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Differential cross sections as a function of transverse momentum p(T) are presented for the production of Upsilon(nS) (n = 1, 2, 3) states decaying into a pair of muons. Data corresponding to an integrated luminosity of 4.9 fb(-1) in pp collisions at root s = 7 TeV were collected with the CMS detector at the LHC. The analysis selects events with dimuon rapidity vertical bar y vertical bar < 1.2 and dimuon transverse momentum in the range 10 < p(T) < 100 GeV. The measurements show a transition from an exponential to a power-law behavior at p(T) approximate to 20 GeV for the three Upsilon states. Above that transition, the Upsilon(3S) spectrum is significantly harder than that of the Upsilon(1S). The ratios of the Upsilon(3S) and Upsilon(2S) differential cross sections to the Upsilon(1S) cross section show a rise as p(T)-increases at low p(T), then become flatter at higher p(T). (C) 2015 CERN for the benefit of the CMS Collaboration. Published by Elsevier B.V.

A search for a heavy Higgs boson in the H -> WW and H -> ZZ decay channels is reported. The search is based upon proton-proton collision data samples corresponding to an integrated luminosity of up to 5.1 fb(-1) at root s = 7 TeV and up to 19.7 fb(-1) at root s = 8 TeV, recorded by the CMS experiment at the CERN LHC. Several final states of the H -> WW and H -> ZZ decays are analyzed. The combined upper limit at the 95% confidence level on the product of the cross section and branching fraction exclude a Higgs boson with standard model-like couplings and decays in the range 145 < m(H) < 1000 GeV. We also interpret the results in the context of an electroweak singlet extension of the standard model.

In a short hairpin RNA screen for genes that affect AKT phosphorylation, we identified the RAB35 small guanosine triphosphatase (GTPase)-a protein previously implicated in endomembrane trafficking-as a regulator of the phosphatidylinositol 3'-OH kinase (PI3K) pathway. Depletion of RAB35 suppresses AKT phosphorylation in response to growth factors, whereas expression of a dominant active GTPase-deficient mutant of RAB35 constitutively activates the PI3K/AKT pathway. RAB35 functions downstream of growth factor receptors and upstream of PDK1 and mTORC2 and copurifies with PI3K in immunoprecipitation assays. Two somatic RAB35 mutations found in human tumors generate alleles that constitutively activate PI3K/AKT signaling, suppress apoptosis, and transform cells in a PI3K-dependent manner. Furthermore, oncogenic RAB35 is sufficient to drive platelet-derived growth factor receptor a to LAMP2-positive endomembranes in the absence of ligand, suggesting that there may be latent oncogenic potential in dysregulated endomembrane trafficking.

Geoffrey W. Smith is currently the Managing Director of Mars Ventures. He actually started his studies with a Bachelor of Arts degree and a Doctorate in Law but then, in part by chance and in part by following in his family footsteps, he stepped into the healthcare and biotech field. Since then, he has successfully contributed to the birth of a number of healthcare companies and has also held academic positions at the Icahn School of Medicine at Mount Sinai and at The Rockefeller University in New York, teaching about the interface between science and business. During 2014 he served as Senior Editor on Disease Models & Mechanisms, bringing to the editorial team his valuable experience in drug development and discovery. In this interview, Geoff talks to Ross Cagan, Editor-in-Chief of Disease Models & Mechanisms, about how he developed his incredibly varied career, sharing his views about industry, academia and science publishing, and discussing how academia and industry can fruitfully meet to advance bioscience, train the scientists and stakeholders of the future, and drive the successful discovery of new therapeutics to treat human disease.

Cell wall anchored virulence factors are critical for infection and colonization of the host by Gram-positive bacteria. Such proteins have an N-terminal leader sequence and a C-terminal sorting signal, composed of an LPXTG motif, a hydrophobic stretch, and a few positively charged amino acids. The sorting signal halts translocation across the membrane, allowing sortase to cleave the LPXTG motif, leading to surface anchoring. Deletion of sortase prevents the anchoring of virulence factors to the wall; the effects on bacterial physiology however, have not been thoroughly characterized. Here we show that deletion of Streptococcus pyogenes sortase A leads to accumulation of sorting intermediates, particularly at the septum, altering cellular morphology and physiology, and compromising membrane integrity. Such cells are highly sensitive to cathelicidin, and are rapidly killed in blood and plasma. These phenomena are not a loss-of-function effect caused by the absence of anchored surface proteins, but specifically result from the accumulation of sorting intermediates. Reduction in the level of sorting intermediates leads to a return of the sortase mutant to normal morphology, while expression of M protein with an altered LPXTG motif in wild type cells leads to toxicity in the host environment, similar to that observed in the sortase mutant. These unanticipated effects suggest that inhibition of sortase by small-molecule inhibitors could similarly lead to the rapid elimination of pathogens from an infected host, making such inhibitors much better anti-bacterial agents than previously believed.

Long non-coding RNAs (lncRNAs) have recently been found to widely exist in eukaryotes and play important roles in key biological processes. To extend our knowledge of lncRNAs in crop plants we performed both non-directional and strand-specific RNA-sequencing experiments to profile non-coding transcriptomes of various rice and maize organs at different developmental stages. Analysis of more than 3 billion reads identified 22334 long intergenic non-coding RNAs (lincRNAs) and 6673 pairs of sense and natural antisense transcript (NAT). Many lincRNA genes were associated with epigenetic marks. Expression of rice lincRNA genes was significantly correlated with that of nearby protein-coding genes. A set of NAT genes also showed expression correlation with their sense genes. More than 200 rice lincRNA genes had homologous non-coding sequences in the maize genome. Much more lincRNA and NAT genes were derived from conserved genomic regions between the two cereals presenting positional conservation. Protein-coding genes flanking or having a sense-antisense relationship to these conserved lncRNA genes were mainly involved in development and stress responses, suggesting that the associated lncRNAs might have similar functions. Integrating previous genome-wide association studies (GWAS), we found that hundreds of lincRNAs contain trait-associated SNPs (single nucleotide polymorphisms [SNPs]) suggesting their putative contributions to developmental and agriculture traits. Significance Statement Long noncoding RNAs (lncRNAs) play key roles in numerous biological processes. Here we sequenced and characterized lncRNAs from many rice and maize tissues.Hundreds of the lncRNAs have single nucleotide polymorphisms associated with agricultural traits, suggesting that they may play roles in controlling such traits.

Background & Aims: Hepatitis B virus (HBV) infects and replicates in quiescent hepatocytes, which are deficient in dNTPs, the critical precursors of HBV replication. Most tumor viruses promote dNTP production in host cells by inducing cell proliferation. Although HBV is known as a major cause of hepatocellular carcinoma, it does not lead to cellular proliferation. Instead, HBV acquires dNTPs by activating the expression of the R2 subunit of the Ribonucleotide Reductase (RNR) holoenzyme, the cell cycle gene that is rate-limiting for generation of dNTPs, without inducing the cell cycle. We wished to elucidate the molecular basis of HBV-dependent R2 expression in quiescent cells. Methods: Quiescent HepG2 cells were transduced with an HBV-containing lentiviral vector, and primary human hepatocytes were infected with HBV. DNA damage response and RNR-R2 gene expression were monitored under this condition. Results: We report here that HBV-induced R2 expression is mediated by the E2F1 transcription factor, and that HBV induces E2F1 accumulation, modification and binding to the R2 promoter. We found that Chk1, a known E2F1 kinase that functions in response to DNA damage, was activated by HBV. In cells where Chk1 was pharmacologically inhibited, or depleted by shRNA-mediated knockdown, HBV-mediated R2 expression was severely attenuated. Furthermore, we found that HBV attenuates DNA repair, thus reducing cellular dNTP consumption. Conclusions: Our findings demonstrate that HBV exploits the Chk1-E2F1 axis of the DNA damage response pathway to induce R2 expression in a cell cycle-independent manner. This suggests that inhibition of this pathway may have a therapeutic value for HBV carriers. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Measurements of the ZZ production cross sections in proton-proton collisions at center-of-mass energies of 7 and 8 TeV are presented. Candidate events for the leptonic decay mode ZZ -> 2l2 nu. where l denotes an electron or a muon, are reconstructed and selected from data corresponding to an integrated luminosity of 5.1 (19.6) fb(-1) at 7 (8) TeV collected with the CMS experiment. The measured cross sections, sigma(pp -> ZZ) = 5.1(1.4)(+1.5) (stat)(-1.1)(+1.4) (syst) +/- 0.1 (lumi) pb at 7 TeV, and 7.2(-0.8)(+0.8) (stat)(1.5)(+1.9) (syst) +/- 0.2 (lumi) pb at 8 TeV, are in good agreement with the standard model predictions with next-to-leading-order accuracy. The selected data are analyzed to search for anomalous triple gauge couplings involving the ZZ final state. In the absence of any deviation from the standard model predictions, limits are set on the relevant parameters. These limits are then combined with the previously published CMS results for ZZ in 4l final states, yielding the most stringent constraints on the anomalous couplings.

Aberrant viral RNAs produced in infected plant cells serve as templates for the synthesis of dsRNAs. The derived virus-related small interfering RNAs (siRNA) mediate cleavage of viral RNAs by post-transcriptional gene silencing (PTGS), thus blocking virus multiplication. Here, we identified ASYMMETRIC LEAVES2 (AS2) as a new component of plant P body complex which mediates mRNA decapping and degradation. We found that AS2 promotes DCP2 decapping activity, accelerates mRNA turnover rate, inhibits siRNA accumulation and functions as an endogenous suppressor of PTGS. Consistent with these findings, as2 mutant plants are resistant to virus infection whereas AS2 over-expression plants are hypersensitive. The geminivirus nuclear shuttle protein BV1 protein, which shuttles between nuclei and cytoplasm, induces AS2 expression, causes nuclear exit of AS2 to activate DCP2 decapping activity and renders infected plants more sensitive to viruses. These principles of gene induction and shuttling of induced proteins to promote mRNA decapping in the cytosol may be used by viral pathogens to weaken antiviral defenses in host plants.

DNA double-strand break repair involves phosphorylation of histone variant H2AX ('gamma H2AX'), which accumulates in foci at sites of DNA damage. In current models, the recruitment of multiple DNA repair proteins to gamma H2AX foci depends mainly on recognition of this 'mark' by a single protein, MDC1. However, DNA repair proteins accumulate at gH2AX sites without MDC1, suggesting that other 'readers' of this mark exist. Here, we use a quantitative chemical proteomics approach to profile direct, phospho-selective gamma H2AX binders in native proteomes. We identify gamma H2AX binders, including the DNA repair mediator 53BP1, which we show recognizes gamma H2AX through its BRCT domains. Furthermore, we investigate the targeting of wild-type 53BP1, or a mutant form deficient in gamma H2AX binding, to chromosomal breaks resulting from endogenous and exogenous DNA damage. Our results show how direct recognition of gamma H2AX modulates protein localization at DNA damage sites, and suggest how specific chromatin mark-reader interactions contribute to essential mechanisms ensuring genome stability.