Comparison of the Spatial Organization in Colorectal Tumors using Second-Order Statistics and Functional ANOVA

International audienceWe propose an automatic method to quantitatively describe the spatial organization governing populations of biological objects, such as cells, which exist in stationary histology images. This quantification is of prime importance when striving to compare different tumoral models in order to evaluate potential therapies. We compare two animal models of colorectal cancer. Our approach is based on the topographic map to automatically extract the location of the relevant biological objects. We describe their spatial organization along a continuous range of scales using second-order statistics. Using a functional analysis of variance test, we show that there are significant differences in these statistics depending on cancer model, and on the day after tumor implant

Wac: a new Augmin subunit required for chromosome alignment but not for acentrosomal microtubule assembly in female meiosis

The bipolar spindle forms without centrosomes naturally in female meiosis and by experimental manipulation in mitosis. Augmin is a recently discovered protein complex required for centrosome-independent microtubule generation within the spindle in Drosophila melanogaster cultured cells. Five subunits of Augmin have been identified so far, but neither their organization within the complex nor their role in developing organisms is known. In this study, we report a new Augmin subunit, wee Augmin component (Wac). Wac directly interacts with another Augmin subunit, Dgt2, via its coiled-coil domain. Wac depletion in cultured cells, especially without functional centrosomes, causes severe defects in spindle assembly. We found that a wac deletion mutant is viable but female sterile and shows only a mild impact on somatic mitosis. Unexpectedly, mutant female meiosis showed robust microtubule assembly of the acentrosomal spindle but frequent chromosome misalignment. For the first time, this study establishes the role of an Augmin subunit in developing organisms and provides an insight into the architecture of the complex

Acoustic scale from the angular power spectra of SDSS-III DR8 photometric luminous galaxies

We measure the acoustic scale from the angular power spectra of the Sloan Digital Sky Survey III (SDSS-III) Data Release 8 imaging catalog that includes 872,921 galaxies over ~ 10,000 deg^2 between 0.45<z<0.65. The extensive spectroscopic training set of the Baryon Oscillation Spectroscopic Survey (BOSS) luminous galaxies allows precise estimates of the true redshift distributions of galaxies in our imaging catalog. Utilizing the redshift distribution information, we build templates and fit to the power spectra of the data, which are measured in our companion paper, Ho et al. 2011, to derive the location of Baryon acoustic oscillations (BAO) while marginalizing over many free parameters to exclude nearly all of the non-BAO signal. We derive the ratio of the angular diameter distance to the sound horizon scale D_A/r_s= 9.212 + 0.416 -0.404 at z=0.54, and therefore, D_A= 1411+- 65 Mpc at z=0.54; the result is fairly independent of assumptions on the underlying cosmology. Our measurement of angular diameter distance D_A is 1.4 \sigma higher than what is expected for the concordance LCDM (Komatsu et al. 2011), in accordance to the trend of other spectroscopic BAO measurements for z >~ 0.35. We report constraints on cosmological parameters from our measurement in combination with the WMAP7 data and the previous spectroscopic BAO measurements of SDSS (Percival et al. 2010) and WiggleZ (Blake et al. 2011). We refer to our companion papers (Ho et al. 2011; de Putter et al. 2011) for investigations on information of the full power spectrum.Comment: 16 pages, 14 figures, 3 tables, submitted to Ap

Apology after medical errors: a qualitative vignette study:Medical errors: impact of apology and admission on the resolution and compensation of claims

Studies investigating the impact of apologies and admission of responsibility for medical errors have been primarily observational, making it hard to attach a causal effect to the admission of responsibility and apologies. Second, most research on the settlement of medical malpractice cases were conducted in the US, with its particular litigation laws and culture. In this multi-jurisdictional study, we investigate the impact of apology and admission of responsibility on preferred resolution and compensation of claims. Employing a vignette design, we examine, among a sample of 327 respondents from 10 different countries, whether admission and apology by the doctor impact respondents' preference for resolution through a civil court case, mediation or a disciplinary board, as well as preferred damages for pain and suffering. Admission and apology by the physician in the vignette did not impact respondents' preference for settlement through a civil court case or mediation, nor did it affect the amount respondents found suitable compensation for pains and damages. We perceived the absence of an apology as particularly aggravating. Thematic analysis of open answers reveals that the impact of admission and apology differs for the three resolution modes and is often contextual and conditional. Future (vignette) studies should investigate whether different cases of medical errors yield similar results and whether more knowledgeable or experienced respondents (such as lawyers) would have other preferences and arguments. <br/

Hierarchical information clustering by means of topologically embedded graphs

We introduce a graph-theoretic approach to extract clusters and hierarchies in complex data-sets in an unsupervised and deterministic manner, without the use of any prior information. This is achieved by building topologically embedded networks containing the subset of most significant links and analyzing the network structure. For a planar embedding, this method provides both the intra-cluster hierarchy, which describes the way clusters are composed, and the inter-cluster hierarchy which describes how clusters gather together. We discuss performance, robustness and reliability of this method by first investigating several artificial data-sets, finding that it can outperform significantly other established approaches. Then we show that our method can successfully differentiate meaningful clusters and hierarchies in a variety of real data-sets. In particular, we find that the application to gene expression patterns of lymphoma samples uncovers biologically significant groups of genes which play key-roles in diagnosis, prognosis and treatment of some of the most relevant human lymphoid malignancies.Comment: 33 Pages, 18 Figures, 5 Table

Childhood bullying victimization, self-labelling and help-seeking for mental health problems

Purpose: Previous research found sustained high levels of mental health service use among adults who experienced bullying victimization during childhood. This could be due to increased psychopathology among this group, but other factors, such as self-perception as having a mental health problem, might contribute to increased service use. Additionally, the relationship between informal help-seeking for mental health problems and bullying victimization is incompletely understood. Methods: The present study examined associations between the frequency of bullying victimization and both formal service use and informal help-seeking for mental health problems independent from psychopathology. Data on bullying victimization, service use, informal help-seeking for mental health problems, psychopathology, and self-labelling as a person with mental illness were collected among 422 young people aged 13-22 years. Results: In logistic regression models, controlling for past and current psychopathology and using no bullying victimization as the reference category, we identified a greater likelihood of mental health service use among persons who experienced frequent bullying victimization, as well as a greater likelihood of seeking informal help among persons who experienced occasional victimization. Increased self-identification as a person with mental illness completely mediated the positive association between frequent bullying victimization and mental health service use. Conclusions: Our findings suggest that services to support persons who experienced frequent bullying victimization should focus on improving empowerment and self-perception. Additionally, there might be unserved need for formal support among those who experienced occasional bullying victimization

CD95-mediated calcium signaling promotes T helper 17 trafficking to inflamed organs in lupus-prone mice

CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase Cγ1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment

Molecular and Structural Discrimination of Proline Racemase and Hydroxyproline-2-Epimerase from Nosocomial and Bacterial Pathogens

The first eukaryotic proline racemase (PRAC), isolated from the human Trypanosoma cruzi pathogen, is a validated therapeutic target against Chagas' disease. This essential enzyme is implicated in parasite life cycle and infectivity and its ability to trigger host B-cell nonspecific hypergammaglobulinemia contributes to parasite evasion and persistence. Using previously identified PRAC signatures and data mining we present the identification and characterization of a novel PRAC and five hydroxyproline epimerases (HyPRE) from pathogenic bacteria. Single-mutation of key HyPRE catalytic cysteine abrogates enzymatic activity supporting the presence of two reaction centers per homodimer. Furthermore, evidences are provided that Brucella abortus PrpA [for ‘proline racemase’ virulence factor A] and homologous proteins from two Brucella spp are bona fide HyPREs and not ‘one way’ directional PRACs as described elsewhere. Although the mechanisms of aminoacid racemization and epimerization are conserved between PRAC and HyPRE, our studies demonstrate that substrate accessibility and specificity partly rely on contraints imposed by aromatic or aliphatic residues distinctively belonging to the catalytic pockets. Analysis of PRAC and HyPRE sequences along with reaction center structural data disclose additional valuable elements for in silico discrimination of the enzymes. Furthermore, similarly to PRAC, the lymphocyte mitogenicity displayed by HyPREs is discussed in the context of bacterial metabolism and pathogenesis. Considering tissue specificity and tropism of infectious pathogens, it would not be surprising if upon infection PRAC and HyPRE play important roles in the regulation of the intracellular and extracellular amino acid pool profiting the microrganism with precursors and enzymatic pathways of the host

Clonality and α-a Recombination in the Australian Cryptococcus gattii VGII Population - An Emerging Outbreak in Australia

BACKGROUND: Cryptococcus gattii is a basidiomycetous yeast that causes life-threatening disease in humans and animals. Within C. gattii, four molecular types are recognized (VGI to VGIV). The Australian VGII population has been in the spotlight since 2005, when it was suggested as the possible origin for the ongoing outbreak at Vancouver Island (British Columbia, Canada), with same-sex mating being suggested as the driving force behind the emergence of this outbreak, and is nowadays hypothesized as a widespread phenomenon in C. gattii. However, an in-depth characterization of the Australian VGII population is still lacking. The present work aimed to define the genetic variability within the Australian VGII population and determine processes shaping its population structure. METHODOLOGY/PRINCIPAL FINDINGS: A total of 54 clinical, veterinary and environmental VGII isolates from different parts of the Australian continent were studied. To place the Australian population in a global context, 17 isolates from North America, Europe, Asia and South America were included. Genetic variability was assessed using the newly adopted international consensus multi-locus sequence typing (MLST) scheme, including seven genetic loci: CAP59, GPD1, LAC1, PLB1, SOD1, URA5 and IGS1. Despite the overall clonality observed, the presence of MATa VGII isolates in Australia was demonstrated for the first time in association with recombination in MATα-MATa populations. Our results also support the hypothesis of a "smouldering" outbreak throughout the Australian continent, involving a limited number of VGII genotypes, which is possibly caused by a founder effect followed by a clonal expansion. CONCLUSIONS/SIGNIFICANCE: The detection of sexual recombination in MATα-MATa population in Australia is in accordance with the natural life cycle of C. gattii involving opposite mating types and presents an alternative to the same-sex mating strategy suggested elsewhere. The potential for an Australian wide outbreak highlights the crucial issue to develop active surveillance procedures.Fabian Carriconde, Félix Gilgado, Ian Arthur, David Ellis, Richard Malik, Nathalie van de Wiele, Vincent Robert, Bart J. Currie, Wieland Meye

Hydrothermal origin of halogens at Home Plate, Gusev Crater

In the Inner Basin of the Columbia Hills, Gusev Crater is Home Plate, an 80 m platform of layered clastic rocks of the Barnhill class with microscopic and macroscopic textures, including a bomb sag, suggestive of a phreatomagmatic origin. We present data acquired by the Spirit Mars Exploration Rover by Alpha Particle X-Ray Spectrometer (APXS), M&ouml;ssbauer Spectrometer, Miniature Thermal Emission Spectrometer (Mini- TES), and Panoramic Camera (Pancam) for the Barnhill class rocks and nearby vesicular Irvine class basalts. In major element concentrations (e.g., SiO2, Al2O3, MgO, and FeO*), the two rock classes are similar, suggesting that they are derived from a similar magmatic source. The Barnhill class, however, has higher abundances of Cl, Br, Zn, and Ge with comparable SO3 to the Irvine basalts. Nanophase ferric oxide (np ox) and volcanic glass were detected in the Barnhill class rocks by M&ouml;ssbauer and Mini-TES, respectively, and imply greater alteration and cooling rates in the Barnhill than in the Irvine class rocks. The high volatile elements in the Barnhill class agree with volcanic textures that imply interaction with a briny groundwater during eruption and (or) by later alteration. Differences in composition between the Barnhill and Irvine classes allow the fingerprinting of a Na-Mg-Zn-Ge-Cl-Br (&plusmn;Fe &plusmn; Ca &plusmn; CO2) brine with low S. Nearby sulfate salt soils of fumarolic origin may reflect fractionation of an acidic S-rich vapor during boiling of a hydrothermal brine at depth. Persistent groundwater was likely present during and after the formation of Home Plate