Prevalent Polymorphism in Thyroid Hormone-Activating Enzyme Leaves a Genetic Fingerprint that Underlies Associated Clinical Syndromes

Context: A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated. Objective: To define the molecular mechanisms underlying associated conditions in carriers of the Thr92Ala-D2 polymorphism. Design, Setting, Patients: Microarray analyses of nineteen postmortem human cerebral cortex samples were performed to establish a foundation for molecular studies via a cell model of HEK-293 cells stably expressing Thr92 or Ala92 D2. Results: The cerebral cortex of Thr92Ala-D2 carriers exhibits a transcriptional fingerprint that includes sets of genes involved in CNS diseases, ubiquitin, mitochondrial dysfunction (chromosomal genes encoding mitochondrial proteins), inflammation, apoptosis, DNA repair and growth factor signaling. Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected, i.e. the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated. The combined microarray analyses (brain/cells) led to the development of an 81-gene classifier that correctly predicts the genotype of homozygous brain samples. In contrast to Thr92-D2, Ala92-D2 exhibits longer half-life and was consistently found in the Golgi. A number of Golgi-related genes were down-regulated in Ala92-D2-expressing cells but were normalized after 24h-treatment with the antioxidant N-acetylecysteine. Conclusions: Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative disorders such as Huntington's disease, and could contribute to the unresolved neurocognitive symptoms of affected carriers

Closure development for high-level nuclear waste containers for the tuff repository; Phase 1, Final report

This report summarizes Phase 1 activities for closure development of the high-level nuclear waste package task for the tuff repository. Work was conducted under U.S. Department of Energy (DOE) Contract 9172105, administered through the Lawrence Livermore National Laboratory (LLNL), as part of the Yucca Mountain Project (YMP), funded through the DOE Office of Civilian Radioactive Waste Management (OCRWM). The goal of this phase was to select five closure processes for further evaluation in later phases of the program. A decision tree methodology was utilized to perform an objective evaluation of 15 potential closure processes. Information was gathered via a literature survey, industrial contacts, and discussions with project team members, other experts in the field, and the LLNL waste package task staff. The five processes selected were friction welding, electron beam welding, laser beam welding, gas tungsten arc welding, and plasma arc welding. These are felt to represent the best combination of weldment material properties and process performance in a remote, radioactive environment. Conceptual designs have been generated for these processes to illustrate how they would be implemented in practice. Homopolar resistance welding was included in the Phase 1 analysis, and developments in this process will be monitored via literature in Phases 2 and 3. Work was conducted in accordance with the YMP Quality Assurance Program. 223 refs., 20 figs., 9 tabs

The three- and four-nucleon systems from chiral effective field theory

Recently developed chiral nucleon-nucleon (NN) forces at next-to-leading order (NLO) that describe NN phase shifts up to about 100 MeV fairly well have been applied to 3N and 4N systems. Faddeev-Yakubovsky equations have been solved rigorously. The chiral NLO forces depend on a momentum cut-off \Lambda lying between 540-600 MeV/c. The resulting 3N and 4N binding energies are in the same range as found using standard NN potentials. In additon, low-energy 3N scattering observables are very well reproduced like for standard NN forces. Surprisingly, the long standing A_y-puzzle is resolved at NLO. The cut-off dependence of the scattering observables is rather mild.Comment: 4 pp, revtex, 3 figure

Analyzing power in nucleon-deuteron scattering and three-nucleon forces

Three-nucleon forces have been considered to be one possibility to resolve the well known discrepancy between experimental values and theoretical calculations of the nucleon analyzing power in low energy nucleon-deuteron scattering. In this paper, we investigate possible effects of two-pion exchange three-nucleon forces on the analyzing power and the differential cross section. We found that the reason for different effects on the analyzing power by different three-nucleon forces found in previous calculations is related to the existence of the contact term. Effects of some variations of two-pion exchange three-nucleon forces are investigated. Also, an expression for the measure of the nucleon analyzing power with quartet P-wave phase shifts is presented.Comment: 11 pages including 2 eps figures, use epsfig.sty, to appear in Phys. Rev.

The one-pion-exchange three-nucleon force and the AyA_y puzzle

We consider a new three-nucleon force generated by the exchange of one pion in the presence of a 2N correlation. The underlying irreducible diagram has been recently suggested by the authors as a possible candidate to explain the puzzle of the vector analyzing powers $A_y$ and $iT_{11}$ for nucleon-deuteron scattering. Herein, we have calculated the elastic neutron-deuteron differential cross section, $A_y$, $iT_{11}$, $T_{20}$, $T_{21}$, and $T_{22}$ below break-up threshold by accurately solving the Alt-Grassberger-Sandhas equations with realistic interactions. We have also studied how $A_y$ evolves below 30 MeV. The results indicate that this new 3NF diagram provides one possible additional contribution, with the correct spin-isospin structure, for the explanation of the origin of this puzzle.Comment: revised version: We have also studied how Ay evolves below 30 MeV, 4 Pages (twocolumn), 2 figures, uses psfig, RevTe

Three-Nucleon Forces from Chiral Effective Field Theory

We perform the first complete analysis of nd scattering at next-to-next-to-leading order in chiral effective field theory including the corresponding three-nucleon force and extending our previous work, where only the two-nucleon interaction has been taken into account. The three-nucleon force appears first at this order in the chiral expansion and depends on two unknown parameters. These two parameters are determined from the triton binding energy and the nd doublet scattering length. We find an improved description of various scattering observables in relation to the next-to-leading order results especially at moderate energies (E_lab = 65 MeV). It is demonstrated that the long-standing A_y-problem in nd elastic scattering is still not solved by the leading 3NF, although some visible improvement is observed. We discuss possibilities of solving this puzzle. The predicted binding energy for the alpha-particle agrees with the empirical value.Comment: 36 pp, 20 figure

The AyA_y Puzzle and the Nuclear Force

The nucleon-deuteron analyzing power $A_y$ in elastic nucleon-deuteron scattering poses a longstanding puzzle. At energies $E_{lab}$ below approximately 30 MeV $A_y$ cannot be described by any realistic NN force. The inclusion of existing three-nucleon forces does not improve the situation. Because of recent questions about the $^3P_J$ NN phases, we examine whether reasonable changes in the NN force can resolve the puzzle. In order to do this we investigate the effect on the $^3P_J$ waves produced by changes in different parts of the potential (viz., the central force, tensor force, etc.), as well as on the 2-body observables and on $A_y$. We find that it is not possible with reasonable changes in the NN potential to increase the 3-body $A_y$ and at the same time to keep the 2-body observables unchanged. We therefore conclude that the $A_y$ puzzle is likely to be solved by new three-nucleon forces, such as those of spin-orbit type, which have not yet been taken into account.Comment: 35 pages in REVTeX, 1 figure in postscript and 3 figures in PiCTe

Nucleon-deuteron elastic scattering as a tool to probe properties of three-nucleon forces

Faddeev equations for elastic Nd scattering have been solved using modern NN forces combined with the Tucson-Melbourne two-pion exchange three-nucleon force, with a modification thereof closer to chiral symmetry and the Urbana IX three-nucleon force. Theoretical predictions for the differential cross section and several spin observables using NN forces only and NN forces combined with three-nucleon force models are compared to each other and to the existing data. A wide range of energies from 3 to 200 MeV is covered. Especially at the higher energies striking three-nucleon force effects are found, some of which are supported by the still rare set of data, some are in conflict with data and thus very likely point to defects in those three-nucleon force models.Comment: 30 pages, 14 Postscript figures; now minor changes in figures and reference

Mechanistic insight into the pathology of polyalanine expansion disorders revealed by a mouse model for x linked hypopituitarism

Extent: 9 p.Polyalanine expansions in transcription factors have been associated with eight distinct congenital human diseases. It is thought that in each case the polyalanine expansion causes misfolding of the protein that abrogates protein function. Misfolded proteins form aggregates when expressed in vitro; however, it is less clear whether aggregation is of relevance to these diseases in vivo. To investigate this issue, we used targeted mutagenesis of embryonic stem (ES) cells to generate mice with a polyalanine expansion mutation in Sox3 (Sox3-26ala) that is associated with X-linked Hypopituitarism (XH) in humans. By investigating both ES cells and chimeric mice, we show that endogenous polyalanine expanded SOX3 does not form protein aggregates in vivo but rather is present at dramatically reduced levels within the nucleus of mutant cells. Importantly, the residual mutant protein of chimeric embryos is able to rescue a block in gastrulation but is not sufficient for normal development of the hypothalamus, a region that is functionally compromised in Sox3 null embryos and individuals with XH. Together, these data provide the first definitive example of a disease-relevant PA mutant protein that is both nuclear and functional, thereby manifesting as a partial loss-of-function allele.James Hughes Sandra Piltz, Nicholas Rogers, Dale McAninch, Lynn Rowley and Paul Thoma