Urban Design of Bristol Waterfront, Lower Thames Street

The marketplace is going to be one of the highlights on Thames Street, serving as a destination for leisure, shopping and dining. The concept of the project is to have indoor space continue out to the water, providing an outdoor space for dining and leisure, but also giving the boardwalk a resting point. The building is planned as two floors, with the fish market and multipurpose area on the first and an eatery, sitting area, balcony and facilities on the second. The building will be made of a light metal frame with panels to enclose the space and is designed with a folded glass panel that can be opened up to the outside, yet decrease wind pressure in a storm

Erythrocyte G Protein as a Novel Target for Malarial Chemotherapy

BACKGROUND: Malaria remains a serious health problem because resistance develops to all currently used drugs when their parasite targets mutate. Novel antimalarial drug targets are urgently needed to reduce global morbidity and mortality. Our prior results suggested that inhibiting erythrocyte G(s) signaling blocked invasion by the human malaria parasite Plasmodium falciparum. METHODS AND FINDINGS: We investigated the erythrocyte guanine nucleotide regulatory protein G(s) as a novel antimalarial target. Erythrocyte “ghosts” loaded with a G(s) peptide designed to block G(s) interaction with its receptors, were blocked in β-adrenergic agonist-induced signaling. This finding directly demonstrates that erythrocyte G(s) is functional and that propranolol, an antagonist of G protein–coupled β-adrenergic receptors, dampens G(s) activity in erythrocytes. We subsequently used the ghost system to directly link inhibition of host G(s) to parasite entry. In addition, we discovered that ghosts loaded with the peptide were inhibited in intracellular parasite maturation. Propranolol also inhibited blood-stage parasite growth, as did other β(2)-antagonists. β-blocker growth inhibition appeared to be due to delay in the terminal schizont stage. When used in combination with existing antimalarials in cell culture, propranolol reduced the 50% and 90% inhibitory concentrations for existing drugs against P. falciparum by 5- to 10-fold and was also effective in reducing drug dose in animal models of infection. CONCLUSIONS: Together these data establish that, in addition to invasion, erythrocyte G protein signaling is needed for intracellular parasite proliferation and thus may present a novel antimalarial target. The results provide proof of the concept that erythrocyte G(s) antagonism offers a novel strategy to fight infection and that it has potential to be used to develop combination therapies with existing antimalarials

Embodied spatial practices and everyday organization: the work of tour guides and their audiences

This article introduces an interactional perspective to the analysis of organizational space. The study is based on the analysis of over 100 hours of video recordings of guided tours undertaken within two sites (an historic house and a world-famous museum), coupled with interviews and field observations. The analysis is informed by ethnomethodology and conversation analysis in order to focus on the everyday organization of these tours, and the lived experience of inhabiting museum spaces. We use an interactional lens to unpack the ‘embodied spatial practices’ critical to the work of tour guides and their audiences, which reveals how the sense and significance of the workspace emerges moment to moment, and in relation to the ongoing work at hand. As a result, for those with an interest in organizational space, the article introduces a novel perspective, and methods, to highlight the dynamic and interactional production of workspaces. Additionally, for those with an interest in practice, the article demonstrates the fundamental import of taking spatial arrangements seriously when analysing the organization of work

An Investigation of perceptual processing in autistic spectrum disorder using mis-tuned harmonics

Time-shifted dichotic pitch (DP) elicits Object Related Negativity (ORN; associated with object segregation) and Positive 400 (P400; associated with response formation) components in the auditory event related potential (AERP). Our recent work shows that autistics, when compared to matched controls, do not exhibit the ORN but do exhibit a P400 component, when listening to DP stimuli. The aim of this study was to investigate whether components of interest (ORN and P400) are elicited in the AERP of autistics by mistuned harmonics. Participants were ten 18-to-47-year-old adults with ASD and ten matched controls. A mixture of tuned (0%) and mis-tuned (0.5% & 1.5%) harmonic stimulus types were presented. Both controls and autistic s obtained ORN and P400 components in the AERP. Group differences were only found for the autistics for the N1 and N2 in interactions when the location (left/centre/ right) and level (0%, 0.5%, & 1.5%) of the mis-tuned harmonic were factors. This may reflect timing processing deficits in autism. The findings from this study will expand our knowledge on how the brain systematically organises simultaneous incoming auditory information and allow for greater understanding about perceptual processing in Autism.1 page(s

Erythrocyte Ghosts Support Malarial Invasion and Growth

<div><p>(A) LY-D–loaded erythrocyte ghosts (yellow) were infected with P. falciparum (detected by blue DNA stain Hoechst 33342; indicated by arrow). Bar represents 5 μm.</p> <p>(B) Ghosts (white bars) or erythrocytes (grey bars) infected at low (left) or high (right) parasitemias were monitored by Giemsa staining of thin blood smears at the indicated times of infection; mean values are shown. Error bars show standard deviation of triplicate measurements of a representative experiment.</p> <p>(C) An infected culture containing 50% ghosts and 50% erythrocytes was monitored for cell type-specific parasitemias by counting the number of Hoechst 33342–stained parasite nuclei in fluorescent ghosts (white bars) versus non-fluorescent erythrocytes (grey bars) using DIC and fluorescence microscopy of live cells (see <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030528#st2" target="_blank">Methods</a>). Error bars show standard deviation of triplicate measurements of a representative experiment.</p> <p>(D) Giemsa-stained thin blood smears showing ring-, trophozoite-, and schizont-stage parasites in normal (upper) and ghosted (lower) erythrocytes. Bar represents 5 μm.</p> <p>(E) Growth of P. falciparum in ghosts (Ghs) or in erythrocytes (RBCs) in culture over multiple life cycles. Parasites were cultured in ghosts (indicated by dashed line) or in normal erythrocytes (indicated by solid line) for 60 h to ~25% parasitemia, and then were diluted into normal erythrocytes and grown for an additional 50 h. Parasitemia was assessed by counting Giemsa-stained thin blood smears. Error bars show 95% CIs of duplicate measurements at each time point.</p></div

β-Blockers Inhibit Maturation of <i>P. falciparum</i> in In Vitro Cultures

<div><p><b>(</b>A) [³H]-hypoxanthine incorporation of P. falciparum 3D7 when treated with racemic propranolol (indicated by black diamonds) or its inactive isomer (indicated by grey squares). Error bars show the standard deviation of triplicate measurements. IC₅₀ values were determined by fitting the data as described in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030528#st2" target="_blank">Methods</a>; the IC₅₀ value obtained for racemic propranolol (1.2 μM; 95% CI 1.0–1.6 μM) is shown. Three experiments; hatched sign indicates <i>p</i> < 0.001; asterisks indicate <i>p</i> < 0.03 compared to equimolar inactive propranolol.</p> <p>(B) Effect of 2 μM propranolol on intracellular growth in normal erythrocytes. Mock- and drug-treated cultures were monitored at 15, 32, and 44 h after invasion by examination of Giemsa-stained thin blood smears. The number of ring (R)–, trophozoite (T)–, and schizont (S)–stage parasites per 1,000 total erythrocytes at each time point are shown; numbers in parentheses indicate the standard deviation of triplicate measurements from one experiment; the total number of experiments was three.</p> <p>(C) [³H]-hypoxanthine incorporation of P. falciparum 3D7–infected erythrocytes treated with 1 or 10 μM concentrations of adrenergic-acting drugs (nonspecific β₁/β₂–antagonists: propranolol, alprenolol, and nadolol; β₂-specific antagonists: ICI118,551 and butoxamine; β₁-specific antagonists: acebutalol, atenolol, and metoprolol; and α₂-specific agonist [ag]: clonidine). Chloroquine (50 nM) was used as an inhibitory control. Triplicate samples; asterisks denote a treatment with <i>p</i> < 0.001 compared to control-treated cultures.</p></div