Measurement of cos⁡2β\cos{2\beta} in B0→D(∗)h0B^{0} \to D^{(*)} h^{0} with D→KS0π+π−D \to K_{S}^{0} \pi^{+} \pi^{-} decays by a combined time-dependent Dalitz plot analysis of BaBar and Belle data

We report measurements of $\sin{2\beta}$ and $\cos{2\beta}$ from a time-dependent Dalitz plot analysis of $B^{0} \to D^{(*)} h^{0}$ with $D \to K_{S}^{0} \pi^{+} \pi^{-}$ decays, where the light unflavored and neutral hadron $h^{0}$ is a $\pi^{0}$, $\eta$, or $\omega$ meson. The analysis is performed with a combination of the final data sets of the \babar\ and Belle experiments containing $471 \times 10^{6}$ and $772 \times 10^{6}$ $B\bar{B}$ pairs collected at the $\Upsilon\left(4S\right)$ resonance at the asymmetric-energy B factories PEP-II at SLAC and KEKB at KEK, respectively. We measure $\sin{2\beta} = 0.80 \pm 0.14 \,(\rm{stat.}) \pm 0.06 \,(\rm{syst.}) \pm 0.03 \,(\rm{model})$ and $\cos{2\beta} = 0.91 \pm 0.22 \,(\rm{stat.}) \pm 0.09 \,(\rm{syst.}) \pm 0.07 \,(\rm{model})$. The result for the direct measurement of the angle is $\beta = \left( 22.5 \pm 4.4 \,(\rm{stat.}) \pm 1.2 \,(\rm{syst.}) \pm 0.6 \,(\rm{model}) \right)^{\circ}$. The last quoted uncertainties are due to the composition of the $D^{0} \to K_{S}^{0} \pi^{+} \pi^{-}$ decay amplitude model, which is newly established by a Dalitz plot amplitude analysis of a high-statistics $e^{+}e^{-} \to c\bar{c}$ data sample as part of this analysis. We find the first evidence for $\cos2\beta>0$ at the level of $3.7$ standard deviations. The measurement excludes the trigonometric multifold solution $\pi/2 - \beta = (68.1 \pm 0.7)^{\circ}$ at the level of $7.3$ standard deviations and therefore resolves an ambiguity in the determination of the apex of the CKM Unitarity Triangle. The hypothesis of $\beta = 0^{\circ}$ is ruled out at the level of $5.1$ standard deviations, and thus CP violation is observed in $B^{0} \to D^{(*)} h^{0}$ decays.Comment: To be submitted to Physical Review

Nat Genet

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.Comment in : Genetic differential calculus. [Nat Genet. 2015] Comment in : Scaling up phenotyping studies. [Nat Biotechnol. 2015

Relative contribution of IL-1a, IL-1b and TNF to the host response to Mycobacterium tuberculosis and attenuated M. bovis BCG

TNF and IL-1 are major mediators involved in severe inflammatory diseases against which therapeutic neutralizing antibodies are developed. However, both TNF and IL-1 receptor pathways are essential for the control of Mycobacterium tuberculosis infection, and it is critical to assess the respective role of IL-1α, IL-1β, and TNF. Using gene-targeted mice we show that absence of both IL-1α and IL-1β recapitulates the uncontrolled M. tuberculosis infection with increased bacterial burden, exacerbated lung inflammation, high IFNγ, reduced IL-23 p19 and rapid death seen in IL-1R1-deficient mice. However, presence of either IL-1α or IL-1β in single-deficient mice is sufficient to control acute M. tuberculosis infection, with restrained bacterial burden and lung pathology, in conditions where TNF deficient mice succumbed within 4 weeks with overwhelming infection. Systemic infection by attenuated M. bovis BCG was controlled in the absence of functional IL-1 pathway, but not in the absence of TNF. Therefore, although both IL-1α and IL-1β are required for a full host response to virulent M. tuberculosis, the presence of either IL-1α or IL-1β allows some control of acute M. tuberculosis infection, and IL-1 pathway is dispensable for controlling M. bovis BCG acute infection. This is in sharp contrast with TNF, which is essential for host response to both attenuated and virulent mycobacteria and may have implications for anti-inflammatory therapy with IL-1β neutralizing antibodies

Diagnostic and Prognostic Microbial Biomarkers in Inflammatory Bowel Diseases

The microbiome plays multifaceted roles in the pathogenesis of inflammatory bowel diseases (IBD). Accordingly, the clinical challenge of patient heterogeneity in disease phenotype and response to treatment should in part be addressed by biomarkers that detect the host response to microbiota, and the levels of microbial taxa and products eliciting the host response in susceptible individuals. Molecular analysis has revealed much evidence for microbial taxonomic membership and microbial products in association with IBD, but their utility as clinical biomarkers is still in its infancy. A rich area of progress has been the development and validation of host serologic microbial biomarkers, which have achieved a distinctive position in the diagnosis and prognosis in IBD, and as a template for defining other categories of microbial biomarkers in disease state and phenotype

Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems

Measurement of cos⁡2β\cos{2\beta} in B0→D(∗)h0B^{0} \to D^{(*)} h^{0} with D→KS0π+π−D \to K_{S}^{0} \pi^{+} \pi^{-} decays by a combined time-dependent Dalitz plot analysis of BaBar and Belle data

We report measurements of $\sin{2\beta}$ and $\cos{2\beta}$ from a time-dependent Dalitz plot analysis of $B^{0} \to D^{(*)} h^{0}$ with $D \to K_{S}^{0} \pi^{+} \pi^{-}$ decays, where the light unflavored and neutral hadron $h^{0}$ is a $\pi^{0}$, $\eta$, or $\omega$ meson. The analysis is performed with a combination of the final data sets of the \babar\ and Belle experiments containing $471 \times 10^{6}$ and $772 \times 10^{6}$ $B\bar{B}$ pairs collected at the $\Upsilon\left(4S\right)$ resonance at the asymmetric-energy B factories PEP-II at SLAC and KEKB at KEK, respectively. We measure $\sin{2\beta} = 0.80 \pm 0.14 \,(\rm{stat.}) \pm 0.06 \,(\rm{syst.}) \pm 0.03 \,(\rm{model})$ and $\cos{2\beta} = 0.91 \pm 0.22 \,(\rm{stat.}) \pm 0.09 \,(\rm{syst.}) \pm 0.07 \,(\rm{model})$. The result for the direct measurement of the angle is $\beta = \left( 22.5 \pm 4.4 \,(\rm{stat.}) \pm 1.2 \,(\rm{syst.}) \pm 0.6 \,(\rm{model}) \right)^{\circ}$. The last quoted uncertainties are due to the composition of the $D^{0} \to K_{S}^{0} \pi^{+} \pi^{-}$ decay amplitude model, which is newly established by a Dalitz plot amplitude analysis of a high-statistics $e^{+}e^{-} \to c\bar{c}$ data sample as part of this analysis. We find the first evidence for $\cos2\beta>0$ at the level of $3.7$ standard deviations. The measurement excludes the trigonometric multifold solution $\pi/2 - \beta = (68.1 \pm 0.7)^{\circ}$ at the level of $7.3$ standard deviations and therefore resolves an ambiguity in the determination of the apex of the CKM Unitarity Triangle. The hypothesis of $\beta = 0^{\circ}$ is ruled out at the level of $5.1$ standard deviations, and thus CP violation is observed in $B^{0} \to D^{(*)} h^{0}$ decays