Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fc␥ receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fc␥ receptor affinity and specificity. The designed variants display >2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.antibody-dependent cell-mediated cytotoxicity ͉ Fc␥R ͉ protein engineering ͉ cancer

Treatment efforts for cocaine addiction are hampered by high relapse rates. To map brain areas underlying relapse, we used electrical brain stimulation and intracranial injection of pharmacological compounds after extinction of cocaine self-administration behavior in rats. Electrical stimulation of the hippocampus containing glutamatergic fibers, but not the medial forebrain bundle containing dopaminergic fibers, elicited cocaine-seeking behavior dependent on glutamate in the ventral tegmental area. This suggests a role for glutamatergic neurotransmission in relapse to cocaine abuse. The medial forebrain bundle electrodes supported intense electrical self-stimulation. These findings suggest a dissociation of neural systems subserving positive reinforcement (self-stimulation) and incentive motivation (relapse).

dopamine D3 receptor is preferentially localized to the mesocorticolimbic dopaminergic system and has been hypothesized to play a role in cocaine addiction. To study the involvement of the D3 receptor in brain mechanisms and behaviors commonly assumed to be involved in the addicting properties of cocaine, the potent and selective D3 receptor antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide (SB-277011-A) was administered to laboratory rats, and the following measures were assessed: (1) cocaine-enhanced electrical brain-stimulation reward, (2) cocaine-induced conditioned place preference, and (3) cocaine-triggered reinstatement of cocaine seeking behavior. Systemic injections of SB-277011-A were found to (1) block enhancement of electrical brain stimulation reward by cocaine, (2) dose-dependently attenuate cocaine-induced conditioned place preference, and (3) dose-dependently attenuate cocaine-triggered reinstatement of cocaine seeking behavior. Thus, D3 receptor blockade attenuates both the rewarding effects of cocaine and cocaine-induced drug-seeking behavior. These data suggest an important role for D3 receptors in mediating the addictive properties of cocaine and suggest that blockade of dopamine D3 receptors may constitute a new and useful target for prospective pharmacotherapies for cocaine addiction.

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In the absence of efficient transcription termination correct 3′‐end processing is an essential step in the synthesis of stable chloroplast mRNAs in higher plants. We show here that 3′‐end processing in vitro involves endonucleolytic cleavage downstream from the mature terminus, followed by exonucleolytic processing to a stem‐loop within the 3′‐untranslated region. These processing steps require a high molecular weight complex that contains both endoribonucleases and an exoribonuclease. In the presence of ancillary RNA binding proteins the complex correctly processes the 3′‐end of precursor RNA. In the absence of these ancillary proteins 3′‐end maturation is prevented and plastid mRNAs are degraded. Based on these results we propose a novel mechanism for the regulation of mRNA 3′‐end processing and stability in chloroplasts.