The rockefeller university

We present the first comprehensive analysis of a diploid human genome that combines single-molecule sequencing with single-molecule genome maps. Our hybrid assembly markedly improves upon the contiguity observed from traditional shotgun sequencing approaches, with scaffold N50 values approaching 30 Mb, and we identified complex structural variants (SVs) missed by other high-throughput approaches. Furthermore, by combining Illumina short-read data with long reads, we phased both single-nucleotide variants and SVs, generating haplotypes with over 99% consistency with previous trio-based studies. Our work shows that it is now possible to integrate single-molecule and high-throughput sequence data to generate de novo assembled genomes that approach reference quality.

Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. In vitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio of mutant to wild-type RAD51 in cells. Instead, patient cells are sensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination-independent manner to maintain genomic integrity.

A first search is reported for a standard model Higgs boson (H) that is produced through vector boson fusion and decays to a bottom-quark pair. Two data samples, corresponding to integrated luminosities of 19.8 fb(-1) and 18.3 fb(-1) of proton-proton collisions at root s = 8 TeV were selected for this channel at the CERN LHC. The observed significance in these data samples for a H -> b (b) over bar signal at a mass of 125 GeV is 2.2 standard deviations, while the expected significance is 0.8 standard deviations. The fitted signal strength mu = sigma/sigma(SM) = 2.8(-1.4)(+1.6). The combination of this result with other CMS searches for the Higgs boson decaying to a b-quark pair yields a signal strength of 1.0 +/- 0.4, corresponding to a signal significance of 2.6 standard deviations for a Higgs boson mass of 125 GeV.

MYC2 is an important regulator for jasmonic acid (JA) signaling, but little is known about its posttranslational regulation. Here, we show that the MYC2 C-terminal region interacted with the PLANT U-BOX PROTEIN10 (PUB10) armadillo repeats in vitro. MYC2 was efficiently polyubiquitinated by PUB10 with UBC8 as an E2 enzyme and the conserved C249 in PUB10 was required for activity. The inactive PUB10(C249A) mutant protein retained its ability to heterodimerize with PUB10, thus blocking PUB10 E3 activity as a dominant-negative mutant. Both MYC2 and PUB10 were nucleus localized and coimmunoprecipitation experiments confirmed their interaction in vivo. Although unstable in the wild type, MYC2 stability was enhanced in pub10, suggesting destabilization by PUB10. Moreover, MYC2 half-life was shortened or prolonged by induced expression of PUB10 or the dominant-negative PUB10(C249A) mutant, respectively. Root growth of pub10 seedlings phenocopied 35S:MYC2 seedlings and was hypersensitive to methyl jasmonate, whereas 35S: PUB10 and jin1-9 (myc2) seedlings were hyposensitive. In addition, the root phenotype conferred by MYC2 overexpression in double transgenic plants was reversed or enhanced by induced expression of PUB10 or PUB10(C249A), respectively. Similar results were obtained with three other JA-regulated genes, TAT, JR2, and PDF1.2. Collectively, our results show that MYC2 is targeted by PUB10 for degradation during JA responses.

Background: IL-23 is associated with plaque psoriasis susceptibility and pathogenesis. BI 655066 is a fully human IgG(1) mAb specific for the IL-23 p19 subunit. Objective: This first-in-human proof-of-concept study evaluated the clinical and biological effects of BI 655066 in patients with moderate-to-severe plaque psoriasis. Methods: We performed a single-rising-dose, multicenter, randomized, double-blind, placebo-controlled, within-dose cohort phase I trial. Patients received 0.01, 0.05, 0.25, 1, 3, or 5 mg/kg BI 655066 intravenously, 0.25 or 1 mg/kg BI 655066 subcutaneously, or matched placebo. The primary objective was safety evaluation. Results: Thirty-nine patients received single-dose BI 655066 intravenously (n = 18) or subcutaneously (n = 13) or placebo (n = 8). Adverse events were reported with similar frequency in the BI 655066 and placebo groups. Four serious adverse events (not considered treatment related) were reported among BI 655066-treated patients. BI 655066 was associated with clinical improvement from week 2 and maintained for up to 66 weeks after treatment. At week 12, 75%, 90%, and 100% decreases in the Psoriasis Area and Severity Index were achieved by 87%, 58%, and 16% of BI 655066-treated patients (any dose), respectively, versus none receiving placebo. BI 655066 treatment resulted in reduced expression of lesional skin genes associated with IL-23/IL-17 signaling pathways and normalization of psoriatic lesion gene expression profiles to a profile approaching that of nonlesional skin. Significant correlation between treatment-associated molecular changes and psoriasis area and severity index improvement was observed (r = 0.73, P = 2 x 10(-6)). Conclusions: BI 655066 was well tolerated and associated with rapid, substantial, and durable clinical improvement in patients with moderate-to-severe psoriasis, supporting a central role for IL-23 in psoriasis pathogenesis.

Psoriasis, which presents as red, scaly patches on the body, is a common, autoimmune skin disease that affects 2 to 3 percent of the world population. To leverage recent molecular findings into the personalized treatment of psoriasis, we need a strategy that integrates clinical stratification with molecular phenotyping. In this study, we sought to stratify psoriasis patients by histological measurements of epidermal thickness, and to compare their molecular characterizations by gene expression, serum cytokines, and response to biologics. We obtained histological measures of epidermal thickness in a cohort of 609 psoriasis patients, and identified a mixture of two subpopulations-thick and thin plaque psoriasis-from which they were derived. This stratification was verified in a subcohort of 65 patients from a previously published study with significant differences in inflammatory cell infiltrates in the psoriatic skin. Thick and thin plaque psoriasis shared 84.8% of the meta-analysis-derived psoriasis transcriptome, but a stronger dysregulation of the meta-analysis-derived psoriasis transcriptome was seen in thick plaque psoriasis on microarray. RT-PCR revealed that gene expression in thick and thin plaque psoriasis was different not only within psoriatic lesional skin but also in peripheral non-lesional skin. Additionally, differences in circulating cytokines and their changes in response to biologic treatments were found between the two subgroups. All together, we were able to integrate histological stratification with molecular phenotyping as a way of exploring clinical phenotypes with different expression levels of the psoriasis transcriptome and circulating cytokines.

test0310:Measurements of diffractive dissociation cross sections in pp collisions at root s = 7 TeV are presented in kinematic regions defined by the masses M-X and M-Y of the two final-state hadronic systems separated by the largest rapidity gap in the event. Differential cross sections are measured as a function of xi= M-X(2)/s in the region -5.5 < log(10)xi 10(X) < -2.5, for logio M-Y < 0.5, dominated by single dissociation (SD), and 0.5 < log(10)M(Y) < 1.1, dominated by double dissociation (DD), where M-x and M-y are given in GeV. The inclusive pp cross section is also measured as a function of the width of the central pseudorapidity gap Delta eta for Delta eta > 3, logio M-X > 1.1, and logioMy > 1.1, a region dominated by DD. The cross sections integrated over these regions are found to be, respectively, 2.99 0.02(staf)12392(sysf) mb, 1.18 +/- 0.02(stat) +/- 0.13(syst) mh, and 0.58 +/- 0.01(stat)(-0.11)(+0.13) (syst) mh, and are used to extract extrapolated total SD and DD cross sections. In addition, the inclusive differential cross section, d sigma/d Delta eta(F), for events with a pseudorapidity gap adjacent to the edge of the detector, is measured over Delta eta F = 8.4 units of pseudorapidity. The results are compared to those of other experiments and to theoretical predictions and found compatible with slowly 'rising diffractive cross sections as a function of center-of-mass energy.

Stringent limits are set on the long-lived lepton-like sector of the phenomenological minimal supersymmetric standard model (pMSSM) and the anomaly-mediated super-symmetry breaking (AMSB) model. The limits are derived from the results presented in a recent search for long-lived charged particles in proton-proton collisions, based on data collected by the CMS detector at a centre-of-mass energy of 8 TeV at the Large Hadron Collider. In the pMSSM parameter sub-space considered, 95.9% of the points predicting charginos with a lifetime of at least 10 ns are excluded. These constraints on the pMSSM are the first obtained at the LHC. Charginos with a lifetime greater than 100 ns and masses up to about 800 GeV in the AMSB model are also excluded. The method described can also be used to set constraints on other models.