Selective Depletion of Eosinophils or Neutrophils in Mice Impacts the Efficiency of Apoptotic Cell Clearance in the Thymus

Developing thymocytes undergo a rigorous selection process to ensure that the mature T cell population expresses a T cell receptor (TCR) repertoire that can functionally interact with major histocompatibility complexes (MHC). Over 90% of thymocytes fail this selection process and die. A small number of macrophages within the thymus are responsible for clearing the large number of dying thymocytes that must be continuously cleared. We studied the capacity of thymic macrophages to clear apoptotic cells under acute circumstances. This was done by synchronously inducing cell death in the thymus and then monitoring the clearance of apoptotic thymocytes. Interestingly, acute cell death was shown to recruit large numbers of CD11b+ cells into the thymus. In the absence of a minor CSF-1 dependent population of macrophages, the recruitment of these CD11b+ cells into the thymus was greatly reduced and the clearance of apoptotic cells was disrupted. To assess a possible role for the CD11b+ cells in the clearance of apoptotic cells, we analyzed mice deficient for eosinophils and mice with defective trafficking of neutrophils. Failure to attract either eosinophils or neutrophils to the thymus resulted in the impaired clearance of apoptotic cells. These results suggested that there is crosstalk between cells of the innate immune system that is necessary for maximizing the efficiency of apoptotic cell removal

Multiple Origins of Knockdown Resistance Mutations in the Afrotropical Mosquito Vector Anopheles gambiae

How often insecticide resistance mutations arise in natural insect populations is a fundamental question for understanding the evolution of resistance and also for modeling its spread. Moreover, the development of resistance is regarded as a favored model to study the molecular evolution of adaptive traits. In the malaria vector Anopheles gambiae two point mutations (L1014F and L1014S) in the voltage-gated sodium channel gene, that confer knockdown resistance (kdr) to DDT and pyrethroid insecticides, have been described. In order to determine whether resistance alleles result from single or multiple mutation events, genotyping of the kdr locus and partial sequencing of the upstream intron-1 was performed on a total of 288 A. gambiae S-form collected from 28 localities in 15 countries. Knockdown resistance alleles were found to be widespread in West Africa with co-occurrence of both 1014S and 1014F in West-Central localities. Differences in intron-1 haplotype composition suggest that kdr alleles may have arisen from at least four independent mutation events. Neutrality tests provided evidence for a selective sweep acting on this genomic region, particularly in West Africa. The frequency and distribution of these kdr haplotypes varied geographically, being influenced by an interplay between different mutational occurrences, gene flow and local selection. This has important practical implications for the management and sustainability of malaria vector control programs

Current and Future Patterns of Global Marine Mammal Biodiversity

Quantifying the spatial distribution of taxa is an important prerequisite for the preservation of biodiversity, and can provide a baseline against which to measure the impacts of climate change. Here we analyse patterns of marine mammal species richness based on predictions of global distributional ranges for 115 species, including all extant pinnipeds and cetaceans. We used an environmental suitability model specifically designed to address the paucity of distributional data for many marine mammal species. We generated richness patterns by overlaying predicted distributions for all species; these were then validated against sightings data from dedicated long-term surveys in the Eastern Tropical Pacific, the Northeast Atlantic and the Southern Ocean. Model outputs correlated well with empirically observed patterns of biodiversity in all three survey regions. Marine mammal richness was predicted to be highest in temperate waters of both hemispheres with distinct hotspots around New Zealand, Japan, Baja California, the Galapagos Islands, the Southeast Pacific, and the Southern Ocean. We then applied our model to explore potential changes in biodiversity under future perturbations of environmental conditions. Forward projections of biodiversity using an intermediate Intergovernmental Panel for Climate Change (IPCC) temperature scenario predicted that projected ocean warming and changes in sea ice cover until 2050 may have moderate effects on the spatial patterns of marine mammal richness. Increases in cetacean richness were predicted above 40° latitude in both hemispheres, while decreases in both pinniped and cetacean richness were expected at lower latitudes. Our results show how species distribution models can be applied to explore broad patterns of marine biodiversity worldwide for taxa for which limited distributional data are available

Revisiting QRS detection methodologies for portable, wearable, battery-operated, and wireless ECG systems

Cardiovascular diseases are the number one cause of death worldwide. Currently, portable battery-operated systems such as mobile phones with wireless ECG sensors have the potential to be used in continuous cardiac function assessment that can be easily integrated into daily life. These portable point-of-care diagnostic systems can therefore help unveil and treat cardiovascular diseases. The basis for ECG analysis is a robust detection of the prominent QRS complex, as well as other ECG signal characteristics. However, it is not clear from the literature which ECG analysis algorithms are suited for an implementation on a mobile device. We investigate current QRS detection algorithms based on three assessment criteria: 1) robustness to noise, 2) parameter choice, and 3) numerical efficiency, in order to target a universal fast-robust detector. Furthermore, existing QRS detection algorithms may provide an acceptable solution only on small segments of ECG signals, within a certain amplitude range, or amid particular types of arrhythmia and/or noise. These issues are discussed in the context of a comparison with the most conventional algorithms, followed by future recommendations for developing reliable QRS detection schemes suitable for implementation on battery-operated mobile devices.Mohamed Elgendi, Björn Eskofier, Socrates Dokos, Derek Abbot

Improved Cellular Specificity of Plasmonic Nanobubbles versus Nanoparticles in Heterogeneous Cell Systems

The limited specificity of nanoparticle (NP) uptake by target cells associated with a disease is one of the principal challenges of nanomedicine. Using the threshold mechanism of plasmonic nanobubble (PNB) generation and enhanced accumulation and clustering of gold nanoparticles in target cells, we increased the specificity of PNB generation and detection in target versus non-target cells by more than one order of magnitude compared to the specificity of NP uptake by the same cells. This improved cellular specificity of PNBs was demonstrated in six different cell models representing diverse molecular targets such as epidermal growth factor receptor, CD3 receptor, prostate specific membrane antigen and mucin molecule MUC1. Thus PNBs may be a universal method and nano-agent that overcome the problem of non-specific uptake of NPs by non-target cells and improve the specificity of NP-based diagnostics, therapeutics and theranostics at the cell level

A Graphical and Computational Modelling Platform for Biological Pathways

A major endeavor of systems biology is the construction of graphical and computational models of biological pathways as a means to better understand their structure and function. Here, we present a protocol for a biologist-friendly graphical modeling scheme that facilitates the construction of detailed network diagrams, summarizing the components of a biological pathway (such as proteins and biochemicals) and illustrating how they interact. These diagrams can then be used to simulate activity flow through a pathway, thereby modeling its dynamic behavior. The protocol is divided into four sections: (i) assembly of network diagrams using the modified Edinburgh Pathway Notation (mEPN) scheme and yEd network editing software with pathway information obtained from published literature and databases of molecular interaction data; (ii) parameterization of the pathway model within yEd through the placement of 'tokens' on the basis of the known or imputed amount or activity of a component; (iii) model testing through visualization and quantitative analysis of the movement of tokens through the pathway, using the network analysis tool Graphia Professional and (iv) optimization of model parameterization and experimentation. This is the first modeling approach that combines a sophisticated notation scheme for depicting biological events at the molecular level with a Petri net–based flow simulation algorithm and a powerful visualization engine with which to observe the dynamics of the system being modeled. Unlike many mathematical approaches to modeling pathways, it does not require the construction of a series of equations or rate constants for model parameterization. Depending on a model's complexity and the availability of information, its construction can take days to months, and, with refinement, possibly years. However, once assembled and parameterized, a simulation run, even on a large model, typically takes only seconds. Models constructed using this approach provide a means of knowledge management, information exchange and, through the computation simulation of their dynamic activity, generation and testing of hypotheses, as well as prediction of a system's behavior when perturbed

Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Effect of a primary care walking intervention with and without nurse support on physical activity levels in 45- to 75-year-olds: The pedometer and consultation evaluation (PACE-UP) cluster randomised clinical trial

Background Pedometers can increase walking and moderate-to-vigorous physical activity (MVPA) levels, but their effectiveness with or without support has not been rigorously evaluated. We assessed the effectiveness of a pedometer-based walking intervention in predominantly inactive adults, delivered by post or through primary care nurse-supported physical activity (PA) consultations. Methods and Findings A parallel three-arm cluster randomised trial was randomised by household, with 12-mo follow-up, in seven London, United Kingdom, primary care practices. Eleven thousand fifteen randomly selected patients aged 45–75 y without PA contraindications were invited. Five hundred forty-eight self-reporting achieving PA guidelines were excluded. One thousand twenty-three people from 922 households were randomised between 2012–2013 to one of the following groups: usual care (n = 338); postal pedometer intervention (n = 339); and nurse-supported pedometer intervention (n = 346). Of these, 956 participants (93%) provided outcome data (usual care n = 323, postal n = 312, nurse-supported n = 321). Both intervention groups received pedometers, 12-wk walking programmes, and PA diaries. The nurse group was offered three PA consultations. Primary and main secondary outcomes were changes from baseline to 12 mo in average daily step-counts and time in MVPA (in ≥10-min bouts), respectively, measured objectively by accelerometry. Only statisticians were masked to group. Analysis was by intention-to-treat. Average baseline daily step-count was 7,479 (standard deviation [s.d.] 2,671), and average time in MVPA bouts was 94 (s.d. 102) min/wk. At 12 mo, mean steps/d, with s.d. in parentheses, were as follows: control 7,246 (2,671); postal 8,010 (2,922); and nurse support 8,131 (3,228). PA increased in both intervention groups compared with the control group; additional steps/d were 642 for postal (95% CI 329–955) and 677 for nurse support (95% CI 365–989); additional MVPA in bouts (min/wk) were 33 for postal (95% CI 17–49) and 35 for nurse support (95% CI 19–51). There were no significant differences between the two interventions at 12 mo. The 10% (1,023/10,467) recruitment rate was a study limitation. Conclusions A primary care pedometer-based walking intervention in predominantly inactive 45- to 75-y-olds increased step-counts by about one-tenth and time in MVPA in bouts by about one-third. Nurse and postal delivery achieved similar 12-mo PA outcomes. A primary care pedometer intervention delivered by post or with minimal support could help address the public health physical inactivity challenge.The PACE-UP trial was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number HTA 10/32/02 ISRCTN42122561) and will be published in full in Health Technology Assessment. The funders had no role in study design (beyond the commissioned call outline), data collection and analysis, decision to publish, or preparation of the manuscript

Modelling the structure and dynamics of biological pathways

There is a need for formalised diagrams that both summarise current biological pathway knowledge and support modelling approaches that explain and predict their behaviour. Here, we present a new, freely available modelling framework that includes a biologist-friendly pathway modelling language (mEPN), a simple but sophisticated method to support model parameterisation using available biological information; a stochastic flow algorithm that simulates the dynamics of pathway activity; and a 3-D visualisation engine that aids understanding of the complexities of a system's dynamics. We present example pathway models that illustrate of the power of approach to depict a diverse range of systems