Systemic activation of dendritic cells by toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity

The mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. Here we show that infection with a malaria parasite (Plasmodium berghei) or simple systemic exposure to bacterial or viral Toll-like receptor ligands inhibited cross-priming. Reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit T cell proliferation. Although activated dendritic cells retained their capacity to present viral antigens via the endogenous major histocompatibility complex class I processing pathway, antiviral responses were greatly impaired in mice exposed to Toll-like receptor ligands. This is consistent with a key function for cross-presentation in antiviral immunity and helps explain the immunosuppressive effects of systemic infection. Moreover, inhibition of cross-presentation was overcome by injection of dendritic cells bearing antigen, which provides a new strategy for generating immunity during immunosuppressive blood infections.

Differential tumor necrosis factor receptor 2-mediated editing of virus-specific CD8+ effector T cells

Much of the CD8+ T cell response in H2b mice with influenza pneumonia is directed at the nucleoprotein366-374 (NP366) and acid polymerase224-233 (PA224) peptides presented by the H2Db MHC class I glycoprotein. These DbNP366- and DbPA224-specific T cell populations are readily analyzed by staining with tetrameric complexes of MHC+ peptide (tetramers) or by cytokine production subsequent to in vitro stimulation with the cognate peptides. The DbPA224-specific CD8+ effector T cells make more tumor necrosis factor (TNF) α than the comparable CD8+DbNP366+ set, a difference reflected in the greater sensitivity of the CD8+DbPA224+ population to TNF receptor (TNFR) 2-mediated apoptosis under conditions of in vitro culture. Freshly isolated CD8+DbNP366+ and CD8+DbPA224+ T cells from influenza-infected TNFR2-/- mice produce higher levels of IFN-γ and TNF-α after in vitro stimulation with peptide, although the avidity of the T cell receptor-epitope interaction does not change. Increased numbers of both CD8+DbPA224+ and CD8+DbNP366+ T cells were recovered from the lungs (but not the spleens) of secondarily challenged TNFR2-/- mice, a pattern that correlates with the profiles of TNFR expression in the TNFR2+/+ controls. Thus, it seems that TNFR2-mediated editing of influenza-specific CD8+ T cells functions to limit the numbers of effectors that have localized to the site of pathology in the lung but does not modify the size of the less activated responder T cell populations in the spleen. Therefore, the massive difference in magnitude for the secondary, although not the primary, response to these DbNP366 and DbPA224 epitopes cannot be considered to reflect differential TNFR2-mediated T cell editing.

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.

Urban–rural comparison of weight status among women and children living in socioeconomically disadvantaged neighbourhoods

Objective: To compare the weight status of women and children living in socioeconomically disadvantaged rural and urban neighbourhoods in Victoria.

Design, setting and participants: Cross-sectional study of data collected between August 2007 and July 2008 as part of the Resilience for Eating and Activity Despite Inequality (READI) study. Women aged 18–45 years living in 40 rural and 40 urban socioeconomically disadvantaged Victorian areas were surveyed by postal questionnaire. Data from a subset of their children aged 5–12 years were also analysed. Weight and height were self-reported for women and measured for children.

Main outcome measures: Women’s weight status based on body mass index (BMI): underweight; healthy; overweight; or obese Class I, II or III; children’s weight status based on International Obesity Taskforce BMI cut-off points.

Results: Of 11 940 women randomly selected, 4934 (41%) replied to a postal invitation to participate. After exclusions for various reasons, data were available on 3879 women and 636 of their children. Twenty-four per cent of urban and 26% of rural women were classified as overweight; a further 19% of urban and 23% of rural women were classified as obese. Twenty per cent of both urban and rural children were classified as overweight; a further 10% of urban and rural children were classified as obese. In crude analyses, rural women had higher odds of Class I and II obesity (odds ratio [OR], 1.34 and 1.72, respectively) compared with urban women. After adjusting for sociodemographic factors (age, number of children, country of birth, education level, employment status and marital status), there was no difference between urban and rural women in odds of overweight or obesity Class I, II or III. No significant urban–rural difference in odds of overweight/obesity was evident among children.

Conclusions: The higher prevalence of obesity in rural women compared with urban women was largely explained by individual-level sociodemographic factors, such as age, number of children, country of birth, education level, employment status and marital status. This suggests that higher obesity levels among women in rural areas may be attributable to the sociodemographic composition of these areas.

A single PDZ domain protein interacts with the menkes copper ATPase, ATP7A : a new protein implicated in copper homeostasis

The homeostatic regulation of essential elements such as copper requires many proteins whose activities are often mediated and tightly coordinated through protein-protein interactions. This regulation ensures that cells receive enough copper without intracellular concentrations reaching toxic levels. To date, only a small number of proteins implicated in copper homeostasis have been identified, and little is known of the protein-protein interactions required for this process. To identify other proteins important for copper homeostasis, while also elucidating the protein-protein interactions that are integral to the process, we have utilized a known copper protein, the copper ATPase ATP7A, as a bait in a yeast two-hybrid screen of a human cDNA library to search for interacting partners. One of the ATP7A-interacting proteins identified is a novel protein with a single PDZ domain. This protein was recently identified to interact with the plasma membrane calcium ATPase b-splice variants. We propose a change in name for this protein from PISP (plasma membrane calcium ATPase-interacting single-PDZ protein) to AIPP1 (ATPase-interacting PDZ protein) and suggest that it represents the protein that interacts with the class I PDZ binding motif identified at the ATP7A C terminus. The interaction in mammalian cells was confirmed and an additional splice variant of AIPP1 was identified. This study represents an essential step forward in identifying the proteins and elucidating the network of protein-protein interactions involved in maintaining copper homeostasis and validates the use of the yeast two-hybrid approach for this purpose.

Utility-based quality of life associated with overweight and obesity : the Australian diabetes, obesity, and lifestyle study

This study aimed to estimate utility-based quality of life (UQoL) differences between healthy body weight and excess body weight categories. Cross-sectional analysis of 10,959 adults, participating in baseline data collection of the nationally representative Australian Diabetes, Obesity, and Lifestyle (AusDiab) Study was undertaken. Height and weight were measured by trained personnel. Body weight categories were assigned as healthy weight, overweight, and obesity subclasses I, II and III. UQoL was assessed using the SF-6D, which captures physical functioning, role limitation, social functioning, pain, mental health, and vitality on a score of 0.00–1.00 (worst-best). The relationship between body weight categories and UQoL was assessed using linear regression, adjusting for age, sex, education, and smoking. Relative to the healthy weight group (mean UQoL score 0.77), mean adjusted UQoL differences (95% confidence intervals) were 0.001 (−0.008, 0.010) for overweight, −0.012 (−0.022, −0.001) for class-I obese, −0.020 (−0.041, 0.001) for class-II obese, and −0.069 (−0.099, −0.039) for class-III obese groups. Adding metabolic syndrome markers to the covariates had little impact on these differences. Results confirmed an inverse dose–response relationship between body weight and UQoL in this study of Australian adults. This highlights the need to incorporate UQoL measures which are sensitive to the subclasses of obesity when evaluating obesity interventions.

Glassimations

Short movie that was the outcome of a class I taught at Pilchuck Glass School, USA

The copyright wars

Forty minutes through my first body pump exercise class, I was panting, sweating and uncomfortable. Starved of calcium, my muscles were groaning. No ... that was me groaning, as I struggled through the final rep of a rotator cuff move with four-kilogram hand weights. As the class wore on, my execution of the choreographed movements that are integral to Body Pump got progressively more ragged. I was hurting.

Influenza A virus infection impairs mycobacteria-specific T cell responses and mycobacterial clearance in the lung during pulmonary coinfection.

Individuals infected with mycobacteria are likely to experience episodes of concurrent infections with unrelated respiratory pathogens, including the seasonal or pandemic circulating influenza A virus strains. We analyzed the impact of influenza A virus and mycobacterial respiratory coinfection on the development of CD8 T cell responses to each pathogen. Coinfected mice exhibited reduced frequency and numbers of CD8 T cells specific to Mycobacterium bovis bacille Calmette-Guérin (BCG) in the lungs, and the IFN-γ CD8 T cell response to BCG-encoded OVA was decreased in the lungs of coinfected mice, when compared with mice infected with BCG alone. Moreover, after 2 wk of infection, mice coinfected with both pathogens showed a significant increase in the number of mycobacteria present in the lung compared with mice infected with BCG only. Following adoptive transfer into coinfected mice, transgenic CD8 T cells specific for OVA257–264 failed to proliferate as extensively in the mediastinal lymph nodes as in mice infected only with BCG-OVA. Also noted was a reduction in the proliferation of BCG-specific CD4 transgenic T cells in mice coinfected with influenza compared with mice infected with BCG alone. Furthermore, phenotypic analysis of CD11c+ dendritic cells from mediastinal lymph nodes of the infected mice showed that coinfection was associated with decreased surface expression of MHC class II and class I. Thus, concurrent pulmonary infection with influenza A virus is associated with decreased MHC expression on dendritic cells, reduced activation of BCG-specific CD4 and CD8 T cells, and impaired clearance of mycobacteria.

Evidence-based chronic heart-failure management programs : myth or reality?

Background Chronic heart-failure management programmes (CHF-MPs) have become part of standard care for patients with chronic heart failure (CHF). Objective To investigate whether programmes had applied evidence-based expert clinical guidelines to optimise patient outcomes. Design A prospective cross-sectional survey was used to conduct a national audit. Setting Community setting of CHF-MPs for patients postdischarge. Sample All CHF-MPs operating during 2005–2006 (n=55). Also 10–50 consecutive patients from 48 programmes were recruited (n=1157). Main outcome measures (1) Characteristics and interventions used within each CHF-MP; and (2) characteristics of patients enrolled into these programmes. Results Overall, there was a disproportionate distribution of CHF-MPs across Australia. Only 6.3% of hospitals nationally provided a CHF-MP. A total of 8000 postdischarge CHF patients (median: 126; IQR: 26–260) were managed via CHF-MPs, representing only 20% of the potential national case load. Significantly, 16% of the caseload comprised patients in functional New York Heart Association Class I with no evidence of these patients having had previous echocardiography to confirm a diagnosis of CHF. Heterogeneity of CHF-MPs in applied models of care was evident, with 70% of CHF-MPs offering a hybrid model (a combination of heart-failure outpatient clinics and home visits), 20% conducting home visits and 16% conducting an extended rehabilitation model of care. Less than half (44%) allowed heart-failure nurses to titrate medications. The main medications that were titrated in these programmes were diuretics (n=23, 96%), β-blockers (n=17, 71%), ACE inhibitors (ACEIs) (n=14, 58%) and spironolactone (n=9, 38%). Conclusion CHF-MPs are being implemented rapidly throughout Australia. However, many of these programmes do not adhere to expert clinical guidelines for the management of patients with CHF. This poor translation of evidence into practice highlights the inconsistency and questions the quality of health-related outcomes for these patients.

New insights into the role of MHC diversity in devil facial tumour disease

Devil facial tumour disease (DFTD) is a fatal contagious cancer that has decimated Tasmanian devil populations. The tumour has spread without invoking immune responses, possibly due to low levels of Major Histocompatibility Complex (MHC) diversity in Tasmanian devils. Animals from a region in north-western Tasmania have lower infection rates than those in the east of the state. This area is a genetic transition zone between sub-populations, with individuals from north-western Tasmania displaying greater diversity than eastern devils at MHC genes, primarily through MHC class I gene copy number variation. Here we test the hypothesis that animals that remain healthy and tumour free show predictable differences at MHC loci compared to animals that develop the disease.

Increasing body weight and risk of limitations in activities of daily living: a systematic review and meta-analysis

This study examined the relationship between normal weight, overweight and obesity class I and II+, and the risk of disability, which is defined as impairment in activities of daily living (ADL). Systematic searching of the literature identified eight cross-sectional studies and four longitudinal studies that were comparable for meta-analysis. An additional four cross-sectional studies and one longitudinal study were included for qualitative review. Results from the meta-analysis of cross-sectional studies revealed a graded increase in the risk of ADL limitations from overweight (1.04, 95% confidence interval [CI] 1.00-1.08), class I obesity (1.16, 95% CI 1.11-1.21) and class II+ obesity (1.76, 95% CI 1.28-2.41), relative to normal weight. Meta-analyses of longitudinal studies revealed a similar graded relationship; however, the magnitude of this relationship was slightly greater for all body mass index categories. Qualitative analysis of studies that met the inclusion criteria but were not compatible for meta-analysis supported the pooled results. No studies identified met all of the pre-defined quality criteria, and subgroup analysis was inhibited due to insufficient comparable studies. We conclude that increasing body weight increases the risk of disability in a graded manner, but also emphasize the need for additional studies using contemporary longitudinal cohorts with large numbers of obese class III individuals, a range of ages and with measured height and weight, and incident ADL questions.

Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells

SAHA is a class I HDAC/HDAC6 co-inhibitor and an autophagy inducer currently undergoing clinical investigations in breast cancer patients. However, the molecular mechanism of action of SAHA in breast cancer cells remains unclear. In this study, we found that SAHA is equally effective in targeting cells of different breast cancer subtypes and tamoxifen sensitivity. Importantly, we found that down-regulation of survivin plays an important role in SAHA-induced autophagy and cell viability reduction in human breast cancer cells. SAHA decreased survivin and XIAP gene transcription, induced survivin protein acetylation and early nuclear translocation in MCF7 and MDA-MB-231 breast cancer cells. It also reduced survivin and XIAP protein stability in part through modulating the expression and activation of the 26S proteasome and heat-shock protein 90. Interestingly, targeting HDAC3 and HDAC6, but not other HDAC isoforms, by siRNA/pharmacological inhibitors mimicked the effects of SAHA in modulating the acetylation, expression, and nuclear translocation of survivin and induced autophagy in MCF7 and MDA-MB-231 cancer cells. Targeting HDAC3 also mimicked the effect of SAHA in up-regulating the expression and activity of proteasome, which might lead to the reduced protein stability of survivin in breast cancer cells. In conclusion, this study provides new insights into SAHA's molecular mechanism of actions in breast cancer cells. Our findings emphasize the complexity of the regulatory roles in different HDAC isoforms and potentially assist in predicting the mechanism of novel HDAC inhibitors in targeted or combinational therapies in the future.

Evolution of cytokine receptor signaling.

Cytokines represent essential mediators of cell-cell communication with particularly important roles within the immune system. These secreted factors are produced in response to developmental and/or environmental cues and act via cognate cytokine receptors on target cells, stimulating specific intracellular signaling pathways to facilitate appropriate cellular responses. This review describes the evolution of cytokine receptor signaling, focusing on the class I and class II receptor families and the downstream JAK-STAT pathway along with its key negative regulators. Individual components generated over a long evolutionary time frame coalesced to form an archetypal signaling pathway in bilateria that was expanded extensively during early vertebrate evolution to establish a substantial "core" signaling network, which has subsequently undergone limited diversification within discrete lineages. The evolution of cytokine receptor signaling parallels that of the immune system, particularly the emergence of adaptive immunity, which has likely been a major evolutionary driver.

A new semi-automated method for assessing avian acoustic networks reveals that juvenile and adult zebra finches have separate calling networks

Social networks are often inferred from spatial associations, but other parameters like acoustic communication are likely to play a central role in within group interactions. However, it is currently difficult to determine which individual initiates vocalizations, or who responds to whom. To this aim, we designed a method that allows analyzing group vocal network while controlling for spatial networks, by positioning each group member in equidistant individual cages and analyzing continuous vocal interactions semi-automatically. We applied this method to two types of zebra finch groups, composed of either two adult females and two juveniles, or four young adults (juveniles from the first groups). Young often co-occur in the same social group as adults but are likely to have a different social role, which may be reflected in their vocal interactions. Therefore, we tested the hypothesis that the social structure of the group influences the parameters of the group vocal network. We found that groups including juveniles presented periods with higher level of activity than groups composed of young adults. Using two types of analyses (Markov analysis and cross-correlation), we showed that juveniles as well as adults were more likely to respond to individuals of their own age-class (i.e. to call one after another, in terms of turn-taking, and within a short time-window, in terms of time delay). When juveniles turned into adulthood, they showed adult characteristics of vocal patterns. Together our results suggest that vocal behavior changes during ontogeny, and individuals are more strongly connected with individuals of the same age-class within acoustic networks.