imaged GBM is approximately 1 mm. Our derived ETV centered at BLT-reconstructed CoM covers >95% of the tumor volume. Using the second-week GBM as an example, the ETV-based BLT-guided irradiation can cover 95.4% ± 4.7% tumor volume at prescribed dose. The pathologic staining demonstrated the BLT-guided irradiated area overlapped well with the GBM location. CONCLUSIONS: The BLT-guided RT enables 3-dimensional conformal radiation for important orthotopic tumor models, which provides investigators a new preclinical research capability.

4.
Biophys J ; 117(12): 2438-2454, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31447109

RESUMO

Predicting how pharmaceuticals may affect heart rhythm is a crucial step in drug development and requires a deep understanding of a compound's action on ion channels. In vitro hERG channel current recordings are an important step in evaluating the proarrhythmic potential of small molecules and are now routinely performed using automated high-throughput patch-clamp platforms. These machines can execute traditional voltage-clamp protocols aimed at specific gating processes, but the array of protocols needed to fully characterize a current is typically too long to be applied in a single cell. Shorter high-information protocols have recently been introduced that have this capability, but they are not typically compatible with high-throughput platforms. We present a new 15 second protocol to characterize hERG (Kv11.1) kinetics, suitable for both manual and high-throughput systems. We demonstrate its use on the Nanion SyncroPatch 384PE, a 384-well automated patch-clamp platform, by applying it to Chinese hamster ovary cells stably expressing hERG1a. From these recordings, we construct 124 cell-specific variants/parameterizations of a hERG model at 25°C. A further eight independent protocols are run in each cell and are used to validate the model predictions. We then combine the experimental recordings using a hierarchical Bayesian model, which we use to quantify the uncertainty in the model parameters, and their variability from cell-to-cell; we use this model to suggest reasons for the variability. This study demonstrates a robust method to measure and quantify uncertainty and shows that it is possible and practical to use high-throughput systems to capture full hERG channel kinetics quantitatively and rapidly.

5.
Biophys J ; 117(12): 2455-2470, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31451180

RESUMO

Ion channel behavior can depend strongly on temperature, with faster kinetics at physiological temperatures leading to considerable changes in currents relative to room temperature. These temperature-dependent changes in voltage-dependent ion channel kinetics (rates of opening, closing, inactivating, and recovery) are commonly represented with Q10 coefficients or an Eyring relationship. In this article, we assess the validity of these representations by characterizing channel kinetics at multiple temperatures. We focus on the human Ether-à-go-go-Related Gene (hERG) channel, which is important in drug safety assessment and commonly screened at room temperature so that results require extrapolation to physiological temperature. In Part I of this study, we established a reliable method for high-throughput characterization of hERG1a (Kv11.1) kinetics, using a 15-second information-rich optimized protocol. In this Part II, we use this protocol to study the temperature dependence of hERG kinetics using Chinese hamster ovary cells overexpressing hERG1a on the Nanion SyncroPatch 384PE, a 384-well automated patch-clamp platform, with temperature control. We characterize the temperature dependence of hERG gating by fitting the parameters of a mathematical model of hERG kinetics to data obtained at five distinct temperatures between 25 and 37°C and validate the models using different protocols. Our models reveal that activation is far more temperature sensitive than inactivation, and we observe that the temperature dependency of the kinetic parameters is not represented well by Q10 coefficients; it broadly follows a generalized, but not the standardly-used, Eyring relationship. We also demonstrate that experimental estimations of Q10 coefficients are protocol dependent. Our results show that a direct fit using our 15-s protocol best represents hERG kinetics at any given temperature and suggests that using the Generalized Eyring theory is preferable if no experimental data are available to derive model parameters at a given temperature.

6.
J Am Coll Radiol ; 16(10): 1464-1470, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31319078

RESUMO

Artificial intelligence (AI) will reshape radiology over the coming years. The radiology community has a strong history of embracing new technology for positive change, and AI is no exception. As with any new technology, rapid, successful implementation faces several challenges that will require creation and adoption of new integration technology. Use cases important to real-world application of AI are described, including clinical registries, AI research, AI product validation, and computer assistance for radiology reporting. Furthermore, the informatics technologies required for successful implementation of the use cases are described, including open Computer-Assisted Radiologist Decision Support, ACR Assist, ACR Data Science Institute use cases, common data elements (radelement.org), RadLex (radlex.org), LOINC/RSNA RadLex Playbook (loinc.org), and Radiology Report Templates (radreport.org).

7.
Pract Radiat Oncol ; 9(6): e591-e598, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31252089

RESUMO

PURPOSE: Nonhomogeneous dose optimization (NHDO) is exploited in stereotactic body radiation therapy (SBRT) to increase dose delivery to the tumor and allow rapid dose falloff to surrounding normal tissues. We investigate changes in plan quality when NHDO is applied to inverse-planned conventionally fractionated radiation therapy (CF-RT) plans in patients with non-small cell lung cancer. METHODS AND MATERIALS: Patients with near-central non-small cell lung cancer treated with CF-RT in 2018 at a single institution were identified. CF-RT plans were replanned using NHDO techniques, including normalizing to a lower isodose line, while maintaining clinically acceptable normal tissue constraints and target coverage. Tumor control probabilities were calculated. We compared delivered CF-RT plans using homogenous dose optimization (HDO) versus NHDO using Wilcoxon signed-rank tests. Median values are reported. RESULTS: Thirteen patients were replanned with NHDO techniques. Planning target volume coverage by the prescription dose was similar (NHDO = 96% vs HDO = 97%, P = .3). All normal-tissue dose constraints were met. NHDO plans were prescribed to a lower-prescription isodose line compared with HDO plans (85% vs 97%, P = .001). NHDO increased mean dose to the planning target volume (73 Gy vs 67 Gy), dose heterogeneity, and dose falloff gradient (P < .03). NHDO decreased mean dose to surrounding lungs, esophagus, and heart (relative reduction of 6%, 14%, and 15%, respectively; P < .05). Other normal tissue objectives improved with NHDO, including total lung V40 and V60, heart V30, and maximum esophageal dose (P < .05). Tumor control probabilities doubled from 31.6% to 65.4% with NHDO (P = .001). CONCLUSIONS: In select patients, NHDO principles used in SBRT optimization can be applied to CF-RT. NHDO results in increased tumor dose, reduction in select organ-at-risk dose objectives, and better maintenance of target coverage and normal-tissue constraints compared with HDO. Our data demonstrate that principles of NHDO used in SBRT can also improve plan quality in CF-RT.

8.
Environ Pollut ; 250: 196-205, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30995573

RESUMO

In recent years, water pollution caused by radionuclides has become a rising concern, among which uranium is a representative class of actinide element. Since hexavalent uranium, i.e. U(VI), is biologically hazardous with high migration, it's essential to develop efficient adsorbents to minimize the impact on the environment. Towards this end, we have synthesized a novel material (GO/PEDOT:PSS) by direct assembling graphene oxide (GO) and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) through a facile ball milling method, which shows impressing performance for the immobilization of U(VI). On the basis of the batch experiments, GO/PEDOT:PSS exhibits ionic strength-independent sorption edges and temperature-promoted sorption isotherms, revealing an inner-sphere complexation with endothermic nature. The sorption kinetics can be illustrated by the pseudo-second-order model, yielding a rate constant of 1.09. × 10-2 g mg-1∙min-1, while the sorption isotherms are in coincidence with the Langmuir model, according to which the maximum sorption capacity is measured to be 384.51 mg g-1 at pH 4.5 under 298 K, indicating a monolayer sorption mechanism. In the light of the FT-IR and XPS investigations, the surface carboxyl/sulfonate group is responsible to the chelation of U(VI), indicating that the enhanced sorption capacity may be ascribed to the PSS moiety. These findings can greatly contribute to the design strategy for developing highly efficient adsorbents in the field of radioactive wastewater treatment.


Assuntos
Nanocompostos/química , Urânio/química , Eliminação de Resíduos Líquidos/métodos , Poluentes Radioativos da Água/química , Adsorção , Compostos Bicíclicos Heterocíclicos com Pontes/química , Grafite/química , Concentração de Íons de Hidrogênio , Cinética , Polímeros/química , Poliestirenos/química , Temperatura Ambiente
9.
BMC Genomics ; 20(1): 280, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30971198

RESUMO

BACKGROUND: Trichoderma spp. are majorly composed of plant-beneficial symbionts widely used in agriculture as bio-control agents. Studying the mechanisms behind Trichoderma-derived plant benefits has yielded tangible bio-industrial products. To better take advantage of this fungal-plant symbiosis it is necessary to obtain detailed knowledge of which genes Trichoderma utilizes during interaction with its plant host. In this study, we explored the transcriptional activity undergone by T. virens during two phases of symbiosis with maize; recognition of roots and after ingress into the root cortex. RESULTS: We present a model of T. virens - maize interaction wherein T. virens experiences global repression of transcription upon recognition of maize roots and then induces expression of a broad spectrum of genes during colonization of maize roots. The genes expressed indicate that, during colonization of maize roots, T. virens modulates biosynthesis of phytohormone-like compounds, secretes a plant-environment specific array of cell wall degrading enzymes and secondary metabolites, remodels both actin-based and cell membrane structures, and shifts metabolic activity. We also highlight transcription factors and signal transduction genes important in future research seeking to unravel the molecular mechanisms of T. virens activity in maize roots. CONCLUSIONS: T. virens displays distinctly different transcriptional profiles between recognizing the presence of maize roots and active colonization of these roots. A though understanding of these processes will allow development of T. virens as a bio-control agent. Further, the publication of these datasets will target future research endeavors specifically to genes of interest when considering T. virens - maize symbiosis.


Assuntos
Perfilação da Expressão Gênica , Raízes de Plantas/microbiologia , Trichoderma/genética , Trichoderma/fisiologia , Zea mays/microbiologia , Metabolismo Energético , Trichoderma/metabolismo
10.
Nat Commun ; 10(1): 1020, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833569

RESUMO

Miniaturized spectrometers have significant potential for portable applications such as consumer electronics, health care, and manufacturing. These applications demand low cost and high spectral resolution, and are best enabled by single-shot free-space-coupled spectrometers that also have sufficient spatial resolution. Here, we demonstrate an on-chip spectrometer that can satisfy all of these requirements. Our device uses arrays of photodetectors, each of which has a unique responsivity with rich spectral features. These responsivities are created by complex optical interference in photonic-crystal slabs positioned immediately on top of the photodetector pixels. The spectrometer is completely complementary metal-oxide-semiconductor (CMOS) compatible and can be mass produced at low cost.

12.
Drug Discov Today ; 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31899257

RESUMO

Here, we introduce models at three levels-molecular level, cellular and omics level, and organ and system level-that study drug mechanism and safety in preclinical drug discovery. The models differ in both their scope of study and technical details, but are all rooted in mathematical descriptions of complex biological systems, and all require informatics tools that handle large-volume, heterogeneous, and noisy data. We present principles and recent developments with examples at each level and highlight the synergy by a case study. We proffer a multiscale modelling view of drug discovery, call for a seamless flow of information in the form of models, and examine potential impacts.

13.
Opt Lett ; 43(22): 5623-5626, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30439910

RESUMO

We present a fundamental result on the role of time-reversal symmetry in the temporal coupled-mode theory (TCMT). The TCMT is a phenomenological theory that describes resonant wave scattering in photonics, acoustics, and other fields. Modifications to the canonical formulation of the TCMT are required for nonreciprocal devices where time-reversal symmetry is usually absent. We discover that previous results on reciprocity for the TCMT are incomplete, and we provide a mathematical proof to clarify the roles of time-reversal symmetry and reciprocity in the TCMT. The new result leads to a general treatment of nonreciprocity in the TCMT. The theoretical result has many practical applications, including the design of nonreciprocal devices such as optical circulators and isolators.

14.
Nat Nanotechnol ; 13(12): 1191, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30443033

RESUMO

In the version of this Letter originally published, Zongfu Yu was mistakenly not noted as being a corresponding author; this has now been corrected in all versions of the Letter.

15.
Nat Nanotechnol ; 13(12): 1143-1147, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30374161

RESUMO

Sensing the direction of sounds gives animals clear evolutionary advantage. For large animals, with an ear-to-ear spacing that exceeds audible sound wavelengths, directional sensing is simply accomplished by recognizing the intensity and time differences of a wave impinging on its two ears1. Recent research suggests that in smaller, subwavelength animals, angle sensing can instead rely on a coherent coupling of soundwaves between the two ears2-4. Inspired by this natural design, here we show a subwarvelength photodetection pixel that can measure both the intensity and incident angle of light. It relies on an electrical isolation and optical coupling of two closely spaced Si nanowires that support optical Mie resonances5-7. When these resonators scatter light into the same free-space optical modes, a non-Hermitian coupling results that affords highly sensitive angle determination. By straightforward photocurrent measurements, we can independently quantify the stored optical energy in each nanowire and relate the difference in the stored energy between the wires to the incident angle of a light wave. We exploit this effect to fabricate a subwavelength angle-sensitive pixel with angular sensitivity, δθ = 0.32°.


Assuntos
Luz , Nanotecnologia/instrumentação , Nanofios/química , Dispositivos Ópticos , Silício/química , Animais , Biomimética , Desenho de Equipamento , Audição , Lagartos , Som
16.
J Clin Invest ; 128(11): 4924-4937, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30130254

RESUMO

Mutant KRAS drives glycolytic flux in lung cancer, potentially impacting aberrant protein glycosylation. Recent evidence suggests aberrant KRAS drives flux of glucose into the hexosamine biosynthetic pathway (HBP). HBP is required for various glycosylation processes, such as protein N- or O-glycosylation and glycolipid synthesis. However, its function during tumorigenesis is poorly understood. One contributor and proposed target of KRAS-driven cancers is a developmentally conserved epithelial plasticity program called epithelial-mesenchymal transition (EMT). Here we showed in novel autochthonous mouse models that EMT accelerated KrasG12D lung tumorigenesis by upregulating expression of key enzymes of the HBP pathway. We demonstrated that HBP was required for suppressing KrasG12D-induced senescence, and targeting HBP significantly delayed KrasG12D lung tumorigenesis. To explore the mechanism, we investigated protein glycosylation downstream of HBP and found elevated levels of O-linked ß-N-acetylglucosamine (O-GlcNAcylation) posttranslational modification on intracellular proteins. O-GlcNAcylation suppressed KrasG12D oncogene-induced senescence (OIS) and accelerated lung tumorigenesis. Conversely, loss of O-GlcNAcylation delayed lung tumorigenesis. O-GlcNAcylation of proteins SNAI1 and c-MYC correlated with the EMT-HBP axis and accelerated lung tumorigenesis. Our results demonstrated that O-GlcNAcylation was sufficient and required to accelerate KrasG12D lung tumorigenesis in vivo, which was reinforced by epithelial plasticity programs.


Assuntos
Transformação Celular Neoplásica/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares/enzimologia , Mutação de Sentido Incorreto , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Células A549 , Acilação , Substituição de Aminoácidos , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Feminino , Glucose/genética , Glucose/metabolismo , Células HEK293 , Hexosaminas/genética , Hexosaminas/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Camundongos Transgênicos , Proteínas Proto-Oncogênicas p21(ras)/genética
17.
Biomed Opt Express ; 9(9): 4163-4174, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30615705

RESUMO

Bioluminescence imaging (BLI) is a non-contact, optical imaging technique based on measurement of emitted light due to an internal source, which is then often directly related to cellular activity. It is widely used in pre-clinical small animal imaging studies to assess the progression of diseases such as cancer, aiding in the development of new treatments and therapies. For many applications, the quantitative assessment of accurate cellular activity and spatial distribution is desirable as it would enable direct monitoring for prognostic evaluation. This requires quantitative spatially-resolved measurements of bioluminescence source strength inside the animal to be obtained from BLI images. This is the goal of bioluminescence tomography (BLT) in which a model of light propagation through tissue is combined with an optimization algorithm to reconstruct a map of the underlying source distribution. As most models consider only the propagation of light from internal sources to the animal skin surface, an additional challenge is accounting for the light propagation from the skin to the optical detector (e.g. camera). Existing approaches typically use a model of the imaging system optics (e.g. ray-tracing, analytical optical models) or approximate corrections derived from calibration measurements. However, these approaches are typically computationally intensive or of limited accuracy. In this work, a new approach is presented in which, rather than directly using BLI images acquired at several wavelengths, the spectral derivative of that data (difference of BLI images at adjacent wavelengths) is used in BLT. As light at similar wavelengths encounters a near-identical system response (path through the optics etc.) this eliminates the need for additional corrections or system models. This approach is applied to BLT with simulated and experimental phantom data and shown that the error in reconstructed source intensity is reduced from 49% to 4%. Qualitatively, the accuracy of source localization is improved in both simulated and experimental data, as compared to reconstruction using the standard approach. The outlined algorithm can widely be adapted to all commercial systems without any further technological modifications.

18.
Prog Biophys Mol Biol ; 130(Pt B): 212-222, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28688751

RESUMO

RATIONALE: Impaired maturation of human iPSC-derived cardiomyocytes (hiPSC-CMs) currently limits their use in experimental research and further optimization is required to unlock their full potential. OBJECTIVE: To push hiPSC-CMs towards maturation, we recapitulated the intrinsic cardiac properties by electro-mechanical stimulation and explored how these mimetic biophysical cues interplay and influence the cell behaviour. METHODS AND RESULTS: We introduced a novel device capable of applying synchronized electrical and mechanical stimuli to hiPSC-CM monolayers cultured on a PDMS membrane and evaluated effects of conditioning on cardiomyocyte structure and function. Human iPSC-CMs retained their cardiac phenotype and displayed adaptive structural responses to electrical (E), mechanical (M) and combined electro-mechanical (EM) stimuli, including enhanced membrane N-cadherin signal, stress-fiber formation and sarcomeric length shortening, most prominent under the EM stimulation. On the functional level, EM conditioning significantly reduced the transmembrane calcium current, resulting in a shift towards triangulation of intracellular calcium transients. In contrast, E and M stimulation applied independently increased the proportion of cells with L-Type calcium currents. In addition, calcium transients measured in the M-conditioned samples advanced to a more rectangular shape. CONCLUSION: The new methodology is a simple and elegant technique to systematically investigate and manipulate cardiomyocyte remodelling for translational applications. In the present study, we adjusted critical parameters to optimize a regimen for hiPSC-CM transformation. In the future, this technology will open up new avenues for electro-mechanical stimulation by allowing temporal and spatial control of stimuli which can be easily scaled up in complexity for cardiac development and disease modelling.


Assuntos
Fenômenos Eletrofisiológicos , Células-Tronco Pluripotentes Induzidas/citologia , Fenômenos Mecânicos , Miócitos Cardíacos/citologia , Pesquisa Médica Translacional , Transporte Biológico , Fenômenos Biomecânicos , Cálcio/metabolismo , Citoesqueleto/metabolismo , Humanos , Miócitos Cardíacos/metabolismo , Sarcômeros/metabolismo
19.
Front Physiol ; 8: 986, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29311950

RESUMO

Human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) have applications in disease modeling, cell therapy, drug screening and personalized medicine. Computational models can be used to interpret experimental findings in iPSC-CMs, provide mechanistic insights, and translate these findings to adult cardiomyocyte (CM) electrophysiology. However, different cell lines display different expression of ion channels, pumps and receptors, and show differences in electrophysiology. In this exploratory study, we use a mathematical model based on iPSC-CMs from Cellular Dynamic International (CDI, iCell), and compare its predictions to novel experimental recordings made with the Axiogenesis Cor.4U line. We show that tailoring this model to the specific cell line, even using limited data and a relatively simple approach, leads to improved predictions of baseline behavior and response to drugs. This demonstrates the need and the feasibility to tailor models to individual cell lines, although a more refined approach will be needed to characterize individual currents, address differences in ion current kinetics, and further improve these results.

20.
Radiat Res ; 186(6): 592-601, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27869556

RESUMO

In response to the limitations of computed tomography (CT) and cone-beam CT (CBCT) in irradiation guidance, especially for soft-tissue targets without the use of contrast agents, our group developed a solution that implemented bioluminescence tomography (BLT) as the image-guidance modality for preclinical radiation research. However, adding such a system to existing small animal irradiators is no small task. A potential solution is to utilize an off-line BLT system in close proximity to the irradiator, with stable and effective animal transport between the two systems. In this study, we investigated the localization accuracy of an off-line BLT system when used for the small animal radiation research platform (SARRP) and compared the results with those of an on-line system. The CBCT was equipped on both the off-line BLT system and the SARRP, with a distance of 5 m between them. To evaluate the setup error during animal transport between the two systems, the mice underwent CBCT imaging on the SARRP and were then transported to the off-line system for a second CBCT imaging session. The normalized intensity difference of the two images and the corresponding histogram and correlation were computed to evaluate if the transport process perturbed animal positioning. Strong correlation (correlation coefficients >0.95) between the SARRP and the off-line mouse CBCT was observed. The offset of the implanted light source center can be maintained within 0.2 mm during transport. To compare the target localization accuracy using the on-line SARRP BLT and the off-line system, a self-illuminated bioluminescent source was implanted in the abdomen of anesthetized mice. In addition to the application for dose calculation, CBCT imaging was also employed to generate the mesh grid of the imaged mouse for BLT reconstruction. Two scenarios were devised and compared, which involved localization of the luminescence source based on either: 1. on-line SARRP bioluminescence image and CBCT; or 2. off-line bioluminescence image and SARRP CBCT. The first scenario is assumed to have the least setup error, because no animal transport was involved. The second scenario examines if an off-line BLT system, with the mesh generated from the SARRP CBCT, can be used to guide SARRP irradiation when there is minimal target contrast in CBCT. Stability during animal transport between the two systems was maintained. The center of mass (CoM) of the light source reconstructed by the off-line BLT had an offset of 1.0 ± 0.4 mm from the true CoM derived from the SARRP CBCT. These results are comparable to the offset of 1.0 ± 0.2 mm using on-line BLT. With CBCT information provided by the SARRP and effective animal immobilization during transport, these findings support the utilization of an off-line BLT-guided system, in close proximity to the SARRP, for accurate soft-tissue target localization. In addition, a dedicated standalone BLT system for our partner site at the University of Pennsylvania was introduced in this study.


Assuntos
Luminescência , Radioterapia Guiada por Imagem/instrumentação , Tomografia/instrumentação , Animais , Camundongos , Imagens de Fantasmas
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