The Intriguing Parsec-Scale Radio Structure in the "Offset AGN" KISSR 102

We report the detection of an intriguing parsec-scale radio source in the "offset AGN" candidate, KISSR 102. The elliptical host galaxy includes two optical nuclei at a projected separation of 1.54 kpc, N1 and N2, to the south-east and north-west, respectively. Phase-referenced VLBA observations at 1.5 and 4.9 GHz of this LINER galaxy, have detected double radio components (A and B) at a projected separation of 4.8 parsec at 1.5 GHz, and another partially-resolved double radio structure at 4.9 GHz coincident with the brighter radio component A. These radio detections are confined to the optical nucleus N1. The brightness temperatures of all the detected radio components are high, $\gtrsim10^8$ K, consistent with them being components of a radio AGN. The 1.5-4.9 GHz spectral index is inverted ($\alpha\sim+0.64\pm0.08$) for component A and steep for component B ($\alpha \lesssim-1.6$). The dramatic change in the spectral indices of A and B is inconsistent with it being a typical "core-jet" structure from a single AGN or the mini-lobes of a compact symmetric object. To be consistent with a "core-jet" structure, the jet in KISSR 102 would need to be undergoing strong jet-medium interaction with dense surrounding media resulting in a drastic spectral steepening of the jet. Alternatively, the results could be consistent with the presence of a parsec-scale binary radio AGN, which is the end result of a three-body interaction involving three supermassive black holes in the centre of KISSR 102.Comment: 11 pages, 6 figures, ApJ accepte

Finite-Horizon Robust Integrated Guidance-Control of A Moving-Mass Actuated Kinetic Warhead

A game-theoretic approach to the design of robust integrated guidance-control system for a moving-mass actuated kinetic warhead is presented. Feedback linearized form of the kinetic warhead dynamics and a high-order target model are used in the formulation. Nonlinear feedback solution to the robust finite-horizon target interception problem is derived using the recently developed multi-stepping algorithm. Due to its computational efficiency, the multi-stepping algorithm is suitable for real-time implementation. Interception of targets in the presence of modeling uncertainties is demonstrated in nonlinear engagement simulations

CTLA4 mRNA is downregulated by miR-155 in regulatory T cells, and reduced blood CTLA4 levels are associated with poor prognosis in metastatic melanoma patients

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an immune checkpoint expressed in regulatory T (Treg) cells and activated T lymphocytes. Despite its potential as a treatment strategy for melanoma, CTLA-4 inhibition has limited efficacy. Using data from The Cancer Genome Atlas (TCGA) melanoma database and another dataset, we found that decreased CTLA4 mRNA was associated with a poorer prognosis in metastatic melanoma. To investigate further, we measured blood CTLA4 mRNA in 273 whole-blood samples from an Australian cohort and found that it was lower in metastatic melanoma than in healthy controls and associated with worse patient survival. We confirmed these findings using Cox proportional hazards model analysis and another cohort from the US. Fractionated blood analysis revealed that Treg cells were responsible for the downregulated CTLA4 in metastatic melanoma patients, which was confirmed by further analysis of published data showing downregulated CTLA-4 surface protein expression in Treg cells of metastatic melanoma compared to healthy donors. Mechanistically, we found that secretomes from human metastatic melanoma cells downregulate CTLA4 mRNA at the post-transcriptional level through miR-155 while upregulating FOXP3 expression in human Treg cells. Functionally, we demonstrated that CTLA4 expression inhibits the proliferation and suppressive function of human Treg cells. Finally, miR-155 was found to be upregulated in Treg cells from metastatic melanoma patients compared to healthy donors. Our study provides new insights into the underlying mechanisms of reduced CTLA4 expression observed in melanoma patients, demonstrating that post-transcriptional silencing of CTLA4 by miRNA-155 in Treg cells may play a critical role. Since CTLA-4 expression is downregulated in non-responder melanoma patients to anti-PD-1 immunotherapy, targeting miRNA-155 or other factors involved in regulating CTLA4 expression in Treg cells without affecting T cells could be a potential strategy to improve the efficacy of immunotherapy in melanoma. Further research is needed to understand the molecular mechanisms regulating CTLA4 expression in Treg cells and identify potential therapeutic targets for enhancing immune-based therapies

Spacecraft Formation Dynamics and Design

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76961/1/AIAA-13002-440.pd

Inhibition of 5-lipoxygenase activity in mice during cuprizone-induced demyelination attenuates neuroinflammation, motor dysfunction and axonal damage

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Increased expression of 5-lipoxygenase (5-LO), a key enzyme in the biosynthesis of leukotrienes (LTs), has been reported in MS lesions and LT levels are elevated in the cerebrospinal fluid of MS patients. To determine whether pharmacological inhibition of 5-LO attenuates demyelination, MK886, a 5-LO inhibitor, was given to mice fed with cuprizone. Gene and protein expression of 5-LO were increased at the peak of cuprizone-induced demyelination. Although MK886 did not attenuate cuprizone-induced demyelination in the corpus callosum or in the cortex, it attenuated cuprizone-induced axonal damage and motor deficits and reduced microglial activation and IL-6 production. These data suggest that during cuprizone-induced demyelination, the 5-LO pathway contributes to microglial activation and neuroinflammation and to axonal damage resulting in motor dysfunction. Thus, 5-LO inhibition may be a useful therapeutic treatment in demyelinating diseases of the CNS

Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter's transformation

: Richter's Transformation (RT) is a poorly understood and fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. Protein arginine methyltransferase 5 (PRMT5) is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 develop a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice develop a highly aggressive disease with transformation that histologically resembles RT; where large-scale transcriptional profiling identifies oncogenic pathways mediating PRMT5-driven disease progression. Lastly, we report the development of a SAM-competitive PRMT5 inhibitor, PRT382, with exclusive selectivity and optimal in vitro and in vivo activity compared to available PRMT5 inhibitors. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases