Angiotensin Type 1 Receptor Antagonists Protect Against Alpha-Synuclein-Induced Neuroinflammation and Dopaminergic Neuron Death

Altres ajuts: This study received funding from the Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas' intramural program (2014/01 and 2017/02), Galician Government (Xunta de Galicia, Consellería de Educación; GRC2014/002), Navarra Government (Departamento de Salud; 046-2017), and Fondo Europeo de Desarrollo Regional (Regional European Development Fund).The loss of dopaminergic neurons and α-synuclein accumulation are major hallmarks of Parkinson's disease (PD), and it has been suggested that a major mechanism of α-synuclein toxicity is microglial activation. The lack of animal models that properly reproduce PD, and particularly the underlying synucleinopathy, has hampered the clarification of PD mechanisms and the development of effective therapies. Here, we used neurospecific adeno-associated viral vectors serotype 9 coding for either the wild-type or mutated forms of human alpha-synuclein (WT and SynA53T, respectively) under the control of a synapsin promoter to further induce a marked dopaminergic neuron loss together with an important microglial neuroinflammatory response. Overexpression of neuronal alpha-synuclein led to increased expression of angiotensin type 1 receptors and NADPH oxidase activity, together with a marked increase in the number of OX-6-positive microglial cells and expression of markers of phagocytic activity (CD68) and classical pro-inflammatory/M1 microglial phenotype markers such as inducible nitric oxide synthase, tumor necrosis factor alpha, interleukin-1β, and IL-6. Moreover, a significant decrease in the expression of markers of immunoregulatory/M2 microglial phenotype such as the enzyme arginase-1 was constantly observed. Interestingly, alpha-synuclein-induced changes in microglial phenotype markers and dopaminergic neuron death were inhibited by simultaneous treatment with the angiotensin type 1 blockers candesartan or telmisartan. Our results suggest the repurposing of candesartan and telmisartan as a neuroprotective strategy for PD

GREENET - An Early Stage Training Network in Enabling Technologies for Green Radio

International audienceIn this paper, we describe GREENET (an early stage training network in enabling technologies for green radio), which is a new project recently funded by the European Commission under the auspices of the 2010 Marie Curie People Programme. Through the recruitment and personalized training of 17 Early Stage Researchers (ESRs), in GREENET we are committed to the development of new disruptive technologies to address all aspects of energy efficiency in wireless networks, from the user devices to the core network infrastructure, along with the ways the devices and equipment interact with one another. Novel techniques at the physical, link, and network layers to reduce the energy consumption and carbon footprint of 4G devices will be investigated, such as Spatial Modulation (SM) for Multiple-Input-Multiple-Output (MIMO) systems, Cooperative Automatic Repeat reQuest (C-ARQ) protocols, and Network Coding (NC) for lossy networks. Furthermore, cooperation and cognition paradigms will be exploited as additional assets to improve the energy efficiency of wireless networks with the challenging but indispensable constraint of optimizing the system capacity without degrading the user's Quality-of-Service (QoS)

Mechanisms linking excess adiposity and carcinogenesis promotion

Obesity constitutes one of the most important metabolic diseases being associated to insulin resistance development and increased cardiovascular risk. Association between obesity and cancer has also been well established for several tumor types, such as breast cancer in post-menopausal women, colorectal, and prostate cancer. Cancer is the first death cause in developed countries and the second one in developing countries, with high incidence rates around the world. Furthermore, it has been estimated that 15-20% of all cancer deaths may be attributable to obesity. Tumor growth is regulated by interactions between tumor cells and their tissue microenvironment. In this sense, obesity may lead to cancer development through dysfunctional adipose tissue and altered signaling pathways. In this review, three main pathways relating obesity and cancer development are examined: (i) inflammatory changes leading to macrophage polarization and altered adipokine profile; (ii) insulin resistance development; and (iii) adipose tissue hypoxia. Since obesity and cancer present a high prevalence, the association between these conditions is of great public health significance and studies showing mechanisms by which obesity lead to cancer development and progression are needed to improve prevention and management of these diseases

A randomized phase II clinical trial of dendritic cell vaccination following complete resection of colon cancer liver metastasis

Surgically resectable synchronic and metachronic liver metastases of colon cancer have high risk of relapse in spite of standard-of-care neoadjuvant and adjuvant chemotherapy regimens. Dendritic cell vaccines loaded with autologous tumor lysates were tested for their potential to avoid or delay disease relapses (NCT01348256). Patients with surgically amenable liver metastasis of colon adenocarcinoma (n = 19) were included and underwent neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Fifteen patients with disease-free resection margins were randomized 1:1 to receive two courses of four daily doses of dendritic cell intradermal vaccinations versus observation. The trial had been originally designed to include 56 patients but was curtailed due to budgetary restrictions. Follow-up of the patients indicates a clear tendency to fewer and later relapses in the vaccine arm (median disease free survival –DFS-) 25.26 months, 95% CI 8. 74-n.r) versus observation arm (median DFS 9.53 months, 95% CI 5.32–18.88)

Glucocerebrosidase expression patterns in the non-human primate brain

Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 gene. Mutations in GBA1 gene lead to Gaucher’s disease, the most prevalent lysosomal storage disorder. GBA1 mutations reduce GCase activity, therefore promoting the aggregation of alphasynuclein, a common neuropathological finding underlying Parkinson’s disease (PD) and dementia with Lewy bodies. However, it is also worth noting that a direct link between GBA1 mutations and alpha-synuclein aggregation indicating cause and effect is still lacking, with limited experimental evidence to date. Bearing in mind that a number of strategies increasing GCase expression for the treatment of PD are currently under development, here we sought to analyze the baseline expression of GCase in the brain of Macaca fascicularis, which has often been considered as the gold-standard animal model of PD. Although as with other lysosomal enzymes, GCase is expected to be ubiquitously expressed, here a number of regional variations have been consistently found, together with several specific neurochemical phenotypes expressing very high levels of GCase. In this regard, the most enriched expression of GCase was constantly found in cholinergic neurons from the nucleus basalis of Meynert, dopaminergic cells in the substantia nigra pars compacta, serotoninergic neurons from the raphe nuclei, as well as in noradrenergic neurons located in the locus ceruleus. Moreover, it is also worth noting that moderate levels of expression were also found in a number of areas within the paleocortex and archicortex, such as the entorhinal cortex and the hippocampal formation, respectively

New constraints on protostellar jet collimation from high-density gas UV tracers

The analysis of high-resolution profiles of the semiforbidden UV lines of C III](1908) and Si III](1892) in the spectra of T Tauri stars (TTSs) shows the following : (1) There is C III](1908) and Si III](1892) emission at velocities that are similar to those observed in the optical forbidden lines formed in the TTSs jets. The luminosity of the UV lines is comparable to that of the optical lines. (2) The comparison between the optical and UV light curves indicates that the C III](1908) and Si III](1892) emission of RY Tau is not associated with accretion shocks, but it is produced farther than 2 R-* from the star. (3) The profiles of the UV semiforbidden lines are significantly broader than those of the optical forbidden lines. These profiles cannot be produced in a narrow collimated beam, and they are most likely produced in a bow-shaped shock wave formed at the base of the optical jet, where the hot gas emits in a broad range of projected radial velocities. (4) The atmosphere of RU Lup contributes significantly to the Si III](1892) emission. (5) A puzzling narrow feature is observed close to the C III](1908) line. The feature is blueshifted by -260 km s(-1), which corresponds to the wind terminal velocity measured in the P Cygni profile of the Mg II (UV1) lines. Moreover, constraints are derived on the characteristics of the C III](1908) and Si III](1892) emitting region in RY Tau. It is shown that 4.7 less than or equal to log T-e less than or equal to 5.0 and 10(9) cm(-3) less than or equal to N-e less than or equal to 10(11) cm(-3) provided that the emission is produced in a collisional plasma and that the 1665 Angstrom feature observed in low-dispersion International Ultraviolet Explorer (IUE) spectra is confirmed to be O III](1665) emission produced in the wind. These very high densities are difficult to generate in the shocks produced by the magnetic pinching of centrifugally driven magnetized disk winds. The data also suggest that the shocked layer has a radius of some few stellar radii and it is closer than similar to 38 R-* to the star

Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk

Plasma cell-free DNA (cfDNA) is a surrogate marker of neutrophil extracellular traps (NETs) that contribute to immunothrombosis. There is growing interest about the mechanisms underlying NET formation and elevated cfDNA, but little is known about the factors involved. We aimed to identify genes involved in the regulation of cfDNA levels using data from the Genetic Analysis of Idiopathic Thrombophilia (GAIT-2) Project. Imputed genotypes, whole blood RNA-Seq data, and plasma cfDNA quantification were available for 935 of the GAIT-2 participants from 35 families with idiopathic thrombophilia. We performed heritability and GWAS analysis for cfDNA. The heritability of cfDNA was 0.26 ( p  = 3.7 × 10 (−6) ), while the GWAS identified a significant association (rs1687391, p  = 3.55 × 10 (−10) ) near the ORM1 gene, on chromosome 9. An eQTL (expression quantitative trait loci) analysis revealed a significant association between the lead GWAS variant and the expression of ORM1 in whole blood ( p  = 6.14 × 10 (−9) ). Additionally, ORM1 expression correlated with levels of cfDNA ( p  = 4.38 × 10 (−4) ). Finally, genetic correlation analysis between cfDNA and thrombosis identified a suggestive association ( ρ (g)  = 0.43, p  = 0.089). All in all, we show evidence of the role of ORM1 in regulating cfDNA levels in plasma, which might contribute to the susceptibility to thrombosis through mechanisms of immunothrombosis

Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ). PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions.</p> <p>Methods</p> <p>We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers) provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662.</p> <p>Results</p> <p>We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co-administration of GW9662.</p> <p>Conclusion</p> <p>The results suggest that telmisartan provides effective neuroprotection against dopaminergic cell death and that the neuroprotective effect is mediated by PPAR-γ activation. However, the results in AT1-deficient mice show that blockage of AT1, unrelated to the pharmacological properties of AT1 blockers, also protects against dopaminergic cell death and neuroinflammation. Furthermore, the results show that PPAR-γ activation is involved in the anti-inflammatory and neuroprotective effects of AT1 deletion.</p

Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung cancer

Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n=3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (p(combined)=5.66x10(-5); ORcombined=2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (p(combined)=1.02x10(-4); ORcombined=2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10D mRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p=0.01 and p<0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p=0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC

The VLA/ALMA Nascent Disk and Multiplicity (VANDAM) Survey of Orion Protostars. I. Identifying and Characterizing the Protostellar Content of the OMC-2 FIR4 and OMC-2 FIR3 Regions

We present ALMA (0.87~mm) and VLA (9~mm) observations toward OMC2-FIR4 and OMC2-FIR3 within the Orion integral-shaped filament that are thought to be the nearest regions of intermediate mass star formation. We characterize the continuum sources within these regions on $\sim$40~AU (0\farcs1) scales and associated molecular line emission at a factor of $\sim$30 better resolution than previous observations at similar wavelengths. We identify six compact continuum sources within OMC2-FIR4, four in OMC2-FIR3, and one additional source just outside OMC2-FIR4. This continuum emission is tracing the inner envelope and/or disk emission on less than 100~AU scales. HOPS-108 is the only protostar in OMC2-FIR4 that exhibits emission from high-excitation transitions of complex organic molecules (e.g., methanol and other lines) coincident with the continuum emission. HOPS-370 in OMC2-FIR3 with L~$\sim$~360~\lsun, also exhibits emission from high-excitation methanol and other lines. The methanol emission toward these two protostars is indicative of temperatures high enough to thermally evaporate methanol from icy dust grains; overall these protostars have characteristics similar to hot corinos. We do not identify a clear outflow from HOPS-108 in \twco, but find evidence of interaction between the outflow/jet from HOPS-370 and the OMC2-FIR4 region. The multitude of observational constraints indicate that HOPS-108 is likely a low to intermediate-mass protostar in its main mass accretion phase and it is the most luminous protostar in OMC2-FIR4. The high resolution data presented here are essential for disentangling the embedded protostars from their surrounding dusty environments and characterizing them