Development of Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) Methods to Study Pathophysiology Underlying Neurodegenerative Diseases in Murine Models

Manganese-enhanced magnetic resonance imaging (MEMRI) opens the great opportunity to study complex paradigms of central nervous system (CNS) in freely behaving animals and reveals new pathophysiological information that might be otherwise difficult to gain. Due to advantageous chemical and biological properties of manganese (Mn2+), MEMRI has been successfully applied in the studies of several neurological diseases using translational animal models to assess comprehensive information about neuronal activity, morphology, neuronal tracts, and rate of axonal transport. Although previous studies highlight the potential of MEMRI for brain imaging, the limitations concerning the use of Mn2+ in living animals and applications of MEMRI in neuroscience research are in their infancy. Therefore, development of MEMRI methods for experimental studies remains essential for diagnostic findings, development of therapeutic as well as pharmacological intervention strategies. Our lab has been dedicating to develop novel MEMRI methods to study the pathophysiology underlying neurodegenerative diseases in murine models. In the first study, we investigated the cellular mechanism of MEMRI signal change during neuroinflammation in mice. The roles of neural cells (glia and neurons) in MEMRI signal enhancement were delineated, and ability of MEMRI to detect glial (astrocyte and microglia) and neuronal activation was demonstrated in mice treated with inflammatory inducing agents. In vitro work demonstrated that cytokine-induced glial activation facilitates neuronal uptake of Mn2+,and that glial Mn2+ content was not associated with glial activation. The in vivo work confirmed that MEMRI signal enhancement in the CNS is induced by astrocytic activation by stimulating neuronal Mn2+ uptake. In conclusion, our results supported the notion that MEMRI reflects neuronal excitotoxicity and impairment that can occur through a range of insults that include neuroinflammation. In the second study, we evaluated the efficacy of MEMRI in diagnosing the complexities of neuropathology in an ananimal model of a neurodegenerative disease, neuroAIDS. This study demonstrated that MEMRI reflects brain region specific HIV-1-induced neuropathology in virus-infected NOD/scid-IL-2Rγcnull humanized mice. Altered MEMRI signal intensity was observed in affected brain regions. These included, but were not limited to, the hippocampus, amygdala, thalamus, globus pallidus, caudoputamen, substantia nigra and cerebellum. MEMRI signal was coordinated with levels of HIV-1 infection, neuroinflammation (astro- and micro- gliosis), and neuronal injury. Following the application of MEMRI to assess HIV-1 induced neuropathology in immune deficient mice humanized with lymphoid progenitor cells, our successful collaboration with Dr. Sajja BR (Department of Radiology, UNMC, Omaha, NE) led to the generation of a MEMRI-based NOD/scid-IL-2Rγcnull (NSG) mouse brain atlas. Mouse brain MRI atlases allow longitudinal quantitative analyses of neuroanatomical volumes and imaging metrics. As NSG mice allow human cell transplantation to study human disease, these animals are used to assess brain morphology. MEMRI provided sufficient contrast permitting 41 brain structures to be manually labeled on average brain of 19 mice using alignment algorithm. The developed atlas is now made available to researchers through Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC) website (https://www.nitrc.org/projects/memribrainatlas/). Finally, we evaluated the efficacy of N-acetylated-para-aminosalicylic acid (AcPAS) to accelerate Mn2+ elimination from rodent brain, enabling repeated use of MEMRI to follow the CNS longitudinally in weeks or months as well as inhibiting the confounding effects of residual Mn2+ from preceding administrations on imaging results. Two-week treatment with AcPAS (200 mg/kg/dose × 3 daily) accelerated the decline of Mn2+ induced enhancement in MRI. This study demonstrated that AcPAS could enhance MEMRI utility in evaluating brain biology in small animals

X-ray Spectroscopy of QSOs with Broad Ultraviolet Absorption Lines

For the population of QSOs with broad ultraviolet absorption lines, we are just beginning to accumulate X-ray observations with enough counts for spectral analysis at CCD resolution. From a sample of eight QSOs [including four Broad Absorption Line (BAL) QSOs and three mini-BAL QSOs] with ASCA or Chandra spectra with more than 200 counts, general patterns are emerging. Their power-law X-ray continua are typical of normal QSOs with Gamma~2.0, and the signatures of a significant column density [N_H~(0.1-4)x10^{23} cm^{-2}] of intrinsic, absorbing gas are clear. Correcting the X-ray spectra for intrinsic absorption recovers a normal ultraviolet-to-X-ray flux ratio, indicating that the spectral energy distributions of this population are not inherently anomalous. In addition, a large fraction of our sample shows significant evidence for complexity in the absorption. The subset of BAL QSOs with broad MgII absorption apparently suffers from Compton-thick absorption completely obscuring the direct continuum in the 2-10 keV X-ray band, complicating any measurement of their intrinsic X-ray spectral shapes.Comment: 9 pages, 6 figures, uses AASTeX. Accepted to the Astrophysical Journa

Statistics of Cosmological Black Hole Jet Sources: Blazar Predictions for GLAST

A study of the statistics of cosmological black-hole jet sources is applied to EGRET blazar data, and predictions are made for GLAST. Black-hole jet sources are modeled as collimated relativistic plasma outflows with radiation beamed along the jet axis due to strong Doppler boosting. The comoving rate density of blazar flares is assumed to follow a blazar formation rate (BFR), modeled by analytic functions based on astronomical observations and fits to EGRET data. The redshift and size distributions of gamma-ray blazars observed with EGRET, separated into BL Lac object (BL) and flat spectrum radio quasar (FSRQ) distributions, are fit with monoparametric functions for the distributions of the jet Lorentz factor \Gamma, comoving directional power l'_e, and spectral slope. A BFR factor ~10 x greater at z ~ 1 than at present is found to fit the FSRQ data. A smaller comoving rate density and greater luminosity of BL flares at early times compared to the present epoch fits the BL data. Based on the EGRET observations, ~1000 blazars consisting of ~800 FSRQs and FR2 radio galaxies and ~200 BL Lacs and FR1 radio galaxies will be detected with GLAST during the first year of the mission. Additional AGN classes, such as hard-spectrum BL Lacs that were mostly missed with EGRET, could add more GLAST sources. The FSRQ and BL contributions to the EGRET gamma-ray background at 1 GeV are estimated at the level of ~10 - 15% and ~2 - 4%, respectively. EGRET and GLAST sensitivities to blazar flares are considered in the optimal case, and a GLAST analysis method for blazar detection is outlined.Comment: 17 pages, 9 figures, ApJ, in press, v.660, May 1, 2007 (minor changes from previous version

Strong Gravitational Lensing and the Structure of Quasar Outflows

We show that by analyzing the spectra of lensed broad absorption line quasars (BALQSOs), it is possible to reveal key properties of the outflowing gas in the inner regions of these objects. This results from the fact that each image of the quasar corresponds to a different line of sight through the outflow. This combined with dynamical estimates for the location of the flow, adds new information concerning the lateral, non line of sight structure of the absorbing gas. Here we consider a sample of lensed BALQSOs and note that the similarity of BAL profiles of different images of the same quasar implies that the flow is relatively isotropic on small scales. We show that its geometry is inconsistent with the ballistically accelerated spherical cloud model, and that wind models provide a better description of the flow structure. Furthermore, observations seem to disagree with naive interpretations of recent time-dependent wind simulations. This may hint on several important physical processes that govern the structure and dynamics of such flows. Future prospects for the study of quasar outflows with the effect of strong gravitational lensing are discussed.Comment: 4 pages, 1 figure, accepted for publication in ApJ

On the evolutionary behaviour of BL Lac objects

We present a new well defined sample of BL Lac objects selected from the ROSAT All-Sky Survey (RASS). The sample consists of 39 objects with 35 forming a flux limited sample down to f_X = 8 x 10^{-13} cgs, redshifts are known for 33 objects (and 31 of the complete sample). X-ray spectral properties were determined for each object individually with the RASS data. The luminosity function of RASS selected BL Lac objects is compatible with results provided by objects selected with the Einstein observatory, but the RASS selected sample contains objects with luminosities at least tenfold higher. Our analysis confirms the negative evolution for X-ray selected BL Lac objects found in a sample by the Einstein observatory, the parameterization provides similar results. A subdivision of the sample into halves according to the X-ray to optical flux ratio yielded unexpected results. The extremely X-ray dominated objects have higher redshifts and X-ray luminosities and only this subgroup shows clear signs of strong negative evolution. The evolutionary behaviour of objects with an intermediate spectral energy distribution between X-ray and radio dominated is compatible with no evolution at all. Consequences for unified schemes of X-ray and radio selected BL Lac objects are discussed.We suggest that the intermediate BL Lac objects are the basic BL Lac population. The distinction between the two subgroups can be explained if extreme X-ray dominated BL Lac objects are observed in a state of enhanced X-ray activity.Comment: 14 pages incl. 8 figures, accepted by A&

Dolutegravir reduces migration and invasion abilities of trophoblasts by ​decreasing HIF-1α expression and MMPs activities

Dolutegravir (DTG) is a first-line antiretroviral drug used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. Due to roll out of generic DTG-based regimen and rising pretreatment resistance to non-nucleoside reverse transcriptase inhibitors in resource limited countries, 15 million HIV-1 infected people will be treated with DTG by year 2025. This includes women of child-bearing age who remain a significant infected population. However, growing data have suggested that DTG is associated with birth defects. Thus, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained research interest. To this end, there is a knowledge gap of known adverse events reflecting DTG-associated trophoblasts impairments. We previously reported that DTG inhibits matrix metalloproteinases (MMPs) activities. It is known that activity of MMP-2 and MMP-9 are required for the successful invasion of trophoblasts during early pregnancy and abnormalities in the activities of these proteins can influence impairment in placental implantation, vascular restructuring, and fetal development. We now report that DTG reduces invasion abilities of trophoblasts. Herein, we evaluated concentration dependent effects of DTG on HTR-8 trophoblastic cells. DTG was found to inhibit activities of MMP-2 and 9 under normoxic and hypoxic conditions. Moreover, DTG treatment decreased expression of HIF-1α under both normoxic and hypoxic conditions. Interestingly, decrease in expression of beclin 1 protein was observed, suggesting an effect on autophagy. Further assessments to determine the effects of DTG on trophoblasts functions showed that DTG reduces migration and invasion abilities of HTR-8 cells. In addition, studies performed in pregnant mice validated that DTG decreases HIF-1α expression in placenta. Thus, our proof-of-concept work concludes that DTG can potentially impair placental development by affecting HIF-1α expression and MMPs activities.https://digitalcommons.unmc.edu/surp2022/1021/thumbnail.jp

Follow-Up Chandra Observations of Three Candidate Tidal Disruption Events

Large-amplitude, high-luminosity soft X-ray flares were detected by the ROSAT All-Sky Survey in several galaxies with no evidence of Seyfert activity in their ground-based optical spectra. These flares had the properties predicted for a tidal disruption of a star by a central supermassive black hole. We report Chandra observations of three of these galaxies taken a decade after their flares that reveal weak nuclear X-ray sources that are from 240 to 6000 times fainter than their luminosities at peak, supporting the theory that these were special events and not ongoing active galactic nucleus (AGN) variability. The decline of RX J1624.9+7554 by a factor of 6000 is consistent with the (t-t_D)^(-5/3) decay predicted for the fall-back phase of a tidal disruption event, but only if ROSAT was lucky enough to catch the event exactly at its peak in 1990 October. RX J1242.6-1119A has declined by a factor of 240, also consistent with (t-t_D)^(-5/3). In the H II galaxy NGC 5905 we find only resolved, soft X-ray emission that is undoubtedly associated with starburst activity. When accounting for the starburst component, the ROSAT observations of NGC 5905, as well as the Chandra upper limit on its nuclear flux, are consistent with a (t-t_D)^(-5/3) decay by at least a factor of 1000. Although we found weak Seyfert~2 emission lines in Hubble Space Telescope spectra of NGC 5905, indicating that a low-luminosity AGN was present prior to the X-ray flare, we favor a tidal disruption explanation for the flare itself.Comment: 17 pages, 4 figures, to appear in ApJ April 1 200

The QSO evolution derived from the HBQS and other complete QSO surveys

An ESO Key programme dedicated to an Homogeneous Bright QSO Survey (HBQS) has been completed. 327 QSOs (Mb<-23, 0.3<z<2.2) have been selected over 555 deg^2 with 15<B<18.75. For B<16.4 the QSO surface density turns out to be a factor 2.2 higher than what measured by the PG survey, corresponding to a surface density of 0.013+/-.006 deg^{-2}. If the Edinburgh QSO Survey is included, an overdensity of a factor 2.5 is observed, corresponding to a density of 0.016+/-0.005 deg^{-2}. In order to derive the QSO optical luminosity function (LF) we used Monte Carlo simulations that take into account of the selection criteria, photometric errors and QSO spectral slope distribution. The LF can be represented with a Pure Luminosity Evolution (L(z)\propto(1+z)^k) of a two power law both for q_0=0.5 and q_0=0.1. For q_0=0.5 k=3.26, slower than the previous Boyle's (1992) estimations of k=3.45. A flatter slope beta=-3.72 of the bright part of the LF is also required. The observed overdensity of bright QSOs is concentrated at z<0.6. It results that in the range 0.3<z<0.6 the luminosity function is flatter than observed at higher redshifts. In this redshift range, for Mb<-25, 32 QSOs are observed instead of 19 expected from our best-fit PLE model. This feature requires a luminosity dependent luminosity evolution in order to satisfactorily represent the data in the whole 0.3<z<2.2 interval.Comment: Invited talk in "Wide Field Spectroscopy" (20-24 May 1996, Athens), eds. M. Kontizas et al. 6 pages and 3 eps figures, LaTex file, uses epfs.sty and crckapb.sty (included