The rockefeller university

Constraints are presented on the total width of the recently discovered Higgs boson, Gamma(H), using its relative on-shell and off-shell production and decay rates to a pair of Z bosons, where one Z boson decays to an electron or muon pair, and the other to an electron, muon, or neutrino pair. The analysis is based on the data collected by the CMS experiment at the LHC in 2011 and 2012, corresponding to integrated luminosities of 5.1 fb(-1) at a center-of-mass energy root s = 7 TeV and 19.7 fb(-1) at root s = 8 TeV. A simultaneous maximum likelihood fit to the measured kinematic distributions near the resonance peak and above the Z-boson pair production threshold leads to an upper limit on the Higgs boson width of Gamma(H) < 22 MeV at a 95% confidence level, which is 5.4 times the expected value in the standard model at the measured mass of m(H) = 125.6 GeV. (C) 2014 The Authors. Published by Elsevier B.V.

Infection of macaques with chimeric viruses based on SIVMAC but expressing the HIV-1 envelope (Env) glycoproteins (SHIVs) remains the most powerful model for evaluating prevention and therapeutic strategies against AIDS. Unfortunately, only a few SHIVs are currently available. Furthermore, their generation has required extensive adaptation of the HIV-1 Env sequences in macaques so they may not accurately represent HIV-1 Env proteins circulating in humans, potentially limiting their translational utility. We developed a strategy for generating large numbers of SHIV constructs expressing Env proteins from newly transmitted HIV-1 strains. By inoculating macaques with cocktails of multiple SHIV variants, we selected SHIVs that can replicate and cause AIDS-like disease in immunologically intact rhesus macaques without requiring animal-to-animal passage. One of these SHIVs could be transmitted mucosally. We demonstrate the utility of the SHIVs generated by this method for evaluating neutralizing antibody administration as a protection against mucosal SHIV challenge.

A search for the standard model Higgs boson produced in association with a top-quark pair (t (t) over barH) is presented, using data samples corresponding to integrated luminosities of up to 5.1 fb(-1) and 19.7 fb(-1) collected in pp collisions at center-of-mass energies of 7 TeV and 8 TeV respectively. The search is based on the following signatures of the Higgs boson decay: H -> hadrons, H -> photons, and H -> leptons. The results are characterized by an observed t (t) over barH signal strength relative to the standard model cross section, mu = sigma/sigma(SM), under the assumption that the Higgs boson decays as expected in the standard model. The best fit value is mu = 2.8 +/- 1.0 for a Higgs boson mass of 125.6 GeV.

The drug DMXAA (5,6-dimethylxanthenone-4-acetic acid) showed therapeutic promise against solid tumors in mouse models but subsequently failed in human clinical trials. DMXAA was later discovered to activate mouse, but not human, STING, an adaptor protein in the cyclic dinucleotide cGAMP-mediated signaling pathway, inducing type I interferon expression. To facilitate the development of compounds that target human STING, we combined structural, biophysical, and cellular assays to study mouse and human chimeric proteins and their interaction with DMXAA. We identified a single substitution (G230I) that enables a DMXAA-induced conformational transition of hSTING from an inactive "open" to an active "closed" state. We also identified a substitution within the binding pocket (Q266I) that cooperates with G230I and the previously identified S162A binding-pocket point substitution, rendering hSTING highly sensitive to DMXAA. These findings should facilitate the reciprocal engineering of DMXAA analogs that bind and stimulate wild-type hSTING and their exploitation for vaccine-adjuvant and anticancer drug development.

Mutations in the cytosine-5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post-transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine-5 RNA methylomes in patient fibroblasts and NSun2-deficient mice, we find that loss of cytosine-5 RNA methylation increases the angiogenin-mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 50 tRNA-derived small RNA fragments. Accumulation of 50 tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site-specific NSun2-mediated methylation and that the presence of 50 tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2-deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2-mediated tRNA methylation contributes to human diseases via stress-induced RNA cleavage.

Production of prompt J/psi meson pairs in proton-proton collisions at root s = 7 TeV is measured with the CMS experiment at the LHC in a data sample corresponding to an integrated luminosity of about 4.7 fb(-1). The two J/psi mesons are fully reconstructed via their decays into mu(+)mu(-) pairs. This observation provides for the first time access to the high-transverse-momentum region of J/psi pair production where model predictions are not yet established. The total and differential cross sections are measured in a phase space defined by the individual J/psi transverse momentum (p(T)(J/psi)) and rapidity (vertical bar y(J/psi)vertical bar): vertical bar y(J/psi)vertical bar < 1.2 for p(T)(J/psi) > 6.5 GeV/c; 1.2 < vertical bar y(J/psi)vertical bar < 1.43 for a pT threshold that scales linearly with vertical bar y(J/psi)vertical bar from 6.5 to 4.5 GeV/c; and 1.43 < vertical bar y(J/psi)vertical bar < 2.2 for p(T)(J/psi) > 4.5 GeV/c. The total cross section, assuming unpolarized prompt J/psi pair production is 1.49 +/- 0.07 (stat) +/- 0.13 (syst) nb. Different assumptions about the J/psi polarization imply modifications to the cross section ranging from -31% to +27%.

Accelerated ovarian failure (AOF) can be induced in young mice with low doses of 4-vinylcyclohexene diepoxide (VCD), modeling the hormone changes observed across menopause. We assessed markers of synaptic plasticity in the hippocampus, anxiety-like behavior, and spatial learning longitudinally at 4 time points across the AOF model: premenopause, early perimenopause, late perimenopause, and postmenopause (POST). As others have shown, VCD administration decreased ovarian follicle counts and increased acyclicity as the model progressed to POST but with no impact on organ or body weights. The morphology of Iba1 immunoreactive microglia did not differ between vehicle- and VCD-administered mice. Hippocampal postsynaptic density 95 levels were minimally altered across the AOF model but decreased at POST in CA3b 24 hours after exogenous estradiol benzoate (EB). In contrast, hippocampal phosphorylated AKT levels transiently decreased in premenopause but increased at POST after 24 hours of EB in select subregions. Electron microscopy revealed fewer estrogen receptor alpha containing dendritic spines and terminals in CA1 stratum radiatum at POST. mRNA levels of most brain-derived neurotrophic factor exons (except V and VI) were lower in POST compared with ovariectomized mice. Exon V was sensitive to 24 hours of EB administration in POST-VCD. Anxiety-like behavior was unaffected at any menopause phase. Spatial learning was unaffected in all groups, but POST-VCD mice performed below chance. Our results suggest that the AOF model is suitable for longitudinal studies of neurobiological changes across the menopause transition in mice. Our findings also point to complex interactions between estrogen receptors and pathways involved in synaptic plasticity.

Aberrant regulation of RNA stability has an important role in many disease states(1,2). Deregulated post-transcriptional modulation, such as that governed by microRNAs targeting linear sequence elements in messenger RNAs, has been implicated in the progression of many cancer types(3-7). A defining feature of RNA is its ability to fold into structures. However, the roles of structural mRNA elements in cancer progression remain unexplored. Here we performed an unbiased search for post-transcriptional modulators of mRNA stability in breast cancer by conducting whole-genome transcript stability measurements in poorly and highly metastatic isogenic human breast cancer lines. Using a computational framework that searches RNA sequence and structure space(8), we discovered a family of GC-rich structural cis-regulatory RNA elements, termed sRSEs for structural RNA stability elements, which are significantly overrepresented in transcripts displaying reduced stability in highly metastatic cells. By integrating computational and biochemical approaches, we identified TARBP2, a double-stranded RNA-binding protein implicated in microRNA processing, as the trans factor that binds the sRSE family and similar structural elements collectively termed TARBP2-binding structural elements (TBSEs) in transcripts. TARBP2 is overexpressed in metastatic cells and metastatic human breast tumours and destabilizes transcripts containing TBSEs. Endogenous TARBP2 promotes metastatic cell invasion and colonization by destabilizing amyloid precursor protein (APP) and ZNF395 transcripts, two genes previously associated with Alzheimer's and Huntington's disease, respectively. We reveal these genes to be novel metastasis suppressor genes in breast cancer. The cleavage product of APP, extracellular alpha-myloida peptide, directly suppresses invasion while ZNF395 transcriptionally represses a pro-metastatic gene expression program. The expression levels of TARBP2, APP and ZNF395 in human breast carcinomas support their experimentally uncovered roles in metastasis. Our findings establish a non-canonical and direct role for TARBP2 in mammalian gene expression regulation and reveal that regulated RNA destabilization through protein-mediated binding of mRNA structural elements can govern cancer progression.

Ants have evolved an amazing variety of feeding habits to utilize diverse food sources. However, only one ant species, Euprenolepis pro cera (EMERY, 1900) (Formicidae: Formicinae), has been described as a specialist harvester of wild-growing mushrooms. Mushrooms are a very abundant food source in certain habitats, but utilizing them is expected to require specific adaptations. Here, we report the discovery of another, sympatric, and widespread mushroom harvesting ant, Euprenolepis wittei LAPOLLA, 2009. The similarity in nutritional niches of both species was expected to be accompanied by similarities in adaptive behavior and differences due to competitive avoidance. Similarities were found in mushroom acceptance and harvesting behavior: Both species harvested a variety of wild-growing mushrooms and formed characteristic mushroom piles inside the nest that were processed continuously by adult workers. Euprenolepis procera was apparently dominant at mushroom baits displacing the smaller, less numerous E. wittei foragers. However, interspecific competition for mushrooms is likely relaxed by differences in other niche dimensions, particularly the temporal activity pattern. The discovery of a second, widespread mushroom harvesting ant suggests that this life style is more common than previously thought, at least in Southeast Asia, and has implications for the ecology of tropical rainforests. Exploitation of the reproductive organs of fungi likely impacts spore development and distribution and thus affects the fungal community.