BMP action in skeletogenesis involves attenuation of retinoid signaling

The bone morphogenetic protein (BMP) and growth and differentiation factor (GDF) signaling pathways have well-established and essential roles within the developing skeleton in coordinating the formation of cartilaginous anlagen. However, the identification of bona fide targets that underlie the action of these signaling molecules in chondrogenesis has remained elusive. We have identified the gene for the retinoic acid (RA) synthesis enzyme Aldh1a2 as a principal target of BMP signaling; prochondrogenic BMPs or GDFs lead to attenuation of Aldh1a2 expression and, consequently, to reduced activation of the retinoid signaling pathway. Consistent with this, antagonism of retinoid signaling phenocopies BMP4 action, whereas RA inhibits the chondrogenic stimulatory activity of BMP4. BMP4 also down-regulates Aldh1a2 expression in organ culture and, consistent with this, Aldh1a2 is actively excluded from the developing cartilage anlagens. Collectively, these findings provide novel insights into BMP action and demonstrate that BMP signaling governs the fate of prechondrogenic mesenchyme, at least in part, through regulation of retinoid signaling

Hyperactivity and attention deficits in mice with decreased levels of stress-inducible phosphoprotein 1 (STIP1)

Stress-inducible phosphoprotein I (STIP1, STI1 or HOP) is a cochaperone intermediating Hsp70/Hsp90 exchange of client proteins, but it can also be secreted to trigger prion protein-mediated neuronal signaling. Some mothers of children with autism spectrum disorders (ASD) present antibodies against certain brain proteins, including antibodies against STIP1. Maternal antibodies can cross the fetus blood-brain barrier during pregnancy, suggesting the possibility that they can interfere with STIP1 levels and, presumably, functions. However, it is currently unknown whether abnormal levels of STIP1 have any impact in ASD-related behavior. Here, we used mice with reduced (50%) or increased STIP1 levels (fivefold) to test for potential ASD-like phenotypes. We found that increased STIP1 regulates the abundance of Hsp70 and Hsp90, whereas reduced STIP1 does not affect Hsp70, Hsp90 or the prion protein. Interestingly, BAC transgenic mice presenting fivefold more STIP1 show no major phenotype when examined in a series of behavioral tasks, including locomotor activity, elevated plus maze, Morris water maze and five-choice serial reaction time task (5-CSRTT). In contrast, mice with reduced STIP1 levels are hyperactive and have attentional deficits on the 5-CSRTT, but exhibit normal performance for the other tasks. We conclude that reduced STIP1 levels can contribute to phenotypes related to ASD. However, future experiments are needed to define whether it is decreased chaperone capacity or impaired prion protein signaling that contributes to these phenotypes

Assessing the bias of molybdenum catalytic conversion in the measurement of NO2 in rural air quality networks

The measurement method of NO2 with continuous analysers is specified for EU Ambient Air Quality Directive compliance reporting, which provides a consistent methodology and concurrent NO measurements (85/203/EEC-NO2). While the established method of measurement of NO2, following conversion of NO2 to NO using a molybdenum-conversion process, has known interference uncertainties (due to conversion of other oxidised nitrogen (NOy) chemicals, the consistency and traceability of compliance measurement is important. This study compared three continuous NO2 analyser instruments: a Thermo-NOx molybdenum convertor chemiluminescence analyser (Model 42C, ThermoFisher Scientific Inc., MA, USA), a photolytic chemiluminescence analyser (T200UP, Teledyne Technologies Inc., San Diego, USA) and a Cavity Attenuated Phase Shift (CAPS) analyser (T500U, Teledyne Technologies Inc., CA, USA). The instruments were run for over a year at the Auchencorth Moss long-term peatland monitoring site (Southeast Scotland) which is a low NOx atmosphere away from sources. NOy and NHx chemicals were also measured concurrently. This study concludes that there is a strong artefact in molybdenum catalyst chemiluminescent instruments as a result of unselective catalysis of airborne NOy compounds that causes an overestimate of NO2 measured in the atmosphere. The observed artefact in concentration measurements is likely to be observed at the entire UK scale as almost the entirety of the rural air network relies on molybdenum catalyst instruments. We therefore recommend that molybdenum catalyst instruments should be phased out and replaced in air quality monitoring networks with molecule specific (spectroscopy) instrumentation (equivalent in cost, such as those described in this study) that do not suffer from the same measurement artefacts

Present and Future CP Measurements

We review theoretical and experimental results on CP violation summarizing the discussions in the working group on CP violation at the UK phenomenology workshop 2000 in Durham.Comment: 104 pages, Latex, to appear in Journal of Physics

Modeling and Inferring Cleavage Patterns in Proliferating Epithelia

The regulation of cleavage plane orientation is one of the key mechanisms driving epithelial morphogenesis. Still, many aspects of the relationship between local cleavage patterns and tissue-level properties remain poorly understood. Here we develop a topological model that simulates the dynamics of a 2D proliferating epithelium from generation to generation, enabling the exploration of a wide variety of biologically plausible cleavage patterns. We investigate a spectrum of models that incorporate the spatial impact of neighboring cells and the temporal influence of parent cells on the choice of cleavage plane. Our findings show that cleavage patterns generate “signature” equilibrium distributions of polygonal cell shapes. These signatures enable the inference of local cleavage parameters such as neighbor impact, maternal influence, and division symmetry from global observations of the distribution of cell shape. Applying these insights to the proliferating epithelia of five diverse organisms, we find that strong division symmetry and moderate neighbor/maternal influence are required to reproduce the predominance of hexagonal cells and low variability in cell shape seen empirically. Furthermore, we present two distinct cleavage pattern models, one stochastic and one deterministic, that can reproduce the empirical distribution of cell shapes. Although the proliferating epithelia of the five diverse organisms show a highly conserved cell shape distribution, there are multiple plausible cleavage patterns that can generate this distribution, and experimental evidence suggests that indeed plants and fruitflies use distinct division mechanisms

Inferring stabilizing mutations from protein phylogenies : application to influenza hemagglutinin

One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution

Assessing the Impact of Holocaust Education on Adolescents’ Civic Values: Experimental Evidence from Arkansas

American adults overwhelmingly agree that the Holocaust should be taught in schools, yet few studies investigate the potential benefits of Holocaust education. We evaluate the impact of Holocaust education on several civic outcomes, including “upstander” efficacy (willingness to intervene on behalf of others), likelihood of exercising civil disobedience, empathy for the suffering of others, and tolerance of others with different values and lifestyles. We recruit students from two local high schools and randomize access to the Arkansas Holocaust Education Conference, where students have the chance to hear from a Holocaust survivor and to participate in breakout sessions with leading Holocaust experts. We find that students randomly assigned to attend the conference become more knowledgeable about the Holocaust and are more willing to act as an upstander on behalf of others. In our subgroup analysis, we find that minority students are significantly more willing to act as an upstander relative to their white peers

4th Biennial Employment Law Institute

Materials from the 4th Biennial Employment Law Institute held by UK/CLE in June 1994

The Science of Sungrazers, Sunskirters, and Other Near-Sun Comets

This review addresses our current understanding of comets that venture close to the Sun, and are hence exposed to much more extreme conditions than comets that are typically studied from Earth. The extreme solar heating and plasma environments that these objects encounter change many aspects of their behaviour, thus yielding valuable information on both the comets themselves that complements other data we have on primitive solar system bodies, as well as on the near-solar environment which they traverse. We propose clear definitions for these comets: We use the term near-Sun comets to encompass all objects that pass sunward of the perihelion distance of planet Mercury (0.307 AU). Sunskirters are defined as objects that pass within 33 solar radii of the Sun’s centre, equal to half of Mercury’s perihelion distance, and the commonly-used phrase sungrazers to be objects that reach perihelion within 3.45 solar radii, i.e. the fluid Roche limit. Finally, comets with orbits that intersect the solar photosphere are termed sundivers. We summarize past studies of these objects, as well as the instruments and facilities used to study them, including space-based platforms that have led to a recent revolution in the quantity and quality of relevant observations. Relevant comet populations are described, including the Kreutz, Marsden, Kracht, and Meyer groups, near-Sun asteroids, and a brief discussion of their origins. The importance of light curves and the clues they provide on cometary composition are emphasized, together with what information has been gleaned about nucleus parameters, including the sizes and masses of objects and their families, and their tensile strengths. The physical processes occurring at these objects are considered in some detail, including the disruption of nuclei, sublimation, and ionisation, and we consider the mass, momentum, and energy loss of comets in the corona and those that venture to lower altitudes. The different components of comae and tails are described, including dust, neutral and ionised gases, their chemical reactions, and their contributions to the near-Sun environment. Comet-solar wind interactions are discussed, including the use of comets as probes of solar wind and coronal conditions in their vicinities. We address the relevance of work on comets near the Sun to similar objects orbiting other stars, and conclude with a discussion of future directions for the field and the planned ground- and space-based facilities that will allow us to address those science topics

p53 Expression in Node-Positive Breast Cancer Patients: Results from the Cancer and Leukemia Group B 9344 Trial (159905)

p53 as a prognostic and predictive factor in early stage breast cancer, has had mixed results. We studied p53 protein expression, by immunohistochemistry, in a randomized clinical trial of stage II patients treated with adjuvant doxorubicin and cyclophosphamide with or without paclitaxel (CALGB 9344, INT0148)