Ceramide is a cardiotoxin in lipotoxic cardiomyopathy

Ceramide is among a number of potential lipotoxic molecules that are thought to modulate cellular energy metabolism. The heart is one of the tissues thought to become dysfunctional due to excess lipid accumulation. Dilated lipotoxic cardiomyopathy, thought to be the result of diabetes and severe obesity, has been modeled in several genetically altered mice, including animals with cardiac-specific overexpression of glycosylphosphatidylinositol (GPI)-anchored human lipoprotein lipase (LpL(GPI)). To test whether excess ceramide was implicated in cardiac lipotoxicity, de novo ceramide biosynthesis was inhibited pharmacologically by myriocin and genetically by heterozygous deletion of LCB1, a subunit of serine palmitoyltransferase (SPT). Inhibition of SPT, a rate-limiting enzyme in ceramide biosynthesis, reduced fatty acid and increased glucose oxidation in isolated perfused LpL(GPI) hearts, improved systolic function, and prolonged survival rates. Our results suggest a critical role for ceramide accumulation in the pathogenesis of lipotoxic cardiomyopathy.     

A warmer ambient temperature increases the passage of interleukin-1beta into the brains of old rats

We have demonstrated that after intraperitoneal lipopolysaccharide (LPS) injection, old rats mount fevers similar to those of young rats at an ambient temperature (Ta) of 31 degrees C, but not at 21 degrees C. The same is true for intraperitoneal or intravenous IL-1beta administration. The underlying mechanism responsible for blunted fever in old rats may be a deficiency in communication between the periphery and the brain. Possibly, peripheral cytokine actions are altered in old rats, such that the signal that reaches the brain is diminished. Here, we hypothesized that at standard laboratory temperatures, not enough IL-1beta is reaching the brain for fever to occur and that a warmer Ta would increase the influx of IL-1beta into the brain, enabling old rats to generate fever. Young (3-5 mo) and old (23-29 mo) Long-Evans rats were maintained for 3 days at either Ta 21 or 31 degrees C prior to intravenous injection with radiolabeled IL-1beta to measure passage across the blood-brain barrier. Young rats showed similar influx of IL-1beta into the brain at the two Tas, but old rats showed significant influx only at the warmer Ta. These data suggest that the lack of fever at a cool Ta may be due to a reduced influx of IL-1beta into the brain.     

Exacerbated fatigue and motor deficits in interleukin-10-deficient mice after peripheral immune stimulation

The anti-inflammatory cytokine interleukin (IL)-10 is important for regulating inflammation in the periphery and brain, but whether it protects against infection- or age-related psychomotor disturbances and fatigue is unknown. Therefore, the present study evaluated motor coordination, time to fatigue, and several central and peripheral proinflammatory cytokines in male young adult (3-mo-old) and middle-aged (12-mo-old) wild-type (IL-10(+/+)) and IL-10-deficient (IL-10(-/-)) mice after intraperitoneal injection of lipopolysaccharide (LPS) or saline. No age-related differences were observed; therefore, data from the two ages were pooled and analyzed to determine effects of genotype and treatment. LPS treatment increased IL-1beta, IL-6, and TNFalpha mRNA in all brain areas examined in IL-10(+/+) and IL-10(-/-) mice, but to a greater extent and for a longer time in IL-10(-/-) mice. Plasma IL-1beta and IL-6 were increased similarly in IL-10(+/+) and IL-10(-/-) mice 4 h after LPS but remained elevated longer in IL-10(-/-) mice, whereas TNFalpha was higher in IL-10(-/-) mice throughout after LPS treatment. Motor performance and motor learning in IL-10(+/+) mice were not affected by LPS treatment; however, both were reduced in IL-10(-/-) mice treated with LPS compared with those treated with saline. Furthermore, although LPS reduced the time to fatigue in IL-10(+/+) and IL-10(-/-) mice, the effects were exacerbated in IL-10(-/-) mice. Thus the increased brain and peripheral inflammation induced by LPS in IL-10(-/-) mice was associated with increased coordination deficits and fatigue. These data suggest that IL-10 may inhibit motor deficits and fatigue associated with peripheral infections via its anti-inflammatory effects.     

Substrate uptake and metabolism are preserved in hypertrophic caveolin-3 knockout hearts

Caveolin-3 (Cav3), the primary protein component of caveolae in muscle cells, regulates numerous signaling pathways including insulin receptor signaling and facilitates free fatty acid (FA) uptake by interacting with several FA transport proteins. We previously reported that Cav3 knockout mice (Cav3KO) develop cardiac hypertrophy with diminished contractile function; however, the effects of Cav3 gene ablation on cardiac substrate utilization are unknown. The present study revealed that the uptake and oxidation of FAs and glucose were normal in hypertrophic Cav3KO hearts. Real-time PCR analysis revealed normal expression of lipid metabolism genes including FA translocase (CD36) and carnitine palmitoyl transferase-1 in Cav3KO hearts. Interestingly, myocardial cAMP content was significantly increased by 42%; however, this had no effect on PKA activity in Cav3KO hearts. Microarray expression analysis revealed a marked increase in the expression of genes involved in receptor trafficking to the plasma membrane, including Rab4a and the expression of WD repeat/FYVE domain containing proteins. We observed a fourfold increase in the expression of cellular retinol binding protein-III and a 3.5-fold increase in 17beta-hydroxysteroid dehydrogenase type 11, a member of the short-chain dehydrogenase/reductase family involved in the biosynthesis and inactivation of steroid hormones. In summary, a loss of Cav3 in the heart leads to cardiac hypertrophy with normal substrate utilization. Moreover, a loss of Cav3 mRNA altered the expression of several genes not previously linked to cardiac growth and function. Thus we have identified a number of new target genes associated with the pathogenesis of cardiac hypertrophy.     

Integrating nitrogen fixing structures into above- and belowground functional trait spectra in soy (Glycine max)

Plant and Soil - Phenotypic trait variation across environmental gradients and through plant ontogeny is critical in driving ecological processes, especially in agroecosystems where single...     

Target-Specific Expression of Presynaptic NMDA Receptors in Neocortical Microcircuits

Traditionally, NMDA receptors are located postsynaptically; yet, putatively presynaptic NMDA receptors (preNMDARs) have been reported. Although implicated in controlling synaptic plasticity, their function is not well understood and their expression patterns are debated. We demonstrate that, in layer 5 of developing mouse visual cortex, preNMDARs specifically control synaptic transmission at pyramidal cell inputs to other pyramidal cells and to Martinotti cells, while leaving those to basket cells unaffected. We also reveal a type of interneuron that mediates ascending inhibition. In agreement with synapse-specific expression, we find preNMDAR-mediated calcium signals in a subset of pyramidal cell terminals. A tuned network model predicts that preNMDARs specifically reroute information flow in local circuits during high-frequency firing, in particular by impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells, a finding that we experimentally verify. We conclude that postsynaptic cell type determines presynaptic terminal molecular identity and that preNMDARs govern information processing in neocortical columns.     

An illustration of variable precision rough set theory: the gender classification of the European barn swallow (Hirundo rustica)

This paper introduces a new technique in the investigation of object classification and illustrates the potential use of this technique for the analysis of a range of biological data, using avian morphometric data as an example. The nascent variable precision rough sets (VPRS) model is introduced and compared with the decision tree method ID3 (through a ‘leave n out’ approach), using the same dataset of morphometric measures of European barn swallows (Hirundo rustica) and assessing the accuracy of gender classification based on these measures. The results demonstrate that the VPRS model, allied with the use of a modern method of discretization of data, is comparable with the more traditional non-parametric ID3 decision tree method. We show that, particularly in small samples, the VPRS model can improve classification and to a lesser extent prediction aspects over ID3. Furthermore, through the ‘leave n out’ approach, some indication can be produced of the relative importance of the different morphometric measures used in this problem. In this case we suggest that VPRS has advantages over ID3, as it intelligently uses more of the morphometric data available for the data classification, whilst placing less emphasis on variables with low reliability. In biological terms, the results suggest that the gender of swallows can be determined with reasonable accuracy from morphometric data and highlight the most important variables in this process. We suggest that both analysis techniques are potentially useful for the analysis of a range of different types of biological datasets, and that VPRS in particular has potential for application to a range of biological circumstances.     

The type-specific substance from Pneumococcus type 10A(34). The phosphodiester linkages

1. The phosphate groups in the type-specific substance S. 10A from Pneumococcus type 10A (34) were shown to join the hydroxyl group at position 1 or 5 of ribitol and the hydroxyl group at position 5 or 6 of a d-galactofuranosyl residue in the next repeating unit. 2. A partial formula of the type-specific substance was derived.