Function of CMV-encoded MHC class I homologues

Homologues of MHC class I proteins have been identified in the genomes of human, murine and rat cytomegaloviruses (CMVs). Given the pivotal role of the MHC class I protein in cellular immunity, it has been postulated that the viral homologues subvert the normal antiviral immune response of the host, thus promoting virus replication and dissemination in an otherwise hostile environment. This review focuses on recent studies of the CMV MHC class I homologues at the molecular, cellular and whole animal level and presents current hypotheses for their roles in the CMV life cycle.

Dormancy release in Lolium rigidum seeds is a function of thermal after-ripening time and seed water content

Dormancy release in seeds of Lolium rigidum Gaud. (annual ryegrass) was investigated in relation to temperature and seed water content. Freshly matured seeds were collected from cropping fields at Wongan Hills and Merredin, Western Australia. Seeds from Wongan Hills were equilibrated to water contents between 6 and 18% dry weight and after-ripened at constant temperatures between 9 and 50degreesC for up to 23 weeks. Wongan Hills and Merredin seeds at water contents between 7 and 17% were also after-ripened in full sun or shade conditions. Dormancy was tested at regular intervals during after-ripening by germinating seeds on agar at 12-h alternating 15degreesC (dark) and 25degreesC (light) periods. Rate of dormancy release for Wongan Hills seeds was a positive linear function of after-ripening temperature above a base temperature (T-b) of 5.4degreesC. A thermal after-ripening time model for dormancy loss accounting for seed moisture in the range 6-18% was developed using germination data for Wongan Hills seeds after-ripened at constant temperatures. The model accurately predicted dormancy release for Wongan Hills seeds after-ripened under naturally fluctuating temperatures. Seeds from Merredin responded similarly but had lower dormancy at collection and a faster rate of dormancy release in seeds below 9% water content.

Calcium-activated potassium channels: Multiple contributions to neuronal function

Calcium-activated potassium channels are a large family of potassium channels that are found throughout the central nervous system and in many other cell types. These channels are activated by rises in cytosolic calcium largely in response to calcium influx via voltage-gated calcium channels that open during action potentials. Activation of these potassium channels is involved in the control of a number of physiological processes from the firing properties of neurons to the control of transmitter release. These channels form the target for modulation for a range of neurotransmitters and have been implicated in the pathogenesis of neurological and psychiatric disorders. Here the authors summarize the varieties of calcium-activated potassium channels present in central neurons and their defining molecular and biophysical properties.

Discriminating between task-relevant and task-irrelevant stimuli - The effects on autonomic orienting and secondary task reaction time

The effect that the difficulty of the discrimination between task-relevant and task-irrelevant stimuli has on the relationship between skin conductance orienting and secondary task reaction time (RT) was examined. Participants (N = 72) counted the number of longer-than-usual presentations of one shape (task-relevant) and ignored presentations of another shape (task-irrelevant). The difficulty of discriminating between the two shapes varied across three groups (low, medium, and high difficulty). Simultaneous with the primary counting task, participants performed a secondary RT task to acoustic probes presented 50, 150, and 2000 ms following shape onset. Skin conductance orienting was larger, and secondary RT at the 2000 ms probe position was slower during task-relevant shapes than during task-irrelevant shapes in the low-difficulty group. This difference declined as the discrimination difficulty was increased, such that there was no difference in the high-difficulty group. Secondary RT was slower during task-irrelevant shapes than during task-relevant shapes only in the medium-difficulty group-and only at the 150 ms probe position in the first half of the experiment. The close relationship between autonomic orienting and secondary RT at the 2000 ms probe position suggests that orienting reflects the resource allocation that results from the number of matching features between a stimulus input and a mental representation primed as significant.

Cytokine expanded myeloid precursors function as regulatory antigen presenting cells and induce tolerance through IL-10 producing regulatory T cells

The initiation of graft vs. host disease (GVHD) after stem cell transplantation is dependent on direct antigen presentation by host antigen presenting cells (APC) while the effect of indirect antigen presentation by donor APC is unknown. We have studied the role of indirect antigen presentation in allogenic responses by adding populations of cytokine-expanded donor APC to haematopoietic grafts that would otherwise induce lethal GVHD. Progenipoietin-1 (a synthetic G-CSF/Flt-3 L molecule) and G-CSF expanded myeloid DC, plasmacytoid DC and a novel granulocyte-monocyte precursor population (GM) that differentiate into class IIpos, CD80/CD86pos, CD40neg APC during GVHD. Whereas addition of plasmacytoid and myeloid donor DC augmented GVHD, GM cells induced transplant tolerance via MHC class II restricted generation of IL-10-secreting regulatory T cells. Thus a population of cytokine expanded granulocyte-monocyte precursors function as regulatory antigen presenting cells, suggesting that G-CSF derivatives may have application in disorders characterised by a loss of self-tolerance.

Response selection deficits in melancholic but not nonmelancholic unipolar major depression

One consistent functional imaging finding from patients with major depression has been abnormality of the anterior cingulate cortex (ACC). Hypoperfusion has been most commonly reported, but some studies suggest relative hyperperfusion is associated with response to somatic treatments. Despite these indications of the possible importance of the ACC in depression there have been relatively few cognitive studies ACC function in patients with major depression. The present study employed a series of reaction time (RT) tasks involving selection with melancholic and nonmelancholic depressed patients, as well as age-matched controls. Fifteen patients with unipolar major depression (7 melancholic, 8 nonmelancholic) and 8 healthy age-matched controls performed a series of response selection tasks (choice RT, spatial Stroop, spatial stimulus-response compatibility (SRC), and a combined Stroop + SRC condition). Reaction time and error data were collected. Melancholic patients were significantly slower than controls on all tasks but were slower than nonmelancholic patients only on the Stroop and Stroop + SRC conditions. Nonmelancholic patients did not differ from the control group on any task. The Stroop task seems crucial in differentiating the two depressive groups, they did not differ on the choice RT or SRC tasks. This may reflect differential task demands, the SRC involved symbolic manipulation that might engage the dorsal ACC and dorsolateral prefrontal cortex (DLPFC) to a greater extent than the, primarily inhibitory, Stroop task which may engage the ventral ACC and orbitofrontal cortex (OFC). This might suggest the melancholic group showed a greater ventral ACC-OFC deficit than the nonmelancholic group, while both groups showed similar dorsal ACC-DLPFC deficit.

Alterations in cardiac dihydropyridine receptors and calcium channel function in mdx mice

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular condition affecting approximately one in 3500 live male births resulting from the lack of the myocyte protein dystrophin. The absence of dystrophin in cardiac myocytes is associated with calcium overload which in turn activates calcium-dependent proteolytic enzymes contributing to congestive heart failure, muscle necrosis and fibrosis. To date, the basis for the calcium overload has not been determined. Since L-type calcium channels are a major mediator of calcium influx we determined their potential contribution to the calcium overload. Male muscular dystrophy (mdx) mice and control C57BL10ScSn (C57) mice aged 12– 16 weeks were used in all experiments. In tissue bath studies, isolated contracting left atria from mdx revealed a reduced potency to the dihydropyridine (DHP) agonist BayK8644 and antagonist nifedipine (P < 0.05). Similarly, radioligand binding studies using the DHP antagonist [3H]-PN 200-110 showed a reduced potency (P < 0.05) in isolated membranes, associated with an increased receptor density (P < 0.05). The increased receptor density was supported by RT-PCR experiments revealing increased RNAfor the DHP receptor. Patch clamp studies revealed the presence of a diltiazem sensitive calcium current that showed delayed inactivation in isolated mdx myocytes (P < 0.01). In conclusion, the increased number of DHP binding sites and the delay in L-type current inactivation may both contribute to increased calcium influx and hence calcium overload in the dystrophin deficient mdx cardiac myocytes.

Association of tumor necrosis factor-alpha polymorphisms and ozone-induced change in lung function

Ozone is a major air pollutant with adverse health effects which exhibit marked inter-individual variability. In mice, regions of genetic linkage with ozone-induced lung injury include the tumor necrosis factor-alpha (TNF), lymphotoxin-alpha (LTA), Toll-like receptor 4 (TLR4), superoxide dismutase (SOD2), and glutathione peroxidase (GPX1) genes. We genotyped polymorphisms in these genes in 51 individuals who had undergone ozone challenge. Mean change in FEV1 with ozone challenge, as a percentage of baseline, was -3% in TNF -308G/A or A/A individuals, compared with -9% in G/G individuals (p = 0.024). When considering TNF haplotypes, the smallest change in FEV1 with ozone exposure was associated with the TNF haplotype comprising LTA +252G/TNF -1031T/TNF -308A/TNF -238G. This association remained statistically significant after correction for age, sex, disease, and ozone concentration (p = 0.047). SOD2 or GPX1 genotypes were not associated with lung function, and the TLR4 polymorphism was too infrequent to analyze. The results of this study support TNF as a genetic factor for susceptibility to ozone-induced changes in lung function in humans, and has potential implications for stratifying health risks of air pollution.

Il-1 beta breaks tolerance through inhibition of regulatory T cell function

IL-1 is a key proinflammatory driver of several autoimmune diseases including juvenile inflammatory arthritis, diseases with mutations in the NALP/cryopyrin complex and Crohn’s disease, and is genetically or clinically associated with many others. IL-1 is a pleiotropic proinflammatory cytokine; however the mechanisms by which increased IL-1 signaling promotes autoreactive T cell activity are not clear. Here we show that autoimmune-prone NOD and IL-1 receptor antagonist-deficient C57BL/6 mice both produce high levels of IL-1, which drives autoreactive effector cell expansion. IL-1beta drives proliferation and cytokine production by CD4+CD25+FoxP3– effector/memory T cells, attenuates CD4+CD25+FoxP3+ regulatory T cell function, and allows escape of CD4+CD25– autoreactive effectors from suppression. Thus, inflammation or constitutive overexpression of IL-1beta in a genetically predisposed host can promote autoreactive effector T cell expansion and function, which attenuates the ability of regulatory T cells to maintain tolerance to self.

IL-1 breaks tolerance through inhibition of regulatory T cell function

Diverse infectious and inflammatory environmental triggers, through unknown mechanisms, initiate autoimmune disease in genetically predisposed individuals. Here we show that IL-1b, a key cytokine mediator of the inflammatory response, suppresses CD25+CD4+ regulatory T cell function. Surprisingly, suppression by IL-1b occurs only where antigen is presented simultaneously to CD25+CD4+ T cells and to CD25CD4+ antigen-specific effector T cells. Further, NOD mice show an intrinsic over-production of IL-1 that contributes to reduced CD25+CD4+ regulatory T cell function. Thus, inflammation or constitutive over-expression of IL-1b in a genetically predisposed host can initiate a positive feedback loop licensing autoantigen-specific effector cells to inhibit the regulatory T cells maintaining tolerance to self.

Lateralized deficit of response inhibition in early-onset schizophrenia

Background. The ability to inhibit inappropriate or unwanted actions is a key element of executive control. The existence OF executive function deficits in schizophrenia is consistent with frontal lobe theories of the disorder. Relatively few Studies have examined response inhibition in schizophrenia, and none in adolescent patients with early-onset schizophrenia (EOS). Methods. Twenty-one adolescents with (lie onset of clinically impairing psychosis before 19 years of age and 16 matched controls performed a stop-signal task to assess response inhibition. The patients with EOS were categorized Lis paranoid (n= 10) and Undifferentiated subtypes (n= 11). The undifferentiated group had higher levels of negative symptomatology. Stop-signal reaction time (SSRT) and go-signal reaction time (Go-RT) were analysed with respect to hand of response. Results. The Undifferentiated early-onset patients had significantly longer SSRTs, indicative of poor response inhibition, for the left hand compared to the paranoid early-onset patients and control participants. No differences existed for inhibitory control with the right hand. The three groups did not differ in Go-RT. Conclusions. Our results indicate a specific lateralized impairment of response inhibition in patients With Undifferentiated, but not paranoid, EOS. These findings are consistent with reports of immature frontostriatal networks in EOS and implicate areas such as the pre-motor cortex and Supplementary motor area (SMA) that are thought to play a role in both voluntary initiation and inhibition of movement.