Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

The front-line tuberculosis (TB) chemotherapeutics isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA) have been labeled with carbon-11 and the biodistribution of each labeled drug has been determined in baboons using positron emission tomography (PET). Each radiosynthesis and formulation has been accomplished in 1 h, using [11C]CH3I to label RIF and [11C]HCN to label INH and PZA. Following iv administration, INH, PZA, RIF, and/or their radiolabeled metabolites clear rapidly from many tissues; however, INH, PZA, and/or their radiolabeled metabolites accumulate in the bladder while RIF and/or its radiolabeled metabolites accumulates in the liver and gall bladder, consistent with the known routes of excretion of the drugs. In addition, the biodistribution data demonstrate that the ability of the three drugs and their radiolabeled metabolites to cross the blood−brain barrier decreases in the order PZA > INH > RIF, although in all cases the estimated drug concentrations are greater than the minimum inhibitory concentration (MIC) values for inhibiting bacterial growth of Mycobacterium tuberculosis (MTB). The pharmacokinetic (PK) and drug distribution data have important implications for treatment of disseminated TB in the brain and pave the way for imaging the distribution of the pathogen in vivo.Chemistry and Chemical Biolog

An Exploratory Pilot Study of Mechanisms of Action Within Normative Feedback for Adult Drinkers

Background. Normative feedback (NF), or receiving information about one\u27s drinking compared to peer drinking norms, is one of the most widely used brief interventions for prevention and intervention for hazardous alcohol use. NF has demonstrated predominantly small but significant effect sizes for intention to change and other drinking related outcomes. Identifying mechanisms of action may improve the effectiveness of NF; however, few studies have examined NF\u27s mechanisms of action, particularly among adults. Objective. This study is an exploratory analysis of two theorized mechanisms of NF: discrepancy (specifically, personal dissonance--the affective response to feedback) and belief in the accuracy of feedback. Method. Using Amazon\u27s Mechanical Turk, 87 men (n = 56) and women (n = 31) completed an online survey during which they were asked about their perceptions about their drinking and actual drinking behaviors. Then participants were provided tailored NF and evaluated for their reactions. Severity of discrepancy was measured by the difference between one\u27s estimated percentile ranking of drinking compared to peers and actual percentile ranking. Surprise and worry reported due to the discrepancy were proxies for personal dissonance. Participants were also asked if they believed the feedback and if they had any plans to change their drinking. Mediation analyses were implemented, exploring whether surprise, worry, or belief in the accuracy of feedback mediated severity of discrepancy\u27s impact on plan for change. Results. Among this sample of adult drinkers, severity of discrepancy did not predict plan for change, and personal dissonance did not mediate severity of discrepancy. Severity of discrepancy was mediated by belief in the accuracy of feedback. In addition, viewing one\u27s drinking as a problem prior to feedback and post-NF worry both predicted plan for change independently. Conclusions. Results revealed that NF may not work to create personal dissonance through discrepancy, but belief in the accuracy of feedback may be important. It appears the more one believes the feedback, the more one makes a plan for change, suggesting practitioners should be mindful of how information within feedback is presented. Findings also indicate NF may work by validating a preexisting perception that drinking is a problem instead of creating concern related to discrepancy where none existed. Limitations regarding generalizability are discussed

Radionuclide Labeling and Evaluation of Candidate Radioligands for PET Imaging of Histone Deacetylase in the Brain

Histone deacetylases (HDACs) regulate gene expression by inducing conformational changes in chromatin. Ever since the discovery of a naturally occurring HDAC inhibitor, trichostatin A (TSA) stimulated the recent development of suberoylanilide (SAHA, Zolinza®), HDAC has become an important molecular target for drug development. This has created the need to develop specific in vivo radioligands to study epigenetic regulation and HDAC engagement for drug development for diseases including cancer and psychiatric disorders. 6-([18F]Fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) was recently developed as a HDAC substrate and shows moderate blood–brain barrier (BBB) permeability and specific signal (by metabolic trapping/or deacetylation) but rapid metabolism. Here, we report the radiosynthesis of two carbon-11 labeled candidate radiotracers (substrate- and inhibitor-based radioligand) for HDAC and their evaluation in non-human primate brain. PET studies showed very low brain uptake and rapid metabolism of both labeled compounds but revealed a surprising enhancement of brain penetration by F for H substitution when comparing one of these to [18F]FAHA. Further structural refinement is needed for the development of brain-penetrant, metabolically stable HDAC radiotracers and to understand the role of fluorine substitution on brain penetration.Chemistry and Chemical Biolog

A CENP-S/X complex assembles at the centromere in S and G2 phases of the human cell cycle

The functional identity of centromeres arises from a set of specific nucleoprotein particle subunits of the centromeric chromatin fibre. These include CENP-A and histone H3 nucleosomes and a novel nucleosome-like complex of CENPs -T,-W,-S and -X. Fluorescence cross-correlation spectroscopy and Forster resonance energy transfer (FRET) revealed that human CENP-S and -X exist principally in complex in soluble form and retain proximity when assembled at centromeres. Conditional labelling experiments show that they both assemble de novo during S phase and G2, increasing approximately three-to fourfold in abundance at centromeres. Fluorescence recovery after photobleaching (FRAP) measurements documented steady-state exchange between soluble and assembled pools, with CENP-X exchanging approximately 10 times faster than CENP-S (t(1/2) similar to 10 min versus 120 min). CENP-S binding to sites of DNA damage was quite distinct, with a FRAP half-time of approximately 160 s. Fluorescent two-hybrid analysis identified CENP-T as a uniquely strong CENP-S binding protein and this association was confirmed by FRET, revealing a centromere-bound complex containing CENP-S, CENP-X and CENP-T in proximity to histone H3 but not CENP-A. We propose that deposition of the CENP-T/W/S/X particle reveals a kinetochore-specific chromatin assembly pathway that functions to switch centromeric chromatin to a mitosis-competent state after DNA replication. Centromeres shuttle between CENP-A-rich, replication-competent and H3-CENP-T/W/S/X-rich mitosis-competent compositions in the cell cycle

Population and dynamical state of the eta Chamaeleontis sparse young open cluster

We report new results in our continuing study of the unique compact (1 pc extent), nearby (d = 97 pc), young (t = 9 Myr) stellar cluster dominated by the B9 star eta Chamaeleontis. An optical photometric survey spanning 1.3 x 1.3 pc adds two M5-M5.5 weak-lined T Tauri (WTT) stars to the cluster inventory which is likely to be significantly complete for primaries with masses > 0.15 M_sun. The cluster now consists of 17 primaries and approximately 9 secondaries lying within 100 AU of their primaries. The apparent distribution of 9:7:1 single:binary:triple systems shows 2-4 x higher multiplicity than in the field main sequence stars, and is comparable to that seen in other pre-main sequence (PMS) populations. The initial mass function (IMF) is consistent with that of rich young clusters and field stars. By extending the cluster IMF to lower masses, we predict 10-14 additional low mass stars with 0.08 < M < 0.15 M-sun and 10-15 brown dwarfs with 0.025 < M < 0.08 M_sun remain to be discovered. The eta Cha cluster extends the established stellar density and richness relationship for young open clusters. The radial distribution of stars is consistent with an isothermal sphere, but mass segregation is present with > 50 percent of the stellar mass residing in the inner 6 arcmin (0.17 pc). Considering that the eta Cha cluster is sparse, diffuse and young, the cluster may be an ideal laboratory for distinguishing between mass segregation that is primordial in nature, or arising from dynamical interaction processes.Comment: 10 pages, 7 figures, 2 tables, accepted for MNRA

In vivo characterization of connective tissue remodeling using infrared photoacoustic spectra

Premature cervical remodeling is a critical precursor of spontaneous preterm birth, and the remodeling process is characterized by an increase in tissue hydration. Nevertheless, current clinical measurements of cervical remodeling are subjective and detect only late events, such as cervical effacement and dilation. Here, we present a photoacoustic endoscope that can quantify tissue hydration by measuring near-infrared cervical spectra. We quantify the water contents of tissue-mimicking hydrogel phantoms as an analog of cervical connective tissue. Applying this method to pregnant women in vivo, we observed an increase in the water content of the cervix throughout pregnancy. The application of this technique in maternal healthcare may advance our understanding of cervical remodeling and provide a sensitive method for predicting preterm birth

Multi-core fibre-fed integral-field unit (MCIFU):Overview and first-light

The Multi-Core Integral-Field Unit (MCIFU) is a new diffraction-limited near-infrared integral-field unit for exoplanet atmosphere characterization with extreme adaptive optics (xAO) instruments. It has been developed as an experimental pathfinder for spectroscopic upgrades for SPHERE+/VLT and other xAO systems. The wavelength range covers 1.0 um to 1.6um at a resolving power around 5000 for 73 points on-sky. The MCIFU uses novel astrophotonic components to make this very compact and robust spectrograph. We performed the first successful on-sky test with CANARY at the 4.2 meter William Herschel Telescope in July 2019, where observed standard stars and several stellar binaries. An improved version of the MCIFU will be used with MagAO-X, the new extreme adaptive optics system at the 6.5 meter Magellan Clay telescope in Chile. We will show and discuss the first-light performance and operations of the MCIFU at CANARY and discuss the integration of the MCIFU with MagAO-X.</p

Effects of Modafinil on Dopamine and Dopamine Transporters in the Male Human Brain

Context: Modafinil, a wake-promoting drug used to treat narcolepsy, is increasingly being used as a cognitive enhancer. Although initially launched as distinct from stimulants that increase extracellular dopamine by targeting dopamine transporters, recent preclinical studies suggest otherwise. Objective: To measure the acute effects of modafinil at doses used therapeutically (200 mg and 400 mg given orally) on extracellular dopamine and on dopamine transporters in the male human brain. Design, Setting, and Participants: Positron emission tomography with [11C]raclopride (D2 / D3 radioligand sensitive to changes in endogenous dopamine) and [11C]cocaine (dopamine transporter radioligand) was used to measure the effects of modafinil on extracellular dopamine and on dopamine transporters in 10 healthy male participants. The study took place over an 8-month period (2007-2008) at Brookhaven National Laboratory. Main Outcome Measures: Primary outcomes were changes in dopamine D2 / D3 receptor and dopamine transporter availability (measured by changes in binding potential) after modafinil when compared with after placebo. Results: Modafinil decreased mean (SD) [11C]raclopride binding potential in caudate (6.1% [6.5%]; 95% confidence interval [CI], 1.5% to 10.8%; P = .02), putamen (6.7% [4.9%]; 95% CI, 3.2% to 10.3%; P = .002), and nucleus accumbens (19.4% [20%]; 95% CI, 5% to 35%; P = .02), reflecting increases in extracellular dopamine. Modafinil also decreased [11C]cocaine binding potential in caudate (53.8% [13.8%]; 95% CI, 43.9% to 63.6%; P < .001), putamen (47.2% [11.4%]; 95% CI, 39.1% to 55.4%; P < .001), and nucleus accumbens (39.3% [10%]; 95% CI, 30% to 49%; P = .001), reflecting occupancy of dopamine transporters. Conclusions: In this pilot study, modafinil blocked dopamine transporters and increased dopamine in the human brain (including the nucleus accumbens). Because drugs that increase dopamine in the nucleus accumbens have the potential for abuse, and considering the increasing use of modafinil, these results highlight the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations.Chemistry and Chemical Biolog