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Dabrafenib,an inhibitor of rIP3 kinase-dependent necroptosis,reduces ischemic brain injury

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Neural regeneration research 2018年第2期13卷 252-256页

作者： Shelly A.Cruz Zhaohong Qin alexandre e r.stewart Hsiao-Huei Chen Ottawa Hospital research Institute OttawaCanada University of Ottawa Brain and Mind InstituteOttawaCanada University of Ottawa Heart Institute OttawaCanada Canadian Partnership for Storke recovery OttawaCanada

Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （rIPK） associated with the tumor necrosis factor-alpha （TNF-a）/death receptor. recent evidence shows rIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent rIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.

关键词： ischemic brain injury inflammation macrophage Dabrafenib tumor necrosis factor-alpha photothrombosis receptor-interacting protein kinases necroptosis microgIia stroke neural regeneration

Opposite Interplay Between the Canonical WNT/β-Catenin Pathway and PPAr Gamma： A Potential Therapeutic Target in Gliomas

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Neuroscience Bulletin 2018年第3期34卷 573-588页

作者： alexandre Vallée Yves Lecarpentier rémy Guillevin Jean-Noёl Vallée Laboratory of Mathematics and Applications Unites Mixtes de Recherche (UMR) Centre National de la Recherche Scientifique (CNRS) 7348 University of Poitiers PoitiersFrance Delegation a la recherche Clinique et a l'Innovation (DrCI) Hopital Foch Suresnes France Centre de recherche Clinique Grand Hopital de l'EstFrancilien Meaux France DACTIM UMR CNRS 7348 University of Poitiers et CHU de Poitiers Poitiers France CHU Amiens Picardie University of Picardie Jules VerneAmiens France

In gliomas, the canonical Wingless/Int（WNT）/b-catenin pathway is increased while peroxisome proliferator-activated receptor gamma（PPAr-c） is *** two systems act in an opposite manner. This review focuses on the interplay between WNT/b-catenin signaling and PPAr-c and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/bcatenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis,tumor growth, and angiogenesis. Activation of PPAr-c agonists inhibits various signaling pathways such as the JAK/STAT, WNT/b-catenin, and PI3 K/Akt pathways,which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin,and sulforaphane downregulate the WNT/b-catenin pathway through the upregulation of PPAr-c and thus appear to provide an interesting therapeutic approach for ***（TMZ） is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.

关键词： WNT/beta-catenin pathway PPAr gamma Glioma STAT3 pathway PI3K/Akt pathway NSAID Curcumin

Detecting polygenic selection in marine populations by combining population genomics and quantitative genetics approaches

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Current Zoology 2016年第6期62卷 603-616页

作者： Pierre-alexandre GAGNAIre Oscar e. GAGGIOTTI Universite Montpellier 2 Place Eugene Bataillon 34095 Montpellier Cedex 5 France ISeM - CNrS UMR 5554 SMEL 2 rue des Chantiers Sete 34200 France Scottish Oceans Institute University of St Andrews East Sands St Andrews KY16 9LB UK

Highly fecund marine species with dispersive life-history stages often display large population sizes and wide geographic distribution ranges. Consequently, they are expected to experience reduced genetic drift, efficient selection fueled by frequent adaptive mutations, and high migration loads. This has important consequences for understanding how local adaptation proceeds in the sea. A key issue in this regard, relates to the genetic architecture underlying fitness traits. Theory predicts that adaptation may involve many genes but with a high variance in effect size. Therefore, the effect of selection on allele frequencies may be substantial for the largest effect size loci, but insignificant for small effect genes. In such a context, the performance of population genomic methods to unravel the genetic basis of adaptation depends on the fraction of adaptive genetic variance explained by the cumulative effect of outlier loci. Here, we address some methodological challenges associated with the detection of local adaptation using molecular approaches. We provide an overview of genome scan methods to detect selection, including those assuming complex demographic models that better describe spatial population structure. We then focus on quantitative genetics approaches that search for genotype-phenotype associations at different genomic scales, including genome-wide methods evaluating the cumulative effect of variants. We argue that the limited power of single locus tests can be alleviated by the use of polygenic scores to estimate the joint contribution of candidate variants to phenotypic variation.

关键词： local adaptation genome scans quantitative genetics genotype-phenotype association polygenic scores.

WNT/β-catenin pathway and circadian rhythms in obsessive-compulsive disorder

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Neural regeneration research 2022年第10期17卷 2126-2130页

作者： alexandre Vallée Yves Lecarpentier Jean-Noël Vallée Department of Clinical research and Innovation(DrCI) Foch HospitalSuresnesFrance Centre de recherche Clinique Grand Hôpital de l’Est Francilien(GHEF)MeauxFrance Laboratoire de Mathématiques et Applications(LMA) Universitéde PoitiersPoitiersFrance Centre Hospitalier Universitaire(CHU)Amiens Picardie UniversitéPicardie Jules Verne(UPJV)AmiensFrance

The neuropsychiatric disease named obsessive-compulsive disorder is composed by obsessions and/or ***-compulsive disorder etiologies are ***,numerous mechanisms in several localizations are *** studies showed that both glutamate,inflammatory factors and oxidative stress could have main functions in obsessive-compulsive *** synthase kinase-3β,the major negative controller of the WNT/β-catenin pathway is upregulated in obsessive-compulsive *** obsessive-compulsive disorder,some studies presented the actions of the different circadian clock ***/β-catenin pathway and circadian clock genes appear to be ***,this review focuses on the interaction between circadian clock genes and the WNT/β-catenin pathway in obsessive-compulsive disorder.

关键词： circadian rhythms glutamatergic pathway inflammation obsessive-compulsive disorder oxidative stress WNT/β-catenin pathway

Light management with quantum nanostructured dots-in-host semiconductors

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Light(Science & Applications) 2021年第12期10卷 2399-2407页

作者： M.alexandre H.Águas e.Fortunato r.Martins M.J.Mendes i3N/CeNIMAT Department of Materials ScienceFaculty of Science and TechnologyUniversidade NOVA de Lisboa and CEMOP/UNINOVACampus de Caparica2829-516 CaparicaPortugal

Insightful knowledge on quantum nanostructured materials is paramount to engineer and exploit their vast gamut of ***,a formalism based on the single-band effective mass equation was developed to determine the light absorption of colloidal quantum dots(CQDs)embedded in a wider bandgap semiconductor host,employing only three parameters(dots/host potential barrier,effective mass,and QD size).It was ascertained how to tune such parameters to design the energy level structure and consequent optical *** findings show that the CQD size has the biggest effect on the number and energy of the confined levels,while the potential barrier causes a linear shift of their *** smaller QDs allow wider energetic separation between levels(as desired for most quantumbased technologies),the larger dots with higher number of levels are those that exhibit the strongest ***,it was unprecedently shown that such quantum-enabled absorption coefficients can reach the levels(10^(4)–10^(5) cm^(−1))of bulk semiconductors.

关键词： quantum dots absorption

Pharmaceutical applications of spouted beds: A review on solid dosage forms

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Particuology 2019年第1期17卷 126-136页

作者： Luis alexandre Pedro de Freitas Faculdade de Ciencias Farmaceuticas de ribeirao Preto University of Sao PauloVia do Cafe s/n. Campus USPRibeirao Preto14040-903Sao Paulo. Brazil

Spouted beds (SBs) have a long history of successful applications for preparation of solid dosage forms of pharmaceuticals. The well-known versatility of SBs, provided by different design and operational factors, and their efficient mixing of solids allow for engineering of technological characteristics of pharmaceutical solid forms. Particle properties like morphology, size, porosity, flowability, and dissolution rate can be improved by managing geometric and operational conditions for spouting. Drying is probably the most disseminated operation for pharmaceutical processing in SBs, and many studies have investigated drying of medicinal plant extracts such as achiote (Bixa orellana sp.), guarana (Paullinia cupana sp.), passion flower (Passiflora alata D.), and rosemary (rosmarinus officinalis L.) with excellent pharmacotechnical and stability results. Another important application is coating of tablets and gelatin capsules, and previous studies have shown that SBs and spout–fluid beds may be advantageous over traditional pan coating, especially for polymeric film coating. recently, an alternative process for improving drug bioavailability has involved preparation of β-cyclodextrin inclusion complexes in SBs. The first study to propose SBs for this pharmaceutical application explored the advantage of obtaining solid forms of inclusion complexes in just one step, and obtained expressive increases in drug solubility. The technique has been applied in subsequent studies on inclusion complexes of the medication carvedilol and uxi (endopleura uchi L.) extracts.

关键词： Coating Drying Granulation Inclusion Microencapsulation

A POSTerIOrI eNerGY-NOrM errOr eSTIMATeS FOr ADVeCTION-DIFFUSION eQUATIONS APPrOXIMATeD BY WeIGHTeD INTerIOr PeNALTY MeTHODS

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Journal of Computational Mathematics 2008年第4期26卷 488-510页

作者： alexandre ern AnnetteF.Stephansen Université Paris-est CermicsEcole des Ponts6 et 8 avenue Blaise PascalChamps sur Marne77455 Marne la Vallée Cedex 2France Université Paris-est CermicsEcole des Ponts6 et 8 avenue Blaise PascalChamps sur Marne77455 Marne la Vallée Cedex 2France AndraParc de la Croix-Blanche1-7 rue Jean Monnet92298 Ch■tenay-Malabry cedexFrance

We propose and analyze a posteriori energy-norm error estimates for weighted interior penalty discontinuous Galerkin approximations of advection-diffusion-reaction equations with heterogeneous and anisotropic diffusion. The weights, which play a key role in the analysis, depend on the diffusion tensor and are used to formulate the consistency terms in the discontinuous Galerkin method. The error upper bounds, in which all the constants are specified, consist of three terms： a residual estimator which depends only on the elementwise fluctuation of the discrete solution residual, a diffusive flux estimator where the weights used in the method enter explicitly, and a non-conforming estimator which is nonzero because of the use of discontinuous finite element spaces. The three estimators can be bounded locally by the approximation error. A particular attention is given to the dependency on problem parameters of the constants in the local lower error bounds. For moderate advection, it is shown that full robustness with respect to diffusion heterogeneities is achieved owing to the specific design of the weights in the discontinuous Galerkin method, while diffusion anisotropies remain purely local and impact the constants through the square root of the condition number of the diffusion tensor. For dominant advection, it is shown, in the spirit of previous work by Verfiirth on continuous finite elements, that the local lower error bounds can be written with constants involving a cut-off for the ratio of local mesh size to the reciprocal of the square root of the lowest local eignevalue of the diffusion tensor.

关键词： Discontinuous Galerkin Weighted interior penalty A posteriori error estimate,Heterogeneous diffusion Advection-diffusion.

Dynamical machine learning volumetric reconstruction of objects’ interiors from limited angular views

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Light(Science & Applications) 2021年第5期10卷 824-844页

作者： Iksung Kang alexandre Goy George Barbastathis Department of electrical engineering and Computer Science Massachusetts Institute of Technology77 Massachusetts AveCambridgeMAUSA Department of Mechanical engineering Massachusetts Institute of TechnologyCambridgeMA 02139USA Singapore-MIT Alliance for research and Technology(SMArT)Centre 1 Create WaySingapore 117543Singapore Omnisens SA Morges 1110Switzerland

Limited-angle tomography of an interior volume is a challenging, highly ill-posed problem with practical implications in medical and biological imaging, manufacturing, automation, and environmental and food security. regularizing priors are necessary to reduce artifacts by improving the condition of such problems. recently, it was shown that one effective way to learn the priors for strongly scattering yet highly structured 3D objects, e.g. layered and Manhattan, is by a static neural network [Goy et al. Proc. Natl. Acad. Sci. 116, 19848–19856 (2019)]. Here, we present a radically different approach where the collection of raw images from multiple angles is viewed analogously to a dynamical system driven by the object-dependent forward scattering operator. The sequence index in the angle of illumination plays the role of discrete time in the dynamical system analogy. Thus, the imaging problem turns into a problem of nonlinear system identification, which also suggests dynamical learning as a better fit to regularize the reconstructions. We devised a recurrent Neural Network (rNN) architecture with a novel Separable-Convolution Gated recurrent Unit (SC-GrU) as the fundamental building block. Through a comprehensive comparison of several quantitative metrics, we show that the dynamic method is suitable for a generic interior-volumetric reconstruction under a limited-angle scheme. We show that this approach accurately reconstructs volume interiors under two conditions: weak scattering, when the radon transform approximation is applicable and the forward operator well defined;and strong scattering, which is nonlinear with respect to the 3D refractive index distribution and includes uncertainty in the forward operator.

关键词： interior dynamical angular

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World Journal of Gastrointestinal Oncology 2013年第11期5卷 198-203页

作者： Osama e rahma Mauricio Burotto Luisa Matos Do Canto alexandre A Germanos Bassem r Haddad John L Marshall Medical Oncology Branch National Cancer Institute the Lombardi Comprehensive Cancer Center Georgetown University Medical Center Whitman College the ruesch Center for the Cure of GI Cancers Georgetown University Medical Center

We are reporting the longest disease-free interval ever published for colorectal cancer, using gene profiling to confirm the linkage of the primary and metastasis. This rare case reports on a patient with late recurrence of colorectal cancer in the lung 19 years after its initial diagnosis. We used high-resolution array CGH(aCGH) to analyze the genetic aberrations of both the primary rectal and the recurrent metastatic lung lesions. Interestingly, we found striking similarities between the two lesions, despite the 19 years disease-free *** addition, most of the genes that were previously reported to be associated with a high recurrence score showed copy number gains by aCGH in one or both lesions. Our findings suggest that aCGH may be a helpful tool in analyzing the origin of metastatic lesions and reflect the need for a better understanding of the characteristics of the rectal tumors with a late recurrence potential.

关键词： Colorectal cancer Genetic aberrations Delayed recurrence High-resolution array CGH