Effects of sex and remifentanil dose on rats' acquisition of responding for a remifentanil-conditioned reinforcer.

Opioid-conditioned reinforcement is thought to exacerbate opioid abuse and dependence. Sex/gender can influence opioid abuse behaviors, but the effects of sex/gender on opioid-conditioned reinforcement, specifically, are unclear. In this study, we compared new-response acquisition with opioid-conditioned reinforcement in male and female rats. First, separate groups received response-independent remifentanil injections (0.0-32.0 µg/kg, intravenous) and presentations of a light-noise stimulus. In the experimental groups, injections and stimulus presentations always co-occurred [paired Pavlovian conditioning (PAV)]; in the control groups, the two occurred independently of each other (random PAV). Next, in the instrumental acquisition (ACQ) sessions, two novel nose-poke manipulanda were introduced. All animals (regardless of sex, dose, and PAV type) could respond in the active nose-poke, which produced the stimulus alone, or in the inactive nose-poke. Both males and females dose-dependently acquired nose-poke responding (active>inactive) after paired PAV, but not after random PAV. Therefore, the stimulus was a conditioned reinforcer. We identified three sex differences. First, only females acquired responding after paired PAV with 32.0 µg/kg remifentanil. Second, using a progressive ratio schedule for ACQ, both sexes acquired responding, but females made significantly more active responses. Third, when a single session of PAV was conducted, only males acquired responding. Thus, rats' sex interacts with pharmacological and environmental factors to determine opioid-conditioned reinforcement.

Comparative transcriptomics of infectious spores from the fungal pathogen Histoplasma capsulatum reveals a core set of transcripts that specify infectious and pathogenic states.

Histoplasma capsulatum is a fungal pathogen that infects both healthy and immunocompromised hosts. In regions where it is endemic, H. capsulatum grows in the soil and causes respiratory and systemic disease when inhaled by humans. An interesting aspect of H. capsulatum biology is that it adopts specialized developmental programs in response to its environment. In the soil, it grows as filamentous chains of cells (mycelia) that produce asexual spores (conidia). When the soil is disrupted, conidia aerosolize and are inhaled by mammalian hosts. Inside a host, conidia germinate into yeast-form cells that colonize immune cells and cause disease. Despite the ability of conidia to initiate infection and disease, they have not been explored on a molecular level. We developed methods to purify H. capsulatum conidia, and we show here that these cells germinate into filaments at room temperature and into yeast-form cells at 37°C. Conidia internalized by macrophages germinate into the yeast form and proliferate within macrophages, ultimately lysing the host cells. Similarly, infection of mice with purified conidia is sufficient to establish infection and yield viable yeast-form cells in vivo. To characterize conidia on a molecular level, we performed whole-genome expression profiling of conidia, yeast, and mycelia from two highly divergent H. capsulatum strains. In parallel, we used homology and protein domain analysis to manually annotate the predicted genes of both strains. Analyses of the resultant data defined sets of transcripts that reflect the unique molecular states of H. capsulatum conidia, yeast, and mycelia.

Impulsivity is associated with treatment non-completion in cocaine- and methamphetamine-dependent patients but differs in nature as a function of stimulant-dependence diagnosis.

Greater impulsivity, assessed by the Barratt Impulsiveness Scale-11 (BIS-11) and Stroop interference scores, has been associated with treatment completion in cocaine-dependent patients. This study evaluated the relationships among impulsivity, stimulant-dependence diagnosis, and treatment completion. Six sites evaluating 12-step facilitation for stimulant abusers obtained the BIS-11 and Stroop from 182 methamphetamine- and/or cocaine-dependent participants. Methamphetamine-dependent, relative to cocaine-dependent, participants evidenced significantly greater BIS-11 non-planning and total scores. There was a trend for poorer response inhibition, measured by the Stroop, in cocaine-dependent, relative to methamphetamine-dependent, participants. Accounting for other factors related to treatment completion, BIS-11 motor score, assessing the tendency to act without thinking, predicted treatment completion for both cocaine-dependent and methamphetamine-dependent patients. These results suggest that methamphetamine-dependent and cocaine-dependent patients may have different impulsivity profiles but that the BIS-11 may be useful in identifying both methamphetamine-dependent and cocaine-dependent patients who are at risk for treatment non-completion.

Competition between surfactant micellization and complexation by cyclodextrin.

Supramolecular property systems composed of alkyltrimethylammonium surfactants and ß-cyclodextrin were studied by means of a chemical probe. Solvolysis of 4-methoxybenzenesulfonyl chloride (MBSC) was used in the mixed systems with the aim of being able to determine the concentration of uncomplexed cyclodextrin in equilibrium with the micellar system. The surfactants used enabled us to vary the length of the hydrocarbon chain between 6 and 18 carbon atoms. In all cases the existence of a significant concentration of uncomplexed CD was observable in equilibrium with the micellar system. The percentage of uncomplexed cyclodextrin increases both on increasing and decreasing the surfactant alkyl chain length, being minimal for alkyl chains between 10-12 carbon atoms. This behavior is a consequence of two simultaneous processes: complexation of surfactant monomers by the cyclodextrin and surfactant self-assembly to form micellar aggregates. By using Gibbs free energies for micellization and surfactant complexation by ß-CD, we can quantitatively explain the observed behavior.

Conidia but not yeast cells of the fungal pathogen Histoplasma capsulatum trigger a type I interferon innate immune response in murine macrophages.

Histoplasma capsulatum is the most common cause of fungal respiratory infections and can lead to progressive disseminated infections, particularly in immunocompromised patients. Infection occurs upon inhalation of the aerosolized spores, known as conidia. Once inside the host, conidia are phagocytosed by alveolar macrophages. The conidia subsequently germinate and produce a budding yeast-like form that colonizes host macrophages and can disseminate throughout host organs and tissues. Even though conidia are the predominant infectious particle for H. capsulatum and are the first cell type encountered by the host during infection, very little is known at a molecular level about conidia or about their interaction with cells of the host immune system. We examined the interaction between conidia and host cells in a murine bone-marrow-derived macrophage model of infection. We used whole-genome expression profiling and quantitative reverse transcription-PCR (qRT-PCR) to monitor the macrophage signaling pathways that are modulated during infection with conidia. Our analysis revealed that type I interferon (IFN)-responsive genes and the beta type I IFN (IFN-beta) were induced in macrophages during infection with H. capsulatum conidia but not H. capsulatum yeast cells. Further analysis revealed that the type I IFN signature induced in macrophages in response to conidia is independent of Toll-like receptor (TLR) signaling and the cytosolic RNA sensor MAVS but is dependent on the transcription factor interferon regulatory factor 3 (IRF3). Interestingly, H. capsulatum growth was restricted in mice lacking the type I IFN receptor, indicating that an intact host type I IFN response is required for full virulence of H. capsulatum in mice.