Mtss1 promotes cell-cell junction assembly and stability through the small GTPase Rac1

Cell-cell junctions are an integral part of epithelia and are often disrupted in cancer cells during epithelial-to-mesenchymal transition (EMT), which is a main driver of metastatic spread. We show here that Metastasis suppressor-1 (Mtss1; Missing in Metastasis, MIM), a member of the IMD-family of proteins, inhibits cell-cell junction disassembly in wound healing or HGF-induced scatter assays by enhancing cell-cell junction strength. Mtss1 not only makes cells more resistant to cell-cell junction disassembly, but also accelerates the kinetics of adherens junction assembly. Mtss1 drives enhanced junction formation specifically by elevating Rac-GTP. Lastly, we show that Mtss1 depletion reduces recruitment of F-actin at cell-cell junctions. We thus propose that Mtss1 promotes Rac1 activation and actin recruitment driving junction maintenance. We suggest that the observed loss of Mtss1 in cancers may compromise junction stability and thus promote EMT and metastasis

Spatial effects of mosquito bednets on child mortality

<p>Abstract</p> <p>Background</p> <p>Insecticide treated nets (ITN) have been proven to be an effective tool in reducing the burden of malaria. Few randomized clinical trials examined the spatial effect of ITNs on child mortality at a high coverage level, hence it is essential to better understand these effects in real-life situation with varying levels of coverage. We analyzed for the first time data from a large follow-up study in an area of high perennial malaria transmission in southern Tanzania to describe the spatial effects of bednets on all-cause child mortality.</p> <p>Methods</p> <p>The study was carried out between October 2001 and September 2003 in 25 villages in Kilombero Valley, southern Tanzania. Bayesian geostatistical models were fitted to assess the effect of different bednet density measures on child mortality adjusting for possible confounders.</p> <p>Results</p> <p>In the multivariate model addressing potential confounding, the only measure significantly associated with child mortality was the bed net density at household level; we failed to observe additional community effect benefit from bed net coverage in the community.</p> <p>Conclusion</p> <p>In this multiyear, 25 village assessment, despite substantial known inadequate insecticide-treatment for bed nets, the density of household bed net ownership was significantly associated with all cause child mortality reduction. The absence of community effect of bednets in our study area might be explained by (1) the small proportion of nets which are treated with insecticide, and (2) the relative homogeneity of coverage with nets in the area. To reduce malaria transmission for both users and non-users it is important to increase the ITNs and long-lasting nets coverage to at least the present untreated nets coverage.</p

A meta-analysis of long-term effects of conservation agriculture on maize grain yield under rain-fed conditions

Conservation agriculture involves reduced tillage, permanent soil cover and crop rotations to enhance soil fertility and to supply food from a dwindling land resource. Recently, conservation agriculture has been promoted in Southern Africa, mainly for maize-based farming systems. However, maize yields under rain-fed conditions are often variable. There is therefore a need to identify factors that influence crop yield under conservation agriculture and rain-fed conditions. Here, we studied maize grain yield data from experiments lasting 5 years and more under rain-fed conditions. We assessed the effect of long-term tillage and residue retention on maize grain yield under contrasting soil textures, nitrogen input and climate. Yield variability was measured by stability analysis. Our results show an increase in maize yield over time with conservation agriculture practices that include rotation and high input use in low rainfall areas. But we observed no difference in system stability under those conditions. We observed a strong relationship between maize grain yield and annual rainfall. Our meta-analysis gave the following findings: (1) 92% of the data show that mulch cover in high rainfall areas leads to lower yields due to waterlogging; (2) 85% of data show that soil texture is important in the temporal development of conservation agriculture effects, improved yields are likely on well-drained soils; (3) 73% of the data show that conservation agriculture practices require high inputs especially N for improved yield; (4) 63% of data show that increased yields are obtained with rotation but calculations often do not include the variations in rainfall within and between seasons; (5) 56% of the data show that reduced tillage with no mulch cover leads to lower yields in semi-arid areas; and (6) when adequate fertiliser is available, rainfall is the most important determinant of yield in southern Africa. It is clear from our results that conservation agriculture needs to be targeted and adapted to specific biophysical conditions for improved impact

Combining Fungal Biopesticides and Insecticide-Treated Bednets to Enhance Malaria Control

In developing strategies to control malaria vectors, there is increased interest in biological methods that do not cause instant vector mortality, but have sublethal and lethal effects at different ages and stages in the mosquito life cycle. These techniques, particularly if integrated with other vector control interventions, may produce substantial reductions in malaria transmission due to the total effect of alterations to multiple life history parameters at relevant points in the life-cycle and transmission-cycle of the vector. To quantify this effect, an analytically tractable gonotrophic cycle model of mosquito-malaria interactions is developed that unites existing continuous and discrete feeding cycle approaches. As a case study, the combined use of fungal biopesticides and insecticide treated bednets (ITNs) is considered. Low values of the equilibrium EIR and human prevalence were obtained when fungal biopesticides and ITNs were combined, even for scenarios where each intervention acting alone had relatively little impact. The effect of the combined interventions on the equilibrium EIR was at least as strong as the multiplicative effect of both interventions. For scenarios representing difficult conditions for malaria control, due to high transmission intensity and widespread insecticide resistance, the effect of the combined interventions on the equilibrium EIR was greater than the multiplicative effect, as a result of synergistic interactions between the interventions. Fungal biopesticide application was found to be most effective when ITN coverage was high, producing significant reductions in equilibrium prevalence for low levels of biopesticide coverage. By incorporating biological mechanisms relevant to vectorial capacity, continuous-time vector population models can increase their applicability to integrated vector management

Does left atrial volume affect exercise capacity of heart transplant recipients?

<p>Abstract</p> <p>Background</p> <p>Heart transplant (HT) recipients demonstrate limited exercise capacity compared to normal patients, very likely for multiple reasons. In this study we hypothesized that left atrial volume (LAV), which is known to predict exercise capacity in patients with various cardiac pathologies including heart failure and hypertrophic cardiomyopathy is associated with limited exercise capacity of HT recipients.</p> <p>Methods</p> <p>We analyzed 50 patients [age 57 ±2 (SEM), 12 females] who had a post-HT echocardiography and cardiopulmonary exercise test (CPX) within 9 weeks time at clinic follow up. The change in LAV (ΔLAV) was also computed as the difference in LAV from the preceding one-year to the study echocardiogram. Correlations among the measured parameters were assessed with a Pearson's correlation analysis.</p> <p>Results</p> <p>LAV (n = 50) and ΔLAV (n = 40) indexed to body surface area were 40.6 ± 11.5 ml·m^-2and 1.9 ± 8.5 ml·m^-2·year^-1, data are mean ± SD, respectively. Indexed LAV and ΔLAV were both significantly correlated with the ventilatory efficiency, assessed by the VE/VCO₂slope (r = 0.300, p = 0.038; r = 0.484, p = 0.002, respectively). LAV showed a significant correlation with peak oxygen consumption (r = -0.328, p = 0.020).</p> <p>Conclusions</p> <p>Although our study is limited by a retrospective study design and relatively small number of patients, our findings suggest that enlarged LAV and increasing change in LAV is associated with the diminished exercise capacity in HT recipients and warrants further investigation to better elucidate this relationship.</p

Variable Fitness Impact of HIV-1 Escape Mutations to Cytotoxic T Lymphocyte (CTL) Response

Human lymphocyte antigen (HLA)-restricted CD8+ cytotoxic T lymphocytes (CTL) target and kill HIV-infected cells expressing cognate viral epitopes. This response selects for escape mutations within CTL epitopes that can diminish viral replication fitness. Here, we assess the fitness impact of escape mutations emerging in seven CTL epitopes in the gp120 Env and p24 Gag coding regions of an individual followed longitudinally from the time of acute HIV-1 infection, as well as some of these same epitopes recognized in other HIV-1-infected individuals. Nine dominant mutations appeared in five gp120 epitopes within the first year of infection, whereas all four mutations found in two p24 epitopes emerged after nearly two years of infection. These mutations were introduced individually into the autologous gene found in acute infection and then placed into a full-length, infectious viral genome. When competed against virus expressing the parental protein, fitness loss was observed with only one of the nine gp120 mutations, whereas four had no effect and three conferred a slight increase in fitness. In contrast, mutations conferring CTL escape in the p24 epitopes significantly decreased viral fitness. One particular escape mutation within a p24 epitope was associated with reduced peptide recognition and high viral fitness costs but was replaced by a fitness-neutral mutation. This mutation appeared to alter epitope processing concomitant with a reduced CTL response. In conclusion, CTL escape mutations in HIV-1 Gag p24 were associated with significant fitness costs, whereas most escape mutations in the Env gene were fitness neutral, suggesting a balance between immunologic escape and replicative fitness costs

Burden of childhood-onset arthritis

Juvenile arthritis comprises a variety of chronic inflammatory diseases causing erosive arthritis in children, often progressing to disability. These children experience functional impairment due to joint and back pain, heel pain, swelling of joints and morning stiffness, contractures, pain, and anterior uveitis leading to blindness. As children who have juvenile arthritis reach adulthood, they face possible continuing disease activity, medication-associated morbidity, and life-long disability and risk for emotional and social dysfunction. In this article we will review the burden of juvenile arthritis for the patient and society and focus on the following areas: patient disability; visual outcome; other medical complications; physical activity; impact on HRQOL; emotional impact; pain and coping; ambulatory visits, hospitalizations and mortality; economic impact; burden on caregivers; transition issues; educational occupational outcomes, and sexuality

Analysis of infectious virus clones from two HIV-1 superinfection cases suggests that the primary strains have lower fitness

<p>Abstract</p> <p>Background</p> <p>Two HIV-1 positive patients, L and P, participating in the Amsterdam Cohort studies acquired an HIV-1 superinfection within half a year from their primary HIV-1 infection (Jurriaans <it>et al</it>., <it>JAIDS </it>2008, <b>47:</b>69-73). The aim of this study was to compare the replicative fitness of the primary and superinfecting HIV-1 strains of both patients. The use of isolate-specific primer sets indicated that the primary and secondary strains co-exist in plasma at all time points after the moment of superinfection.</p> <p>Results</p> <p>Biological HIV-1 clones were derived from peripheral blood CD4 + T cells at different time point, and identified as the primary or secondary virus through sequence analysis. Replication competition assays were performed with selected virus pairs in PHA/IL-2 activated peripheral blood mononuclear cells (PBMC's) and analyzed with the Heteroduplex Tracking Assay (HTA) and isolate-specific PCR amplification. In both cases, we found a replicative advantage of the secondary HIV-1 strain over the primary virus. Full-length HIV-1 genomes were sequenced to find possible explanations for the difference in replication capacity. Mutations that could negatively affect viral replication were identified in the primary infecting strains. In patient L, the primary strain has two insertions in the LTR promoter, combined with a mutation in the <it>tat </it>gene that has been associated with decreased replication capacity. The primary HIV-1 strain isolated from patient P has two mutations in the LTR that have been associated with a reduced replication rate. In a luciferase assay, only the LTR from the primary virus of patient P had lower transcriptional activity compared with the superinfecting virus.</p> <p>Conclusions</p> <p>These preliminary findings suggest the interesting scenario that superinfection occurs preferentially in patients infected with a relatively attenuated HIV-1 isolate.</p

The normal breast microenvironment of premenopausal women differentially influences the behavior of breast cancer cells in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>Breast cancer studies frequently focus on the role of the tumor microenvironment in the promotion of cancer; however, the influence of the normal breast microenvironment on cancer cells remains relatively unknown. To investigate the role of the normal breast microenvironment on breast cancer cell tumorigenicity, we examined whether extracellular matrix molecules (ECM) derived from premenopausal African-American (AA) or Caucasian-American (CAU) breast tissue would affect the tumorigenicity of cancer cells <it>in vitro </it>and <it>in vivo</it>. We chose these two populations because of the well documented predisposition of AA women to develop aggressive, highly metastatic breast cancer compared to CAU women.</p> <p>Methods</p> <p>The effects of primary breast fibroblasts on tumorigenicity were analyzed via real-time PCR arrays and mouse xenograft models. Whole breast ECM was isolated, analyzed via zymography, and its effects on breast cancer cell aggressiveness were tested <it>in vitro </it>via soft agar and invasion assays, and <it>in vivo </it>via xenograft models. Breast ECM and hormone metabolites were analyzed via mass spectrometry.</p> <p>Results</p> <p>Mouse mammary glands humanized with premenopausal CAU fibroblasts and injected with primary breast cancer cells developed significantly larger tumors compared to AA humanized glands. Examination of 164 ECM molecules and cytokines from CAU-derived fibroblasts demonstrated a differentially regulated set of ECM proteins and increased cytokine expression. Whole breast ECM was isolated; invasion and soft agar assays demonstrated that estrogen receptor (ER)^-, progesterone receptor (PR)/PR^-cells were significantly more aggressive when in contact with AA ECM, as were ER⁺/PR⁺cells with CAU ECM. Using zymography, protease activity was comparatively upregulated in CAU ECM. In xenograft models, CAU ECM significantly increased the tumorigenicity of ER⁺/PR⁺cells and enhanced metastases. Mass spectrometry analysis of ECM proteins showed that only 1,759 of approximately 8,000 identified were in common. In the AA dataset, proteins associated with breast cancer were primarily related to tumorigenesis/neoplasia, while CAU unique proteins were involved with growth/metastasis. Using a novel mass spectrometry method, 17 biologically active hormones were measured; estradiol, estriol and 2-methoxyestrone were significantly higher in CAU breast tissue.</p> <p>Conclusions</p> <p>This study details normal premenopausal breast tissue composition, delineates potential mechanisms for breast cancer development, and provides data for further investigation into the role of the microenvironment in cancer disparities.</p

A Novel Role for the NLRC4 Inflammasome in Mucosal Defenses against the Fungal Pathogen Candida albicans

Candida sp. are opportunistic fungal pathogens that colonize the skin and oral cavity and, when overgrown under permissive conditions, cause inflammation and disease. Previously, we identified a central role for the NLRP3 inflammasome in regulating IL-1β production and resistance to dissemination from oral infection with Candida albicans. Here we show that mucosal expression of NLRP3 and NLRC4 is induced by Candida infection, and up-regulation of these molecules is impaired in NLRP3 and NLRC4 deficient mice. Additionally, we reveal a role for the NLRC4 inflammasome in anti-fungal defenses. NLRC4 is important for control of mucosal Candida infection and impacts inflammatory cell recruitment to infected tissues, as well as protects against systemic dissemination of infection. Deficiency in either NLRC4 or NLRP3 results in severely attenuated pro-inflammatory and antimicrobial peptide responses in the oral cavity. Using bone marrow chimeric mouse models, we show that, in contrast to NLRP3 which limits the severity of infection when present in either the hematopoietic or stromal compartments, NLRC4 plays an important role in limiting mucosal candidiasis when functioning at the level of the mucosal stroma. Collectively, these studies reveal the tissue specific roles of the NLRP3 and NLRC4 inflammasome in innate immune responses against mucosal Candida infection