Specific recognition of a multiply phosphorylated motif in the DNA repair scaffold XRCC1 by the FHA domain of human PNK.

Short-patch repair of DNA single-strand breaks and gaps (SSB) is coordinated by XRCC1, a scaffold protein that recruits the DNA polymerase and DNA ligase required for filling and sealing the damaged strand. XRCC1 can also recruit end-processing enzymes, such as PNK (polynucleotide kinase 3'-phosphatase), Aprataxin and APLF (aprataxin/PNK-like factor), which ensure the availability of a free 3'-hydroxyl on one side of the gap, and a 5'-phosphate group on the other, for the polymerase and ligase reactions respectively. PNK binds to a phosphorylated segment of XRCC1 (between its two C-terminal BRCT domains) via its Forkhead-associated (FHA) domain. We show here, contrary to previous studies, that the FHA domain of PNK binds specifically, and with high affinity to a multiply phosphorylated motif in XRCC1 containing a pSer-pThr dipeptide, and forms a 2:1 PNK:XRCC1 complex. The high-resolution crystal structure of a PNK-FHA-XRCC1 phosphopeptide complex reveals the basis for this unusual bis-phosphopeptide recognition, which is probably a common feature of the known XRCC1-associating end-processing enzymes

Matrix Gravity and Massive Colored Gravitons

We formulate a theory of gravity with a matrix-valued complex vierbein based on the SL(2N,C)xSL(2N,C) gauge symmetry. The theory is metric independent, and before symmetry breaking all fields are massless. The symmetry is broken spontaneously and all gravitons corresponding to the broken generators acquire masses. If the symmetry is broken to SL(2,C) then the spectrum would correspond to one massless graviton coupled to $2N^2 -1$ massive gravitons. A novel feature is the way the fields corresponding to non-compact generators acquire kinetic energies with correct signs. Equally surprising is the way Yang-Mills gauge fields acquire their correct kinetic energies through the coupling to the non-dynamical antisymmetric components of the vierbeins.Comment: One reference adde

Deriving the Hirshfeld partitioning using distance metrics

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Complete gluon bremsstrahlung corrections to the process b -> s l+ l-

In a recent paper, we presented the calculation of the order (alpha_s) virtual corrections to b->s l+ l- and of those bremsstrahlung terms which are needed to cancel the infrared divergences. In the present paper we work out the remaining order(alpha_s) bremsstrahlung corrections to b->s l+ l- which do not suffer from infrared and collinear singularities. These new contributions turn out to be small numerically. In addition, we also investigate the impact of the definition of the charm quark mass on the numerical results.Comment: 20 pages including 11 postscript figure

Intrabodies Binding the Proline-Rich Domains of Mutant Huntingtin Increase Its Turnover and Reduce Neurotoxicity

Although expanded polyglutamine (polyQ) repeats are inherently toxic, causing at least nine neurodegenerative diseases, the protein context determines which neurons are affected. The polyQ expansion that causes Huntington's disease (HD) is in the first exon (HDx-1) of huntingtin (Htt). However, other parts of the protein, including the 17 N-terminal amino acids and two proline (polyP) repeat domains, regulate the toxicity of mutant Htt. The role of the P-rich domain that is flanked by the polyP domains has not been explored. Using highly specific intracellular antibodies (intrabodies), we tested various epitopes for their roles in HDx-1 toxicity, aggregation, localization, and turnover. Three domains in the P-rich region (PRR) of HDx-1 are defined by intrabodies: MW7 binds the two polyP domains, and Happ1 and Happ3, two new intrabodies, bind the unique, P-rich epitope located between the two polyP epitopes. We find that the PRR-binding intrabodies, as well as VL12.3, which binds the N-terminal 17 aa, decrease the toxicity and aggregation of HDx-1, but they do so by different mechanisms. The PRR-binding intrabodies have no effect on Htt localization, but they cause a significant increase in the turnover rate of mutant Htt, which VL12.3 does not change. In contrast, expression of VL12.3 increases nuclear Htt. We propose that the PRR of mutant Htt regulates its stability, and that compromising this pathogenic epitope by intrabody binding represents a novel therapeutic strategy for treating HD. We also note that intrabody binding represents a powerful tool for determining the function of protein epitopes in living cells

Mutation in the guanine nucleotide-binding protein beta-3 causes retinal degeneration and embryonic mortality in chickens

PURPOSE. To identify the gene defect that causes blindness and the predisposition to embryonic death in the retinopathy globe enlarged (rge) chicken. METHODS. Linkage analysis, with previously uncharacterized microsatellite markers from chicken chromosome 1, was performed on 138 progeny of an rge/+ and an rge/rge cross, and candidate genes were sequenced. RESULTS. The rge locus was refined and the gene for guanine nucleotide-binding protein β-3 (GNB3), which encodes a cone transducin β subunit, was found to have a 3-bp deletion (D153del) that segregated with the rge phenotype. This mutation deleted a highly conserved aspartic acid residue in the third of seven WD domains in GNB3. In silico modeling suggested that this mutation destabilized the protein. Furthermore, a 70% reduction was found in immunoreactivity to anti-GNB3 in the rge-affected retina. CONCLUSIONS. These findings implicate the β-subunit of cone transducin as the defective protein underlying the rge phenotype. Furthermore, GNB3 is ubiquitously expressed, and the c.825C→T GNB3 splicing variant (MIM 139130) has been associated with hypertension, obesity, diabetes, low birth weight, coronary heart disease, and stroke in the human population. It therefore seems likely that the defect underlying these human diseases also causes reduced embryonic viability in the rge chicken, making it a powerful model for studying the pathology involved in these associations

Pulsed Laser Deposition of High Temperature Protonic Films

Pulsed laser deposition has been used to fabricate nanostructured BaCe(0.85)Y(0.15)O3- sigma) films. Protonic conduction of fabricated BaCe(0.85)Y(0.15)O(3-sigma) films was compared to sintered BaCe(0.85)Y(0.15)O(3-sigma). Sintered samples and laser targets were prepared by sintering BaCe(0.85)Y(0.15)O(3-sigma) powders derived by solid state synthesis. Films 1 to 8 micron thick were deposited by KrF excimer laser on porous Al2O3 substrates. Thin films were fabricated at deposition temperatures of 700 to 950 C at O2 pressures up to 200 mTorr using laser pulse energies of 0.45 - 0.95 J. Fabricated films were characterized by X-ray diffraction, electron microscopy and electrical impedance spectroscopy. Single phase BaCe(0.85)Y(0.15)O(3-sigma) films with a columnar growth morphology are observed with preferred crystal growth along the [100] or [001] direction. Results indicate [100] growth dependence upon laser pulse energy. Electrical conductivity of bulk samples produced by solid state sintering and thin film samples were measured over a temperature range of 100 C to 900 C. Electrical conduction behavior was dependent upon film deposition temperature. Maximum conductivity occurs at deposition temperature of 900 oC; the electrical conductivity exceeds the sintered specimen. All other deposited films exhibit a lower electrical conductivity than the sintered specimen. Activation energy for electrical conduction showed dependence upon deposition temperature, it varie

Mechanism, dynamics, and biological existence of multistability in a large class of bursting neurons

Multistability, the coexistence of multiple attractors in a dynamical system, is explored in bursting nerve cells. A modeling study is performed to show that a large class of bursting systems, as defined by a shared topology when represented as dynamical systems, is inherently suited to support multistability. We derive the bifurcation structure and parametric trends leading to multistability in these systems. Evidence for the existence of multirhythmic behavior in neurons of the aquatic mollusc Aplysia californica that is consistent with our proposed mechanism is presented. Although these experimental results are preliminary, they indicate that single neurons may be capable of dynamically storing information for longer time scales than typically attributed to nonsynaptic mechanisms.Comment: 24 pages, 8 figure

A multiband envelope function model for quantum transport in a tunneling diode

We present a simple model for electron transport in semiconductor devices that exhibit tunneling between the conduction and valence bands. The model is derived within the usual Bloch-Wannier formalism by a k-expansion, and is formulated in terms of a set of coupled equations for the electron envelope functions. Its connection with other models present in literature is discussed. As an application we consider the case of a Resonant Interband Tunneling Diode, demonstrating the ability of the model to reproduce the expected behaviour of the current as a function of the applied voltageComment: 8 pages, 4 figure