“Design of Molecular Mechanics Modeling Techniques For Exploring Molecular Recognition Using Cyclodextrins.

Molecular mechanics modeling techniques have been developed to study the behavior of cyclodextrins (CDs) in capillary electrophoresis (CE) separations. Using the commercial computational package, Sybyl, the mechanisms of molecular recognition between organic analytes and CDs are investigated. Cyclodextrin-modified capillary electrochromatography (CDCE) experiments were conducted to separate neutral derivitized naphthalene solutes using carboxymethyl-beta-cyclodextrin (CM-b-CD). Grid conformation-searching programs were developed to explore the interaction space between CD and solute and to calculate their interaction energies using molecular mechanics. The interaction energies correlated remarkably well with the separation behavior. It was found that extensive minimization (more than 3000 iterations) was required at each of the docking positions to achieve the best agreement between computational and experimental distribution coefficients (Kd). Molecular modeling techniques were also used to guide the development of a new charged cyclodextrin resolving agent, heptakis (6-O-carboxymethyl-2,3-dimethyl)-b-cyclodextrin (HDMCM-b-CD). Molecular computer aided design (MolCAD) analysis and docking techniques revealed that HDMCM-b-CD would be superior to commercially available CDs for forming inclusion complexes with the target naphthalene derivative analytes. Molecular modeling studies also showed that significant intermolecular CD-CD interactions can occur under certain conditions, explaining some anomalous experimental findings. Additionally, the grid conformation-searching modeling technique was applied to chiral CDCE separations of dansyl amino acids (AAs) to explain separation behavior and to investigate different CD-CD interactions

Late-Time Circumstellar Interaction in a Spitzer Selected Sample of Type IIn Supernovae

Type IIn supernovae (SNe IIn) are a rare (< 10%) subclass of core-collapse SNe that exhibit relatively narrow emission lines from a dense, pre-existing circumstellar medium (CSM). In 2009, a warm Spitzer survey observed 30 SNe IIn discovered in 2003 - 2008 and detected 10 SNe at distances out to 175 Mpc with unreported late-time infrared emission, in some cases more than 5 years post-discovery. For this single epoch of data, the warm-dust parameters suggest the presence of a radiative heating source consisting of optical/X-ray emission continuously generated by ongoing CSM interaction. Here we present multi-wavelength follow-up observations of this sample of 10 SNe IIn and the well-studied Type IIn SN 2010jl. A recent epoch of Spitzer observations reveals ongoing mid-infrared emission from nine of the SNe in this sample. We also detect three of the SNe in archival WISE data, in addition to SNe 1987A, 2004dj, and 2008iy. For at least five of the SNe in the sample, optical and/or X-ray emission confirms the presence of radiative emission from ongoing CSM interaction. The two Spitzer nondetections are consistent with the forward shock overrunning and destroying the dust shell, a result that places upper limits on the dust-shell size. The optical and infrared observations confirm the radiative heating model and constrain a number of model parameters, including progenitor mass-loss characteristics. All of the SNe in this sample experienced an outburst on the order of tens to hundreds of years prior to the SN explosion followed by periods of less intense mass loss. Although all evidence points to massive progenitors, the variation in the data highlights the diversity in SN IIn progenitor evolution. While these observations do not identify a particular progenitor system, they demonstrate that future, coordinated, multi-wavelength campaigns can constrain theoretical mass-loss models.Comment: 10 pages, 6 figures, accepted to AJ (with comments

Soluble tau species, not neurofibrillary aggregates, disrupt neural system integration in a tau transgenic model

Neurofibrillary tangles are a feature of Alzheimer disease and other tauopathies, and while they are generally believed to be markers of neuronal pathology, there is little evidence evaluating whether tangles directly impact neuronal function. To investigate the response of cells in hippocampal circuits to complex behavioral stimuli, we used an environmental enrichment paradigm to induce expression of an immediate-early gene, Arc, in the rTg4510 mouse model of tauopathy. These mice reversibly overexpress P301L tau and exhibit substantial neurofibrillary tangle deposition, neuronal loss, and memory deficits. Employing fluorescent in situ hybridization to detect Arc mRNA, we found that rTg4510 mice have impaired hippocampal Arc expression both without stimulation and in response to environmental enrichment; this likely reflects the combination of functional impairments of existing neurons and loss of neurons. However, tangle-bearing cells were at least as likely as non-tangle-bearing neurons to exhibit Arc expression in response to enrichment. Transgene suppression with doxycycline for 6 weeks resulted in increased percentages of Arc-positive cells in rTg4510 brains compared to untreated transgenics, restoring enrichment-induced Arc mRNA levels to that of wild-type controls despite the continued presence of neurofibrillary pathology. We interpret these data to indicate that soluble tau contributes to impairment of hippocampal function, while tangles do not preclude neurons from responding in a functional circuit