Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

Opioids are first-line drugs for moderate to severe acute pain and cancer pain. However, these medications are associated with severe side effects, and whether they are efficacious in treatment of chronic nonmalignant pain remains controversial. Medications that act through alternative molecular mechanisms are critically needed. Antagonists of α9α10 nicotinic acetylcholine receptors (nAChRs) have been proposed as an important nonopioid mechanism based on studies demonstrating prevention of neuropathology after trauma-induced nerve injury. However, the key α9α10 ligands characterized to date are at least two orders of magnitude less potent on human vs. rodent nAChRs, limiting their translational application. Furthermore, an alternative proposal that these ligands achieve their beneficial effects by acting as agonists of GABA(B) receptors has caused confusion over whether blockade of α9α10 nAChRs is the fundamental underlying mechanism. To address these issues definitively, we developed RgIA4, a peptide that exhibits high potency for both human and rodent α9α10 nAChRs, and was at least 1,000-fold more selective for α9α10 nAChRs vs. all other molecular targets tested, including opioid and GABA(B) receptors. A daily s.c. dose of RgIA4 prevented chemotherapy-induced neuropathic pain in rats. In wild-type mice, oxaliplatin treatment produced cold allodynia that could be prevented by RgIA4. Additionally, in α9 KO mice, chemotherapy-induced development of cold allodynia was attenuated and the milder, temporary cold allodynia was not relieved by RgIA4. These findings establish blockade of α9-containing nAChRs as the basis for the efficacy of RgIA4, and that α9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapy-induced neuropathic pain

Dynamical decoupling of unbounded Hamiltonians

We investigate the possibility to suppress interactions between a finite dimensional system and an infinite dimensional environment through a fast sequence of unitary kicks on the finite dimensional system. This method, called dynamical decoupling, is known to work for bounded interactions, but physical environments such as bosonic heat baths are usually modelled with unbounded interactions, whence here we initiate a systematic study of dynamical decoupling for unbounded operators. We develop a sufficient decoupling criterion for arbitrary Hamiltonians and a necessary decoupling criterion for semibounded Hamiltonians. We give examples for unbounded Hamiltonians where decoupling works and the limiting evolution as well as the convergence speed can be explicitly computed. We show that decoupling does not always work for unbounded interactions and provide both physically and mathematically motivated examples.Comment: 18 pages, 3 figure

The Gaseous Environment of High-z Galaxies: Precision Measurements of Neutral Hydrogen in the Circumgalactic Medium of z ~ 2-3 Galaxies in the Keck Baryonic Structure Survey

We present results from the Keck Baryonic Structure Survey (KBSS), a unique spectroscopic survey designed to explore the connection between galaxies and intergalactic baryons. The KBSS is optimized for the redshift range z ~ 2-3, combining S/N ~ 100 Keck/HIRES spectra of 15 hyperluminous QSOs with densely sampled galaxy redshift surveys surrounding each QSO sightline. We perform Voigt profile decomposition of all 6000 HI absorbers within the full Lya forest in the QSO spectra. Here we present the distribution, column density, kinematics, and absorber line widths of HI surrounding 886 star-forming galaxies with 2.0 < z < 2.8 and within 3 Mpc of a QSO sightline. We find that N_HI and the multiplicity of HI components increase rapidly near galaxies. The strongest HI absorbers within ~ 100 physical kpc of galaxies have N_HI ~ 3 dex higher than those near random locations in the IGM. The circumgalactic zone of most enhanced HI absorption (CGM) is found within 300 kpc and 300 km/s of galaxies. Nearly half of absorbers with log(N_HI) > 15.5 are found within the CGM of galaxies meeting our photometric selection, while their CGM occupy only 1.5% of the cosmic volume. The spatial covering fraction, multiplicity of absorption components, and characteristic N_HI remain elevated to transverse distances of 2 physical Mpc. Absorbers with log(N_HI) > 14.5 are tightly correlated with the positions of galaxies, while absorbers with lower N_HI are correlated only on Mpc scales. Redshift anisotropies on Mpc scales indicate coherent infall toward galaxies, while on scales of ~100 physical kpc peculiar velocities of 260 km/s are indicated. The median Doppler widths of absorbers within 1-3 virial radii of galaxies are ~50% larger than randomly chosen absorbers of the same N_HI, suggesting higher gas temperatures and/or increased turbulence likely caused by accretion shocks and/or galactic winds.Comment: Accepted to Ap

Characterization of the Conus bullatus genome and its venom-duct transcriptome

<p>Abstract</p> <p>Background</p> <p>The venomous marine gastropods, cone snails (genus <it>Conus</it>), inject prey with a lethal cocktail of conopeptides, small cysteine-rich peptides, each with a high affinity for its molecular target, generally an ion channel, receptor or transporter. Over the last decade, conopeptides have proven indispensable reagents for the study of vertebrate neurotransmission. <it>Conus bullatus </it>belongs to a clade of <it>Conus </it>species called <it>Textilia</it>, whose pharmacology is still poorly characterized. Thus the genomics analyses presented here provide the first step toward a better understanding the enigmatic <it>Textilia </it>clade.</p> <p>Results</p> <p>We have carried out a sequencing survey of the <it>Conus bullatus </it>genome and venom-duct transcriptome. We find that conopeptides are highly expressed within the venom-duct, and describe an <it>in silico </it>pipeline for their discovery and characterization using RNA-seq data. We have also carried out low-coverage shotgun sequencing of the genome, and have used these data to determine its size, genome-wide base composition, simple repeat, and mobile element densities.</p> <p>Conclusions</p> <p>Our results provide the first global view of venom-duct transcription in any cone snail. A notable feature of <it>Conus bullatus </it>venoms is the breadth of A-superfamily peptides expressed in the venom duct, which are unprecedented in their structural diversity. We also find SNP rates within conopeptides are higher compared to the remainder of <it>C. bullatus </it>transcriptome, consistent with the hypothesis that conopeptides are under diversifying selection.</p

Polyfunctional T cell responses in children in early stages of chronic Trypanosoma cruzi infection contrast with monofunctional responses of long-term infected adults

Background: Adults with chronic Trypanosoma cruzi exhibit a poorly functional T cell compartment, characterized by monofunctional (IFN-γ-only secreting) parasite-specific T cells and increased levels of terminally differentiated T cells. It is possible that persistent infection and/or sustained exposure to parasites antigens may lead to a progressive loss of function of the immune T cells. Methodology/Principal Findings: To test this hypothesis, the quality and magnitude of T. cruzi-specific T cell responses were evaluated in T. cruzi-infected children and compared with long-term T. cruzi-infected adults with no evidence of heart failure. The phenotype of CD4+ T cells was also assessed in T. cruzi-infected children and uninfected controls. Simultaneous secretion of IFN-γ and IL-2 measured by ELISPOT assays in response to T. cruzi antigens was prevalent among T. cruzi-infected children. Flow cytometric analysis of co-expression profiles of CD4+ T cells with the ability to produce IFN-γ, TNF-α, or to express the co-stimulatory molecule CD154 in response to T. cruzi showed polyfunctional T cell responses in most T. cruzi-infected children. Monofunctional T cell responses and an absence of CD4+TNF-α+-secreting T cells were observed in T. cruzi-infected adults. A relatively high degree of activation and differentiation of CD4+ T cells was evident in T. cruzi-infected children. Conclusions/Significance: Our observations are compatible with our initial hypothesis that persistent T. cruzi infection promotes eventual exhaustion of immune system, which might contribute to disease progression in long-term infected subjects.Fil: Albareda, María Cecilia. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: de Rissio, Ana María. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Tomas, Gonzalo. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Serjan, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Alvarez, María Gabriela. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Viotti, Rodolfo Jorge. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Fichera, Laura Edith. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Esteva, Mónica Inés. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Potente, Daniel Fernando. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Armenti, Alejandro. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Tarleton, Rick L.. University of Georgia; Estados UnidosFil: Laucella, Susana Adriana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Frustration - how it can be measured

A misfit parameter is used to characterize the degree of frustration of ordered and disordered systems. It measures the increase of the ground-state energy due to frustration in comparison with that of a relevant reference state. The misfit parameter is calculated for various spin-glass models. It allows one to compare these models with each other. The extension of this concept to other combinatorial optimization problems with frustration, e.g. p-state Potts glasses, graph-partitioning problems and coloring problems is given.Comment: 10 pages, 1 table, no figures, uses revtex.st

The Fornax Cluster through S-PLUS

The Southern Photometric Local Universe Survey (S-PLUS) aims to map ≈ 9300 deg2of the southernsky using the Javalambre filter system of 12 optical bands, 5 Sloan-like filters and 7 narrow-band filters centeredon several prominent stellar features ([OII], Ca H+K, D4000, Hδ, Mgb, Hα and CaT). S-PLUS is carried outwith the T80-South, a new robotic 0.826 m telescope located on CTIO, equipped with a wide field of view camera(2 deg2). In this poster we introduce project #59 of the S-PLUS collaboration aimed at studying the Fornaxgalaxy cluster covering an sky area of ≈ 11 × 7 deg2, and with homogeneous photometry in the 12 optical bandsof S-PLUS (Coordinator: A. Smith Castelli).Fil: Smith Castelli, Analia Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; ArgentinaFil: Mendez de Olivera, C.. Universidade do Sao Paulo. Instituto de Astronomia, Geofísica e Ciências Atmosféricas; BrasilFil: Herpic, F.. Universidade do Sao Paulo. Instituto de Astronomia, Geofísica e Ciências Atmosféricas; BrasilFil: Barbosa, C.. Universidade do Sao Paulo. Instituto de Astronomia, Geofísica e Ciências Atmosféricas; BrasilFil: Escudero, Carlos Gabriel. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Grossi, M.. Observatorio de Valongo; BrasilFil: Sodré, L.. Universidade do Sao Paulo. Instituto de Astronomia, Geofísica e Ciências Atmosféricas; BrasilFil: de Bom, .. Centro Brasileiro de Pesquisas Físicas; BrasilFil: Zenocratti, Lucas Jesús. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: de Rossi, Maria Emilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio(i); ArgentinaFil: Cortesi, A.. Observatorio de Valongo; BrasilFil: Cid Fernandes, R.. Universidade Federal de Santa Catarina; BrasilFil: Lopes, A.. Ministerio de Ciencia, Tecnología E Innovacao. Observatorio Nacional. Departamento Astronomia y Astrofísica; BrasilFil: Telles, E.. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Oliveira Schwarz, G. B.. Universidade Anhembi Morumbi; BrasilFil: Dantas, M. L. L.. Nicolaus Copernicus Astronomical Center; PoloniaFil: Faifer, Favio Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; ArgentinaFil: Chies Santos, A.. Universidade Federal de Santa Catarina; BrasilFil: Saponara, Juliana. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Argentino de Radioastronomía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Argentino de Radioastronomía; ArgentinaFil: Reynaldi, María Victoria. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; ArgentinaFil: Andruchow, Ileana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; ArgentinaFil: Sesto, Leandro Alberto. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Mestre, M.. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: de Amorim, A. L.. Universidade Federal de Santa Catarina; BrasilFil: de Lima, E. V. R.. Universidade do Sao Paulo. Instituto de Astronomia, Geofísica e Ciências Atmosféricas; BrasilFil: Abboud, J.. Universidade do Sao Paulo. Instituto de Astronomia, Geofísica e Ciências Atmosféricas; BrasilFil: Cernic, V.. Universidade do Sao Paulo. Instituto de Astronomia, Geofísica e Ciências Atmosféricas; BrasilFil: Souza de Almeida Garcia, I.. Universidade do Sao Paulo. Instituto de Astronomia, Geofísica e Ciências Atmosféricas; Brasil62° Reunión Anual de la Asociación Argentina de AstronomíaRosarioArgentinaUniversidad Nacional de RosarioComplejo Astronómico Municipal Galileo Galile

Neonatal Astrocyte Damage Is Sufficient to Trigger Progressive Striatal Degeneration in a Rat Model of Glutaric Acidemia-I

BACKGROUND: We have investigated whether an acute metabolic damage to astrocytes during the neonatal period may critically disrupt subsequent brain development, leading to neurodevelopmental disorders. Astrocytes are vulnerable to glutaric acid (GA), a dicarboxylic acid that accumulates in millimolar concentrations in Glutaric Acidemia I (GA-I), an inherited neurometabolic childhood disease characterized by degeneration of striatal neurons. While GA induces astrocyte mitochondrial dysfunction, oxidative stress and subsequent increased proliferation, it is presently unknown whether such astrocytic dysfunction is sufficient to trigger striatal neuronal loss. METHODOLOGY/PRINCIPAL FINDINGS: A single intracerebroventricular dose of GA was administered to rat pups at postnatal day 0 (P0) to induce an acute, transient rise of GA levels in the central nervous system (CNS). GA administration potently elicited proliferation of astrocytes expressing S100β followed by GFAP astrocytosis and nitrotyrosine staining lasting until P45. Remarkably, GA did not induce acute neuronal loss assessed by FluoroJade C and NeuN cell count. Instead, neuronal death appeared several days after GA treatment and progressively increased until P45, suggesting a delayed onset of striatal degeneration. The axonal bundles perforating the striatum were disorganized following GA administration. In cell cultures, GA did not affect survival of either striatal astrocytes or neurons, even at high concentrations. However, astrocytes activated by a short exposure to GA caused neuronal death through the production of soluble factors. Iron porphyrin antioxidants prevented GA-induced astrocyte proliferation and striatal degeneration in vivo, as well as astrocyte-mediated neuronal loss in vitro. CONCLUSIONS/SIGNIFICANCE: Taken together, these results indicate that a transient metabolic insult with GA induces long lasting phenotypic changes in astrocytes that cause them to promote striatal neuronal death. Pharmacological protection of astrocytes with antioxidants during encephalopatic crisis may prevent astrocyte dysfunction and the ineluctable progression of disease in children with GA-I

Measurement of the ppbar to ttbar production cross section at sqrt(s)=1.96 TeV in the fully hadronic decay channel

A measurement of the top quark pair production cross section in proton anti-proton collisions at an interaction energy of sqrt(s)=1.96 TeV is presented. This analysis uses 405 pb-1 of data collected with the D0 detector at the Fermilab Tevatron Collider. Fully hadronic ttbar decays with final states of six or more jets are separated from the multijet background using secondary vertex tagging and a neural network. The ttbar cross section is measured as sigma(ttbar)=4.5 -1.9 +2.0 (stat) -1.1 +1.4 (syst) +/- 0.3 (lumi) pb for a top quark mass of m(t) = 175 GeV/c^2.Comment: 10 pages, 10 figures, submitted to Phys. Rev.