Phosphorylation of the liver X receptors

AbstractThe liver X receptors (LXRs) function as nutritional sensors for cholesterol and have important roles in lipid metabolism, glucose homeostasis, and inflammation. We provide the first evidence that LXRs are phosphorylated proteins. Mutational analysis and metabolic labeling indicate LXRα is phosphorylated on serine 198 in the hinge region. This is a consensus target for the MAPK family. A phosphorylation-deficient mutant, LXRα S198A, remains nuclear and responds to ligands like the wild-type protein. The biological significance of LXR phosphorylation remains to be elucidated but could provide a novel mechanism for the regulation of LXR signaling pathways and cellular metabolism

A Simulation Model of Periarterial Clearance of Amyloid-β from the Brain

The accumulation of soluble and insoluble amyloid-β (Aβ) in the brain indicates failure of elimination of Aβ from the brain with age and Alzheimer's disease (AD). There is a variety of mechanisms for elimination of Aβ from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of Aβ into the blood and periarterial lymphatic drainage of Aβ. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as Aβ, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of Aβ in the walls of human arteries with age and AD as cerebral amyloid angiopathy (CAA). Initially, Aβ diffuses through the extracellular spaces of gray matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterized, the exact mechanism whereby perivascular elimination of Aβ occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy

Non-Markovian Dynamics of Entanglement for Multipartite Systems

Entanglement dynamics for a couple of two-level atoms interacting with independent structured reservoirs is studied using a non-perturbative approach. It is shown that the revival of atom entanglement is not necessarily accompanied by the sudden death of reservoir entanglement, and vice versa. In fact, atom entanglement can revive before, simultaneously or even after the disentanglement of reservoirs. Using a novel method based on the population analysis for the excited atomic state, we present the quantitative criteria for the revival and death phenomena. For giving a more physically intuitive insight, the quasimode Hamiltonian method is applied. Our quantitative analysis is helpful for the practical engineering of entanglement.Comment: 10 pages and 4 figure

Euclidean three-point function in loop and perturbative gravity

We compute the leading order of the three-point function in loop quantum gravity, using the vertex expansion of the Euclidean version of the new spin foam dynamics, in the region of gamma<1. We find results consistent with Regge calculus in the limit gamma->0 and j->infinity. We also compute the tree-level three-point function of perturbative quantum general relativity in position space, and discuss the possibility of directly comparing the two results.Comment: 16 page

Asymptotics of Spinfoam Amplitude on Simplicial Manifold: Lorentzian Theory

The present paper studies the large-j asymptotics of the Lorentzian EPRL spinfoam amplitude on a 4d simplicial complex with an arbitrary number of simplices. The asymptotics of the spinfoam amplitude is determined by the critical configurations. Here we show that, given a critical configuration in general, there exists a partition of the simplicial complex into three type of regions R_{Nondeg}, R_{Deg-A}, R_{Deg-B}, where the three regions are simplicial sub-complexes with boundaries. The critical configuration implies different types of geometries in different types of regions, i.e. (1) the critical configuration restricted into R_{Nondeg}$implies a nondegenerate discrete Lorentzian geometry, (2) the critical configuration restricted into R_{Deg-A}$ is degenerate of type-A in our definition of degeneracy, but implies a nondegenerate discrete Euclidean geometry on R_{Deg-A}, (3) the critical configuration restricted into R_{Deg-B} is degenerate of type-B, and implies a vector geometry on R_{Deg-B}. With the critical configuration, we further make a subdivision of the regions R_{Nondeg} and R_{Deg-A} into sub-complexes (with boundary) according to their Lorentzian/Euclidean oriented 4-simplex volume V_4(v), such that sgn(V_4(v)) is a constant sign on each sub-complex. Then in the each sub-complex, the spinfoam amplitude at the critical configuration gives the Regge action in Lorentzian or Euclidean signature respectively on R_{Nondeg} or R_{Deg-A}. The Regge action reproduced here contains a sign factor sgn(V_4(v)) of the oriented 4-simplex volume. Therefore the Regge action reproduced here can be viewed a discretized Palatini action with on-shell connection. Finally the asymptotic formula of the spinfoam amplitude is given by a sum of the amplitudes evaluated at all possible critical configurations, which are the products of the amplitudes associated to different type of geometries.Comment: 54 pages, 2 figures, reference adde

Asymptotics of Spinfoam Amplitude on Simplicial Manifold: Euclidean Theory

We study the large-j asymptotics of the Euclidean EPRL/FK spin foam amplitude on a 4d simplicial complex with arbitrary number of simplices. We show that for a critical configuration (j_f, g_{ve}, n_{ef}) in general, there exists a partition of the simplicial complex into three regions: Non-degenerate region, Type-A degenerate region and Type-B degenerate region. On both the non-degenerate and Type-A degenerate regions, the critical configuration implies a non-degenerate Euclidean geometry, while on the Type-B degenerate region, the critical configuration implies a vector geometry. Furthermore we can split the Non-degenerate and Type-A regions into sub-complexes according to the sign of Euclidean oriented 4-simplex volume. On each sub-complex, the spin foam amplitude at critical configuration gives a Regge action that contains a sign factor sgn(V_4(v)) of the oriented 4-simplices volume. Therefore the Regge action reproduced here can be viewed as a discretized Palatini action with on-shell connection. The asymptotic formula of the spin foam amplitude is given by a sum of the amplitudes evaluated at all possible critical configurations, which are the products of the amplitudes associated to different type of geometries.Comment: 27 pages, 5 figures, references adde

Speech Spectrum's Correlation with Speakers' Eysenck Personality Traits

The current study explored the correlation between speakers' Eysenck personality traits and speech spectrum parameters. Forty-six subjects completed the Eysenck Personality Questionnaire. They were instructed to verbally answer the questions shown on a computer screen and their responses were recorded by the computer. Spectrum parameters of /sh/ and /i/ were analyzed by Praat voice software. Formant frequencies of the consonant /sh/ in lying responses were significantly lower than that in truthful responses, whereas no difference existed on the vowel /i/ speech spectrum. The second formant bandwidth of the consonant /sh/ speech spectrum was significantly correlated with the personality traits of Psychoticism, Extraversion, and Neuroticism, and the correlation differed between truthful and lying responses, whereas the first formant frequency of the vowel /i/ speech spectrum was negatively correlated with Neuroticism in both response types. The results suggest that personality characteristics may be conveyed through the human voice, although the extent to which these effects are due to physiological differences in the organs associated with speech or to a general Pygmalion effect is yet unknown

Telomerase mutations in families with idiopathic pulmonary fibrosis

BACKGROUND: Idiopathic pulmonary fibrosis is progressive and often fatal; causes of familial clustering of the disease are unknown. Germ-line mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase and telomerase RNA, respectively, cause autosomal dominant dyskeratosis congenita, a rare hereditary disorder associated with premature death from aplastic anemia and pulmonary fibrosis. METHODS: To test the hypothesis that familial idiopathic pulmonary fibrosis may be caused by short telomeres, we screened 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for mutations in hTERT and hTR. RESULTS: Six probands (8%) had heterozygous mutations in hTERT or hTR; mutant telomerase resulted in short telomeres. Asymptomatic subjects with mutant telomerase also had short telomeres, suggesting that they may be at risk for the disease. We did not identify any of the classic features of dyskeratosis congenita in five of the six families. CONCLUSIONS: Mutations in the genes encoding telomerase components can appear as familial idiopathic pulmonary fibrosis. Our findings support the idea that pathways leading to telomere shortening are involved in the pathogenesis of this disease

Identification of novel mutations in Chinese Hans with autosomal dominant polycystic kidney disease

<p>Abstract</p> <p>Background</p> <p>Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease with an incidence of 1 in 400 to 1000. The disease is genetically heterogeneous, with two genes identified: <it>PKD1 </it>(16p13.3) and <it>PKD2 </it>(4q21). Molecular diagnosis of the disease in at-risk individuals is complicated due to the structural complexity of <it>PKD1 </it>gene and the high diversity of the mutations. This study is the first systematic ADPKD mutation analysis of both <it>PKD1 </it>and <it>PKD2 </it>genes in Chinese patients using denaturing high-performance liquid chromatography (DHPLC).</p> <p>Methods</p> <p>Both <it>PKD1 </it>and <it>PKD2 </it>genes were mutation screened in each proband from 65 families using DHPLC followed by DNA sequencing. Novel variations found in the probands were checked in their family members available and 100 unrelated normal controls. Then the pathogenic potential of the variations of unknown significance was examined by evolutionary comparison, effects of amino acid substitutions on protein structure, and effects of splice site alterations using online mutation prediction resources.</p> <p>Results</p> <p>A total of 92 variations were identified, including 27 reported previously. Definitely pathogenic mutations (ten frameshift, ten nonsense, two splicing defects and one duplication) were identified in 28 families, and probably pathogenic mutations were found in an additional six families, giving a total detection level of 52.3% (34/65). About 69% (20/29) of the mutations are first reported with a recurrent mutation rate of 31%.</p> <p>Conclusions</p> <p>Mutation study of <it>PKD1 </it>and <it>PKD2 </it>genes in Chinese Hans with ADPKD may contribute to a better understanding of the genetic diversity between different ethnic groups and enrich the mutation database. Besides, evaluating the pathogenic potential of novel variations should also facilitate the clinical diagnosis and genetic counseling of the disease.</p