Protection and compensation in the influenza virus-specific CD8+ T cell response.

Influenza virus-specific CD8+ T cells generally recognize peptides derived from conserved, internal proteins that are not subject to antibody-mediated selection pressure. Prior exposure to any one influenza A virus (H1N1) can prime for a secondary CD8+ T cell response to a serologically different influenza A virus (H3N2). The protection afforded by this recall of established CD8+ T cell memory, although limited, is not negligible. Key characteristics of primary and secondary influenza-specific host responses are probed here with recombinant viruses expressing modified nucleoprotein (NP) and acid polymerase (PA) genes. Point mutations were introduced into the epitopes derived from the NP and PA such that they no longer bound the presenting H2Db MHC class I glycoprotein, and reassortant H1N1 and H3N2 viruses were made by reverse genetics. Conventional (C57BL/6J, H2b, and Ig+/+) and Ig-/- (muMT) mice were more susceptible to challenge with the single NP [HKx31 influenza A virus (HK)-NP] and PA (HK-PA) mutants, but unlike the Ig-/- mice, Ig+/+ mice were surprisingly resistant to the HK-NP/-PA double mutant. This virus was found to promote an enhanced IgG response resulting, perhaps, from the delayed elimination of antigen-presenting cells. Antigen persistence also could explain the increase in size of the minor KbPB1703 CD8+ T cell population in mice infected with the mutant viruses. The extent of such compensation was always partial, giving the impression that any virus-specific CD8+ T cell response operates within constrained limits. It seems that the relationship between protective humoral and cellular immunity is neither simple nor readily predicted.

Toll like receptors play a role in general immunity, eye infection and inflammation : TLRs for nanodelivery

Dendritic cells [DCs] are potent antigen presenting cells [APC], which plays a vital role in immune system by detecting and capturing pathogens in the body. DCs perform a pivotal role in induction of T cell response. Regulation of immune response can be achieved by specific antigen [Ag] delivery to DCs. A delivery system that can efficiently target and present Ags to DCs for the purpose of anti-tumour activity is currently a topic of significant research interest. DCs are receiving attention due to their key role in anti cancer host response and due to their adjuvanic property in tumour vaccines. Role of toll like receptors [TLR] in innate immune system and their part in eventual stimulation of adaptive immunity is exploited to develop vaccines. TLR agonists in conjugation with vaccines are shown to increase therapeutic efficacy in some cases. TLRs also play a vital role in protecting the cornea from invading pathogens. Due to adverse effects in the treatment of ocular inflammations, cancer and in viral infections, an alternate approach such as the use of TLRs will solve the inquisitive question regarding side effects. The intended delivery is attained by the use of nanoparticles which in turn leads to prolonged half-life in the body. Co-delivery of Ags, TLRs and immunomodulators using nanoparticles has been demonstrated to elicit potent cellular immune responses and are currently under development of clinically applicable immunisations and vaccines.

Innate immunity and intracellular trafficking : insights for novel anti-HIV-1 therapeutics

It is now evident that host cells have evolved a remarkable variety of antiretroviral activities to defend themselves against viral invaders and in return viruses have developed ingenious ways to circumvent these defences and, in some cases, actually hijack cellular proteins in order to facilitate their replication. Study of this cat and mouse interplay between viruses and their host cells throughout evolution has lead to the identification of some of the most sophisticated antiviral strategies that mammals have developed to prevent viral infection. Recently, a wave of publications has significantly enhanced our understanding of the relationship between human immunodeficiency virus type 1 (HIV-1) and its host, including: 1) the HIV-1 protein Vif and its interaction with host cell nucleic acid editing enzymes; 2) the host cell restrictive factors that provide protection against retroviral infection, such as TRIM5; and 3) the late domains of retroviruses and their relationship with the host cell vacuolar protein sorting pathway. The focus of this review is to provide an up-to-date account of these important areas of HIV-1 research and highlight how some of these new discoveries can potentially be exploited for the development of novel anti-retroviral therapeutics.

RNA interference : more than a research tool in the vertebrates' adaptive immunity

In recent years, RNA silencing, usage of small double stranded RNAs of ~21 – 25 base pairs to regulate gene expression, has emerged as a powerful research tool to dissect the role of unknown host cell factors in this 'post-genomic' era. While the molecular mechanism of RNA silencing has not been precisely defined, the revelation that small RNA molecules are equipped with this regulatory function has transformed our thinking on the role of RNA in many facets of biology, illustrating the complexity and the dynamic interplay of cellular regulation. As plants and invertebrates lack the protein-based adaptive immunity that are found in jawed vertebrates, the ability of RNA silencing to shut down gene expression in a sequence-specific manner offers an explanation of how these organisms counteract pathogen invasions into host cells. It has been proposed that this type of RNA-mediated defence mechanism is an ancient form of immunity to offset the transgene-, transposon- and virus-mediated attack. However, whether 1) RNA silencing is a natural immune response in vertebrates to suppress pathogen invasion; or 2) vertebrate cells have evolved to counteract invasion in a 'RNA silencing' independent manner remains to be determined. A number of recent reports have provided tantalizing clues to support the view that RNA silencing functions as a physiological response to regulate viral infection in vertebrate cells. Amongst these, two manuscripts that are published in recent issues of Science and Immunity, respectively, have provided some of the first direct evidences that RNA silencing is an important component of antiviral defence in vertebrate cells. In addition to demonstrating RNA silencing to be critical to vertebrate innate immunity, these studies also highlight the potential of utilising virus-infection systems as models to refine our understanding on the molecular determinants of RNA silencing in vertebrate cells.

Molecular basis of copper transport: cellular and physiological functions of Menkes and Wilson disease proteins (ATP7A and ATPB)

Eukaryotic cells prevent copper-induced, free radical damage to cell components by employing copper-binding proteins and transporters that minimize the likelihood of free copper ions existing in the cell. In the cell, copper is actively transported from the cytoplasm during the biosynthesis of secreted coppercontaining proteins and, as a protective measure, when there is an excess of copper. In humans, this is accomplished by two related copper-transporting ATPases (ATP7A and ATP7B), which are the affected genes in two distinct human genetic disorders of copper transport, Menkes disease (copper deficiency) and Wilson disease (copper toxicosis). The study of these ATPases has revealed their molecular mechanisms of copper transport and their roles in physiological copper homeostasis. Both ATP7A and ATP7B are expressed in specific brain regions and neurological abnormalities are important clinical features in Menkes and Wilson disease.

Molecular and cellular aspects of copper transport in developing mammals

Copper is an essential trace element that requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects because of the ability of the metal ion to catalyze the formation of free radicals. The Cu-ATPases, ATP7A and ATP7B, play an important role in the physiological regulation of copper. Adequate supplies of copper are particularly important in developing animals, and in humans this is illustrated by mutations of ATP7A that cause the copper deficiency condition Menkes disease, which is fatal in early childhood. In contrast, mutations in ATP7B result in the genetic toxicosis, Wilson disease. We propose that the physiological regulation of copper is accomplished mainly by the intracellular copper-regulated trafficking of the Cu-ATPases. This process allows the overall copper status in the body to be maintained when levels of copper in the diet alter. A study of the defects in mouse models of Menkes and Wilson diseases has demonstrated that both ATPases play an important role in supplying copper to the developing fetus and neonate

Effects of the density on compressive properties in cellular aluminum produced by the sintering method

The cellular aluminum materials with relative densities of 0.1"-'0.25 were fabricated by the sintering method and effects of the density on mechanical properties of the cellular aluminum were investigated by compressive tests. The cellular aluminum exhibited a plateau region with a nearly constant flow stress. The stress in the plateau region increased with increasing relative density, on the other hand, the densification strain decreased with increasing relative density. Observation of the deformed cells revealed that the cell walls were bent. Besides, the stress in the plateau region was proportional to 1.9 power of the density. These suggest that plastic collapse is dominated by bending of the cell walls for the cellular aluminum produced by the sintering method.

Speed control and policing in a cellular mobile network: speedNet

In this paper, we describe SpeedNet, a GSM network variant which resembles an ad hoc wireless mobile network where base stations keep track of the velocities of mobile users (cars). SpeedNet is intended to track mobile users and their speed passively for both speed policing and control of traffic. The speed of the vehicle is controlled in a speed critical zone by means of an electro-mechanical control system, suitably referred to as VVLS (Vehicular Velocity Limiting System). VVLS is mounted on the vehicle and responds to the command signals generated by the base station. It also determines the next base station to handoff, in order to improve the connection reliability and bandwidth efficiency of the underlying network. Robust Extended Kalman Filter (REKF) is used as a passive velocity estimator of the mobile user with the widely used proportional and integral controller speed control. We demonstrate through simulation and analysis that our prediction algorithm can successfully estimate the mobile user’s velocity with low system complexity as it requires two closest mobile base station measurements and also it is robust against system uncertainties due to the inherent deterministic nature in the mobility model.

Mobility modelling and trajectory prediction for cellular networks with mobile base stations

This paper provides mobility estimation and prediction for a variant of GSM network which resembles an adhoc wireless mobile network where base stations and users are both mobile. We propose using Robust Extended Kalman Filter (REKF)as a location heading altitude estimator of mobile user for next node (mobile-base station)in order to improve the connection reliability and bandwidth efficiency of the underlying system. Through analysis we demonstrate that our algorithm can successfully track the mobile users with less system complexity as it requires either one or two closest mobile-basestation measurements. Further, the technique is robust against system uncertainties due to inherent deterministic nature in the mobility model. Through simulation, we show the accuracy and simplicity in implementation of our prediction algorithm.

Speed control and policing in a cellular mobile network: SpeedNet

In this paper, we describe SpeedNet, a GSM network variant which resembles an ad hoc wireless mobile network where base stations (possibly other vehicles in the network) keep track of the velocities of mobile users (cars). SpeedNet is intended to track mobile users and their speed passively for both speed policing and control of traffic. The speed of the vehicle is controlled in a speed critical zone by means of an electro-mechanical control system, suitably referred to as VVLS (vehicular velocity limiting system). VVLS is mounted in the vehicle and responds to the command signals generated by the base station. It also determines the next basestation to handoff, in order to improve the connection reliability and bandwidth efficiency of the underlying network. Robust extended Kalman filter (REKF) is used as a passive velocity estimator of the mobile user with the widely used proportional and integral controller speed control. We demonstrate through simulation and analysis that our prediction algorithm can successfully estimate the mobile users velocity with low system complexity as it requires two closet mobile-base station measurement and also it is robust against system uncertainties due to the inherent deterministic nature in the mobility model.

Location based power control for mobile devices in a cellular network

This paper provides location estimation based power control strategy for cellular radio systems via a location based interference management scheme. Our approach considers the carrier-to-interference as dependent on the transmitter and receiver separation distance and therefore an accurate estimation of the precise locations can provide the power critical mobile user to control the transition power accordingly. In this fully
distributed algorithms, we propose using a Robust Extended Kalman Filter (REKF) to derive an estimate of the mobile user’s closest mobile base station from the user’s location, heading and altitude. Our analysis demonstrates that this algorithm can successfully track the mobile users with less system complexity, as it requires measurements from only one or two closest mobile base stations and hence enable the user to transmit at the rate that is sufficient for the interference management. Our power control
algorithms based on this estimation converges to the desired power trajectory. Further, the technique is robust against system uncertainties caused by the inherent deterministic nature of the mobility model. Through simulation, we show the accuracy of our prediction algorithm and the simplicity of its implementation.