Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model

BACKGROUND: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel(®)) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. METHODS: Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. RESULTS: Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). CONCLUSION: These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV

Structural and biochemical characterization of the exopolysaccharide deacetylase Agd3 required for Aspergillus fumigatus biofilm formation

The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Deletion of a gene encoding a putative deacetylase, Agd3, leads to defects in GAG deacetylation, biofilm formation, and virulence. Here, we show that Agd3 deacetylates GAG in a metal-dependent manner, and is the founding member of carbohydrate esterase family CE18. The active site is formed by four catalytic motifs that are essential for activity. The structure of Agd3 includes an elongated substrate-binding cleft formed by a carbohydrate binding module (CBM) that is the founding member of CBM family 87. Agd3 homologues are encoded in previously unidentified putative bacterial exopolysaccharide biosynthetic operons and in other fungal genomes. The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Here, the authors study an A. fumigatus enzyme that deacetylates GAG in a metal-dependent manner and constitutes a founding member of a new carbohydrate esterase family.Bio-organic Synthesi

Cancer incidence among the south Asian and non-south Asian population under 30 years of age in Yorkshire, UK.

Few studies have examined epidemiological differences between ethnic groups for children and young adults with cancer

VennPlex--a novel Venn diagram program for comparing and visualizing datasets with differentially regulated datapoints.

With the development of increasingly large and complex genomic and proteomic data sets, an enhancement in the complexity of available Venn diagram analytical programs is becoming increasingly important. Current freely available Venn diagram programs often fail to represent extra complexity among datasets, such as regulation pattern differences between different groups. Here we describe the development of VennPlex, a program that illustrates the often diverse numerical interactions among multiple, high-complexity datasets, using up to four data sets. VennPlex includes versatile output features, where grouped data points in specific regions can be easily exported into a spreadsheet. This program is able to facilitate the analysis of two to four gene sets and their corresponding expression values in a user-friendly manner. To demonstrate its unique experimental utility we applied VennPlex to a complex paradigm, i.e. a comparison of the effect of multiple oxygen tension environments (1–20% ambient oxygen) upon gene transcription of primary rat astrocytes. VennPlex accurately dissects complex data sets reliably into easily identifiable groups for straightforward analysis and data output. This program, which is an improvement over currently available Venn diagram programs, is able to rapidly extract important datasets that represent the variety of expression patterns available within the data sets, showing potential applications in fields like genomics, proteomics, and bioinformatics

Terrorism in Australia: factors associated with perceived threat and incident-critical behaviours

<p>Abstract</p> <p>Background</p> <p>To help improve incident preparedness this study assessed socio-demographic and socio-economic predictors of perceived risk of terrorism within Australia and willingness to comply with public safety directives during such incidents.</p> <p>Methods</p> <p>The terrorism perception question module was incorporated into the New South Wales Population Health Survey and was completed by a representative sample of 2,081 respondents in early 2007. Responses were weighted against the New South Wales population.</p> <p>Results</p> <p>Multivariate analyses indicated that those with no formal educational qualifications were significantly more likely (OR = 2.10, 95%CI:1.32–3.35, p < 0.001) to think that a terrorist attack is very or extremely likely to occur in Australia and also more likely (OR = 3.62, 95%CI:2.25–5.83, p < 0.001) to be very or extremely concerned that they or a family member would be directly affected, compared to those with a university-level qualification. Speaking a language other than English at home predicted high concern (very/extremely) that self or family would be directly affected (OR = 3.02, 95%CI:2.02–4.53, p < 0.001) and was the strongest predictor of having made associated changes in living (OR = 3.27, 95%CI:2.17–4.93, p < 0.001). Being female predicted willingness to evacuate from public facilities. Speaking a language other than English at home predicted low willingness to evacuate.</p> <p>Conclusion</p> <p>Low education level is a risk factor for high terrorism risk perception and concerns regarding potential impacts. The pattern of concern and response among those of migrant background may reflect secondary social impacts associated with heightened community threat, rather than the direct threat of terrorism itself. These findings highlight the need for terrorism risk communication and related strategies to address the specific concerns of these sub-groups as a critical underpinning of population-level preparedness.</p

Functional kinds: a skeptical look

The functionalist approach to kinds has suffered recently due to its association with law-based approaches to induction and explanation. Philosophers of science increasingly view nomological approaches as inappropriate for the special sciences like psychology and biology, which has led to a surge of interest in approaches to natural kinds that are more obviously compatible with mechanistic and model-based methods, especially homeostatic property cluster theory. But can the functionalist approach to kinds be weaned off its dependency on laws? Dan Weiskopf has recently offered a reboot of the functionalist program by replacing its nomological commitments with a model-based approach more closely derived from practice in psychology. Roughly, Weiskopf holds that the natural kinds of psychology will be the functional properties that feature in many empirically successful cognitive models, and that those properties need not be localized to parts of an underlying mechanism. I here skeptically examine the three modeling practices that Weiskopf thinks introduce such non-localizable properties: fictionalization, reification, and functional abstraction. In each case, I argue that recognizing functional properties introduced by these practices as autonomous kinds comes at clear cost to those explanations’ counterfactual explanatory power. At each step, a tempting functionalist response is parochialism: to hold that the false or omitted counterfactuals fall outside the modeler’s explanatory aims, and so should not be counted against functional kinds. I conclude by noting the dangers this attitude poses to scientific disagreement, inviting functionalists to better articulate how the individuation conditions for functional kinds might outstrip the perspective of a single modeler

Cross-sectional interactions between quality of the physical and social environment and self-reported physical activity in adults living in income-deprived communities

Background: Understanding the environmental determinants of physical activity in populations at high risk of inactivity could contribute to the development of effective interventions. Socioecological models of activity propose that environmental factors have independent and interactive effects of physical activity but there is a lack of research into interactive effects. Objectives: This study aimed to explore independent and interactive effects of social and physical environmental factors on self-reported physical activity in income-deprived communities. Methods: Participants were 5,923 adults in Glasgow, United Kingdom. Features of the social environment were self-reported. Quality of the physical environment was objectively-measured. Neighbourhood walking and participation in moderate physical activity [MPA] on ≥5 days/week was self-reported. Multilevel multivariate logistic regression models tested independent and interactive effects of environmental factors on activity. Results: ‘Social support’ (walking: OR:1.22,95%CI=1.06-1.41,p<0.01; MPA: OR:0.79,95%CI=0.67-0.94,p<0.01), ‘social interaction’ (walking: OR:1.25,95%CI=1.10-1.42,p<0.01; MPA: OR:6.16,95%CI=5.14-7.37,p<0.001) and ‘cohesion and safety’ (walking: OR:1.78,95%CI=1.56-2.03,p<0.001; MPA: OR:1.93,95%CI=1.65-2.27,p<0.001), but not ‘trust and empowerment’, had independent effects on physical activity. ‘Aesthetics of built form’ (OR:1.47,95%CI=1.22-1.77,p<0.001) and ‘aesthetics and maintenance of open space’ (OR:1.32, 95%CI=1.13-1.54,p<0.01) were related to walking. ‘Physical disorder’ (OR:1.63,95%CI=1.31-2.03,p<0.001) had an independent effect on MPA. Interactive effects of social and physical factors on walking and MPA were revealed. Conclusions: Findings suggest that intervening to create activity-supportive environments in deprived communities may be most effective when simultaneously targeting the social and physical neighbourhood environment