Fingolimod Limits Acute Aβ Neurotoxicity and Promotes Synaptic Versus Extrasynaptic NMDA Receptor Functionality in Hippocampal Neurons

Fingolimod, also known as FTY720, is an analogue of the sphingolipid sphingosine, which has been proved to be neuroprotective in rodent models of Alzheimer's disease (AD). Several cellular and molecular targets underlying the neuroprotective effects of FTY720 have been recently identified. However, whether the drug directly protects neurons from toxicity of amyloid-beta (A\u3b2) still remains poorly defined. Using a combination of biochemical assays, live imaging and electrophysiology we demonstrate that FTY720 induces a rapid increase in GLUN2A-containing neuroprotective NMDARs on the surface of dendritic spines in cultured hippocampal neurons. In addition, the drug mobilizes extrasynaptic GLUN2B-containing NMDARs, which are coupled to cell death, to the synapses. Altered ratio of synaptic/extrasynaptic NMDARs decreases calcium responsiveness of neurons to neurotoxic soluble A\u3b2 1-42 and renders neurons resistant to early alteration of calcium homeostasis. The fast defensive response of FTY720 occurs through a Sphingosine-1-phosphate receptor (S1P-R) -dependent mechanism, as it is lost in the presence of S1P-R1 and S1P-R3 antagonists. We propose that rapid synaptic relocation of NMDARs might have direct impact on amelioration of cognitive performance in transgenic APPswe/PS1dE9 AD mice upon sub-chronic treatment with FTY720

HIV-1 matrix protein p17 misfolding forms toxic amyloidogenic assemblies that induce neurocognitive disorders

© 2017 The Author(s). Human immunodeficiency virus type-1 (HIV-1)-Associated neurocognitive disorder (HAND) remains an important neurological manifestation that adversely affects a patient's quality of life. HIV-1 matrix protein p17 (p17) has been detected in autoptic brain tissue of HAND individuals who presented early with severe AIDS encephalopathy. We hypothesised that the ability of p17 to misfold may result in the generation of toxic assemblies in the brain and may be relevant for HAND pathogenesis. A multidisciplinary integrated approach has been applied to determine the ability of p17 to form soluble amyloidogenic assemblies in vitro. To provide new information into the potential pathogenic role of soluble p17 species in HAND, their toxicological capability was evaluated in vivo. In C. elegans, capable of recognising toxic assemblies of amyloidogenic proteins, p17 induces a specific toxic effect which can be counteracted by tetracyclines, drugs able to hinder the formation of large oligomers and consequently amyloid fibrils. The intrahippocampal injection of p17 in mice reduces their cognitive function and induces behavioral deficiencies. These findings offer a new way of thinking about the possible cause of neurodegeneration in HIV-1-seropositive patients, which engages the ability of p17 to form soluble toxic assemblies

Lipid-based nanoparticles with high binding affinity for amyloid-\u3b21-42 peptide

The neurotoxic beta-amyloid peptide (A\u3b2), formed in anomalous amounts in Alzheimer\u2019s disease (AD), is released as monomer and then undergoes aggregation forming oligomers, fibrils and plaques in diseased brains. A\u3b2 aggregates are considered as possible targets for therapy and/or diagnosis of AD. Since nanoparticles (NPs) are promising vehicles for imaging probes and therapeutic agents, we realized and characterized two types of NPs (liposomes and solid lipid nanoparticles, 145 and 76 nm average size, respectively) functionalized to target A\u3b21\u201342 with high affinity. Preliminary immunostaining studies identified anionic phospholipids [phosphatidic acid (PA) and cardiolipin (CL)] as suitable A\u3b21\u201342 ligands. PA/CL-functionalized, but not plain, NPs interacted with A\u3b21\u201342 aggregates as indicated by ultracentrifugation experiments, in which binding reaction occurred in solution, and by Surface Plasmon Resonance (SPR) experiments, in which NPs flowed onto immobilized A\u3b21\u201342. All these experiments were carried out in buffered saline. SPR studies indicated that, when exposed on NPs surface, PA/CL display very high affinity for A\u3b21\u201342 fibrils (22\u201360 nm), likely because of the occurrence of multivalent interactions which markedly decrease the dissociation of PA/CL NPs from A\u3b2. Noteworthy, PA/CL NPs did not bind to bovine serum albumin. The PA/CL NPs described in this work are endowed with the highest affinity for A\u3b2 so far reported. These characteristics make our NPs a very promising vector for the targeted delivery of potential new diagnostic and therapeutic molecules to be tested in appropriate animal models

Qualidade da irrigação controlada por tensiômetros em pivô central Quality of center pivot irrigation controlled by tensiometers

A qualidade da irrigação foi avaliada durante a safra de inverno do ano de 1988 na cultura do feijoeiro (Phaseolus vulgaris L.), irrigado por pivô central, em área de ocorrência de Latossolo Roxo (A moderado, textura argilosa a muito argilosa, distrófico), em Guaíra, SP. Os critérios utilizados para esta avaliação foram a eficiência do uso da água pela cultura e a efetividade da irrigação, esta última representada pela eficiência de aplicação da água, a uniformidade de distribuição da água sobre o solo e a eficiência de armazenagem da água no solo. O monitoramento das irrigações foi realizado através da instalação de 20 baterias de tensiômetros e 60 coletores de água de chuva e irrigação ao longo de uma transeção de 300 metros na direção radial do pivô. Os tensiômetros de cada bateria foram instalados a 15 cm e 30 cm de profundidade e espaçados entre si de 15 metros. Os coletores foram instalados a uma altura de 50 cm da superfície do terreno e distanciados entre si de 5 metros. O controle da irrigação foi feito com base na média ponderada dos 20 valores diários de potencial mátrico a 15 cm de profundidade, tendo como fator de ponderação a área representativa de cada tensiômetro. O valor mínimo de potencial mátrico estabelecido para a definição do momento da irrigação foi -0,06 MPa à profundidade de 15 cm e o valor da lâmina de água a ser aplicada em cada irrigação, calculado tendo-se em conta o valor de -0,008 MPa para o potencial mátrico a capacidade de campo. Os resultados obtidos mostraram que as irrigações efetuadas foram de alta qualidade uma vez que foram elevados os valores da eficiência de aplicação (80%) e dos coeficientes de uniformidade de distribuição (94 e 91%) calculados a partir das 16 irrigações acumuladas, o mesmo ocorrendo com a eficiência de armazenagem (95%) e a eficiência de uso da água (0,8 kg/m³).<br>The irrigation quality was evaluated for a center pivot winter bean (Phaseolus vulgaris, L) crop in a Typic Hapludox of the county of Guaíra (SP), Brazil (20&deg; 27'30"S, 48&deg;19'30"W, 495m). Criteria used for this evaluation were the crop water use efficiency and the irrigation "effectivity", the latter being assessed by the water application efficiency, the water distribution uniformity on the soil surface and the soil water storage efficiency. The irrigation monitoring was done by means of 20 sets of two tensiometers (15 and 30 cm soil depths) installed at each 15 m on a 300 m transect along the radial direction of the pivot, and 60 rain/irrigation gages installed at each 5 m on the same transect. The irrigation control was done by means of the 15 cm-soil depth tensiometers. The minimum matric potential value used to define the irrigation timing was -0,06 MPa and the water depth to be applied by the pivot was calculated taking into account the value of -0,008 MPa for the soil at field capacity. Results showed that irrigations were of high quality since high values of water application efficiency (80%) and water distribution uniformity coefficients (94% and 91%) were obtained, the same occurring with the soil water storage (95%) and crop water use (0,8 kg/m³) efficiencies

Formation of a 2D Meta stable Oxide by Differential Oxidation of AgCu Alloys

Metal alloy catalysts can develop complex surface structures when exposed to reactive atmospheres. The structures of the resulting surfaces have intricate relationships with a myriad of factors, such as the affinity of the individual alloying elements to the components of the gas atmosphere, and the bond strengths of the multitude of low-energy surface compounds that can be formed. Identifying the atomic structure of such surfaces is a prerequisite for establishing structure-property relationships, as well as for modeling such catalysts in ab initio calculations. Here we show that an alloy, consisting of an oxophilic metal (Cu) diluted into a noble metal (Ag), forms a meta-stable 2-dimensional oxide monolayer the more oxophilic metal, when the alloy is subjected to oxidative reaction conditions. The presence of this oxide is correlated with selectivity in the corresponding test reaction of ethylene epoxidation. In the present study, using a combination of in-situ, ex-situ and theoretical methods (NAP-XPS, XPEEM, LEED, and DFT) we determine the structure to be a 2-dimensional analogue of Cu2O, resembling a single lattice plane of Cu2O. The overlayer holds an pseudo-epitaxial relationship with the underlying noble metal. Spectroscopic evidence shows that the oxide’s electronic structure is qualitatively distinct from its 3-dimensional counterpart, and due to weak electronic coupling with the underlying noble metal, it exhibits metallic properties. These findings provide precise details of this peculiar structure, and valuable insights into how alloying can enhance catalytic properties