Nucleosome dynamics: HMGB1 relaxes canonical nucleosome structure to facilitate estrogen receptor binding.

High mobility group protein 1 (HMGB1) interacts with DNA and chromatin to influence the regulation of transcription, DNA repair and recombination. We show that HMGB1 alters the structure and stability of the canonical nucleosome (N) in a nonenzymatic, ATP-independent manner. Although estrogen receptor (ER) does not bind to its consensus estrogen response element within a nucleosome, HMGB1 restructures the nucleosome to facilitate strong ER binding. The isolated HMGB1-restructured nucleosomes (N' and N″) remain stable and exhibit characteristics distinctly different from the canonical nucleosome. These findings complement previous studies that showed (i) HMGB1 stimulates in vivo transcriptional activation at estrogen response elements and (ii) knock down of HMGB1 expression by siRNA precipitously reduced transcriptional activation. The findings indicate that one aspect of the mechanism of HMGB1 action involves a restructuring of the nucleosome that appears to relax structural constraints within the nucleosome.

Sodium magnesium sulfate decahydrate, Na(2)Mg(SO(4))(2).10H(2)O, a new sulfate salt.

The structure of synthetic disodium magnesium disulfate decahydrate at 180 K consists of alternating layers of water-coordinated [Mg(H(2)O)(6)](2+) octahedra and [Na(2)(SO(4))(2)(H(2)O)(4)](2-) sheets, parallel to [100]. The [Mg(H(2)O)(6)](2+) octahedra are joined to one another by a single hydrogen bond, the other hydrogen bonds being involved in inter-layer linkage. The Mg(2+) cation occupies a crystallographic inversion centre. The sodium-sulfate sheets consist of chains of water-sharing [Na(H(2)O)(6)](+) octahedra along b, which are then connected by sulfate tetrahedra through corner-sharing. The associated hydrogen bonds are the result of water-sulfate interactions within the sheets themselves. This is believed to be the first structure of a mixed monovalent/divalent cation sulfate decahydrate salt.

Plasma urate and progression of mild cognitive impairment.

BACKGROUND: Impaired antioxidant defenses are implicated in neurodegenerative disease. The plasma levels of urate, a water-soluble antioxidant, are reduced in Alzheimer's disease (AD). OBJECTIVE: We aimed to test the hypotheses that high plasma urate at baseline is associated with: (1) a reduced rate of conversion from mild cognitive impairment (MCI) to AD and (2) a lower rate of cognitive decline in MCI. METHODS: Plasma urate was obtained at baseline from 747 participants in a 3-year, randomized, double-blind, placebo-controlled study of donepezil, vitamin E or placebo for delaying the progression of MCI to AD.The association between baseline urate and conversion from MCI to AD was examined by Cox proportional hazards regression. The relationship between baseline urate and cognitive change on the cognitive subscale of the Alzheimer's Disease Assessment Scale was evaluated by longitudinal analysis. RESULTS: Baseline plasma urate was not associated with the rate of conversion of MCI to AD. In the placebo arm, high plasma urate was related to a slower rate of cognitive decline over 3 years, although this was not reproduced in the other treatment arms. CONCLUSION: While plasma urate levels did not predict the progression of MCI to AD, high urate may be associated with a reduced rate of cognitive decline in MCI patients not treated with donepezil or vitamin E. The results support the investigation of biomarkers of antioxidant status as risk factors for cognitive decline in MCI.

High mobility group B proteins facilitate strong estrogen receptor binding to classical and half-site estrogen response elements and relax binding selectivity.

The estrogen receptor alpha (ER) is a ligand-dependent transcription factor that regulates the expression of estrogen-responsive genes. A key step in the activation process is the initial binding of the ER dimer to the estrogen response element (ERE). We examined the effect of the coactivator proteins, HMGB1 and HMGB2, in enhancing ER binding affinity to single and tandem EREs. Using EMSAs, both HMGB proteins are shown to enhance ER binding and induce cooperative ER binding on tandem ERE elements. We demonstrate that HMGB proteins facilitate strong ER binding to ERE consensus half-sites, exhibiting binding affinities comparable with ER binding to consensus ERE in the absence of HMGB proteins. These findings reveal that although HMGB proteins enhance binding affinity, they also relax ER binding specificity. Deoxyribonuclease I footprinting demonstrates that ER binds very differently to consensus ERE and ERE consensus half-sites, whereas both deoxyribonuclease I and exonuclease III digestions show that the presence of HMGB1/2 does not alter the DNA protection in ER/ERE complexes. Protease digestions of the complexes support this conclusion and show that a global conformation change occurs in ER when bound to the different ER binding sites. Models for these interactions are discussed, together with a hit-and-run mechanism that HMGB proteins may utilize to produce these effects.