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

Demonstration: Economic Analysis and Expert Testimony—Plaintiff\u27s Conference

This article is a demonstration on the use of economic experts. The demonstration is based loosely on Mobil’s attempted take-over of Marathon Oil Company. However, the oil companies involved here are named Major, which is the second largest oil company in the United States, and Olympic, which is the largest supplier to independents. Any resemblance of Major and Olympic to any other firm, entity or person, living or not, is purely coincidental. The demonstration is divided into two parts. The first part is the conference. A conference of plaintiff’s team will be followed by a conference of defendant’s team

Demonstration: Economic Analysis and Expert Testimony—Plaintiff\u27s Conference

This article is a demonstration on the use of economic experts. The demonstration is based loosely on Mobil’s attempted take-over of Marathon Oil Company. However, the oil companies involved here are named Major, which is the second largest oil company in the United States, and Olympic, which is the largest supplier to independents. Any resemblance of Major and Olympic to any other firm, entity or person, living or not, is purely coincidental. The demonstration is divided into two parts. The first part is the conference. A conference of plaintiff’s team will be followed by a conference of defendant’s team

Inhibition of Sirtuin 2 with Sulfobenzoic Acid Derivative AK1 is Non-Toxic and Potentially Neuroprotective in a Mouse Model of Frontotemporal Dementia

Tauopathies including tau-associated Frontotemporal dementia (FTD) and Alzheimer’s disease are characterized pathologically by the formation of tau-containing neurofibrillary aggregates and neuronal loss, which contribute to cognitive decline. There are currently no effective treatments to prevent or slow this neural systems failure. The rTg4510 mouse model, which expresses a mutant form of the tau protein associated with FTD with Parkinsonism-17, undergoes dramatic hippocampal and cortical neuronal loss making it an ideal model to study treatments for FTD-related neuronal loss. Sirtuins are a family of proteins involved in cell survival that have the potential to modulate neuronal loss in neurodegenerative disorders. Here we tested the hypothesis that sirtuin 2 (SIRT2) inhibition would be non-toxic and prevent neurodegeneration in rTg4510 brain. In this study we delivered SIRT2 inhibitor AK1 directly to the hippocampus with an osmotic minipump and confirmed that it reached the target region both with histological assessment of delivery of a dye and with a pharmacodynamic marker, ABCA1 transcription, which was upregulated with AK1 treatment. AK1 treatment was found to be safe in wild-type mice and in the rTg4510 mouse model, and further, it provided some neuroprotection in the rTg4510 hippocampal circuitry. This study provides proof-of-concept for therapeutic benefits of SIRT2 inhibitors in both tau-associated FTD and Alzheimer’s disease, and suggests that development of potent, brain permeable SIRT2 inhibitors is warranted

Mechanisms of Selective Attention in Generalized Anxiety Disorder

A well-established literature has identified different selective attentional orienting mechanisms underlying anxiety-related attentional bias, such as engagement and disengagement of attention. These mechanisms are thought to contribute to the onset and maintenance of anxiety disorders. However, conclusions to date have relied heavily on experimental work from subclinical samples. We therefore investigated individuals with diagnosed generalized anxiety disorder (GAD), healthy volunteers, and individuals with high trait anxiety (but not meeting GAD diagnostic criteria). Across two experiments we found faster disengagement from negative (angry and fearful) faces in GAD groups, an effect opposite to that expected on the basis of the subclinical literature. Together these data challenge current assumptions that we can generalize, to those with GAD, the pattern of selective attentional orienting to threat found in subclinical groups. We suggest a decisive two-stage experiment identifying stimuli of primary salience in GAD, then using these to reexamine orienting mechanisms across groups. </jats:p

The distances of short-hard GRBs and the SGR connection

We present a search for nearby (D<100 Mpc) galaxies in the error boxes of six well-localized short-hard gamma-ray bursts (GRBs). None of the six error boxes reveals the presence of a plausible nearby host galaxy. This allows us to set lower limits on the distances and, hence, the isotropic-equivalent energy of these GRBs. Our lower limits are around $1 \times 10^{49}$ erg (at $2\sigma$ confidence level); as a consequence, some of the short-hard GRBs we examine would have been detected by BATSE out to distances greater than 1 Gpc and therefore constitute a bona fide cosmological population. Our search is partially motivated by the December 27, 2004 hypergiant flare from SGR 1806-20, and the intriguing possibility that short-hard GRBs are extragalactic events of a similar nature. Such events would be detectable with BATSE to a distance of \~50 Mpc, and their detection rate should be comparable to the actual BATSE detection rate of short-hard GRBs. The failure of our search, by contrast, suggests that such flares constitute less than 15% of the short-hard GRBs (<40% at 95% confidence). We discuss possible resolutions of this discrepancy.Comment: Enlarged sample of bursts; ApJ in pres

Relativistic Iron Emission and Disk Reflection in Galactic Microquasar XTE J1748-288

We report evidence for an Fe K-alpha fluorescence line feature and disk reflection in the Very High, High, and Low State X-ray spectra of the galactic microquasar XTE J1748-288 during its June~1998 outburst. Spectral analyses are made on data gathered throughout the outburst by the Rossi X-ray Timing Explorer Proportional Counter Array. Gaussian line, relativistic disk emission line, and ionized disk reflection models are fit to the data. In the Very High State the line profile appears strongly redshifted, consistent with disk emission from the innermost stable orbits around a maximally rotating Kerr black hole. In the High State the line profile is less redshifted and increasingly prominent. The Low State line profile is very strong (~0.5 keV equivalent width) and centered at 6.7 +/- 0.10 keV; disk line emission model fits indicate that the inner edge of the disk fluctuates between ~20 and ~100 gravitational radii in this state. The disk reflection fraction is traced through the outburst; reflection from an ionized disk is preferred in the VHS and HS, and reflection from a relatively neutral disk is preferred in the LS. We discuss the implications of our findings for the binary system dynamics and accretion flow geometry in XTE J1748-288.Comment: 32 pages, 8 figures, 5 tables. ApJ accepted 8/16/0

SPIRITS 15c and SPIRITS 14buu: Two Obscured Supernovae in the Nearby Star-Forming Galaxy IC 2163

SPIRITS---SPitzer InfraRed Intensive Transients Survey---is an ongoing survey of nearby galaxies searching for infrared (IR) transients with Spitzer/IRAC. We present the discovery and follow-up observations of one of our most luminous ($M_{[4.5]} = -17.1\pm0.4$ mag, Vega) and red ($[3.6] - [4.5] = 3.0 \pm 0.2$ mag) transients, SPIRITS 15c. The transient was detected in a dusty spiral arm of IC 2163 ($D\approx35.5$ Mpc). Pre-discovery ground-based imaging revealed an associated, shorter-duration transient in the optical and near-IR (NIR). NIR spectroscopy showed a broad ($\approx 8400$ km s$^{-1}$), double-peaked emission line of He I at $1.083 \mu$m, indicating an explosive origin. The NIR spectrum of SPIRITS 15c is similar to that of the Type IIb SN 2011dh at a phase of $\approx 200$ days. Assuming $A_V = 2.2$ mag of extinction in SPIRITS 15c provides a good match between their optical light curves. The IR light curves and the extreme $[3.6]-[4.5]$ color cannot be explained using only a standard extinction law. Another luminous ($M_{4.5} = -16.1\pm0.4$ mag) event, SPIRITS 14buu, was serendipitously discovered in the same galaxy. The source displays an optical plateau lasting $\gtrsim 80$ days, and we suggest a scenario similar to the low-luminosity Type IIP SN 2005cs obscured by $A_V \approx 1.5$ mag. Other classes of IR-luminous transients can likely be ruled out in both cases. If both events are indeed SNe, this may suggest $\gtrsim 18\%$ of nearby core-collapse SNe are missed by currently operating optical surveys.Comment: 19 pages, 7 Figures, 4 Table

Heterodimeric IL-15 delays tumor growth and promotes intratumoral CTL and dendritic cell accumulation by a cytokine network involving XCL1, IFN-γ, CXCL9 and CXCL10.

BACKGROUND: Interleukin-15 (IL-15) promotes growth and activation of cytotoxic CD8 METHODS: The antitumor activity of hetIL-15 produced from mammalian cells was tested in mouse tumor models (MC38 colon carcinoma and TC-1 epithelial carcinoma). The functional diversity of the immune infiltrate and the cytokine/chemokine network within the tumor was evaluated by flow cytometry, multicolor immunohistochemistry (IHC), gene expression profiling by Nanostring Technologies, and protein analysis by electrochemiluminescence and ELISA assays. RESULTS: hetIL-15 treatment resulted in delayed primary tumor growth. Increased NK and CD8 CONCLUSIONS: Our results show that hetIL-15 administration enhances T cell entry into tumors, increasing the success rate of immunotherapy interventions. Our study further supports the incorporation of hetIL-15 in tumor immunotherapy approaches to promote the development of antitumor responses by favoring effector over regulatory cells and by promoting lymphocyte and DC localization into tumors through the modification of the tumor chemokine and cytokine milieu