Dynamic regulation of the transcription initiation landscape at single nucleotide resolution during vertebrate embryogenesis

Spatiotemporal control of gene expression is central to animal development. Core promoters represent a previously unanticipated regulatory level by interacting with cis-regulatory elements and transcription initiation in different physiological and developmental contexts. Here, we provide a first and comprehensive description of the core promoter repertoire and its dynamic use during the development of a vertebrate embryo. By using cap analysis of gene expression (CAGE), we mapped transcription initiation events at single nucleotide resolution across 12 stages of zebrafish development. These CAGE-based transcriptome maps reveal genome-wide rules of core promoter usage, structure, and dynamics, key to understanding the control of gene regulation during vertebrate ontogeny. They revealed the existence of multiple classes of pervasive intra- and intergenic post-transcriptionally processed RNA products and their developmental dynamics. Among these RNAs, we report splice donor site-associated intronic RNA (sRNA) to be specific to genes of the splicing machinery. For the identification of conserved features, we compared the zebrafish data sets to the first CAGE promoter map of Tetraodon and the existing human CAGE data. We show that a number of features, such as promoter type, newly discovered promoter properties such as a specialized purine-rich initiator motif, as well as sRNAs and the genes in which they are detected, are conserved in mammalian and Tetraodon CAGE-defined promoter maps. The zebrafish developmental promoterome represents a powerful resource for studying developmental gene regulation and revealing promoter features shared across vertebrates.publishedVersio

Study of the B^0 Semileptonic Decay Spectrum at the Upsilon(4S) Resonance

We have made a first measurement of the lepton momentum spectrum in a sample of events enriched in neutral B's through a partial reconstruction of B0 --> D*- l+ nu. This spectrum, measured with 2.38 fb**-1 of data collected at the Upsilon(4S) resonance by the CLEO II detector, is compared directly to the inclusive lepton spectrum from all Upsilon(4S) events in the same data set. These two spectra are consistent with having the same shape above 1.5 GeV/c. From the two spectra and two other CLEO measurements, we obtain the B0 and B+ semileptonic branching fractions, b0 and b+, their ratio, and the production ratio f+-/f00 of B+ and B0 pairs at the Upsilon(4S). We report b+/b0=0.950 (+0.117-0.080) +- 0.091, b0 = (10.78 +- 0.60 +- 0.69)%, and b+ = (10.25 +- 0.57 +- 0.65)%. b+/b0 is equivalent to the ratio of charged to neutral B lifetimes, tau+/tau0.Comment: 14 page, postscript file also available at http://w4.lns.cornell.edu/public/CLN

Observation of the Ξc+\Xi_c^+ Charmed Baryon Decays to Σ+K−π+\Sigma^+ K^-\pi^+, Σ+Kˉ∗0\Sigma^+ \bar{K}^{*0}, and ΛK−π+π+\Lambda K^-\pi^+\pi^+

We have observed two new decay modes of the charmed baryon $\Xi_c^+$ into $\Sigma^+ K^-\pi^+$ and $\Sigma^+ \bar{K}^{*0}$ using data collected with the CLEO II detector. We also present the first measurement of the branching fraction for the previously observed decay mode $\Xi_c^+\to\Lambda K^-\pi^+\pi^+$. The branching fractions for these three modes relative to $\Xi_c^+\to\Xi^-\pi^+\pi^+$ are measured to be $1.18 \pm 0.26 \pm 0.17$, $0.92 \pm 0.27 \pm 0.14$, and $0.58 \pm 0.16 \pm 0.07$, respectively.Comment: 12 page uuencoded postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN

Muscle Loss: The New Malnutrition Challenge in Clinical Practice

Recent definitions of malnutrition include low muscle mass within its diagnostic criteria. In fact, malnutrition is one of the main risk factors of skeletal muscle loss contributing to the onset of sarcopenia. However, differences in the screening and diagnosis of skeletal muscle loss, especially as a result of malnutrition in clinical and community settings, still occur mainly as techniques and thresholds used vary in clinical practice. The objectives of this position paper are firstly to emphasize the link between skeletal muscle loss and malnutrition-related conditions and secondly to raise awareness for the timely identification of loss of skeletal muscle mass and function in high risk populations. Thirdly to recognize the need to implement appropriate nutritional strategies for prevention and treatment of skeletal muscle loss and malnutrition across the healthcare continuum. Malnutrition needs to be addressed clinically as a muscle-related disorder and clinicians should integrate nutritional assessment with muscle mass measurements for optimal evaluation of these two interrelated entities to tailor interventions appropriately. The design of monitoring/evaluation and discharge plans need to include multimodal interventions with nutrition and physical exercise that are key to preserve patient’s muscle mass and function in clinical and community settings

Anisotropic flow of charged hadrons, pions and (anti-)protons measured at high transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}=2.76 TeV

The elliptic, $v_2$, triangular, $v_3$, and quadrangular, $v_4$, azimuthal anisotropic flow coefficients are measured for unidentified charged particles, pions and (anti-)protons in Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV with the ALICE detector at the Large Hadron Collider. Results obtained with the event plane and four-particle cumulant methods are reported for the pseudo-rapidity range $|\eta|<0.8$ at different collision centralities and as a function of transverse momentum, $p_{\rm T}$, out to $p_{\rm T}=20$ GeV/$c$. The observed non-zero elliptic and triangular flow depends only weakly on transverse momentum for $p_{\rm T}>8$ GeV/$c$. The small $p_{\rm T}$ dependence of the difference between elliptic flow results obtained from the event plane and four-particle cumulant methods suggests a common origin of flow fluctuations up to $p_{\rm T}=8$ GeV/$c$. The magnitude of the (anti-)proton elliptic and triangular flow is larger than that of pions out to at least $p_{\rm T}=8$ GeV/$c$ indicating that the particle type dependence persists out to high $p_{\rm T}$.Comment: 16 pages, 5 captioned figures, authors from page 11, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/186

Centrality dependence of charged particle production at large transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm{NN}}} = 2.76 TeV

The inclusive transverse momentum ($p_{\rm T}$) distributions of primary charged particles are measured in the pseudo-rapidity range $|\eta|<0.8$ as a function of event centrality in Pb-Pb collisions at $\sqrt{s_{\rm{NN}}}=2.76$ TeV with ALICE at the LHC. The data are presented in the $p_{\rm T}$ range $0.15<p_{\rm T}<50$ GeV/$c$ for nine centrality intervals from 70-80% to 0-5%. The Pb-Pb spectra are presented in terms of the nuclear modification factor $R_{\rm{AA}}$ using a pp reference spectrum measured at the same collision energy. We observe that the suppression of high-$p_{\rm T}$ particles strongly depends on event centrality. In central collisions (0-5%) the yield is most suppressed with $R_{\rm{AA}}\approx0.13$ at $p_{\rm T}=6$-7 GeV/$c$. Above $p_{\rm T}=7$ GeV/$c$, there is a significant rise in the nuclear modification factor, which reaches $R_{\rm{AA}} \approx0.4$ for $p_{\rm T}>30$ GeV/$c$. In peripheral collisions (70-80%), the suppression is weaker with $R_{\rm{AA}} \approx 0.7$ almost independently of $p_{\rm T}$. The measured nuclear modification factors are compared to other measurements and model calculations.Comment: 17 pages, 4 captioned figures, 2 tables, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/284

Measurement of charm production at central rapidity in proton-proton collisions at s=2.76\sqrt{s} = 2.76 TeV

The $p_{\rm T}$-differential production cross sections of the prompt (B feed-down subtracted) charmed mesons D$^0$, D$^+$, and D$^{*+}$ in the rapidity range $|y|<0.5$, and for transverse momentum $1< p_{\rm T} <12$ GeV/$c$, were measured in proton-proton collisions at $\sqrt{s} = 2.76$ TeV with the ALICE detector at the Large Hadron Collider. The analysis exploited the hadronic decays D$^0 \rightarrow$K$\pi$, D$^+ \rightarrow$K$\pi\pi$, D$^{*+} \rightarrow$D$^0\pi$, and their charge conjugates, and was performed on a $L_{\rm int} = 1.1$ nb$^{-1}$ event sample collected in 2011 with a minimum-bias trigger. The total charm production cross section at $\sqrt{s} = 2.76$ TeV and at 7 TeV was evaluated by extrapolating to the full phase space the $p_{\rm T}$-differential production cross sections at $\sqrt{s} = 2.76$ TeV and our previous measurements at $\sqrt{s} = 7$ TeV. The results were compared to existing measurements and to perturbative-QCD calculations. The fraction of cdbar D mesons produced in a vector state was also determined.Comment: 20 pages, 5 captioned figures, 4 tables, authors from page 15, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/307

Particle-yield modification in jet-like azimuthal di-hadron correlations in Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The yield of charged particles associated with high-$p_{\rm T}$ trigger particles ($8 < p_{\rm T} < 15$ GeV/$c$) is measured with the ALICE detector in Pb-Pb collisions at $\sqrt{s_{\rm NN}}$ = 2.76 TeV relative to proton-proton collisions at the same energy. The conditional per-trigger yields are extracted from the narrow jet-like correlation peaks in azimuthal di-hadron correlations. In the 5% most central collisions, we observe that the yield of associated charged particles with transverse momenta $p_{\rm T}> 3$ GeV/$c$ on the away-side drops to about 60% of that observed in pp collisions, while on the near-side a moderate enhancement of 20-30% is found.Comment: 15 pages, 2 captioned figures, 1 table, authors from page 10, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/350

BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival

Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.FWN – Publicaties zonder aanstelling Universiteit Leide

Studies of the Cabbibo-Suppressed Decays D+→π0ℓ+νD^+ \to \pi^0 \ell^+ \nu and D+→ηe+νeD^+ \to \eta e^+ \nu_e

Using 4.8 fb$^{-1}$ of data taken with the CLEO II detector, the branching fraction for the Cabibbo-suppressed decay $D^+\to\pi^0\ell^+\nu$ measured relative to the Cabibbo favored decay $D^+\to\bar{K^0}\ell^+\nu$ is found to be $0.046\pm 0.014\pm 0.017$. Using $V_{cs}$ and $V_{cd}$ from unitarity constraints, we determine $| f_+^{\pi}(0)/f_+^K(0)|^2=0.9\pm 0.3\pm 0.3$ We also present a 90% confidence level upper limit for the branching ratio of the decay $D^+ \to \eta e^+\nu_e$ relative to that for $D^+ \to \pi^0 e^+\nu_e$ of 1.5.Comment: 10 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN