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The production of (1S), (2S), and (3S) is investigated in pPb and pp collisions at centre-of-mass energies per nucleon pair of 5.02 TeV and 2.76 TeV, respectively. The datasets correspond to integrated luminosities of about 31 nb(-1) (pPb) and 5.4 pb(-1) (pp), collected in 2013 by the CMS experiment at the LHC. Upsilons that decay into muons are reconstructed within the rapidity interval |y (CM)| < 1.93 in the nucleon-nucleon centre-of-mass frame. Their production is studied as a function of two measures of event activity, namely the charged-particle multiplicity measured in the pseudorapidity interval |eta| < 2.4, and the sum of transverse energy deposited at forward pseudorapidity, 4.0 < |eta| < 5.2. The cross sections normalized by their event activity integrated values, (nS)/aEuro(nS)aEuro parts per thousand, are found to rise with both measures of the event activity in pp and pPb. In both collision systems, the ratios of the excited to the ground state cross sections, (nS)/ (1S), are found to decrease with the charged-particle multiplicity, while as a function of the transverse energy the variation is less pronounced. The event activity integrated double ratios, [(nS)/ (1S)](pPb) /[(nS)/ (1S)](pp), are also measured and found to be 0.83 +/- 0.05 (stat.) +/- 0.05 (syst.) and 0.71 +/- 0.08 (stat.) +/- 0.09 (syst.) for (2S) and (3S), respectively.

HLA-restricted immune escape mutations that persist following HIV transmission could gradually spread through the viral population, thereby compromising host antiviral immunity as the epidemic progresses. To assess the extent and phenotypic impact of this phenomenon in an immunogenetically diverse population, we genotypically and functionally compared linked HLA and HIV (Gag/Nef) sequences from 358 historic (1979-1989) and 382 modern (2000-2011) specimens from four key cities in the North American epidemic (New York, Boston, San Francisco, Vancouver). Inferred HIV phylogenies were star-like, with approximately two-fold greater mean pairwise distances in modern versus historic sequences. The reconstructed epidemic ancestral (founder) HIV sequence was essentially identical to the North American subtype B consensus. Consistent with gradual diversification of a "consensus-like" founder virus, the median "background" frequencies of individual HLA-associated polymorphisms in HIV (in individuals lacking the restricting HLA[s]) were similar to 2-fold higher in modern versus historic HIV sequences, though these remained notably low overall (e. g. in Gag, medians were 3.7% in the 2000s versus 2.0% in the 1980s). HIV polymorphisms exhibiting the greatest relative spread were those restricted by protective HLAs. Despite these increases, when HIV sequences were analyzed as a whole, their total average burden of polymorphisms that were "pre-adapted" to the average host HLA profile was only similar to 2% greater in modern versus historic eras. Furthermore, HLA-associated polymorphisms identified in historic HIV sequences were consistent with those detectable today, with none identified that could explain the few HIV codons where the inferred epidemic ancestor differed from the modern consensus. Results are therefore consistent with slow HIV adaptation to HLA, but at a rate unlikely to yield imminent negative implications for cellular immunity, at least in North America. Intriguingly, temporal changes in protein activity of patient-derived Nef (though not Gag) sequences were observed, suggesting functional implications of population-level HIV evolution on certain viral proteins.

Background: IRAK4 is a central kinase in IL-1R/TLR signaling. Results: IRAK4 is activated by autophosphorylation, and its inhibition reduces cytokine induction in human monocytes but not dermal fibroblasts. Conclusion: IL-1R/TLR-induced autophosphorylation activates IRAK4 and controls cytokine induction in a cell type-specific manner. Significance: Our data provide the mechanism of IRAK4 activation and role in cytokine induction in human cells. IRAK4 is a central kinase in innate immunity, but the role of its kinase activity is controversial. The mechanism of activation for IRAK4 is currently unknown, and little is known about the role of IRAK4 kinase in cytokine production, particularly in different human cell types. We show IRAK4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues Thr-342, Thr-345, and Ser-346 is required for full activity, and the death domain regulates the activation of IRAK4. Using antibodies against activated IRAK4, we demonstrate that IRAK4 becomes phosphorylated in human cells following stimulation by IL-1R and Toll-like receptor agonists, which can be blocked pharmacologically by a dual inhibitor of IRAK4 and IRAK1. Interestingly, in dermal fibroblasts, although complete inhibition of IRAK4 kinase activity does not inhibit IL-1-induced IL-6 production, NF-B, or MAPK activation, there is complete ablation of these processes in IRAK4-deficient cells. In contrast, the inhibition of IRAK kinase activity in primary human monocytes reduces R848-induced IL-6 production with minimal effect on NF-B or MAPK activation. Taken together, these studies define the mechanism of IRAK4 activation and highlight the differential role of IRAK4 kinase activity in different human cell types as well as the distinct roles IRAK4 scaffolding and kinase functions play.

We present a measurement of the W-boson mass, M-W, using data corresponding to 2.2 fb(-1) of integrated luminosity collected in p (p) over bar collisions at root s = 1.96 TeV with the CDF II detector at the Fermilab Tevatron. The selected sample of 470 126 W -> ev candidates and 624 708 W -> mu nu candidates yields the measurement M-W = 80387 +/- 12 (stat) +/- 15(syst) = 80387 +/- 19 MeV/c(2). This is the most precise single measurement of the W-boson mass to date.

Faithful chromosome segregation during meiosis is indispensable to prevent birth defects and infertility. Canonical genetic manipulations have not been very useful for studying meiosis II, since mutations of genes involved in cell cycle regulation or chromosome segregation may affect meiosis I, making interpretations of any defects observed in meiosis II complicated. Here we present a powerful strategy to dissect meiosis I and meiosis II, using chemical inhibitors in genetically tractable model organism fission yeast (Schizosaccharomyces pombe). As various chemical probes are not active in fission yeast, mainly due to an effective multidrug resistance (MDR) response, we have recently developed a drug-hypersensitive MDR-sup strain by suppression of the key genes responsible for MDR response. We further developed the MDR-supML (marker-less) strain by deleting 7 MDR genes without commonly used antibiotic markers. The new strain makes fluorescent tagging and gene deletion much simpler, which enables effective protein visualization in varied genetic backgrounds. Using the MDR-supML strain with chemical inhibitors and live cell fluorescence microscopy, we established cell cycle arrest at meiosis I and meiosis II and examined Aurora-dependent spindle assembly checkpoint (SAC) regulation during meiosis. We found that Aurora B/Ark1 kinase activity is required for recruitment of Bub1, an essential SAC kinase, to unattached kinetochore in prometaphase I and prometaphase II as in mitosis. Thus, Aurora's role in SAC activation is likely conserved in mitosis, meiosis I, and meiosis II. Together, our MDR-supML strain will be useful to dissect complex molecular mechanisms in mitosis and 2 successive meiotic divisions.

Clustered regularly interspaced short palindromic repeats (CRISPR), and associated proteins (Cas) comprise the CRISPR-Cas system, which confers adaptive immunity against exogenic elements in many bacteria and most archaea. CRISPR-mediated immunization occurs through the uptake of DNA from invasive genetic elements such as plasmids and viruses, followed by its integration into CRISPR loci. These loci are subsequently transcribed and processed into small interfering RNAs that guide nucleases for specific cleavage of complementary sequences. Conceptually, CRISPR-Cas shares functional features with the mammalian adaptive immune system, while also exhibiting characteristics of Lamarckian evolution. Because immune markers spliced from exogenous agents are integrated iteratively in CRISPR loci, they constitute a genetic record of vaccination events and reflect environmental conditions and changes over time. Cas endonucleases, which can be reprogrammed by small guide RNAs have shown unprecedented potential and flexibility for genome editing and can be repurposed for numerous DNA targeting applications including transcriptional control.

Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.

Measurements are presented by the CMS Collaboration at the Large Hadron Collider (LHC) of the higher-order harmonic coefficients that describe the azimuthal anisotropy of charged particles emitted in root s(NN) = 2.76 TeV PbPb collisions. Expressed in terms of the Fourier components of the azimuthal distribution, the n = 3-6 harmonic coefficients are presented for charged particles as a function of their transverse momentum (0.3 < p(T) < 8.0 GeV/c), collision centrality (0%-70%), and pseudorapidity (|eta| < 2.0). The data are analyzed using the event plane, multiparticle cumulant, and Lee-Yang zeros methods, which provide different sensitivities to initial-state fluctuations. Taken together with earlier LHC measurements of elliptic flow (n = 2), the results on higher-order harmonic coefficients develop a more complete picture of the collective motion in high-energy heavy-ion collisions and shed light on the properties of the produced medium.

The inhibitory Fc gamma R Fc gamma RIIB is widely expressed on B cells, dendritic cells (DCs), and myeloid effector cells and modulates a variety of Ab-driven in vivo functions. Although it has been established that Fc gamma RIIB plays an important role in the maintenance of peripheral tolerance, the responsible cell-specific Fc gamma RIIB expression remains to be determined. In this study, we generated mice with selective deletion of Fc gamma RIIB in B cells, DCs, and myeloid effector cells and evaluated these novel strains in models of tolerance and autoimmune diseases. Our results demonstrate that mice with selective deletion of Fc gamma RIIB expression in B cells and DCs have increased Ab and T cell responses, respectively, and display enhanced susceptibility to disease in distinct models, suggesting that Fc gamma RIIB expression in distinct cellular populations contributes to the maintenance of peripheral tolerance through different mechanisms.