Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine tract in ataxin-1 (ATXN1). SCA1 pathogenesis studies support a model in which the expanded glutamine tract causes toxicity by modulating the normal activities of ATXN1. To explore native interactions that modify the toxicity of ATXN1, we generated a targeted duplication of the mouse ataxin-1-like (Atxn1l, also known as Boat) locus, a highly conserved paralog of SCA1, and tested the role of this protein in SCA1 pathology. Using a knock-in mouse model of SCA1 that recapitulates the selective neurodegeneration seen in affected individuals, we found that elevated Atxn1l levels suppress neuropathology by displacing mutant Atxn1 from its native complex with Capicua (CIC). Our results provide genetic evidence that the selective neuropathology of SCA1 arises from modulation of a core functional activity of ATXN1, and they underscore the importance of studying the paralogs of genes mutated in neurodegenerative diseases to gain insight into mechanisms of pathogenesis.     

Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans

Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression.     

Palmitate-induced skeletal muscle insulin resistance does not require NF-κB activation

Palmitate activates the NF-κB pathway, and induces accumulation of lipid metabolites and insulin resistance in skeletal muscle cells. Little information is available whether and how these processes are causally related. Therefore, the objectives were to investigate whether intra-cellular lipid metabolites are involved in FA-induced NF-κB activation and/or insulin resistance in skeletal muscle and to investigate whether FA-induced insulin resistance and NF-κB activation are causally related. Inhibiting DGAT or CPT-1 by using, respectively, amidepsine or etomoxir increased DAG accumulation and sensitized myotubes to palmitate-induced insulin resistance. While co-incubation of palmitate with etomoxir increased NF-κB transactivation, co-incubation with amidepsine did not, indicating that DAG accumulation is associated with insulin resistance but not with NF-κB activation. Furthermore, pharmacological or genetic inhibition of the NF-κB pathway could not prevent palmitate-induced insulin resistance. In conclusion, we have demonstrated that activation of the NF-κB pathway is not required for palmitate-induced insulin resistance in skeletal muscle cells.     

Proteolytic enzymes in the Rhodnius prolixus midgut.

Sequential chromatographic fractionation of Rhodnius prolixus midgut homogenate yielded only one endopeptidase, but revealed the presence of carboxypeptidase-A and B-like enzyme, di- and tripeptidases, as well as aminopeptidase activities.     

Microhabitat affinities of Gambel oak seedlings

Previous work suggested that Gambel oak seedlings are rare in the northern parts of its range in Utah where summer rainfall is relatively low but should be abundant in southern parts of the range where summer rainfall is usually high. Gambel oak grades from a relatively minor component of a ponderosa pine/mixed conifer assemblage in the south to a virtually monotypic formation in the north, where it exists as long-lived clones.   Quadrat analysis in Arizona and New Mexico, within the oak zone, revealed a seedling density ranging from 120 to 1320 per hectare. We found a significant tendency of seedlings to be located on the NE (cool, shady) side of sheltering objects in the environment. Mature ponderosa pine ranged in density from ca 40 to 500 stems per hectare, whereas mature Gambel oak ranged from ca 10 to 20 genets per hectare with ca 1 to 7 ramets per clone. These results support our previous conclusion that Gambel oak in northern Utah probably became established as a minor component of a mixed pine/oak woodland at a time in mid-Holocene when summer rainfall was much higher than today.     

New species of Primula (Primulaceae) from Utah

Named as a new species from the House Range of Millard County, Utah, as Primula domensis Kass & Welsh.