The renin angiotensin system in the central nervous system

The first evidences indicating that angiotensin II (ANG II) was a peptide with action on the brain were shown in 1961 when it was found that the intraventricular injection of ANG II induces a centrally mediated pressor response (1). As a neuropeptide, ANG II belongs to the class of neuromodulators. The brain renin angiotensin system (RAS) exerts paracrine, autocrine and intracrine functions independently of circulating blood-borne ANG II which has a limited access to the brain by the blood-brain barrier (BBB) in the circumventricular organs (CVOs) (2). Brain-generated ANG II controls several physiological processes like stimulation of thirst, water intake and sodium appetite, acting as a neurotransmitter in neurons of brain areas such as the Subfornical organ (SFO) and Organum vasculosum of the lamina terminalis (OVLT). Generated angiotensins (ANGs) at the central nervous system (CNS) also stimulate endocrine secretions like argininevasopressin (AVP), oxytocin (OT), corticotrophin-releasing hormone (CRH) and adenocorticotrophin (ACTH secretion). Brain ANG II modulates the sympathetic autonomic functions and regulates blood pressure by increasing AVP and ACTH secretion and modulating the baroceptor reflex and the sympathetic output (3). During the last decade it has been established that, apart from its classical actions, ANG II exhibits other effects induced by direct action on its receptors or via local effects of its metabolites (4). Thereby, central actions of ANGs are not exclusively associated with their traditional roles. Indeed, several studies have shown that central ANGs are also involved in sexual behavior, stress, learning, and memory (5).Sociedad Argentina de Fisiologí

4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection.

BackgroundChagas disease, caused by the protozoan Trypanosoma cruzi, is the leading cause of heart failure in Latin America. The clinical treatment of Chagas disease is limited to two 60 year-old drugs, nifurtimox and benznidazole, that have variable efficacy against different strains of the parasite and may lead to severe side effects. CYP51 is an enzyme in the sterol biosynthesis pathway that has been exploited for the development of therapeutics for fungal and parasitic infections. In a target-based drug discovery program guided by x-ray crystallography, we identified the 4-aminopyridyl-based series of CYP51 inhibitors as being efficacious versus T.cruzi in vitro; two of the most potent leads, 9 and 12, have now been evaluated for toxicity and efficacy in mice.Methodology/principal findingsBoth acute and chronic animal models infected with wild type or transgenic T. cruzi strains were evaluated. There was no evidence of toxicity in the 28-day dosing study of uninfected animals, as judged by the monitoring of multiple serum and histological parameters. In two acute models of Chagas disease, 9 and 12 drastically reduced parasitemia, increased survival of mice, and prevented liver and heart injury. None of the compounds produced long term sterile cure. In the less severe acute model using the transgenic CL-Brenner strain of T.cruzi, parasitemia relapsed upon drug withdrawal. In the chronic model, parasitemia fell to a background level and, as evidenced by the bioluminescence detection of T. cruzi expressing the red-shifted luciferase marker, mice remained negative for 4 weeks after drug withdrawal. Two immunosuppression cycles with cyclophosphamide were required to re-activate the parasites. Although no sterile cure was achieved, the suppression of parasitemia in acutely infected mice resulted in drastically reduced inflammation in the heart.Conclusions/significanceThe positive outcomes achieved in the absence of sterile cure suggest that the target product profile in anti-Chagasic drug discovery should be revised in favor of safe re-administration of the medication during the lifespan of a Chagas disease patient. A medication that reduces parasite burden may halt or slow progression of cardiomyopathy and therefore improve both life expectancy and quality of life

Longitudinal Spin Transfer to Λ\Lambda and Λˉ\bar{\Lambda} Hyperons in Polarized Proton-Proton Collisions at s\sqrt{s} = 200 GeV

The longitudinal spin transfer, $D_{LL}$, from high energy polarized protons to $\Lambda$ and $\bar{\Lambda}$ hyperons has been measured for the first time in proton-proton collisions at $\sqrt{s} = 200 \mathrm{GeV}$ with the STAR detector at RHIC. The measurements cover pseudorapidity, $\eta$, in the range $|\eta| < 1.2$ and transverse momenta, $p_\mathrm{T}$, up to $4 \mathrm{GeV}/c$. The longitudinal spin transfer is found to be $D_{LL}= -0.03\pm 0.13(\mathrm{stat}) \pm 0.04(\mathrm{syst})$ for inclusive $\Lambda$ and $D_{LL} = -0.12 \pm 0.08(\mathrm{stat}) \pm 0.03(\mathrm{syst})$ for inclusive $\bar{\Lambda}$ hyperons with $= 0.5$ and $= 3.7 \mathrm{GeV}/c$. The dependence on $\eta$ and $p_\mathrm{T}$ is presented.Comment: 5 pages, 4 figure

Observation of the antimatter helium-4 nucleus

High-energy nuclear collisions create an energy density similar to that of the universe microseconds after the Big Bang, and in both cases, matter and antimatter are formed with comparable abundance. However, the relatively short-lived expansion in nuclear collisions allows antimatter to decouple quickly from matter, and avoid annihilation. Thus, a high energy accelerator of heavy nuclei is an efficient means of producing and studying antimatter. The antimatter helium-4 nucleus ($^4\bar{He}$), also known as the anti-{\alpha} ($\bar{\alpha}$), consists of two antiprotons and two antineutrons (baryon number B=-4). It has not been observed previously, although the {\alpha} particle was identified a century ago by Rutherford and is present in cosmic radiation at the 10% level. Antimatter nuclei with B < -1 have been observed only as rare products of interactions at particle accelerators, where the rate of antinucleus production in high-energy collisions decreases by about 1000 with each additional antinucleon. We present the observation of the antimatter helium-4 nucleus, the heaviest observed antinucleus. In total 18 $^4\bar{He}$ counts were detected at the STAR experiment at RHIC in 10$^9$ recorded Au+Au collisions at center-of-mass energies of 200 GeV and 62 GeV per nucleon-nucleon pair. The yield is consistent with expectations from thermodynamic and coalescent nucleosynthesis models, which has implications beyond nuclear physics.Comment: 19 pages, 4 figures. Submitted to Nature. Under media embarg

Strangeness Enhancement in Cu+Cu and Au+Au Collisions at \sqrt{s_{NN}} = 200 GeV

We report new STAR measurements of mid-rapidity yields for the $\Lambda$, $\bar{\Lambda}$, $K^{0}_{S}$, $\Xi^{-}$, $\bar{\Xi}^{+}$, $\Omega^{-}$, $\bar{\Omega}^{+}$ particles in Cu+Cu collisions at \sNN{200}, and mid-rapidity yields for the $\Lambda$, $\bar{\Lambda}$, $K^{0}_{S}$ particles in Au+Au at \sNN{200}. We show that at a given number of participating nucleons, the production of strange hadrons is higher in Cu+Cu collisions than in Au+Au collisions at the same center-of-mass energy. We find that aspects of the enhancement factors for all particles can be described by a parameterization based on the fraction of participants that undergo multiple collisions

Growth of Long Range Forward-Backward Multiplicity Correlations with Centrality in Au+Au Collisions at sNN\sqrt{s_{NN}} = 200 GeV

Forward-backward multiplicity correlation strengths have been measured with the STAR detector for Au+Au and $\textit{p+p}$ collisions at $\sqrt{s_{NN}}$ = 200 GeV. Strong short and long range correlations (LRC) are seen in central Au+Au collisions. The magnitude of these correlations decrease with decreasing centrality until only short range correlations are observed in peripheral Au+Au collisions. Both the Dual Parton Model (DPM) and the Color Glass Condensate (CGC) predict the existence of the long range correlations. In the DPM the fluctuation in the number of elementary (parton) inelastic collisions produces the LRC. In the CGC longitudinal color flux tubes generate the LRC. The data is in qualitative agreement with the predictions from the DPM and indicates the presence of multiple parton interactions.Comment: 6 pages, 3 figures The abstract has been slightly modifie

K/pi Fluctuations at Relativistic Energies

We report results for $K/\pi$ fluctuations from Au+Au collisions at $\sqrt{s_{NN}}$ = 19.6, 62.4, 130, and 200 GeV using the STAR detector at the Relativistic Heavy Ion Collider. Our results for $K/\pi$ fluctuations in central collisions show little dependence on the incident energies studied and are on the same order as results observed by NA49 at the Super Proton Synchrotron in central Pb+Pb collisions at $\sqrt{s_{NN}}$ = 12.3 and 17.3 GeV. We also report results for the collision centrality dependence of $K/\pi$ fluctuations as well as results for $K^{+}/\pi^{+}$, $K^{-}/\pi^{-}$, $K^{+}/\pi^{-}$, and $K^{-}/\pi^{+}$ fluctuations. We observe that the $K/\pi$ fluctuations scale with the multiplicity density, $dN/d\eta$, rather than the number of participating nucleons.Comment: 6 pages, 4 figure

Forward Neutral Pion Transverse Single Spin Asymmetries in p+p Collisions at \sqrt{s}=200 GeV

We report precision measurements of the Feynman-x dependence, and first measurements of the transverse momentum dependence, of transverse single spin asymmetries for the production of \pi^0 mesons from polarized proton collisions at \sqrt{s}=200 GeV. The x_F dependence of the results is in fair agreement with perturbative QCD model calculations that identify orbital motion of quarks and gluons within the proton as the origin of the spin effects. Results for the p_T dependence at fixed x_F are not consistent with pQCD-based calculations.Comment: 6 pages, 4 figure

An Effective Assessment of Simvastatin-Induced Toxicity with NMR-Based Metabonomics Approach

BACKGROUND: Simvastatin, which is used to control elevated cholesterol levels, is one of the most widely prescribed drugs. However, a daily excessive dose can induce drug-toxicity, especially in muscle and liver. Current markers for toxicity reflect mostly the late stages of tissue damage; thus, more efficient methods of toxicity evaluation are desired. METHODOLOGY/PRINCIPAL FINDINGS: As a new way to evaluate toxicity, we performed NMR-based metabonomics analysis of urine samples. Compared to conventional markers, such as AST, ALT, and CK, the urine metabolic profile provided clearer distinction between the pre- and post-treatment groups treated with toxic levels of simvastatin. Through multivariate statistical analysis, we identified marker metabolites associated with the toxicity. Importantly, we observed that the treatment group could be further categorized into two subgroups based on the NMR profiles: weak toxicity (WT) and high toxicity (HT). The distinction between these two groups was confirmed by the enzyme values and histopathological exams. Time-dependent studies showed that the toxicity at 10 days could be reliably predicted from the metabolic profiles at 6 days. CONCLUSIONS/SIGNIFICANCE: This metabonomics approach may provide a non-invasive and effective way to evaluate the simvastatin-induced toxicity in a manner that can complement current measures. The approach is expected to find broader application in other drug-induced toxicity assessments