Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity

The BARD1 protein, which heterodimerizes with BRCA1, is encoded by a known breast cancer susceptibility gene. While several BARD1 variants have been identified as pathogenic, many more missense variants exist that do not occur frequently enough to assign a clinical risk. In this paper, whole exome sequencing of over 10,000 cancer samples from 33 cancer types identified from somatic mutations and loss of heterozygosity in tumors 76 potentially cancer-associated BARD1 missense and truncation variants. These variants were tested in a functional assay for homology-directed repair (HDR), as HDR deficiencies have been shown to correlate with clinical pathogenicity for BRCA1 variants. From these 76 variants, 4 in the ankyrin repeat domain and 5 in the BRCT domain were found to be non-functional in HDR. Two known benign variants were found to be functional in HDR, and three known pathogenic variants were non-functional, supporting the notion that the HDR assay can be used to predict the clinical risk of BARD1 variants. The identification of HDR-deficient variants in the ankyrin repeat domain indicates there are DNA repair functions associated with this domain that have not been closely examined. In order to examine whether BARD1-associated loss of HDR function results in DNA damage sensitivity, cells expressing non-functional BARD1 variants were treated with ionizing radiation or cisplatin. These cells were found to be more sensitive to DNA damage, and variations in the residual HDR function of non-functional variants did not correlate with variations in sensitivity. These findings improve the understanding of BARD1 functional domains in DNA repair and support that this functional assay is useful for predicting the cancer association of BARD1 variants.</div

Contrast of LiFeAs with isostructural, isoelectronic, and non-superconducting MgFeGe

Stoichiometric LiFeAs at ambient pressure is an 18 K superconductor while isoelectronic MgFeGe is not, despite their extremely similar electronic structures. To investigate possible sources of this distinctively different superconducting behavior, we quantify the differences using first principles density functional theory, establishing first that the Fe total 3d occupations are identical in the two compounds. Individual 3d orbital occupations also differ very little ($\sim 0.01$). The differences in Fermi surfaces (FSs) do not seem significant; however a redistribution of bands just above the Fermi level does represent a possibly significant distinction. Because the bands and FSs of LiFeAs are less in agreement with experiment than for other iron-pnictides, we study the effects of additional exchange-correlations effects beyond GGA (the generalized gradient approximation) by applying the modified Becke-Johnson potential (mBJ) exchange potential, which gives much improved bandgaps in insulators compared to GGA and might be useful for semimetals such as the Fe-based superconductors. Overall, we conclude that the mBJ corrections do not improve the description of LiFeAs as compared to experiment

Toroidal Compactification in String Theory from Chern-Simons Theory

A detailed study of the charge spectrum of three dimensional Abelian Topological Massive Gauge Theory (TMGT) is given. When this theory is defined on a manifold with two disconnected boundaries there are induced chiral Conformal Field Theories (CFT's) on the boundaries which can be interpreted as the left and right sectors of closed strings. We show that Narain constraints on toroidal compactification (integer, even, self-dual momentum lattice) have a natural interpretation in purely three dimensional terms. This is an important result which is necessary to construct toroidal compactification and heterotic string from Topological Membrane (TM) approach to string theory. We also derive the block structure of $c=1$ Rational Conformal Field Theory (RCFT) from the three dimensional gauge theory.Comment: 32+2 pages, 9 figures. Comments added and minor changes in section 3. Content not altere

Studies of Impurity-Doping Effects and NMR Measurement5s of La1111 and/or Nd 1111 Fe-Pnictide Superconductors

Measurements of the electrical resistivities, Hall coefficients, thermoelectric powers, electronic specific heat coefficients have been carried out for samples of LnFe1-yMyAsO1-xFx (Ln=La, Nd; M=Co, Mn; x=0.11) obtained by M atom dopings to the superconducting LnFeAsO1-xFx (Ln1111) system. The NMR longitudinal relaxation rates 1/T1 have also been measured for samples of LaFe1-yCoyAsO1-xFx with various x values. Co atoms doped to the superconducting LnFeAsO1-xFx are nonmagnetic, and the Tc-suppression by the Co atoms has been found to be too weak to understand by the pair breaking effect expected for the S+- superconducting symmetry proposed as the most probable one for the system. It throws a serious doubt whether the symmetry is realized in this system. Instead of the pair breaking, two mechanisms of the Tc-suppression by the doped impurities have been found: One is the electron localization, which appears when the sheet resistance exceeds h/4e2=6.45 kohm, and another is the disappearance or reduction of the hole-Fermi-surfaces around the gamma point in the reciprocal space. The latter mechanism has been observed, when the electron number increases with increasing Co-doping level and the system changes from an anomalous metal to an ordinary one. On the two distinct T dependences of 1/T1 of LaFeAsO1-xFx, 1/T1 T6 reported by our group in the T region from Tc to ~0.4 Tc for samples with the highest Tc values with varying x, and 1/T1 T2.5-3.0 observed by many groups in the almost entire T region studied below Tc, we discuss what the origin of the difference is, and show that, at least, the T2.5-3.0-like dependence of 1/T1 cannot be considered as the experimental evidence for the S+- symmetry of the order parameter.Comment: 11 pages, 14 figures, accepted for publication in J. Phys. Soc. Jpn., Fig. 14 adde

Short-Term Immunosuppression Promotes Engraftment of Embryonic and Induced Pluripotent Stem Cells

SummaryEmbryonic stem cells (ESCs) are an attractive source for tissue regeneration and repair therapies because they can be differentiated into virtually any cell type in the adult body. However, for this approach to succeed, the transplanted ESCs must survive long enough to generate a therapeutic benefit. A major obstacle facing the engraftment of ESCs is transplant rejection by the immune system. Here we show that blocking leukocyte costimulatory molecules permits ESC engraftment. We demonstrate the success of this immunosuppressive therapy for mouse ESCs, human ESCs, mouse induced pluripotent stem cells (iPSCs), human induced pluripotent stem cells, and more differentiated ESC/(iPSCs) derivatives. Additionally, we provide evidence describing the mechanism by which inhibition of costimulatory molecules suppresses T cell activation. This report describes a short-term immunosuppressive approach capable of inducing engraftment of transplanted ESCs and iPSCs, providing a significant improvement in our mechanistic understanding of the critical role costimulatory molecules play in leukocyte activation

Optimal control of a multilevel DC-link converter photovoltaic system for maximum power generation

This paper describes a new algorithm for optimal control of a PV system under partial shading. A multilevel DC-link is the essential part of the proposed system and its control engages a voltage-hold perturbation and observation (VH-P&O) method combined with a PWM algorithm with permutation of PV sources. The algorithm enables achieving the maximum power generation for any number of PV and converter modules. The main features of the control are: (i) a continual operation of all PV sources, shaded and non-shaded, at their maximum power points, (ii) delivery of all extracted power from PV sources to the load and (iii) generation of multilevel output voltage waveform with a low total harmonic distortion

The Alliance for Cellular Signaling Plasmid Collection: A Flexible Resource for Protein Localization Studies and Signaling Pathway Analysis

Cellular responses to inputs that vary both temporally and spatially are determined by complex relationships between the components of cell signaling networks. Analysis of these relationships requires access to a wide range of experimental reagents and techniques, including the ability to express the protein components of the model cells in a variety of contexts. As part of the Alliance for Cellular Signaling, we developed a robust method for cloning large numbers of signaling ORFs into Gateway® entry vectors, and we created a wide range of compatible expression platforms for proteomics applications. To date, we have generated over 3000 plasmids that are available to the scientific community via the American Type Culture Collection. We have established a website at www.signaling-gateway.org/data/plasmid/ that allows users to browse, search, and blast Alliance for Cellular Signaling plasmids. The collection primarily contains murine signaling ORFs with an emphasis on kinases and G protein signaling genes. Here we describe the cloning, databasing, and application of this proteomics resource for large scale subcellular localization screens in mammalian cell lines

Functional Selectivity of Allosteric Interactions within GPCR oligomers: the Dopamine D1-D3 Receptor Heterotetramer

The dopamine D1 receptor-D3 receptor (D1R-D3R) heteromer is being considered as a potential therapeutic target for neuropsychiatric disorders. Previous studies suggested that this heteromer could be involved in the ability of D3R agonists to potentiate locomotor activation induced by D1R agonists. It has also been postulated that its overexpression plays a role in L-dopa-induced dyskinesia and in drug addiction. However, little is known about its biochemical properties. By combining bioluminescence resonance energy transfer, bimolecular complementation techniques and cell signaling experiments in transfected cells, evidence was obtained for a tetrameric stoichiometry of the D1R-D3R heteromer, constituted by two interacting D1R and D3R homodimers coupled to Gs and GI proteins, respectively. Co-activation of both receptors led to the canonical negative interaction at the level of adenylyl cyclase signaling, to a strong recruitment of β-arrestin-1 and to a positive crosstalk of D1R and D3R agonists at the level of mitogen-activated protein kinase (MAPK) signaling. Furthermore, D1R or D3R antagonists counteracted β-arrestin-1 recruitment and MAPK activation induced by D3R and D1R agonists, respectively (cross-antagonism). Positive crosstalk and cross-antagonism at the MAPK level were counteracted by specific synthetic peptides with amino acid sequences corresponding to D1R transmembrane (TM) domains TM5 and TM6, which also selectively modified the quaternary structure of the D1R-D3R heteromer, as demonstrated by complementation of hemiproteins of YFP fused to D1R and D3R. These results demonstrate functional selectivity of allosteric modulations within the D1R-D3R heteromer, which can be involved with the reported behavioral synergism of D1R and D3R agonists

Pressure versus concentration tuning of the superconductivity in Ba(Fe(1-x)Cox)2As2

In the iron arsenide compound BaFe2As2, superconductivity can be induced either by a variation of its chemical composition, e.g., by replacing Fe with Co, or by a reduction of the unit-cell volume through the application of hydrostatic pressure p. In contrast to chemical substitutions, pressure is expected to introduce no additional disorder into the lattice. We compare the two routes to superconductivity by measuring the p dependence of the superconducting transition temperature Tc of Ba(Fe(1-x)Cox)2As2 single crystals with different Co content x. We find that Tc(p) of underdoped and overdoped samples increases and decreases, respectively, tracking quantitatively the Tc(x) dependence. To clarify to which extent the superconductivity relies on distinct structural features we analyze the crystal structure as a function of x and compare the results with that of BaFe2As2 under pressure.Comment: 14 pages, 4 figures, to be published in JPSJ Vol. 79 No. 12. The copyright is held by The Physical Society of Japa