The role of norepinephrine in spatial reference and spatial working memory

The adrenergic system (utilizing norepinephrine, NE, as a neurotransmitter) is implicated in hippocampus-based learning and memory, in addition to its well known peripheral actions mediated by the sympathetic nervous system. We have produced a strain of mice in which the gene coding for the enzyme dopamine beta-hydroxylase (Dbh), which catalyzes the synthesis of NE from dopamine, has been disrupted. Mice recessive (Dbh-/-) for the Dbh gene mutation lack endogenous NE and epinephrine, while heterozygous mice (Dbh+/-) have normal levels of NE and epinephrine and display normal phenotype. Previous studies have indicated that NE is necessary and sufficient for the retrieval of intermediate-term contextual and spatial memories, but is not necessary for the retrieval or consolidation of emotional memories in general (Thomas et al. 1996). We tested whether this relationship would stand for memories that were appetitive rather than aversive. We tested 20 Dbh-/- and 20 Dbh+/- mice in an eight-arm radial maze. We found no difference between KOs and controls in ability to recall spatial cues 24 hours after training. This negative result indicated that NE may not be critical for retrieval of all hippocampus-dependent memories but specifically those that are aversive. Using a more standard variation of the above protocol on the radial arm maze, we used this apparatus to test the role of NE in spatial working memory. We found significant, robust differences between Dbh-/- and Dbh+/- mice after a training period of approximately 14 days. To test whether this difference was due to a potential deficit in acquisition or performance, we restored NE in Dbh-/- mice by administering the synthetic precursor L-DOPS after four days of stable behavioral differences between genotypes. In a separate trial, we also restored NE signaling with dexmedetomidine, a selective alpha-2 receptor agonist. A gradual improvement by Dbh-/- mice to levels comparable to Dbh+/- mice indicated that NE is critical for the acquisition of spatial working memory, and suggested a role for the alpha-2 adrenergic receptor in the processing of spatial working memory

Assessment of targeting accuracy of a low-energy stereotactic radiosurgery treatment for age-related macular degeneration

Age-related macular degeneration (AMD), a leading cause of blindness in the United States, is a neovascular disease that may be controlled with radiation therapy. Early patient outcomes of external beam radiotherapy, however, have been mixed. Recently, a novel multimodality treatment was developed, comprising external beam radiotherapy and concomitant treatment with a vascular endothelial growth factor inhibitor. The radiotherapy arm is performed by stereotactic radiosurgery, delivering a 16 Gy dose in the macula (clinical target volume, CTV) using three external low-energy x-ray fields while adequately sparing normal tissues. The purpose of our study was to test the sensitivity of the delivery of the prescribed dose in the CTV using this technique and of the adequate sparing of normal tissues to all plausible variations in the position and gaze angle of the eye. Using Monte Carlo simulations of a 16 Gy treatment, we varied the gaze angle by ±5° in the polar and azimuthal directions, the linear displacement of the eye ±1mm in all orthogonal directions, and observed the union of the three fields on the posterior wall of spheres concentric with the eye that had diameters between 20 and 28 mm. In all cases, the dose in the CTV fluctuated \u3c6%, the maximum dose in the sclera was \u3c20 Gy, the dose in the optic disc, optic nerve, lens and cornea were \u3c0.7 Gy and the three-field junction was adequately preserved. The results of this study provide strong evidence that for plausible variations in the position of the eye during treatment, either by the setup error or intrafractionmotion, the prescribed dose will be delivered to the CTV and the dose in structures at risk will be kept far below tolerance doses. © 2010 Institute of Physics and Engineering in Medicine

CpG-ODN-induced sustained expression of BTLA mediating selective inhibition of human B cells.

BTLA (B- and T-lymphocyte attenuator) is a prominent co-receptor that is structurally and functionally related to CTLA-4 and PD-1. In T cells, BTLA inhibits TCR-mediated activation. In B cells, roles and functions of BTLA are still poorly understood and have never been studied in the context of B cells activated by CpG via TLR9. In this study, we evaluated the expression of BTLA depending on activation and differentiation of human B cell subsets in peripheral blood and lymph nodes. Stimulation with CpG upregulated BTLA, but not its ligand: herpes virus entry mediator (HVEM), on B cells in vitro and sustained its expression in vivo in melanoma patients after vaccination. Upon ligation with HVEM, BTLA inhibited CpG-mediated B cell functions (proliferation, cytokine production, and upregulation of co-stimulatory molecules), which was reversed by blocking BTLA/HVEM interactions. Interestingly, chemokine secretion (IL-8 and MIP1β) was not affected by BTLA/HVEM ligation, suggesting that BTLA-mediated inhibition is selective for some but not all B cell functions. We conclude that BTLA is an important immune checkpoint for B cells, as similarly known for T cells

Knowledge protection in firms: A conceptual framework and evidence from HP Labs

This paper proposes a simple framework to examine organizational methods of knowledge protection. The framework highlights a basic trade‐off between improving decision‐making and innovation through communication and mitigating security risks by imposing restrictions on communication flows. The trade‐off is mediated by factors such as the sensitivity of information, the degree to which employees can be trusted to handle sensitive information appropriately, and firms’ investments in legal protection mechanisms. Evidence from HP Labs supports the basic predictions of the model, in particular the importance of employee trustworthiness and internalized codes of behavior in promoting open communication. Our interviews also suggest a potential conflict between two of the most important appropriability mechanisms: secrecy and lead‐time advantage

Towards the Prediction of User Actions on Exercises with Hints Based on Survey Results

Proceedings of: 6th European Conference of Technology Enhanced Learning, EC-TEL 2011, Palermo, Italy, September 20-23, 2011.The actions a user performs on exercises depending on the different hinting techniques applied, can be used to adapt future exercises. In this paper, we propose a survey for users in order to know their different actions depending on different conditions. The analysis of preliminary results for some questions of the model shows that there is a correlation between some survey questions and the real student actions, but there is a case in which there is not such correlation. For the cases where that correlation exists, this correlation leads to think that some prediction of users actions based on survey results is possible.Work partially funded by the Learn3 project TIN2008-05163/TSI within the Spanish “Plan Nacional de I+D+I”, and the Madrid regional community project eMadrid S2009/TIC-1650