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Huntington's disease (HD) is a devastating neurological disorder that is caused by an expansion of the poly-Q tract in exon 1 of the Huntingtin gene (HTT). HTT is an evolutionarily conserved and ubiquitously expressed protein that has been linked to a variety of functions including transcriptional regulation, mitochondrial function, and vesicle transport. This large protein has numerous caspase and calpain cleavage sites and can be decorated with several post-translational modifications such as phosphorylations, acetylations, sumoylations, and palmitoylations. However, the exact function of HTT and the role played by its modifications in the cell are still not well understood. Scrutiny of HTT function has been focused on a single, full length mRNA. In this study, we report the discovery of 5 novel HTT mRNA splice isoforms that are expressed in normal and HTT-expanded human embryonic stem cell (hESC) lines as well as in cortical neurons differentiated from hESCs. Interestingly, none of the novel isoforms generates a truncated protein. Instead, 4 of the 5 new isoforms specifically eliminate domains and modifications to generate smaller HTT proteins. The fifth novel isoform incorporates a previously unreported additional exon, dubbed 41b, which is hominid-specific and introduces a potential phosphorylation site in the protein. The discovery of this hominid-specific isoform may shed light on human-specific pathogenic mechanisms of HTT, which could not be investigated with current mouse models of the disease.

The differential cross sections for the production of photons in Z -> mu(+)mu(-)gamma decays are presented as a function of the transverse energy of the photon and its separation from the nearest muon. The data for these measurements are collected with the CMS detector and correspond to an integrated luminosity of 4.7 fb(-1) of pp collisions at root s = 7 TeV delivered by the CERN LHC. The cross sections are compared to simulations with POWHEG and PYTHIA, where PYTHIA is used to simulate parton showers and final- state photons. These simulations match the data to better than 5%. ffiffiffi

The double-differential cross sections of promptly produced J/psi and psi(2S) mesons are measured in pp collisions at root s = 7 TeV, as a function of transverse momentum p(T) and absolute rapidity y. The analysis uses J/psi and psi(2S) dimuon samples collected by the CMS experiment, corresponding to integrated luminosities of 4.55 and 4.90 fb(-1), respectively. The results are based on a two-dimensional analysis of the dimuon invariant mass and decay length, and extend to p(T) = 120 and 100 GeV for the J/psi and psi(2S), respectively, when integrated over the interval y < 1.2. The ratio of the psi(2S) to J/psi cross sections is also reported for y < 1.2, over the range 10 < p(T) < 100 GeV. These are the highest p(T) values for which the cross sections and ratio have been measured.

Enzyme-mediated modifications at the wobble position of tRNAs are essential for the translation of the genetic code. We report the genetic, biochemical and structural characterization of CmoB, the enzyme that recognizes the unique metabolite carboxy-S-adenosine-L-methionine (Cx-SAM) and catalyzes a carboxymethyl transfer reaction resulting in formation of 5-oxyacetyluridine at the wobble position of tRNAs. CmoB is distinctive in that it is the only known member of the SAM-dependent methyltransferase (SDMT) superfamily that utilizes a naturally occurring SAM analog as the alkyl donor to fulfill a biologically meaningful function. Biochemical and genetic studies define the in vitro and in vivo selectivity for Cx-SAM as alkyl donor over the vastly more abundant SAM. Complementary high-resolution structures of the apo- and Cx-SAM bound CmoB reveal the determinants responsible for this remarkable discrimination. Together, these studies provide mechanistic insight into the enzymatic and non-enzymatic feature of this alkyl transfer reaction which affords the broadened specificity required for tRNAs to recognize multiple synonymous codons.

A search is presented for a standard model-like Higgs boson decaying to the mu(+)mu(-) or e(+)e(-) final states based on proton-proton collisions recorded by the CMS experiment at the CERN LHC. The data correspond to integrated luminosities of 5.0 fb(-1) at a centre-of-mass energy of 7 TeV and 19.7 fb(-1) at 8 TeV for the mu(+)mu(-) search, and of 19.7 fb(-1) at 8 TeV for the e(+)e(-) search. Upper limits on the production cross section times branching fraction at the 95% confidence level are reported for Higgs boson masses in the range from 120 to 150 GeV. For a Higgs boson with a mass of 125 GeV decaying to mu(+)mu(-), the observed (expected) upper limit on the production rate is found to be 7.4 (6.5(-1.9)(+2.8)) times the standard model value. This corresponds to an upper limit on the branching fraction of 0.0016. Similarly, for e(+)e(-), an upper limit of 0.0019 is placed on the branching fraction, which is approximate to 3.7 x 10(5) times the standard model value. These results, together with recent evidence of the 125 GeV boson coupling to tau-leptons with a larger branching fraction consistent with the standard model, confirm that the leptonic couplings of the new boson are not flavour-universal. (C) 2015 CERN for the benefit of the CMS Collaboration. Published by Elsevier B.V.

The CA125 antigen is found in the serum of many patients with serous ovarian cancer and has been widely used as a disease marker. CA125 has been shown to be an independent factor for clinical outcome in this disease. In The Cancer Genome Atlas ovarian cancer project, MUC16 expression levels are frequently increased, and the highest levels of MUC16 expression are linked to a significantly worse survival. To examine the biologic effect of the proximal portion of MUC16/CA125, NIH/3T3 (3T3) fibroblast cell lines were stably transfected with the carboxy elements of MUC16. As few as 114 amino acids from the carboxyterminal portion of MUC16 were sufficient to increase soft agar growth, promote matrigel invasion, and increase the rate of tumor growth in athymic nude mice. Transformation with carboxy elements of MUC16 was associated with activation of the AKT and ERK pathways. MUC16 transformation was associated with up-regulation of a number of metastases and invasion gene transcripts, including IL-1 beta, MMP2, and MMP9. All observed oncogenic changes were exclusively dependent on the extracellular "ectodomain" of MUC16. The biologic impact of MUC16 was also explored through the creation of a transgenic mouse model expressing 354 amino acids of the carboxy-terminal portion of MUC16 (MUC16(c354)). Under a CMV, early enhancer plus chicken beta actin promoter (CAG) MUC16(c354) was well expressed in many organs, including the brain, colon, heart, kidney, liver, lung, ovary, and spleen. MUC16(c354) transgenic animals appear to be viable, fertile, and have a normal lifespan. However, when crossed with p53-deficient mice, the MUC16(c354): p53(+/-) progeny displayed a higher frequency of spontaneous tumor development compared to p53(+/-) mice alone. We conclude that the carboxy-terminal portion of the MUC16/CA125 protein is oncogenic in NIH/3T3 cells, increases invasive tumor properties, activates the AKT and ERK pathways, and contributes to the biologic properties of ovarian cancer.

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies.

Passively administered anti-tumor monoclonal antibodies (mAbs) rapidly kill tumor targets via Fc gamma R-mediated cytotoxicity (ADCC), a short-term process. However, anti-tumor mAb treatment can also induce a vaccinal effect, in which mAb-mediated tumor death induces a long-term anti-tumor cellular immune response. To determine how such responses are generated, we utilized a murine model of an anti-tumor vaccinal effect against a model neoantigen. We demonstrate that Fc gamma R expression by CD11c(+) antigen-presenting cells is required to generate antitumor T cell responses upon ADCC-mediated tumor clearance. Using Fc gamma R-humanized mice, we demonstrate that anti-tumor human (h)IgG1 must engage hFc gamma RIIIA on macrophages to mediate ADCC, but also engage hFc gamma RIIA, the sole hFc gamma R expressed by human dendritic cells (DCs), to generate a potent vaccinal effect. Thus, while next-generation antitumor antibodies with enhanced binding to only hFc gamma RIIIA are now in clinical use, ideal anti-tumor antibodies must be optimized for both cytotoxic effects as well as hFc gamma RIIA engagement on DCs to stimulate long-term anti-tumor cellular immunity.