Recent progress in understanding immune activation in the pathogenesis in HIV-TB coinfection

Purpose of review Tuberculosis is the leading infectious cause of death worldwide, and HIV-1 the best recognized risk factor for active TB. This review focuses on immune complex formation; the interplay of type I and II interferon signaling; and T-cell activation in HIV–TB pathogenesis. Recent findings Circulating immune complexes and complement, and Fcγ signaling in whole blood act as early markers of TB disease in HIV-1-infected persons. HIV-1 is associated with a type I interferon response in whole blood, reducing the specificity of TB biomarkers dependent on type I and II interferon genes. Type I and type II interferons are implicated in both protection and TB disease, a protective outcome may depend on modulating these pathways. Whilst M. tuberculosis-specific CD4 T cells are preferentially depleted during HIV-1 infection, activation markers on M. tuberculosis-specific CD4 T cells, in particular HLA-DR, reflect immune activation and have promise as biomarkers of M. tuberculosis disease activity in individuals with HIV-1. Summary TB pathogenesis in HIV-1 involves a complex interaction of underlying activation of both the innate and adaptive immune systems. Further research is required to understand whether biomarkers of activation could be used to predict or quantify TB disease in the context of HIV-1 infection

The significance of heat transport by shallow fluid flow at an active plate boundary: the Southern Alps, New Zealand

Fluid flow can influence fault behavior. Here we quantify the role of groundwater heat advection in establishing the thermal structure of the Alpine Fault, a major tectonic boundary in southern New Zealand that accommodates most of the motion between the Australian and Pacific Plates. Convergence on the Alpine Fault has rapidly uplifted the Southern Alps, resulting in high geothermal gradients and a thin seismogenic zone. A new equilibrium temperature profile from the 818-m-deep Deep Fault Drilling Project 2B borehole has been interrogated using one-dimensional analytical models of fluid and rock advection. Models indicate a total heat flux of 720-mW m2 results from groundwater flow with Darcy velocities approximating to 7.8 × 1010 m s1. Groundwaters advect significantly more heat than rock advection in the shallow orogen (<6-km depth) and are the major control on the subsurface temperature field

Ethnic Variation in Inflammatory Profile in Tuberculosis

PMCID: PMC3701709This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Beyond Hebb: Exclusive-OR and Biological Learning

A learning algorithm for multilayer neural networks based on biologically plausible mechanisms is studied. Motivated by findings in experimental neurobiology, we consider synaptic averaging in the induction of plasticity changes, which happen on a slower time scale than firing dynamics. This mechanism is shown to enable learning of the exclusive-OR (XOR) problem without the aid of error back-propagation, as well as to increase robustness of learning in the presence of noise.Comment: 4 pages RevTeX, 2 figures PostScript, revised versio

The effect of antiretroviral treatment on selected genes in whole blood from HIV-infected adults sensitised by Mycobacterium tuberculosis

HIV-1 co-infection is a leading cause of susceptibility to tuberculosis (TB), with the risk of TB being increased at all stages of HIV-1 infection. Antiretroviral treatment (ART) is the most effective way to reduce the risk of TB in HIV-1 co-infected people. Studying protective, ART-induced, immune restoration in HIV-1 infected individuals sensitised by Mycobacterium tuberculosis (Mtb) can thus help identify mechanisms of protection against TB. In order to understand ART-mediated prevention of TB in HIV-1 infected adults, we investigated the expression of 30 genes in whole blood from HIV-1 infected patients during the first 6 months of ART-induced immune reconstitution. The 30 selected genes were previously described to be differentially expressed between sorted Mtb specific central and effector memory CD4 T cells. HIV-1 infected persons sensitised by Mtb were recruited in Khayelitsha, South Africa, when initiating ART. RNA was extracted from whole blood at initiation and 1, 3 and 6 months of ART. qRT-PCR was used to determine gene expression and three reference 'housekeeping' genes were used to calculate the fold change in the expression of each gene relative to day 0 of ART. Results were assessed longitudinally. We observed a decrease in the expression of a number of genes at 6 months of ART, reflecting a decrease in immune activation. However, following correction for multiple comparisons and increasing CD4 counts, only the decrease in CD27 gene expression remained statistically significant. While not statistically significant, a number of genes also showed increased expression at various timepoints, illustrating the broad regeneration of the T cell pool in HIV-1 infected adults on ART. Our findings generate hypotheses underlying ART- induced protective immune reconstitution and may pave the way for future studies to evaluate ART mediated prevention of TB in HIV-1 infected persons

Photoswitchable diacylglycerols enable optical control of protein kinase C.

Increased levels of the second messenger lipid diacylglycerol (DAG) induce downstream signaling events including the translocation of C1-domain-containing proteins toward the plasma membrane. Here, we introduce three light-sensitive DAGs, termed PhoDAGs, which feature a photoswitchable acyl chain. The PhoDAGs are inactive in the dark and promote the translocation of proteins that feature C1 domains toward the plasma membrane upon a flash of UV-A light. This effect is quickly reversed after the termination of photostimulation or by irradiation with blue light, permitting the generation of oscillation patterns. Both protein kinase C and Munc13 can thus be put under optical control. PhoDAGs control vesicle release in excitable cells, such as mouse pancreatic islets and hippocampal neurons, and modulate synaptic transmission in Caenorhabditis elegans. As such, the PhoDAGs afford an unprecedented degree of spatiotemporal control and are broadly applicable tools to study DAG signaling

The inflammatory microenvironment in colorectal neoplasia

Peer reviewedPublisher PD

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic and macrophage infiltration, microvessel density and survival in patients with primary operable breast cancer

The significance of the inter-relationship between tumour and host local/systemic inflammatory responses in primary operable invasive breast cancer is limited. The inter-relationship between the systemic inflammatory response (pre-operative white cell count, C-reactive protein and albumin concentrations), standard clinicopathological factors, tumour T-lymphocytic (CD4+ and CD8+) and macrophage (CD68+) infiltration, proliferative (Ki-67) index and microvessel density (CD34+) was examined using immunohistochemistry and slide-counting techniques, and their prognostic values were examined in 168 patients with potentially curative resection of early-stage invasive breast cancer. Increased tumour grade and proliferative activity were associated with greater tumour T-lymphocyte (P&lt;0.05) and macrophage (P&lt;0.05) infiltration and microvessel density (P&lt;0.01). The median follow-up of survivors was 72 months. During this period, 31 patients died; 18 died of their cancer. On univariate analysis, increased lymph-node involvement (P&lt;0.01), negative hormonal receptor (P&lt;0.10), lower albumin concentrations (P&lt;0.01), increased tumour proliferation (P&lt;0.05), increased tumour microvessel density (P&lt;0.05), the extent of locoregional control (P&lt;0.0001) and limited systemic treatment (Pless than or equal to0.01) were associated with cancer-specific survival. On multivariate analysis of these significant covariates, albumin (HR 4.77, 95% CI 1.35–16.85, P=0.015), locoregional treatment (HR 3.64, 95% CI 1.04–12.72, P=0.043) and systemic treatment (HR 2.29, 95% CI 1.23–4.27, P=0.009) were significant independent predictors of cancer-specific survival. Among tumour-based inflammatory factors, only tumour microvessel density (P&lt;0.05) was independently associated with poorer cancer-specific survival. The host inflammatory responses are closely associated with poor tumour differentiation, proliferation and malignant disease progression in breast cancer

Sirt1 Deficiency Attenuates Spermatogenesis and Germ Cell Function

In mammals, Sirt1, a member of the sirtuin family of proteins, functions as a nicotinamide adenine dinucleotide-dependent protein deactylase, and has important physiological roles, including the regulation of glucose metabolism, cell survival, and mitochondrial respiration. The initial investigations of Sirt1 deficient mice have revealed a phenotype that includes a reduced lifespan, small size, and an increased frequency of abnormal sperm. We have now performed a detailed analysis of the molecular and functional effects of Sirt1 deficiency in the germ line of Sirt1 knock-out (−/−) mice. We find that Sirt1 deficiency markedly attenuates spermatogenesis, but not oogenesis. Numbers of mature sperm and spermatogenic precursors, as early as d15.5 of development, are significantly reduced (∼2-10-fold less; P≤0.004) in numbers in Sirt1−/− mice, whereas Sirt1 deficiency did not effect the efficiency oocyte production following superovulation of female mice. Furthermore, the proportion of mature sperm with elevated DNA damage (∼7.5% of total epididymal sperm; P = 0.02) was significantly increased in adult Sirt1−/− males. Analysis of global gene expression by microarray analysis in Sirt1 deficient testis revealed dysregulated expression of 85 genes, which were enriched (P<0.05) for genes involved in spermatogenesis and protein sumoylation. To assess the function of Sirt1 deficient germ cells, we compared the efficiency of generating embryos and viable offspring in in vitro fertilization (IVF) experiments using gametes from Sirt1−/− and sibling Sirt1+/− mice. While viable animals were derived in both Sirt1−/− X wild type and Sirt1−/− X Sirt1−/− crosses, the efficiency of producing both 2-cell zygotes and viable offspring was diminished when IVF was performed with Sirt1−/− sperm and/or oocytes. Together, these data support an important role for Sirt1 in spermatogenesis, including spermatogenic stem cells, as well as germ cell function