Infection-induced IL-10 and Jak-Stat: A review of the molecular circuitry controlling immune hyperactivity in response to pathogenic microbes

Generation of effective immune responses against pathogenic microbes depends on a fine balance between pro- and anti-inflammatory responses. Interleukin-10 (IL-10) is essential in regulating this balance and has garnered renewed interest recently as a modulator of the response to infection at the JAK-STAT signaling axis of host responses. Here, we examine how IL-10 functions as the “master regulator” of immune responses through JAK-STAT, and provide a perspective from recent insights on bacterial, protozoan, and viral infection model systems. Pattern recognition and subsequent molecular events that drive activation of IL-10-associated JAK-STAT circuitry are reviewed and the implications for microbial pathogenesis are discussed.

Characterization of the antibody response in birds following infection with wild-type and attenuated strains of Eimeria tenella and Eimeria necatrix.

Live vaccines containing attenuated parasite strains are increasingly used to control chicken coccidiosis. In this paper antibody responses elicited by infections with wild-type and attenuated strains of Eimeria tenella and E.necatrix were characterized by immunoblotting and ELISA with homologous and heterologous antisera. Few differences between antisera from birds infected with wild and attenuated strains of E. tenella were evident in immunoblots conducted with merozoite antigen preparations from both E. tenella strains, however the reactivity of sera raised in birds infected with the wild-type strain was noticeably more intense. In ELISAs conducted with merozoite antigen preparations, antisera from birds infected with the wild-type strains of E. tenella and E. necatrix consistently produced a significantly higher (P < 0.05) antibody response than antisera from birds infected with the attenuated strains. Likewise, avidity ELISAs conducted with the E. tenella strains demonstrated that antibodies in birds infected with the wild-type strain were of significantly higher avidity (P < 0.05) than antibodies in birds infected with the attenuated strain. The differences in the antibody responses are probably due to changes in the attenuated strain as a result of selection for precocious development and the less severe tissue damage and inflammation of the intestine resulting from infection with the attenuated strain.

To reactivate or not to reactivate : Control of KSHV lytic replication is essential for apoptosis in response to p53 restoration

Kaposi's sarcoma herpesvirus (KSHV) is an oncogenic human virus and the causative agent of three human malignancies: Kaposi's sarcoma (KS), Multicentric Castleman's Disease (MCD), and primary effusion lymphoma (PEL). In tumors, KSHV establishes latent infection during which it produces no infectious particles. Latently infected cells can enter the lytic replication cycle, and upon provision of appropriate cellular signals, produce progeny virus. PEL, commonly described in patients with AIDS, represents a diffuse large-cell non-Hodgkin's lymphoma, with median survival time less than six months after diagnosis. As tumor suppressor gene TP53 mutations occur rarely in PEL, the aim of this thesis was to investigate whether non-genotoxic activation of the p53 pathway can eradicate malignant PEL cells. This thesis demonstrates that Nutlin-3, a small-molecule inhibitor of the p53-MDM2 interaction, efficiently restored p53 function in PEL cells, leading to cell cycle arrest and massive apoptosis. Furthermore, we found that KSHV infection activated DNA damage signaling, rendering the cells more sensitive to p53-dependent cell death. We also showed in vivo the therapeutic potential of p53 restoration that led to regression of subcutaneous and intraperitoneal PEL tumor xenografts without adversely affecting normal cells. Importantly, we demonstrated that in a small subset of intraperitoneal PEL tumors, spontaneous induction of viral reactivation dramatically impaired Nutlin-3-induced p53-mediated apoptosis. Accordingly, we found that elevated KSHV lytic transcripts correlated with PEL tumor burden in animals and that inhibition of viral reactivation in vitro restored cytotoxic activity of a small-molecule inhibitor of the p53-MDM2 interaction. Latency provides a unique opportunity for KSHV to escape host immune surveillance and to establish persistent infections. However, to maintain viral reservoirs and spread to other hosts, KSHV must be reactivated from latency and enter into the lytic growth phase. We showed that phosphorylation of nucleolar phosphoprotein nucleophosmin (NPM) by viral cyclin-CDK6 is critical for establishment and maintenance of the KSHV latency. In short, this study provides evidence that the switch between latent phase and lytic replication is a critical step that determines the outcome of viral infection and the pathogenesis of KSHV-induced malignancies. Our data may thus contribute to development of novel targeted therapies for intervention and treatment of KSHV-associated cancers.

Baker's yeast expressing the Japanese encephalitis virus envelope protein on its cell surface: induction of an antigen-specific but non-neutralizing antibody response

Live recombinant Saccharomyces cerevisiae yeast expressing the envelope antigen of Japanese encephalitis virus (JEV) on the outer mannoprotein layer of the cell wall were examined for their ability to induce antigen-specific antibody responses in mice. When used as a modelantigen, parenteral immunization of mice with surface-expressing GFP yeast induced a strong anti-GFP antibody response in the absence of adjuvants. This antigen delivery approach was then used for a more stringent system, such as the envelope protein of JEV, which is a neurotropic virus requiring neutralizing antibodies for protection.Although 70% of cells were detected to express the total envelope protein on the surface by antibodies raised to the bacterially expressed protein, polyclonal anti-JEV antibodies failed to react with them. In marked contrast, yeast expressing the envelope fragments 238-398, 373-399 and 373-500 in front of a Gly-Ser linker were detected by anti-JEV antibodies as well as a monoclonal antibody but not by antibodies raised to the bacterially expressed protein. Immunization of mice with these surface-expressing recombinants resulted in a strong antibody response. However, the antibodies failed to neutralize the virus, although the fragments were selected based on neutralizing determinants.

Probabilistic Seismic Design of Pile Foundations in Non Liquefiable Soil by Response Spectrum Approach

The behavior of pile foundations in non liquefiable soil under seismic loading is considerably influenced by the variability in the soil and seismic design parameters. Hence, probabilistic models for the assessment of seismic pile design are necessary. Deformation of pile foundation in non liquefiable soil is dominated by inertial force from superstructure. The present study considers a pseudo-static approach based on code specified design response spectra. The response of the pile is determined by equivalent cantilever approach. The soil medium is modeled as a one-dimensional random field along the depth. The variability associated with undrained shear strength, design response spectrum ordinate, and superstructure mass is taken into consideration. Monte Carlo simulation technique is adopted to determine the probability of failure and reliability indices based on pile failure modes, namely exceedance of lateral displacement limit and moment capacity. A reliability-based design approach for the free head pile under seismic force is suggested that enables a rational choice of pile design parameters.

Thermal characterization of microheaters from the dynamic response

Thermal characterization of surface-micromachined microheaters is carried out from their dynamic response to electrothermal excitations. An electrical equivalent circuit model is developed for the thermo-mechanical system. The mechanical parameters are extracted from the frequency response obtained using a laser Doppler vibrometer. The resonant frequencies of the microheaters are measured and compared with FEM simulations. The thermal time constants are obtained from the electrical equivalent model by fitting the model response to the measured frequency response. Microheaters with an active area of 140 µm × 140 µm have been realized on two different layers (poly-1 and poly-2) with two different air gaps (2 µm and 2.75 µm). The effective time constants, combining thermal and mechanical responses, are in the range of 0.13–0.22 ms for heaters on the poly-1 layer and 1.9 µs–0.15 ms for microheaters on the poly-2 layer. The thermal time constants of the microheaters are in the range of a few microseconds, thus making them suitable for sensor applications that need a faster thermal response.

The August 2007 equine influenza response management framework.

This section outlines the most important issues addressed in the management of the response in the two infected states, New South Wales and Queensland. There were differences in the management of the response between the states for logistic, geographic and organisation structural reasons. Issues included the use of control centres, information centres, the problems associated with the lack of trained staff to undertake all the roles, legislative issues, controls of horse movements, the availability of resources for adequate surveillance, the challenges of communication between disparate groups and tracing the movements of both humans and horses.

High-level coordination and strategy in the 2007 equine influenza outbreak response.

The equine influenza (EI) outbreak presented many challenges that required high-level coordination and decision making, as well as the development of new approaches for satisfactory and consistent resolution. This paper outlines the elements of the national coordination arrangements, preparatory arrangements in place prior to the outbreak that facilitated national coordination, and some of the issues faced and resolved in the response.

Complex permittivity measurements of RF plasma polymerized polyterpenol organic thin films employing split post dielectric resonator

In the fields of organic electronics and biotechnology, applications for organic polymer thin films fabricated using low-temperature non-equilibrium plasma techniques are gaining significant attention because of the physical and chemical stability of thin films and the low cost of production. Polymer thin films were fabricated from non-synthetic terpinen-4-ol using radiofrequency polymerization (13.56 MHz) on low loss dielectric substrates and their permittivity properties were ascertained to determine potential applications for these organic films. Real and imaginary parts of permittivity as a function of frequency were measured using the variable angle spectroscopic ellipsometer. The real part of permittivity (k) was found to be between 2.34 and 2.65 in the wavelength region of 400–1100 nm, indicating a potential low-k material. These permittivity values were confirmed at microwave frequencies. Dielectric properties of polyterpenol films were measured by means of split post dielectric resonators (SPDRs) operating at frequencies of 10 GHz and 20 GHz. Permittivity increased for samples deposited at higher RF energy – from 2.65 (25 W) to 2.83 (75 W) measured by a 20-GHz SPDR and from 2.32 (25 W) to 2.53 (100 W) obtained using a 10-GHz SPDR. The error in permittivity measurement was predominantly attributed to the uncertainty in film thickness measurement.

Effect of organic gate dielectric material properties on interfacial charging and discharging of pentacene MIM device

The effect of material properties of an environmentally friendly, optically transparent dielectric material, polyterpenol, on the carrier transients within the pentacene-based double-layer MTM device was investigated. Polyterpenol films were RF plasma polymerised under varied process conditions, with resultant films differing in surface chemistry and morphology. Independent of type of polyterpenol, time-resolved EFISHG study of IZO/polyterpenol/pentacene/Au structures showed similar transient behaviour with carriers injected into pentacene from Au electrode only, confirming polyterpenol to be a suitable blocking layer for visualisation of single-species carrier transportation during charging and discharging under different bias conditions. Polyterpenol fabricated under higher input power show better promise due to higher chemical and thermal stability, improved uniformity, and absence of defects.

Measurement of resistivity and dielectric constant of beach-sand minerals

Resistivity and dielectric constant are important parameters which influence the separation of particles in a drum-type electrostatic separator. The paper provides details of the measurement of the parameters and data on the magnitude of resistivity and dielectric constant of the minerals of beach sand.

Gel growth and dielectric studies of K. Rb and Cs perchlorates

Single crystals of K, Rb and Cs perchlorates have been grown by the counter diffusion of the respective ions and CIO4 through the gel medium. Studies on nucleation, growth kinetics, morphological aspects and purity are discussed in this paper. The dielectric constant, ~b, as well as loss measured along the longest axis, exhibits an anomaly at the transition temperature, Tt, in all the three crystals. It is found that the peak values of Tt are approximately 800, 100 and 53 in K, Rb and Cs perchlorates, respectively. The dielectric anomaly and the large value of c b in the cubic phase are discussed in terms of the degree of disorder of the CIO~ group and the possible contribution from defects.