Pharmacokinetic and Biodistribution Assessment of a Near Infrared-Labeled PSMA-Specific Small Molecule in Tumor-Bearing Mice

Prostate cancer is themost frequently diagnosed cancer in men and often requires surgery. Use of near infrared (NIR) technologies to perform image-guided surgery may improve accurate delineation of tumor margins. To facilitate preclinical testing of such outcomes, here we developed and characterized a PSMA-targeted small molecule, YC-27. IRDye 800CW was conjugated to YC-27 or an anti-PSMA antibody used for reference. Human 22Rv1, PC3M-LN4, and/or LNCaP prostate tumor cells were exposed to the labeled compounds. In vivo targeting and clearance properties were determined in tumor-bearing mice. Organs and tumors were excised and imaged to assess probe localization. YC-27 exhibited a dose dependent increase in signal upon binding. Binding specificity and internalization were visualized by microscopy. In vitro and in vivo blocking studies confirmed YC-27 specificity. In vivo, YC-27 showed good tumor delineation and tissue contrast at doses as low as 0.25 nmole. YC-27 was cleared via the kidneys but bound the proximal tubules of the renal cortex and epididymis. Since PSMA is also broadly expressed on the neovasculature of most tumors, we expect YC-27 will have clinical utility for image-guided surgery and tumor resections

Accumbens Cholinergic Interneurons Mediate Cue-Induced Nicotine Seeking and Associated Glutamatergic Plasticity

Nicotine, the primary addictive substance in tobacco, is widely abused. Relapse to cues associated with nicotine results in increased glutamate release within nucleus accumbens core (NAcore), modifying synaptic plasticity of medium spiny neurons (MSNs), which contributes to reinstatement of nicotine seeking. However, the role of cholinergic interneurons (ChIs) within the NAcore in mediating these neurobehavioral processes is unknown. ChIs represent less than 1% of the accumbens neuronal population and are activated during drug seeking and reward-predicting events. Thus, we hypothesized that ChIs may play a significant role in mediating glutamatergic plasticity that underlies nicotine-seeking behavior. Using chemogenetics in transgenic rats expressing Cre under the control of the choline acetyltransferase (ChAT) promoter, ChIs were bidirectionally manipulated before cue-induced reinstatement. Following nicotine self-administration and extinction, ChIs were activated or inhibited before a cue reinstatement session. Following reinstatement, whole-cell electrophysiology from NAcore MSNs was used to assess changes in plasticity, measured via AMPA/NMDA (A/N) ratios. Chemogenetic inhibition of ChIs inhibited cued nicotine seeking and resulted in decreased A/N, relative to control animals, whereas activation of ChIs was unaltered, demonstrating that ChI inhibition may modulate plasticity underlying cue-induced nicotine seeking. These results demonstrate that ChI neurons play an important role in mediating cue-induced nicotine reinstatement and underlying synaptic plasticity within the NAcore

Sharpening the predictions of big-bang nucleosynthesis

Motivated by the recent measurement of the primeval abundance of deuterium, we re-examine the nuclear inputs to big-bang nucleosynthesis (BBN). Using Monte-Carlo realization of the nuclear cross-section data to directly estimate the theoretical uncertainties for the yields of D, 3-He and 7-Li, we show that previous estimates were a factor of 2 too large. We sharpen the BBN determination of the baryon density based upon deuterium, rho_B = (3.6 +/- 0.4) * 10^{-31} g/cm^3 (Omega_B h^2 = 0.019 +/- 0.0024), which leads to a predicted 4-He abundance, Y_P = 0.246 +/- 0.0014 and a stringent limit to the equivalent number of light neutrino species: N_nu < 3.20 (all at 95% cl). The predicted 7-Li abundance, 7-Li/H = (3.5 + 1.1 - 0.9) * 10^{-10}, is higher than that observed in pop II stars, (1.7 +/- 0.3) * 10^{-10} (both, 95% cl). We identify key reactions and the energies where further work is needed.Comment: 5 pages, 4 figures (epsfig), REVTeX; submitted to Phys. Rev. Let

Effect of Finite Mass on Primordial Nucleosynthesis

We have calculated the small effect of finite nucleon mass on the weak-interaction rates that interconvert protons and neutrons in the early Universe. We have modified the standard code for primordial nucleosynthesis to include these corrections and find a small, systematic increase in the 4He yield, $\delta Y / Y \simeq (0.47 - 0.50)$, depending slightly on the baryon-to-photon ratio. The fractional changes in the abundances of the other light elements are a few percent or less for interesting values of the baryon-to-photon ratio.Comment: 15 pages, 8 figures, uses psfig.st

Precision Prediction for the Big-Bang Abundance of Primordial Helium

Within the standard models of particle physics and cosmology we have calculated the big-bang prediction for the primordial abundance of \he to a theoretical uncertainty of less than 0.1 \pct $(\delta Y_P < \pm 0.0002)$, improving the current theoretical precision by a factor of 10. At this accuracy the uncertainty in the abundance is dominated by the experimental uncertainty in the neutron mean lifetime, $\tau_n = 885.4 \pm 2.0 sec$. The following physical effects were included in the calculation: the zero and finite-temperature radiative, Coulomb and finite-nucleon-mass corrections to the weak rates; order-$\alpha$ quantum-electrodynamic correction to the plasma density, electron mass, and neutrino temperature; and incomplete neutrino decoupling. New results for the finite-temperature radiative correction and the QED plasma correction were used. In addition, we wrote a new and independent nucleosynthesis code designed to control numerical errors to be less than 0.1\pct. Our predictions for the \EL[4]{He} abundance are presented in the form of an accurate fitting formula. Summarizing our work in one number, $Y_P(\eta = 5\times 10^{-10}) = 0.2462 \pm 0.0004 (expt) \pm < 0.0002 (theory)$. Further, the baryon density inferred from the Burles-Tytler determination of the primordial D abundance, $\Omega_B h^2 = 0.019\pm 0.001$, leads to the prediction: $Y_P = 0.2464 \pm 0.0005 (D/H) \pm < 0.0002 (theory) \pm 0.0005 (expt)$. This ``prediction'' and an accurate measurement of the primeval \he abundance will allow an important consistency test of primordial nucleosynthesis.Comment: Replaced fitting formulas - new versions differ by small but significant amount. Other minor changes. 30 pages, 17 figures, 5 table

Effect of Neutrino Heating on Primordial Nucleosynthesis

We have modified the standard code for primordial nucleosynthesis to include the effect of the slight heating of neutrinos by $e^\pm$ annihilations. There is a small, systematic change in the $^4$He yield, $\Delta Y \simeq +1.5\times 10^{-4}$, which is insensitive to the value of the baryon-to-photon ratio $\eta$ for 10^{-10}\la \eta \la 10^{-9}. We also find that the baryon-to-photon ratio decreases by about 0.5\% less than the canonical factor of 4/11 because some of the entropy in $e^\pm$ pairs is transferred to neutrinos. These results are in accord with recent analytical estimates.Comment: 14 pages/4 Figs (upon request

Raman Spectroscopic Analysis of Fingernail Clippings Can Help Differentiate between Postmenopausal Women Who Have and Have Not Suffered a Fracture

Raman spectroscopy was applied to nail clippings from 633 postmenopausal British and Irish women, from six clinical sites, of whom 42% had experienced a fragility fracture. The objective was to build a prediction algorithm for fracture using data from four sites (known as the calibration set) and test its performance using data from the other two sites (known as the validation set). Results from the validation set showed that a novel algorithm, combining spectroscopy data with clinical data, provided area under the curve (AUC) of 74% compared to an AUC of 60% from a reduced QFracture score (a clinically accepted risk calculator) and 61% from the dual-energy X-ray absorptiometry T-score, which is in current use for the diagnosis of osteoporosis. Raman spectroscopy should be investigated further as a noninvasive tool for the early detection of enhanced risk of fragility fracture

A Comprehensive Analysis of Electric Dipole Moment Constraints on CP-violating Phases in the MSSM

We analyze the constraints placed on individual, flavor diagonal CP-violating phases in the minimal supersymmetric extension of the Standard Model (MSSM) by current experimental bounds on the electric dipole moments (EDMs) of the neutron, Thallium, and Mercury atoms. We identify the four CP-violating phases that are individually highly constrained by current EDM bounds, and we explore how these phases and correlations among them are constrained by current EDM limits. We also analyze the prospective implications of the next generation of EDM experiments. We point out that all other CP-violating phases in the MSSM are not nearly as tightly constrained by limits on the size of EDMs. We emphasize that a rich set of phenomenological consequences is potentially associated with these generically large EDM-allowed phases, ranging from B physics, electroweak baryogenesis, and signals of CP-violation at the CERN Large Hadron Collider and at future linear colliders. Our numerical study takes into account the complete set of contributions from one- and two-loop EDMs of the electron and quarks, one- and two-loop Chromo-EDMs of quarks, the Weinberg 3-gluon operator, and dominant 4-fermion CP-odd operator contributions, including contributions which are both included and not included yet in the CPsuperH2.0 package. We also introduce an open-source numerical package, 2LEDM, which provides the complete set of two-loop electroweak diagrams contributing to the electric dipole moments of leptons and quarks.Comment: 23 pages, 11 figures; v2: references added, minor change

Assessing Big-Bang Nucleosynthesis

Systematic uncertainties in the light-element abundances and their evolution make a rigorous statistical assessment difficult. However, using Bayesian methods we show that the following statement is robust: the predicted and measured abundances are consistent with 95\% credibility only if the baryon-to-photon ratio is between $2\times 10^{-10}$ and $6.5\times 10^{-10}$ and the number of light neutrino species is less than 3.9. Our analysis suggests that the $^4$He abundance may have been systematically underestimated.Comment: 7 pages, LaTeX(2.09), 6 postscript figures (attached). A postscript version with figures can be found at ftp://astro.uchicago.edu/pub/astro/copi/assessing_BBN . (See the README file for details