Interplay between hormones, the immune system, and metabolic disorders

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Co-Stimulation of PAFR and CD36 Is Required for oxLDL-Induced Human Macrophages Activation

The oxidative process of LDL particles generates molecules which are structurally similar to platelet-activating factor (PAF), and some effects of oxidized LDL (oxLDL) have been shown to be dependent on PAF receptor (PAFR) activation. In a previous study, we showed that PAFR is required for upregulation of CD36 and oxLDL uptake. In the present study we analyzed the molecular mechanisms activated by oxLDL in human macrophages and the contribution of PAFR to this response. Human adherent monocytes/macrophages were stimulated with oxLDL. Uptake of oxLDL and CD36 expression were determined by flow cytometry; MAP kinases and Akt phosphorylation by Western blot; IL-8 and MCP-1 concentration by ELISA and mRNA expression by real-time PCR. To investigate the participation of the PI3K/Akt pathway, Gαi-coupled protein or PAFR, macrophages were treated with LY294002, pertussis toxin or with the PAFR antagonists WEB2170 and CV3988, respectively before addition of oxLDL. It was found that the addition of oxLDL to human monocytes/macrophages activates the PI3K/Akt pathway which in turn activates the MAPK (p38 and JNK). Phosphorylation of Akt requires the engagement of PAFR and a Gαi-coupled protein. The upregulation of CD36 protein and the uptake of oxLDL as well as the IL-8 production are dependent on PI3K/Akt pathway activation. The increased CD36 protein expression is dependent on PAFR and Gαi-coupled protein. Transfection studies using HEK 293t cells showed that oxLDL uptake occurs with either PAFR or CD36, but IL-8 production requires the co-transfection of both PAFR and CD36. These findings show that PAFR has a pivotal role in macrophages response to oxLDL and suggest that pharmacological intervention at the level of PAFR activation might be beneficial in atherosclerosis

Auto anti oxLDL, IgM and IgG: comparison between sedentary and athletes

Introduction: The practice of regular physical activity contributes to reduce the prevalence of coronary hearth disease (CHD) and aerobic exercises are associated with beneficial changes in the profile of circulating lipids and lipoproteins. However in the past years the oxidative hypothesis assumed great importance in the pathogenesis of CHD. During exhaustive exercises there is a greater possibility of oxidation of LDL, forming oxidized LDL (oxLDL) that has a key role in atherogenesis. However the incidence of coronary events in athletes is lower than in sedentary persons. It is described in the literature that we can found in serum auto autoantibodies anti-oxLDL, of the isotypes IgG and IgM. The former involved with atherogenesis and the latter with an atheroprotective function. The aim of this study was to verify if there are differences in the prevalence of the different autoantibodies between athletes and sedentary persons. Methods: Twenty male recreational runners and twenty male sedentary individuals living in the city of São Paulo were recruited for the study. Both the study protocol and consent form had been approved by the UNIFESP-EPM Ethics Committee. None of the participants were using lipid-lowering medications, no smokers, addicted to alcohol consumption, obese or had systemic arterial hypertension, neither liver, renal, metabolic, inflammatory or neoplastic diseases. Blood sample were collected at rest. Blood draws for all the individuals were performed after 12 hours of fasting. IgM and IgG anti ox LDL specific reactivity in serum, were measured by ELISA using previously stored serum. Student’s t-test was used to analyze differences in age and body mass index (BMI). The Mann-Whitney test was used to determine if the differences between the results for sedentary individuals and those for runners at rest were significant. Results: We found that at rest the group of athletes studied showed a statistically higher concentration of IgM autoantibodies against ox-LDL than controls (figure 1 a). At the same time, IgG autoantibodies anti ox-LDL presented the same concentration in controls and athletes (Figure 1 b). Conclusion: This finding is of extreme importance when we consider the prevalence of CHD in those different populations and the opposite actions of these two isotypes of antibodies

Uptake of oxLDL and IL-10 production by macrophages requires PAFR and CD36 recruitment into the same lipid rafts

Macrophage interaction with oxidized low-density lipoprotein (oxLDL) leads to its differentiation into foam cells and cytokine production, contributing to atherosclerosis development. In a previous study, we showed that CD36 and the receptor for platelet-activating factor (PAFR) are required for oxLDL to activate gene transcription for cytokines and CD36. Here, we investigated the localization and physical interaction of CD36 and PAFR in macrophages stimulated with oxLDL. We found that blocking CD36 or PAFR decreases oxLDL uptake and IL-10 production. OxLDL induces IL-10 mRNA expression only in HEK293T expressing both receptors (PAFR and CD36). OxLDL does not induce IL-12 production. The lipid rafts disruption by treatment with βCD reduces the oxLDL uptake and IL-10 production. OxLDL induces co-immunoprecipitation of PAFR and CD36 with the constitutive raft protein flotillin-1, and colocalization with the lipid raft-marker GM1-ganglioside. Finally, we found colocalization of PAFR and CD36 in macrophages from human atherosclerotic plaques. Our results show that oxLDL induces the recruitment of PAFR and CD36 into the same lipid rafts, which is important for oxLDL uptake and IL-10 production. This study provided new insights into how oxLDL interact with macrophages and contributing to atherosclerosis development

Electron microprobe chemical U-Th-Pb and La-ICP-MS U-Pb dating of multiple hydrothermal and metamorphic events recorded in minerals of the Lagoa Real uraniferous albitites (Brazil)

Os albititos uraníferos de Lagoa Real são rochas que passaram por várias modificações após a formação. A datação química U-Th-Pb por microssonda eletrônica e datação U-Pb por LAICP-MS dos minerais dos albititos revelaram cristalização e metamorfismo isoquímico do protólito (sienitos sódicos portadores de U) em cerca de 2,0-1,9 Ga durante as fases finais do evento orogênico Orosiriano, quando a primeira geração de uraninitas foi formada. Mobilizações múltiplas de urânio e chumbo promovidas por pelo menos cinco eventos hidrotermais (1,7 Ga, 1,5 Ga, 1,3 Ga, 1,1 Ga e 1,0 Ga) foram detectadas nos albititos. A provável formação de um segundo grupo de uraninitas e/ou o reajuste do relógio U-Pb das uraninitas mais antigas durante o evento orogênico Brasiliano (0,5 Ga) também ocorreram.Lagoa Real uraniferous albitites are rocks which went through multiple modifications after formation. Electron microprobe chemical U-Th-Pb and LA-ICP-MS U-Pb dating of minerals of albitites reveal protolith (U-bearing sodic syenites) crystallization and isochemical metamorphism at ca. 2.0-1.9 Ga during the final stages of the Orosirian orogenic event, when the first generation of uraninites was formed. Multiple uranium and lead mobilization promoted by at least five hydrothermal events (ca. 1.7 Ga, ca. 1.5 Ga, ca. 1.3 Ga, ca. 1.1 Ga, and ca. 1.0 Ga) was detected in the albitites. A probable formation of a second uraninite group and/or resetting of UPb clock of older uraninites during the Brasiliano orogenic event at ca. 0.5 Ga also took place

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

Observation of excited Lambda_b0 baryons

Using pp collision data corresponding to 1.0 fb-1 integrated luminosity collected by the LHCb detector, two narrow states are observed in the Lambda_b0pi+pi- spectrum with masses 5911.97 +- 0.12(stat) +- 0.02(syst) +- 0.66(Lambda_b0 mass) MeV/c^2 and 5919.77 +- 0.08(stat) +- 0.02(syst) +- 0.66(Lambda_b0 mass) MeV/c^2. The significances of the observations are 5.2 and 10.2 standard deviations, respectively. These states are interpreted as the orbitally-excited Lambda_b0 baryons, Lambda_b*0(5912) and Lambda_b*0(5920).Comment: Replaced by version published in Phys. Rev. Lett, modified fit with better mass resolution treatmen

Observation of two new Ξb−\Xi_b^- baryon resonances

Two structures are observed close to the kinematic threshold in the $\Xi_b^0 \pi^-$ mass spectrum in a sample of proton-proton collision data, corresponding to an integrated luminosity of 3.0 fb$^{-1}$ recorded by the LHCb experiment. In the quark model, two baryonic resonances with quark content $bds$ are expected in this mass region: the spin-parity $J^P = \frac{1}{2}^+$ and $J^P=\frac{3}{2}^+$ states, denoted $\Xi_b^{\prime -}$ and $\Xi_b^{*-}$. Interpreting the structures as these resonances, we measure the mass differences and the width of the heavier state to be $m(\Xi_b^{\prime -}) - m(\Xi_b^0) - m(\pi^{-}) = 3.653 \pm 0.018 \pm 0.006$ MeV$/c^2$, $m(\Xi_b^{*-}) - m(\Xi_b^0) - m(\pi^{-}) = 23.96 \pm 0.12 \pm 0.06$ MeV$/c^2$, $\Gamma(\Xi_b^{*-}) = 1.65 \pm 0.31 \pm 0.10$ MeV, where the first and second uncertainties are statistical and systematic, respectively. The width of the lighter state is consistent with zero, and we place an upper limit of $\Gamma(\Xi_b^{\prime -}) < 0.08$ MeV at 95% confidence level. Relative production rates of these states are also reported.Comment: 17 pages, 2 figure

Strong constraints on the rare decays Bs -> mu+ mu- and B0 -> mu+ mu-

A search for Bs -> mu+ mu- and B0 -> mu+ mu- decays is performed using 1.0 fb^-1 of pp collision data collected at \sqrt{s}=7 TeV with the LHCb experiment at the Large Hadron Collider. For both decays the number of observed events is consistent with expectation from background and Standard Model signal predictions. Upper limits on the branching fractions are determined to be BR(Bs -> mu+ mu-) mu+ mu-) < 1.0 (0.81) x 10^-9 at 95% (90%) confidence level.Comment: 2+6 pages; 4 figures; Accepted for publication in Physical Review Letter

Differential branching fraction and angular analysis of the decay B0→K∗0μ+μ−

The angular distribution and differential branching fraction of the decay B 0→ K ∗0 μ + μ − are studied using a data sample, collected by the LHCb experiment in pp collisions at s√=7 TeV, corresponding to an integrated luminosity of 1.0 fb−1. Several angular observables are measured in bins of the dimuon invariant mass squared, q 2. A first measurement of the zero-crossing point of the forward-backward asymmetry of the dimuon system is also presented. The zero-crossing point is measured to be q20=4.9±0.9GeV2/c4 , where the uncertainty is the sum of statistical and systematic uncertainties. The results are consistent with the Standard Model predictions