Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells

Activation-induced cytidine deaminase (AID), the enzyme responsible for induction of sequence variation in immunoglobulins (Igs) during the process of somatic hypermutation (SHM) and also Ig class switching, can have a potent mutator phenotype in the development of lymphoma. Using various Epstein-Barr virus (EBV) recombinants, we provide definitive evidence that the viral nuclear protein EBNA3C is essential in EBV-infected primary B cells for the induction of AID mRNA and protein. Using lymphoblastoid cell lines (LCLs) established with EBV recombinants conditional for EBNA3C function, this was confirmed, and it was shown that transactivation of the AID gene (AICDA) is associated with EBNA3C binding to highly conserved regulatory elements located proximal to and upstream of the AICDA transcription start site. EBNA3C binding initiated epigenetic changes to chromatin at specific sites across the AICDA locus. Deep sequencing of cDNA corresponding to the IgH V-D-J region from the conditional LCL was used to formally show that SHM is activated by functional EBNA3C and induction of AID. These data, showing the direct targeting and induction of functional AID by EBNA3C, suggest a novel role for EBV in the etiology of B cell cancers, including endemic Burkitt lymphoma

Fostering implementation of health services research findings into practice: a consolidated framework for advancing implementation science

Abstract Background Many interventions found to be effective in health services research studies fail to translate into meaningful patient care outcomes across multiple contexts. Health services researchers recognize the need to evaluate not only summative outcomes but also formative outcomes to assess the extent to which implementation is effective in a specific setting, prolongs sustainability, and promotes dissemination into other settings. Many implementation theories have been published to help promote effective implementation. However, they overlap considerably in the constructs included in individual theories, and a comparison of theories reveals that each is missing important constructs included in other theories. In addition, terminology and definitions are not consistent across theories. We describe the Consolidated Framework For Implementation Research (CFIR) that offers an overarching typology to promote implementation theory development and verification about what works where and why across multiple contexts. Methods We used a snowball sampling approach to identify published theories that were evaluated to identify constructs based on strength of conceptual or empirical support for influence on implementation, consistency in definitions, alignment with our own findings, and potential for measurement. We combined constructs across published theories that had different labels but were redundant or overlapping in definition, and we parsed apart constructs that conflated underlying concepts. Results The CFIR is composed of five major domains: intervention characteristics, outer setting, inner setting, characteristics of the individuals involved, and the process of implementation. Eight constructs were identified related to the intervention (e.g., evidence strength and quality), four constructs were identified related to outer setting (e.g., patient needs and resources), 12 constructs were identified related to inner setting (e.g., culture, leadership engagement), five constructs were identified related to individual characteristics, and eight constructs were identified related to process (e.g., plan, evaluate, and reflect). We present explicit definitions for each construct. Conclusion The CFIR provides a pragmatic structure for approaching complex, interacting, multi-level, and transient states of constructs in the real world by embracing, consolidating, and unifying key constructs from published implementation theories. It can be used to guide formative evaluations and build the implementation knowledge base across multiple studies and settings.http://deepblue.lib.umich.edu/bitstream/2027.42/78272/1/1748-5908-4-50.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/2/1748-5908-4-50-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/3/1748-5908-4-50-S3.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/4/1748-5908-4-50-S4.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/5/1748-5908-4-50.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/6/1748-5908-4-50-S2.PDFPeer Reviewe

Long term time variability of cosmic rays and possible relevance to the development of life on Earth

An analysis is made of the manner in which the cosmic ray intensity at Earth has varied over its existence and its possible relevance to both the origin and the evolution of life. Much of the analysis relates to the 'high energy' cosmic rays ($E>10^{14}eV;=0.1PeV$) and their variability due to the changing proximity of the solar system to supernova remnants which are generally believed to be responsible for most cosmic rays up to PeV energies. It is pointed out that, on a statistical basis, there will have been considerable variations in the likely 100 My between the Earth's biosphere reaching reasonable stability and the onset of very elementary life. Interestingly, there is the increasingly strong possibility that PeV cosmic rays are responsible for the initiation of terrestrial lightning strokes and the possibility arises of considerable increases in the frequency of lightnings and thereby the formation of some of the complex molecules which are the 'building blocks of life'. Attention is also given to the well known generation of the oxides of nitrogen by lightning strokes which are poisonous to animal life but helpful to plant growth; here, too, the violent swings of cosmic ray intensities may have had relevance to evolutionary changes. A particular variant of the cosmic ray acceleration model, put forward by us, predicts an increase in lightning rate in the past and this has been sought in Korean historical records. Finally, the time dependence of the overall cosmic ray intensity, which manifests itself mainly at sub-10 GeV energies, has been examined. The relevance of cosmic rays to the 'global electrical circuit' points to the importance of this concept.Comment: 18 pages, 5 figures, accepted by 'Surveys in Geophysics

Two Earth-sized planets orbiting Kepler-20

Since the discovery of the first extrasolar giant planets around Sun-like stars, evolving observational capabilities have brought us closer to the detection of true Earth analogues. The size of an exoplanet can be determined when it periodically passes in front of (transits) its parent star, causing a decrease in starlight proportional to its radius. The smallest exoplanet hitherto discovered has a radius 1.42 times that of the Earth's radius (R Earth), and hence has 2.9 times its volume. Here we report the discovery of two planets, one Earth-sized (1.03R Earth) and the other smaller than the Earth (0.87R Earth), orbiting the star Kepler-20, which is already known to host three other, larger, transiting planets. The gravitational pull of the new planets on the parent star is too small to measure with current instrumentation. We apply a statistical method to show that the likelihood of the planetary interpretation of the transit signals is more than three orders of magnitude larger than that of the alternative hypothesis that the signals result from an eclipsing binary star. Theoretical considerations imply that these planets are rocky, with a composition of iron and silicate. The outer planet could have developed a thick water vapour atmosphere.Comment: Letter to Nature; Received 8 November; accepted 13 December 2011; Published online 20 December 201

Recurrent Modification of a Conserved Cis-Regulatory Element Underlies Fruit Fly Pigmentation Diversity

The development of morphological traits occurs through the collective action of networks of genes connected at the level of gene expression. As any node in a network may be a target of evolutionary change, the recurrent targeting of the same node would indicate that the path of evolution is biased for the relevant trait and network. Although examples of parallel evolution have implicated recurrent modification of the same gene and cis-regulatory element (CRE), little is known about the mutational and molecular paths of parallel CRE evolution. In Drosophila melanogaster fruit flies, the Bric-à-brac (Bab) transcription factors control the development of a suite of sexually dimorphic traits on the posterior abdomen. Female-specific Bab expression is regulated by the dimorphic element, a CRE that possesses direct inputs from body plan (ABD-B) and sex-determination (DSX) transcription factors. Here, we find that the recurrent evolutionary modification of this CRE underlies both intraspecific and interspecific variation in female pigmentation in the melanogaster species group. By reconstructing the sequence and regulatory activity of the ancestral Drosophila melanogaster dimorphic element, we demonstrate that a handful of mutations were sufficient to create independent CRE alleles with differing activities. Moreover, intraspecific and interspecific dimorphic element evolution proceeded with little to no alterations to the known body plan and sex-determination regulatory linkages. Collectively, our findings represent an example where the paths of evolution appear biased to a specific CRE, and drastic changes in function were accompanied by deep conservation of key regulatory linkages. © 2013 Rogers et al

Effects of intraspecific competition and body mass on diet specialization in a mammalian scavenger

Animals that rely extensively on scavenging rather than hunting must exploit resources that are inherently patchy, dangerous, or subject to competition. Though it may be expected that scavengers should therefore form opportunistic feeding habits in order to survive, a broad species diet may mask specialization occurring at an individual level. To test this, we used stable isotope analysis to analyze the degree of specialization in the diet of the Tasmanian devil, one of few mammalian species to develop adaptations for scavenging. We found that the majority of individuals were dietary specialists, indicating that they fed within a narrow trophic niche despite their varied diet as a species. Even in competitive populations, only small individuals could be classified as true trophic generalists; larger animals in those populations were trophic specialists. In populations with reduced levels of competition, all individuals were capable of being trophic specialists. Heavier individuals showed a greater degree of trophic specialization, suggesting either that mass is an important driver of diet choice or that trophic specialization is an efficient foraging strategy allowing greater mass gain. Devils may be unique among scavenging mammals in the extent to which they can specialize their diets, having been released from the competitive pressure of larger carnivores

Living in human-modified landscapes narrows the dietary niche of a specialised mammalian scavenger

Anthropogenic impacts on carnivores can be complex, posing numerous threats to many species, yet also benefits to those able to exploit certain resources. This balancing act is particularly precarious for those adapters that exploit dietary resources provided by humans, but still require other resources only available in native habitat. Here we measure the dietary niche of one such species, the Tasmanian devil (Sarcophilus harrisii), a specialised mammalian scavenger, across an anthropogenic habitat gradient stretching from cleared pasture to undisturbed rainforest. Populations inhabiting areas of greater disturbance showed restricted dietary niches, suggesting that all individuals fed on similar food items, even within regenerated native forest. Populations in undisturbed rainforest habitats had comparatively broad diets and showed evidence of niche partitioning by body size, which may reduce intraspecific competition. Despite the potential benefits of reliable access to high-quality food items in anthropogenically-modified habitats, the constrained niches we observed may be harmful, indicating altered behaviours and potentially increasing the rate of fights between individuals over food. This is of particular concern for a species at risk of extinction due to a deadly cancer primarily transmitted through aggressive interactions. The lack of diversity in devil diets within regenerated native forest compared to those in old-growth rainforest also indicates the conservation value of the latter for both the devil and the species which they consume

Framework, principles and recommendations for utilising participatory methodologies in the co-creation and evaluation of public health interventions

Background: Due to the chronic disease burden on society, there is a need for preventive public health interventions to stimulate society towards a healthier lifestyle. To deal with the complex variability between individual lifestyles and settings, collaborating with end-users to develop interventions tailored to their unique circumstances has been suggested as a potential way to improve effectiveness and adherence. Co-creation of public health interventions using participatory methodologies has shown promise but lacks a framework to make this process systematic. The aim of this paper was to identify and set key principles and recommendations for systematically applying participatory methodologies to co-create and evaluate public health interventions. Methods: These principles and recommendations were derived using an iterative reflection process, combining key learning from published literature in addition to critical reflection on three case studies conducted by research groups in three European institutions, all of whom have expertise in co-creating public health interventions using different participatory methodologies. Results: Key principles and recommendations for using participatory methodologies in public health intervention co-creation are presented for the stages of: Planning (framing the aim of the study and identifying the appropriate sampling strategy); Conducting (defining the procedure, in addition to manifesting ownership); Evaluating (the process and the effectiveness) and Reporting (providing guidelines to report the findings). Three scaling models are proposed to demonstrate how to scale locally developed interventions to a population level. Conclusions: These recommendations aim to facilitate public health intervention co-creation and evaluation utilising participatory methodologies by ensuring the process is systematic and reproducible

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation