2,764 research outputs found
Notch3 Is Dispensable for Thymocyte β-Selection and Notch1-Induced T Cell Leukemogenesis
Notch1 (N1) signaling induced by intrathymic Delta-like (DL) ligands is required for T cell lineage commitment as well as self-renewal during “β-selection” of TCRβ+ CD4−CD8− double negative 3 (DN3) T cell progenitors. However, over-expression of the N1 intracellular domain (ICN1) renders N1 activation ligand-independent and drives leukemic transformation during β-selection. DN3 progenitors also express Notch3 (N3) mRNA, and over-expression of ligand-independent mutant N3 (ICN3) influences β-selection and drives T cell leukemogenesis. However, the importance of ligand-activated N3 in promoting β-selection and ICN1-induced T cell leukemogenesis has not been examined. To address these questions we generated mice lacking functional N3. We confirmed that DN3 progenitors express N3 protein using a N3-specific antibody. Surprisingly however, N3-deficient DN3 thymocytes were not defective in generating DP thymocytes under steady state conditions or in more stringent competition assays. To determine if N3 co-operates with N1 to regulate β-selection, we generated N1;N3 compound mutants. However, N3 deficiency did not exacerbate the competitive defect of N1+/− DN3 progenitors, demonstrating that N3 does not compensate for limiting N1 during T cell development. Finally, N3 deficiency did not attenuate T cell leukemogenesis induced by conditional expression of ICN1 in DN3 thymocytes. Importantly, we showed that in contrast to N1, N3 has a low binding affinity for DL4, the most abundant intrathymic DL ligand. Thus, despite the profound effects of ectopic ligand-independent N3 activation on T cell development and leukemogenesis, physiologically activated N3 is dispensable for both processes, likely because N3 interacts poorly with intrathymic DL4
The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus
The frequency of antifungal resistance, particularly to the azole class of ergosterol biosynthetic inhibitors, is a growing global health problem. Survival rates for those infected with resistant isolates are exceptionally low. Beyond modification of the drug target, our understanding of the molecular basis of azole resistance in the fungal pathogen Aspergillus fumigatus is limited. We reasoned that clinically relevant antifungal resistance could derive from transcriptional rewiring, promoting drug resistance without concomitant reductions in pathogenicity. Here we report a genome-wide annotation of transcriptional regulators in A. fumigatus and construction of a library of 484 transcription factor null mutants. We identify 12 regulators that have a demonstrable role in itraconazole susceptibility and show that loss of the negative cofactor 2 complex leads to resistance, not only to the azoles but also the salvage therapeutics amphotericin B and terbinafine without significantly affecting pathogenicity
Mass equidistribution of Hilbert modular eigenforms
Let F be a totally real number field, and let f traverse a sequence of
non-dihedral holomorphic eigencuspforms on GL(2)/F of weight (k_1,...,k_n),
trivial central character and full level. We show that the mass of f
equidistributes on the Hilbert modular variety as max(k_1,...,k_n) tends to
infinity.
Our result answers affirmatively a natural analogue of a conjecture of
Rudnick and Sarnak (1994). Our proof generalizes the argument of
Holowinsky-Soundararajan (2008) who established the case F = Q. The essential
difficulty in doing so is to adapt Holowinsky's bounds for the Weyl periods of
the equidistribution problem in terms of manageable shifted convolution sums of
Fourier coefficients to the case of a number field with nontrivial unit group.Comment: 40 pages; typos corrected, nearly accepted for
2,2,3,3′-Tetraphenyl-7,7′-biquinoxaline
In the crystal structure of the title compound, C40H26N4, molecules reside on crystallographic centers of inversion and are linked via C—H⋯N interactions about inversion centers into one-dimensional chains: longer C—H⋯π(arene) interactions complete the intermolecular interactions
Jet production in charged current deep inelastic e⁺p scatteringat HERA
The production rates and substructure of jets have been studied in charged current deep inelastic e⁺p scattering for Q² > 200 GeV² with the ZEUS detector at HERA using an integrated luminosity of 110.5 pb⁻¹. Inclusive jet cross sections are presented for jets with transverse energies E_{T}^{jet} > 5 GeV. Measurements of the mean subjet multiplicity, 〈n_{sbj}〉, of the inclusive jet sample are presented. Predictions based on parton-shower Monte Carlo models and next-to-leading-order QCD calculations are compared to the measurements. The value of α_{s} (M_{z}), determined from 〈n_{sbj}〉 at y_{cut} = 10⁻² for jets with 25 < E_{T}^{jet} < 119 GeV, is α_{s} (M_{z}) = 0.1202 ± 0.0052 (stat.)_{-0.0019}^{+0.0060} (syst.)_{-0.0053}^{+0.0065} (th.). The mean subjet multiplicity as a function of Q² is found to be consistent with that measured in NC DIS
Combined QCD and electroweak analysis of HERA data
A simultaneous fit of parton distribution functions (PDFs) and electroweak
parameters to HERA data on deep inelastic scattering is presented. The input
data are the neutral current and charged current inclusive cross sections which
were previously used in the QCD analysis leading to the HERAPDF2.0 PDFs. In
addition, the polarisation of the electron beam was taken into account for the
ZEUS data recorded between 2004 and 2007. Results on the vector and
axial-vector couplings of the Z boson to u- and d-type quarks, on the value of
the electroweak mixing angle and the mass of the W boson are presented. The
values obtained for the electroweak parameters are in agreement with Standard
Model predictions.Comment: 32 pages, 10 figures, accepted by Phys. Rev. D. Small corrections
from proofing process and small change to Fig. 12 and Table
Limits on the effective quark radius from inclusive scattering at HERA
The high-precision HERA data allows searches up to TeV scales for Beyond the
Standard Model contributions to electron-quark scattering. Combined
measurements of the inclusive deep inelastic cross sections in neutral and
charged current scattering corresponding to a luminosity of around 1
fb have been used in this analysis. A new approach to the beyond the
Standard Model analysis of the inclusive data is presented; simultaneous
fits of parton distribution functions together with contributions of "new
physics" processes were performed. Results are presented considering a finite
radius of quarks within the quark form-factor model. The resulting 95% C.L.
upper limit on the effective quark radius is cm.Comment: 10 pages, 4 figures, accepted by Phys. Lett.
Search for a narrow baryonic state decaying to and in deep inelastic scattering at HERA
A search for a narrow baryonic state in the and
system has been performed in collisions at HERA with the ZEUS detector
using an integrated luminosity of 358 pb taken in 2003-2007. The search
was performed with deep inelastic scattering events at an centre-of-mass
energy of 318 GeV for exchanged photon virtuality, , between 20 and 100
. Contrary to evidence presented for such a state around 1.52
GeV in a previous ZEUS analysis using a sample of 121 pb taken in
1996-2000, no resonance peak was found in the invariant-mass
distribution in the range 1.45-1.7 GeV. Upper limits on the production cross
section are set.Comment: 16 pages, 4 figures, accepted by Phys. Lett. B. Minor changes from
journal reviewing process, including a small correction to figure
Measurement of the cross-section ratio sigma_{psi(2S)}/sigma_{J/psi(1S)} in deep inelastic exclusive ep scattering at HERA
The exclusive deep inelastic electroproduction of and
at an centre-of-mass energy of 317 GeV has been studied with the ZEUS
detector at HERA in the kinematic range GeV,
GeV and GeV, where is the photon virtuality, is the
photon-proton centre-of-mass energy and is the squared four-momentum
transfer at the proton vertex. The data for GeV were taken in
the HERA I running period and correspond to an integrated luminosity of 114
pb. The data for GeV are from both HERA I and HERA II
periods and correspond to an integrated luminosity of 468 pb. The decay
modes analysed were and for the
and for the . The cross-section ratio
has been measured as a function of
and . The results are compared to predictions of QCD-inspired
models of exclusive vector-meson production.Comment: 24 pages, 8 figure
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