Global huntingtin knockout in adult mice leads to fatal neurodegeneration that spares the pancreas.

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG tract in the huntingtin (HTT) gene, leading to toxic gains of function. HTT-lowering treatments are in clinical trials, but the risks imposed are unclear. Recent studies have reported on the consequences of widespread HTT loss in mice, where one group described early HTT loss leading to fatal pancreatitis, but later loss as benign. Another group reported no pancreatitis but found widespread neurological phenotypes including subcortical calcification. To better understand the liabilities of widespread HTT loss, we knocked out Htt with two separate tamoxifen-inducible Cre lines. We find that loss of HTT at 2 mo of age leads to progressive tremors and severe subcortical calcification at examination at 14 mo of age but does not result in acute pancreatitis or histological changes in the pancreas. We, in addition, report that HTT loss is followed by sustained induction of circulating neurofilament light chain. These results confirm that global loss of HTT in mice is associated with pronounced risks, including progressive subcortical calcification and neurodegeneration.

Identification of genes and networks driving cardiovascular and metabolic phenotypes in a mouse F2 intercross.

To identify the genes and pathways that underlie cardiovascular and metabolic phenotypes we performed an integrated analysis of a mouse C57BL/6JxA/J F2 (B6AF2) cross by relating genome-wide gene expression data from adipose, kidney, and liver tissues to physiological endpoints measured in the population. We have identified a large number of trait QTLs including loci driving variation in cardiac function on chromosomes 2 and 6 and a hotspot for adiposity, energy metabolism, and glucose traits on chromosome 8. Integration of adipose gene expression data identified a core set of genes that drive the chromosome 8 adiposity QTL. This chromosome 8 trans eQTL signature contains genes associated with mitochondrial function and oxidative phosphorylation and maps to a subnetwork with conserved function in humans that was previously implicated in human obesity. In addition, human eSNPs corresponding to orthologous genes from the signature show enrichment for association to type II diabetes in the DIAGRAM cohort, supporting the idea that the chromosome 8 locus perturbs a molecular network that in humans senses variations in DNA and in turn affects metabolic disease risk. We functionally validate predictions from this approach by demonstrating metabolic phenotypes in knockout mice for three genes from the trans eQTL signature, Akr1b8, Emr1, and Rgs2. In addition we show that the transcriptional signatures for knockout of two of these genes, Akr1b8 and Rgs2, map to the F2 network modules associated with the chromosome 8 trans eQTL signature and that these modules are in turn very significantly correlated with adiposity in the F2 population. Overall this study demonstrates how integrating gene expression data with QTL analysis in a network-based framework can aid in the elucidation of the molecular drivers of disease that can be translated from mice to humans.

Aberration-corrected STEM investigation of the M2 phase of MoVNbTeO selective oxidation catalyst.

The 'M2' phase of the oxidation catalyst MoVNbTeO was studied with an aberration-corrected STEM using HAADF imaging, and three 60 degrees twin orientations were identified. Comparisons between the experimental HAADF images and image simulations suggest that the there are two different Te sites, as has been previously reported; however, there are differences between the structure proposed in DeSanto et al. (2004) Z. Kristogr. 219: 152 and the experimental HAADF images.

Synthesis, structure, and magnetic properties of Sr2NiOsO6 and Ca2NiOsO6: two new osmium-containing double perovskites.

Two new double perovskite oxides, Ca(2)NiOsO(6) and Sr(2)NiOsO(6), have been prepared as polycrystalline powders by solid state synthesis. The two oxides were structurally characterized by variable-temperature powder neutron diffraction. Ca(2)NiOsO(6) was found to adopt a monoclinic structure (P2(1)/n), while Sr(2)NiOsO(6) was found to be tetragonal (I4/m). Magnetic susceptibility measurements indicate that Ca(2)NiOsO(6) orders in a canted antiferromagnetic state at about 175 K while Sr(2)NiOsO(6) orders antiferromagnetically at about 50 K.

Three-dimensional structure of nanocomposites from atomic pair distribution function analysis: study of polyaniline and (polyaniline)(0.5)V(2)O(5) x 1.0 H(2)O.

The three-dimensional structures of emeraldine base polyaniline (PANI) and (polyaniline)(0.5)V(2)O(5) x 1.0 H(2)O have been determined by total X-ray scattering experiments. Atomic pair distribution functions (PDF) were measured to obtain experimental observables against which structural models were tested and refined. The PDF approach is necessary because of the limited structural coherence in these nanostructured materials. Polyaniline possesses a well-defined local atomic arrangement that can be described in terms of an 84-atom orthorhombic unit cell. The nanocomposite (PANI)(0.5)V(2)O(5) x 1.0 H(2)O too is locally well ordered and may be described in terms of a small number of structure-sensible parameters. The PDF approach allows the construction of structure models of PANI and (PANI)(0.5)V(2)O(5) x 1.0 H(2)O on the basis of which important materials' properties can be explained predicted and possibly improved.