Search for New Physics in B Rare Decays at LHCb

The LHCb experiment, bolstered up by the 10^12 b-hadrons to be produced yearly in its interaction region, is an excellent place to study rare B decays. Flavor-changing neutral currents are forbidden at tree level in the Standard Model. They proceed through loop diagrams and hence are indirectly sensitive to New Physics through the effect of new particles on observable quantities. In this paper, we present preparation studies of the three most promising B rare decay analyzes. These aim at the observation of the photon polarization in B_s to phi gamma, the measurement of the angular distribution of the B^0 to K* mu^+ mu^- decay, and the search for the yet unobserved B_s to mu^+ mu^- decay. The current analysis strategies and the expected sensitivities are presented.Comment: To be published in the proceedings of DPF-2009, Detroit, MI, July 2009, eConf C090726; one reference adde

Nanoscale ion sequestration to determine the polarity selectivity of ion conductance in carriers and channels

© 2014 American Chemical Society. The nanoscale spacing between a tethered lipid bilayer membrane (tBLM) and its supporting gold electrode can be utilized to determine the polarity selectivity of the conduction of ion channels and ion carriers embedded in a membrane. The technique relies upon a bias voltage sequestering or eliminating ions, of a particular polarity, into or out of the aqueous electrolyte region between the gold electrode and the tethered membrane. A demonstration is given, using ac swept frequency impedance spectrometry, of the bias polarity dependence of the ionophore conductance of gramicidin A, a cationic selective channel, and valinomycin, a potassium ion selective carrier. We further use pulsed amperometry to show that the intrinsic voltage dependence of the ion conduction is actually selective of the polarity of the transported ion and not simply of the direction of the ionic current flow

Conditional gene deletion reveals functional redundancy of GABAB receptors in peripheral nociceptors in vivo

Background Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter which mainly mediates its effects on neurons via ionotropic (GABAA) and metabotropic (GABAB) receptors. GABAB receptors are widely expressed in the central and the peripheral nervous system. Although there is evidence for a key function of GABAB receptors in the modulation of pain, the relative contribution of peripherally- versus centrally-expressed GABAB receptors is unclear. Results In order to elucidate the functional relevance of GABAB receptors expressed in peripheral nociceptive neurons in pain modulation we generated and analyzed conditional mouse mutants lacking functional GABAB(1) subunit specifically in nociceptors, preserving expression in the spinal cord and brain (SNS-GABAB(1)-/- mice). Lack of the GABAB(1) subunit precludes the assembly of functional GABAB receptor. We analyzed SNS-GABAB(1)-/- mice and their control littermates in several models of acute and neuropathic pain. Electrophysiological studies on peripheral afferents revealed higher firing frequencies in SNS-GABAB(1)-/- mice compared to corresponding control littermates. However no differences were seen in basal nociceptive sensitivity between these groups. The development of neuropathic and chronic inflammatory pain was similar across the two genotypes. The duration of nocifensive responses evoked by intraplantar formalin injection was prolonged in the SNS-GABAB(1)-/- animals as compared to their control littermates. Pharmacological experiments revealed that systemic baclofen-induced inhibition of formalin-induced nociceptive behaviors was not dependent upon GABAB(1) expression in nociceptors. Conclusion This study addressed contribution of GABAB receptors expressed on primary afferent nociceptive fibers to the modulation of pain. We observed that neither the development of acute and chronic pain nor the analgesic effects of a systematically-delivered GABAB agonist was significantly changed upon a specific deletion of GABAB receptors from peripheral nociceptive neurons in vivo. This lets us conclude that GABAB receptors in the peripheral nervous system play a less important role than those in the central nervous system in the regulation of pain

Behavioral evaluation of mice deficient in GABAB(1) receptor isoforms in tests of unconditioned anxiety

Rationale: Emerging data support a role for GABAB receptors in anxiety. GABAB receptors are comprised of a heterodimeric complex of GABAB1 and GABAB2 receptor subunits. The predominant neuronal GABAB1 receptor isoforms are GABAB(1a) and GABAB(1b). Recent findings indicate specific roles for these isoforms in conditioned fear responses, although their influence on behavior in tests of unconditioned anxiety is unknown. Objective: The aim of this study was to examine the role of the GABAB(1) isoforms in unconditioned anxiety. Materials and methods: Mice deficient in the GABAB(1a) or GABAB(1b) receptor isoforms were examined in a battery of anxiety tests. Results: In most tests, genotype did not significantly affect anxious behavior, including the elevated plus maze, marble burying, and stress-induced hypothermia tests. Corticosterone and adrenocorticotropic hormone levels were similarly unaffected by genotype. Female, but not male, {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{a}}} \right)}}} and {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{b}}} \right)}}} mice showed increased anxiety relative to wild-type controls in the elevated zero maze. In the staircase test, male {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{b}}} \right)}}} mice defecated more than male {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{a}}} \right)}}} mice, although no other test parameter was influenced by genotype. In the light-dark box, female {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{a}}} \right)}}} mice spent less time in the light compartment compared to the {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{b}}} \right)}}} females, whereas male {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{b}}} \right)}}} mice made fewer light-dark transitions than {\text{GABA}}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}_{{{\text{B}}{\left( {1{\text{a}}} \right)}}} males. Conclusions: Specific roles for either GABAB(1) isoform in unconditioned anxiety were not explicit. This differs from their contribution in conditioned anxiety and from the anxious phenotype of GABAB1 and GABAB2 subunit knockout mice. The findings suggest that the GABAB(1) isoforms have specific relevance for anxiety with a cognitive component, rather than for innate anxiety per s

Selective loss of GABAB receptors in orexin/hypocretin-producing neurons results in disrupted sleep/wakefulness architecture

We generated mice with a selective loss of GABAB receptors in orexin neurons. Orexin neurons in these GABAB1<sup>-/-(orexin)</sup> mice showed reduced responsiveness to GABA<sub>A</sub> receptor agonists due to a compensatory increase in GABAA receptor-mediated inhibition. This increased GABA<sub>A</sub> receptor-mediated inhibition of orexin neurons is due to orexin-1 receptor-mediated activation of local GABAergic interneurons. Surprisingly, orexin neurons were also less responsive to glutamate, apparently because the augmented GABA<sub>A</sub> receptor-mediated inhibition increases the membrane conductance and shunts excitatory currents. These observations indicate that absence of GABA<sub>B</sub> receptors decreases the sensitivity of orexin neurons to both excitatory and inhibitory inputs. GABAB1<sup>-/-(orexin)</sup>mice exhibited severe fragmentation of sleep/wake states during both the light and dark periods without affecting total sleep time or inducing cataplexy, indicating that GABA<sub>B</sub> receptors are crucial regulators of orexin neurons and that "fine tuning" of orexin neurons by inhibitory and excitatory inputs is important for the stability of sleep/waking states