Internalization of cationic peptides: the road less (or more?) traveled

Facilitating the entry of molecules into mammalian cells is of great interest to fields as diverse as cell biology and drug delivery. The discovery of natural protein transduction domains and the development of artificial ones, including polyarginine, provides a means to achieve this goal. Here, we comment on key chemical and biological aspects of cationic peptide internalization, including the physiological relevance of this process. Received 13 April 2006; received after revision 21 May 2006; accepted 2 June 2006     

A GIS model to predict the location of fossil packrat ( Neotoma ) middens in central Nevada

Fossil packrat ( Neotoma ) middens provide an important source of paleoecologic data in the arid West. This study describes and tests a predictive GIS model that uses the eights-of-evidence method for determining areas with a high probability of containing fossil middens in central Nevada. Model variables included geology, elevation, and aspect. Geology was found to be the most important variable tested. We produced a map of 4 probability classes validated by field-checking 21 randomly selected 1-km 2 sites throughout the study area. Our high-probability category reduced the search area to only 3.5% of the total study area. Fossil middens were found on 8 of 21 sites (38%). Geologic types that contained middens were granite, limestone, and volcanic tuff. A 2nd run of the model with the new midden localities added to the training set helped narrow the total search area even further. This analysis demonstrates that the weights-of-evidence method provides an effective tool both for guiding research design and for helping locate midden sites within specific localities. With only a limited training dataset and a simple set of mapped criteria, a model can be constructed that is both predictive and testable. We intend to continue development of the model to improve our ability to predict the location of Pleistocene-age middens and to locate middens on low-probability sites. This method, designed for mineral exploration, has wide potential application within the natural sciences.     

Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus

We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus.