A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection

The transduction of sound in the auditory periphery, the cochlea, is inhibited by efferent cholinergic neurons projecting from the brainstem and synapsing directly on mechanosensory hair cells. One fundamental question in auditory neuroscience is what role(s) this feedback plays in our ability to hear. In the present study, we have engineered a genetically modified mouse model in which the magnitude and duration of efferent cholinergic effects are increased, and we assess the consequences of this manipulation on cochlear function. We generated the Chrna9L9′T of knockin mice with a threonine for leucine change (L9′T) at position 9′ of the second transmembrane domain of the α9 nicotinic cholinergic subunit, rendering α9-containing receptors that were hypersensitive to acetylcholine and had slower desensitization kinetics. The Chrna9L9′T allele produced a 3-fold prolongation of efferent synaptic currents in vitro. In vivo, Chrna9L9′T mice had baseline elevation of cochlear thresholds and efferent-mediated inhibition of cochlear responses was dramatically enhanced and lengthened: both effects were reversed by strychnine blockade of the α9α10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9L9′T/L9′T mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter α9α10 receptor gating has provided an animal model in which not only is efferent inhibition more powerful, but also one in which sound-induced hearing loss can be restrained, indicating the ability of efferent feedback to ameliorate sound trauma.Fil: Taranda, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Tufts University School of Medicine; Estados UnidosFil: Maison, Stéphane F.. Massachusetts Eye and Ear Infirmary; Estados UnidosFil: Ballestero, Jimena Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Savino, Jessica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Vetter, Douglas E.. Tufts University School of Medicine; Estados UnidosFil: Boulter, Jim. University of California at Los Angeles; Estados UnidosFil: Liberman, M. Charles. Massachusetts Eye and Ear Infirmary; Estados UnidosFil: Fuchs, Paul A.. The Johns Hopkins University School of Medicine; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentin

Diffusion-limited reactions on disordered surfaces with continuous distributions of binding energies

We study the steady state of a stochastic particle system on a two-dimensional lattice, with particle influx, diffusion and desorption, and the formation of a dimer when particles meet. Surface processes are thermally activated, with (quenched) binding energies drawn from a \emph{continuous} distribution. We show that sites in this model provide either coverage or mobility, depending on their energy. We use this to analytically map the system to an effective \emph{binary} model in a temperature-dependent way. The behavior of the effective model is well-understood and accurately describes key quantities of the system: Compared with discrete distributions, the temperature window of efficient reaction is broadened, and the efficiency decays more slowly at its ends. The mapping also explains in what parameter regimes the system exhibits realization dependence.Comment: 23 pages, 8 figures. Submitted to: Journal of Statistical Mechanics: Theory and Experimen

Electronic nicotine delivery devices, and their impact on health and patterns of tobacco use: a systematic review protocol

Introduction E-cigarettes or electronic nicotine delivery systems (ENDS) have recently attracted considerable attention. Among some individuals there is strong debate and a polarisation of views about the public health benefits versus harms of ENDS. With little regulation, the ENDS market is evolving, and new products are introduced and marketed constantly. Rapid developments in manufacturing, marketing and consumer domains related to ENDS will warrant frequent re-evaluation, based on the state of the evolving science. The purpose of this article is to describe a protocol for an ongoing comprehensive review of the published scientific literature on ENDS. Methods and analysis We will undertake a systematic review of published empirical research literature on ENDS using the National Library of Medicine\u27s PubMed electronic database to search for relevant articles. Data from included studies will be extracted into a standardised form, tables with study details and key outcomes for each article will be created, and studies will be synthesised qualitatively. Ethics and dissemination This review synthesises published literature and presents no primary data. Therefore, no ethical approval is required for this study. Subsequent papers will provide greater detail on results, within select categories, that represent gaps in the literature base

The local Gromov-Witten theory of CP^1 and integrable hierarchies

In this paper we begin the study of the relationship between the local Gromov-Witten theory of Calabi-Yau rank two bundles over the projective line and the theory of integrable hierarchies. We first of all construct explicitly, in a large number of cases, the Hamiltonian dispersionless hierarchies that govern the full descendent genus zero theory. Our main tool is the application of Dubrovin's formalism, based on associativity equations, to the known results on the genus zero theory from local mirror symmetry and localization. The hierarchies we find are apparently new, with the exception of the resolved conifold O(-1) + O(-1) -> P1 in the equivariantly Calabi-Yau case. For this example the relevant dispersionless system turns out to be related to the long-wave limit of the Ablowitz-Ladik lattice. This identification provides us with a complete procedure to reconstruct the dispersive hierarchy which should conjecturally be related to the higher genus theory of the resolved conifold. We give a complete proof of this conjecture for genus g<=1; our methods are based on establishing, analogously to the case of KdV, a "quasi-triviality" property for the Ablowitz-Ladik hierarchy at the leading order of the dispersive expansion. We furthermore provide compelling evidence in favour of the resolved conifold/Ablowitz-Ladik correspondence at higher genus by testing it successfully in the primary sector for g=2.Comment: 30 pages; v2: an issue involving constant maps contributions is pointed out in Sec. 3.3-3.4 and is now taken into account in the proofs of Thm 1.3-1.4, whose statements are unchanged. Several typos, formulae, notational inconsistencies have been fixed. v3: typos fixed, minor textual changes, version to appear on Comm. Math. Phy

Torus knots and mirror symmetry

We propose a spectral curve describing torus knots and links in the B-model. In particular, the application of the topological recursion to this curve generates all their colored HOMFLY invariants. The curve is obtained by exploiting the full Sl(2, Z) symmetry of the spectral curve of the resolved conifold, and should be regarded as the mirror of the topological D-brane associated to torus knots in the large N Gopakumar-Vafa duality. Moreover, we derive the curve as the large N limit of the matrix model computing torus knot invariants.Comment: 30 pages + appendix, 3 figure

Cosmogenic 11C production and sensitivity of organic scintillator detectors to pep and CNO neutrinos

Several possible background sources determine the detectability of pep and CNO solar neutrinos in organic liquid scintillator detectors. Among such sources, the cosmogenic 11C nuclide plays a central role. 11C is produced underground in reactions induced by the residual cosmic muon flux. Experimental data available for the effective cross section for 11C by muons indicate that 11C will be the dominant source of background for the observation of pep and CNO neutrinos. 11C decays are expected to total a rate 2.5 (20) times higher than the combined rate of pep and CNO neutrinos in Borexino (KamLAND) in the energy window preferred for the pep measurement, between 0.8 and 1.3 MeV. This study examines the production mechanism of 11C by muon-induced showers in organic liquid scintillators with a novel approach: for the first time, we perform a detailed ab initio calculation of the production of a cosmogenic nuclide, 11C, taking into consideration all relevant production channels. Results of the calculation are compared with the effective cross sections measured by target experiments in muon beams. This paper also discusses a technique for reduction of background from 11C in organic liquid scintillator detectors, which allows to identify on a one-by-one basis and remove from the data set a large fraction of 11C decays. The background reduction technique hinges on an idea proposed by Martin Deutsch, who suggested that a neutron must be ejected in every interaction producing a 11C nuclide from 12C. 11C events are tagged by a three-fold coincidence with the parent muon track and the subsequent neutron capture on protons.Comment: 11 pages, 6 figures; added one section detailing comparison with previous estimates; added reference

Decoupling A and B model in open string theory -- Topological adventures in the world of tadpoles

In this paper we analyze the problem of tadpole cancellation in open topological strings. We prove that the inclusion of unorientable worldsheet diagrams guarantees a consistent decoupling of A and B model for open superstring amplitudes at all genera. This is proven by direct microscopic computation in Super Conformal Field Theory. For the B-model we explicitly calculate one loop amplitudes in terms of analytic Ray-Singer torsions of appropriate vector bundles and obtain that the decoupling corresponds to the cancellation of D-brane and orientifold charges. Local tadpole cancellation on the worldsheet then guarantees the decoupling at all loops. The holomorphic anomaly equations for open topological strings at one loop are also obtained and compared with the results of the Quillen formula