Transcriptional and phenotypic comparisons of Ppara knockout and siRNA knockdown mice

RNA interference (RNAi) has great potential as a tool for studying gene function in mammals. However, the specificity and magnitude of the in vivo response to RNAi remains to be fully characterized. A molecular and phenotypic comparison of a genetic knockout mouse and the corresponding knockdown version would help clarify the utility of the RNAi approach. Here, we used hydrodynamic delivery of small interfering RNA (siRNA) to knockdown peroxisome proliferator activated receptor alpha (Ppara), a gene that is central to the regulation of fatty acid metabolism. We found that Ppara knockdown in the liver results in a transcript profile and metabolic phenotype that is comparable to those of Ppara(−/−) mice. Combining the profiles from mice treated with the PPARα agonist fenofibrate, we confirmed the specificity of the RNAi response and identified candidate genes proximal to PPARα regulation. Ppara knockdown animals developed hypoglycemia and hypertriglyceridemia, phenotypes observed in Ppara(−/−) mice. In contrast to Ppara(−/−) mice, fasting was not required to uncover these phenotypes. Together, these data validate the utility of the RNAi approach and suggest that siRNA can be used as a complement to classical knockout technology in gene function studies

Constraints on the Timing and Extent of Deglacial Grounding Line Retreat in West Antarctica

Projections of Antarctica\u27s contribution to future sea level rise are associated with significant uncertainty, in part because the observational record is too short to capture long-term processes necessary to estimate ice mass changes over societally relevant timescales. Records of grounding line retreat from the geologic past offer an opportunity to extend our observations of these processes beyond the modern record and to gain a more comprehensive understanding of ice-sheet change. Here, we present constraints on the timing and inland extent of deglacial grounding line retreat in the southern Ross Sea, Antarctica, obtained via direct sampling of a subglacial lake located 150 km inland from the modern grounding line and beneath \u3e1 km of ice. Isotopic measurements of water and sediment from the lake enabled us to evaluate how the subglacial microbial community accessed radiocarbon-bearing organic carbon for energy, as well as where it transferred carbon metabolically. Using radiocarbon as a natural tracer, we found that sedimentary organic carbon was microbially translocated to dissolved carbon pools in the subglacial hydrologic system during the 4.5-year period of water accumulation prior to our sampling. This finding indicates that the grounding line along the Siple Coast of West Antarctica retreated more than 250 km inland during the mid-Holocene (6.3 ± 1.0 ka), prior to re-advancing to its modern position

Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Patients With Previously Treated Multiple Myeloma: Three-year Follow-up of CASTOR

Background: In the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone. Outcomes after 40.0 months of median follow-up are discussed. Patients and Methods: Eligible patients had received ≥ 1 line of treatment and were administered bortezomib (1.3 mg/m2) and dexamethasone (20 mg) for 8 cycles with or without daratumumab (16 mg/kg) until disease progression. Results: Of 498 patients in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247), 47% had 1 prior line of treatment (1PL; D-Vd, n = 122; Vd, n = 113). Median progression-free survival (PFS) was significantly prolonged with D-Vd versus Vd in the ITT population (16.7 vs. 7.1 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.25-0.40; P < .0001) and the 1PL subgroup (27.0 vs. 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P < .0001). In lenalidomide-refractory patients, the median PFS was 7.8 versus 4.9 months (HR, 0.44; 95% CI, 0.28-0.68; P = .0002) for D-Vd (n = 60) versus Vd (n = 81). Minimal residual disease (MRD)–negativity rates (10−5) were greater with D-Vd versus Vd (ITT: 14% vs. 2%; 1PL: 20% vs. 3%; both P < .0001). PFS2 was significantly prolonged with D-Vd versus Vd (ITT: HR, 0.48; 95% CI, 0.38-0.61; 1PL: HR, 0.35; 95% CI, 0.24-0.51; P < .0001). No new safety concerns were observed. Conclusion: After 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D-Vd provided the greatest benefit at first relapse and increased MRD-negativity rates.CASTOR showed the significant clinical benefit of daratumumab plus bortezomib and dexamethasone for patients with previously treated multiple myeloma. With ∼3 years median follow-up, this regimen continues to demonstrate significantly improved progression-free survival with higher minimal residual dis

Colors 1971

CONTENTS Eternal Nevada, E. Lawrence Roberts 3; 3-6-66, Doug Whalen 10; Penumbra, Doug Whalen 15; Iphigenia Doesn't Live Here Anymore, E. Lawrence Roberts 20; On the Other Side, Linda Chapman 30; No Ripples, Margaret Poore 44; Louis' Masquerade, E. Lawrence Roberts 53; The Best Years of My Life, Anonymous 61; Tamberlei, Toni Spencer 1; Death of the Grandfather, Pattie Linehan 2; Ah, Sunflower of My Life, Kathleen Ross 4; for you, man, Linda Stump 5; Neanderthal, Jeff Holmes 6; xxx, Charles D. Floro 8; kite-flying, Charles D. Floro 11; The Sea Carnival, Toni Spencer 12; Momentary Meditation: Toothaches and Poetry, Jan Fuglevand 13; The Colors of this Particular Morning, Jan Fuglevand 13; To Love a Drifter, Willa A. Smith 14; Carnival, Jeff Holmes 16; Oh, Well, Judy Smith 17; Stoneworts Magnified, Pattie Linehan 18; As we pass by, Connie Lynn Kelly 21; From: A Wonderer, A Wanderer, Or What, Jon Lokowich 23; Personification, Jan Fuglevand 29; Even Steps, Pattie Linehan 40; For Walt Whitman, Doug Whalen 42; Combat Is a Sometimes Place, Carol Davis 49; Days to be Remembered, Banna Hintz 50; To Harvest Men, Kathleen Ross 51; Paddy, Toni Spencer 52; Warm Places, Judy Smith 56; Words About One Bad Time, Jan Fuglevand 57; the manifesto, Charles D. Floro 58; suckers, Linda Stump 59; On Sameness, Pattie Linehan 60; And the Days Were Accomplished, Carol Davis 63; The cover sketch was done by Betty Schutt, the drawing on page fifty-five was done by Jenny Broderick, and the drawings on pages seven, twenty-two and forty-one were done by Maureen McMahon

Hunt for new phenomena using large jet multiplicities and missing transverse momentum with ATLAS in 4.7 fb−1 of s√=7TeV proton-proton collisions

Results are presented of a search for new particles decaying to large numbers of jets in association with missing transverse momentum, using 4.7 fb−1 of pp collision data at s√=7TeV collected by the ATLAS experiment at the Large Hadron Collider in 2011. The event selection requires missing transverse momentum, no isolated electrons or muons, and from ≥6 to ≥9 jets. No evidence is found for physics beyond the Standard Model. The results are interpreted in the context of a MSUGRA/CMSSM supersymmetric model, where, for large universal scalar mass m 0, gluino masses smaller than 840 GeV are excluded at the 95% confidence level, extending previously published limits. Within a simplified model containing only a gluino octet and a neutralino, gluino masses smaller than 870 GeV are similarly excluded for neutralino masses below 100 GeV

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde

Measurement of the top quark pair cross section with ATLAS in pp collisions at √s=7 TeV using final states with an electron or a muon and a hadronically decaying τ lepton

A measurement of the cross section of top quark pair production in proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 7 TeV is reported. The data sample used corresponds to an integrated luminosity of 2.05 fb -1. Events with an isolated electron or muon and a τ lepton decaying hadronically are used. In addition, a large missing transverse momentum and two or more energetic jets are required. At least one of the jets must be identified as originating from a b quark. The measured cross section, σtt-=186±13(stat.)±20(syst.)±7(lumi.) pb, is in good agreement with the Standard Model prediction