Vacuolating cytotoxin (vacA) alleles of Helicobacter pylori comprise two geographically widespread types, m1 and m2, and have evolved through limited recombination

Vacuolating cytotoxin (vacA) alleles of Helicobacter pylori vary, particularly in their mid region (which may be type m1 or m2) and their signal peptide coding region (type s1 or s2). We investigated nucleotide diversity among vacA alleles in strains from several locales in Asia, South America, and the USA. Phylogenetic analysis of vacA mid region sequences from 18 strains validated the division into two main groups (m1 and m2) and showed further significant divisions within these groups. Informative site analysis demonstrated one example of recombination between m1 and m2 alleles, and several examples of recombination among alleles within these groups. Recombination was not sufficiently extensive to destroy phylogenetic structure entirely. Synonymous nucleotide substitution rates were markedly different between regions of vacA, suggesting different evolutionary divergence times and implying horizontal transfer of genetic elements within vacA. Non-synonymous/synonymous rate ratios were greater between m1 and m2 sequences than among m1 sequences, consistent with m1 and m2 alleles encoding functions fitting strains for slightly different ecological niches

ACE Insertion / Deletion polymorphism and human performance at high altitude

The hypoxia of high altitude (‘hypobaric hypoxia’) presents a profound physiological challenge to the human body and at extreme high altitude the human body nears the limits of its tolerance for oxygen deprivation. Physical performance in this environment is limited by two major physiological elements: ‘acclimatisation’ to hypobaric hypoxia sufficient to allow strenuous physical exertion, and the avoidance of Acute High Altitude Illnesses (AHAI). The rate and effectiveness of acclimatisation and the susceptibility to AHAI varies markedly between individuals, suggesting a possible genetic influence on high altitude performance. A polymorphism of the human Angiotensin Converting Enzyme (ACE) gene has been identified in which the deletion (D-allele), rather than the insertion (I-allele), of a 287 base pair sequence is associated with higher circulating and tissue ACE activity. This polymorphism has also been associated with physical performance phenotypes, the ACE I-allele being associated with elite endurance performance. An excess frequency of the ACE I-allele has also been identified in a small sample of elite UK high altitude mountaineers. This thesis set out to test the hypothesis that the ACE I-allele is indeed associated with successful physical performance at high altitude, and to explore the mechanism by which such an advantage may be mediated. I conducted a series of prospective geneenvironment interaction studies to assess whether the ACE I-allele is associated with successful ascent to high altitude and, if such an advantage exists, whether this is mediated by reduced susceptibility to Acute Mountain Sickness (AMS) or improved oxygen saturations. To further define the underlying mechanism, I explored the association of bradykinin 2 receptor genotype with high altitude performance to investigate whether the ACE I allele contribution is mediated by increased kinin activity. Additionally I extended these observations to those who have faced the most extreme hypoxic challenge - a successful ascent of Mount Everest

Moving the research forward: The best of british biology using the tractable model system dictyostelium discoideum

The social amoeba Dictyostelium discoideum provides an excellent model for research across a broad range of disciplines within biology. The organism diverged from the plant, yeast, fungi and animal kingdoms around 1 billion years ago but retains common aspects found in these kingdoms. Dictyostelium has a low level of genetic complexity and provides a range of molecular, cellular, biochemical and developmental biology experimental techniques, enabling multidisciplinary studies to be carried out in a wide range of areas, leading to research breakthroughs. Numerous laboratories within the United Kingdom employ Dictyostelium as their core research model. This review introduces Dictyostelium and then highlights research from several leading British research laboratories, covering their distinct areas of research, the benefits of using the model, and the breakthroughs that have arisen due to the use of Dictyostelium as a tractable model system

General practitioners' use of risk prediction tools and their application to Barretts Oesophagus : a qualitative study

Background: Risk prediction tools are widely used for the early identification of disease and expediting referrals to medical specialists for further assessment. This study provides an understanding of general practitioners preferences for using some prediction tools over others. The recent development of a risk prediction model for Barrett’s oesophagus prompted our investigation of General Practitioners perspectives of the barriers and enablers to its use and screening tools per se. Method: Individual semi-structured interviews explored the use of risk prediction tools in the general practice setting. A case scenario was used to create a schema that described the risk assessment process for Barrett’s oesophagus. A content analysis of verbatim transcripts was coded for barriers and enablers to tool use and linked to explanatory themes. Results: Data was collected from five general practitioners and one gastroenterologist. Barriers to regular use of risk prediction tools were identified and grouped using five themes; time poverty, tool format style, remembering to use, relevance of questions, and reduced autonomy in clinical decision making. Five key reasons for regular use were also identified; simple to use, memory prompt, provides a clear guide, aids in keeping me focused, and easy to access. All participants acknowledged the need for identifying Barrett’s oesophagus, the precursor to oesophageal adenocarcinoma, and viewed our tool as a significant contribution to risk assessment of this condition. Conclusion: Identifying barriers and enablers is essential to wide implementation of risk prediction tools. Participants provided information crucial to the translation of our risk prediction model for Barrett’s oesophagus into clinical practice. They also confirmed that the developed model would be useful in the clinical setting

Uptake and transport of novel amphiphilic polyelectrolyte-insulin nanocomplexes by caco-2 cells - towards oral insulin

“The original publication is available at www.springerlink.com”. Copyright SpringerPurpose: The influence of polymer architecture on cellular uptake and transport across Caco-2 cells of novel amphiphilic polyelectrolyte-insulin nanocomplexes was investigated. Method: Polyallylamine (PAA) (15 kDa) was grafted with palmitoyl chains (Pa) and subsequently modified with quaternary ammonium moieties (QPa). These two amphiphilic polyelectrolytes (APs) were tagged with rhodamine and their uptake by Caco-2 cells or their polyelectrolyte complexes (PECs) with fluorescein isothiocyanate-insulin (FITC-insulin) uptake were investigated using fluorescence microscopy. The integrity of the monolayer was determined by measurement of transepithelial electrical resistance (TEER). Insulin transport through Caco-2 monolayers was determined during TEER experiments. Result: Pa and insulin were co-localised in the cell membranes while QPa complexes were found within the cytoplasm. QPa complex uptake was not affected by calcium, cytochalasin D or nocodazole. Uptake was reduced by co-incubation with sodium azide, an active transport inhibitor. Both polymers opened tight junctions reversibly where the TEER values fell by up to 35 % within 30 minutes incubation with Caco-2 cells. Insulin transport through monolayers increased when QPa was used (0.27 ngmL-1 of insulin in basal compartment) compared to Pa (0.14 ngmL-1 of insulin in basal compartment) after 2 hours. Conclusion: These APs have been shown to be taken up by Caco-2 cells and reversibly open tight cell junctions. Further work is required to optimise these formulations with a view to maximising their potential to facilitate oral delivery of insulin.Peer reviewe

Endocranial volume is heritable and is associated with longevity and fitness in a wild mammal

Research on relative brain size in mammals suggests that increases in brain size may generate benefits to survival and costs to fecundity: comparative studies of mammals have shown that interspecific differences in relative brain size are positively correlated with longevity and negatively with fecundity. However, as yet, no studies of mammals have investigated whether similar relationships exist within species, nor whether individual differences in brain size within a wild population are heritable. Here we show that, in a wild population of red deer ($\textit{Cervus elaphus}$), relative endocranial volume was heritable (h² = 63%; 95% credible intervals (CI) = 50-76%). In females, it was positively correlated with longevity and lifetime reproductive success, though there was no evidence that it was associated with fecundity. In males, endocranial volume was not related to longevity, lifetime breeding success or fecundity.Leverhulme Trust; Isaac Newton Trust; Natural Environmental Research Council (NE/L00688X/1); European Research Council (grant nos. 250098 and 294494); Australian Research Counci

Two cases of food aversion with semantic dementia

Accounts of altered eating behavior in semantic dementia generally emphasize gluttony and abnormal food preferences. Here we describe two female patients with no past history of eating disorders who developed early prominent aversion to food in the context of an otherwise typical semantic dementia syndrome. One patient (aged 57) presented features in line with anorexia nervosa while the second patient (aged 58) presented with a syndrome more suggestive of bulimia nervosa. These cases add to the growing spectrum of apparently dichotomous behavior patterns in the frontotemporal dementias and illustrate a potentially under-recognized cause of eating disorders presenting in later life

Developing predictive insight into changing water systems: use-inspired hydrologic science for the Anthropocene

Globally, many different kinds of water resources management issues call for policy- and infrastructure-based responses. Yet responsible decision-making about water resources management raises a fundamental challenge for hydrologists: making predictions about water resources on decadal - to century-long timescales. Obtaining insight into hydrologic futures over 100 yr timescales forces researchers to address internal and exogenous changes in the properties of hydrologic systems. To do this, new hydrologic research must identify, describe and model feedbacks between water and other changing, coupled environmental subsystems. These models must be constrained to yield useful insights, despite the many likely sources of uncertainty in their predictions. Chief among these uncertainties are the impacts of the increasing role of human intervention in the global water cycle – a defining challenge for hydrology in the Anthropocene. Here we present a research agenda that proposes a suite of strategies to address these challenges from the perspectives of hydrologic science research. The research agenda focuses on the development of co-evolutionary hydrologic modeling to explore coupling across systems, and to address the implications of this coupling on the long-time behavior of the coupled systems. Three research directions supportthe development of these models: hydrologic reconstruction, comparative hydrology and model-data learning. These strategies focus on understanding hydrologic processes and feedbacks over long timescales, across many locations, and through strategic coupling of observational and model data in specific systems. We highlight the value of use-inspired and team-based science that is motivated by real-world hydrologic problems but targets improvements in fundamental understanding to support decision-making and management. Fully realizing the potential of this approach will ultimately require detailed integration of social science and physical science understanding of water systems, and is a priority for the developing field of sociohydrology

The 5.2 ka climate event: Evidence from stable isotope and multi-proxy palaeoecological peatland records in Ireland

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Evidence for a major climate event at 5.2 ka has been reported globally and is associated with considerable societal disruption, but is poorly characterised in northwest Europe. This event forms part of a broader period of re-organisation in the Earth's ocean-atmosphere circulation system between 6 and 5 ka. This study tests the nature and timing of the event in northwest Europe, a region highly sensitive to change in meridional overturning circulation and mid-latitude westerly airflow. Here we report three high-resolution Irish multi-proxy records obtained from ombrotrophic peatlands that have robust chronological frameworks. We identify the 5.2 ka event by a sustained decrease in δ 18 O cellulose at all three sites, with additional and parallel changes in δ 13 C cellulose and palaeoecological (testate amoebae, plant macrofossil and humification) data from two sites in northern Ireland. Data from Sluggan Moss demonstrate a particularly coherent shift towards wetter conditions. These data support the hypothesis that the event was caused by a prolonged period of positive North Atlantic Oscillation conditions, resulting in pervasive cyclonic weather patterns across northwest Europe, increasing precipitation over Ireland.This research was carried out while T.P.R. held UK Natural Environment Research Council studentship at the University of Exeter (NE/G524328/1) and T.J.D held a studentship at the University of Southampton tied to the NERC RAPID Programme (NER/T/S/2002/00460). Radiocarbon support was provided by the NERC 14C Steering Committee (Allocation No.: 1523.0910), the NERC RAPID Programme and the Irish Quaternary Association via the IQUA Bill Watts 14Chrono award