The purinergic P2X7 receptor as a potential drug target to combat neuroinflammation in neurodegenerative diseases

Neurodegenerative diseases (NDDs) represent a huge social burden, particularly in Alzheimer's disease (AD) in which all proposed treatments investigated in murine models have failed during clinical trials (CTs). Thus, novel therapeutic strategies remain crucial. Neuroinflammation is a common pathogenic feature of NDDs. As purinergic P2X7 receptors (P2X7Rs) are gatekeepers of inflammation, they could be developed as drug targets for NDDs. Herein, we review this challenging hypothesis and comment on the numerous studies that have investigated P2X7Rs, emphasizing their molecular structure and functions, as well as their role in inflammation. Then, we elaborate on research undertaken in the field of medicinal chemistry to determine potential P2X7R antagonists. Subsequently, we review the state of neuroinflammation and P2X7R expression in the brain, in animal models and patients suffering from AD, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. Next, we summarize the in vivo studies testing the hypothesis that by mitigating neuroinflammation, P2X7R blockers afford neuroprotection, increasing neuroplasticity and neuronal repair in animal models of NDDs. Finally, we reviewed previous and ongoing CTs investigating compounds directed toward targets associated with NDDs; we propose that CTs with P2X7R antagonists should be initiated. Despite the high expectations for putative P2X7Rs antagonists in various central nervous system diseases, the field is moving forward at a relatively slow pace, presumably due to the complexity of P2X7Rs. A better pharmacological approach to combat NDDs would be a dual strategy, combining P2X7R antagonism with drugs targeting a selective pathway in a given NDD.The authors would like to acknowledge the support received from the EU Horizon 2020 Research and Innovation Program under Maria Sklodowska‐Curie (Grant Agreement No. 766124). The authors would also like to thank the support received from the Ministerio de Economía y Competitividad (MINECO, Spain; Grant No. SAF2016‐78892R to Luis Gandía and Antonio G. García) and Fundación Teófilo Hernando

Potentiation of 5-fluorouracil encapsulated in zeolites as drug delivery systems for in vitro models of colorectal carcinoma

The studies of potentiation of 5-fluorouracil (5-FU), a traditional drug used in the treatment of several cancers, including colorectal (CRC), were carried out with zeolites Faujasite in the sodium form, with different particle sizes (NaY, 700nm and nanoNaY, 150nm) and Linde type L in the potassium form (LTL) with a particle size of 80nm. 5-FU was loaded into zeolites by liquid-phase adsorption. Characterization by spectroscopic techniques (FTIR, 1H NMR and 13C and 27Al solid-state MAS NMR), chemical analysis, thermal analysis (TGA), nitrogen adsorption isotherms and scanning electron microscopy (SEM), demonstrated the successful loading of 5-FU into the zeolite hosts. In vitro drug release studies (PBS buffer pH 7.4, 37°C) revealed the release of 80-90% of 5-FU in the first 10min. To ascertain the drug release kinetics, the release profiles were fitted to zero-order, first-order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas and Weibull kinetic models. The in vitro dissolution from the drug delivery systems (DDS) was explained by the Weibull model. The DDS efficacy was evaluated using two human colorectal carcinoma cell lines, HCT-15 and RKO. Unloaded zeolites presented no toxicity to both cancer cells, while all DDS allowed an important potentiation of the 5-FU effect on the cell viability. Immunofluorescence studies provided evidence for zeolite-cell internalization.RA is recipient of fellowship SFRH/BI/51118/2010 from Fundacao para a Ciencia e a Tecnologia (FCT, Portugal). This work was supported by the FCT projects refs. PEst-C/QUI/UI0686/2011 and PEst-C/CTM/LA0011/2011 and the Centre of Chemistry and Life and Health Sciences Research Institute (University of Minho, Portugal). The NMR spectrometer is part of the National NMR Network (RNRMN), supported with funds from FCT/QREN (Quadro de Referencia Estrategico Nacional)

Modulating the photoluminescence of bridged silsesquioxanes incorporating Eu(3+)-complexed n,n '-diureido-2,2 '-bipyridine isomers: application for luminescent solar concentrators

Two new urea-bipyridine derived bridged organosilanes (P5 and P6) have been synthesized and their hydrolysis-condensation under nucleophilic catalysis in the presence of Eu(3+) salts led to luminescent bridged silsesquioxanes (M5-Eu and M6-Eu). An important loading of Eu(3+) (up to 11%(w)) can be obtained for the material based on the 6,6'-isomer. Indeed the photoluminescence properties of these materials, that have been investigated in depth (photoluminescence (PL), quantum yield, lifetimes), show a significantly different complexation mode of the Eu(3+) ions for M6-Eu, compared with M4-Eu (obtained from the already-reported 4,4'-isomer) and M5-Eu. Moreover, M6-Eu exhibits the highest absolute emission quantum yield value (0.18 +/- 0.02) among these three materials. The modification of the sol composition upon the addition of a malonamide derivative led to similar luminescent features but with an increased quantum yield (026 +/- 0.03). In addition, M6-Eu can be processed as thin films by spin-coating on glass substrates, leading to plates coated by a thin layer (similar to 54 nm) of Eu(3+)-containing hybrid silica exhibiting one of the highest emission quantum yields reported so far for films of Eu(3+)-containing hybrids (0.34 +/- 0.03) and an interesting potential as new luminescent solar concentrators (LSCs) with an optical conversion efficiency of similar to 4%. The ratio between the light guided to the film edges and the one emitted by the surface of the film was quantified through the mapping of the intensity of the red pixels (in the RGB color model) from a film image. This quantification enabled a more accurate estimation of the transport losses due to the scattering of the emitted light in the film (0.40), thereby correcting the initial optical conversion efficiency to a value of 1.7%.FCT - PTDC/CTM/101324/2008COMPETEFEDE

Triple-GEM discharge probability studies at CHARM: Simulations and experimental results

The CMS muon system in the region with 2.03<|η|<2.82 is characterized by a very harsh radiation environment which can generate hit rates up to 144 kHz/cm$^{2}$ and an integrated charge of 8 C/cm$^{2}$ over ten years of operation. In order to increase the detector performance and acceptance for physics events including muons, a new muon station (ME0) has been proposed for installation in that region. The technology proposed is Triple—Gas Electron Multiplier (Triple-GEM), which has already been qualified for the operation in the CMS muon system. However, an additional set of studies focused on the discharge probability is necessary for the ME0 station, because of the large radiation environment mentioned above. A test was carried out in 2017 at the Cern High energy AcceleRator Mixed (CHARM) facility, with the aim of giving an estimation of the discharge probability of Triple-GEM detectors in a very intense radiation field environment, similar to the one of the CMS muon system. A dedicated standalone Geant4 simulation was performed simultaneously, to evaluate the behavior expected in the detector exposed to the CHARM field. The geometry of the detector has been carefully reproduced, as well as the background field present in the facility. This paper presents the results obtained from the Geant4 simulation, in terms of sensitivity of the detector to the CHARM environment, together with the analysis of the energy deposited in the gaps and of the processes developed inside the detector. The discharge probability test performed at CHARM will be presented, with a complete discussion of the results obtained, which turn out to be consistent with measurements performed by other groups

Detector Control System for the GE1/1 slice test

Gas Electron Multiplier (GEM) technology, in particular triple-GEM, was selected for the upgrade of the CMS endcap muon system following several years of intense effort on R&D. The triple-GEM chambers (GE1/1) are being installed at station 1 during the second long shutdown with the goal of reducing the Level-1 muon trigger rate and improving the tracking performance in the harsh radiation environment foreseen in the future LHC operation [1]. A first installation of a demonstrator system started at the beginning of 2017: 10 triple-GEM detectors were installed in the CMS muon system with the aim of gaining operational experience and demonstrating the integration of the GE1/1 system into the trigger. In this context, a dedicated Detector Control System (DCS) has been developed, to control and monitor the detectors installed and integrating them into the CMS operation. This paper presents the slice test DCS, describing in detail the different parts of the system and their implementation

Benchmarking LHC background particle simulation with the CMS triple-GEM detector

In 2018, a system of large-size triple-GEM demonstrator chambers was installed in the CMS experiment at CERN\u27s Large Hadron Collider (LHC). The demonstrator\u27s design mimicks that of the final detector, installed for Run-3. A successful Monte Carlo (MC) simulation of the collision-induced background hit rate in this system in proton-proton collisions at 13 TeV is presented. The MC predictions are compared to CMS measurements recorded at an instantaneous luminosity of 1.5 ×10$^{34}$ cm$^{-2}$ s$^{-1}$. The simulation framework uses a combination of the FLUKA and GEANT4 packages. FLUKA simulates the radiation environment around the GE1/1 chambers. The particle flux by FLUKA covers energy spectra ranging from 10$^{-11}$ to 10$^{4}$ MeV for neutrons, 10$^{-3}$ to 10$^{4}$ MeV for γ\u27s, 10$^{-2}$ to 10$^{4}$ MeV for e$^{±}$, and 10$^{-1}$ to 10$^{4}$ MeV for charged hadrons. GEANT4 provides an estimate of the detector response (sensitivity) based on an accurate description of the detector geometry, the material composition, and the interaction of particles with the detector layers. The detector hit rate, as obtained from the simulation using FLUKA and GEANT4, is estimated as a function of the perpendicular distance from the beam line and agrees with data within the assigned uncertainties in the range 13.7-14.5%. This simulation framework can be used to obtain a reliable estimate of the background rates expected at the High Luminosity LHC

CAD-based computer vision: the automatic generation of recognition stragtegies

Journal ArticleThree-dimensional model-based computer vision uses geometric models of objects and sensed data to recognize objects in a scene. Likewise, Computer Aided Design (CAD) systems are used to interactively generate three-dimensional models during these fields. Recently, the unification of CAD and vision systems has become the focus of research in the context of manufacturing automation. This paper explores the connection between CAD and computer vision. A method for the automatic generation of recognition strategies based on the geometric properties of shape has been devised and implemented. This uses a novel technique developed for quantifying the following properties of features which compose models used in computer vision: robustness, completeness, consistency, cost, and uniqueness. By utilizing this information, the automatic synthesis of a specialized recognition scheme, called a Strategy Tree, is accomplished. Strategy Trees describe, in a systematic and robust manner. the search process used for recognition and localization of particular objects in the given scene. They consist of selected features which satisfy system constraints and Corroborating Evidence Subtrees which are used in the formation of hypotheses. Verification techniques, used to substantiate or refute these hypotheses, are explored. Experiments utilizing 3-D data are presented

Modeling the triple-GEM detector response to background particles for the CMS Experiment

An estimate of environmental background hit rate on triple-GEM chambers is performed using Monte Carlo (MC) simulation and compared to data taken by test chambers installed in the CMS experiment (GE1/1) during Run-2 at the Large Hadron Collider (LHC). The hit rate is measured using data collected with proton-proton collisions at 13 TeV and a luminosity of 1.5$\times10^{34}$ cm$^{-2}$ s$^{-1}$. The simulation framework uses a combination of the FLUKA and Geant4 packages to obtain the hit rate. FLUKA provides the radiation environment around the GE1/1 chambers, which is comprised of the particle flux with momentum direction and energy spectra ranging from $10^{-11}$ to $10^{4}$ MeV for neutrons, $10^{-3}$ to $10^{4}$ MeV for $\gamma$'s, $10^{-2}$ to $10^{4}$ MeV for $e^{\pm}$, and $10^{-1}$ to $10^{4}$ MeV for charged hadrons. Geant4 provides an estimate of detector response (sensitivity) based on an accurate description of detector geometry, material composition and interaction of particles with the various detector layers. The MC simulated hit rate is estimated as a function of the perpendicular distance from the beam line and agrees with data within the assigned uncertainties of 10-14.5%. This simulation framework can be used to obtain a reliable estimate of background rates expected at the High Luminosity LHC.Comment: 16 pages, 9 figures, 6 table

Impact of magnetic field on the stability of the CMS GE1/1 GEM detector operation

The Gas Electron Multiplier (GEM) detectors of the GE1/1 station of the CMS experiment have been operated in the CMS magnetic field for the first time on the 7$^{th}$ of October 2021. During the magnetic field ramps, several discharge phenomena were observed, leading to instability in the GEM High Voltage (HV) power system. In order to reproduce the behavior, it was decided to conduct a dedicated test at the CERN North Area with the Goliath magnet, using four GE1/1 spare chambers. The test consisted in studying the characteristics of discharge events that occurred in different detector configurations and external conditions. Multiple magnetic field ramps were performed in sequence: patterns in the evolution of the discharge rates were observed with these data. The goal of this test is the understanding of the experimental conditions inducing discharges and short circuits in a GEM foil. The results of this test lead to the development of procedure for the optimal operation and performance of GEM detectors in the CMS experiment during the magnet ramps. Another important result is the estimation of the probability of short circuit generation, at 68 % confidence level, p$_{short}$$^{HV}$ $^{OFF}$ = 0.42$^{-0.35+0.94}$% with detector HV OFF and p$_{short}$$^{HV}$ $^{OFF}$ < 0.49% with the HV ON. These numbers are specific for the detectors used during this test, but they provide a first quantitative indication on the phenomenon, and a point of comparison for future studies adopting the same procedure