The rockefeller university

Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding a nuclear factor of kappa light chain enhancer in B cells (NF-kB) activator within skin epidermis, account for PSORS2. Here, we describe fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). Some variants were only seen in a single case, and these included putative pathogenic mutations (c.424G>A [p.Glu142Lys] and c.425A>G [p.Glu142Gly]) and the generalized-pustular-psoriasis mutation, c.413A>C (p.Glu138Ala); these three mutations lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial-psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities; in particular, putative pathogenic variants led to levels >2.5x higher than did wild-type CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with tumor necrosis factor alpha (TNF-alpha) to achieve significant increases in NF-kB levels. Transcriptome profiling of wild-type and variant CARD14 transfectants in keratinocytes differentiated probably pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD 14 polymorphisms were also genotyped, and meta-analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1 x 10(-6)). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw(star)0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease.

We report on a search for the standard model Higgs boson decaying into pairs of tau leptons in p (p) over bar collisions produced by the Tevatron at root s = 1.96 TeV. The analyzed data sample was recorded by the CDFII detector and corresponds to an integrated luminosity of 6.0 fb(-1). The search is performed in the final state with one tau decaying leptonically and the second one identified through its semihadronic decay. Since no significant excess is observed, a 95% credibility level upper limit on the production cross section times branching ratio to the tau tau final state is set for hypothetical Higgs boson masses between 100 and 150 GeV/c(2). For a Higgs boson of 120 GeV/c(2) the observed (expected) limit is 14.6 (15.3) the predicted value.

A study of the substructure of jets with transverse momentum greater than 400 GeV/c produced in proton-antiproton collisions at a center-of-mass energy of 1.96 TeV at the Fermilab Tevatron Collider and recorded by the CDF II detector is presented. The distributions of the jet mass, angularity, and planar flow are measured for the first time in a sample with an integrated luminosity of 5.95 fb(-1). The observed substructure for high mass jets is consistent with predictions from perturbative quantum chromodynamics.

The number of bacterial species estimated to exist on Earth has increased dramatically in recent years. This newly recognized species diversity has raised the possibility that bacterial natural product biosynthetic diversity has also been significantly underestimated by previous culture-based studies. Here, we compare 454-pyrosequenced nonribosomal peptide adenylation domain, type I polyketide ketosynthase domain, and type II polyketide ketosynthase alpha gene fragments amplified from cosmid libraries constructed using DNA isolated from three different arid soils. While 16S rRNA gene sequence analysis indicates these cloned metagenomes contain DNA from similar distributions of major bacterial phyla, we found that they contain almost completely distinct collections of secondary metabolite biosynthetic gene sequences. When grouped at 85% identity, only 1.5% of the adenylation domain, 1.2% of the ketosynthase, and 9.3% of the ketosynthase alpha sequence clusters contained sequences from all three metagenomes. Although there is unlikely to be a simple correlation between biosynthetic gene sequence diversity and the diversity of metabolites encoded by the gene clusters in which these genes reside, our analysis further suggests that sequences in one soil metagenome are so distantly related to sequences in another metagenome that they are, in many cases, likely to arise from functionally distinct gene clusters. The marked differences observed among collections of biosynthetic genes found in even ecologically similar environments suggest that prokaryotic natural product biosynthesis diversity is, like bacterial species diversity, potentially much larger than appreciated from culture-based studies.

Medical applications of nanotechnology typically focus on drug delivery and biosensors. Here, we combine nanotechnology and bioengineering to demonstrate that nanoparticles can be used to remotely regulate protein production in vivo. We decorated a modified temperature-sensitive channel, TRPV1, with antibody-coated iron oxide nanoparticles that are heated in a low-frequency magnetic field. When local temperature rises, TRPV1 gates calcium to stimulate synthesis and release of bioengineered insulin driven by a Ca2+-sensitive promoter. Studying tumor xenografts expressing the bioengineered insulin gene, we show that exposure to radio waves stimulates insulin release from the tumors and lowers blood glucose in mice. We further show that cells can be engineered to synthesize genetically encoded ferritin nanoparticles and inducibly release insulin. These approaches provide a platform for using nanotechnology to activate cells.

Retroviruses have long been a fertile model for discovering host-pathogen interactions and their associated biological principles and processes. These advances have not only informed fundamental concepts of viral replication and pathogenesis but have also provided novel insights into host cell biology. This is illustrated by the recent descriptions of host-encoded restriction factors that can serve as effective inhibitors of retroviral replication. Here, we review our understanding of the three restriction factors that have been widely shown to be potent inhibitors of HIV-1: namely, APOBEC3G, TRIM5 alpha, and tetherin. In each case, we discuss how these unrelated proteins were identified, the mechanisms by which they inhibit replication, the means used by HIV-1 to evade their action, and their potential contributions to viral pathogenesis as well as inter-and intraspecies transmission.

Human CD34 +/- progenitor-derived Langerhans-type dendritic cells (LCs) are more potent stimulators of T-cell immunity against tumor and viral antigens in vitro than are monocyte-derived DCs (moDCs). The exact mechanisms have remained elusive until now, however. LCs synthesize the highest amounts of IL-15R-alpha mRNA and protein, which binds IL-15 for presentation to responder lymphocytes, thereby signaling the phosphorylation of signal transducer and activator of transcription 5 (pSTAT5). LCs electroporated with Wilms tumor 1 (WT1) mRNA achieve sufficiently sustained presentation of antigenic peptides, which together with IL-15R-alpha/IL-15, break tolerance against WT1 by stimulating robust autologous, WT1-specific cytolytic T-lymphocytes (CTLs). These CTLs develop from healthy persons after only 7 days' stimulation without exogenous cytokines and lyse MHC-restricted tumor targets, which include primary WT1(+) leukemic blasts. In contrast, moDCs require exogenous rhuIL-15 to phosphorylate STAT5 and attain stimulatory capacity comparable to LCs. LCs therefore provide a more potent costimulatory cytokine milieu for T-cell activation than do moDCs, thus accounting for their superior stimulation of MHC-restricted Ag-specific CTLs without need for exogenous cytokines. These data support the use of mRNA-electroporated LCs, or moDCs supplemented with exogenous rhuIL-15, as vaccines for cancer immunotherapy to break tolerance against self-differentiation antigens shared by tumors. (Blood. 2012; 119(22): 5182-5190)

Measurements from the CMS experiment at the LHC of dihadron correlations for charged particles produced in PbPb collisions at a nucleon-nucleon centre-of-mass energy of 2.76 TeV are presented. The results are reported as a function of the particle transverse momenta (p(T)) and collision centrality over a broad range in relative pseudorapidity (Delta eta) and the full range of relative azimuthal angle (Delta phi). The observed two-dimensional correlation structure in Delta eta and Delta phi is characterised by a narrow peak at (Delta eta, Delta phi) approximate to (0, 0) from jet-like correlations and a long-range structure that persists up to at least vertical bar Delta eta vertical bar = 4. An enhancement of the magnitude of the short-range jet peak is observed with increasing centrality, especially for particles of p(T) around 1-2 GeV/c. The long-range azimuthal dihadron correlations are extensively studied using a Fourier decomposition analysis. The extracted Fourier coefficients are found to factorise into a product of single-particle azimuthal anisotropies up to p(T) approximate to 3-3.5 GeV/c for at least one particle from each pair, except for the second-order harmonics in the most central PbPb events. Various orders of the single-particle azimuthal anisotropy harmonics are extracted for associated particle p(T) of 1-3 GeV/c, as a function of the trigger particle p(T) up to 20 GeV/c and over the full centrality range.

Results are presented from a search for heavy bottom-like quarks, pair-produced in pp collisions at root s = 7 TeV, undertaken with the CMS experiment at the LHC. The b' quarks are assumed to decay exclusively to tW. The b'(b') over bar -> tW(-)(t) over barW(+) process can be identified by its distinctive signatures of three leptons or two leptons of same charge, and at least one b-quark jet. Using a data sample corresponding to an integrated luminosity of 4.9 fb(-1), observed events are compared to the standard model background predictions, and the existence of b' quarks having masses below 611 GeV/c(2) is excluded at 95% confidence level.

Using data from p (p) over bar collisions at root s = 1.96 TeV recorded by the CDF II detector at the Fermilab Tevatron, we present improved measurements of the masses and first measurements of natural widths of the four bottom baryon resonance states Sigma(+)(b), Sigma*(+)(b) and Sigma(-)(b), Sigma*(-)(b). These states are fully reconstructed in their decay modes to Lambda(0)(b)pi(+/-) where Lambda(0)(b) -> Lambda(+)(c)pi(-) with Lambda(+)(c) -> pK(-) pi(+). The analysis is based on a data sample corresponding to an integrated luminosity of 6.0 fb(-1) collected by an online event selection based on tracks displaced from the p (p) over bar interaction point.