This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.

SummaryThe genetic basis for aging is being intensely investigated in a variety of model systems. Much of the focus in Drosophila has been on the molecular-genetic determinants of lifespan, whereas the molecular-genetic basis for age-related functional declines has been less vigorously explored. We evaluated behavioural aging and lifespan in flies harbouring loss-of-function mutations in myospheroid , the gene that encodes β β β β PS, a β β β β integrin. Integrins are adhesion molecules that regulate a number of cellular processes and developmental events. Their role in aging, however, has received limited attention. We report here that age-related declines in locomotor activity are ameliorated and that mean lifespan is increased in myospheroid mutants. The delayed functional senescence and altered mortality in myospheroid flies are independent of changes in body size, reproduction or stress resistance. Our data indicate that functional senescence and age-dependent mortality are influenced by β β β β integrins in Drosophila .

The 13 C dipolar NMR spectrum of o-benzyne-1,2-13 C 2 in an argon matrix at a temperature of about 20 K is reported. The o-benzyne was generated from matrix-isolated phthalic anhydride-1,2-13 C 2 by UV irradiation. The average conversion to o-benzyne over the entire sample was about 53%; however, spectral simulations of the pure phthalic anhydride and of the o-benzyne-phthalic anhydride mixture were adequate to extract the NMR spectral parameters of both compounds. The simulation of the spectrum of o-benzyne gives a bond length of 1.24 ( 0.02 Å for the "triple" bond, in good agreement with the results of ab initio geometry optimizations. The experimental principal values of the chemical shift tensor of the labeled carbon in o-benzyne are 266, 240, and 73 ppm relative to TMS. The δ 33 component is not perpendicular to the molecular plane as is common in aromatic systems. Instead, the principal axis system is very similar to that of the alkyne carbon in natural abundance cycloctyne, with δ 33 in the molecular plane and about 7°from the "triple" bond. Ab initio calculations of the chemical shift tensor of o-benzyne were completed at the SCF, MP2, and DFT levels using the GIAO method. The DFT calculations agree best with the experimental results.

Context The gene that codes for cannabinoid receptor 1 (CNR1) represents an important target for investigations designed to elucidate individual differences in the etiology of alcohol dependence. Objective To achieve a better understanding of the role of the CNR1 gene in the etiology and treatment of alcohol dependence. Design The present investigation spans multiple levels of analysis, including receptor binding in postmortem brain tissue, neuroimaging, human laboratory models, and analyses of treatment outcome data. Results Findings indicate that the C allele of rs2023239 is associated with greater CB1 binding in the prefrontal cortex, greater alcohol cue–elicited brain activation in the midbrain and prefrontal cortex, greater subjective reward when consuming alcohol, and more positive outcomes after treatment with a medication that targets the mesocorticolimbic neurocircuitry. In addition, there were strong correlations between cue-elicited brain activation and alcohol consumption measures in individuals with the C allele. Conclusion Individuals with the C allele may be more susceptible to changes in the mesocorticolimbic neurocircuitry that is involved in the attribution of incentive salience after repeated exposure to alcohol.

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The efficient processing of olfactory information is crucial for many aspects of life in animals, including behavior in insects. While much is known about the organization of the insect olfactory system, comparatively little is understood about the molecules that support its function. To further elucidate the molecular basis of olfaction, we explored the role of the calcium-binding chaperone calreticulin in the behavioral response of Drosophila to aversive odorants. We show that avoidance of naturally aversive odorants is impaired in flies harboring mutations in Calreticulin. Calreticulin mutants have broad defects in odor avoidance without abnormalities in antennal responses to odorants, alterations in central nervous system structure, or deficits in overall locomotor abilities. Interestingly, Calreticulin mutants exhibit defects in behavioral responses to odorants at low strength, whereas responses to higher odorant concentrations are preserved in these animals. Our studies indicate that calreticulin plays a key role in olfactory system function, possibly by establishing its overall sensitivity to odorants.

The Shaker-like family of voltage-gated K+ channels comprises four functionally independent gene subfamilies, Shaker (Kv1), Shab (Kv2), Shaw (Kv3), and Shal (Kv4), each of which regulates distinct aspects of neuronal excitability. Subfamily-specific assembly of tetrameric channels is mediated by the N-terminal T1 domain and segregates Kv1–4, allowing multiple channel types to function independently in the same cell. Typical Shaker-like Kv subunits can form functional channels as homotetramers, but a group of mammalian Kv2-related genes (Kv5.1, Kv6s, Kv8s, and Kv9s) encodes subunits that have a “silent” or “regulatory” phenotype characterized by T1 self-incompatibility. These channels are unable to form homotetramers, but instead heteromerize with Kv2.1 or Kv2.2 to diversify the functional properties of these delayed rectifiers. While T1 self-incompatibility predicts that these heterotetramers could contain up to two regulatory (R) subunits, experiments show a predominance of 3:1R stoichiometry in which heteromeric channels contain a single regulatory subunit. Substitution of the self-compatible Kv2.1 T1 domain into the regulatory subunit Kv6.4 does not alter the stoichiometry of Kv2.1:Kv6.4 heteromers. Here, to identify other channel structures that might be responsible for favoring the 3:1R stoichiometry, we compare the sequences of mammalian regulatory subunits to independently evolved regulatory subunits from cnidarians. The most widespread feature of regulatory subunits is the presence of atypical substitutions in the highly conserved consensus sequence of the intracellular S6 activation gate of the pore. We show that two amino acid substitutions in the S6 gate of the regulatory subunit Kv6.4 restrict the functional stoichiometry of Kv2.1:Kv6.4 to 3:1R by limiting the formation and function of 2:2R heteromers. We propose a two-step model for the evolution of the asymmetric 3:1R stoichiometry, which begins with evolution of self-incompatibility to establish the regulatory phenotype, followed by drift of the activation gate consensus sequence under relaxed selection to limit stoichiometry to 3:1R.

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