Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets

Overaccumulation of lipids in nonadipose tissues of obese rodents may lead to lipotoxic complications such as diabetes. To assess the pathogenic role of the lipogenic transcription factor, sterol regulatory element binding protein 1 (SREBP-1), we measured its mRNA in liver and islets of obese, leptin-unresponsive fa/fa Zucker diabetic fatty rats. Hepatic SREBP-1 mRNA was 2.4 times higher than in lean +/+ controls, primarily because of increased SREBP-1c expression. mRNA of lipogenic enzymes ranged from 2.4- to 4.6-fold higher than lean controls, and triacylglycerol (TG) content was 5.4 times higher. In pancreatic islets of fa/fa rats, SREBP-1c was 3.4 times higher than in lean +/+ Zucker diabetic fatty rats. The increase of SREBP-1 in liver and islets of untreated fa/fa rats was blocked by 6 weeks of troglitazone therapy, and the diabetic phenotype was prevented. Up-regulation of SREBP-1 also occurred in livers of Sprague–Dawley rats with diet-induced obesity. Hyperleptinemia, induced in lean +/+ rats by adenovirus gene transfer, lowered hepatic SREBP-1c by 74% and the lipogenic enzymes from 35 to 59%. In conclusion, overnutrition increases and adenovirus-induced hyperleptinemia decreases SREBP-1c expression in liver and islets. SREBP-1 overexpression, which is prevented by troglitazone, may play a role in the ectopic lipogenesis and lipotoxicity complicating obesity in Zucker diabetic fatty rats.

Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia

The inducible isoform of the enzyme cyclooxygenase-2 (COX2) is an immediate early gene induced by synaptic activity in the brain. COX2 activity is an important mediator of inflammation, but it is not known whether COX2 activity is pathogenic in brain. To study the role of COX2 activity in ischemic injury in brain, expression of COX2 mRNA and protein and the effect of treatment with a COX2 inhibitor on neuronal survival in a rat model of global ischemia were determined. Expression of both COX2 mRNA and protein was increased after ischemia in CA1 hippocampal neurons before their death. There was increased survival of CA1 neurons in rats treated with the COX2-selective inhibitor SC58125 {1-[(4-methylsulfonyl) phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl] pyrazole} before or after global ischemia compared with vehicle controls. Furthermore, hippocampal prostaglandin E2 concentrations 24 h after global ischemia were decreased in drug-treated animals compared with vehicle-treated controls. These results suggest that COX2 activity contributes to CA1 neuronal death after global ischemia.

Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor

Aberrant blood vessel growth in the retina that underlies the pathology of proliferative diabetic retinopathy and retinopathy of prematurity is the result of the ischemia-driven disruption of the normally antiangiogenic environment of the retina. In this study, we show that a potent inhibitor of angiogenesis found naturally in the normal eye, pigment epithelium-derived growth factor (PEDF), inhibits such aberrant blood vessel growth in a murine model of ischemia-induced retinopathy. Inhibition was proportional to dose and systemic delivery of recombinant protein at daily doses as low as 2.2 mg/kg could prevent aberrant endothelial cells from crossing the inner limiting membrane. PEDF appeared to inhibit angiogenesis by causing apoptosis of activated endothelial cells, because it induced apoptosis in cultured endothelial cells and an 8-fold increase in apoptotic endothelial cells could be detected in situ when the ischemic retinas of PEDF-treated animals were compared with vehicle-treated controls. The ability of low doses of PEDF to curtail aberrant growth of ocular endothelial cells without overt harm to retinal morphology suggests that this natural protein may be beneficial in the treatment of a variety of retinal vasculopathies.

Self-recognition in primates: phylogeny and the salience of species-typical features.

Self-recognition has been explored in nonlinguistic organisms by recording whether individuals touch a dye-marked area on visually inaccessible parts of their face while looking in a mirror or inspect parts of their body while using the mirror's reflection. Only chimpanzees, gorillas, orangutans, and humans over the age of approximately 2 years consistently evidence self-directed mirror-guided behavior without experimenter training. To evaluate the inferred phylogenetic gap between hominoids and other animals, a modified dye-mark test was conducted with cotton-top tamarins (Saguinus oedipus), a New World monkey species. The white hair on the tamarins' head was color-dyed, thereby significantly altering a visually distinctive species-typical feature. Only individuals with dyed hair and prior mirror exposure touched their head while looking in the mirror. They looked longer in the mirror than controls, and some individuals used the mirror to observe visually inaccessible body parts. Prior failures to pass the mirror test may have been due to methodological problems, rather than to phylogenetic differences in the capacity for self-recognition. Specifically, an individual's sensitivity to experimentally modified parts of its body may depend crucially on the relative saliency of the modified part (e.g., face versus hair). Moreover, and in contrast to previous claims, we suggest that the mirror test may not be sufficient for assessing the concept of self or mental state attribution in nonlinguistic organisms.

Grasshopper crop and midgut extract effects on plants: an example of reward feedback.

Acid extracts and a resultant fraction from solid-phase extraction (SPE) of Romalea guttata crop and midgut tissues induce sorghum (Sorghum bicolor var. Rio) coleoptile growth in 24-h incubations an average of 49% above untreated controls. When combined with plant auxin, indole-3-acetic acid (IAA), the SPE fraction shows a synergistic reaction, yielding increases in coleoptile growth that average 295% above untreated controls and 8% above IAA standards. The interaction lowered the point of maximum sensitivity of IAA 3 orders of magnitude, resulting in a new IAA physiological set point at 10(-7) g/ml. This synergism suggests that contents in animal regurgitants making their way into plant tissue during feeding may produce a positive feedback in plant growth and development following herbivory. Such a process, also known as reward feedback, may exert major controls on ecosystem-level relationships in nature.

A simple test of the vicarious trial-and-error hypothesis of hippocampal function.

Vicarious trial-and-error (VTE) is a term that Muenzinger and Tolman used to describe the rat's conflict-like behavior before responding to choice. Recently, VTE was proposed as a mechanism alternative to the concept of "cognitive map" in accounts of hippocampal function. That is, many phenomena of impaired learning and memory related to hippocampal interventions may be explained by behavioral first principles: reduced conflicting, incipient, pre-choice tendencies to approach and avoid. The nonspatial black-white discrimination learning and VTE behavior of the rat were investigated. Hippocampal-lesioned and sham-lesioned animals were trained for 25 days (20 trials per day) starting at 60 days of age. Each movement of the head from one discriminative stimulus to the other was counted as a VTE instance. Lesioned rats had fewer VTEs than sham controls, and the former learned much more slowly or never learned. After learning, VTE frequency declined. Male and female rats showed no significant differences in VTE behavior or discrimination learning.

Invasion, Proliferation and Control of Invasive Aquatic Plants in Colorado State Parks

Nonnative aquatic species are invasive worldwide. These species adversely affect natural aquatic ecosystems in a variety of ways and can negatively affect agriculture, recreation and industry. This study addresses identification and control of aquatic plant species of concern in Colorado State Parks. Seventeen species identified as potential threats to the parks and safe, effective chemical control methodologies were determined for each species. A matrix was developed to include the plants, appropriate chemical controls and the type of aquatic habitat where chemical use would be safe and effective. The matrix and recommendations for its use will be provided to the Colorado Division of Parks and Outdoor Recreation to develop a management plan under Section 1204 of the National Invasive Species Act.

Tauroursodeoxycholic acid prevents retinal degeneration in transgenic P23H rats

Purpose. To evaluate the preventive effect of tauroursodeoxycholic acid (TUDCA) on photoreceptor degeneration, synaptic connectivity and functional activity of the retina in the transgenic P23H rat, an animal model of autosomal dominant retinitis pigmentosa (RP). Methods. P23H line-3 rats were injected with TUDCA once a week from postnatal day (P)21 to P120, in parallel with vehicle-administered controls. At P120, functional activity of the retina was evaluated by electroretinographic (ERG) recording. The effects of TUDCA on the number, morphology, integrity, and synaptic connectivity of retinal cells were characterized by immunofluorescence confocal microscopy. Results. The amplitude of ERG a- and b-waves was significantly higher in TUDCA-treated animals under both scotopic and photopic conditions than in control animals. In the central area of the retina, TUDCA-treated P23H rats showed threefold more photoreceptors than control animals. The number of TUNEL-positive cells was significantly smaller in TUDCA-treated rats, in which photoreceptor morphology was preserved. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were preserved in TUDCA-treated P23H rats. Furthermore, in TUDCA-treated rat retinas, the number of both rod bipolar and horizontal cell bodies, as well as the density of their synaptic terminals in the outer plexiform layer, was greater than in control rats. Conclusions. TUDCA treatment was capable of preserving cone and rod structure and function, together with their contacts with their postsynaptic neurons. The neuroprotective effects of TUDCA make this compound potentially useful for delaying retinal degeneration in RP.

Long time remodeling during retinal degeneration evaluated by optical coherence tomography, immunocytochemistry and fundus autofluorescence

Purpose: To characterize the relationship between fundus autofluorescence (FAF), Optical Coherence Tomography (OCT) and immunohistochemistry (IHC) over the course of chronic retinal degeneration in the P23H rat. Methods: Homozygous albino P23H rats, Sprague–Dawley (SD) rats as controls and pigmented Long Evans (LE) rats were used. A Spectralis HRA OCT system was used for scanning laser ophthalmoscopy (SLO) imaging OCT and angiography. To determine FAF, fluorescence was excited using diode laser at 488 nm. A fast retina map OCT was performed using the optic nerve as a landmark. IHC was performed to correlate with the findings of OCT and FAF changes. Results: During the course of retinal degeneration, the FAF pattern evolved from some spotting at 2 months old to a mosaic of hyperfluorescent dots in rats 6 months and older. Retinal thicknesses progressively diminished over the course of the disease. At later stages of degeneration, OCT documented changes in the retinal layers, however, IHC better identified the cell loss and remodeling changes. Angiography revealed attenuation of the retinal vascular plexus with time. Conclusion: We provide for the first time a detailed long-term analysis of the course of retinal degeneration in P23H rats using a combination of SLO and OCT imaging, angiography, FAF and IHC. Although, the application of noninvasive methods enables longitudinal studies and will decrease the number of animals needed for a study, IHC is still an essential tool to identify retinal changes at the cellular level.

Associative Behaviours and Political Participation of EU migrants

Civic culture is structured on a network of interpersonal associations with different degrees of formalization. According to theories on civic and political action, certain agents, such as associations, play a key role in setting targets, socializing or coordinating sociopolitical actions, among other functions. Associations strengthen the political and civic system of societies. Likewise, they are a vehicle for individuals’ integration, which is particularly important in the case of immigrants. For these, associations are both a vehicle for integration and an instrument for political participation. This article explores the use and purpose of associations according to immigrants from Romania, Poland, the United Kingdom and Germany living in Spain.

Cortical Abnormalities in Adults and Adolescents with Major Depression based on Brain Scans from 20 Cohorts Worldwide in the ENIGMA Major Depressive Disorder Working Group

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen’s d effect sizes: −0.10 to −0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: −0.26 to −0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Multiple regulatory variants located in cell type-specific enhancers within the PKP2 locus form major risk and protective haplotypes for canine atopic dermatitis in German shepherd dogs.

BACKGROUND Canine atopic dermatitis (CAD) is a chronic inflammatory skin disease triggered by allergic reactions involving IgE antibodies directed towards environmental allergens. We previously identified a ~1.5 Mb locus on canine chromosome 27 associated with CAD in German shepherd dogs (GSDs). Fine-mapping indicated association closest to the PKP2 gene encoding plakophilin 2. RESULTS Additional genotyping and association analyses in GSDs combined with control dogs from five breeds with low-risk for CAD revealed the top SNP 27:19,086,778 (p = 1.4 × 10(-7)) and a rare ~48 kb risk haplotype overlapping the PKP2 gene and shared only with other high-risk CAD breeds. We selected altogether nine SNPs (four top-associated in GSDs and five within the ~48 kb risk haplotype) that spanned ~280 kb forming one risk haplotype carried by 35 % of the GSD cases and 10 % of the GSD controls (OR = 5.1, p = 5.9 × 10(-5)), and another haplotype present in 85 % of the GSD cases and 98 % of the GSD controls and conferring a protective effect against CAD in GSDs (OR = 0.14, p = 0.0032). Eight of these SNPs were analyzed for transcriptional regulation using reporter assays where all tested regions exerted regulatory effects on transcription in epithelial and/or immune cell lines, and seven SNPs showed allelic differences. The DNA fragment with the top-associated SNP 27:19,086,778 displayed the highest activity in keratinocytes with 11-fold induction of transcription by the risk allele versus 8-fold by the control allele (pdifference = 0.003), and also mapped close (~3 kb) to an ENCODE skin-specific enhancer region. CONCLUSIONS Our experiments indicate that multiple CAD-associated genetic variants located in cell type-specific enhancers are involved in gene regulation in different cells and tissues. No single causative variant alone, but rather multiple variants combined in a risk haplotype likely contribute to an altered expression of the PKP2 gene, and possibly nearby genes, in immune and epithelial cells, and predispose GSDs to CAD.

Nd and Sr isotope record of ODP Sites 121-756 and 122-762 sediments

We have analyzed the Nd isotopic composition of both ancient seawater and detrital material from long sequences of carbonated oozes of the South Indian Ocean which are ODP Site 756 (Ninety East Ridge (-30°S), 1518 m water depth) and ODP Site 762 (Northwest Australian margin, 1360 m water depth). The measurements indicate that the epsilon-Nd changes in Indian seawater over the last 35 Ma result from changes in the oceanic circulation, large volcanic and continental weathering Nd inputs. This highlights the diverse nature of those controls and their interconnections in a small area of the ocean. These new records combined with those previously obtained at the equatorial ODP Sites 757 and 707 in the Indian Ocean (Gourlan et al., 2008, doi:10.1016/j.epsl.2007.11.054) established that the distribution of intermediate seawater epsilon-Nd was uniform over most of the Indian Ocean from 35 Ma to 10 Ma within a geographical area extending from 40°S to the equator and from -60°E to 120°E. However, the epsilon-Nd value of Indian Ocean seawater which kept an almost constant value (at about -7 to -8) from 35 to 15 Ma rose by 3 epsilon-Nd units from 15 to 10 Ma. This sharp increase has been caused by a radiogenic Nd enrichment of the water mass originating from the Pacific flowing through the Indonesian Passage. Using a two end-members model we calculated that the Nd transported to the Indian Ocean through the Indonesian Pathway was 1.7 times larger at 10 Ma than at 15 Ma. The Nd isotopic composition of ancient seawater and that of the sediment detrital component appear to be strongly correlated for some specific events. A first evidence occurs between 20 and 15 Ma with two positive spikes recorded in both epsilon-Nd signals that are clearly induced by a volcanic crisis of, most likely, the St. Paul hot-spot. A second evidence is the very large epsilon-Nd decrease recorded at ODP Sites 756 and 762 during the past 10 Ma which has never been previously observed. The synchronism between the epsilon-Nd decrease in seawater from 10 to 5 Ma and evidences of desertification in the western part of the nearly Australian continent suggests enhanced weathering inputs in this ocean from this continent as a result of climatic changes.

Disturbances of agency and ownership in schizophrenia: An auditory verbal event related potentials study

A ‘sense of self’ is essentially the ability to distinguish between self-generated and external stimuli. It consists of at least two very basic senses: a sense of agency and a sense of ownership. Disturbances seem to provide a basic deficit in many psychiatric diseases. The aim of our study was to manipulate those qualities separately in 28 patients with schizophrenia (14 auditory hallucinators and 14 non-hallucinators) and 28 healthy controls (HC) and to investigate the effects on the topographies and the power of the event-related potential (ERP). We performed a 76-channel EEG while the participants performed the task as in our previous paper. We computed ERPs and difference maps for the conditions and compared the amount of agency and ownership between the HC and the patients. Furthermore, we compared the global field power and the topographies of these effects. Our data showed effects of agency and ownership in the healthy controls and the hallucinator group and to a lesser degree in the non-hallucinator group. We found a reduction of the N100 during the presence of agency, and a bilateral temporal negativity related to the presence of ownership. For the agency effects, we found significant differences between HC and the patients. Contrary to the expectations, our findings were more pronounced in non-hallucinators, suggesting a more profoundly disturbed sense of agency compared to hallucinators. A contemporary increase of global field power in both patient groups indicates a compensatory recruitment of other mechanisms not normally associated with the processing of agency and ownership.

Truck noise IV-G. Field test results on a heavy duty, diesel truck having reduced noise emissions. Seventh report.

Transportation Department, Office of Noise Abatement, Washington, D.C.