The Role of T cell Costimulation in the Development and Progression of Citrulline-induced Arthritis

MHC Class II molecules (e.g. DR4) expressing the Rheumatoid Arthritis (RA) shared epitope are strongly linked to the development of anti-citrulline (Cit) immune responses and the pathogenesis of RA. We have established a Cit-induced arthritis model (DR4 tg mice) where injection of citrullinated human fibrinogen (CithFib) induces anti- Cit immune responses and arthritis. The main objective of this study was to assess the role of T cells in this Cit- induced arthritis mouse model using CTLA4-Ig, an agent that blocks T cell activation. To accomplish this, DR4 tg mice were immunized with CithFib to induce arthritis. At the disease onset or peak, DR4 tg mice were treated with CTLA4-Ig or control human IgGl (hlgGl) or left untreated. Arthritis progression was monitored for 30 days, and then anti- Cit immune responses and the arthritogenicity of splenic lymphocytes from these mice were examined. The latter were done using adoptive lymphocyte transfers from CTLA4- Ig-treated mice or controls via intraperitoneal injection into naïve DR4 tg mice. The recipient mice also received intraarticular injection of CithFib or vehicle. The results demonstrated that CTLA4-Ig but not hlgGl treatment of arthritic DR4 tg mice significantly reduced ankle swelling and pathological joint damage in these mice. CTLA4-Ig, but not hlgGl treatment suppressed T cell proliferative responses to Cit. Unlike splenic lymphocytes from untreated arthritic mice, lymphocytes transferred from CTLA4-Ig-treated arthritic mice did not cause arthritis in recipient mice. The conclusion from this study is that Cit-specific T cells play a direct role in the development and progression of arthritis in this Cit-induced model for human RA

The Mason Test: A Defense Against Sybil Attacks in Wireless Networks Without Trusted Authorities

Wireless networks are vulnerable to Sybil attacks, in which a malicious node poses as many identities in order to gain disproportionate influence. Many defenses based on spatial variability of wireless channels exist, but depend either on detailed, multi-tap channel estimation - something not exposed on commodity 802.11 devices - or valid RSSI observations from multiple trusted sources, e.g., corporate access points - something not directly available in ad hoc and delay-tolerant networks with potentially malicious neighbors. We extend these techniques to be practical for wireless ad hoc networks of commodity 802.11 devices. Specifically, we propose two efficient methods for separating the valid RSSI observations of behaving nodes from those falsified by malicious participants. Further, we note that prior signalprint methods are easily defeated by mobile attackers and develop an appropriate challenge-response defense. Finally, we present the Mason test, the first implementation of these techniques for ad hoc and delay-tolerant networks of commodity 802.11 devices. We illustrate its performance in several real-world scenarios

Systematic mapping of the state dependence of voltage- and Ca2+-dependent inactivation using simple open-channel measurements

The state from which channel inactivation occurs is both biologically and mechanistically critical. For example, preferential closed-state inactivation is potentiated in certain Ca2+ channel splice variants, yielding an enhancement of inactivation during action potential trains, which has important consequences for short-term synaptic plasticity. Mechanistically, the structural substrates of inactivation are now being resolved, yielding a growing library of molecular snapshots, ripe for functional interpretation. For these reasons, there is an increasing need for experimentally direct and systematic means of determining the states from which inactivation proceeds. Although many approaches have been devised, most rely upon numerical models that require detailed knowledge of channel-state topology and gating parameters. Moreover, prior strategies have only addressed voltage-dependent forms of inactivation (VDI), and have not been readily applicable to Ca2+-dependent inactivation (CDI), a vital form of regulation in numerous contexts. Here, we devise a simple yet systematic approach, applicable to both VDI and CDI, for semiquantitative mapping of the states from which inactivation occurs, based only on open-channel measurements. The method is relatively insensitive to the specifics of channel gating and does not require detailed knowledge of state topology or gating parameters. Rather than numerical models, we derive analytic equations that permit determination of the states from which inactivation occurs, based on direct manipulation of data. We apply this methodology to both VDI and CDI of CaV1.3 Ca2+ channels. VDI is found to proceed almost exclusively from the open state. CDI proceeds equally from the open and nearby closed states, but is disfavored from deep closed states distant from the open conformation. In all, these outcomes substantiate and enrich conclusions of our companion paper in this issue (Tadross et al. 2010. J. Gen. Physiol. doi:10.1085/jgp.200910308) that deduces endpoint mechanisms of VDI and CDI in CaV1.3. More broadly, the methods introduced herein can be readily generalized for the analysis of other channel types

Smart charging for electric vehicles to minimize charging cost

This paper assumes a smart grid framework where the driving patterns for electric vehicles are known, time variations in electricity prices are communicated to householders, and data on voltage variation throughout the distribution system is available. Based on this information an aggregator with access to this data can be employed to minimize EV owner charging costs whilst maintaining acceptable distribution system voltages. In this study EV charging is assumed to take place only in the home. A single-phase LV distribution network is investigated where the local EV penetration level is assumed to be 100%. EV use patterns have been extracted from the UK Time of Use Survey data with 10-minute resolution and the domestic base load is generated from an existing public domain model. Apart from the so-called real time price signal, which is derived from the electricity system wholesale price, the cost of battery degradation is also considered in the optimal scheduling of EV charging. A simple and effective heuristic method is proposed to minimize the EV charging cost whilst satisfying the requirement of state of charge for the EV battery. A simulation in OpenDSS over a period of 24 hours has been implemented, taking care of the network constraints for voltage level at the customer connection points. The optimization results are compared with those obtained using dynamic optimal power flow