Virus Targeting of the Tumor Necrosis Factor Superfamily

AbstractHerpesviruses appear to peacefully coexist with their natural hosts, with infection typically manifested as a benign, but lifelong process. However, coexistence depends on active resistance by innate and specific immune defenses as revealed in the striking virulence of herpesviruses when immunity fails. This pattern of infection is characteristic of a viral pathogen, such as cytomegalovirus, that has evolved efficient strategies targeted at host defense systems. Targeting members of the tumor necrosis factor (TNF)/lymphotoxin (LT) superfamily of cytokines is a strategy found in all herpesviruses, which suggests the existence of an intimate evolutionary link in their host–parasite relationship. Here we examine some of the strategies used by herpesvirus that target members of the TNF superfamily and discuss a recent study that revealed a novel mechanism that links LT-related ligands and interferons (IFN) to the establishment of coexistence between herpesvirus and its host cell

Stellarator Optimization with Poloidal Field Coils

Stellarators are devices that use magnetic fields to optimize the conditions needed for plasmas to undergo fusion. Unlike tokamaks, stellarators do not rely on a plasma current but can produce a helical magnetic field using only external coils. In a stellarator, the coils surrounding the plasma are called modular coils and those that follow the plasma are called poloidal field coils. Modular coils can be difficult to build if they are too complex. An effort is underway to develop coil conditions that meet both physics and engineering constraints. The FOCUS code was developed to flexibly optimize stellarator coil configurations [C. Zhu, et al., Plasma Phys. Contr. Fusion 60, 065008 (2018)]. In this work, we will use the FOCUS code to develop and analyze coil configurations for a plasma boundary that is optimized for particle confinement. We will examine modular coil configurations with and without a set of poloidal field coils

Cytomegalovirus exploits IL-10–mediated immune regulation in the salivary glands

The salivary glands represent a major site of cytomegalovirus replication and transmission to other hosts. Despite control of viral infection by strong T cell responses in visceral organs cytomegalovirus replication continues in the salivary glands of mice, suggesting that the virus exploits the mucosal microenvironment. Here, we show that T cell immunity in the salivary glands is limited by the induction of CD4 T cells expressing the regulatory cytokine interleukin (IL)-10. Blockade of IL-10 receptor (IL-10R) with an antagonist antibody dramatically reduced viral load in the salivary glands, but not in the spleen. The mucosa-specific protection afforded by IL-10R blockade was associated with an increased accumulation of CD4 T cells expressing interferon γ, suggesting that IL-10R signaling limits effector T cell differentiation. Consistent with this, an agonist antibody targeting the tumor necrosis factor receptor superfamily member OX40 (TNFRSF4) enhanced effector T cell differentiation and increased the number of interferon γ–producing T cells, thus limiting virus replication in the salivary glands. Collectively, the results indicate that modulating effector T cell differentiation can counteract pathogen exploitation of the mucosa, thus limiting persistent virus replication and transmission

Indian teachers and environmental identity in Aotearoa New Zealand early childhood education

The Aotearoa New Zealand early childhood education (ECE) landscape is becoming increasingly multicultural, in particular with a significant number of migrant Indian teachers working in the field. This paper explores the potential role of environmental identity as migrant Indian ECE teachers navigate between the Indian and New Zealand cultures, wherein the environment may hold different meanings and place in these two cultural systems. The natural environment holds a special place in Aotearoa New Zealand’s cultural systems and is an integral part of the national identity. It can be argued that early childhood environmental education is important, and is already playing a part, in developing children’s environmental identity across the country. In facilitating this, teachers’ environmental identities can be equally important, especially in the case of migrant teachers, whose identities are influenced by different cultural systems. Our interest is in the environmental identities of migrant Indian teachers’ given their growing numbers in Aotearoa New Zealand ECE

Randomised controlled feasibility trial of a web-based weight management intervention with nurse support for obese patients in primary care

<b>Background</b><p></p> There is a need for cost-effective weight management interventions that primary care can deliver to reduce the morbidity caused by obesity. Automated web-based interventions might provide a solution, but evidence suggests that they may be ineffective without additional human support. The main aim of this study was to carry out a feasibility trial of a web-based weight management intervention in primary care, comparing different levels of nurse support, to determine the optimal combination of web-based and personal support to be tested in a full trial.<p></p> <b>Methods</b><p></p> This was an individually randomised four arm parallel non-blinded trial, recruiting obese patients in primary care. Following online registration, patients were randomly allocated by the automated intervention to either usual care, the web-based intervention only, or the web-based intervention with either basic nurse support (3 sessions in 3 months) or regular nurse support (7 sessions in 6 months). The main outcome measure (intended as the primary outcome for the main trial) was weight loss in kg at 12 months. As this was a feasibility trial no statistical analyses were carried out, but we present means, confidence intervals and effect sizes for weight loss in each group, uptake and retention, and completion of intervention components and outcome measures.<p></p> <b>Results</b><p></p> All randomised patients were included in the weight loss analyses (using Last Observation Carried Forward). At 12 months mean weight loss was: usual care group (n = 43) 2.44 kg; web-based only group (n = 45) 2.30 kg; basic nurse support group (n = 44) 4.31 kg; regular nurse support group (n = 47) 2.50 kg. Intervention effect sizes compared with usual care were: d = 0.01 web-based; d = 0.34 basic nurse support; d = 0.02 regular nurse support. Two practices deviated from protocol by providing considerable weight management support to their usual care patients.<p></p> <b>Conclusions</b><p></p> This study demonstrated the feasibility of delivering a web-based weight management intervention supported by practice nurses in primary care, and suggests that the combination of the web-based intervention with basic nurse support could provide an effective solution to weight management support in a primary care context

Explaining Adherence Success in Sub-Saharan Africa: An Ethnographic Study

Background: Individuals living with HIV/AIDS in sub-Saharan Africa generally take more than 90% of prescribed doses of antiretroviral therapy (ART). This number exceeds the levels of adherence observed in North America and dispels early scale-up concerns that adherence would be inadequate in settings of extreme poverty. This paper offers an explanation and theoretical model of ART adherence success based on the results of an ethnographic study in three sub-Saharan African countries. Methods and Findings: Determinants of ART adherence for HIV-infected persons in sub-Saharan Africa were examined with ethnographic research methods. 414 in-person interviews were carried out with 252 persons taking ART, their treatment partners, and health care professionals at HIV treatment sites in Jos, Nigeria; Dar es Salaam, Tanzania; and Mbarara, Uganda. 136 field observations of clinic activities were also conducted. Data were examined using category construction and interpretive approaches to analysis. Findings indicate that individuals taking ART routinely overcome economic obstacles to ART adherence through a number of deliberate strategies aimed at prioritizing adherence: borrowing and “begging” transport funds, making “impossible choices” to allocate resources in favor of treatment, and “doing without.” Prioritization of adherence is accomplished through resources and help made available by treatment partners, other family members and friends, and health care providers. Helpers expect adherence and make their expectations known, creating a responsibility on the part of patients to adhere. Patients adhere to promote good will on the part of helpers, thereby ensuring help will be available when future needs arise. Conclusion: Adherence success in sub-Saharan Africa can be explained as a means of fulfilling social responsibilities and thus preserving social capital in essential relationships

Variation in prescribing for anxiety and depression: a reflection of health inequalities, cultural differences or variations in access to care?

BACKGROUND: There are large variations in mental health prescribing in UK populations. However the underlying reasons for these differences, which may be related to differences in prevalence, cultural expectations or practical difficulties in access to treatment, remain uncertain. METHODS: Linear modelling was used to investigate whether population characteristics or access to primary care account for variations in mental health prescribing across 39 deprived neighbourhoods. RESULTS: The proportion of sampled respondents whose first language was not English and the ratio of general practitioners to population explained 61% of variation. Deprivation and mental health status were not significant predictors of prescribing in these relatively deprived communities. CONCLUSION: These findings suggest that mental health prescribing, within deprived areas, as well as reflecting cultural and social differences in prescribing, may also be a proxy measure of access to care

Evidence of mTOR Activation by an AKT-Independent Mechanism Provides Support for the Combined Treatment of PTEN-Deficient Prostate Tumors with mTOR and AKT Inhibitors

AbstractActivation of the phosphoinositide 3-kinase pathway is commonly observed in human prostate cancer. Loss of function of phosphatase and tensin homolog (PTEN) is associated with the activation of AKT and mammalian target of rapamycin (mTOR) in many cancer cell lines as well as in other model systems. However, activation of mTOR is also dependent of kinases other than AKT. Here, we show that activation of mTOR is not dependent on AKT in a prostate-specific PTEN-deficient mouse model of prostate cancer. Pathway bifurcation of AKT and mTOR was noted in both mouse and human prostate tumors. We demonstrated for the first time that cotargeting mTOR and AKT with ridaforolimus/MK-8669 and M1K-2206, respectively, delivers additive antitumor effects in vivo when compared to single agents. Our preclinical data suggest that the combination of AKT and mTOR inhibitors might be more effective in treating prostate cancer patients than current treatment regimens or either treatment alone