HIV-1 Nef limits communication between linker of activated T cells and SLP-76 to reduce formation of SLP-76-signaling microclusters following TCR stimulation

Signal initiation by engagement of the TCR triggers actin rearrangements, receptor clustering, and dynamic organization of signaling complexes to elicit and sustain downstream signaling. Nef, a pathogenicity factor of HIV, disrupts early TCR signaling in target T cells. To define the mechanism underlying this Nef-mediated signal disruption, we employed quantitative single-cell microscopy following surface-mediated TCR stimulation that allows for dynamic visualization of distinct signaling complexes as microclusters (MCs). Despite marked inhibition of actin remodeling and cell spreading, the induction of MCs containing TCR-CD3 or ZAP70 was not affected significantly by Nef. However, Nef potently inhibited the subsequent formation of MCs positive for the signaling adaptor Src homology-2 domain-containing leukocyte protein of 76 kDa (SLP-76) to reduce MC density in Nef-expressing and HIV-1-infected T cells. Further analyses suggested that Nef prevents formation of SLP-76 MCs at the level of the upstream adaptor protein, linker of activated T cells (LAT), that couples ZAP70 to SLP-76. Nef did not disrupt pre-existing MCs positive for LAT. However, the presence of the viral protein prevented de novo recruitment of active LAT into MCs due to retargeting of LAT to an intracellular compartment. These modulations in MC formation and composition depended on Nef's ability to simultaneously disrupt both actin remodeling and subcellular localization of TCR-proximal machinery. Nef thus employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 and preventing the dynamic formation of SLP-76-signaling MCs.

Mapping Medieval Geographies: Geographical Encounters in the Latin West and Beyond, 300–1600

'Mapping Medieval Geographies' explores the ways in which geographical knowledge, ideas and traditions were formed in Europe during the Middle Ages. Leading scholars reveal the connections between Islamic, Christian, Biblical, and Classical geographical traditions from Antiquity to the later Middle Ages and Renaissance. The book is divided into two parts: Part I focuses on the notion of geographical tradition and charts the evolution of celestial and earthly geography in terms of its intellectual, visual and textual representations; whilst Part II explores geographical imaginations; that is to say, those 'imagined geographies' that came into being as a result of everyday spatial and spiritual experience. Bringing together approaches from art, literary studies, intellectual history and historical geography, this pioneering volume will be essential reading for scholars concerned with visual and textual modes of geographical representation and transmission, as well as the spaces and places of knowledge creation and consumption.

"From Indomania to Indophobia":Thomas De Quincey's Providential Orientalism

Thomas De Quincey’s terrifying oriental nightmares, reported to sensational acclaim in his Confessions of an English Opium-Eater (1821), have become a touchstone of romantic imperialism in recent studies of the literature of the period (Leask 1991; Barrell 1992 et al). De Quincey’s collocation of “all creatures, birds, beasts, reptiles, all trees and plants, usages and appearances, that are found in all tropical regions” in the hypnagogic hallucinations that characterized what he called “the pains of opium” seems to anticipate neatly Said’s theory of orientalism, whereby the orient was supplied by the west with “a mentality, a genealogy, an atmosphere,” the attitudinal basis as he argues for the continuing march of imperialism from the late eighteenth century. Yet, as Thomas Trautmann (1997) has pointed out, orientalist scholarship based in India and led by the influential Asiatic Society of Bengal in the late eighteenth century was extremely enthusiastic about Indian classical antiquity. The early orientalist scholarship posited ethnic, linguistic, cultural and religious links between Europe and India, while recognizing the greater antiquity of Indian civilization. This favourable attitude (which Trautmann calls “Indomania”) was overtaken in the nineteenth century by disavowal of that scholarship and repugnance (which he calls “Indophobia”), influenced by utilitarian and evangelical attitudes to colonialism. De Quincey’s lifespan covers this crucial period of change. My paper examines his evangelical upbringing and interest in biblical and orientalist scholarship to suggest his anxious investment in these modes of thinking. I will suggest that the bizarre orientalist fusions of his dreams can be better understood in the context of changing attitudes to the imperialism during the period. An examination of his work provides a far more dynamic understanding of the processes of orientalism than the binary model suggested by Said. The transformation implied from imperial scholarship to governance, I will suggest, is not irrelevant to a world which continues to pull apart on various grounds of race and ethnicity, and reflects on our own role in the academy today.

Swarm scheduling approaches for work-flow applications with security constraints in distributed data-intensive computing environments

The scheduling problem in distributed data-intensive computing environments has become an active research topic due to the tremendous growth in grid and cloud computing environments. As an innovative distributed intelligent paradigm, swarm intelligence provides a novel approach to solving these potentially intractable problems. In this paper, we formulate the scheduling problem for work-flow applications with security constraints in distributed data-intensive computing environments and present a novel security constraint model. Several meta-heuristic adaptations to the particle swarm optimization algorithm are introduced to deal with the formulation of efficient schedules. A variable neighborhood particle swarm optimization algorithm is compared with a multi-start particle swarm optimization and multi-start genetic algorithm. Experimental results illustrate that population based meta-heuristics approaches usually provide a good balance between global exploration and local exploitation and their feasibility and effectiveness for scheduling work-flow applications. © 2010 Elsevier Inc. All rights reserved.

Environmental Challenges and Physiological Solutions: Comparative Energetic Daily Rhythms of Field Mice Populations from Different Ecosystems

Daily and seasonal variations in physiological characteristics of mammals can be considered adaptations to temporal habitat variables. Across different ecosystems, physiological adjustments are expected to be sensitive to different environmental signals such as changes in photoperiod, temperature or water and food availability; the relative importance of a particular signal being dependent on the ecosystem in question. Energy intake, oxygen consumption (VO) and body temperature (T) daily rhythms were compared between two populations of the broad-toothed field mouse Apodemus mystacinus, one from a Mediterranean and another from a sub-Alpine ecosystem. Mice were acclimated to short-day (SD) 'winter' and long-day (LD) 'summer' photoperiods under different levels of salinity simulating osmotic challenges. Mediterranean mice had higher VO values than sub-Alpine mice. In addition, mice exposed to short days had higher VO values when given water with a high salinity compared with mice exposed to long days. By comparison, across both populations, increasing salinity resulted in a decreased T in SD- but not in LD-mice. Thus, SD-mice may conserve energy by decreasing T during ('winter') conditions which are expected to be cool, whereas LD-mice might do the opposite and maintain a higher T during ('summer') conditions which are expected to be warm. LD-mice behaved to reduce energy expenditure, which might be considered a useful trait during 'summer' conditions. Overall, increasing salinity was a clear signal for Mediterranean-mice with resultant effects on VO and T daily rhythms but had less of an effect on sub-Alpine mice, which were more responsive to changes in photoperiod. Results provide an insight into how different populations respond physiologically to various environmental challenges.

Beyond Pietism and Prosperity: Religious Resources for Reconstruction and Reconciliation in Zimbabwe

It is often assumed that charismatic Christianity in Africa promotes either a pietist withdrawal from social and political concerns, or a preoccupation with gaining individual health and wealth (the prosperity gospel). This research presents an alternative vision of the role of charismatic Christianity in Zimbabwe. Drawing on an ethnographic case study of a charismatic congregation, it analyzes how these Christians are drawing links between spirituality and social action. This congregation is developing an egalitarian conception of power, promoting service to the poor, and using biblical discourses to support their actions. This can be understood as part of a wider process in which Zimbabwean Christians are using religious resources to develop a vision for reconstruction and reconciliation. This article points to further areas in which the churches could use their public position to raise sensitive issues, including how to deal with the past and heal relationships between previously antagonistic groups.

King David’s City at Khirbet Qeiyafa: Results of the Second Radiocarbon Dating Project

Fifteen samples of burnt olive pits discovered inside a jar in the destruction layer of the Iron Age city of Khirbet Qeiyafa were analyzed by accelerator mass spectrometry (AMS) radiocarbon dating. Of these, four were halved and sent to two different laboratories to minimize laboratory bias. The dating of these samples is ~1000 BC. Khirbet Qeiyafa is currently the earliest known example of a fortified city in the Kingdom of Judah and contributes direct evidence to the heated debate on the biblical narrative relating to King David. Was he the real historical ruler of an urbanized state-level society in the early 10th century BC or was this level of social development reached only at the end of the 8th century BC? We can conclude that there were indeed fortified centers in the Davidic kingdom from the studies presented. In addition, the dating of Khirbet Qeiyafa has far-reaching implications for the entire Levant. The discovery of Cypriot pottery at the site connects the 14C datings to Cyprus and the renewal of maritime trade between the island and the mainland in the Iron Age. A stone temple model from Khirbet Qeiyafa, decorated with triglyphs and a recessed doorframe, points to an early date for the development of this typical royal architecture of the Iron Age Levant.

Seven key actions to eradicate rheumatic heart disease in Africa: the Addis Ababa communiqué

Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain major causes of heart failure, stroke and death among African women and children, despite being preventable and imminently treatable. From 21 to 22 February 2015, the Social Cluster of the Africa Union Commission (AUC) hosted a consultation with RHD experts convened by the Pan-African Society of Cardiology (PASCAR) in Addis Ababa, Ethiopia, to develop a 'roadmap' of key actions that need to be taken by governments to eliminate ARF and eradicate RHD in Africa. Seven priority areas for action were adopted: (1) create prospective disease registers at sentinel sites in affected countries to measure disease burden and track progress towards the reduction of mortality by 25% by the year 2025, (2) ensure an adequate supply of high-quality benzathine penicillin for the primary and secondary prevention of ARF/RHD, (3) improve access to reproductive health services for women with RHD and other non-communicable diseases (NCD), (4) decentralise technical expertise and technology for diagnosing and managing ARF and RHD (including ultrasound of the heart), (5) establish national and regional centres of excellence for essential cardiac surgery for the treatment of affected patients and training of cardiovascular practitioners of the future, (6) initiate national multi-sectoral RHD programmes within NCD control programmes of affected countries, and (7) foster international partnerships with multinational organisations for resource mobilisation, monitoring and evaluation of the programme to end RHD in Africa. This Addis Ababa communiqué has since been endorsed by African Union heads of state, and plans are underway to implement the roadmap in order to end ARF and RHD in Africa in our lifetime.

Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study)

AIMS: Rheumatic heart disease (RHD) accounts for over a million premature deaths annually; however, there is little contemporary information on presentation, complications, and treatment.

METHODS AND RESULTS: This prospective registry enrolled 3343 patients (median age 28 years, 66.2% female) presenting with RHD at 25 hospitals in 12 African countries, India, and Yemen between January 2010 and November 2012. The majority (63.9%) had moderate-to-severe multivalvular disease complicated by congestive heart failure (33.4%), pulmonary hypertension (28.8%), atrial fibrillation (AF) (21.8%), stroke (7.1%), infective endocarditis (4%), and major bleeding (2.7%). One-quarter of adults and 5.3% of children had decreased left ventricular (LV) systolic function; 23% of adults and 14.1% of children had dilated LVs. Fifty-five percent (n = 1761) of patients were on secondary antibiotic prophylaxis. Oral anti-coagulants were prescribed in 69.5% (n = 946) of patients with mechanical valves (n = 501), AF (n = 397), and high-risk mitral stenosis in sinus rhythm (n = 48). However, only 28.3% (n = 269) had a therapeutic international normalized ratio. Among 1825 women of childbearing age (12-51 years), only 3.6% (n = 65) were on contraception. The utilization of valvuloplasty and valve surgery was higher in upper-middle compared with lower-income countries.

CONCLUSION: Rheumatic heart disease patients were young, predominantly female, and had high prevalence of major cardiovascular complications. There is suboptimal utilization of secondary antibiotic prophylaxis, oral anti-coagulation, and contraception, and variations in the use of percutaneous and surgical interventions by country income level.

Assessment of the impact speed and angle conditions for the EN1317 barrier tests

Roadside safety barriers designs are tested with passenger cars in Europe using standard EN1317 in which the impact angle for normal, high and very high containment level tests is 20°. In comparison to EN1317, the US standard MASH has higher impact angles for cars and pickups (25°) and different vehicle masses. Studies in Europe (RISER) and the US have shown values for the 90th percentile impact angle of 30°–34°. Thus, the limited evidence available suggests that the 20° angle applied in EN 1317 may be too low.
The first goal of this paper is to use the US NCHRP database (Project NCHRP 17–22) to assess the distribution of impact angle and collision speed in recent ROR accidents. Second, based on the findings of the statistical analysis and on analysis of impact angles and speeds in the literature, an LS-DYNA finite element analysis was carried out to evaluate the normal containment level of concrete barriers in non-standard collisions. The FE model was validated against a crash test of a portable concrete barrier carried out at the UK Transport Research Laboratory (TRL).
The accident data analysis for run-off road accidents indicates that a substantial proportion of accidents have an impact angle in excess of 20°. The baseline LS-DYNA model showed good comparison with experimental acceleration severity index (ASI) data and the parametric analysis indicates a very significant influence of impact angle on ASI. Accordingly, a review of European run-off road accidents and the configuration of EN 1317 should be performed.

Peace by Piece: (Re) imagining Division in Belfast’s Contested Spaces through Memory

This paper investigates processes and actions of diversifying memories of division in Northern Ireland’s political conflict known as the Troubles. Societal division is manifested in its built fabric and territories that have been adopted by predominant discourses of a fragmented society in Belfast; the unionist east and the nationalist west. The aim of the paper is to explore current approaches in planning contested spaces that have changed over time, leading to success in many cases. The argument is that divided cities, like Belfast, feature spatial images and memories of division that range from physical, clear-cut segregation to manifested actions of violence and have become influential representations in the community’s associative memory. While promoting notions of ‘re-imaging’ by current councils demonstrates a total erasure of the Troubles through cleansing its local collective memory, there yet remains an attempt to communicate a different tale of the city’s socio-economic past, to elaborate its supremacy for shaping future lived memories. Yet, planning Belfast’s contested areas is still suffering from a poor understanding of the context and its complexity against overambitious visions.