425 research outputs found
Unitary differential space-time-frequency codes for MB-OFDM UWB
In a multiple-input multiple-output (MIMO) multiband orthogonal frequency division multiplexing (MB-OFDM) ultra-wideband (UWB) system, coherent detection where the channel state information (CSI) is assumed to be exactly known at the receiver requires the transmission of a large number of symbols for channel estimation, thus reducing the bandwidth efficiency. This paper examines the use of unitary differential space-time frequency codes (DSTFCs) in MB-OFDM UWB, which increases the system bandwidth efficiency due to the fact that no CSI is required for differential detection. The proposed DSTFC MB-OFDM system would be useful when the transmission of multiple channel estimation symbols is impractical or uneconomical. Simulation results show that the application of DSTFCs can significantly improve the bit error performance of conventional differential MB-OFDM system (without MIMO). ©2009 IEEE
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
First Order Static Excitation Potential: Scheme for Excitation Energies and Transition Moments
We present an approximation scheme for the calculation of the principal
excitation energies and transition moments of finite many-body systems. The
scheme is derived from a first order approximation to the self energy of a
recently proposed extended particle-hole Green's function. A hermitian
eigenvalue problem is encountered of the same size as the well-known Random
Phase Approximation (RPA). We find that it yields a size consistent description
of the excitation properties and removes an inconsistent treatment of the
ground state correlation by the RPA. By presenting a hermitian eigenvalue
problem the new scheme avoids the instabilities of the RPA and should be well
suited for large scale numerical calculations. These and additional properties
of the new approximation scheme are illuminated by a very simple exactly
solvable model.Comment: 15 pages revtex, 1 eps figure included, corrections in Eq. (A1) and
Sec. II
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
Deconstructing sarcomeric structure-function relations in titin-BioID knock-in mice
Proximity proteomics has greatly advanced the analysis of native protein complexes and subcellular structures in culture, but has not been amenable to study development and disease in vivo. Here, we have generated a knock-in mouse with the biotin ligase (BioID) inserted at titin's Z-disc region to identify protein networks that connect the sarcomere to signal transduction and metabolism. Our census of the sarcomeric proteome from neonatal to adult heart and quadriceps reveals how perinatal signaling, protein homeostasis and the shift to adult energy metabolism shape the properties of striated muscle cells. Mapping biotinylation sites to sarcomere structures refines our understanding of myofilament dynamics and supports the hypothesis that myosin filaments penetrate Z-discs to dampen contraction. Extending this proof of concept study to BioID fusion proteins generated with Crispr/CAS9 in animal models recapitulating human pathology will facilitate the future analysis of molecular machines and signaling hubs in physiological, pharmacological, and disease context
GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium
Growth arrest-specific 1 (GAS1) acts as a co-receptor to patched 1, promoting sonic hedgehog (SHH) signaling in the developing nervous system. GAS1 mutations in humans and animal models result in forebrain and craniofacial malformations, defects ascribed to a function for GAS1 in SHH signaling during early neurulation. Here, we confirm loss of SHH activity in the forebrain neuroepithelium in GAS1-deficient mice and in induced pluripotent stem cell-derived cell models of human neuroepithelial differentiation. However, our studies document that this defect can be attributed, at least in part, to a novel role for GAS1 in facilitating NOTCH signaling, which is essential to sustain a persistent SHH activity domain in the forebrain neuroepithelium. GAS1 directly binds NOTCH1, enhancing ligand-induced processing of the NOTCH1 intracellular domain, which drives NOTCH pathway activity in the developing forebrain. Our findings identify a unique role for GAS1 in integrating NOTCH and SHH signal reception in neuroepithelial cells, and they suggest that loss of GAS1-dependent NOTCH1 activation contributes to forebrain malformations in individuals carrying GAS1 mutations
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
A CRISPR/Cas9-mediated screen identifies determinants of early plasma cell differentiation
INTRODUCTION: The differentiation of B cells into antibody-secreting plasma cells depends on cell division-coupled, epigenetic and other cellular processes that are incompletely understood. METHODS: We have developed a CRISPR/Cas9-based screen that models an early stage of T cell-dependent plasma cell differentiation and measures B cell survival or proliferation versus the formation of CD138+ plasmablasts. Here, we refined and extended this screen to more than 500 candidate genes that are highly expressed in plasma cells. RESULTS: Among known genes whose deletion preferentially or mostly affected plasmablast formation were the transcription factors Prdm1 (BLIMP1), Irf4 and Pou2af1 (OBF-1), and the Ern1 gene encoding IRE1a, while deletion of XBP1, the transcriptional master regulator that specifies the expansion of the secretory program in plasma cells, had no effect. Defective plasmablast formation caused by Ern1 deletion could not be rescued by the active, spliced form of XBP1 whose processing is dependent on and downstream of IRE1a, suggesting that in early plasma cell differentiation IRE1a acts independently of XBP1. Moreover, we newly identified several genes involved in NF-kB signaling (Nfkbia), vesicle trafficking (Arf4, Preb) and epigenetic regulators that form part of the NuRD complex (Hdac1, Mta2, Mbd2) to be required for plasmablast formation. Deletion of ARF4, a small GTPase required for COPI vesicle formation, impaired plasmablast formation and blocked antibody secretion. After Hdac1 deletion plasmablast differentiation was consistently reduced by about 50%, while deletion of the closely related Hdac2 gene had no effect. Hdac1 knock-out led to strongly perturbed protein expression of antagonistic transcription factors that govern plasma cell versus B cell identity (by decreasing IRF4 and BLIMP1 and increasing BACH2 and PAX5). DISCUSSION: Taken together, our results highlight specific and non-redundant roles for Ern1, Arf4 and Hdac1 in the early steps of plasma cell differentiation
Cyclin-dependent kinase 18 controls trafficking of aquaporin-2 and its abundance through ubiquitin ligase STUB1, which functions as an AKAP
Arginine-vasopressin (AVP) facilitates water reabsorption in renal collecting duct principal cells through regulation of the water channel aquaporin-2 (AQP2). The hormone binds to vasopressin V2 receptors (V2R) on the surface of the cells and stimulates cAMP synthesis. The cAMP activates protein kinase A (PKA), which initiates signaling that causes an accumulation of AQP2 in the plasma membrane of the cells facilitating water reabsorption from primary urine and fine-tuning of body water homeostasis. AVP-mediated PKA activation also causes an increase in the AQP2 protein abundance through a mechanism that involves dephosphorylation of AQP2 at serine 261 and a decrease in its poly-ubiquitination. However, the signaling downstream of PKA that controls the localization and abundance of AQP2 is incompletely understood. We carried out an siRNA screen targeting 719 kinase-related genes, representing the majority of the kinases of the human genome and analyzed the effect of the knockdown on AQP2 by high-content imaging and biochemical approaches. The screening identified 13 hits whose knockdown inhibited the AQP2 accumulation in the plasma membrane. Amongst the candidates was the so far hardly characterized cyclin-dependent kinase 18 (CDK18). Our further analysis revealed a hitherto unrecognized signalosome comprising CDK18, an E3 ubiquitin ligase, STUB1 (CHIP), PKA and AQP2 that controls the localization and abundance of AQP2. CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. STUB1 functions as an A-kinase anchoring protein (AKAP) tethering PKA to the protein complex and bridging AQP2 and CDK18. The modulation of the protein complex may lead to novel concepts for the treatment of disorders which are caused or are associated with dysregulated AQP2 and for which a satisfactory treatment is not available, e.g., hyponatremia, liver cirrhosis, diabetes insipidus, ADPKD or heart failure
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
- …