High-throughput single-nucleotide polymorphism-based typing of shared Pseudomonas aeruginosa strains in cystic fibrosis patients using the Sequenom iPLEX platform

Shared strains of Pseudomonas aeruginosa are now well recognized in people with cystic fibrosis (CF), and suitable P. aeruginosa laboratory typing tools are pivotal to understanding their clinical significance and guiding infection control policies in CF clinics. We therefore compared a single-nucleotide polymorphism (SNP)-based typing method using Sequenom iPLEX matrix-assisted laser desorption ionization with time-of-flight mass spectrometry (MALDI-TOF MS) with typing methods used routinely by our laboratory. We analysed 617 P. aeruginosa isolates that included 561 isolates from CF patients collected between 2001 and 2009 in two Brisbane CF clinics and typed previously by enterobacterial repetitive intergenic consensus (ERIC)-PCR, as well as 56 isolates from non-CF patients analysed previously by multilocus sequence typing (MLST). The isolates were tested using a P. aeruginosa Sequenom iPLEX MALDI-TOF (PA iPLEX) method comprising two multiplex reactions, a 13-plex and an 8-plex, to characterize 20 SNPs from the P. aeruginosa housekeeping genes acsA, aroE, guaA, mutL, nuoD, ppsA and trpE. These 20 SNPs were employed previously in a real-time format involving 20 separate assays in our laboratory. The SNP analysis revealed 121 different SNP profiles for the 561 CF isolates. Overall, there was at least 96% agreement between the ERIC-PCR and SNP analyses for all predominant shared strains among patients attending our CF clinics: AUST-01, AUST-02 and AUST-06. For the less frequently encountered shared strain AUST-07, 6/25 (24%) ERIC-PCR profiles were misidentified initially as AUST-02 or as unique, illustrating the difficulty of gel-based analyses. SNP results for the 56 non-CF isolates were consistent with previous MLST data. Thus, the PA iPLEX format provides an attractive high-throughput alternative to ERIC-PCR for large-scale investigations of shared P. aeruginosa strains.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

GPCR structure, function, drug discovery and crystallography: report from Academia-Industry International Conference (UK Royal Society) Chicheley Hall, 1-2 September 2014

G-protein coupled receptors (GPCRs) are the targets of over half of all prescribed drugs today. The UniProt database has records for about 800 proteins classified as GPCRs, but drugs have only been developed against 50 of these. Thus, there is huge potential in terms of the number of targets for new therapies to be designed. Several breakthroughs in GPCRs biased pharmacology, structural biology, modelling and scoring have resulted in a resurgence of interest in GPCRs as drug targets. Therefore, an international conference, sponsored by the Royal Society, with world-renowned researchers from industry and academia was recently held to discuss recent progress and highlight key areas of future research needed to accelerate GPCR drug discovery. Several key points emerged. Firstly, structures for all three major classes of GPCRs have now been solved and there is increasing coverage across the GPCR phylogenetic tree. This is likely to be substantially enhanced with data from x-ray free electron sources as they move beyond proof of concept. Secondly, the concept of biased signalling or functional selectivity is likely to be prevalent in many GPCRs, and this presents exciting new opportunities for selectivity and the control of side effects, especially when combined with increasing data regarding allosteric modulation. Thirdly, there will almost certainly be some GPCRs that will remain difficult targets because they exhibit complex ligand dependencies and have many metastable states rendering them difficult to resolve by crystallographic methods. Subtle effects within the packing of the transmembrane helices are likely to mask and contribute to this aspect, which may play a role in species dependent behaviour. This is particularly important because it has ramifications for how we interpret pre-clinical data. In summary, collaborative efforts between industry and academia have delivered significant progress in terms of structure and understanding of GPCRs and will be essential for resolving problems associated with the more difficult targets in the future.

Northern Ireland: Religion, Religiosity and Politics in a Changing Society

The Handbook of Global Contemporary Christianity: Themes and Developments in Culture, Politics, and Society maps the transformations, as well as the continuities, of the largest of the major religions - engaging with the critical global issues which relate to the faith in a fast changing world. International experts in the area offer contributions focusing on global movements; regional trends and developments; Christianity, the state, politics and polity; and Christianity and social diversity. Collectively the contributors provide a comprehensive treatment of health of the religion as Christianity enters its third millennium in existence and details the challenges and dilemmas facing its various expressions, both old and new. The volume is a companion to the Handbook of Contemporary Global Christianity: Movements, Institutions, and Allegiance.

Living in the Landscape: Essays in Honour of Graeme Barker

This edited volume reflects on the multitude of ways by which humans shape and are shaped by the natural world, and how Archaeology and its cognate disciplines recover this relationship. The structure and content of the book recognize Graeme Barker’s pioneering contribution to the scientific study of human-environment interaction, and form a secondary dialectic between his many colleagues and past students and the academic vista which he has helped define. The volume comprises 22 thematic papers, arranged chronologically, each a presentation of front-line research in their respective fields. They mirror the scope of Barker’s legacy through a focus on transitions in the human-environment relationship, how they are enacted and perceived. The assembled chapters illustrate how climate, demographic, subsistence, social and ecological change have affected cultures from the Palaeolithic to Historical, from North Africa and West-Central Eurasia to Southeast Asia and China. They also chronicle the innovations and renegotiated relations that communities have devised to meet and exploit the many shifting realities involved with Living in the Landscape.

Holocene landscape intervention and plant food production strategies in island and mainland Southeast Asia

In the areas adjacent to the drowned Pleistocene continent of Sunda – present-day Mainland and Island SE Asia – the Austronesian Hypothesis of a diaspora of rice cultivators from Taiwan ∼4200 years ago has often been linked with the start of farming. Mounting evidence suggests that these developments should not be conflated and that alternative explanations should be considered, including indigenous inception of complex patterns of plant food production and early exchange of plants, animals, technology and genes. We review evidence for widespread forest disturbance in the Early Holocene which may accompany the beginnings of complex food-production. Although often insubstantial, evidence for incipient and developing management of rainforest vegetation and of developing complex relationships with plants is present, and early enough to suggest that during the Early to mid-Holocene this vast region was marked by different approaches to plant food production. The trajectory of the increasingly complex relationships between people and their food organisms was strongly locally contingent and in many cases did not result in the development of agricultural systems that were recognisable as such at the time of early European encounters. Diverse resource management economies in the Sunda and neighbouring regions appear to have accompanied rather than replaced a reliance on hunting and gathering. This, together with evidence for Early Holocene interaction between these neighbours, gives cause for us to question some authors continued adherence to a singular narrative of the Austronesian Hypothesis and the ‘Neolithisation’ of this part of the world. It also leads us to suggest that the forests of this vast region are, to an extent, a cultural artefact.

The 'human revolution' in lowland tropical Southeast Asia:the antiquity and behavior of anatomically modern humans at Niah Cave (Sarawak, Borneo)

Recent research in Europe, Africa, and Southeast Asia suggests that we can no longer assume a direct and exclusive link between anatomically modern humans and behavioral modernity (the 'human revolution'), and assume that the presence of either one implies the presence of the other: discussions of the emergence of cultural complexity have to proceed with greater scrutiny of the evidence on a site-by-site basis to establish secure associations between the archaeology present there and the hominins who created it. This paper presents one such case study: Niah Cave in Sarawak on the island of Borneo, famous for the discovery in 1958 in the West Mouth of the Great Cave of a modern human skull, the 'Deep Skull,' controversially associated with radiocarbon dates of ca. 40,000 years before the present. A new chronostratigraphy has been developed through a re-investigation of the lithostratigraphy left by the earlier excavations, AMS-dating using three different comparative pre-treatments including ABOX of charcoal, and U-series using the Diffusion-Absorption model applied to fragments of bones from the Deep Skull itself. Stratigraphic reasons for earlier uncertainties about the antiquity of the skull are examined, and it is shown not to be an `intrusive' artifact. It was probably excavated from fluvial-pond-desiccation deposits that accumulated episodically in a shallow basin immediately behind the cave entrance lip, in a climate that ranged from times of comparative aridity with complete desiccation, to episodes of greater surface wetness, changes attributed to regional climatic fluctuations. Vegetation outside the cave varied significantly over time, including wet lowland forest, montane forest, savannah, and grassland. The new dates and the lithostratigraphy relate the Deep Skull to evidence of episodes of human activity that range in date from ca. 46,000 to ca. 34,000 years ago. Initial investigations of sediment scorching, pollen, palynomorphs, phytoliths, plant macrofossils, and starch grains recovered from existing exposures, and of vertebrates from the current and the earlier excavations, suggest that human foraging during these times was marked by habitat-tailored hunting technologies, the collection and processing of toxic plants for consumption, and, perhaps, the use of fire at some forest-edges. The Niah evidence demonstrates the sophisticated nature of the subsistence behavior developed by modern humans to exploit the tropical environments that they encountered in Southeast Asia, including rainforest. (c) 2006 Elsevier Ltd. All rights reserved.

The Cyrenaican Prehistory Project 2012: the sixth season of excavations in the Haua Fteah cave

The paper reports on the sixth season of fieldwork of the Cyrenaican Prehistory Project (CPP) undertaken in September 2012. As in the spring 2012 season, work focussed on the Haua Fteah cave and on studies of materials excavated in previous seasons, with no fieldwork undertaken elsewhere in the Gebel Akhdar. An important discovery, in a sounding excavated below the base of McBurney's 1955 Deep Sounding (Trench S), is of a rockfall or roof collapse conceivably dating to the cold climatic regime of Marine Isotope Stage (MIS) 6 (globally dated to c. 190-130 ka) but more likely the result of a seismic event within MIS 5 (globally dated to c. 130-80 ka). The sediments and associated molluscan fauna in Trench S and in Trench D, a trench being cut down the side of the Deep Sounding, indicate that this part of the cave was at least seasonally waterlogged during the accumulation, probably during MIS 5, of the -6.5 rn of sediment cut through by the Deep Sounding. Evidence for human fréquentation of the cave in this period is more or less visible depending on how close the trench area was to standing water as it fluctuated through time. Trench M, the trench being cut down the side of McBurney's Middle Trench, has now reached the depth of the latest Middle Stone Age or Middle Palaeolithic (Levalloiso-Mousterian) industries. The preliminary indications from its excavation are that the transition from the Levalloiso-Mousterian to the blade-based Upper Palaeolithic or Late Stone Age Dabban industry was complex and perhaps protracted, at a time when the climate was oscillating between warmstage stable environmental conditions and colder and more arid environments. The estimated age of the sediments, c. 50-40 ka, places these oscillations within the earlier part of MIS 3 (globally dated to 60-24 ka), when global climates experienced rapid fluctuations as part of an overall trend to increasing aridity and cold.

Prehistoric foragers and farmers in south-east Asia:Renewed investigations at Niah Cave, Sarawak

The paper describes the initial results from renewed investigations at Niah Cave in Sarawak on the island of Borneo, famous for the discovery in 1958 of the c. 40,000-year old 'Deep Skull'. The archaeological sequences from the West Mouth and the other entrances of the cave complex investigated by Tom and Barbara Harrisson and other researchers have potential implications for three major debates regarding the prehistory of south-east Asia: the timing of initial settlement by anatomically modern humans; the means by which they subsisted in the late Pleistocene and early Holocene; and the timing, nature, and causation of the transition from foraging to farming. The new project is informing on all three debates. The critical importance of the Niah stratigraphies was commonly identified - including by Tom Harrisson himself - as because the site provided a continuous sequence of occupation over the past 40,000 years. The present project indicates that Niah was first used at least 45,000 years ago, and probably earlier; that the subsequent Pleistocene and Holocene occupations were highly variable in intensity and character; and that in some periods, perhaps of significant duration, the caves may have been more or less abandoned. The cultural sequence that is emerging from the new investigations may be more typical of cave use in tropical rainforests in south-east Asia than the Harrisson model.