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Identification and optimization of a potent and highly selective D3 dopamine receptor agonist

中国药理学与毒理学杂志 2017年第10期31卷 950-951页

作者： Amy E MORITZ R Benjamin FREE Warren WEINER Muzna BACHANI Trevor DOYLE Noel SOUTHALL marc ferrer Jonathan A JAVITCH Joseph STEINER Ara ABRAMYAN Lei SHI Jeffrey AUBé Kevin FRANKOWSKI David R SIBLEY Molecular Neuropharmacology Section National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD 20814 University of North Carolina Chapel Hill NC27599 Neurotherapeutic Development Unit National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD 20814 National Center for Advancing Translational Sciences Rockville MD 20892 Columbia University New York NY 10032 Computational Chemistry and Molecular Biophysics Unit Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse National Institutes of Health Baltimore MD 21224

OBJECTIVE Dopamine receptors(DRs) are involved in the development and treatment of many neuropsychiatric *** available dopaminergic drugs modulate both DRD2 and DRD3,leading to side effects and uncertainty as to the roles each DR subtype plays *** lab employed high throughput screening paradigms to discover highly selective modulators for the *** The NIH Molecular Libraries Program 400,000 + small molecule library was screened using the Discove Rx Path Hunter?β-arrestin assay for compounds that activate the DRD3 without effects on the *** and counter-screens assessed selectivity and mechanisms of *** identified 62 potential agonists,and chose the most promising to perform a structure-activity relationship(SAR) study to increase potency while maintaining *** lead compound identified through this process,ML417,was also characterized using bioluminescence resonance energy transfer(BRET)-based β-arrestin recruitment and G-protein activation assays as well as p-ERK *** neuroprotective properties of this compound were assessed using a SHSY5 Y neuronal cell *** ML417 displays potent,DRD3-selective agonist activity in multiple functional *** and functional GPCR screens(>165 receptors) show ML417 has limited cross-reactivity with other ***417 also displays superior(compared to the reference compound pramipexole),dose-dependent protection against a decrease in neurite length induced by 10 μmol·L^(-1) of the neurotoxin,6-hydroxydopamine,in the SHSY5 Y cell *** We have discovered and characterized ML417,a potent and highly selective DRD3 *** compound will be useful as a research tool,and may prove useful as a therapeutic drug lead.

关键词： Dopamine receptor high throughput screening subtype selectivity neuroprotection

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Cued aversive classical conditioning in humans: The role of trait-anxiety

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Open Journal of Psychiatry 2013年第2期3卷 230-237页

作者： óscar Andión Xavier Caseras Miquel àngel Fullana Alberto Fernandez-Teruel marc ferrer Miquel Casas Rafael Torrubia Departament de Psiquiatria i Medicina Legal Institut de Neurociencies Universitat Autonoma de Barcelona Bellaterra Spain Department of Psychological Medicine Cardiff University Cardiff United Kingdom Servei de Psiquiatria Hospital Vall d’Hebron Barcelona Spain

No study so far has specifically addressed the influence of individual differences in trait-anxiety on aversive classical conditioning as indexed by the startle reflex response. We compared the startle reflex responses between participants classified as high (n = 25) and low (n = 26) in trait-anxiety while undergoing a single-cue aversive classical conditioning procedure. High trait-anxiety group showed a greater startle response to the CS relative to the ITI at the post-acquisition compared with the pre-acquisition phase. Low trait-anxiety group did not show such a clear pattern of conditioning, and results from this group seem to be concealed by differences in the startle responses to the CS and the ITI during the pre-acquisition phase. However, a post-hoc analysis in which such differences at pre-conditioning were removed showed no conditioning effects in low trait-anxiety participants. Taking together, these results suggest differences between high and low trait-anxiety groups in the acquisition of the CS-US association. However, further research should clarify the unexpected pattern of responses shown by low trait-anxiety group.

关键词： Classical Conditioning Startle Reflex Trait-Anxiety Cued Conditioning Fear-Potentiated Startle

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Extract of Codiaeum luzonicum Merr. overcomes multidrug resistance in human colon cancer cells by modulating P-glycoprotein

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Asian Pacific Journal of Tropical Biomedicine 2022年第9期12卷 400-410页

作者： Regina Joyce E.ferrer marc Justin C.Ong Sonia D.Jacinto Institute of Biology University of the Philippines DilimanQuezon CityMetro ManilaPhilippines

Objective:To investigate anti-multidrug resistance(MDR)activity and safety of the bioactive fraction(CL11)from Codiaeum luzonicum crude leaf ***:Cytotoxic activity of CL11 against MDR and nonresistant colon cancer cells was assessed using MTT *** of cell death was investigated by annexin V-propidium iodide staining,TUNEL,and JC-1 *** examine mechanism of action,the effect on the expression and function of the MDR-implicated protein P-glycoprotein was tested using Western blotting and calcein assay,***:CL11 had an EC50 of 0.18,1.03 and 38.52µg/mL against HCT-15,HCT-15/Dox and HCT116,*** was mediated by inhibition of P-glycoprotein function and *** mode of cell death involved mitochondrial membrane depolarization and was mostly non-apoptotic at EC50 concentrations against HCT-15 and HCT-15/***:Fraction CL11 of Codiaeum luzonicum induces nonapoptotic cell death in MDR cancer cells by overcoming MDR through inhibition of P-glycoprotein expression and function.

关键词： Natural product Leaf extract Codiaeum luzonicum MDR cancer P-gp inhibitor Colorectal cancer

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On Banach Spaces Whose Unit Sphere Determines Polynomials

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Acta Mathematica Sinica,English Series 2007年第1期23卷 175-188页

作者： Jesús ferrer Departamentode Análisis Matemático Universidad de ValenciaDr.Moliner5046100 Burjasot(Valencia)

In this paper we study the problem of characterizing the real Banach spaces whose unit sphere determines polynomials, i.e., if two polynomials coincide in the unit sphere, is this sufficient to guarantee that they are identical？ We show that, in the frame of spaces with unconditional basis, non- reflexivity is a sufficient, although not necessary, condition for the above question to have an affirmative answer. We prove that the only lp^n spaces having this property are those with p irrational, while the only lp spaces which do not enjoy it are those with p an even integer. We also introduce a class of polynomial determining sets in any real Banach space.

关键词： unconditional basis polynomial determining property lp spaces

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Numerical modeling of cracking pattern's influence on the dynamic response of thickened tailings disposals: a periodic approach

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Earthquake Engineering and Engineering Vibration 2018年第1期17卷 179-190页

作者： Gabriel ferrer Esteban Sáez Christian Ledezma School of Engineering Pontificia Universidad Católica de Chile National Research Center for Integrated Natural Disaster Management

Copper production is an essential component of the Chilean economy. During the extraction process of copper, large quantities of waste materials（tailings） are produced, which are typically stored in large tailing ponds. Thickened Tailings Disposal（TTD） is an alternative to conventional tailings ponds. In TTD, a considerable amount of water is extracted from the tailings before their deposition. Once a thickened tailings layer is deposited, it loses water and it shrinks, forming a relatively regular structure of tailings blocks with vertical cracks in between, which are then filled up with ＂fresh＂ tailings once the new upper layer is deposited. The dynamic response of a representative column of this complex structure made out of tailings blocks with softer material in between was analyzed using a periodic half-space finite element model. The tailings＇ behavior was modeled using an elasto-plastic multi-yielding constitutive model, and Chilean earthquake records were used for the seismic analyses. Special attention was given to the liquefaction potential evaluation of TTD.

关键词： Thickened tailings Liquefaction Periodic modeling

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Sub Farm Interface of the ATLAS Dataflow System

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Plasma Science and Technology 2006年第3期8卷 355-357页

作者：刘尉悦安琪 Maria Lorenza ferrer School of Information Science and Engineering Ningbo University Ningbo 315211 China Fast Electronics Laboratory Department of Modern Physics University of Science and Technology of China Hefei 230026 China Fast Electronics Laboratory Department of Modern Physics University of Science and Technology of China Hefei 230026 China Laboratori Nazionali di Frascati Istituto Nazionale di Fisica Nucleare 00044 FrascatiItaly

Sub Farm Interface is the event builder of the ATLAS（A Toroidal LHC ApparatuS） Dataflow System. It receives event fragments from the Read Out System, builds full events and sends complete events to the Event Filter for high level event selection. This paper describes the implementation of the Sub Farm Interface. Furthermore, this paper introduces some issues on SFI（Sub Farm Interface） optimization and the monitoring service inside SFI.

关键词： nuclear physics event building data acquisition monitoring dataflow

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Germ-free, carefree: injured skin uses IL-24 to kick-start repair independent of pathogen-recognition

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Signal Transduction and Targeted Therapy 2023年第11期8卷 5129-5131页

作者： Ruben A.ferrer Marta Torregrossa Sandra Franz Department of Dermatology Allergology and VenerologyUniversity LeipzigLeipzigGermany

Skin injury releases damage-associated molecular patterns(DAMPs)represented by tissue-components and intracellular contents as well as changes in the levels of certain molecules and metabolites that signal the“non-homeostatic”state of the *** addition,microorganisms entering a wound release molecules,which are sensed as“non-self”(pathogen-associated molecular patterns,PAMPs).Together,DAMPs and PAMPs initiate a complex and coordinated repair process aimed at restoring *** exciting work from Liu et *** of an additional novel mechanism by which a“non-homeostatic”state in murine cutaneous wounds elicits a response through IL-24 to mediate repair(Fig.1).

关键词： wound homeostasis release

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Reduction of NO by CO using Pd–CeTb and Pd–CeZr catalysts supported on SiO_2 and La_2O_3–Al_2O_3

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Journal of Environmental Sciences 2015年第1期27卷 87-96页

作者： Victor ferrer Dora Finol Roger Solano Alexander Moronta Miguel Ramos Instituto de Superficies y Catálisis Facultad de Ingeniería Universidad del Zulia Instituto Zuliano de Investigaciones Tecnológicas km 15 carretera Vía a la Ca?ada Apartado 331 Venezuela

The catalytic activity of Pd catalysts supported on Ce0.73Tb0.27Ox/SiO2, Ce0.6Zr0.4Ox/Si O2,Ce0.73Tb0.27Ox/La2O3–Al2O3and Ce0.6Zr0.4Ox/La2O3–Al2O3was studied using the reduction of NO by CO. The catalysts were characterized by X-ray fluorescence, surface area, X-ray diffraction, temperature-programmed reduction, CO chemisorption and oxygen storage capacity. Temperature-programmed reduction results indicated that Tb or Zr incorporation improves the reducibility and oxygen storage capacity. CO chemisorption data suggested the presence of large Pd O particles due to the low CO/Pd ratio. No significant differences were obtained in light off temperatures（T Light off） for all Pd catalysts and the most active was1.5%Pd/Ce0.6Zr0.4Ox/SiO2.

关键词： Mixed oxides OSC Reduction of NO by CO Three way catalysts

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Resection *** for hepatocellular carcinoma:a never ending challenge

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Hepatobiliary Surgery and Nutrition 2023年第3期12卷 443-446页

作者： Joana ferrer-Fàbrega Jordi Bruix Barcelona Clínic Liver Cancer Group(BCLC) IDIBAPSBarcelonaSpain Hepatic Oncology Unit Hospital ClínicBarcelonaSpain Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit Department of SurgeryInstitute Clínic of Digestive and Metabolic Diseases(ICMDiM)Hospital ClínicBarcelonaSpain Department of Medicine and Departament of Surgery University of BarcelonaBarcelonaSpain CIBERehd BarcelonaSpain Liver Unit Institute Clínic of Digestive and Metabolic Diseases(ICMDiM)Hospital ClínicBarcelonaSpain

Liver transplantation(LT)is fully established in conventional clinical care for patients with hepatocellular carcinoma(HCC).The long-term survival of transplanted patients competes with the survival offered by surgical resection and this sets the scene for a debate for which a consensus answer based in evidence is not *** outcomes have steadily improved due a refined selection of patients and the availability of other effective options such as ablation or locoregional approach(chemoembolization or radioembolization)has allowed to avoid its indication as a last effective resource for desperate *** evolution has taken place for LT as it was early shown that if the tumor burden was reduced the survival results would be encouraging(1).

关键词： Hepatocellular carcinoma(HCC) liver resection liver transplantation(LT) survival recurrence

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A transition prediction method for flow over airfoils based on high-order dynamic mode decomposition

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Chinese Journal of Aeronautics 2019年第11期32卷 2408-2421页

作者： Mengmeng WU Zhonghua HAN Han NIE Wenping SONG Soledad Le CLAINCHE Esteban ferrer School of Aeronautics Northwestern Poly technical UniversityX i’an 710072China ETSIAE-UPM School of AeronauticsUniversidad Politecnica de MadridPza Cardenal Cisneros 3Spain

This article presents a novel approach for predicting transition locations over airfoils,which are used to activate turbulence model in a Reynolds-averaged Navier-Stokes flow *** approach combines Dynamic Mode Decomposition(DMD)with e^*** core idea is to use a spatial DMD analysis to extract the modes of unstable perturbations from a steady flowfield and substitute the local Linear Stability Theory(LST)analysis to quantify the spatial growth of Tollmien–Schlichting(TS)*** is assumed to take place at the stream-wise location where the most amplified mode’s N-factor reaches a prescribed threshold and a turbulence model is activated *** improve robustness,the high-order version of DMD technique(known as HODMD)is employed.A theoretical derivation is conducted to interpret how a spatial highorder DMD analysis can extract the growth rate of the unsteady *** new method is validated by transition predictions of flows over a low-speed Natural-Laminar-Flow(NLF)airfoil NLF0416 at various angles of attack and a transonic NLF airfoil *** transition locations predicted by our HODMD/e^Nmethod agree well with experimental data and compare favorably to those obtained by some existing methods■.It is shown that the proposed method is able to predict transition locations for flows over different types of airfoils and offers the potential for application to 3D wings as well as more complex configurations.

关键词： Airfoil Dynamic mode decomposition(DMD) e^N criterion Navier-Stokes equations Transition prediction

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