A Multi-Factorial Risk Prioritization Framework for Food-Borne Pathogens

To lower the incidence of human food-borne disease, experts and stakeholders have urged the development of a science- and risk-based management system in which food-borne hazards are analyzed and prioritized. A literature review shows that most approaches to risk prioritization developed to date are based on measures of health outcomes and do not systematically account for other factors that may be important to decision making. The Multi-Factorial Risk Prioritization Framework developed here considers four factors that may be important to risk managers: public health, consumer risk perceptions and acceptance, market-level impacts, and social sensitivity. The framework is based on the systematic organization and analysis of data on these multiple factors. The basic building block of the information structure is a three-dimensional cube based on pathogen-food-factor relationships. Each cell of the cube has an information card associated with it and data from the cube can be aggregated along different dimensions. The framework is operationalized in three stages, with each stage adding another dimension to decision-making capacity. The first stage is the information cards themselves that provide systematic information that is not pre-processed or aggregated across factors. The second stage maps the information on the various information cards into cobweb diagrams that create a graphical profile of, for example, a food-pathogen combination with respect to each of the four risk prioritization factors. The third stage is formal multi-criteria decision analysis in which decision makers place explicit values on different criteria in order to develop risk priorities. The process outlined above produces a ‘List A’ of priority food-pathogen combinations according to some aggregate of the four risk prioritization factors. This list is further vetted to produce ‘List B’, which brings in feasibility analysis by ranking those combinations where practical actions that have a significant impact are feasible. Food-pathogen combinations where not enough is known to identify any or few feasible interventions are included in ‘List C’. ‘List C’ highlights areas with significant uncertainty where further research may be needed to enhance the precision of the risk prioritization process. The separation of feasibility and uncertainty issues through the use of ‘Lists A, B, and C’ allows risk managers to focus separately on distinct dimensions of the overall prioritization. The Multi-Factorial Risk Prioritization Framework provides a flexible instrument that compares and contrasts risks along four dimensions. Use of the framework is an iterative process. It can be used to establish priorities across pathogens for a particular food, across foods for a particular pathogen and/or across specific food-pathogen combinations. This report provides a comprehensive conceptual paper that forms the basis for a wider process of consultation and for case studies applying the framework.risk analysis, risk prioritization, food-borne pathogens, benefits and costs

Low Genetic Differentiation across Three Major Ocean Populations of the Whale Shark, Rhincodon typus

BACKGROUND:Whale sharks are a declining species for which little biological data is available. While these animals are protected in many parts of their range, they are fished legally and illegally in some countries. Baseline biological and ecological data are needed to allow the formulation of an effective conservation plan for whale sharks. It is not known, for example, whether the whale shark is represented by a single worldwide panmictic population or by numerous, reproductively isolated populations. Genetic analysis of population structure is one essential component of the baseline data required for whale shark conservation. METHODOLOGY/PRINCIPAL FINDINGS:We have identified 8 polymorphic microsatellites in the whale shark and used these markers to assess genetic variation and population structure in a panel of whale sharks covering a broad geographic region. This is the first record of microsatellite loci in the whale shark, which displayed an average of 9 alleles per locus and mean H(o) = 0.66 and H(e) = 0.69. All but one of the eight loci meet the expectations of Hardy-Weinberg equilibrium. Analysis of these loci in whale sharks representing three major portions of their range, the Pacific (P), Caribbean (C), and Indian (I) Oceans, determined that there is little population differentiation between animals sampled in different geographic regions, indicating historical gene flow between populations. F(ST) values for inter-ocean comparisons were low (PxC = 0.0387, CxI = 0.0296 and PxI = -0.0022), and only CxI approached statistical significance (p = 0.0495). CONCLUSIONS/SIGNIFICANCE:We have shown only low levels of genetic differentiation between geographically distinct whale shark populations. Existing satellite tracking data have revealed both regional and long-range migration of whale sharks throughout their range, which supports the finding of gene flow between populations. Whale sharks traverse geographic and political boundaries during their life history and interbreed with animals from distant populations; conservation efforts must therefore target international protection for this species

Lepton Mixing and Cancellation of the Dirac Mass Hierarchy in SO(10) GUTs with Flavor Symmetries T7 and Sigma(81)

In SO(10) grand unified theories (GUTs) the hierarchy which is present in the Dirac mass term of the neutrinos is generically as strong as the one in the up-type quark mass term. We propose a mechanism to partially or completely cancel this hierarchy in the light neutrino mass matrix in the seesaw context. The two main ingredients of the cancellation mechanism are the existence of three fermionic gauge singlets and of a discrete flavor symmetry G_f which is broken at a higher scale than SO(10). Two realizations of the cancellation mechanism are presented. The realization based on the Frobenius group T7 = Z7 x Z3 leads to a partial cancellation of the hierarchy and relates maximal 2-3 lepton mixing with the geometric hierarchy of the up-quark masses. In the realization with the group Sigma(81) the cancellation is complete and tri-bimaximal lepton mixing is reproduced at the lowest order. In both cases, to fully accommodate the leptonic data we take into account additional effects such as effects of higher-dimensional operators involving more than one flavon. The heavy neutral fermion mass spectra are considered. For both realizations we analyze the flavon potential at the renormalizable level as well as ways to generate the Cabibbo angle.Comment: 31 page

Latent regulatory potential of human-specific repetitive elements

At least half of the human genome is derived from repetitive elements, which are often lineage specific and silenced by a variety of genetic and epigenetic mechanisms. Using a transchromosomic mouse strain that transmits an almost complete single copy of human chromosome 21 via the female germline, we show that a heterologous regulatory environment can transcriptionally activate transposon-derived human regulatory regions. In the mouse nucleus, hundreds of locations on human chromosome 21 newly associate with activating histone modifications in both somatic and germline tissues, and influence the gene expression of nearby transcripts. These regions are enriched with primate and human lineage-specific transposable elements, and their activation corresponds to changes in DNA methylation at CpG dinucleotides. This study reveals the latent regulatory potential of the repetitive human genome and illustrates the species specificity of mechanisms that control it

Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo

We treated 10 children with X-linked SCID (SCID-X1) using gammaretrovirus-mediated gene transfer. Those with sufficient follow-up were found to have recovered substantial immunity in the absence of any serious adverse events up to 5 years after treatment. To determine the influence of vector integration on lymphoid reconstitution, we compared retroviral integration sites (RISs) from peripheral blood CD3(+) T lymphocytes of 5 patients taken between 9 and 30 months after transplantation with transduced CD34(+) progenitor cells derived from 1 further patient and I healthy donor. Integration occurred preferentially in gene regions on either side of transcription start sites, was clustered, and correlated with the expression level in CD34(+) progenitors during transduction. In contrast to those in CD34(+) cells, RISs recovered from engrafted CD3(+)T cells were significantly overrepresented within or near genes encoding proteins with kinase or transferase activity or involved in phosphorus metabolism. Although gross patterns of gene expression were unchanged in transduced cells, the divergence of RIS target frequency between transduced progenitor cells and post-thymic T lymphocytes indicates that vector integration influences cell survival, engraftment, or proliferation

Cyclometallated Au(III) dithiocarbamate complexes: synthesis, anticancer evaluation and mechanistic studies

A series of cationic mixed cyclometallated (C^N)Au(III) dithiocarbamate complexes has been synthesized in good yields [HC^N = 2-(p-t-butylphenyl)pyridine]. The crystal structure of [(C^N)AuS2CNEt2]PF6 (3) has been determined. The cytotoxic properties of the new complexes have been evaluated in vitro against a panel of human cancer cell lines and healthy cells and compared with a neutral mixed (C^C)Au(III) dithiocarbamate complex (C^C = 4,4′-di-t-butylbiphenyl-2,2′-diyl). The complexes appeared to be susceptible to reduction by glutathione but were stable in the presence of N-acetyl cysteine. The potential mechanism of action of this class of compounds has been investigated by measuring the intracellular uptake of some selected complexes, by determining their interactions with higher order DNA structures, and by assessing the ability to inhibit thioredoxin reductase. The complexes proved unable to induce the formation of reactive oxygen species. The investigations add to the picture of the possible mode of action of this class of complexes

The role of electronic correlation in the Si(100) reconstruction: a quantum Monte Carlo study

Recent low-temperature scanning tunneling experiments have challenged the generally accepted picture of buckled silicon dimers as the ground state reconstruction of the Si(100) surface. Together with the symmetric dimer model of the surface suggested by quantum chemistry calculations on small clusters, these findings question our general understanding of electronic correlations at surfaces and its proper description within density functional theory. We present quantum Monte Carlo calculations on large cluster models of the symmetric and buckled surface, and conclude that buckling remains energetically more favorable even when the present-day best treatment of electronic correlation is employed.Comment: 5 pages, Revtex, 10 figure

Psychologische Merkmale jugendlicher Patienten vor einer Gewichtsreduktionsbehandlung

Übergewicht und Adipositas zeigen bei Kindern und Jugendlichen eine hohe Prävalenz und Persistenz. Entsprechende Therapien sind kaum individualisiert und zeigen nur moderate Erfolge. Die Psychopathologie bleibt zumeist unberücksichtigt. Die vorliegende Studie hat die Psychopathologie von Jugendlichen mit Übergewicht und Adipositas (N = 201, Alter 12 – 17 Jahre) vor einer Gewichtsreduktionsbehandlung erhoben und Alters- sowie Geschlechtseffekte untersucht. Mittels Fragebögen wurden selbstberichtet die allgemeine Symptombelastung, Essstörungs- und allgemeine Psychopathologie, gewichtsbezogene Selbststigmatisierung und die körperliche und psychische Lebensqualität erhoben. Mädchen zeigten hypothesenkonform ein höheres Maß an gewichtsbezogener Selbststigmatisierung und eine stärkere Essstörungspsychopathologie als Jungen. Ältere Jugendliche berichteten eine geringere Lebensqualität als jüngere. Vergleiche zu Referenzgruppen aus Bevölkerungs- und Normierungsstichproben zeigten auffälligere Werte bei Jugendlichen mit Übergewicht und Adipositas für alle untersuchten Parameter. Eine auffällige Psychopathologie ist demzufolge ein wichtiges Korrelat bei Jugendlichen mit hohem Gewichtsstatus und ein potenzieller Einflussfaktor auf den Erfolg einer Gewichtsreduktionsbehandlung. Zukünftige Studien sollten die Psychopathologie bei Übergewicht und Adipositas weiter differenzieren und therapeutische Ressourcen evaluieren.Overweight and obesity in children and adolescents are highly prevalent and persistent. Current weight loss treatments are rarely individualized and show only small to moderate efficacy. Only rarely, psychopathological parameters are considered. The present study evaluated the psychopathology of adolescents with overweight and obesity (N = 201, ages 12 – 17 years) prior to obesity treatment. The data were analyzed for age and sex effects. Self-report questionnaires assessed general symptom burden, eating disorder and general psychopathology, weight-related self-stigmatization, and physical and mental quality of life. Girls showed higher rates of weight-related self-stigmatization and higher disordered eating behavior compared to boys. Older adolescents reported a lower quality of life compared to younger adolescents. In normative comparisons with population-based samples and norms, adolescents with overweight and obesity showed significantly adverse outcomes in all parameters. Thus, this study identified psychopathology as an important factor in adolescents with high weight status that may affect obesity treatment. Future studies should examine psychopathology more differentially and determine therapeutic resources in adolescent overweight and obesity

Super Resolution Fluorescence Microscopy and Tracking of Bacterial Flotillin (Reggie) Paralogs Provide Evidence for Defined-Sized Protein Microdomains within the Bacterial Membrane but Absence of Clusters Containing Detergent-Resistant Proteins

Biological membranes have been proposed to contain microdomains of a specific lipid composition, in which distinct groups of proteins are clustered. Flotillin-like proteins are conserved between pro—and eukaryotes, play an important function in several eukaryotic and bacterial cells, and define in vertebrates a type of so-called detergent-resistant microdomains. Using STED microscopy, we show that two bacterial flotillins, FloA and FloT, form defined assemblies with an average diameter of 85 to 110 nm in the model bacterium Bacillus subtilis. Interestingly, flotillin microdomains are of similar size in eukaryotic cells. The soluble domains of FloA form higher order oligomers of up to several hundred kDa in vitro, showing that like eukaryotic flotillins, bacterial assemblies are based in part on their ability to self-oligomerize. However, B. subtilis paralogs show significantly different diffusion rates, and consequently do not colocalize into a common microdomain. Dual colour time lapse experiments of flotillins together with other detergent-resistant proteins in bacteria show that proteins colocalize for no longer than a few hundred milliseconds, and do not move together. Our data reveal that the bacterial membrane contains defined-sized protein domains rather than functional microdomains dependent on flotillins. Based on their distinct dynamics, FloA and FloT confer spatially distinguishable activities, but do not serve as molecular scaffolds