Design, Synthesis, and Evaluation of Hydroxamic Acid-Based Molecular Probes for In Vivo Imaging of Histone Deacetylase (HDAC) in Brain

Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the importance of in vivo PET imaging tools in characterizing putative CNS drug lead compounds and the continued need to discover effect PET tracers for neuroepigenetic imaging.Chemistry and Chemical Biolog

A Significantly Neutral Intergalactic Medium Around the Luminous z=7 Quasar J0252-0503

Luminous $z\ge7$ quasars provide direct probes of the evolution of supermassive black holes (SMBHs) and the intergalactic medium (IGM) during the epoch of reionization (EoR). The Ly$\alpha$ damping wing absorption imprinted by neutral hydrogen in the IGM can be detected in a single EoR quasar spectrum, allowing the measurement of the IGM neutral fraction towards that line of sight. However, damping wing features have only been detected in two $z>7$ quasars in previous studies. In this paper, we present new high quality optical and near-infrared spectroscopy of the $z=7.00$ quasar DES J025216.64--050331.8 obtained with Keck/NIRES and Gemini/GMOS. By using the MgII single-epoch virial method, we find that it hosts a $\rm (1.39\pm0.16) \times10^{9} ~M_\odot$ SMBH accreting at an Eddington ratio of $\lambda_{\rm Edd}=0.7\pm0.1$, consistent with the values seen in other luminous $z\sim 7$ quasars. Furthermore, the Ly$\alpha$ region of the spectrum exhibits a strong damping wing absorption feature. The lack of associated metal absorption in the quasar spectrum indicates that this absorption is imprinted by a neutral IGM. Using a state-of-the-art model developed by Davies et al., we measure a volume-averaged neutral hydrogen fraction at $z=7$ of $\langle x_{\rm HI} \rangle = 0.70^{+0.20}_{-0.23} (^{+0.28}_{-0.48})$ within 68% (95%) confidence intervals when marginalizing over quasar lifetimes of $10^3\le t_{\rm Q}\le10^8$ yr. This is the highest IGM neutral fraction yet measured using reionization-era quasar spectra.Comment: 13 pages, 6 figures. Accepted for publication in The Astrophysical Journa

P\={o}niu\={a}'ena: A Luminous z=7.5z=7.5 Quasar Hosting a 1.5 Billion Solar Mass Black Hole

We report the discovery of a luminous quasar, J1007+2115 at $z=7.515$ ("P\={o}niu\={a}'ena"), from our wide-field reionization-era quasar survey. J1007+2115 is the second quasar now known at $z>7.5$, deep into the reionization epoch. The quasar is powered by a $(1.5\pm0.2)\times10^9$ $M_{\odot}$ supermassive black hole (SMBH), based on its broad MgII emission-line profile from Gemini and Keck near-IR spectroscopy. The SMBH in J1007+2115 is twice as massive as that in quasar J1342+0928 at $z=7.54$, the current quasar redshift record holder. The existence of such a massive SMBH just 700 million years after the Big Bang significantly challenges models of the earliest SMBH growth. Model assumptions of Eddington-limited accretion and a radiative efficiency of 0.1 require a seed black hole of $\gtrsim 10^{4}$ $M_{\odot}$ at $z=30$. This requirement suggests either a massive black hole seed as a result of direct collapse or earlier periods of rapid black hole growth with hyper-Eddington accretion and/or a low radiative efficiency. We measure the damping wing signature imprinted by neutral hydrogen absorption in the intergalactic medium (IGM) on J1007+2115's Ly$\alpha$ line profile, and find that it is weaker than that of J1342+0928 and two other $z\gtrsim7$ quasars. We estimate an IGM volume-averaged neutral fraction $\langle x\rm_{HI}\rangle=0.39^{+0.22}_{-0.13}$. This range of values suggests a patchy reionization history toward different IGM sightlines. We detect the 158 $\mu$m [C II] emission line in J1007+2115 with ALMA; this line centroid yields a systemic redshift of $z=7.5149\pm0.0004$ and indicates a star formation rate of $\sim210$ $M_{\odot}$ yr$^{-1}$ in its host galaxy.Comment: 9 pages, 4 figures, ApJL in pres

Original Article Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain

Abstract: Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the importance of in vivo PET imaging tools in characterizing putative CNS drug lead compounds and the continued need to discover effect PET tracers for neuroepigenetic imaging

The diffusion of financial supervisory governance ideas

Who is watching the financial services industry? Since 1980, there have been multiple waves of thought about whether the ministry of finance, the central bank, a specialized regulator or some combination of these should have supervisory authority. These waves have been associated with the convergence of actual practices. How much and through what channels did internationally promoted ideas about supervisory 'best practice' influence institutional design choices? I use a new dataset of 83 countries and jurisdictions between the 1980s and 2007 to examine the diffusion of supervisory ideas. With this data, I employ Cox Proportional Hazard and Competing Risks Event History Analyses to evaluate the possible causal roles best practice policy ideas might have played. I find that banking crises and certain peer groups can encourage policy convergence on heavily promoted ideas

A SPectroscopic Survey of Biased Halos in the Reionization Era (ASPIRE): A First Look at the Rest-frame Optical Spectra of z > 6.5 Quasars Using JWST

© 2023. The Author(s). Published by the American Astronomical Society. This is an open access article distributed under the Creative Commons Attribution License, to view a copy of the license, see: https://creativecommons.org/licenses/by/4.0/Studies of rest-frame optical emission in quasars at z > 6 have historically been limited by the wavelengths accessible by ground-based telescopes. The James Webb Space Telescope (JWST) now offers the opportunity to probe this emission deep into the reionization epoch. We report the observations of eight quasars at z > 6.5 using the JWST/NIRCam Wide Field Slitless Spectroscopy as a part of the “A SPectroscopic survey of biased halos In the Reionization Era (ASPIRE)” program. Our JWST spectra cover the quasars’ emission between rest frame ∼4100 and 5100 Å. The profiles of these quasars’ broad Hβ emission lines span a full width at half maximum from 3000 to 6000 km s−1. The Hβ-based virial black hole (BH) masses, ranging from 0.6 to 2.1 billion solar masses, are generally consistent with their Mg ii-based BH masses. The new measurements based on the more reliable Hβ tracer thus confirm the existence of a billion solar-mass BHs in the reionization epoch. In the observed [O iii] λ λ 4960,5008 doublets of these luminous quasars, broad components are more common than narrow core components (≤ 1200 km s−1), and only one quasar shows stronger narrow components than broad. Two quasars exhibit significantly broad and blueshifted [O iii] emission, thought to trace galactic-scale outflows, with median velocities of −610 and −1430 km s−1 relative to the [C ii] 158 μm line. All eight quasars show strong optical Fe ii emission and follow the eigenvector 1 relations defined by low-redshift quasars. The entire ASPIRE program will eventually cover 25 quasars and provide a statistical sample for the studies of the BHs and quasar spectral properties.Peer reviewe

The Lick AGN Monitoring Project 2016 : dynamical modeling of velocity-resolved Hβ lags in luminous Seyfert galaxies

K.H. acknowledges support from STFC grant ST/R000824/1.We have modeled the velocity-resolved reverberation response of the Hβ broad emission line in nine Seyfert 1 galaxies from the Lick Active Galactic Nucleus (AGN) Monitoring Project 2016 sample, drawing inferences on the geometry and structure of the low-ionization broad-line region (BLR) and the mass of the central supermassive black hole. Overall, we find that the Hβ BLR is generally a thick disk viewed at low to moderate inclination angles. We combine our sample with prior studies and investigate line-profile shape dependence, such as log10(FWHM/σ), on BLR structure and kinematics and search for any BLR luminosity-dependent trends. We find marginal evidence for an anticorrelation between the profile shape of the broad Hβ emission line and the Eddington ratio, when using the rms spectrum. However, we do not find any luminosity-dependent trends, and conclude that AGNs have diverse BLR structure and kinematics, consistent with the hypothesis of transient AGN/BLR conditions rather than systematic trends.Publisher PDFPeer reviewe

The Lick AGN Monitoring Project 2016: Dynamical Modeling of Velocity-Resolved H\b{eta} Lags in Luminous Seyfert Galaxies

We have modeled the velocity-resolved reverberation response of the H\b{eta} broad emission line in nine Seyfert 1 galaxies from the Lick Active Galactic Nucleus (AGN) Monitioring Project 2016 sample, drawing inferences on the geometry and structure of the low-ionization broad-line region (BLR) and the mass of the central supermassive black hole. Overall, we find that the H\b{eta} BLR is generally a thick disk viewed at low to moderate inclination angles. We combine our sample with prior studies and investigate line-profile shape dependence, such as log10(FWHM/{\sigma}), on BLR structure and kinematics and search for any BLR luminosity-dependent trends. We find marginal evidence for an anticorrelation between the profile shape of the broad H\b{eta} emission line and the Eddington ratio, when using the root-mean-square spectrum. However, we do not find any luminosity-dependent trends, and conclude that AGNs have diverse BLR structure and kinematics, consistent with the hypothesis of transient AGN/BLR conditions rather than systematic trends