TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle

The activity of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone (11-dehydrocorticosterone (11-DHC)) (in mice) into the active glucocorticoid (GC) cortisol (corticosterone in mice), can amplify tissue GC exposure. Elevated TNFα is a common feature in a range of inflammatory disorders and is detrimental to muscle function in diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease.We have previously demonstrated that 11β-HSD1 activity is increased in the mesenchymal stromal cells (MSCs) by TNFα treatment and suggested that this is an autoregulatory anti-inflammatory mechanism. This upregulation was mediated by the P2 promoter of the Hsd11β1 gene and was dependent on the NF-kB signalling pathway. In this study, we show that in contrast to MSCs, in differentiated C2C12 and primary murine myotubes, TNFα suppresses Hsd11β1 mRNA expression and activity through the utilization of the alternative P1 promoter. As with MSCs, in response to TNFα treatment, NF-κB p65 was translocated to the nucleus. However, ChIP analysis demonstrated that the direct binding was seen at positionK218 toK245 bp of the Hsd11β1 gene's P1 promoter but not at the P2 promoter. These studies demonstrate the existence of differential regulation of 11β-HSD1 expression in muscle cells through TNFα/p65 signalling and the P1 promoter, further enhancing our understanding of the role of 11β-HSD1 in the context of inflammatory disease

Uranium(III) coordination chemistry and oxidation in a flexible small-cavity macrocycle

U(III) complexes of the conformationally flexible, small-cavity macrocycle trans-calix[2]benzene[2]pyrrolide (L)2–, [U(L)X] (X = O-2,6-tBu2C6H3, N(SiMe3)2), have been synthesized from [U(L)BH4] and structurally characterized. These complexes show binding of the U(III) center in the bis(arene) pocket of the macrocycle, which flexes to accommodate the increase in the steric bulk of X, resulting in long U–X bonds to the ancillary ligands. Oxidation to the cationic U(IV) complex [U(L)X][B(C6F5)4] (X = BH4) results in ligand rearrangement to bind the smaller, harder cation in the bis(pyrrolide) pocket, in a conformation that has not been previously observed for (L)2–, with X located between the two ligand arene rings

Temperature dependence of the spin and orbital magnetization density in Sm1−xGdxAl2Sm_{1-x}Gd_{x} Al_{2} around the spin-orbital compensation point

Non-resonant ferromagnetic x-ray diffraction has been used to separate the spin and orbital contribution to the magnetization density of the proposed zero-moment ferromagnet $Sm_{0.982}Gd_{0.018} Al_{2}$. The alignment of the spin and orbital moments relative to the net magnetization shows a sign reversal at 84K, the compensation temperature. Below this temperature the orbital moment is larger than the spin moment, and vice versa above it. This result implies that the compensation mechanism is driven by the different temperature dependencies of the $4f$ spin and orbital moments. Specific heat data indicate that the system remains ferromagnetically ordered throughout

Strong electron-phonon coupling in delta-phase stabilized Pu

Heat capacity measurements of the delta-phase stabilized alloy Pu-Al suggest that strong electron-phonon coupling is required to explain the moderate renormalization of the electronic density of states near the Fermi energy. We calculate the heat capacity contributions from the lattice and electronic degrees of freedom as well as from the electron-lattice coupling term and find good overall agreement between experiment and theory assuming a dimensionless electron-phonon coupling parameter of order unity, lambda ~ 0.8. This large electron-phonon coupling parameter is comparable to reported values in other superconducting metals with face-centered cubic crystal structure, for example, Pd (lambda ~ 0.7) and Pb (lambda ~ 1.5). Further, our analysis shows evidence of a sizable residual low-temperature entropy contribution, S_{res} ~ 0.4 k_B (per atom). We can fit the residual specific heat to a two-level system. Therefore, we speculate that the observed residual entropy originates from crystal-electric field effects of the Pu atoms or from self-irradiation induced defects frozen in at low temperatures.Comment: 9 pages, 11 figures, to appear in Phys. Rev.

Magnetic state of plutonium ion in metallic Pu and its compounds

By LDA+U method with spin-orbit coupling (LDA+U+SO) the magnetic state and electronic structure have been investigated for plutonium in \delta and \alpha phases and for Pu compounds: PuN, PuCoGa5, PuRh2, PuSi2, PuTe, and PuSb. For metallic plutonium in both phases in agreement with experiment a nonmagnetic ground state was found with Pu ions in f^6 configuration with zero values of spin, orbital, and total moments. This result is determined by a strong spin-orbit coupling in 5f shell that gives in LDA calculation a pronounced splitting of 5f states on f^{5/2} and f^{7/2} subbands. A Fermi level is in a pseudogap between them, so that f^{5/2} subshell is already nearly completely filled with six electrons before Coulomb correlation effects were taken into account. The competition between spin-orbit coupling and exchange (Hund) interaction (favoring magnetic ground state) in 5f shell is so delicately balanced, that a small increase (less than 15%) of exchange interaction parameter value from J_H=0.48eV obtained in constrain LDA calculation would result in a magnetic ground state with nonzero spin and orbital moment values. For Pu compounds investigated in the present work, predominantly f^6 configuration with nonzero magnetic moments was found in PuCoGa5, PuSi2, and PuTe, while PuN, PuRh2, and PuSb have f^5 configuration with sizeable magnetic moment values. Whereas pure jj coupling scheme was found to be valid for metallic plutonium, intermediate coupling scheme is needed to describe 5f shell in Pu compounds. The results of our calculations show that both spin-orbit coupling and exchange interaction terms in the Hamiltonian must be treated in a general matrix form for Pu and its compounds.Comment: 20 pages, LaTeX; changed discussion on reference pape

Differential expression, function and response to inflammatory stimuli of 11β-hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue-specific regulation of inflammation

Stromal cells such as fibroblasts play an important role in defining tissue-specific responses during the resolution of inflammation. We hypothesized that this involves tissue-specific regulation of glucocorticoids, mediated via differential regulation of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Expression, activity and function of 11β-HSD1 was assessed in matched fibroblasts derived from various tissues (synovium, bone marrow and skin) obtained from patients with rheumatoid arthritis or osteoarthritis. 11β-HSD1 was expressed in fibroblasts from all tissues but mRNA levels and enzyme activity were higher in synovial fibroblasts (2-fold and 13-fold higher mRNA levels in dermal and synovial fibroblasts, respectively, relative to bone marrow). Expression and activity of the enzyme increased in all fibroblasts following treatment with tumour necrosis factor-α or IL-1β (bone marrow: 8-fold and 37-fold, respectively, compared to vehicle; dermal fibroblasts: 4-fold and 14-fold; synovial fibroblasts: 7-fold and 31-fold; all P < 0.01 compared with vehicle). Treatment with IL-4 or interferon-γ was without effect, and there was no difference in 11β-HSD1 expression between fibroblasts (from any site) obtained from patients with rheumatoid arthritis or osteoarthritis. In the presence of 100 nmol/l cortisone, IL-6 production – a characteristic feature of synovial derived fibroblasts – was significantly reduced in synovial but not dermal or bone marrow fibroblasts. This was prevented by co-treatment with an 11β-HSD inhibitor, emphasizing the potential for autocrine activation of glucocorticoids in synovial fibroblasts. These data indicate that differences in fibroblast-derived glucocorticoid production (via the enzyme 11β-HSD1) between cells from distinct anatomical locations may play a key role in the predeliction of certain tissues to develop persistent inflammation

The prevalence and incidence of mental ill-health in adults with autism and intellectual disabilities

The prevalence, and incidence, of mental ill-health in adults with intellectual disabilities and autism were compared with the whole population with intellectual disabilities, and with controls, matched individually for age, gender, ability-level, and Down syndrome. Although the adults with autism had a higher point prevalence of problem behaviours compared with the whole adult population with intellectual disabilities, compared with individually matched controls there was no difference in prevalence, or incidence of either problem behaviours or other mental ill-health. Adults with autism who had problem behaviours were less likely to recover over a two-year period than were their matched controls. Apparent differences in rates of mental ill-health are accounted for by factors other than autism, including Down syndrome and ability level

Does the universe in fact contain almost no information?

At first sight, an accurate description of the state of the universe appears to require a mind-bogglingly large and perhaps even infinite amount of information, even if we restrict our attention to a small subsystem such as a rabbit. In this paper, it is suggested that most of this information is merely apparent, as seen from our subjective viewpoints, and that the algorithmic information content of the universe as a whole is close to zero. It is argued that if the Schr\"odinger equation is universally valid, then decoherence together with the standard chaotic behavior of certain non-linear systems will make the universe appear extremely complex to any self-aware subsets that happen to inhabit it now, even if it was in a quite simple state shortly after the big bang. For instance, gravitational instability would amplify the microscopic primordial density fluctuations that are required by the Heisenberg uncertainty principle into quite macroscopic inhomogeneities, forcing the current wavefunction of the universe to contain such Byzantine superpositions as our planet being in many macroscopically different places at once. Since decoherence bars us from experiencing more than one macroscopic reality, we would see seemingly complex constellations of stars etc, even if the initial wavefunction of the universe was perfectly homogeneous and isotropic.Comment: 17 pages, LATeX, no figures. Online with refs at http://astro.berkeley.edu/~max/nihilo.html (faster from the US), from http://www.mpa-garching.mpg.de/~max/nihilo.html (faster from Europe) or from [email protected]