Genetic regulation of mouse liver metabolite levels.

We profiled and analyzed 283 metabolites representing eight major classes of molecules including Lipids, Carbohydrates, Amino Acids, Peptides, Xenobiotics, Vitamins and Cofactors, Energy Metabolism, and Nucleotides in mouse liver of 104 inbred and recombinant inbred strains. We find that metabolites exhibit a wide range of variation, as has been previously observed with metabolites in blood serum. Using genome-wide association analysis, we mapped 40% of the quantified metabolites to at least one locus in the genome and for 75% of the loci mapped we identified at least one candidate gene by local expression QTL analysis of the transcripts. Moreover, we validated 2 of 3 of the significant loci examined by adenoviral overexpression of the genes in mice. In our GWAS results, we find that at significant loci the peak markers explained on average between 20 and 40% of variation in the metabolites. Moreover, 39% of loci found to be regulating liver metabolites in mice were also found in human GWAS results for serum metabolites, providing support for similarity in genetic regulation of metabolites between mice and human. We also integrated the metabolomic data with transcriptomic and clinical phenotypic data to evaluate the extent of co-variation across various biological scales

Intraosseous Nerve Sheath Tumors in the Jaws

Although the head and neck region is recognized as the most common location for peripheral nerve sheath tumors, central involvement, particularly in the jaw bones, is quite unusual. Neurofibroma is one of the most common nerve sheath tumors occurring in the soft tissue and generally appears in neurofibromatosis 1 (NF1 or von Recklinghausen's disease). Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon sarcomas that almost always arise in the soft tissue. Here, we report four cases of intraosseous peripheral nerve sheath tumors occurring in the jaw bones and compare the clinical, radiologic, and pathologic findings in order to make a differential diagnosis

Catalyst stability determines the catalytic activity of non-heme iron catalysts in the oxidation of alkanes

A series of iron(II) bis(triflate) complexes [Fe(L)(OTf)2] containing linear tetradentate bis(pyridylmethyl)diamine ligands with a range of ligand backbones has been prepared. The backbone of the ligand series has been varied from a two-carbon linkage [ethylene (1), 4,5-dichlorophenylene (2) and cyclohexyl (3)] to a three-carbon [propyl (4)) and a four-carbon linkage (butyl (5)]. The coordination geometries of these complexes have been investigated in the solid state by X-ray crystallography and in solution by 1H and 19F NMR spectroscopy. Due to the labile nature of high-spin iron(II) complexes in solution, dynamic equilibria of complexes with different coordination geometries (cis-α, cis-β and trans) are observed with ligands 2–5. In these cases, the geometry observed in the solid state does not necessarily represent the only or even the major geometry present in solution. The ligand field strength in the various complexes has been investigated by variable temperature magnetic moment measurements and UV-vis spectroscopy. The strongest ligand field is observed with the most rigid ligands 1 and 2, which generate complexes [Fe(L)(OTf)2] with a cis-α coordination geometry and the corresponding complexes [Fe(L)(CH3CN)2]2+ display spin crossover behaviour. The catalytic properties of the complexes for the oxidation of cyclohexane, using hydrogen peroxide as the oxidant, have been investigated. An increased flexibility in the ligand results in a weaker ligand field, which increases the lability of the complexes. The activity and selectivity of the catalysts appear to be related to the strength of the ligand field and the stability of the catalyst in the oxidising environmen

Thermal Conductivity of Carbon Nanotubes and their Polymer Nanocomposites: A Review

Thermally conductive polymer composites offer new possibilities for replacing metal parts in several applications, including power electronics, electric motors and generators, heat exchangers, etc., thanks to the polymer advantages such as light weight, corrosion resistance and ease of processing. Current interest to improve the thermal conductivity of polymers is focused on the selective addition of nanofillers with high thermal conductivity. Unusually high thermal conductivity makes carbon nanotube (CNT) the best promising candidate material for thermally conductive composites. However, the thermal conductivities of polymer/CNT nanocomposites are relatively low compared with expectations from the intrinsic thermal conductivity of CNTs. The challenge primarily comes from the large interfacial thermal resistance between the CNT and the surrounding polymer matrix, which hinders the transfer of phonon dominating heat conduction in polymer and CNT. This article reviews the status of worldwide research in the thermal conductivity of CNTs and their polymer nanocomposites. The dependence of thermal conductivity of nanotubes on the atomic structure, the tube size, the morphology, the defect and the purification is reviewed. The roles of particle/polymer and particle/particle interfaces on the thermal conductivity of polymer/CNT nanocomposites are discussed in detail, as well as the relationship between the thermal conductivity and the micro- and nano-structure of the composite

Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis

We performed silencing and overexpression studies of flavin containing monooxygenase (FMO) 3 in hyperlipidemic mouse models to examine its effects on trimethylamine N-oxide (TMAO) levels and atherosclerosis. Knockdown of hepatic FMO3 in LDL receptor knockout mice using an antisense oligonucleotide resulted in decreased circulating TMAO levels and atherosclerosis. Surprisingly, we also observed significant decreases in hepatic lipids and in levels of plasma lipids, ketone bodies, glucose, and insulin. FMO3 overexpression in transgenic mice, on the other hand, increased hepatic and plasma lipids. Global gene expression analyses suggested that these effects of FMO3 on lipogenesis and gluconeogenesis may be mediated through the PPARα and Kruppel-like factor 15 pathways. In vivo and in vitro results were consistent with the concept that the effects were mediated directly by FMO3 rather than trimethylamine/TMAO; in particular, overexpression of FMO3 in the human hepatoma cell line, Hep3B, resulted in significantly increased glucose secretion and lipogenesis. Our results indicate a major role for FMO3 in modulating glucose and lipid homeostasis in vivo, and they suggest that pharmacologic inhibition of FMO3 to reduce TMAO levels would be confounded by metabolic interactions

Wound contraction effects and antibacterial properties of Tualang honey on full-thickness burn wounds in rats in comparison to hydrofibre

<p>Abstract</p> <p>Background</p> <p>Full-thickness burn wounds require excision and skin grafting. Multiple surgical procedures are inevitable in managing moderate to severe full-thickness burns. Wound bed preparations prior to surgery are necessary in order to prevent wound infection and promote wound healing. Honey can be used to treat burn wounds. However, not all the honey is the same. This study aims to evaluate the wound contraction and antibacterial properties of locally-produced <it>Tualang </it>honey on managing full-thickness burn wounds <it>in vivo</it>.</p> <p>Methods</p> <p>Thirty-six female <it>Sprague Dawley </it>rats were randomly divided into three groups. Under anaesthesia, three full-thickness burn wounds were created on the dorsum of the rats. The full-thickness burn wounds were inoculated with a specific organism (10⁴), namely <it>Pseudomonas aeruginosa </it>(n = 12), <it>Klebsiella pneumoniae </it>(n = 12), or <it>Acinetobacter baumannii </it>(n = 12). The three burn wounds were dressed with <it>Tualang </it>honey, hydrofibre and hydrofibre silver respectively. Swab samples were obtained every 3 days (day 3, 6, 9, 12, 15, 18 and 21) for quantitative and semi-quantitative microbiological analyses. Clinical assessments, including observations concerning the appearance and wound size, were measured at the same time.</p> <p>Results</p> <p>There was a rapid 32.26% reduction in wound size by day 6 (<it>p </it>= 0.008) in the <it>Tualang </it>honey-treated wounds, and 49.27% by day 15 (<it>p </it>= 0.005). The wounds remained smaller by day 18 (<it>p </it>< 0.032). <it>Tualang </it>honey-treated rats demonstrated a reduction in bacterial growth in <it>Pseudomonas aeruginosa </it>inoculated wounds (<it>p </it>= 0.005). However, hydrofibre silver and hydrofibre-treated wounds are superior to honey-treated wounds with <it>Acinetobacter baumannii </it>(<it>p </it>= 0.035). There was no statistical significant of antibacterial property in <it>Klebsiella pneumonia </it>inoculated wounds.</p> <p>Conclusions</p> <p><it>Tualang </it>honey has better results with regards to its control of <it>Pseudomonas aeruginosa </it>and its wound contraction effects on full-thickness burn wound <it>in vivo</it>.</p

Functional Role of the Polymorphic 647 T/C Variant of ENT1 (SLC29A1) and Its Association with Alcohol Withdrawal Seizures

Adenosine is involved in several neurological and behavioral disorders including alcoholism. In cultured cell and animal studies, type 1 equilibrative nucleoside transporter (ENT1, slc29a1), which regulates adenosine levels, is known to regulate ethanol sensitivity and preference. Interestingly, in humans, the ENT1 (SLC29A1) gene contains a non-synonymous single nucleotide polymorphism (647 T/C; rs45573936) that might be involved in the functional change of ENT1. Our functional analysis showed that prolonged ethanol exposure increased adenosine uptake activity of mutant cells (ENT1-216Thr) compared to wild-type (ENT1-216Ile) transfected cells, which might result in reduced extracellular adenosine levels. We found that mice lacking ENT1 displayed increased propensity to ethanol withdrawal seizures compared to wild-type littermates. We further investigated a possible association of the 647C variant with alcoholism and the history of alcohol withdrawal seizures in subjects of European ancestry recruited from two independent sites. Analyses of the combined data set showed an association of the 647C variant and alcohol dependence with withdrawal seizures at the nominally significant level. Together with the functional data, our findings suggest a potential contribution of a genetic variant of ENT1 to the development of alcoholism with increased risk of alcohol withdrawal-induced seizures in humans

Transcription Factor MAFF (MAF Basic Leucine Zipper Transcription Factor F) Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism

BACKGROUND: Coronary artery disease (CAD) is a multifactorial condition with both genetic and exogenous causes. The contribution of tissue-specific functional networks to the development of atherosclerosis remains largely unclear. The aim of this study was to identify and characterize central regulators and networks leading to atherosclerosis. METHODS: Based on several hundred genes known to affect atherosclerosis risk in mouse (as demonstrated in knockout models) and human (as shown by genome-wide association studies), liver gene regulatory networks were modeled. The hierarchical order and regulatory directions of genes within the network were based on Bayesian prediction models, as well as experimental studies including chromatin immunoprecipitation DNA-sequencing, chromatin immunoprecipitation mass spectrometry, overexpression, small interfering RNA knockdown in mouse and human liver cells, and knockout mouse experiments. Bioinformatics and correlation analyses were used to clarify associations between central genes and CAD phenotypes in both human and mouse. RESULTS: The transcription factor MAFF (MAF basic leucine zipper transcription factor F) interacted as a key driver of a liver network with 3 human genes at CAD genome-wide association studies loci and 11 atherosclerotic murine genes. Most importantly, expression levels of the low-density lipoprotein receptor (LDLR) gene correlated with MAFF in 600 CAD patients undergoing bypass surgery (STARNET [Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task]) and a hybrid mouse diversity panel involving 105 different inbred mouse strains. Molecular mechanisms of MAFF were tested in noninflammatory conditions and showed positive correlation between MAFF and LDLR in vitro and in vivo. Interestingly, after lipopolysaccharide stimulation (inflammatory conditions), an inverse correlation between MAFF and LDLR in vitro and in vivo was observed. Chromatin immunoprecipitation mass spectrometry revealed that the human CAD genome-wide association studies candidate BACH1 (BTB domain and CNC homolog 1) assists MAFF in the presence of lipopolysaccharide stimulation with respective heterodimers binding at the MAF recognition element of the LDLR promoter to transcriptionally downregulate LDLR expression. CONCLUSIONS: The transcription factor MAFF was identified as a novel central regulator of an atherosclerosis/CAD-relevant liver network. MAFF triggered context-specific expression of LDLR and other genes known to affect CAD risk. Our results suggest that MAFF is a missing link between inflammation, lipid and lipoprotein metabolism, and a possible treatment target