Single-Cell RNA-seq Reveals Profound Alterations in Mechanosensitive Dorsal Root Ganglion Neurons with Vitamin E Deficiency.

Ninety percent of Americans consume less than the estimated average requirements of dietary vitamin E (vitE). Severe vitE deficiency due to genetic mutations in the tocopherol transfer protein (TTPA) in humans results in ataxia with vitE deficiency (AVED), with proprioceptive deficits and somatosensory degeneration arising from dorsal root ganglia neurons (DRGNs). Single-cell RNA-sequencing of DRGNs was performed in Ttpa-/- mice, an established model of AVED. In stark contrast to expected changes in proprioceptive neurons, Ttpa-/- DRGNs showed marked upregulation of voltage-gated Ca2+ and K+ channels in mechanosensitive, tyrosine-hydroxylase positive (TH+) DRGNs. The ensuing significant conductance changes resulted in reduced excitability in mechanosensitive Ttpa-/- DRGNs. A highly supplemented vitE diet (600 mg dl-α-tocopheryl acetate/kg diet) prevented the cellular and molecular alterations and improved mechanosensation. VitE deficiency profoundly alters the molecular signature and functional properties of mechanosensitive TH+ DRGN, representing an intriguing shift of the prevailing paradigm from proprioception to mechanical sensation

Design and Implementation of Views: Isolated Perspectives of a File System for Regulatory Compliance

We present Views, a file system architecture designed to meet the role-based access control (RBAC) requirement of federal regulations, such as those in HIPAA. Views allows for discrete IO entities, such as users, groups or processes, to have a logically complete but isolated perspective of the file system. Entities may perform IO using the standard system call interface without affecting the views of other entities. Views is designed to be file system independent, extremely easy to use and manage, and flexible in defining isolation and sharing polices. Our implementation of Views is built on ext3cow, which additionally provides versioning capabilities to all entities. Preliminary results show the performance of Views is comparable with other traditional disk file systems.The Johns Hopkins Universit

Open-target sparse sensing of biological agents using DNA microarray

Background Current biosensors are designed to target and react to specific nucleic acid sequences or structural epitopes. These 'target-specific' platforms require creation of new physical capture reagents when new organisms are targeted. An 'open-target' approach to DNA microarray biosensing is proposed and substantiated using laboratory generated data. The microarray consisted of 12,900 25 bp oligonucleotide capture probes derived from a statistical model trained on randomly selected genomic segments of pathogenic prokaryotic organisms. Open-target detection of organisms was accomplished using a reference library of hybridization patterns for three test organisms whose DNA sequences were not included in the design of the microarray probes. Results A multivariate mathematical model based on the partial least squares regression (PLSR) was developed to detect the presence of three test organisms in mixed samples. When all 12,900 probes were used, the model correctly detected the signature of three test organisms in all mixed samples (mean(R2)) = 0.76, CI = 0.95), with a 6% false positive rate. A sampling algorithm was then developed to sparsely sample the probe space for a minimal number of probes required to capture the hybridization imprints of the test organisms. The PLSR detection model was capable of correctly identifying the presence of the three test organisms in all mixed samples using only 47 probes (mean(R2)) = 0.77, CI = 0.95) with nearly 100% specificity. Conclusions We conceived an 'open-target' approach to biosensing, and hypothesized that a relatively small, non-specifically designed, DNA microarray is capable of identifying the presence of multiple organisms in mixed samples. Coupled with a mathematical model applied to laboratory generated data, and sparse sampling of capture probes, the prototype microarray platform was able to capture the signature of each organism in all mixed samples with high sensitivity and specificity. It was demonstrated that this new approach to biosensing closely follows the principles of sparse sensing.Mitre Corporatio

The HBI in a quasi-global model of the intracluster medium

In this paper we investigate how convective instabilities influence heat conduction in the intracluster medium (ICM) of cool-core galaxy clusters. The ICM is a high-beta, weakly collisional plasma in which the transport of momentum and heat is aligned with the magnetic field. The anisotropy of heat conduction, in particular, gives rise to instabilities that can access energy stored in a temperature gradient of either sign. We focus on the heat-flux buoyancy-driven instability (HBI), which feeds on the outwardly increasing temperature profile of cluster cool cores. Our aim is to elucidate how the global structure of a cluster impacts on the growth and morphology of the linear HBI modes when in the presence of Braginskii viscosity, and ultimately on the ability of the HBI to thermally insulate cores. We employ an idealised quasi-global model, the plane-parallel atmosphere, which captures the essential physics -- e.g. the global radial profile of the cluster -- while letting the problem remain analytically tractable. Our main result is that the dominant HBI modes are localised to the the innermost (~<20%) regions of cool cores. It is then probable that, in the nonlinear regime, appreciable field-line insulation will be similarly localised. Thus, while radio-mode feedback appears necessary in the central few tens of kpc, heat conduction may be capable of offsetting radiative losses throughout most of a cool core over a significant fraction of the Hubble time. Finally, our linear solutions provide a convenient numerical test for the nonlinear codes that tackle the saturation of such convective instabilities in the presence of anisotropic transport.Comment: MNRAS, in press; minor modifications from v

The Lick AGN Monitoring Project: Broad-Line Region Radii and Black Hole Masses from Reverberation Mapping of Hbeta

We have recently completed a 64-night spectroscopic monitoring campaign at the Lick Observatory 3-m Shane telescope with the aim of measuring the masses of the black holes in 12 nearby (z < 0.05) Seyfert 1 galaxies with expected masses in the range ~10^6-10^7 M_sun and also the well-studied nearby active galactic nucleus (AGN) NGC 5548. Nine of the objects in the sample (including NGC 5548) showed optical variability of sufficient strength during the monitoring campaign to allow for a time lag to be measured between the continuum fluctuations and the response to these fluctuations in the broad Hbeta emission. We present here the light curves for the objects in this sample and the subsequent Hbeta time lags for the nine objects where these measurements were possible. The Hbeta lag time is directly related to the size of the broad-line region, and by combining the lag time with the measured width of the Hbeta emission line in the variable part of the spectrum, we determine the virial mass of the central supermassive black hole in these nine AGNs. The absolute calibration of the black hole masses is based on the normalization derived by Onken et al. We also examine the time lag response as a function of velocity across the Hbeta line profile for six of the AGNs. The analysis of four leads to ambiguous results with relatively flat time lags as a function of velocity. However, SBS 1116+583A exhibits a symmetric time lag response around the line center reminiscent of simple models for circularly orbiting broad-line region (BLR) clouds, and Arp 151 shows an asymmetric profile that is most easily explained by a simple gravitational infall model. Further investigation will be necessary to fully understand the constraints placed on physical models of the BLR by the velocity-resolved response in these objects.Comment: 24 pages, 16 figures and 13 tables, submitted to Ap

Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation.

Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity-a phenomenon known as paradoxical excitation. Previous studies have identified GABAA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABAA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish

Intensive HST, RXTE and ASCA Monitoring of NGC 3516: Evidence Against Thermal Reprocessing

During 1998 April 13-16, NGC 3516 was monitored almost continuously with HST for 10.3 hr in the UV and 2.8 d in the optical, and simultaneous RXTE and ASCA monitoring covered the same period. The X-rays were strongly variable with the soft (0.5-2 keV) showing stronger variations (~65% peak-to-peak) than the hard (2-10 keV; ~50% peak-to-peak). The optical continuum showed much smaller but highly significant variations: a slow ~2.5% rise followed by a faster ~3.5% decline. The short UV observation did not show significant variability. The soft and hard X-ray light curves were strongly correlated with no significant lag. Likewise, the optical continuum bands (3590 and 5510 A) were also strongly correlated with no measurable lag above limits of <0.15 d. However no significant correlation or simple relationship could be found for the optical and X-ray light curves. These results appear difficult to reconcile with previous reports of correlations between X-ray and optical variations and of measurable lags within the optical band for some other Seyfert 1s. These results also present serious problems for "reprocessing" models in which the X-ray source heats a stratified accretion disk which then reemits in the optical/ultraviolet: the synchronous variations within the optical would suggest that the emitting region is <0.3 lt-d across, while the lack of correlation between X-ray and optical variations would indicate, in the context of this model, that any reprocessing region must be >1 lt-d in size. It may be possible to resolve this conflict by invoking anisotropic emission or special geometry, but the most natural explanation appears to be that the bulk of the optical luminosity is generated by some other mechanism than reprocessing.Comment: 23 pages including 6 figures, accepted for publication in Ap

The Lick AGN Monitoring Project: Reverberation Mapping of Optical Hydrogen and Helium Recombination Lines

We have recently completed a 64-night spectroscopic monitoring campaign at the Lick Observatory 3-m Shane telescope with the aim of measuring the masses of the black holes in 12 nearby (z < 0.05) Seyfert 1 galaxies with expected masses in the range ~10^6-10^7M_sun and also the well-studied nearby active galactic nucleus (AGN) NGC 5548. Nine of the objects in the sample (including NGC 5548) showed optical variability of sufficient strength during the monitoring campaign to allow for a time lag to be measured between the continuum fluctuations and the response to these fluctuations in the broad Hbeta emission, which we have previously reported. We present here the light curves for the Halpha, Hgamma, HeII 4686, and HeI 5876 emission lines and the time lags for the emission-line responses relative to changes in the continuum flux. Combining each emission-line time lag with the measured width of the line in the variable part of the spectrum, we determine a virial mass of the central supermassive black hole from several independent emission lines. We find that the masses are generally consistent within the uncertainties. The time-lag response as a function of velocity across the Balmer line profiles is examined for six of the AGNs. Finally we compare several trends seen in the dataset against the predictions from photoionization calculations as presented by Korista & Goad. We confirm several of their predictions, including an increase in responsivity and a decrease in the mean time lag as the excitation and ionization level for the species increases. Further confirmation of photoionization predictions for broad-line gas behavior will require additional monitoring programs for these AGNs while they are in different luminosity states. [abridged]Comment: 37 pages, 18 figures and 15 tables, accepted for publication in the Astrophysical Journa

The Lick AGN Monitoring Project: Recalibrating Single-Epoch Virial Black Hole Mass Estimates

We investigate the calibration and uncertainties of black hole mass estimates based on the single-epoch (SE) method, using homogeneous and high-quality multi-epoch spectra obtained by the Lick Active Galactic Nucleus (AGN) Monitoring Project for 9 local Seyfert 1 galaxies with black hole masses < 10^8 M_sun. By decomposing the spectra into their AGN and stellar components, we study the variability of the single-epoch Hbeta line width (full width at half-maximum intensity, FWHM_Hbeta; or dispersion, sigma_Hbeta) and of the AGN continuum luminosity at 5100A (L_5100). From the distribution of the "virial products" (~ FWHM_Hbeta^2 L_5100^0.5 or sigma_Hbeta^2 L_5100^0.5) measured from SE spectra, we estimate the uncertainty due to the combined variability as ~ 0.05 dex (12%). This is subdominant with respect to the total uncertainty in SE mass estimates, which is dominated by uncertainties in the size-luminosity relation and virial coefficient, and is estimated to be ~ 0.46 dex (factor of ~ 3). By comparing the Hbeta line profile of the SE, mean, and root-mean-square (rms) spectra, we find that the Hbeta line is broader in the mean (and SE) spectra than in the rms spectra by ~ 0.1 dex (25%) for our sample with FWHM_Hbeta < 3000 km/s. This result is at variance with larger mass black holes where the difference is typically found to be much less than 0.1 dex. To correct for this systematic difference of the Hbeta line profile, we introduce a line-width dependent virial factor, resulting in a recalibration of SE black hole mass estimators for low-mass AGNs.Comment: Accepted for publication in ApJ. 18 pages, 17 figure

The Lick AGN Monitoring Project: Alternate Routes to a Broad-line Region Radius

It is now possible to estimate black hole masses across cosmic time, using broad emission lines in active galaxies. This technique informs our views of how galaxies and their central black holes coevolve. Unfortunately, there are many outstanding uncertainties associated with these "virial" mass estimates. One of these comes from using the accretion luminosity to infer a size for the broad-line region. Incorporating the new sample of low-luminosity active galaxies from our recent monitoring campaign at Lick Observatory, we recalibrate the radius-luminosity relation with tracers of the accretion luminosity other than the optical continuum. We find that the radius of the broad-line region scales as the square root of the X-ray and Hbeta luminosities, in agreement with recent optical studies. On the other hand, the scaling appears to be marginally steeper with narrow-line luminosities. This is consistent with a previously observed decrease in the ratio of narrow-line to X-ray luminosity with increasing total luminosity. The radius of the broad-line region correlates most tightly with Hbeta luminosity, while the X-ray and narrow-line relations both have comparable scatter of a factor of two. These correlations provide useful alternative virial BH masses in objects with no detectable optical/UV continuum emission, such as high-redshift galaxies with broad emission lines, radio-loud objects, or local active galaxies with galaxy-dominated continua.Comment: 8 pages, 1 figure, accepted for publication in Ap