Anthrax Toxin Receptor 2 Determinants that Dictate the pH Threshold of Toxin Pore Formation

The anthrax toxin receptors, ANTXR1 and ANTXR2, act as molecular clamps to prevent the protective antigen (PA) toxin subunit from forming pores until exposure to low pH. PA forms pores at pH ∼6.0 or below when it is bound to ANTXR1, but only at pH ∼5.0 or below when it is bound to ANTXR2. Here, structure-based mutagenesis was used to identify non-conserved ANTXR2 residues responsible for this striking 1.0 pH unit difference in pH threshold. Residues conserved between ANTXR2 and ANTXR1 that influence the ANTXR2-associated pH threshold of pore formation were also identified. All of these residues contact either PA domain 2 or the neighboring edge of PA domain 4. These results provide genetic evidence for receptor release of these regions of PA as being necessary for the protein rearrangements that accompany anthrax toxin pore formation

Correction of anaemia through the use of darbepoetin alfa improves chemotherapeutic outcome in a murine model of Lewis lung carcinoma

Darbepoetin alfa (Aranesp®, Amgen) is a novel erythropoiesis-stimulating protein with a serum half-life longer than recombinant human erythropoietin (Epo), used in the treatment of cancer-associated anaemia. Anaemia is known to adversely affect prognosis and response to treatment in cancer patients. Solid tumours contain regions of hypoxia due to poor vascular supply and cellular compaction. Although hypoxic stress usually results in cell death, hypoxia-resistant tumour cells are genetically unstable and often acquire a drug-resistant phenotype. Increasing tumour oxygenation and perfusion during treatment could have the doubly beneficial outcome of reducing the fraction of treatment-resistant cells, while increasing drug delivery to previously hypoxic tissue. In this study, we examined the effect of darbepoetin alfa on chemotherapy sensitivity and delivery in an in vivo model of Lewis lung carcinoma, shown here to express the Epo receptor (EpoR). We identified that weekly darbepoetin alfa treatment, commencing 10 days before chemotherapy, resulted in a significant reduction in tumour volume compared to chemotherapy alone. This was mediated by the prevention of anaemia, a reduction in tumour hypoxia and a concomitant increase in drug delivery. Darbepoetin alfa treatment alone did not modulate the growth of the EpoR-expressing tumour cells. This study identifies an important role for darbepoetin alfa in increasing the therapeutic index of chemotherapy

On the interpretation of removable interactions: A survey of the field 33 years after Loftus

In a classic 1978 Memory &Cognition article, Geoff Loftus explained why noncrossover interactions are removable. These removable interactions are tied to the scale of measurement for the dependent variable and therefore do not allow unambiguous conclusions about latent psychological processes. In the present article, we present concrete examples of how this insight helps prevent experimental psychologists from drawing incorrect conclusions about the effects of forgetting and aging. In addition, we extend the Loftus classification scheme for interactions to include those on the cusp between removable and nonremovable. Finally, we use various methods (i.e., a study of citation histories, a questionnaire for psychology students and faculty members, an analysis of statistical textbooks, and a review of articles published in the 2008 issue of Psychology andAging) to show that experimental psychologists have remained generally unaware of the concept of removable interactions. We conclude that there is more to interactions in a 2 × 2 design than meets the eye

Serum screening with Down's syndrome markers to predict pre-eclampsia and small for gestational age: Systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Reliable antenatal identification of pre-eclampsia and small for gestational age is crucial to judicious allocation of monitoring resources and use of preventative treatment with the prospect of improving maternal/perinatal outcome. The purpose of this systematic review was to determine the accuracy of five serum analytes used in Down's serum screening for prediction of pre-eclampsia and/or small for gestational age.</p> <p>Methods</p> <p>The data sources included Medline, Embase, Cochrane library, Medion (inception to February 2007), hand searching of relevant journals, reference list checking of included articles, contact with experts. Two reviewers independently selected the articles in which the accuracy of an analyte used in Downs's serum screening before the 25^thgestational week was associated with the occurrence of pre-eclampsia and/or small for gestational age without language restrictions. Two authors independently extracted data on study characteristics, quality and results.</p> <p>Results</p> <p>Five serum screening markers were evaluated. 44 studies, testing 169,637 pregnant women (4376 pre-eclampsia cases) and 86 studies, testing 382,005 women (20,339 fetal growth restriction cases) met the selection criteria. The results showed low predictive accuracy overall. For pre-eclampsia the best predictor was inhibin A>2.79MoM positive likelihood ratio 19.52 (8.33,45.79) and negative likelihood ratio 0.30 (0.13,0.68) (single study). For small for gestational age it was AFP>2.0MoM to predict birth weight < 10^thcentile with birth < 37 weeks positive likelihood ratio 27.96 (8.02,97.48) and negative likelihood ratio 0.78 (0.55,1.11) (single study). A potential clinical application using aspirin as a treatment is given as an example.</p> <p>There were methodological and reporting limitations in the included studies thus studies were heterogeneous giving pooled results with wide confidence intervals.</p> <p>Conclusion</p> <p>Down's serum screening analytes have low predictive accuracy for pre-eclampsia and small for gestational age. They may be a useful means of risk assessment or of use in prediction when combined with other tests.</p

Evidence-based Kernels: Fundamental Units of Behavioral Influence

This paper describes evidence-based kernels, fundamental units of behavioral influence that appear to underlie effective prevention and treatment for children, adults, and families. A kernel is a behavior–influence procedure shown through experimental analysis to affect a specific behavior and that is indivisible in the sense that removing any of its components would render it inert. Existing evidence shows that a variety of kernels can influence behavior in context, and some evidence suggests that frequent use or sufficient use of some kernels may produce longer lasting behavioral shifts. The analysis of kernels could contribute to an empirically based theory of behavioral influence, augment existing prevention or treatment efforts, facilitate the dissemination of effective prevention and treatment practices, clarify the active ingredients in existing interventions, and contribute to efficiently developing interventions that are more effective. Kernels involve one or more of the following mechanisms of behavior influence: reinforcement, altering antecedents, changing verbal relational responding, or changing physiological states directly. The paper describes 52 of these kernels, and details practical, theoretical, and research implications, including calling for a national database of kernels that influence human behavior