Effects of sham feedback following successful SMR training in an epileptic

After 1 year of SMR biofeedback training of a severe epileptic teenage male, incidence of atonic seizures decreased from 8/hr to less than 1/3 hr. SMR increased from 10% to 70%. Epileptiform discharges decreased from 45% to 15%. Unknown to the patient, his family, or certain members of our research staff, noncontingent feedback was introduced on 7/22/74, ending 9/11/74. A significant decrease occurred for SMR(down 8%), and a significant increase for epileptiform discharges(up 4%). Rate of seizures increased, but was not statistically significant over preceding months of contingent feedback. Incidence of seizures associated with urine loss increased from approximately 6/month to 23/month during noncontingent feedback, a significant increase. Urine-loss results suggest that although seizures did not become more frequent, those the patient did experience were “harder,” i.e., more severe. Contingent feedback was reinstituted following the 7-wk sham, and recovery of all variables to their former levels(prior to sham) occurred.     

Oxidation of sulfhydryl groups to disulfides by sulfoxides.

Oxidation rates of SH groups in penicillamine, cysteine, and glutathione to the corresponding SS forms by dimethyl sulfoxide and other sulfoxides as a function of pH of the solvent and structure of reactants were measured by NMR spectroscopy. The observed second-order rate constant showed a biphasic pH dependence. A mechanism which rationalizes this result is proposed. These oxidations are proposed to have synthetic utility with biochemical implications.     

Immunological probes for oestradiol receptors in human breast tumours

Monoclonal antibodies have been prepared against a soluble oestradiol receptor (REC) preparation partially purified from human myometrium by oestradiol affinity chromatography. The antibodies were detected by their ability to immunoprecipitate receptor bound [125I] oestradiol. One of the antibodies (D5) has been studied in detail. It will only precipitate REC after activation by salt, heat, low pH or KCNS and will not react with nuclear RE. It will not react with androgen, progesterone or glucocorticoid receptors nor with sex hormone binding globulin; it will only combine with REC from human sources. D5 recognizes a cytoplasmic 29 kdalton protein (p29) that can be separated from both type I and II soluble oestradiol binding proteins. p29 can react with activated REC and is qualitatively and quantitatively related to REC. IRMA and histochemical methods have been developed for quantitating p29 and relating its amount to receptors in human breast tumours. With both methods, highly significant (P less than 0.001) correlations with REC but not RP have been obtained. Both methods indicate that many REC-RP+ tumours contain p29. The histochemical method detects marked cellular heterogeneity in some tumours. The function of p29 is not known. It is an REC-related antigen that may be a previously undetected component of the oestradiol receptor machinery.     

Complementary strengths of spatially-explicit and multi-species distribution models

Species distribution models (SDMs) project the outcome of community assembly processes – dispersal, the abiotic environment and biotic interactions – onto geographic space. Recent advances in SDMs account for these processes by simultaneously modeling the species that comprise a community in a multivariate statistical framework or by incorporating residual spatial autocorrelation in SDMs. However, the effects of combining both multivariate and spatially-explicit model structures on the ecological inferences and the predictive abilities of a model are largely unknown. We used data on eastern hemlock Tsuga canadensis and five additional co-occurring overstory tree species in 35 569 forest stands across Michigan, USA to evaluate how the choice of model structure, including spatial and non-spatial forms of univariate and multivariate models, affects ecological inference about the processes that shape community composition as well as model predictive ability. Incorporating residual spatial autocorrelation via spatial random effects did not improve out-of-sample prediction for the six tree species, although in-sample model fit was higher in the spatial models. Spatial models attributed less variation in occurrence probability to environmental covariates than the non-spatial models for all six tree species, and estimated higher (more positive) residual co-occurrence values for most species pairs. The non-spatial multivariate model was better suited for evaluating habitat suitability and hypotheses about the processes that shape community composition. Environmental correlations and residual correlations among species pairs were positively related, perhaps indicating that residual correlations were due to shared responses to unmeasured environmental covariates. This work highlights the importance of choosing a non-spatial model formulation to address research questions about the species–environment relationship or residual co-occurrence patterns, and a spatial model formulation when within-sample prediction accuracy is the main goal.     

Identification of Sphingolipid Metabolites That Induce Obesity via Misregulation of Appetite,Caloric Intake and Fat Storage in Drosophila

Obesity is defined by excessive lipid accumulation. However, the active mechanistic roles that lipids play in its progression are not understood. Accumulation of ceramide, the metabolic hub of sphingolipid metabolism, has been associated with metabolic syndrome and obesity in humans and model systems. Here, we use Drosophila genetic manipulations to cause accumulation or depletion of ceramide and sphingosine-1-phosphate (S1P) intermediates. Sphingolipidomic profiles were characterized across mutants for various sphingolipid metabolic genes using liquid chromatography electrospray ionization tandem mass spectroscopy. Biochemical assays and microscopy were used to assess classic hallmarks of obesity including elevated fat stores, increased body weight, resistance to starvation induced death, increased adiposity, and fat cell hypertrophy. Multiple behavioral assays were used to assess appetite, caloric intake, meal size and meal frequency. Additionally, we utilized DNA microarrays to profile differential gene expression between these flies, which mapped to changes in lipid metabolic pathways. Our results show that accumulation of ceramides is sufficient to induce obesity phenotypes by two distinct mechanisms: 1) Dihydroceramide (C_14:0) and ceramide diene (C_14:2) accumulation lowered fat store mobilization by reducing adipokinetic hormone- producing cell functionality and 2) Modulating the S1P: ceramide (C_14:1) ratio suppressed postprandial satiety via the hindgut-specific neuropeptide like receptor dNepYr, resulting in caloric intake-dependent obesity.     

Genetic modifiers of the Drosophila blue cheese gene link defects in lysosomal transport with decreased life span and altered ubiquitinated-protein profiles

Defects in lysosomal trafficking pathways lead to decreased cell viability and are associated with progressive disorders in humans. Previously we have found that loss-of-function (LOF) mutations in the Drosophila gene blue cheese (bchs) lead to reduced adult life span, increased neuronal death, and widespread CNS degeneration that is associated with the formation of ubiquitinated-protein aggregates. To identify potential genes that participate in the bchs functional pathway, we conducted a genetic modifier screen based on alterations of an eye phenotype that arises from high-level overexpression of Bchs. We found that mutations in select autophagic and endocytic trafficking genes, defects in cytoskeletal and motor proteins, as well as mutations in the SUMO and ubiquitin signaling pathways behave as modifiers of the Bchs gain-of-function (GOF) eye phenotype. Individual mutant alleles that produced viable adults were further examined for bchs-like phenotypes. Mutations in several lysosomal trafficking genes resulted in significantly decreased adult life spans and several mutants showed changes in ubiquitinated protein profiles as young adults. This work represents a novel approach to examine the role that lysosomal transport and function have on adult viability. The genes characterized in this study have direct human homologs, suggesting that similar defects in lysosomal transport may play a role in human health and age-related processes.