Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity.

This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.cell.2015.12.025More than one-half billion people are obese, and despite progress in genetic research, much of the heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of triggering obesity in a non-Mendelian, "on/off" manner. Trim28(+/D9) mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-"on" state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine.This work was supported by funding from the Max-Planck Society, ERC (ERC-StG-281641), DFG (SFB992 “MedEp”; SFB 1052 “ObesityMechanisms”), EU_FP7 (NoE ”Epigenesys”; “Beta-JUDO” n° 279153), BMBF (DEEP), MRC (Metabolic Disease Unit - APC, SOR, GSHY, MRC_MC_UU_12012/1), Wellcome Trust (SOR, 095515/Z/11/Z) and the German Research Council (DFG) for the Clinical Research Center "Obesity Mechanisms" CRC1052/1 C05 and the Federal Ministry of Education and Research, Germany, FKZ, 01EO1001 (Integrated Research and Treatment Center (IFB) Adiposity Diseases

Study of forward Z + jet production in pp collisions at √s=7 TeV

A measurement of the $Z(\rightarrow\mu^+\mu^-)$+jet production cross-section in $pp$ collisions at a centre-of-mass energy $\sqrt{s} = 7$ TeV is presented. The analysis is based on an integrated luminosity of $1.0\,\text{fb}^{-1}$ recorded by the LHCb experiment. Results are shown with two jet transverse momentum thresholds, 10 and 20 GeV, for both the overall cross-section within the fiducial volume, and for six differential cross-section measurements. The fiducial volume requires that both the jet and the muons from the Z boson decay are produced in the forward direction ($2.0<\eta<4.5$). The results show good agreement with theoretical predictions at the second-order expansion in the coupling of the strong interaction.A measurement of the $Z(\rightarrow\mu^+\mu^-)$+jet production cross-section in $pp$ collisions at a centre-of-mass energy $\sqrt{s} = 7$ TeV is presented. The analysis is based on an integrated luminosity of $1.0\,\text{fb}^{-1}$ recorded by the LHCb experiment. Results are shown with two jet transverse momentum thresholds, 10 and 20 GeV, for both the overall cross-section within the fiducial volume, and for six differential cross-section measurements. The fiducial volume requires that both the jet and the muons from the Z boson decay are produced in the forward direction ($2.0<\eta<4.5$). The results show good agreement with theoretical predictions at the second-order expansion in the coupling of the strong interaction

A study of CP violation in B-+/- -&gt; DK +/- and B-+/- -&gt; D pi(+/-) decays with D -&gt; (KSK +/-)-K-0 pi(-/+) final states

A first study of CP violation in the decay modes $B^\pm\to [K^0_{\rm S} K^\pm \pi^\mp]_D h^\pm$ and $B^\pm\to [K^0_{\rm S} K^\mp \pi^\pm]_D h^\pm$, where $h$ labels a $K$ or $\pi$ meson and $D$ labels a $D^0$ or $\overline{D}^0$ meson, is performed. The analysis uses the LHCb data set collected in $pp$ collisions, corresponding to an integrated luminosity of 3 fb$^{-1}$. The analysis is sensitive to the CP-violating CKM phase $\gamma$ through seven observables: one charge asymmetry in each of the four modes and three ratios of the charge-integrated yields. The results are consistent with measurements of $\gamma$ using other decay modes

Study of the rare B-s(0) and B-0 decays into the pi(+) pi(-) mu(+) mu(-) final state

A search for the rare decays $B_s^0 \to \pi^+\pi^-\mu^+\mu^-$ and $B^0 \to \pi^+\pi^-\mu^+\mu^-$ is performed in a data set corresponding to an integrated luminosity of 3.0 fb$^{-1}$ collected by the LHCb detector in proton-proton collisions at centre-of-mass energies of 7 and 8 TeV. Decay candidates with pion pairs that have invariant mass in the range 0.5-1.3 GeV/$c^2$ and with muon pairs that do not originate from a resonance are considered. The first observation of the decay $B_s^0 \to \pi^+\pi^-\mu^+\mu^-$ and the first evidence of the decay $B^0 \to \pi^+\pi^-\mu^+\mu^-$ are obtained and the branching fractions are measured to be $\mathcal{B}(B_s^0 \to \pi^+\pi^-\mu^+\mu^-)=(8.6\pm 1.5\,({\rm stat}) \pm 0.7\,({\rm syst})\pm 0.7\,({\rm norm}))\times 10^{-8}$ and $\mathcal{B}(B^0 \to \pi^+\pi^-\mu^+\mu^-)=(2.11\pm 0.51\,({\rm stat}) \pm 0.15\,({\rm syst})\pm 0.16\,({\rm norm}) )\times 10^{-8}$, where the third uncertainty is due to the branching fraction of the decay $B^0\to J/\psi(\to \mu^+\mu^-)K^*(890)^0(\to K^+\pi^-)$, used as a normalisation.A search for the rare decays Bs0→π+π−μ+μ− and B0→π+π−μ+μ− is performed in a data set corresponding to an integrated luminosity of 3.0 fb−1 collected by the LHCb detector in proton–proton collisions at centre-of-mass energies of 7 and 8 TeV . Decay candidates with pion pairs that have invariant mass in the range 0.5–1.3 GeV/c2 and with muon pairs that do not originate from a resonance are considered. The first observation of the decay Bs0→π+π−μ+μ− and the first evidence of the decay B0→π+π−μ+μ− are obtained and the branching fractions, restricted to the dipion-mass range considered, are measured to be B(Bs0→π+π−μ+μ−)=(8.6±1.5 (stat)±0.7 (syst)±0.7(norm))×10−8 and B(B0→π+π−μ+μ−)=(2.11±0.51(stat)±0.15(syst)±0.16(norm))×10−8 , where the third uncertainty is due to the branching fraction of the decay B0→J/ψ(→μ+μ−)K⁎(892)0(→K+π−) , used as a normalisation.A search for the rare decays Bs0→π+π−μ+μ− and B0→π+π−μ+μ− is performed in a data set corresponding to an integrated luminosity of 3.0 fb−1 collected by the LHCb detector in proton–proton collisions at centre-of-mass energies of 7 and 8 TeV . Decay candidates with pion pairs that have invariant mass in the range 0.5–1.3 GeV/c2 and with muon pairs that do not originate from a resonance are considered. The first observation of the decay Bs0→π+π−μ+μ− and the first evidence of the decay B0→π+π−μ+μ− are obtained and the branching fractions, restricted to the dipion-mass range considered, are measured to be B(Bs0→π+π−μ+μ−)=(8.6±1.5 (stat)±0.7 (syst)±0.7(norm))×10−8 and B(B0→π+π−μ+μ−)=(2.11±0.51(stat)±0.15(syst)±0.16(norm))×10−8 , where the third uncertainty is due to the branching fraction of the decay B0→J/ψ(→μ+μ−)K⁎(892)0(→K+π−) , used as a normalisation.A search for the rare decays $B_s^0 \to \pi^+\pi^-\mu^+\mu^-$ and $B^0 \to \pi^+\pi^-\mu^+\mu^-$ is performed in a data set corresponding to an integrated luminosity of 3.0 fb$^{-1}$ collected by the LHCb detector in proton-proton collisions at centre-of-mass energies of 7 and 8 TeV. Decay candidates with pion pairs that have invariant mass in the range 0.5-1.3 GeV/$c^2$ and with muon pairs that do not originate from a resonance are considered. The first observation of the decay $B_s^0 \to \pi^+\pi^-\mu^+\mu^-$ and the first evidence of the decay $B^0 \to \pi^+\pi^-\mu^+\mu^-$ are obtained and the branching fractions, restricted to the dipion-mass range considered, are measured to be $\mathcal{B}(B_s^0 \to \pi^+\pi^-\mu^+\mu^-)=(8.6\pm 1.5\,({\rm stat}) \pm 0.7\,({\rm syst})\pm 0.7\,({\rm norm}))\times 10^{-8}$ and $\mathcal{B}(B^0 \to \pi^+\pi^-\mu^+\mu^-)=(2.11\pm 0.51\,({\rm stat}) \pm 0.15\,({\rm syst})\pm 0.16\,({\rm norm}) )\times 10^{-8}$, where the third uncertainty is due to the branching fraction of the decay $B^0\to J/\psi(\to \mu^+\mu^-)K^*(890)^0(\to K^+\pi^-)$, used as a normalisation

Measurement of the lifetime of the Bc+B_c^+ meson using the Bc+→J/ψπ+B_c^+\rightarrow J/\psi\pi^+ decay mode

The difference in total widths between the $B_c^+$ and $B^+$ mesons is measured using 3.0fb$^{-1}$ of data collected by the LHCb experiment in 7 and 8 TeV centre-of-mass energy proton-proton collisions at the LHC. Through the study of the time evolution of $B_c^+ \rightarrow J/\psi \pi^+$ and $B^+\rightarrow J/\psi K^+$ decays, the width difference is measured to be $\Delta\Gamma \equiv \Gamma_{B_c^+} - \Gamma_{B^+} = 4.46 \pm 0.14 \pm 0.07mm^{-1}c,$ where the first uncertainty is statistical and the second systematic. The known lifetime of the $B^+$ meson is used to convert this to a precise measurement of the $B_c^+$ lifetime, $\tau_{B_c^+} = 513.4 \pm 11.0 \pm 5.7fs,$ where the first uncertainty is statistical and the second systematic.The difference in total widths between the B+ c and B+ mesons is measured using 3.0 fb−1 of data collected by the LHCb experiment in 7 and 8 TeV centre-of-mass energy proton-proton collisions at the LHC. Through the study of the time evolution of B+ c → J/ψπ+ and B+ → J/ψK+ decays, the width difference is measured to be ∆Γ ≡ ΓB + c − ΓB+ = 4.46 ± 0.14 ± 0.07 mm−1 c, where the first uncertainty is statistical and the second systematic. The known lifetime of the B+ meson is used to convert this to a precise measurement of the B+ c lifetime, τB + c = 513.4 ± 11.0 ± 5.7 fs, where the first uncertainty is statistical and the second systematic.The difference in total widths between the Bc+ and B+ mesons is measured using a data sample corresponding to an integrated luminosity of 3.0 fb−1 collected by the LHCb experiment in 7 and 8 TeV centre-of-mass energy proton–proton collisions at the LHC. Through the study of the time evolution of Bc+→J/ψπ+ and B+→J/ψK+ decays, the width difference is measured to be ΔΓ≡ΓBc+−ΓB+=4.46±0.14±0.07 mm−1c, where the first uncertainty is statistical and the second systematic. The known lifetime of the B+ meson is used to convert this to a precise measurement of the Bc+ lifetime, τBc+=513.4±11.0±5.7 fs, where the first uncertainty is statistical and the second is systematic.The difference in total widths between the Bc+ and B+ mesons is measured using a data sample corresponding to an integrated luminosity of 3.0 fb−1 collected by the LHCb experiment in 7 and 8 TeV centre-of-mass energy proton–proton collisions at the LHC. Through the study of the time evolution of Bc+→J/ψπ+ and B+→J/ψK+ decays, the width difference is measured to be ΔΓ≡ΓBc+−ΓB+=4.46±0.14±0.07 mm−1c, where the first uncertainty is statistical and the second systematic. The known lifetime of the B+ meson is used to convert this to a precise measurement of the Bc+ lifetime, τBc+=513.4±11.0±5.7 fs, where the first uncertainty is statistical and the second is systematic

Search for the lepton flavour violating decay tau(-) -&gt; mu(-)mu(+)mu(-)

A search for the lepton flavour violating decay $\tau^-\rightarrow\mu^-\mu^+\mu^-$ is performed with the LHCb experiment. The data sample corresponds to an integrated luminosity of 1.0 fb$^{−1}$ of proton-proton collisions at a centre-of-mass energy of 7 TeV and 2.0 fb$^{−1}$ at 8 TeV. No evidence is found for a signal, and a limit is set at 90% confidence level on the branching fraction, $\mathcal{B}(\tau^-\rightarrow\mu^-\mu^+\mu^-)<4.6\times10^{−8}$.A search for the lepton flavour violating decay τ$^{−}$ → μ$^{−}$ μ$^{+}$ μ$^{−}$ is performed with the LHCb experiment. The data sample corresponds to an integrated luminosity of 1.0 fb$^{−1}$ of proton-proton collisions at a centre-of-mass energy of 7 TeV and 2.0 fb$^{−1}$ at 8 TeV. No evidence is found for a signal, and a limit is set at 90% confidence level on the branching fraction, $\mathrm{\mathcal{B}}\left({\tau}^{-}\to {\mu}^{-}{\mu}^{+}{\mu}^{-}\right)<4.6\times {10}^{-8}$ .A search for the lepton flavour violating decay $\tau^-\to \mu^-\mu^+\mu^-$ is performed with the LHCb experiment. The data sample corresponds to an integrated luminosity of $1.0\mathrm{\,fb}^{-1}$ of proton-proton collisions at a centre-of-mass energy of $7\mathrm{\,Te\kern -0.1em V}$ and $2.0\mathrm{\,fb}^{-1}$ at $8\mathrm{\,Te\kern -0.1em V}$. No evidence is found for a signal, and a limit is set at $90\%$ confidence level on the branching fraction, $\mathcal{B}(\tau^-\to \mu^-\mu^+\mu^-) < 4.6 \times 10^{-8}$

Measurement of the Z plus b-jet cross-section in pp collisions at root s=7 TeV in the forward region

The associated production of a Z boson or an off-shell photon $\gamma^*$ with a bottom quark in the forward region is studied using proton-proton collisions at a centre-of-mass energy of $7{\mathrm{\,Te\kern -0.1em V}}$. The Z bosons are reconstructed in the ${\text{Z}/\gamma^*}\rightarrow{\mu^{+}\mu^{-}}$ final state from muons with a transverse momentum larger than $20{\mathrm{\,Ge\kern -0.1em V}}$, while two transverse momentum thresholds are considered for jets ($10{\mathrm{\,Ge\kern -0.1em V}}$ and $20{\mathrm{\,Ge\kern -0.1em V}}$). Both muons and jets are reconstructed in the pseudorapidity range $2.0 10{\mathrm{\,Ge\kern -0.1em V}}$, and \sigma(\text{\text{Z}/\gamma^*(\mu^{+}\mu^{-})+b-jet}) = 167 \pm 47 (\text{stat}) \pm 29 (\text{syst}) \pm 6 (\text{lumi}) {\,{fb}} for {p_{\rm T}}(jet)$>20{\mathrm{\,Ge\kern -0.1em V}}$

Measurement of Upsilon production in collisions at root s=2.76 TeV

The production of $\Upsilon(1S)$, $\Upsilon(2S)$ and $\Upsilon(3S)$ mesons decaying into the dimuon final state is studied with the LHCb detector using a data sample corresponding to an integrated luminosity of 3.3 $pb^{-1}$ collected in proton-proton collisions at a centre-of-mass energy of $\sqrt{s}=2.76$ TeV. The differential production cross-sections times dimuon branching fractions are measured as functions of the $\Upsilon$ transverse momentum and rapidity, over the ranges $p_{\rm T} Upsilon(1S) X) x B(Upsilon(1S) -> mu+mu-) = 1.111 +/- 0.043 +/- 0.044 nb, sigma(pp -> Upsilon(2S) X) x B(Upsilon(2S) -> mu+mu-) = 0.264 +/- 0.023 +/- 0.011 nb, sigma(pp -> Upsilon(3S) X) x B(Upsilon(3S) -> mu+mu-) = 0.159 +/- 0.020 +/- 0.007 nb, where the first uncertainty is statistical and the second systematic

Search for CP violation using T-odd correlations in D-0 -&gt; K+K-pi(+)pi(-) decays

A search for $CP$ violation using $T$-odd correlations is performed using the four-body $D^0 \to K^+K^-\pi^+\pi^-$ decay, selected from semileptonic $B$ decays. The data sample corresponds to integrated luminosities of $1.0\,\text{fb}^{-1}$ and $2.0\,\text{fb}^{-1}$ recorded at the centre-of-mass energies of 7 TeV and 8 TeV, respectively. The $CP$-violating asymmetry $a_{CP}^{T\text{-odd}}$ is measured to be $(0.18\pm 0.29\text{(stat)}\pm 0.04\text{(syst)})\%$. Searches for $CP$ violation in different regions of phase space of the four-body decay, and as a function of the $D^0$ decay time, are also presented. No significant deviation from the $CP$ conservation hypothesis is found