Doxepin, a tricyclic antidepressant, binds to normal, intact astroglial cells in cultures and inhibits the isoproterenol-induced increase in cyclic AMP production

Doxepin binds to intact astrocytes in primary cultures. The binding is competitively displaceable by excess cold doxepin and it is pronounced (Bmax = 27 nmol/mg protein) but the affinity is rather low (KD = 30 microM). The binding is inhibited by other antidepressants (amitriptyline, desipramine, tranylcypromine, iprindole) and propranolol but not by isoproterenol. Nevertheless, doxepin counteracts effectively the increase in the production of cyclic AMP evoked by isoproterenol.     

Modeling the dynamics of choice

A simple linear-operator model both describes and predicts the dynamics of choice that may underlie the matching relation. We measured inter-food choice within components of a schedule that presented seven different pairs of concurrent variable-interval schedules for 12 food deliveries each with no signals indicating which pair was in force. This measure of local choice was accurately described and predicted as obtained reinforcer sequences shifted it to favor one alternative or the other. The effect of a changeover delay was reflected in one parameter, the asymptote, whereas the effect of a difference in overall rate of food delivery was reflected in the other parameter, rate of approach to the asymptote. The model takes choice as a primary dependent variable, not derived by comparison between alternatives—an approach that agrees with the molar view of behaviour.     

Exposure to Cobalt Causes Transcriptomic and Proteomic Changes in Two Rat Liver Derived Cell Lines

Cobalt is a transition group metal present in trace amounts in the human diet, but in larger doses it can be acutely toxic or cause adverse health effects in chronic exposures. Its use in many industrial processes and alloys worldwide presents opportunities for occupational exposures, including military personnel. While the toxic effects of cobalt have been widely studied, the exact mechanisms of toxicity remain unclear. In order to further elucidate these mechanisms and identify potential biomarkers of exposure or effect, we exposed two rat liver-derived cell lines, H4-II-E-C3 and MH1C1, to two concentrations of cobalt chloride. We examined changes in gene expression using DNA microarrays in both cell lines and examined changes in cytoplasmic protein abundance in MH1C1 cells using mass spectrometry. We chose to closely examine differentially expressed genes and proteins changing in abundance in both cell lines in order to remove cell line specific effects. We identified enriched pathways, networks, and biological functions using commercial bioinformatic tools and manual annotation. Many of the genes, proteins, and pathways modulated by exposure to cobalt appear to be due to an induction of a hypoxic-like response and oxidative stress. Genes that may be differentially expressed due to a hypoxic-like response are involved in Hif-1α signaling, glycolysis, gluconeogenesis, and other energy metabolism related processes. Gene expression changes linked to oxidative stress are also known to be involved in the NRF2-mediated response, protein degradation, and glutathione production. Using microarray and mass spectrometry analysis, we were able to identify modulated genes and proteins, further elucidate the mechanisms of toxicity of cobalt, and identify biomarkers of exposure and effect in vitro, thus providing targets for focused in vivo studies.     

Species Detection and Identification in Sexual Organisms Using Population Genetic Theory and DNA Sequences

Phylogenetic trees of DNA sequences of a group of specimens may include clades of two kinds: those produced by stochastic processes (random genetic drift) within a species, and clades that represent different species. The ratio of the mean pairwise sequence difference between a pair of clades (K) to the mean pairwise sequence difference within a clade (θ) can be used to determine whether the clades are samples from different species (K/θ≥4) or the same species (K/θ<4) with probability ≥0.95. Previously I applied this criterion to delimit species of asexual organisms. Here I use data from the literature to show how it can also be applied to delimit sexual species using four groups of sexual organisms as examples: ravens, spotted leopards, sea butterflies, and liverworts. Mitochondrial or chloroplast genes are used because these segregate earlier during speciation than most nuclear genes and hence detect earlier stages of speciation. In several cases the K/θ ratio was greater than 4, confirming the original authors'' intuition that the clades were sufficiently different to be assigned to different species. But the K/θ ratio split each of two liverwort species into two evolutionary species, and showed that support for the distinction between the common and Chihuahuan raven species is weak. I also discuss some possible sources of error in using the K/θ ratio; the most significant one would be cases where males migrate between different populations but females do not, making the use of maternally inherited organelle genes problematic. The K/θ ratio must be used with some caution, like all other methods for species delimitation. Nevertheless, it is a simple theory-based quantitative method for using DNA sequences to make rigorous decisions about species delimitation in sexual as well as asexual eukaryotes.     

Detection of Aldehydes and Their Conjugated Hydroperox Ydiene Precursors in Thermally-Stressed Culinary Oils and Fats: Investigations Using High Resolution Proton Nmr Spectroscopy

High field (400 and 600 MHz) proton NMR spectroscopy has been employed to investigate the thermally-induced autoxidation of glycerol-bound polyunsaturated fatty acids present in intact culinary frying oils and fats. Heating of these materials at 180°C for periods of 30, 60 and 90 min. generated a variety of peroxidation products, notably aldehydes (alkanals, trans-2-alkenals and alka-2, 4-dienals) and their conjugated hydroperoxydiene precursors. Since such aldehydes appear to be absorbed into the systemic circulation from the gut in vivo, the toxicological significance of their production during standard frying practices is discussed.     

Size distribution of luteal cells from pregnant and non-pregnant marmoset monkeys and a comparison of the morphology of marmoset luteal cells with those from the human corpus luteum

The size distribution of marmoset luteal cells was determined on Days 6, 14 and 20 after ovulation in non-pregnant cycles and in early pregnancy. Image analysis was used to estimate the cell diameter of dispersed cells prepared from the marmoset corpus luteum (CL). Steroidogenic cells showed a size distribution consistent with one population of cells. There was a significant increase in mean cell diameter (P less than 0.05) from Day 6 to Day 14 in pregnant and non-pregnant animals with no further increase on Day 20. Micrographs of marmoset luteal tissue showed cells of greater than 10 micron containing the organelles typical of steroid-producing cells, and smaller non-steroidogenic cells surrounding the steroid-producing cells. On the basis of microscopy, there were no areas within the CL where cell composition was noticeably different. In contrast, micrographs of human luteal tissue showed two types of steroidogenic cell; most cells were similar to those in the marmoset CL but a smaller population of smaller cells could be distinguished around the periphery and along vascular septa. It is likely that these smaller and larger types of steroidogenic cells are of theca and granulosa cell origin respectively, the two cell populations differing in the degree of electron density and amount of rough endoplasmic reticulum. A distinguishing feature between marmoset and human luteal cells was the shape of the mitochondrian which were considerably rounder in marmoset luteal cells. The origin of steroidogenic cells in the marmoset CL is unclear, although in marmosets and man the luteal cell types display morphological characteristics distinct from the large and small luteal cells described for CL of the domestic ungulates.     

Associations between White Matter Hyperintensities and β Amyloid on Integrity of Projection,Association, and Limbic Fiber Tracts Measured with Diffusion Tensor MRI

The goal of this study was to assess the relationship between Aβ deposition and white matter pathology (i.e., white matter hyperintensities, WMH) on microstructural integrity of the white matter. Fifty-seven participants (mean age: 78±7 years) from an ongoing multi-site research program who spanned the spectrum of normal to mild cognitive impairment (Clinical dementia rating 0–0.5) and low to high risk factors for arteriosclerosis and WMH pathology (defined as WMH volume >0.5% total intracranial volume) were assessed with positron emission tomography (PET) with Pittsburg compound B (PiB) and magnetic resonance and diffusion tensor imaging (DTI). Multivariate analysis of covariance were used to investigate the relationship between Aβ deposition and WMH pathology on fractional anisotropy (FA) from 9 tracts of interest (i.e., corona radiata, internal capsule, cingulum, parahippocampal white matter, corpus callosum, superior longitudinal, superior and inferior front-occipital fasciculi, and fornix). WMH pathology was associated with reduced FA in projection (i.e., internal capsule and corona radiate) and association (i.e., superior longitudinal, superior and inferior fronto-occipital fasciculi) fiber tracts. Aβ deposition (i.e., PiB positivity) was associated with reduced FA in the fornix and splenium of the corpus callosum. There were interactions between PiB and WMH pathology in the internal capsule and parahippocampal white matter, where Aβ deposition reduced FA more among subjects with WMH pathology than those without. However, accounting for apoE ε4 genotype rendered these interactions insignificant. Although this finding suggests that apoE4 may increase amyloid deposition, both in the parenchyma (resulting in PiB positivity) and in blood vessels (resulting in amyloid angiopathy and WMH pathology), and that these two factors together may be associated with compromised white matter microstructural integrity in multiple brain regions, additional studies with a longitudinal design will be necessary to resolve this issue.