Use of Linear Free Energy Relationships (LFERs) to Elucidate the Mechanisms of Reaction of a γ-Methyl-β-alkynyl and an ortho-Substituted Aryl Chloroformate Ester

The specific rates of solvolysis of 2-butyn-1-yl-chloroformate (1) and 2-methoxyphenyl chloroformate (2) are studied at 25.0 °C in a series of binary aqueousorganic mixtures. The rates of reaction obtained are then analyzed using the extended Grunwald-Winstein (G-W) equation and the results are compared to previously published G-W analyses for phenyl chloroformate (3), propargyl chloroformate (4), p-methoxyphenyl choroformate (5), and p-nitrophenyl chloroformate (6). For 1, the results indicate that dual side-by-side addition-elimination and ionization pathways are occurring in some highly ionizing solvents due to the presence of the electron-donating γ-methyl group. For 2, the analyses indicate that the dominant mechanism is a bimolecular one where the formation of a tetrahedral intermediate is rate-determining

A 1-acetamido derivative of 6-epi-valienamine: an inhibitor of a diverse group of β-N-acetylglucosaminidases

The synthesis of an analogue of 6-epi-valienamine bearing an acetamido group and its characterisation as an inhibitor of β-N-acetylglucosaminidases are described. The compound is a good inhibitor of both human O-GlcNAcase and human β-hexosaminidase, as well as two bacterial β-N-acetylglucosaminidases. A 3-D structure of the complex of Bacteroides thetaiotaomicron BtGH84 with the inhibitor shows the unsaturated ring is surprisingly distorted away from its favoured solution phase conformation and reveals potential for improved inhibitor potency

A Hybrid Global Minimization Scheme for Accurate Source Localization in Sensor Networks

We consider the localization problem of multiple wideband sources in a multi-path environment by coherently taking into account the attenuation characteristics and the time delays in the reception of the signal. Our proposed method leaves the space for unavailability of an accurate signal attenuation model in the environment by considering the model as an unknown function with reasonable prior assumptions about its functional space. Such approach is capable of enhancing the localization performance compared to only utilizing the signal attenuation information or the time delays. In this paper, the localization problem is modeled as a cost function in terms of the source locations, attenuation model parameters and the multi-path parameters. To globally perform the minimization, we propose a hybrid algorithm combining the differential evolution algorithm with the Levenberg-Marquardt algorithm. Besides the proposed combination of optimization schemes, supporting the technical details such as closed forms of cost function sensitivity matrices are provided. Finally, the validity of the proposed method is examined in several localization scenarios, taking into account the noise in the environment, the multi-path phenomenon and considering the sensors not being synchronized

Using the Bullet Cluster as a Gravitational Telescope to Study z~7 Lyman Break Galaxies

We use imaging obtained with the Hubble Space Telescope Wide Field Camera 3 to search for z_850 dropouts at z~7 and J_110 dropouts at z~9 lensed by the Bullet Cluster. In total we find 10 z_850 dropouts in our 8.27 arcmin^2 field. Using magnification maps from a combined weak and strong lensing mass reconstruction of the Bullet Cluster and correcting for estimated completeness levels, we calculate the surface density and luminosity function of our z_850 dropouts as a function of intrinsic (accounting for magnification) magnitude. We find results consistent with published blank field surveys, despite using much shallower data, and demonstrate the effectiveness of cluster surveys in the search for z~7 galaxies.Comment: 12 pages, 2 tables, 9 figures. Accepted for publication in ApJ. V3: two new figures, improved calculation of intrinsic counts, better organization, added references; main results did not change significantl

Elevated anxiety-like behavior following ethanol exposure in mutant mice lacking neuropeptide Y (NPY)

Neuropeptide Y (NPY) is a neuromodulator with anxiolytic properties. Recent evidence suggests that NPY modulates neurobiological responses to ethanol. Because withdrawal from ethanol is associated with elevated anxiety-like behavior, and because central NPY modulates anxiety, we assessed anxiety-like behavior in mutant mice lacking normal production of NPY (NPY−/−) and in normal wild-type mice (NPY+/+) 6-hours after removal of a liquid diet containing 4.5% ethanol

Increased Consumption but Not Operant Self-administration of Ethanol in Mice Lacking the RIIbeta Subunit of Protein Kinase A

Accumulating evidence indicates that cAMP-dependent protein kinase A (PKA) is involved in the neurobiological responses to ethanol. Previous reports indicate that mice lacking the RIIβ subunit of PKA (RIIβ−/−) voluntarily consume more ethanol than wild-type controls (RIIβ+/+) using two-bottle testing procedures. While such procedures primarily measure consummatory behavior, operant self-administration procedures allow analysis of consummatory as well as appetitive or “ethanol-seeking” behavior (i.e., lever pressing is required to gain access to the ethanol solution). Therefore, we determined if the high ethanol consumption characteristic of RIIβ−/− mice would be complimented by increased appetitive ethanol-seeking behavior in an operant paradigm

O-GlcNAcase:promiscuous hexosaminidase or key regulator of O-GlcNAc signalling?

O-GlcNAc signaling is regulated by an opposing pair of enzymes: O-GlcNAc transferase installs and O-GlcNAcase (OGA) removes the modification from proteins. The dynamics and regulation of this process are only beginning to be understood as the physiological functions of both enzymes are being probed using genetic and pharmacological approaches. This minireview charts the discovery and functional and structural analysis of OGA and summarizes the insights gained from recent studies using OGA inhibition, gene knock-out, and overexpression. We identify several areas of “known unknowns” that would benefit from future research, such as the enigmatic C-terminal domain of OGA

Predictors of High Ethanol Consumption in RII?? Knock-Out Mice: Assessment of Anxiety and Ethanol-Induced Sedation

Genetic and pharmacological evidence suggests that the cyclic adenosine monophosphate–dependent protein kinase A pathway modulates neurobiological responses to ethanol. Mutant mice lacking the RIIβ subunit of protein kinase A (RIIβ) are resistant to ethanol-induced sedation and drink significantly more ethanol than littermate wild-type mice (RIIβ). We determined whether high ethanol intake by the RIIβ mice on alternate genetic backgrounds is reliably predicted by high basal levels of anxiety or resistance to the sedative effects of ethanol. Two-bottle choice procedures and a battery of behavioral tests (elevated plus maze, open-field activity, and zero maze) were used to assess voluntary ethanol consumption and basal levels of anxiety in RIIβ and RIIβ mice on either a C57BL/6J or a 129/SvEv × C57BL/6J genetic background. Additionally, ethanol-induced sedation and blood ethanol levels were determined in RIIβ and RIIβ mice after intraperitoneal injection of ethanol (3.8 g/kg). RIIβ mice on both genetic backgrounds consumed more ethanol and had a greater preference for ethanol relative to RIIβ mice. However, RIIβ mice showed reduced basal levels of anxiety when maintained on the C57BL/6J background but showed increased anxiety when maintained on the 129/SvEv × C57BL/6J background. Consistent with prior research, RIIβ mice were resistant to the sedative effects of ethanol, regardless of the genetic background. Finally, RIIβ and RIIβ mice showed similar blood ethanol levels. These results indicate that high ethanol consumption is associated with resistance to the sedative effects of ethanol but that basal levels of anxiety, as well as ethanol metabolism, do not reliably predict high ethanol drinking by RIIβ mice

Blockade of the Corticotropin Releasing Factor Type 1 Receptor Attenuates Elevated Ethanol Drinking Associated With Drinking in the Dark Procedures

Drinking in the dark (DID) procedures have recently been developed to induce high levels of ethanol drinking in C57BL/6J mice, which result in blood ethanol concentrations (BECs) reaching levels that have measurable affects on physiology and/or behavior. The present experiments determined whether the increased ethanol drinking caused by DID procedures can be attenuated by pretreatment with CP-154,526; a corticotropin releasing factor type-1 (CRF1) receptor antagonist