Genetic mapping of meander tail, a mouse mutation affecting cerebellar development

The meander tail mouse harbors a recessive mutation on chromosome 4 that affects the anterior lobes of the cerebellum and the caudal vertebrae. Examination of the mea/mea cerebellum reveals that the complete disorganization of all cell types seen in the anterior lobes is separated by a sharp and consistent boundary from the normal cytoarchitecture of the posterior lobes. In the absence of any biochemical information regarding the affected gene product, attempts to clone the gene must rely on the strategy of reverse genetics. As an initial step in this process we have constructed a genetic linkage map spanning 68 cM of chromosome 4 using an intersubspecific phenotypic backcross. The loci included in this analysis are Calb, Ggtb, Lv, b, Ifa, mea, D4Rp1, Glut-1, Lck, Lmyc-1, and Eno-1. This analysis positions the mea phenotypic locus in the interval between Ifa and Glut1. These results also further define regions of homology between mouse chromosome 4 and human chromosomes 8, 1, and 9. This linkage map provides the means to evaluate candidate genes, and to identify tightly linked markers useful for cloning the meander tail locus.     

Neurotoxicity,drugs of abuse,and the CuZn-superoxide dismutase transgenic mice

Administration of methamphetamine (METH) to animals causes loss of DA terminals in the brain. The manner by which METH causes these changes in neurotoxicity is not known. We have tested the effects of this drug in copper/zinc (CuZn)-superoxide dismutase transgenic (SOD Tg) mice, which express the human CuZnSOD gene. In nontransgenic (non-Tg) mice, acute METH administration causes significant decreases in DA and dihydroxyphenylacetic acid (DOPAC) in the striata of non-Tg mice. In contrast, there were no significant decreases in striatal DA in the SOD Tg mice. The effects of METH on DOPAC were also attenuated in SOD Tg mice. Chronic METH administration caused decreases in striatal DA and DOPAC in the non-Tg mice, but not in the SOD-Tg mice. Similar studies were carried out with 1-methyl-1,2,3,6-tetrahydropyridine (MPTP), which also causes striatal DA and DOPAC depletion. As in the case of METH, MPTP causes marked depletion of DA and DOPAC in the non-Tg mice, but not in the SOD Tg mice. These results suggest that the mechanisms of toxicity of both METH and MPTP involve superoxide radical formation.     

Transport of the vesicular stomatitis glycoprotein to trans Golgi membranes in a cell-free system

Terminal steps in the transport of the vesicular stomatitis virus glycoprotein (G protein) in the Golgi stack have been reconstituted in a cell-free system. Incorporation of sialic acid into the oligosaccharide chains of G protein was used to monitor transport into the trans Golgi compartment. Transport-coupled sialylation required cytosol, ATP, an N-ethylmaleimide-sensitive factor extractable from Golgi membranes, and long chain acyl coenzyme A. The G protein receiving sialic acid in the cell-free system begins its in vitro transport bearing galactose residues acquired in vivo. Earlier reports (Balch, W. E., Dunphy, W. G., Braell, W. A., and Rothman, J. E. (1984a) Cell 39, 405-416) documented that transport of G protein into the medial (GlcNAc Transferase-containing) compartment is reconstituted under the same conditions. On the basis of the results reported here, it now appears that a more complete set of transport operations of the Golgi stack may be simultaneously reconstituted.     

Playing it safe? Solitary vervet monkeys (Chlorocebus pygerythrus) choose high‐quality foods more than those in competition

An important goal in foraging ecology is to determine how biotic and abiotic variables impact the foraging decisions of wild animals and how they move throughout their multidimensional landscape. However, the interaction of food quality and feeding competition on foraging decisions is largely unknown. Here we examine the importance of food quality in a patch on the foraging decisions of wild vervet monkeys (Chlorocebus pygerythrus) at Lake Nabugabo, Uganda using a multidestination platform array. The overall nutritional composition of the vervet diet was assessed and found to be low in sodium and lipids, thus we conducted a series of experimental manipulations in which the array was varied in salt and oil content. Although vervets prioritized platforms containing key nutrients (i.e., sodium and lipids) overall, we found that solitary vervets prioritized nutrient‐dense platforms more strongly than competing vervets. This finding was opposite to those in a similar experiment that manipulated food site quantity, suggesting that large, salient rewards may be worth competing over but slight differences in nutritional density may be only chosen when there are no potentially negative social consequences (i.e., aggression received). We also found that vervets chose platforms baited with oil‐only, and oil combined with salt, but not salt‐only, suggesting that energy was an important factor in food choice. Our findings demonstrate that when wild vervets detect differences in feeding patches that reflect nutritional composition, they factor these differences into their navigational and foraging decisions. In addition, our findings suggest that these nutritional differences may be considered alongside social variables, ultimately leading to the complex strategies we observed in this study.     

Tract Profiles of White Matter Properties: Automating Fiber-Tract Quantification

Tractography based on diffusion weighted imaging (DWI) data is a method for identifying the major white matter fascicles (tracts) in the living human brain. The health of these tracts is an important factor underlying many cognitive and neurological disorders. In vivo, tissue properties may vary systematically along each tract for several reasons: different populations of axons enter and exit the tract, and disease can strike at local positions within the tract. Hence quantifying and understanding diffusion measures along each fiber tract (Tract Profile) may reveal new insights into white matter development, function, and disease that are not obvious from mean measures of that tract. We demonstrate several novel findings related to Tract Profiles in the brains of typically developing children and children at risk for white matter injury secondary to preterm birth. First, fractional anisotropy (FA) values vary substantially within a tract but the Tract FA Profile is consistent across subjects. Thus, Tract Profiles contain far more information than mean diffusion measures. Second, developmental changes in FA occur at specific positions within the Tract Profile, rather than along the entire tract. Third, Tract Profiles can be used to compare white matter properties of individual patients to standardized Tract Profiles of a healthy population to elucidate unique features of that patient''s clinical condition. Fourth, Tract Profiles can be used to evaluate the association between white matter properties and behavioral outcomes. Specifically, in the preterm group reading ability is positively correlated with FA measured at specific locations on the left arcuate and left superior longitudinal fasciculus and the magnitude of the correlation varies significantly along the Tract Profiles. We introduce open source software for automated fiber-tract quantification (AFQ) that measures Tract Profiles of MRI parameters for 18 white matter tracts. With further validation, AFQ Tract Profiles have potential for informing clinical management and decision-making.     

“The Ultimate Decision Is Yours”: Exploring Patients’ Attitudes about the Overuse of Medical Interventions

Previous research has found that American patients strongly believe that more testing and more treatment lead to better outcomes and, to a lesser extent, that newer treatments are more effective. We conducted five focus groups with privately insured, healthy, middle-aged Americans (n = 43) to explore these apparent preferences. Contrary to previous research, an unexpected distinction emerged. Participants placed enormous value on testing and screening, reacting with hostility to guidelines recommending less of either. However, they were suspicious of overmedication. The wariness of pharmaceuticals and enthusiasm for testing and screening both appear to reflect participants’ efforts to take responsibility for their health. But recommendations to test and screen less conflicted with their active, engaged, information-seeking roles. Nonetheless, given patients’ concerns about overuse of pharmaceuticals, we maintain that they can learn to understand the connections between over-testing and over-treatment, and can actively choose to do less. We close with suggestions about how treatment guidelines can better communicate these connections to patients. Our findings cannot necessarily be generalized beyond privately-insured, healthy, middle-aged Americans. But because we found that, among these individuals, attitudes towards pharmaceuticals differ from attitudes towards testing and screening, we maintain that future research should also distinguish among and compare attitudes towards different types of medical interventions.     

Explaining geographical variation in the isotope composition of mouse lemurs (Microcebus)

Aim We sought to quantify geographical variation in the stable isotope values of mouse lemurs (Microcebus) and to determine whether this variation reflects trophic differences among populations or baseline isotopic differences among habitats. If the latter pattern is demonstrated, then Microcebus can become a proxy for tracking baseline habitat isotopic variability. Establishing such a baseline is crucial for identifying niche partitioning in modern and ancient communities. Location We studied five species of Microcebus from eight distinct habitats across Madagascar. Methods We compared isotopic variation in C₃ plants and Microcebus fur within and among localities. We predicted that carbon and nitrogen isotope values of Microcebus should: (1) vary as a function of abiotic variables such as rainfall and temperature, and (2) covary with isotopic values in plants. We checked for trophic differences among Microcebus populations by comparing the average difference between mouse lemur and plant isotope values for each locality. We then used multiple regression models to explain spatial isotope variation in mouse lemurs, testing a suite of explanatory abiotic variables. Results We found substantial isotopic variation geographically. Ranges for mean isotope values were similar for both Microcebus and plants across localities (carbon 3.5–4.0‰; nitrogen 10.5–11.0‰). Mean mouse lemur and plant isotope values were lowest in cool, moist localities and highest in hot, dry localities. Rainfall explained 58% of the variation in Microcebus carbon isotope values, and mean plant nitrogen isotope values explained 99.7% of the variation in Microcebus nitrogen isotope values. Average differences between mouse lemur and plant isotope values (carbon 5.0‰; nitrogen 5.9‰) were similar across localities. Main conclusions Isotopic data suggest that trophic differences among Microcebus populations were small. Carbon isotope values in mouse lemurs were negatively correlated with rainfall. Nitrogen isotope values in Microcebus and plants covaried. Such findings suggest that nitrogen isotope values for Microcebus are a particularly good proxy for tracking baseline isotopic differences among habitats. Our results will facilitate future comparative research on modern mouse lemur communities, and ecological interpretations of extinct Holocene communities.     

Colonization of the post-umbilical bowel by cells derived from the sacral neural crest: direct tracing of cell migration using an intercalating probe and a replication-deficient retrovirus

Experiments were done to test the hypothesis that the avian gut is colonized by cells derived from both vagal and sacral regions of the neural crest. A fluorescent dye, diI (1,1-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate), and a replication-deficient retrovirus (LZ10; Galileo et al. 1990) were employed as tracers. Since LZ10 was constructed with lacZ of E. coli as a reporter gene, infected cells were identified by demonstrating beta-galactosidase immunoreactivity. DiI and LZ10 were injected between the neural tube and surface ectoderm (before the migration of crest cells away from the injection sites) at vagal, truncal (diI only), or sacral axial levels. The bowel was examined 4 days later in order to allow crest-derived cells sufficient time to migrate to the gut. Following injections of either tracer into the vagal crest, labelled cells were found in the gizzard and duodenum. When diI or LZ10 was injected into the sacral crest, labelled cells were seen in the post-umbilical bowel and ganglion of Remak. In the hindgut, marked cells were concentrated in the mesenchyme, just internal to the serosa, and were never observed rostral to the umbilicus. No fluorescent cells were ever found in the bowel following truncal injections of diI, although such cells were observed in sympathetic ganglia. Labelled cells were always found in dorsal root ganglia, no matter which tracer or level of the crest was injected. In embryos injected with LZ10, infected cells in the gut and dorsal root ganglia displayed a neural crest marker (NC-1 immunoreactivity). These observations confirm that the gut is colonized by cells from the sacral as well as the vagal region of the neural crest and that the emigrés from the sacral crest are confined to the post-umbilical bowel.