382 research outputs found
YAP and β-catenin co-operate to drive oncogenesis in basal breast cancer
Targeting cancer stem cells (CSCs) can serve as an effective approach toward limiting resistance to therapies and the development of metastases in many forms of cancer. While basal breast cancers encompass cells with CSC features, rational therapies remain poorly established. Here, we show that receptor tyrosine kinase Met signalling promotes the activity of the Hippo component YAP in basal breast cancer. Further analysis revealed enhanced YAP activity within the CSC population. Using both genetic and pharmaceutical approaches, we show that interfering with YAP activity delays basal cancer formation, prevents luminal to basal trans-differentiation and reduces CSC survival. Gene expression analysis of YAP knock-out mammary glands revealed a strong decrease in β-catenin target genes in basal breast cancer, suggesting that YAP is required for nuclear β-catenin activity. Mechanistically, we find that nuclear YAP interacts and overlaps with β-catenin and TEAD4 at common gene regulatory elements. Analysis of proteomic data from primary breast cancer patients identified a significant upregulation of the YAP activity signature in basal compared to other breast cancers, suggesting that YAP activity is limited to basal types. Our findings demonstrate that in basal breast cancers, β-catenin activity is dependent on YAP signalling and controls the CSC program. These findings suggest that targeting the YAP/TEAD4/β-catenin complex offers a potential therapeutic strategy for eradicating CSCs in basal (triple-negative) breast cancers
Review of biorthogonal coupled cluster representations for electronic excitation
Single reference coupled-cluster (CC) methods for electronic excitation are
based on a biorthogonal representation (bCC) of the (shifted) Hamiltonian in
terms of excited CC states, also referred to as correlated excited (CE) states,
and an associated set of states biorthogonal to the CE states, the latter being
essentially configuration interaction (CI) configurations. The bCC
representation generates a non-hermitian secular matrix, the eigenvalues
representing excitation energies, while the corresponding spectral intensities
are to be derived from both the left and right eigenvectors. Using the
perspective of the bCC representation, a systematic and comprehensive analysis
of the excited-state CC methods is given, extending and generalizing previous
such studies. Here, the essential topics are the truncation error
characteristics and the separability properties, the latter being crucial for
designing size-consistent approximation schemes. Based on the general order
relations for the bCC secular matrix and the (left and right) eigenvector
matrices, formulas for the perturbation-theoretical (PT) order of the
truncation errors (TEO) are derived for energies, transition moments, and
property matrix elements of arbitrary excitation classes and truncation levels.
In the analysis of the separability properties of the transition moments, the
decisive role of the so-called dual ground state is revealed. Due to the use of
CE states the bCC approach can be compared to so-called intermediate state
representation (ISR) methods based exclusively on suitably orthonormalized CE
states. As the present analysis shows, the bCC approach has decisive advantages
over the conventional CI treatment, but also distinctly weaker TEO and
separability properties in comparison with a full (and hermitian) ISR method
Comparison of Zn_{1-x}Mn_xTe/ZnTe multiple-quantum wells and quantum dots by below-bandgap photomodulated reflectivity
Large-area high density patterns of quantum dots with a diameter of 200 nm
have been prepared from a series of four Zn_{0.93}Mn_{0.07}Te/ZnTe multiple
quantum well structures of different well width (4 nm, 6 nm, 8 nm and 10 nm) by
electron beam lithography followed by Ar+ ion beam etching. Below-bandgap
photomodulated reflectivity spectra of the quantum dot samples and the parent
heterostructures were then recorded at 10 K and the spectra were fitted to
extract the linewidths and the energy positions of the excitonic transitions in
each sample. The fitted results are compared to calculations of the transition
energies in which the different strain states in the samples are taken into
account. We show that the main effect of the nanofabrication process is a
change in the strain state of the quantum dot samples compared to the parent
heterostructures. The quantum dot pillars turn out to be freestanding, whereas
the heterostructures are in a good approximation strained to the ZnTe lattice
constant. The lateral size of the dots is such that extra confinement effects
are not expected or observed.Comment: 23 pages, LaTeX2e (amsmath, epsfig), 7 EPS figure
Self-consistent Green's function approaches
We present the fundamental techniques and working equations of many-body
Green's function theory for calculating ground state properties and the
spectral strength. Green's function methods closely relate to other polynomial
scaling approaches discussed in chapters 8 and 10. However, here we aim
directly at a global view of the many-fermion structure. We derive the working
equations for calculating many-body propagators, using both the Algebraic
Diagrammatic Construction technique and the self-consistent formalism at finite
temperature. Their implementation is discussed, as well as the inclusion of
three-nucleon interactions. The self-consistency feature is essential to
guarantee thermodynamic consistency. The pairing and neutron matter models
introduced in previous chapters are solved and compared with the other methods
in this book.Comment: 58 pages, 14 figures, Submitted to Lect. Notes Phys., "An advanced
course in computational nuclear physics: Bridging the scales from quarks to
neutron stars", M. Hjorth-Jensen, M. P. Lombardo, U. van Kolck, Editor
Prediction of huge X-ray Faraday rotation at the Gd N_4,5 threshold
X-ray absorption spectra in a wide energy range around the 4d-4f excitation
threshold of Gd were recorded by total electron yield from in-plane magnetized
Gd metal films. Matching the experimental spectra to tabulated absorption data
reveals unprecedented short light absorption lengths down to 3 nm. The
associated real parts of the refractive index for circularly polarized light
propagating parallel or antiparallel to the Gd magnetization, determined
through the Kramers-Kronig transformation, correspond to a magneto-optical
Faraday rotation of 0.7 degrees per atomic layer. This finding shall allow the
study of magnetic structure and magnetization dynamics of lanthanide elements
in nanosize systems and dilute alloys.Comment: 4 pages, 2 figures, final version resubmitted to Phys. Rev. B, Brief
Reports. Minor change
USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells
Altering ubiquitination by disruption of individual deubiquitinating enzymes (DUBs) has proven to affect hematopoietic stem cell (HSC) maintenance. However, comprehensive knowledge of DUB function during hematopoiesis in vivo is lacking. To accomplish this goal, we systematically inactivated DUBs in mouse hematopoietic progenitors using in vivo small hairpin RNAs (shRNAs) screens. We found that multiple DUBs may be individually required for hematopoiesis and that the ubiquitin-specific protease 15 (USP15) is particularly important for the maintenance of murine hematopoietic stem and progenitor cells in vitro and in vivo. Consistently, Usp15 knockout mice exhibited a reduced HSC pool. The defect was intrinsic to HSCs, as demonstrated by competitive repopulation assays. Importantly, USP15 is highly expressed in normal human hematopoietic cells and leukemias, and USP15 depletion in murine early progenitors and myeloid leukemia cells impaired in vitro expansion and increased genotoxic stress. Our study underscores the importance of DUBs in preserving normal hematopoiesis and uncovers USP15 as a critical DUB in safeguarding genome integrity in HSC and in leukemia cells
The dynamical Green's function and an exact optical potential for electron-molecule scattering including nuclear dynamics
We derive a rigorous optical potential for electron-molecule scattering
including the effects of nuclear dynamics by extending the common many-body
Green's function approach to optical potentials beyond the fixed-nuclei limit
for molecular targets. Our formalism treats the projectile electron and the
nuclear motion of the target molecule on the same footing whereby the dynamical
optical potential rigorously accounts for the complex many-body nature of the
scattering target. One central result of the present work is that the common
fixed-nuclei optical potential is a valid adiabatic approximation to the
dynamical optical potential even when projectile and nuclear motion are
(nonadiabatically) coupled as long as the scattering energy is well below the
electronic excitation thresholds of the target. For extremely low projectile
velocities, however, when the cross sections are most sensitive to the
scattering potential, we expect the influences of the nuclear dynamics on the
optical potential to become relevant. For these cases, a systematic way to
improve the adiabatic approximation to the dynamical optical potential is
presented that yields non-local operators with respect to the nuclear
coordinates.Comment: 22 pages, no figures, accepted for publ., Phys. Rev.
Case series: convalescent plasma therapy for patients with COVID-19 and primary antibody deficiency
Patients with primary antibody deficiency are at risk for severe and in many cases for prolonged COVID-19. Convalescent plasma treatment of immunocompromised individuals could be an option especially in countries with limited access to monoclonal antibody therapies. While studies in immunocompetent COVID19 patients have demonstrated only a limited benefit, evidence for the safety, timing, and effectiveness of this treatment in antibody-deficient patients is lacking. Here, we describe 16 cases with primary antibody deficiency treated with convalescent plasma in four medical centers. In our cohort, treatment was associated with a reduction in viral load and improvement of clinical symptoms, even when applied over a week after onset of infection. There were no relevant side effects besides a short-term fever reaction in one patient. Longitudinal full-genome sequencing revealed the emergence of mutations in the viral genome, potentially conferring an antibody escape in one patient with persistent viral RNA shedding upon plasma treatment. However, he resolved the infection after a second course of plasma treatment. Thus, our data suggest a therapeutic benefit of convalescent plasma treatment in patients with primary antibody deficiency even months after infection. While it appears to be safe, PCR follow-up for SARS-CoV-2 is advisable and early re-treatment might be considered in patients with persistent viral shedding
Optical determination of the NĂ©el vector in a CuMnAs thin-film antiferromagnet
Recent breakthroughs in electrical detection and manipulation of antiferromagnets have opened a new avenue in the research of non-volatile spintronic devices.1-10 Antiparallel spin sublattices in antiferromagnets, producing zero dipolar fields, lead to the insensitivity to magnetic field perturbations, multi-level stability, ultrafast spin dynamics and other favorable characteristics which may find utility in fields ranging from magnetic memories to optical signal processing. However, the absence of a net magnetic moment and the ultra-short magnetization dynamics timescales make antiferromagnets notoriously difficult to study by common magnetometers or magnetic resonance techniques. In this paper we demonstrate the experimental determination of the NĂ©el vector in a thin film of antiferromagnetic CuMnAs9,10 which is the prominent material used in the first realization of antiferromagnetic memory chips.10 We employ a femtosecond pump-probe magneto-optical experiment based on magnetic linear dichroism. This table-top optical method is considerably more accessible than the traditionally employed large scale facility techniques like neutron diffraction11 and Xray magnetic dichroism measurements.12-14 This optical technique allows an unambiguous direct determination of the NĂ©el vector orientation in thin antiferromagnetic films utilized in devices directly from measured data without fitting to a theoretical model
Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF
The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at
the Fermilab Long-Baseline Neutrino Facility (LBNF) is described
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