P53 and Beta-Catenin Activity during Estrogen treatment of Osteoblasts

BACKGROUND: This study was undertaken to examine the relationship between the tumor suppressor gene p53 and the nuclear signaling protein beta-catenin during bone differentiation. Cross talk between p53 and beta-catenin pathways has been demonstrated and is important during tumorigenesis and DNA damage, where deregulation of beta catenin activates p53. In this study, we used estrogen treatment of osteoblasts as a paradigm to study the relationship between the two proteins during osteoblast differentiation. RESULTS: We exposed osteoblast-like ROS17/2.8 cells to 17-beta estradiol (E2), in a short term assay, and studied the cellular distribution and expression of beta-catenin. We found beta-catenin to be up regulated several fold following E2 treatment. Levels of p53 and its functional activity mirrored the quantitative changes seen in beta-catenin. Alkaline phosphatase, an early marker of osteoblast differentiation, was increased in a manner similar to beta-catenin and p53. In order to determine if there was a direct relationship between alkaline phosphatase expression and beta-catenin, we used two different approaches. In the first approach, treatment with LiCl, which is known to activate beta-catenin, caused a several fold increase in alkaline phosphatase activity. In the second approach, transient transfection of wild type beta-catenin into osteoblasts increased alkaline phosphatase activity two fold over basal levels, showing that beta catenin expression can directly affect alkaline phosphatase expression. However increase in beta catenin activity was not associated with an increase in its signaling activity through TCF/LEF mediated transcription. Immunofluorescence analyses of p53 and beta-catenin localization showed that E2 first caused an increase in cytosolic beta-catenin followed by the accumulation of beta-catenin in the nucleus. Nuclear p53 localization was detected in several cells. Expression of p53 was accompanied by distribution of beta-catenin to the cytoplasm and cell borders. A sub population of cells staining strongly for both proteins appeared to be apoptotic. CONCLUSION: These results suggest that interactions between p53 and beta-catenin signaling pathways may play a key role in osteoblast differentiation and maintenance of tissue homeostasis

Simultaneous Border-Collision and Period-Doubling Bifurcations

We unfold the codimension-two simultaneous occurrence of a border-collision bifurcation and a period-doubling bifurcation for a general piecewise-smooth, continuous map. We find that, with sufficient non-degeneracy conditions, a locus of period-doubling bifurcations emanates non-tangentially from a locus of border-collision bifurcations. The corresponding period-doubled solution undergoes a border-collision bifurcation along a curve emanating from the codimension-two point and tangent to the period-doubling locus here. In the case that the map is one-dimensional local dynamics are completely classified; in particular, we give conditions that ensure chaos.Comment: 22 pages; 5 figure

The value of technical characteristics for future performance in youth tennis players:A prospective study

The aim of this study is to examine whether technical characteristics predict current and future tennis performance of youth tennis players. Twenty-nine male youth tennis players (age 13.40 ± .51) were assessed on anthropometrical characteristics (height, weight, maturity status) and technical characteristics (ball speed, accuracy and percentage errors) using an on-court tennis test when they were under-14 (U14). Game situations were simulated, which were either fixed or variable. The variable game situations required players to consider the direction of the ball, as opposed to the fixed game situations where players needed to play every ball to the same side. Players' tennis ratings were obtained U14 ('current performance') and under-18 (U18) ('future performance'). According to their rating U18 players were classified as future elite (n = 9) or future competitive (n = 20). A multiple linear regression analysis showed that ball speed and accuracy were significant predictors of current and future performance (p < .001), with R2 of .595 and .463, respectively. When controlling for age, a one-way MANCOVA revealed that future elite players were more accurate than future competitive players (p = .048, 95% CI [.000 to .489]), especially in variable compared to fixed game situations (p < .05). In conclusion, the current study is the first to show that technical characteristics are crucial for current as well as future performance in youth male tennis players. Findings of this prospective study provide essential information to coaches about characteristics that require most attention in performance development in youth players

Computation of Invariants of Lie Algebras by Means of Moving Frames

A new purely algebraic algorithm is presented for computation of invariants (generalized Casimir operators) of Lie algebras. It uses the Cartan's method of moving frames and the knowledge of the group of inner automorphisms of each Lie algebra. The algorithm is applied, in particular, to computation of invariants of real low-dimensional Lie algebras. A number of examples are calculated to illustrate its effectiveness and to make a comparison with the same cases in the literature. Bases of invariants of the real solvable Lie algebras up to dimension five, the real six-dimensional nilpotent Lie algebras and the real six-dimensional solvable Lie algebras with four-dimensional nilradicals are newly calculated and listed in tables.Comment: 17 pages, extended versio

Mitochondrial echoes of first settlement and genetic continuity in El Salvador

Background: From Paleo-Indian times to recent historical episodes, the Mesoamerican isthmus played an important role in the distribution and patterns of variability all around the double American continent. However, the amount of genetic information currently available on Central American continental populations is very scarce. In order to shed light on the role of Mesoamerica in the peopling of the New World, the present study focuses on the analysis of the mtDNA variation in a population sample from El Salvador. Methodology/Principal Findings: We have carried out DNA sequencing of the entire control region of the mitochondrial DNA (mtDNA) genome in 90 individuals from El Salvador. We have also compiled more than 3,985 control region profiles from the public domain and the literature in order to carry out inter-population comparisons. The results reveal a predominant Native American component in this region: by far, the most prevalent mtDNA haplogroup in this country (at ~90%) is A2, in contrast with other North, Meso- and South American populations. Haplogroup A2 shows a star-like phylogeny and is very diverse with a substantial proportion of mtDNAs (45%; sequence range 16090–16365) still unobserved in other American populations. Two different Bayesian approaches used to estimate admixture proportions in El Salvador shows that the majority of the mtDNAs observed come from North America. A preliminary founder analysis indicates that the settlement of El Salvador occurred about 13,400±5,200 Y.B.P.. The founder age of A2 in El Salvador is close to the overall age of A2 in America, which suggests that the colonization of this region occurred within a few thousand years of the initial expansion into the Americas. Conclusions/Significance: As a whole, the results are compatible with the hypothesis that today's A2 variability in El Salvador represents to a large extent the indigenous component of the region. Concordant with this hypothesis is also the observation of a very limited contribution from European and African women (~5%). This implies that the Atlantic slave trade had a very small demographic impact in El Salvador in contrast to its transformation of the gene pool in neighbouring populations from the Caribbean facade

Evaluation of single and double-locus real-time PCR assays for methicillin-resistant Staphylococcus aureus (MRSA) surveillance

<p>Abstract</p> <p>Background</p> <p>Methicillin-resistant <it>Staphylococcus aureus </it>(MRSA) is a human pathogen, representing an infection control challenge. Conventional MRSA screening takes up to three days, therefore development of rapid detection is essential. Real time-PCR (rt-PCR) is the fastest method fulfilling this task. All currently published or commercially available rt-PCR MRSA assays relay on single or double-locus detection. Double-locus assays are based on simultaneous detection of <it>mecA </it>gene and a <it>S. aureus</it>-specific gene. Such assays cannot be applied on clinical samples, which often contain both coagulase-negative staphylococci (CoNS) and <it>S. aureus</it>, either of which can carry <it>mecA</it>. Single-locus assays are based on detection of the staphylococcal cassette chromosome <it>mec </it>(SCC<it>mec</it>) element and the <it>S. aureus</it>-specific <it>orfX </it>gene, assuming that it is equivalent to <it>mecA </it>detection.</p> <p>Findings</p> <p>Parallel evaluation of several published single and double-locus rt-PCR MRSA assays of 150 pure culture strains, followed by analysis of 460 swab-derived clinical samples which included standard identification, susceptibility testing, followed by PCR detection of staphylococcal suspected isolates and in-PCR mixed bacterial populations analysis indicated the following findings.</p> <p>Pure cultures analysis indicated that one of the single-locus assay had very high prevalence of false positives (Positive predictive value = 77.8%) and was excluded from further analysis. Analysis of 460 swab-derived samples indicated that the second single-locus assay misidentified 16 out of 219 MRSA's and 13 out of 90 methicillin-sensitive <it>S</it>. <it>aureus</it>'s (MSSA) were misidentified as MRSA's. The double-locus detection assay misidentified 55 out of 90 MSSA's. 46 MSSA containing samples were misidentified as MRSA and 9 as other than <it>S. aureus </it>ending with low positive predicted value (<85%) and very low specificity (<62%).</p> <p>Conclusion</p> <p>The results indicate that high prevalence of false-positive and false-negative reactions occurs in such assays.</p

A taxonomy of multinational ethical and methodological standards for clinical trials of therapeutic interventions

BACKGROUND: If trials of therapeutic interventions are to serve society’s interests, they must be of high methodological quality and must satisfy moral commitments to human subjects. The authors set out to develop a clinical-trials compendium in which standards for the ethical treatment of human subjects are integrated with standards for research methods. METHODS: The authors rank-ordered the world’s nations and chose the 31 with >700 active trials as of 24 July 2008. Governmental and other authoritative entities of the 31 countries were searched, and 1004 English-language documents containing ethical and/or methodological standards for clinical trials were identified. The authors extracted standards from 144 of those: 50 designated as ‘core’, 39 addressing trials of invasive procedures and a 5% sample (N=55) of the remainder. As the integrating framework for the standards we developed a coherent taxonomy encompassing all elements of a trial’s stages. FINDINGS: Review of the 144 documents yielded nearly 15 000 discrete standards. After duplicates were removed, 5903 substantive standards remained, distributed in the taxonomy as follows: initiation, 1401 standards, 8 divisions; design, 1869 standards, 16 divisions; conduct, 1473 standards, 8 divisions; analysing and reporting results, 997 standards, four divisions; and post-trial standards, 168 standards, 5 divisions. CONCLUSIONS: The overwhelming number of source documents and standards uncovered in this study was not anticipated beforehand and confirms the extraordinary complexity of the clinical trials enterprise. This taxonomy of multinational ethical and methodological standards may help trialists and overseers improve the quality of clinical trials, particularly given the globalisation of clinical research

The X-ray luminous cluster underlying the bright radio-quiet quasar H1821+643

We present a Chandra observation of the only low redshift, z=0.299, galaxy cluster to contain a highly luminous radio-quiet quasar, H1821+643. By simulating the quasar PSF, we subtract the quasar contribution from the cluster core and determine the physical properties of the cluster gas down to 3 arcsec (15 kpc) from the point source. The temperature of the cluster gas decreases from 9.0\pm0.5 keV down to 1.3\pm0.2 keV in the centre, with a short central radiative cooling time of 1.0\pm0.1 Gyr, typical of a strong cool-core cluster. The X-ray morphology in the central 100 kpc shows extended spurs of emission from the core, a small radio cavity and a weak shock or cold front forming a semi-circular edge at 15 arcsec radius. The quasar bolometric luminosity was estimated to be 2 x 10^{47} erg per sec, requiring a mass accretion rate of 40 Msolar per yr, which corresponds to half the Eddington accretion rate. We explore possible accretion mechanisms for this object and determine that Bondi accretion, when boosted by Compton cooling of the accretion material, could provide a significant source of the fuel for this outburst. We consider H1821+643 in the context of a unified AGN accretion model and, by comparing H1821+643 with a sample of galaxy clusters, we show that the quasar has not significantly affected the large-scale cluster gas properties.Comment: 20 pages, 19 figures, accepted by MNRA

Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis

Background: Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). Methods: We estimated the incidence of infections with 16 antibiotic resistance–bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011–12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. Findings: From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148–763 966) infections with antibiotic-resistant bacteria, of which 63·5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480–38 430) attributable deaths and 874 541 (768 837–989 068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece. Interpretation: Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases

A.N. Kolmogorov’s defence of Mendelism

In 1939 N.I. Ermolaeva published the results of an experiment which repeated parts of Mendel’s classical experiments. On the basis of her experiment she concluded that Mendel’s principle that self-pollination of hybrid plants gave rise to segregation proportions 3:1 was false. The great probability theorist A.N. Kolmogorov reviewed Ermolaeva’s data using a test, now referred to as Kolmogorov’s, or Kolmogorov-Smirnov, test, which he had proposed in 1933. He found, contrary to Ermolaeva, that her results clearly confirmed Mendel’s principle. This paper shows that there were methodological flaws in Kolmogorov’s statistical analysis and presents a substantially adjusted approach, which confirms his conclusions. Some historical commentary on the Lysenko-era background is given, to illuminate the relationship of the disciplines of genetics and statistics in the struggle against the prevailing politically-correct pseudoscience in the Soviet Union. There is a Brazilian connection through the person of Th. Dobzhansky