Higher Order Correlations in Quantum Chaotic Spectra

The statistical properties of the quantum chaotic spectra have been studied, so far, only up to the second order correlation effects. The numerical as well as the analytical evidence that random matrix theory can successfully model the spectral fluctuatations of these systems is available only up to this order. For a complete understanding of spectral properties it is highly desirable to study the higher order spectral correlations. This will also inform us about the limitations of random matrix theory in modelling the properties of quantum chaotic systems. Our main purpose in this paper is to carry out this study by a semiclassical calculation for the quantum maps; however results are also valid for time-independent systems.Comment: Revtex, Four figures (Postscript files), Phys. Rev E (in press

Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population

The manner by which genotype and environment affect complex phenotypes is one of the fundamental questions in biology. In this study, we quantified the transcriptome--a subset of the metabolome--and, using targeted proteomics, quantified a subset of the liver proteome from 40 strains of the BXD mouse genetic reference population on two diverse diets. We discovered dozens of transcript, protein, and metabolite QTLs, several of which linked to metabolic phenotypes. Most prominently, Dhtkd1 was identified as a primary regulator of 2-aminoadipate, explaining variance in fasted glucose and diabetes status in both mice and humans. These integrated molecular profiles also allowed further characterization of complex pathways, particularly the mitochondrial unfolded protein response (UPR(mt)). UPR(mt) shows strikingly variant responses at the transcript and protein level that are remarkably conserved among C. elegans, mice, and humans. Overall, these examples demonstrate the value of an integrated multilayered omics approach to characterize complex metabolic phenotypes

Mild inborn errors of metabolism in commonly used inbred mouse strains.

Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, alpha-aminoadipic acidemia and branched-chain ketoacid dehydrogenase deficiency are known in C57BL/6J mice. Using RNA sequencing, we now reveal the causal variants in Dhtkd1 and Bckdhb, and the molecular mechanism underlying these metabolic defects. C57BL/6J mice have decreased Dhtkd1 mRNA expression due to a solitary long terminal repeat (LTR) in intron 4 of Dhtkd1. This LTR harbors an alternate splice donor site leading to a partial splicing defect and as a consequence decreased total and functional Dhtkd1 mRNA, decreased DHTKD1 protein and alpha-aminoadipic acidemia. Similarly, C57BL/6J mice have decreased Bckdhb mRNA expression due to an LTR retrotransposon in intron 1 of Bckdhb. This transposable element encodes an alternative exon 1 causing aberrant splicing, decreased total and functional Bckdhb mRNA and decreased BCKDHB protein. Using a targeted metabolomics screen, we also reveal elevated plasma C5-carnitine in 129 substrains. This biochemical phenotype resembles isovaleric acidemia and is caused by an exonic splice mutation in Ivd leading to partial skipping of exon 10 and IVD protein deficiency. In summary, this study identifies three causal variants underlying mild inborn errors of metabolism in commonly used inbred mouse strains

Nur77-deficiency in bone marrow-derived macrophages modulates inflammatory responses, extracellular matrix homeostasis, phagocytosis and tolerance

The nuclear orphan receptor Nur77 (NR4A1, TR3, or NGFI-B) has been shown to modulate the inflammatory response of macrophages. To further elucidate the role of Nur77 in macrophage physiology, we compared the transcriptome of bone marrow-derived macrophages (BMM) from wild-type (WT) and Nur77-knockout (KO) mice. In line with previous observations, SDF-1α (CXCL12) was among the most upregulated genes in Nur77-deficient BMM and we demonstrated that Nur77 binds directly to the SDF-1α promoter, resulting in inhibition of SDF-1α expression. The cytokine receptor CX3CR1 was strongly downregulated in Nur77-KO BMM, implying involvement of Nur77 in macrophage tolerance. Ingenuity pathway analyses (IPA) to identify canonical pathways regulation and gene set enrichment analyses (GSEA) revealed a potential role for Nur77 in extracellular matrix homeostasis. Nur77-deficiency increased the collagen content of macrophage extracellular matrix through enhanced expression of several collagen subtypes and diminished matrix metalloproteinase (MMP)-9 activity. IPA upstream regulator analyses discerned the small GTPase Rac1 as a novel regulator of Nur77-mediated gene expression. We identified an inhibitory feedback loop with increased Rac1 activity in Nur77-KO BMM, which may explain the augmented phagocytic activity of these cells. Finally, we predict multiple chronic inflammatory diseases to be influenced by macrophage Nur77 expression. GSEA and IPA associated Nur77 to osteoarthritis, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, and allergic airway inflammatory diseases. Altogether these data identify Nur77 as a modulator of macrophage function and an interesting target to treat chronic inflammatory diseas

Ethnic differences in metabolite signatures and type 2 diabetes: a nested case-control analysis among people of South Asian, African and European origin

Accumulation of metabolites may mark or contribute to the development of type 2 diabetes mellitus (T2D), but there is a lack of data from ethnic groups at high risk. We examined sphingolipids, acylcarnitines and amino acids, and their association with T2D in a nested case-control study among 54 South Asian Surinamese, 54 African Surinamese and 44 Dutch in the Netherlands. Plasma metabolites were determined at baseline (2001-2003), and cumulative prevalence and incidence of T2D at follow-up (2011-2012). Weighted linear and logistic regression analyses were used to study associations. The mean level of most sphingolipids was lower, and amino-acid levels higher, in the Surinamese groups than among the Dutch. Surinamese individuals had higher mono- and polyunsaturated acylcarnitines and lower plasma levels of saturated acylcarnitine species than the Dutch. Several sphingolipids and amino acids were associated with T2D. Although only the shorter acylcarnitines seemed associated with prevalent T2D, we found an association of all acylcarnitines (except C0, C18 and C18:2) with incident T2D. Further analyses suggested a potentially different association of several metabolites across ethnic groups. Extension and confirmation of these findings may improve the understanding of ethnic differences and contribute to early detection of increased individual risk.Medical Biochemistr

A mechanistic framework for cardiometabolic and coronary artery diseases

Coronary atherosclerosis results from the delicate interplay of genetic and exogenous risk factors, principally taking place in metabolic organs and the arterial wall. Here we show that 224 gene-regulatory coexpression networks (GRNs) identified by integrating genetic and clinical data from patients with (n = 600) and without (n = 250) coronary artery disease (CAD) with RNA-seq data from seven disease-relevant tissues in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study largely capture this delicate interplay, explaining >54% of CAD heritability. Within 89 cross-tissue GRNs associated with clinical severity of CAD, 374 endocrine factors facilitated inter-organ interactions, primarily along an axis from adipose tissue to the liver (n = 152). This axis was independently replicated in genetically diverse mouse strains and by injection of recombinant forms of adipose endocrine factors (EPDR1, FCN2, FSTL3 and LBP) that markedly altered blood lipid and glucose levels in mice. Altogether, the STARNET database and the associated GRN browser (http://starnet.mssm.edu) provide a multiorgan framework for exploration of the molecular interplay between cardiometabolic disorders and CAD

The Association Between the Peroxisome Proliferator-Activated Receptor-γ2 (PPARG2) Pro12Ala Gene Variant and Type 2 Diabetes Mellitus: A HuGE Review and Meta-Analysis

The peroxisome proliferator-activated receptor-γ gene (PPARG) has been implicated in the etiology of type 2 diabetes mellitus and has been investigated in numerous epidemiologic studies. In this Human Genome Epidemiology review, the authors assessed this relation in an updated meta-analysis of 60 association studies. Electronic literature searches were conducted on September 14, 2009. Population-based cohort, case-control, cross-sectional, or genome-wide association studies reporting associations between the PPARG Pro12Ala gene variant (rs1801282) and type 2 diabetes were included. An updated literature-based meta-analysis involving 32,849 type 2 diabetes cases and 47,456 controls in relation to the PPARG Pro12Ala variant was conducted. The combined overall odds ratio, calculated by per-allele genetic model random-effects meta-analysis for type 2 diabetes and the Pro12Ala polymorphism, was 0.86 (95% confidence interval: 0.81, 0.90). The analysis indicated a moderate level of heterogeneity attributable to genuine variation in gene effect size (I2 = 37%). This may reflect the variation observed between ethnic populations and/or differences in body mass index. Work on PPARG Pro12Ala should now focus on the observed heterogeneity in the magnitude of the association between populations. Further investigations into gene-gene and gene-environment interactions may prove enlightening

Impact of obesity on taste receptor expression in extra-oral tissues: emphasis on hypothalamus and brainstem OPEN

Sweet perception promotes food intake, whereas that of bitterness is inhibitory. Surprisingly, the expression of sweet G protein-coupled taste receptor (GPCTR) subunits (T1R2 and T1R3) and bitter GPCTRs (T2R116, T2R118, T2R138 and T2R104), as well as the α-subunits of the associated signalling complex (αGustducin, Gα14 and αTransducin), in oral and extra-oral tissues from lean and obese mice, remains poorly characterized. We focused on the impact of obesity on taste receptor expression in brain areas involved in energy homeostasis, namely the hypothalamus and brainstem. We demonstrate that many of the GPCTRs and α-subunits are co-expressed in these tissues and that obesity decreases expression of T1R3, T2R116, Gα14, αTrans and TRPM5. In vitro high levels of glucose caused a prominent down-regulation of T1R2 and Gα14 expression in cultured hypothalamic neuronal cells, leptin caused a transient down-regulation of T1R2 and T1R3 expression. Intriguingly, expression differences were also observed in other extra-oral tissues of lean and obese mice, most strikingly in the duodenum where obesity reduced the expression of most bitter and sweet receptors. In conclusion, obesity influences components of sweet and bitter taste sensing in the duodenum as well as regions of the mouse brain involved in energy homeostasis, including hypothalamus and brainstem. Taste perception is an important aspect in the control of food intake. Taste is mainly sensed by taste receptor containing cells located in the taste buds distributed in the different gustatory epitheliums in the tongue, palate, larynx and epiglottis. The sensing of sweet, umami and bitter taste is mediated by two G protein-coupled taste receptor (GPCTR) families: the T1R family, which is mainly involved in the sensing of sweet and umami taste-like signalling molecules and the T2R family, involved in the sensing of bitter taste-like signalling molecules 1 . The T1R family consists of three different GPCTRs that generate at least two heterodimeric receptors: T1R1+T1R3 associated with umami taste sensing and T1R2+T1R3 associated with sweet taste sensing 1,2 . In mice the T2R family consists of at least 36 distinct taste receptor members, which individually sense bitter taste like molecules 3 . The human T2R16 selectively recognizes β-glucopyranosides 4 , while the human T2R38 recognizes phenylthiocarbamide (PTC) 5 . The functional importance of the latter two human receptors was demonstrated by the finding that overexpression of either receptor in mice increases food avoidance 6 . Although the T1R and T2R receptor families drive different taste perceptions, they share similar downstream G protein-coupled signalling pathways. In particular, the taste specific α-subunit of the G protein α-gustducin (αGust) is coupled to both receptor families and has been described as critical for sweet and bitter taste responses 7 . Nevertheless, αGust knockout animals still preserve a moderate sensitivity to some bitter compounds and to sweet compounds in higher mM concentration

Farnesyl pyrophosphate regulates adipocyte functions as an endogenous PPARγ agonist

The cholesterol biosynthetic pathway produces not only sterols but also non-sterol mevalonate metabolites involved in isoprenoid synthesis. Mevalonate metabolites affect transcriptional and post-transcriptional events that in turn affect various biological processes including energy metabolism. In the present study, we examine whether mevalonate metabolites activate PPARγ (peroxisome-proliferator-activated receptor γ), a ligand-dependent transcription factor playing a central role in adipocyte differentiation. In the luciferase reporter assay using both GAL4 chimaera and full-length PPARγ systems, a mevalonate metabolite, FPP (farnesyl pyrophosphate), which is the precursor of almost all isoprenoids and is positioned at branch points leading to the synthesis of other longer-chain isoprenoids, activated PPARγ in a dose-dependent manner. FPP induced the in vitro binding of a co-activator, SRC-1 (steroid receptor co-activator-1), to GST (glutathione transferase)–PPARγ. Direct binding of FPP to PPARγ was also indicated by docking simulation studies. Moreover, the addition of FPP up-regulated the mRNA expression levels of PPARγ target genes during adipocyte differentiation induction. In the presence of lovastatin, an HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitor, both intracellular FPP levels and PPARγ-target gene expressions were decreased. In contrast, the increase in intracellular FPP level after the addition of zaragozic acid, a squalene synthase inhibitor, induced PPARγ-target gene expression. The addition of FPP and zaragozic acid promotes lipid accumulation during adipocyte differentiation. These findings indicated that FPP might function as an endogenous PPARγ agonist and regulate gene expression in adipocytes

Monocyte Gene Expression Signature of Patients with Early Onset Coronary Artery Disease

The burden of cardiovascular disease (CVD) cannot be fully addressed by therapy targeting known pathophysiological pathways. Even with stringent control of all risk factors CVD events are only diminished by half. A number of additional pathways probably play a role in the development of CVD and might serve as novel therapeutic targets. Genome wide expression studies represent a powerful tool to identify such novel pathways. We compared the expression profiles in monocytes from twenty two young male patients with premature familial CAD with those from controls matched for age, sex and smoking status, without a family history of CVD. Since all patients were on statins and aspirin treatment, potentially affecting the expression of genes in monocytes, twelve controls were subsequently treated with simvastatin and aspirin for 6 and 2 weeks, respectively