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The task of transfer learning using pretrained convolutional neural networks is considered. We propose a convolution-SVD layer to analyze the convolution operators with a singular value decomposition computed in the Fourier domain. Singular vectors extracted from the source domain are transferred to the target domain, whereas the singular values are fine-tuned with a target data set. In this way, dimension reduction is achieved to avoid overfitting, while some flexibility to fine-tune the convolution kernels is maintained. We extend an existing convolution kernel reconstruction algorithm to allow for a reconstruction from an arbitrary set of learned singular values. A generalization bound for a single convolution-SVD layer is devised to show the consistency between training and testing errors. We further introduce a notion of transfer learning gap. We prove that the testing error for a single convolution-SVD layer is bounded in terms of the gap, which motivates us to develop a regularization model with the gap as the regularizer. Numerical experiments are conducted to demonstrate the superiority of the proposed model in solving classification problems and the influence of various parameters. In particular, the regularization is shown to yield a significantly higher prediction accuracy.
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The class of multi-relational graph convolutional networks (MRGCNs) is a recent extension of standard graph convolutional networks (GCNs) to handle heterogenous graphs with multiple types of relationships. MRGCNs have been shown to yield results superior than traditional GCNs in various machine learning tasks. The key idea is to introduce a new kind of convolution operated on tensors that can effectively exploit correlations exhibited in multiple relationships. The main objective of this paper is to analyze the algorithmic stability and generalization guarantees of MRGCNs to confirm the usefulness of MRGCNs. Our contributions are of three folds. First, we develop a matrix representation of various tensor operations underneath MRGCNs to simplify the analysis significantly. Next, we prove the uniform stability of MRGCNs and deduce the convergence of the generalization gap to support the usefulness of MRGCNs. The analysis sheds lights on the design of MRGCNs, for instance, how the data should be scaled to achieve the uniform stability of the learning process. Finally, we provide experimental results to demonstrate the stability results.
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Generalización Psicológica , Aprendizaje AutomáticoRESUMEN
The ability to culture pathogenic organisms substantially enhances the quest for fundamental knowledge and the development of vaccines and drugs. Thus, the elaboration of a protocol for the in vitro cultivation of the erythrocytic stages of Plasmodium falciparum revolutionized research on this important parasite. However, for P. vivax, the most widely distributed and difficult to treat malaria parasite, a strict preference for reticulocytes thwarts efforts to maintain it in vitro. Cultivation of P. cynomolgi, a macaque-infecting species phylogenetically close to P. vivax, was briefly reported in the early 1980s, but not pursued further. Here, we define the conditions under which P. cynomolgi can be adapted to long term in vitro culture to yield parasites that share many of the morphological and phenotypic features of P. vivax. We further validate the potential of this culture system for high-throughput screening to prime and accelerate anti-P. vivax drug discovery efforts.
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Eritrocitos/parasitología , Macaca/parasitología , Malaria/veterinaria , Enfermedades de los Monos/parasitología , Plasmodium cynomolgi/crecimiento & desarrollo , Animales , Anopheles/parasitología , Malaria/parasitología , Malaria/transmisiónRESUMEN
Hypnozoites are the liver stage non-dividing form of the malaria parasite that are responsible for relapse and acts as a natural reservoir for human malaria Plasmodium vivax and P. ovale as well as a phylogenetically related simian malaria P. cynomolgi. Our understanding of hypnozoite biology remains limited due to the technical challenge of requiring the use of primary hepatocytes and the lack of robust and predictive in vitro models. In this study, we developed a malaria liver stage model using 3D spheroid-cultured primary hepatocytes. The infection of primary hepatocytes in suspension led to increased infectivity of both P. cynomolgi and P. vivax infections. We demonstrated that this hepatic spheroid model was capable of maintaining long term viability, hepatocyte specific functions and cell polarity which enhanced permissiveness and thus, permitting for the complete development of both P. cynomolgi and P. vivax liver stage parasites in the infected spheroids. The model described here was able to capture the full liver stage cycle starting with sporozoites and ending in the release of hepatic merozoites capable of invading simian erythrocytes in vitro. Finally, we showed that this system can be used for compound screening to discriminate between causal prophylactic and cidal antimalarials activity in vitro for relapsing malaria.
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Antimaláricos/farmacología , Hepatocitos/parasitología , Malaria/tratamiento farmacológico , Plasmodium/efectos de los fármacos , Animales , Técnicas de Cultivo de Célula/métodos , Línea Celular , Células Cultivadas , Hepatocitos/citología , Humanos , Hígado/citología , Hígado/parasitología , Macaca fascicularis , Macaca mulatta , Pruebas de Sensibilidad Parasitaria/métodos , Recurrencia , Prevención Secundaria , Esferoides Celulares/citología , Esferoides Celulares/parasitología , Esporozoítos/efectos de los fármacosRESUMEN
Plasmodium vivax hypnozoites persist in the liver, cause malaria relapse and represent a major challenge to malaria elimination. Our previous transcriptomic study provided a novel molecular framework to enhance our understanding of the hypnozoite biology (Voorberg-van der Wel A, et al., 2017). In this dataset, we identified and characterized the Liver-Specific Protein 2 (LISP2) protein as an early molecular marker of liver stage development. Immunofluorescence analysis of hepatocytes infected with relapsing malaria parasites, in vitro (P. cynomolgi) and in vivo (P. vivax), reveals that LISP2 expression discriminates between dormant hypnozoites and early developing parasites. We further demonstrate that prophylactic drugs selectively kill all LISP2-positive parasites, while LISP2-negative hypnozoites are only sensitive to anti-relapse drug tafenoquine. Our results provide novel biological insights in the initiation of liver stage schizogony and an early marker suitable for the development of drug discovery assays predictive of anti-relapse activity.
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Malaria Vivax/genética , Plasmodium cynomolgi/genética , Plasmodium vivax/genética , Proteínas Protozoarias/genética , Aminoquinolinas/farmacología , Animales , Antimaláricos/farmacología , Biomarcadores/metabolismo , Biomarcadores Farmacológicos , Hepatocitos/metabolismo , Hepatocitos/parasitología , Interacciones Huésped-Parásitos/genética , Humanos , Hígado/efectos de los fármacos , Hígado/parasitología , Macaca mulatta/genética , Macaca mulatta/parasitología , Malaria Vivax/tratamiento farmacológico , Malaria Vivax/parasitología , Plasmodium cynomolgi/parasitología , Plasmodium vivax/efectos de los fármacos , Plasmodium vivax/patogenicidad , Proteínas Protozoarias/metabolismo , Esporozoítos/genética , Transcriptoma/efectos de los fármacosRESUMEN
The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both in vitro and in vivo. The inhibitor was identified through screening of a 1.8-million-compound library by using a DENV-2 replicon assay. The compound selectively inhibits DENV-2 and -3 (50% effective concentration [EC50], 10 to 80 nM) but not DENV-1 and -4 (EC50,>20 M). Resistance analysis showed that a mutation at amino acid 63 of DENV-2 NS4B (a nonenzymatic transmembrane protein and a component of the viral replication complex) could confer resistance to compound inhibition. Genetic studies demonstrate that variations at amino acid 63 of viral NS4B are responsible for the selective inhibition of DENV-2 and -3. Medicinal chemistry improved the physicochemical properties of the initial "hit" (compound 1), leading to compound 14a, which has good in vivo pharmacokinetics. Treatment of DENV-2-infected AG129 mice with compound 14a suppressed viremia, even when the treatment started after viral infection. The results have proven the concept that inhibitors of NS4B could potentially be developed for clinical treatment of DENV infection. Compound 14a represents a potential preclinical candidate for treatment of DENV-2- and -3-infected patients.
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Antivirales/farmacología , Virus del Dengue/efectos de los fármacos , Descubrimiento de Drogas , Compuestos de Espiro/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Línea Celular , Cricetinae , Humanos , Compuestos de Espiro/químicaRESUMEN
Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENV) inhibitor, from a DENV serotype 2 (DENV-2) high-throughput phenotypic screen. As a general trend within this chemical class, chiral resolution of the racemate revealed that R enantiomer was significantly more potent than the S. Cell-based lead optimization of the spiropyrazolopyridones focusing on improving the physicochemical properties is described. As a result, an optimal compound 14a, with balanced in vitro potency and pharmacokinetic profile, achieved about 1.9 log viremia reduction at 3 × 50 mg/kg (bid) or 3 × 100 mg/kg (QD) oral doses in the dengue in vivo mouse efficacy model.
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Dengue virus (DENV) infection could lead to dengue fever (DF), dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). The disease outcome is controlled by both viral and host factors. Inflammation mediators from DENV-infected cells could contribute to increased vascular permeability, leading to severe DHF/DSS. Therefore, suppression of inflammation could be a potential therapeutic approach for treatment of dengue patients. In this context, p38 MAPK (mitogen-activated protein kinase) is a key enzyme that modulates the initiation of stress and inflammatory responses. Here we show that SB203580, a p38 MAPK inhibitor, suppressed the over production of DENV-induced pro-inflammatory mediators such as TNF-α, IL-8, and RANTES from human PBMCs, monocytic THP-1, and granulocyte KU812 cell lines. Oral administration of SB203580 in DENV-infected AG129 mice prevented hematocrit rise and lymphopenia, limited the development of inflammation and pathology (including intestine leakage), and significantly improved survival. These results, for the first time, have provided experimental evidence to imply that a short term inhibition of p38 MAPK may be beneficial to reduce disease symptoms in dengue patients.
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Dengue/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Imidazoles/uso terapéutico , Inflamación/tratamiento farmacológico , Piridinas/uso terapéutico , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Permeabilidad Capilar/efectos de los fármacos , Línea Celular , Quimiocina CCL5/biosíntesis , Cricetinae , Culicidae , Dengue/virología , Virus del Dengue/patogenicidad , Inhibidores Enzimáticos/farmacología , Hematócrito , Humanos , Imidazoles/farmacología , Interleucina-8/biosíntesis , Linfopenia/prevención & control , Ratones , Piridinas/farmacología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Dengue fever is an emerging mosquito-borne flaviviral disease that threatens 2.5 billion people worldwide. No clinically approved vaccine and antiviral therapy are currently available to prevent or treat dengue virus (DENV) infection. Vertebrate animals other than primates are not normally infectable with DENV; however, a small animal dengue infection model would greatly facilitate the development of a vaccine or an antiviral therapy. To this end, a rodent model for DENV infection has been established in IFN-α/ß and IFN-γ receptor-deficient (AG129) mice. This chapter describes the protocol for the DENV infection model in AG129 mice and testing of antiviral compounds by oral gavage or parenteral injection.
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Antivirales/farmacología , Virus del Dengue/efectos de los fármacos , Dengue/tratamiento farmacológico , Animales , Antivirales/administración & dosificación , Línea Celular , Dengue/inmunología , Dengue/patología , Modelos Animales de Enfermedad , Vías de Administración de Medicamentos , Esquema de Medicación , Femenino , Masculino , RatonesRESUMEN
The dengue virus (DENV) is a mosquito-borne pathogen responsible for an estimated 100 million human infections annually. The viral genome encodes a two-component trypsin-like protease that contains the cofactor region from the nonstructural protein NS2B and the protease domain from NS3 (NS3pro). The NS2B-NS3pro complex plays a crucial role in viral maturation and has been identified as a potential drug target. Using a DENV protease construct containing NS2B covalently linked to NS3pro via a Gly4-Ser-Gly4 linker ("linked protease"), previous x-ray crystal structures show that the C-terminal fragment of NS2B is remote from NS3pro and exists in an open state in the absence of an inhibitor; however, in the presence of an inhibitor, NS2B complexes with NS3pro to form a closed state. This linked enzyme produced NMR spectra with severe signal overlap and line broadening. To obtain a protease construct with a resolved NMR spectrum, we expressed and purified an unlinked protease complex containing a 50-residue segment of the NS2B cofactor region and NS3pro without the glycine linker using a coexpression system. This unlinked protease complex was catalytically active at neutral pH in the absence of glycerol and produced dispersed cross-peaks in a (1)H-(15)N heteronuclear single quantum correlation spectrum that enabled us to conduct backbone assignments using conventional techniques. In addition, titration with an active-site peptide aldehyde inhibitor and paramagnetic relaxation enhancement studies demonstrated that the unlinked DENV protease exists predominantly in a closed conformation in solution. This protease complex can serve as a useful tool for drug discovery against DENV.
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Virus del Dengue/enzimología , Complejos Multienzimáticos/química , Proteínas no Estructurales Virales/química , Cristalografía por Rayos X , Virus del Dengue/genética , Humanos , Espectroscopía de Resonancia Magnética , Complejos Multienzimáticos/genética , Resonancia Magnética Nuclear Biomolecular , Estructura Cuaternaria de Proteína , Estructura Secundaria de Proteína , ARN Helicasas/química , ARN Helicasas/genética , Serina Endopeptidasas/química , Serina Endopeptidasas/genética , Proteínas no Estructurales Virales/genéticaRESUMEN
Dengue virus (DENV) is a mosquito-borne flavivirus that affects 2.5 billion people worldwide. There are four dengue serotypes (DENV1 to DENV4), and infection with one elicits lifelong immunity to that serotype but offers only transient protection against the other serotypes. Identification of the protective determinants of the human antibody response to DENV is a vital requirement for the design and evaluation of future preventative therapies and treatments. Here, we describe the isolation of a neutralizing antibody from a DENV1-infected patient. The human antibody 14c10 (HM14c10) binds specifically to DENV1. HM14c10 neutralizes the virus principally by blocking virus attachment; at higher concentrations, a post-attachment step can also be inhibited. In vivo studies show that the HM14c10 antibody has antiviral activity at picomolar concentrations. A 7 Å resolution cryoelectron microscopy map of Fab fragments of HM14c10 in a complex with DENV1 shows targeting of a discontinuous epitope that spans the adjacent surface of envelope protein dimers. As found previously, a human antibody specific for the related West Nile virus binds to a similar quaternary structure, suggesting that this could be an immunodominant epitope. These findings provide a structural and molecular context for durable, serotype-specific immunity to DENV infection.
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Anticuerpos Neutralizantes/uso terapéutico , Antivirales/uso terapéutico , Virus del Dengue/efectos de los fármacos , Animales , Anticuerpos Neutralizantes/farmacología , Antivirales/farmacología , Microscopía por Crioelectrón , Dengue/tratamiento farmacológico , Virus del Dengue/inmunología , Virus del Dengue/ultraestructura , Epítopos/inmunología , Humanos , RatonesRESUMEN
In this paper, we consider the problem of segmentation of large collections of images. We propose a semisupervised optimization model that determines an efficient segmentation of many input images. The advantages of the model are twofold. First, the segmentation is highly controllable by the user so that the user can easily specify what he/she wants. This is done by allowing the user to provide, either offline or interactively, some (fully or partially) labeled pixels in images as strong priors for the model. Second, the model requires only minimal tuning of model parameters during the initial stage. Once initial tuning is done, the setup can be used to automatically segment a large collection of images that are distinct but share similar features. We will show the mathematical properties of the model such as existence and uniqueness of solution and establish a maximum/minimum principle for the solution of the model. Extensive experiments on various collections of biological images suggest that the proposed model is effective for segmentation and is computationally efficient.
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Algoritmos , Biología Computacional/métodos , Diagnóstico por Imagen/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Modelos Teóricos , Inteligencia Artificial , Vasos Sanguíneos/anatomía & histología , Neoplasias de la Mama/patología , Femenino , Humanos , Retina/anatomía & histologíaRESUMEN
Loss of information in a wavelet domain can occur during storage or transmission when the images are formatted and stored in terms of wavelet coefficients. This calls for image inpainting in wavelet domains. In this paper, a variational approach is used to formulate the reconstruction problem. We propose a simple but very efficient iterative scheme to calculate an optimal solution and prove its convergence. Numerical results are presented to show the performance of the proposed algorithm.
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Algoritmos , Artefactos , Aumento de la Imagen/métodos , Interpretación de Imagen Asistida por Computador/métodos , Reconocimiento de Normas Patrones Automatizadas/métodos , Análisis de Ondículas , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Dengue virus infection causes diseases in people, ranging from the acute febrile illness dengue fever, to life-threatening dengue hemorrhagic fever/dengue shock syndrome. We previously reported that a host cellular α-glucosidases I and II inhibitor, imino sugar CM-10-18, potently inhibited dengue virus replication in cultured cells, and significantly reduced viremia in dengue virus infected AG129 mice. In this report we show that CM-10-18 also significantly protects mice from death and/or disease progress in two mouse models of lethal dengue virus infection. Our results thus provide a strong support for the development of CM-10-18 or its derivatives as antiviral agents to treat servere dengue virus infections.
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Antivirales/administración & dosificación , Dengue/tratamiento farmacológico , Dengue/prevención & control , Inhibidores Enzimáticos/administración & dosificación , Inhibidores de Glicósido Hidrolasas , Animales , Dengue/mortalidad , Dengue/patología , Ratones , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
In this paper, we develop a robust and effective algorithm for texture segmentation and feature selection. The approach is to incorporate a patch-based subspace learning technique into the subspace Mumford-Shah (SMS) model to make the minimization of the SMS model robust and accurate. The proposed method is fully unsupervised in that it removes the need to specify training data, which is required by existing methods for the same model. We further propose a novel (to our knowledge) pairwise dissimilarity measure for pixels. Its novelty lies in the use of the relevance scores of the features of each pixel to improve its discriminating power. Some superior results are obtained compared to existing unsupervised algorithms, which do not use a subspace approach. This confirms the usefulness of the subspace approach and the proposed unsupervised algorithm.
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Algoritmos , Reconocimiento de Normas Patrones Automatizadas/estadística & datos numéricos , Animales , Humanos , Aumento de la Imagen/métodos , Interpretación de Imagen Asistida por Computador/métodos , Fenómenos ÓpticosRESUMEN
Dengue (DEN) is a mosquito-borne viral disease that has become an increasing economic and health burden for the tropical and subtropical world. The lack of an appropriate animal model of DEN has greatly impeded the study of its pathogenesis and the development of vaccines/antivirals. We recently reported a DEN virus 2 (DENV-2) strain (D2Y98P) that lethally infects immunocompromised AG129 mice, resulting in organ damage or dysfunction and increased vascular permeability, hallmarks of severe DEN in patients (G. K. Tan et al., PLoS Negl. Trop. Dis. 4:e672, 2010). Here we report the identification of one critical virulence determinant of strain D2Y98P. By mutagenesis, we showed that a Phe-to-Leu alteration at amino acid position 52 in nonstructural protein NS4B completely abolished the pathogenicity of the D2Y98P virus, as evidenced by a lack of lethality and the absence of histological signs of disease, which correlated with reduced viral titers and intact vascular permeability. Conversely, a Leu-to-Phe alteration at position 52 of NS4B in nonvirulent DENV-2 strain TSV01 led to 80% lethality and increased viremia. The NS4B(Phe52) viruses displayed enhanced RNA synthesis in mammalian cells but not in mosquito cells. The increased viral RNA synthesis was independent of the ability of NS4B to interfere with the host type I interferon response. Overall, our results demonstrate that Phe at position 52 in NS4B confers virulence in mice on two independent DENV-2 strains through enhancement of viral RNA synthesis. In addition to providing further insights into the functional role of NS4B protein, our findings further support a direct relationship between viral loads and DEN pathogenesis in vivo, consistent with observations in DEN patients.
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Aminoácidos/química , ADN Viral/biosíntesis , Virus del Dengue/patogenicidad , Proteínas no Estructurales Virales/fisiología , Animales , Línea Celular , Virus del Dengue/genética , Técnica del Anticuerpo Fluorescente , Humanos , Ratones , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas no Estructurales Virales/química , VirulenciaRESUMEN
Cellular α-glucosidases I and II are enzymes that sequentially trim the three terminal glucoses in the N-linked oligosaccharides of viral envelope glycoproteins. This process is essential for the proper folding of viral glycoproteins and subsequent assembly of many enveloped viruses, including dengue virus (DENV). Imino sugars are substrate mimics of α-glucosidases I and II. In this report, we show that two oxygenated alkyl imino sugar derivatives, CM-9-78 and CM-10-18, are potent inhibitors of both α-glucosidases I and II in vitro and in treated animals, and efficiently inhibit DENV infection of cultured human cells. Pharmacokinetic studies reveal that both compounds are well tolerated at doses up to 100mg/kg in rats and have favorable pharmacokinetic properties and bioavailability in mice. Moreover, we showed that oral administration of either CM-9-78 or CM-10-18 reduces the peak viremia of DENV in mice. Interestingly, while treatment of DENV infected mice with ribavirin alone did not reduce the viremia, combination therapy of ribavirin with sub-effective dose of CM-10-18 demonstrated a significantly enhanced antiviral activity, as indicated by a profound reduction of the viremia. Our findings thus suggest that combination therapy of two broad-spectrum antiviral agents may provide a practically useful approach for the treatment of DENV infection.
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Antivirales/administración & dosificación , Virus del Dengue/efectos de los fármacos , Dengue/tratamiento farmacológico , Inhibidores Enzimáticos/administración & dosificación , Inhibidores de Glicósido Hidrolasas , Ribavirina/administración & dosificación , Administración Oral , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Línea Celular , Dengue/prevención & control , Dengue/virología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Concentración 50 Inhibidora , Ratones , Ribavirina/farmacología , Viremia/prevención & controlRESUMEN
We propose a variant of the Mumford-Shah model for the segmentation of a pair of overlapping objects with additive intensity value. Unlike standard segmentation models, it does not only determine distinct objects in the image, but also recover the possibly multiple membership of the pixels. To accomplish this, some a priori knowledge about the smoothness of the object boundary is integrated into the model. Additivity is imposed through a soft constraint which allows the user to control the degree of additivity and is more robust than the hard constraint. We also show analytically that the additivity parameter can be chosen to achieve some stability conditions. To solve the optimization problem involving geometric quantities efficiently, we apply a multiphase level set method. Segmentation results on synthetic and real images validate the good performance of our model, and demonstrate the model's applicability to images with multiple channels and multiple objects.
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Algoritmos , Aumento de la Imagen/métodos , Interpretación de Imagen Asistida por Computador/métodos , Modelos Teóricos , Reconocimiento de Normas Patrones Automatizadas/métodos , Técnica de Sustracción , Simulación por Computador , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen that infects humans. Neither a vaccine nor an antiviral therapy is currently available for DENV. Here, we report an adenosine nucleoside prodrug that potently inhibits DENV replication both in cell culture and in a DENV mouse model. NITD449 (2'-C-acetylene-7-deaza-7-carbamoyladenosine) was initially identified as a parental compound that inhibits all four serotypes of DENV with low cytotoxicity. However, in vivo pharmacokinetic studies indicated that NITD449 had a low level of exposure in plasma when dosed orally. To increase the oral bioavailability, we covalently linked isobutyric acids to the 3'- and 5'-hydroxyl groups of ribose via ester linkage to NITD449, leading to the prodrug NITD203 (3',5'-O-diisobutyryl-2'-C-acetylene-7-deaza-7-carbamoyl-adenosin). Pharmacokinetic analysis showed that upon oral dosing of the prodrug, NITD203 was readily converted to NITD449, resulting in improved exposure of the parental compound in plasma in both mouse and rat. In DENV-infected AG129 mice, oral dosing of the prodrug at 25 mg/kg of body weight reduced peak viremia by 30-fold. Antiviral spectrum analysis showed that NITD203 inhibited various flaviviruses (DENV, yellow fever virus, and West Nile virus) and hepatitis C virus but not Chikungunya virus (an alphavirus). Mode-of-action analysis, using a luciferase-reporting replicon, indicated that NITD203 inhibited DENV RNA synthesis. Although NITD203 exhibited potent in vitro and in vivo efficacies, the compound could not reach a satisfactory no-observable-adverse-effect level (NOAEL) in a 2-week in vivo toxicity study. Nevertheless, our results demonstrate that a prodrug approach using a nucleoside analog could potentially be developed for flavivirus antiviral therapy.
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Adenosina/análogos & derivados , Antivirales/farmacología , Virus del Dengue/efectos de los fármacos , Dengue/tratamiento farmacológico , Profármacos/farmacología , Replicación Viral/efectos de los fármacos , Adenosina/farmacocinética , Adenosina/farmacología , Adenosina/uso terapéutico , Animales , Antivirales/química , Antivirales/farmacocinética , Antivirales/uso terapéutico , Línea Celular , Línea Celular Tumoral , Chlorocebus aethiops , Dengue/virología , Células Epiteliales/virología , Ésteres/química , Humanos , Ratones , Profármacos/química , Profármacos/farmacocinética , Profármacos/uso terapéutico , Ratas , Células VeroRESUMEN
We consider the recovery of degraded videos without complete knowledge about the degradation. A spatially shift-invariant but temporally shift-varying video formation model is used. This leads to a simple multiframe degradation model that relates each original video frame with multiple observed frames and point spread functions (PSFs). We propose a variational method that simultaneously reconstructs each video frame and the associated PSFs from the corresponding observed frames. Total variation (TV) regularization is used on both the video frames and the PSFs to further reduce the ill-posedness and to better preserve edges. In order to make TV minimization practical for video sequences, we propose an efficient splitting method that generalizes some recent fast single-image TV minimization methods to the multiframe case. Both synthetic and real videos are used to show the performance of the proposed method.