2,861 research outputs found
Genetic steps to organ laterality in zebrafish.
All internal organs are asymmetric along the left-right axis. Here we report a genetic screen to discover mutations which perturb organ laterality. Our particular focus is upon whether, and how, organs are linked to each other as they achieve their laterally asymmetric positions. We generated mutations by ENU mutagenesis and examined F3 progeny using a cocktail of probes that reveal early primordia of heart, gut, liver and pancreas. From the 750 genomes examined, we isolated seven recessive mutations which affect the earliest left-right positioning of one or all of the organs. None of these mutations caused discernable defects elsewhere in the embryo at the stages examined. This is in contrast to those mutations we reported previously (Chen et al., 1997) which, along with left-right abnormalities, cause marked perturbation in gastrulation, body form or midline structures. We find that the mutations can be classified on the basis of whether they perturb relationships among organ laterality. In Class 1 mutations, none of the organs manifest any left-right asymmetry. The heart does not jog to the left and normally leftpredominant BMP4 in the early heart tube remains symmetric. The gut tends to remain midline. There frequently is a remarkable bilateral duplication of liver and pancreas. Embryos with Class 2 mutations have organotypic asymmetry but, in any given embryo, organ positions can be normal, reversed or randomized. Class 3 reveals a hitherto unsuspected gene that selectively affects laterality of heart. We find that visceral organ positions are predicted by the direction of the preceding cardiac jog. We interpret this as suggesting that normally there is linkage between cardiac and visceral organ laterality. Class 1 mutations, we suggest, effectively remove the global laterality signals, with the consequence that organ positions are effectively symmetrical. Embryos with Class 2 mutations do manifest linkage among organs, but it may be reversed, suggesting that the global signals may be present but incorrectly orientated in some of the embryos. That laterality decisions of organs may be independently perturbed, as in the Class 3 mutation, indicates that there are distinctive pathways for reception and organotypic interpretation of the global signals
The Portrayal of Complementary and Alternative Medicine in Mass Print Magazines Since 1980
Objectives: The objectives of this study were to examine and describe the portrayal of complementary and alternative medicine (CAM) in mass print media magazines.
Design: The sample included all 37 articles found in magazines with circulation rates of greater than 1 million published in the United States and Canada from 1980 to 2005. The analysis was quantitative and qualitative and included investigation of both manifest and latent magazine story messages.
Results: Manifest analysis noted that CAM was largely represented as a treatment for a patient with a medically diagnosed illness or specific symptoms. Discussions used biomedical terms such as patient rather than consumer and disease rather than wellness. Latent analysis revealed three themes: (1) CAMs were described as good but not good enough; (2) individualism and consumerism were venerated; and (3) questions of costs were raised in the context of confusion and ambivalence
Interactions of B = 4 Skyrmions
It is known that the interactions of single Skyrmions are asymptotically
described by a Yukawa dipole potential. Less is known about the interactions of
solutions of the Skyrme model with higher baryon number. In this paper, it is
shown that Yukawa multipole theory can be more generally applied to Skyrmion
interactions, and in particular to the long-range dominant interactions of the
B = 4 solution of the Skyrme model, which models the alpha-particle. A method
that gives the quadrupole nature of the interaction a more intuitive meaning in
the pion field colour picture is demonstrated. Numerical methods are employed
to find the precise strength of quadrupole and octupole interactions. The
results are applied to the B = 8 and B = 12 solutions and to the Skyrme
crystal.Comment: 21 pages, 11 figure
Least - change bidirectional model transformation With QVT- R and ATL
QVT Relations (QVT-R) is the standard language proposed by the OMG to specify bidirectional model transformations. Unfortunately, in part due to ambiguities and omissions in the original semantics, acceptance and development of effective tool support has been slow. Recently, the checking semantics of QVTR has been clarified and formalized. In this article we propose a QVT-R tool that complies to such semantics. Unlike any other existing tool, it also supports metamodels enriched with OCL constraints (thus avoiding returning ill-formed models), and proposes an alternative enforcement semantics that works according to
the simple and predictable “principle of least change”. The implementation is based on an embedding of both QVT-R transformations and UML class diagrams (annotated with OCL) in Alloy, a lightweight formal specification language with support for automatic model finding
via SAT solving. We also show how this technique can be applied to bidirectionalize ATL, a popular (but unidirectional) model transformation language.This work is funded by ERDF-European Regional Development Fund through the COMPETE Programme (operational programme for competitiveness) and by national funds through the FCT-Fundacao para a Ciencia e a Tecnologia (Portuguese Foundation for Science and Technology) within project FCOMP-01-0124-FEDER-020532. The first author is also sponsored by FCT grant SFRH/BD/69585/2010. The authors would also like to thank all anonymous reviewers for the valuable comments and suggestions
Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis.
Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility
Informal caregivers of clients with neurological conditions: profiles, patterns and risk factors for distress from a home care prevalence study
Oxide Heterostructures from a Realistic Many-Body Perspective
Oxide heterostructures are a new class of materials by design, that open the
possibility for engineering challenging electronic properties, in particular
correlation effects beyond an effective single-particle description. This short
review tries to highlight some of the demanding aspects and questions,
motivated by the goal to describe the encountered physics from first
principles. The state-of-the-art methodology to approach realistic many-body
effects in strongly correlated oxides, the combination of density functional
theory with dynamical mean-field theory, will be briefly introduced. Discussed
examples deal with prominent Mott-band- and band-band-insulating type of oxide
heterostructures, where different electronic characteristics may be stabilized
within a single architectured oxide material.Comment: 19 pages, 9 figure
Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity
MDM2–MDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2–MDMX–E2(UbcH5B)–ubiquitin complex, we designed MDM2 mutants that prevent E2–ubiquitin binding without altering the RING-domain structure. These mutants lack MDM2's E3 activity but retain the ability to limit p53′s transcriptional activity and allow cell proliferation. Cells expressing these mutants respond more quickly to cellular stress than cells expressing wild-type MDM2, but basal p53 control is maintained. Targeting the MDM2 E3-ligase activity could therefore widen the therapeutic window of p53 activation in tumors
Evolutionary connectionism: algorithmic principles underlying the evolution of biological organisation in evo-devo, evo-eco and evolutionary transitions
The mechanisms of variation, selection and inheritance, on which evolution by natural selection depends, are not fixed over evolutionary time. Current evolutionary biology is increasingly focussed on understanding how the evolution of developmental organisations modifies the distribution of phenotypic variation, the evolution of ecological relationships modifies the selective environment, and the evolution of reproductive relationships modifies the heritability of the evolutionary unit. The major transitions in evolution, in particular, involve radical changes in developmental, ecological and reproductive organisations that instantiate variation, selection and inheritance at a higher level of biological organisation. However, current evolutionary theory is poorly equipped to describe how these organisations change over evolutionary time and especially how that results in adaptive complexes at successive scales of organisation (the key problem is that evolution is self-referential, i.e. the products of evolution change the parameters of the evolutionary process). Here we first reinterpret the central open questions in these domains from a perspective that emphasises the common underlying themes. We then synthesise the findings from a developing body of work that is building a new theoretical approach to these questions by converting well-understood theory and results from models of cognitive learning. Specifically, connectionist models of memory and learning demonstrate how simple incremental mechanisms, adjusting the relationships between individually-simple components, can produce organisations that exhibit complex system-level behaviours and improve the adaptive capabilities of the system. We use the term “evolutionary connectionism” to recognise that, by functionally equivalent processes, natural selection acting on the relationships within and between evolutionary entities can result in organisations that produce complex system-level behaviours in evolutionary systems and modify the adaptive capabilities of natural selection over time. We review the evidence supporting the functional equivalences between the domains of learning and of evolution, and discuss the potential for this to resolve conceptual problems in our understanding of the evolution of developmental, ecological and reproductive organisations and, in particular, the major evolutionary transitions
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