Search for the rare decays B0→J/ψγB^{0}\to J/\psi \gamma and Bs0→J/ψγB^{0}_{s} \to J/\psi \gamma

A search for the rare decay of a $B^{0}$ or $B^{0}_{s}$ meson into the final state $J/\psi\gamma$ is performed, using data collected by the LHCb experiment in $pp$ collisions at $\sqrt{s}=7$ and $8$ TeV, corresponding to an integrated luminosity of 3 fb$^{-1}$. The observed number of signal candidates is consistent with a background-only hypothesis. Branching fraction values larger than $1.7\times 10^{-6}$ for the $B^{0}\to J/\psi\gamma$ decay mode are excluded at 90% confidence level. For the $B^{0}_{s}\to J/\psi\gamma$ decay mode, branching fraction values larger than $7.4\times 10^{-6}$ are excluded at 90% confidence level, this is the first branching fraction limit for this decay.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-044.htm

Rules Governing Selective Protein Carbonylation

BACKGROUND:Carbonyl derivatives are mainly formed by direct metal-catalysed oxidation (MCO) attacks on the amino-acid side chains of proline, arginine, lysine and threonine residues. For reasons unknown, only some proteins are prone to carbonylation. METHODOLOGY/PRINCIPAL FINDINGS:we used mass spectrometry analysis to identify carbonylated sites in: BSA that had undergone in vitro MCO, and 23 carbonylated proteins in Escherichia coli. The presence of a carbonylated site rendered the neighbouring carbonylatable site more prone to carbonylation. Most carbonylated sites were present within hot spots of carbonylation. These observations led us to suggest rules for identifying sites more prone to carbonylation. We used these rules to design an in silico model (available at http://www.lcb.cnrs-mrs.fr/CSPD/), allowing an effective and accurate prediction of sites and of proteins more prone to carbonylation in the E. coli proteome. CONCLUSIONS/SIGNIFICANCE:We observed that proteins evolve to either selectively maintain or lose predicted hot spots of carbonylation depending on their biological function. As our predictive model also allows efficient detection of carbonylated proteins in Bacillus subtilis, we believe that our model may be extended to direct MCO attacks in all organisms

Study of the production of Λb0\Lambda_b^0 and B‾0\overline{B}^0 hadrons in pppp collisions and first measurement of the Λb0→J/ψpK−\Lambda_b^0\rightarrow J/\psi pK^- branching fraction

The product of the $\Lambda_b^0$ ($\overline{B}^0$) differential production cross-section and the branching fraction of the decay $\Lambda_b^0\rightarrow J/\psi pK^-$ ($\overline{B}^0\rightarrow J/\psi\overline{K}^*(892)^0$) is measured as a function of the beauty hadron transverse momentum, $p_{\rm T}$, and rapidity, $y$. The kinematic region of the measurements is $p_{\rm T}<20~{\rm GeV}/c$ and $2.0<y<4.5$. The measurements use a data sample corresponding to an integrated luminosity of $3~{\rm fb}^{-1}$ collected by the LHCb detector in $pp$ collisions at centre-of-mass energies $\sqrt{s}=7~{\rm TeV}$ in 2011 and $\sqrt{s}=8~{\rm TeV}$ in 2012. Based on previous LHCb results of the fragmentation fraction ratio, $f_{\Lambda_B^0}/f_d$, the branching fraction of the decay $\Lambda_b^0\rightarrow J/\psi pK^-$ is measured to be \begin{equation*} \mathcal{B}(\Lambda_b^0\rightarrow J/\psi pK^-)= (3.17\pm0.04\pm0.07\pm0.34^{+0.45}_{-0.28})\times10^{-4}, \end{equation*} where the first uncertainty is statistical, the second is systematic, the third is due to the uncertainty on the branching fraction of the decay $\overline{B}^0\rightarrow J/\psi\overline{K}^*(892)^0$, and the fourth is due to the knowledge of $f_{\Lambda_b^0}/f_d$. The sum of the asymmetries in the production and decay between $\Lambda_b^0$ and $\overline{\Lambda}_b^0$ is also measured as a function of $p_{\rm T}$ and $y$. The previously published branching fraction of $\Lambda_b^0\rightarrow J/\psi p\pi^-$, relative to that of $\Lambda_b^0\rightarrow J/\psi pK^-$, is updated. The branching fractions of $\Lambda_b^0\rightarrow P_c^+(\rightarrow J/\psi p)K^-$ are determined.Comment: 29 pages, 19figures. All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-032.htm

Evidence for the strangeness-changing weak decay Ξb−→Λb0π−\Xi_b^-\to\Lambda_b^0\pi^-

Using a $pp$ collision data sample corresponding to an integrated luminosity of 3.0~fb$^{-1}$, collected by the LHCb detector, we present the first search for the strangeness-changing weak decay $\Xi_b^-\to\Lambda_b^0\pi^-$. No $b$ hadron decay of this type has been seen before. A signal for this decay, corresponding to a significance of 3.2 standard deviations, is reported. The relative rate is measured to be ${{f_{\Xi_b^-}}\over{f_{\Lambda_b^0}}}{\cal{B}}(\Xi_b^-\to\Lambda_b^0\pi^-) = (5.7\pm1.8^{+0.8}_{-0.9})\times10^{-4}$, where $f_{\Xi_b^-}$ and $f_{\Lambda_b^0}$ are the $b\to\Xi_b^-$ and $b\to\Lambda_b^0$ fragmentation fractions, and ${\cal{B}}(\Xi_b^-\to\Lambda_b^0\pi^-)$ is the branching fraction. Assuming $f_{\Xi_b^-}/f_{\Lambda_b^0}$ is bounded between 0.1 and 0.3, the branching fraction ${\cal{B}}(\Xi_b^-\to\Lambda_b^0\pi^-)$ would lie in the range from $(0.57\pm0.21)\%$ to $(0.19\pm0.07)\%$.Comment: 7 pages, 2 figures, All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-047.htm

Akt1-associated actomyosin remodelling is required for nuclear lamina dispersal and nuclear shrinkage in epidermal terminal differentiation

Keratinocyte cornification and epidermal barrier formation are tightly controlled processes, which require complete degradation of intracellular organelles, including removal of keratinocyte nuclei. Keratinocyte nuclear destruction requires Akt1-dependent phosphorylation and degradation of the nuclear lamina protein, Lamin A/C, essential for nuclear integrity. However, the molecular mechanisms that result in complete nuclear removal and their regulation are not well defined. Post-confluent cultures of rat epidermal keratinocytes (REKs) undergo spontaneous and complete differentiation, allowing visualisation and perturbation of the differentiation process in vitro. We demonstrate that there is dispersal of phosphorylated Lamin A/C to structures throughout the cytoplasm in differentiating keratinocytes. We show that the dispersal of phosphorylated Lamin A/C is Akt1-dependent and these structures are specific for the removal of Lamin A/C from the nuclear lamina; nuclear contents and Lamin B were not present in these structures. Immunoprecipitation identified a group of functionally related Akt1 target proteins involved in Lamin A/C dispersal, including actin, which forms cytoskeletal microfilaments, Arp3, required for actin filament nucleation, and Myh9, a component of myosin IIa, a molecular motor that can translocate along actin filaments. Disruption of actin filament polymerisation, nucleation or myosin IIa activity prevented formation and dispersal of cytoplasmic Lamin A/C structures. Live imaging of keratinocytes expressing fluorescently tagged nuclear proteins showed a nuclear volume reduction step taking less than 40 min precedes final nuclear destruction. Preventing Akt1-dependent Lamin A/C phosphorylation and disrupting cytoskeletal Akt1-associated proteins prevented nuclear volume reduction. We propose keratinocyte nuclear destruction and differentiation requires myosin II activity and the actin cytoskeleton for two intermediate processes: Lamin A/C dispersal and rapid nuclear volume reduction

Measurements of long-range near-side angular correlations in sNN=5\sqrt{s_{\text{NN}}}=5TeV proton-lead collisions in the forward region

Two-particle angular correlations are studied in proton-lead collisions at a nucleon-nucleon centre-of-mass energy of $\sqrt{s_{\text{NN}}}=5$TeV, collected with the LHCb detector at the LHC. The analysis is based on data recorded in two beam configurations, in which either the direction of the proton or that of the lead ion is analysed. The correlations are measured in the laboratory system as a function of relative pseudorapidity, $\Delta\eta$, and relative azimuthal angle, $\Delta\phi$, for events in different classes of event activity and for different bins of particle transverse momentum. In high-activity events a long-range correlation on the near side, $\Delta\phi \approx 0$, is observed in the pseudorapidity range $2.0<\eta<4.9$. This measurement of long-range correlations on the near side in proton-lead collisions extends previous observations into the forward region up to $\eta=4.9$. The correlation increases with growing event activity and is found to be more pronounced in the direction of the lead beam. However, the correlation in the direction of the lead and proton beams are found to be compatible when comparing events with similar absolute activity in the direction analysed.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-040.htm

Citrullination regulates pluripotency and histone H1 binding to chromatin.

Citrullination is the post-translational conversion of an arginine residue within a protein to the non-coded amino acid citrulline. This modification leads to the loss of a positive charge and reduction in hydrogen-bonding ability. It is carried out by a small family of tissue-specific vertebrate enzymes called peptidylarginine deiminases (PADIs) and is associated with the development of diverse pathological states such as autoimmunity, cancer, neurodegenerative disorders, prion diseases and thrombosis. Nevertheless, the physiological functions of citrullination remain ill-defined, although citrullination of core histones has been linked to transcriptional regulation and the DNA damage response. PADI4 (also called PAD4 or PADV), the only PADI with a nuclear localization signal, was previously shown to act in myeloid cells where it mediates profound chromatin decondensation during the innate immune response to infection. Here we show that the expression and enzymatic activity of Padi4 are also induced under conditions of ground-state pluripotency and during reprogramming in mouse. Padi4 is part of the pluripotency transcriptional network, binding to regulatory elements of key stem-cell genes and activating their expression. Its inhibition lowers the percentage of pluripotent cells in the early mouse embryo and significantly reduces reprogramming efficiency. Using an unbiased proteomic approach we identify linker histone H1 variants, which are involved in the generation of compact chromatin, as novel PADI4 substrates. Citrullination of a single arginine residue within the DNA-binding site of H1 results in its displacement from chromatin and global chromatin decondensation. Together, these results uncover a role for citrullination in the regulation of pluripotency and provide new mechanistic insights into how citrullination regulates chromatin compaction.Cancer Research UKThis is the author accepted manuscript. The final version is available from the Nature Publishing Group via http://dx.doi.org/10.1038/nature1294

B-Cyclin/CDKs Regulate Mitotic Spindle Assembly by Phosphorylating Kinesins-5 in Budding Yeast

Although it has been known for many years that B-cyclin/CDK complexes regulate the assembly of the mitotic spindle and entry into mitosis, the full complement of relevant CDK targets has not been identified. It has previously been shown in a variety of model systems that B-type cyclin/CDK complexes, kinesin-5 motors, and the SCFCdc4 ubiquitin ligase are required for the separation of spindle poles and assembly of a bipolar spindle. It has been suggested that, in budding yeast, B-type cyclin/CDK (Clb/Cdc28) complexes promote spindle pole separation by inhibiting the degradation of the kinesins-5 Kip1 and Cin8 by the anaphase-promoting complex (APCCdh1). We have determined, however, that the Kip1 and Cin8 proteins are present at wild-type levels in the absence of Clb/Cdc28 kinase activity. Here, we show that Kip1 and Cin8 are in vitro targets of Clb2/Cdc28 and that the mutation of conserved CDK phosphorylation sites on Kip1 inhibits spindle pole separation without affecting the protein's in vivo localization or abundance. Mass spectrometry analysis confirms that two CDK sites in the tail domain of Kip1 are phosphorylated in vivo. In addition, we have determined that Sic1, a Clb/Cdc28-specific inhibitor, is the SCFCdc4 target that inhibits spindle pole separation in cells lacking functional Cdc4. Based on these findings, we propose that Clb/Cdc28 drives spindle pole separation by direct phosphorylation of kinesin-5 motors

Metabolites of Purine Nucleoside Phosphorylase (NP) in Serum Have the Potential to Delineate Pancreatic Adenocarcinoma

Pancreatic Adenocarcinoma (PDAC), the fourth highest cause of cancer related deaths in the United States, has the most aggressive presentation resulting in a very short median survival time for the affected patients. Early detection of PDAC is confounded by lack of specific markers that has motivated the use of high throughput molecular approaches to delineate potential biomarkers. To pursue identification of a distinct marker, this study profiled the secretory proteome in 16 PDAC, 2 carcinoma in situ (CIS) and 7 benign patients using label-free mass spectrometry coupled to 1D-SDS-PAGE and Strong Cation-Exchange Chromatography (SCX). A total of 431 proteins were detected of which 56 were found to be significantly elevated in PDAC. Included in this differential set were Parkinson disease autosomal recessive, early onset 7 (PARK 7) and Alpha Synuclein (aSyn), both of which are known to be pathognomonic to Parkinson's disease as well as metabolic enzymes like Purine Nucleoside Phosphorylase (NP) which has been exploited as therapeutic target in cancers. Tissue Microarray analysis confirmed higher expression of aSyn and NP in ductal epithelia of pancreatic tumors compared to benign ducts. Furthermore, extent of both aSyn and NP staining positively correlated with tumor stage and perineural invasion while their intensity of staining correlated with the existence of metastatic lesions in the PDAC tissues. From the biomarker perspective, NP protein levels were higher in PDAC sera and furthermore serum levels of its downstream metabolites guanosine and adenosine were able to distinguish PDAC from benign in an unsupervised hierarchical classification model. Overall, this study for the first time describes elevated levels of aSyn in PDAC as well as highlights the potential of evaluating NP protein expression and levels of its downstream metabolites to develop a multiplex panel for non-invasive detection of PDAC

Cell motility: the integrating role of the plasma membrane

The plasma membrane is of central importance in the motility process. It defines the boundary separating the intracellular and extracellular environments, and mediates the interactions between a motile cell and its environment. Furthermore, the membrane serves as a dynamic platform for localization of various components which actively participate in all aspects of the motility process, including force generation, adhesion, signaling, and regulation. Membrane transport between internal membranes and the plasma membrane, and in particular polarized membrane transport, facilitates continuous reorganization of the plasma membrane and is thought to be involved in maintaining polarity and recycling of essential components in some motile cell types. Beyond its biochemical composition, the mechanical characteristics of the plasma membrane and, in particular, membrane tension are of central importance in cell motility; membrane tension affects the rates of all the processes which involve membrane deformation including edge extension, endocytosis, and exocytosis. Most importantly, the mechanical characteristics of the membrane and its biochemical composition are tightly intertwined; membrane tension and local curvature are largely determined by the biochemical composition of the membrane and the biochemical reactions taking place; at the same time, curvature and tension affect the localization of components and reaction rates. This review focuses on this dynamic interplay and the feedbacks between the biochemical and biophysical characteristics of the membrane and their effects on cell movement. New insight on these will be crucial for understanding the motility process