Passive Energy Recapture in Jellyfish Contributes to Propulsive Advantage over other Metazoans

Gelatinous zooplankton populations are well known for their ability to take over perturbed ecosystems. The ability of these animals to outcompete and functionally replace fish that exhibit an effective visual predatory mode is counterintuitive because jellyfish are described as inefficient swimmers that must rely on direct contact with prey to feed. We show that jellyfish exhibit a unique mechanism of passive energy recapture, which is exploited to allow them to travel 30% further each swimming cycle, thereby reducing metabolic energy demand by swimming muscles. By accounting for large interspecific differences in net metabolic rates, we demonstrate, contrary to prevailing views, that the jellyfish (Aurelia aurita) is one of the most energetically efficient propulsors on the planet, exhibiting a cost of transport (joules per kilogram per meter) lower than other metazoans. We estimate that reduced metabolic demand by passive energy recapture improves the cost of transport by 48%, allowing jellyfish to achieve the large sizes required for sufficient prey encounters. Pressure calculations, using both computational fluid dynamics and a newly developed method from empirical velocity field measurements, demonstrate that this extra thrust results from positive pressure created by a vortex ring underneath the bell during the refilling phase of swimming. These results demonstrate a physical basis for the ecological success of medusan swimmers despite their simple body plan. Results from this study also have implications for bioinspired design, where low-energy propulsion is required

Population structure of multidrug resistant Klebsiella oxytoca within hospitals across the UK and Ireland identifies sharing of virulence and resistance genes with K. pneumoniae.

Klebsiella oxytoca, a member of the Enterobacteriaceae, is a gram-negative pathogenic bacterium of environmental origin, which can cause infection in healthcare settings. Outbreaks of multidrug-resistant K. oxytoca infection have been increasingly reported in hospitalized patients. Despite the growing importance of this pathogen, there is limited knowledge about the population structure and epidemiology of antimicrobial resistant K. oxytoca. We investigated the population structure and genomic basis of antimicrobial resistance of 41 multidrug resistant K. oxytoca isolates recovered from bloodstream infections across the UK and Ireland. Our results show that K. oxytoca has a highly diverse population, which is composed of several distinct clades, and we identified one recent expansion of a clone within our dataset. Although the K. oxytoca genomes are clearly distinct from the genomes of a global collection of Klebsiella pneumoniae complex, pre-dominantly composed of K. pneumoniae, we found evidence for sharing of core genes through recombination, as well as the exchange of accessory antimicrobial resistance and virulence factor genes between the species. Our findings also suggest that the different K. oxytoca clades have acquired antimicrobial resistance and virulence factor genes independently. This highlights the clinical and therapeutic importance of genetic flexibility in K. oxytoca and the relevance of this in its role as an opportunistic pathogen

Long-term interleukin-6 levels and subsequent risk of coronary heart disease: Two new prospective studies and a systematic review

Background The relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two population-based cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context. Methods and Findings Measurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The year-to-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28-0.53, over 4 y, and 0.35, 95% CI 0.23-0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29-1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45-3.15) with long-term average ("usual'') IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42-1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45-4.56] per 2 SD increase in usual [long-term average] IL-6 levels). Conclusions Long-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6-mediated pathways to CH

Human Galectin-9 Is a Potent Mediator of HIV Transcription and Reactivation.

Identifying host immune determinants governing HIV transcription, latency and infectivity in vivo is critical to developing an HIV cure. Based on our recent finding that the host factor p21 regulates HIV transcription during antiretroviral therapy (ART), and published data demonstrating that the human carbohydrate-binding immunomodulatory protein galectin-9 regulates p21, we hypothesized that galectin-9 modulates HIV transcription. We report that the administration of a recombinant, stable form of galectin-9 (rGal-9) potently reverses HIV latency in vitro in the J-Lat HIV latency model. Furthermore, rGal-9 reverses HIV latency ex vivo in primary CD4+ T cells from HIV-infected, ART-suppressed individuals (p = 0.002), more potently than vorinostat (p = 0.02). rGal-9 co-administration with the latency reversal agent "JQ1", a bromodomain inhibitor, exhibits synergistic activity (p<0.05). rGal-9 signals through N-linked oligosaccharides and O-linked hexasaccharides on the T cell surface, modulating the gene expression levels of key transcription initiation, promoter proximal-pausing, and chromatin remodeling factors that regulate HIV latency. Beyond latent viral reactivation, rGal-9 induces robust expression of the host antiviral deaminase APOBEC3G in vitro and ex vivo (FDR<0.006) and significantly reduces infectivity of progeny virus, decreasing the probability that the HIV reservoir will be replenished when latency is reversed therapeutically. Lastly, endogenous levels of soluble galectin-9 in the plasma of 72 HIV-infected ART-suppressed individuals were associated with levels of HIV RNA in CD4+ T cells (p<0.02) and with the quantity and binding avidity of circulating anti-HIV antibodies (p<0.009), suggesting a role of galectin-9 in regulating HIV transcription and viral production in vivo during therapy. Our data suggest that galectin-9 and the host glycosylation machinery should be explored as foundations for novel HIV cure strategies

Human midcingulate cortex encodes distributed representations of task progress

The function of midcingulate cortex (MCC) remains elusive despite decades of investigation and debate. Complicating matters, individual MCC neurons respond to highly diverse task-related events, and MCC activation is reported in most human neuroimaging studies employing a wide variety of task manipulations. Here we investigate this issue by applying a model-based cognitive neuroscience approach involving neural network simulations, functional magnetic resonance imaging, and representational similarity analysis. We demonstrate that human MCC encodes distributed, dynamically evolving representations of extended, goal-directed action sequences. These representations are uniquely sensitive to the stage and identity of each sequence, indicating that MCC sustains contextual information necessary for discriminating between task states. These results suggest that standard univariate approaches for analyzing MCC function overlook the major portion of task-related information encoded by this brain area and point to promising new avenues for investigation

Genetically determined height and coronary artery disease.

BACKGROUND: The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS: We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. RESULTS: We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. CONCLUSIONS: There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.)

Chronic disease research in Europe and the need for integrated population cohorts

The burden of chronic diseases in Europe is sure to increase in coming decades, due primarily to an aging European population. This will place an enormous burden on national health budgets that are already constrained and highlights the urgent need to identify cost-effective and evidence-based public health policies and interventions aimed at preventing chronic diseases that are suitable for the European population. Europe boasts are strong collection of prospective population cohorts, including at least 2.5 million individuals in over 40 cohorts with biological samples. These cohorts need to be viewed as an essential European research infrastructure that provide our best opportunity to identify strategies to reduce chronic disease mortality and morbidity, The true value of these cohorts will also only come through integration, enhanced collaboration and extensive genetic and phenotypic characterizatio

Whole genome sequencing reveals high-resolution epidemiological links between clinical and environmental Klebsiella pneumoniae.

BACKGROUND: Klebsiella pneumoniae is a gram-negative bacterial species capable of occupying a broad range of environmental and clinical habitats. Known as an opportunistic pathogen, it has recently become a major causative agent of clinical infections worldwide. Despite growing knowledge about the highly diverse population of K. pneumoniae, the evolution and clinical significance of environmental K. pneumoniae, as well as the relationship between clinical and environmental K. pneumoniae, are poorly defined. METHODS: We isolated and sequenced K. pneumoniae from in-patients in a single hospital in Thailand, as well as hospital sewage, and surrounding canals and farms within a 20-km radius. RESULTS: Phylogenetic analysis of 77 K. pneumoniae (48 clinical and 29 non-clinical isolates) demonstrated that the two groups were intermixed throughout the tree and in some cases resided in the same clade, suggesting recent divergence from a common ancestor. Phylogenetic comparison of the 77 Thai genomes with 286 K. pneumoniae from a global collection showed that Thai isolates were closely related to the clinical sub-population of the global collection, indicating that Thai clinical isolates belonged to globally circulating lineages. Dating of four Thai K. pneumoniae clades indicated that they emerged between 50 and 150 years ago. Despite their phylogenetic relatedness, virulence factors and β-lactamase resistance genes were more numerous in clinical than in environmental isolates. Our results indicate that clinical and environmental K. pneumoniae are closely related, but that hospitals may select for isolates with a more resistant and virulent genotype. CONCLUSIONS: These findings highlight the clinical relevance of environmental K. pneumoniae isolates

A CD4+ T cell antagonist epitope down-regulates activating signaling proteins, up-regulates inhibitory signaling proteins and abrogates HIV-specific T cell function

BACKGROUND: CD4(+) T cells are critically important in HIV infection, being both the primary cells infected by HIV and likely playing a direct or indirect role in helping control virus replication. Key areas of interest in HIV vaccine research are mechanisms of viral escape from the immune response. Interestingly, in HIV infection it has been shown that peptide sequence variation can reduce CD4(+) T cell responses to the virus, and small changes to peptide sequences can transform agonist peptides into antagonist peptides. RESULTS: We describe, at a molecular level, the consequences of antagonism of HIV p24-specific CD4(+) T cells. Antagonist peptide exposure in the presence of agonist peptide caused a global suppression of agonist-induced gene expression and signaling molecule phosphorylation. In addition to down-regulation of factors associated with T cell activation, a smaller subset of genes associated with negative regulation of cell activation was up-regulated, including KFL-2, SOCS-1, and SPDEY9P. Finally, antagonist peptide in the absence of agonist peptide also delivered a negative signal to T cells. CONCLUSIONS: Small changes in p24-specific peptides can result in T cell antagonism and reductions of both T cell receptor signaling and activation. These changes are at least in part mediated by a dominant negative signal delivered by antagonist peptide, as evidenced by up-regulation of negative regulatory genes in the presence of agonist plus antagonist stimulation. Antagonism can have dramatic effects on CD4(+) T cell function and presents a potential obstacle to HIV vaccine development

The INTERVAL trial to determine whether intervals between blood donations can be safely and acceptably decreased to optimise blood supply: study protocol for a randomised controlled trial.

BACKGROUND: Ageing populations may demand more blood transfusions, but the blood supply could be limited by difficulties in attracting and retaining a decreasing pool of younger donors. One approach to increase blood supply is to collect blood more frequently from existing donors. If more donations could be safely collected in this manner at marginal cost, then it would be of considerable benefit to blood services. National Health Service (NHS) Blood and Transplant in England currently allows men to donate up to every 12 weeks and women to donate up to every 16 weeks. In contrast, some other European countries allow donations as frequently as every 8 weeks for men and every 10 weeks for women. The primary aim of the INTERVAL trial is to determine whether donation intervals can be safely and acceptably decreased to optimise blood supply whilst maintaining the health of donors. METHODS/DESIGN: INTERVAL is a randomised trial of whole blood donors enrolled from all 25 static centres of NHS Blood and Transplant. Recruitment of about 50,000 male and female donors started in June 2012 and was completed in June 2014. Men have been randomly assigned to standard 12-week versus 10-week versus 8-week inter-donation intervals, while women have been assigned to standard 16-week versus 14-week versus 12-week inter-donation intervals. Sex-specific comparisons will be made by intention-to-treat analysis of outcomes assessed after two years of intervention. The primary outcome is the number of blood donations made. A key secondary outcome is donor quality of life, assessed using the Short Form Health Survey. Additional secondary endpoints include the number of 'deferrals' due to low haemoglobin (and other factors), iron status, cognitive function, physical activity, and donor attitudes. A comprehensive health economic analysis will be undertaken. DISCUSSION: The INTERVAL trial should yield novel information about the effect of inter-donation intervals on blood supply, acceptability, and donors' physical and mental well-being. The study will generate scientific evidence to help formulate blood collection policies in England and elsewhere. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24760606, 25 January 2012.The trial is funded by NHS Blood and Transplant. The trial’s coordinating centre at the Department of Public Health and Primary Care at the University of Cambridge has received core support from the UK Medical Research Council, British Heart Foundation, and the UK National Institute of Health Research (Cambridge Biomedical Research Centre). Investigators at the University of Oxford have been supported by Research and Development Programme of NHSBT, the NHSBT Howard Ostin Trust Fund, the UK National Institute of Health Research (Oxford Biomedical Research Centre) through the Programme Grant NIHR-RP-PG-0310-1004 and the Oxford Biomedical Research Centre.This is the published version of the article. It is published by BioMed Central in Trials here: http://www.trialsjournal.com/content/15/1/363