Physiological and subjective responses to controlled oral 3,4-methylenedioxymethamphetamine administration.

A randomized, within-subject, double-blind, inpatient study of the physiological and subjective effects of oral 3,4-methylenedioxymethamphetamine (MDMA) was conducted in human volunteers with previous MDMA experience. Placebo, low (1.0 mg/kg), and high (1.

Plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine after controlled oral administration to young adults.

This study examines the plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA) and metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxyamphetamine (MDA), and 4-hydroxy-3-methoxyamphetamine (HMA) in young adults for up to 143 hours after drug administration. Seventeen female and male participants (black, white, and Hispanic) received placebo, low (1.0 mg/kg), and high (1.

Engineered antibody Fc variants with enhanced effector function.

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 Fcgamma 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 Fcgamma 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.

The basolateral complex of the amygdala mediates the modulation of intracranial self-stimulation threshold by drug-associated cues.

Learning and memory appear to be critical aspects of drug abuse; presumably playing an especially important role in craving and relapse. Thus, understanding the interaction of learning- and memory-related brain areas with the classical reward circuitry is of importance. Toward this goal, the effect of drug-associated contextual cues on intracranial self-stimulation (ICSS) behaviour was assessed in rats.

Electrical and chemical stimulation of the basolateral complex of the amygdala reinstates cocaine-seeking behavior in the rat.

Rationale: The basolateral complex of the amygdala (BLC) is part of a neural circuit that is activated in humans during cocaine craving elicited by exposure to drug-related environmental cues. In animals, the BLC is necessary for cocaine-seeking behavior elicited by cocaine-associated cues. It has not been determined whether BLC activation is sufficient to reinstate cocaine seeking.

Combining computational and experimental screening for rapid optimization of protein properties.

We present a combined computational and experimental method for the rapid optimization of proteins. Using beta-lactamase as a test case, we redesigned the active site region using our Protein Design Automation technology as a computational screen to search the entire sequence space. By eliminating sequences incompatible with the protein fold, Protein Design Automation rapidly reduced the number of sequences to a size amenable to experimental screening, resulting in a library of approximately equal 200,000 mutants.

Cocaine treatment increases expression of a 40 kDa catecholamine-regulated protein in discrete brain regions.

Previous reports from our laboratory have described brain-specific catecholamine-regulated proteins, which bind dopamine and related catecholamines. Evidence from the molecular cloning of a 40 kDa catecholamine-regulated protein (CRP40) revealed that CRP40 is dopamine-inducible and has properties similar to those of the 70 kDa heat shock protein (HSP70) family. The present study investigates the effects of acute and chronic cocaine treatment on CRP40 expression in the striatum, nucleus accumbens, prefrontal cortex, and medulla.

Computational stabilization of human growth hormone.

Recombinant human growth hormone (hGH) is used worldwide for the treatment of pediatric hypopituitary dwarfism and in children suffering from low levels of hGH. It has limited stability in solution, and because of poor oral absorption, is administered by injection, typically several times a week. Development has therefore focused on more stable or sustained-release formulations and alternatives to injectable delivery that would increase bioavailability and make it easier for patients to use.

Development of a cytokine analog with enhanced stability using computational ultrahigh throughput screening.

Granulocyte-colony stimulating factor (G-CSF) is used worldwide to prevent neutropenia caused by high-dose chemotherapy. It has limited stability, strict formulation and storage requirements, and because of poor oral absorption must be administered by injection (typically daily). Thus, there is significant interest in developing analogs with improved pharmacological properties.