Altered distribution of mucosal NK cells during HIV infection.

The human gut mucosa is a major site of human immunodeficiency virus (HIV) infection and infection-associated pathogenesis. Increasing evidence shows that natural killer (NK) cells have an important role in control of HIV infection, but the mechanism(s) by which they mediate antiviral activity in the gut is unclear. Here, we show that two distinct subsets of NK cells exist in the gut, one localized to intraepithelial spaces (intraepithelial lymphocytes, IELs) and the other to the lamina propria (LP). The frequency of both subsets of NK cells was reduced in chronic infection, whereas IEL NK cells remained stable in spontaneous controllers with protective killer immunoglobulin-like receptor/human leukocyte antigen genotypes. Both IEL and LP NK cells were significantly expanded in immunological non-responsive patients, who incompletely recovered CD4+ T cells on highly active antiretroviral therapy (HAART). These data suggest that both IEL and LP NK cells may expand in the gut in an effort to compensate for compromised CD4+ T-cell recovery, but that only IEL NK cells may be involved in providing durable control of HIV in the gut

Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection

Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology. © 2013 Kader et al

CD4 Depletion in SIV-Infected Macaques Results in Macrophage and Microglia Infection with Rapid Turnover of Infected Cells

In rhesus macaques (RMs), experimental depletion of CD4+ T-cells prior to SIV infection results in higher viremia and emergence of CD4-independent SIV-envelopes. In this study we used the rhesus recombinant anti-CD4 antibody CD4R1 to deplete RM CD4+ T-cells prior to SIVmac251 infection and investigate the sources of the increased viral burden and the lifespan of productively infected cells. CD4-depleted animals showed (i) set-point viral load two-logs higher than controls; (ii) macrophages constituting 80% of all SIV vRNA+ cells in lymph node and mucosal tissues; (iii) substantial expansion of pro-inflammatory monocytes; (iv) aberrant activation and infection of microglial cells; and (v) lifespan of productively infected cells significantly longer in comparison to controls, but markedly shorter than previously estimated for macrophages. The net effect of CD4+ T-cell depletion is an inability to control SIV replication and a shift in the tropism of infected cells to macrophages, microglia, and, potentially, other CD4-low cells which all appear to have a shortened in vivo lifespan. We believe these findings have important implications for HIV eradication studies

Massless D-strings and moduli stabilization in type I cosmology

We consider the cosmological evolution induced by the free energy F of a gas of maximally supersymmetric heterotic strings at finite temperature and weak coupling in dimension D>=4. We show that F, which plays the role of an effective potential, has minima associated to enhanced gauge symmetries, where all internal moduli can be attracted and dynamically stabilized. Using the fact that the heterotic/type I S-duality remains valid at finite temperature and can be applied at each instant of a quasi-static evolution, we find in the dual type I cosmology that all internal NS-NS and RR moduli in the closed string sector and the Wilson lines in the open string sector can be stabilized. For the special case of D=6, the internal volume modulus remains a flat direction, while the dilaton is stabilized. An essential role is played by light D-string modes wrapping the internal manifold and whose contribution to the free energy cannot be omitted, even when the type I string is at weak coupling. As a result, the order of magnitude of the internal radii expectation values on the type I side is (lambda_I alpha')^{1/2}, where lambda_I is the ten-dimensional string coupling. The non-perturbative corrections to the type I free energy can alternatively be described as effects of "thermal E1-instantons", whose worldsheets wrap the compact Euclidean time cycle.Comment: 39 pages, 1 figur

The four qualities of life: Ordering concepts and measures of the good life

The terms 'quality-of-life', 'wellbeing' and 'happiness' denote different meanings; sometimes they are used as an umbrella term for all of value, and the other times to denote special merits. This paper is about the specific meanings of the terms. It proposes a classification based on two bi-partitions; between life 'chances' and life 'results', and between 'outer' and 'inner' qualities. Together these dichotomies imply four qualities of life: 1) livability of the environment, 2) life-ability of the individual, 3) external utility of life and 4) inner appreciation of life. This fourfold matrix is applied in three ways: firstly to place related notions and alternative classifications, secondly to explore substantive meanings in various measures for quality of life and thirdly to find out whether quality-of-life can be measured comprehensively. This last question is answered in the negative. Current sum-scores make little sense. The most inclusive summary measure is still how long and happily people live

Interdisciplinary design - Forming and evaluating teams

The College of Architecture and Environmental Design at California Polytechnic State University has offered an upper division, interdisciplinary experience for every student in the form of a project based, team oriented five unit studio laboratory. The course is now in its fifth year and requires small teams of architecture, engineering and construction students to complete the schematic level design of an actual building for a real client. The quality of the projects and student deliverables has been outstanding and students are clearly meeting the objective to prepare an integrated building design. The other course objective is to function as a member of an interdisciplinary team, which is more difficult to quantify. This paper focuses on the selection and assessment of teams in this course. Various personality and skills assessments are completed and used in the formations of teams. Assessment data on team performance are presented and future actions for this project are discussed

Simian Immunodeficiency Virus Infection of Chimpanzees (Pan troglodytes) Shares Features of Both Pathogenic and Non-pathogenic Lentiviral Infections.

The virus-host relationship in simian immunodeficiency virus (SIV) infected chimpanzees is thought to be different from that found in other SIV infected African primates. However, studies of captive SIVcpz infected chimpanzees are limited. Previously, the natural SIVcpz infection of one chimpanzee, and the experimental infection of six chimpanzees was reported, with limited follow-up. Here, we present a long-term study of these seven animals, with a retrospective re-examination of the early stages of infection. The only clinical signs consistent with AIDS or AIDS associated disease was thrombocytopenia in two cases, associated with the development of anti-platelet antibodies. However, compared to uninfected and HIV-1 infected animals, SIVcpz infected animals had significantly lower levels of peripheral blood CD4+ T-cells. Despite this, levels of T-cell activation in chronic infection were not significantly elevated. In addition, while plasma levels of β2 microglobulin, neopterin and soluble TNF-related apoptosis inducing ligand (sTRAIL) were elevated in acute infection, these markers returned to near-normal levels in chronic infection, reminiscent of immune activation patterns in 'natural host' species. Furthermore, plasma soluble CD14 was not elevated in chronic infection. However, examination of the secondary lymphoid environment revealed persistent changes to the lymphoid structure, including follicular hyperplasia in SIVcpz infected animals. In addition, both SIV and HIV-1 infected chimpanzees showed increased levels of deposition of collagen and increased levels of Mx1 expression in the T-cell zones of the lymph node. The outcome of SIVcpz infection of captive chimpanzees therefore shares features of both non-pathogenic and pathogenic lentivirus infections.This work was supported by the Biotechnology and Biological Sciences Research Council and by the Wellcome Trust.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.ppat.100514

Women's job quality across family life stages: An analysis of female employees across 27 European countries

There is little empirical evidence on how working conditions affect women’s employment and fertility choices, despite a number of studies on the impact of individual-level and institutional factors. The article addresses this gap by examining how family life stages are related to particular aspects of job quality among employed women in 27 European countries. The central argument of the analysis is that high-quality jobs are conducive to both transitions to motherhood and employment after childbirth as women select into these roles. Accordingly, mothers of young children, if employed, are expected to have relatively better quality jobs. Four dimensions of job quality are considered: job security, career progression, working time and intrinsic job quality. The results indicate that mothers with young children are more likely to hold high-quality jobs than women at other life stages with respect to working time quality and job security, but with some variation across countries for job security. The findings highlight the importance of high-quality jobs for women’s fertility decisions and labour market attachment after childbirth, with implications for European employment policy

Effects of ecosystem protection on scallop populations within a community-led temperate marine reserve

This study investigated the effects of a newly established, fully protected marine reserve on benthic habitats and two commercially valuable species of scallop in Lamlash Bay, Isle of Arran, United Kingdom. Annual dive surveys from 2010 to 2013 showed the abundance of juvenile scallops to be significantly greater within the marine reserve than outside. Generalised linear models revealed this trend to be significantly related to the greater presence of macroalgae and hydroids growing within the boundaries of the reserve. These results suggest that structurally complex habitats growing within the reserve have substantially increased spat settlement and/or survival. The density of adult king scallops declined threefold with increasing distance from the boundaries of the reserve, indicating possible evidence of spillover or reduced fishing effort directly outside and around the marine reserve. However, there was no difference in the mean density of adult scallops between the reserve and outside. Finally, the mean age, size, and reproductive and exploitable biomass of king scallops were all significantly greater within the reserve. In contrast to king scallops, the population dynamics of queen scallops (Aequipecten opercularis) fluctuated randomly over the survey period and showed little difference between the reserve and outside. Overall, this study is consistent with the hypothesis that marine reserves can encourage the recovery of seafloor habitats, which, in turn, can benefit populations of commercially exploited species, emphasising the importance of marine reserves in the ecosystem-based management of fisheries