Ciglitazone-a human PPARγ agonist-disrupts dorsoventral patterning in zebrafish.

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that regulates lipid/glucose homeostasis and adipocyte differentiation. While the role of PPARγ in adipogenesis and diabetes has been extensively studied, little is known about PPARγ function during early embryonic development. Within zebrafish, maternally-loaded pparγ transcripts are present within the first 6 h post-fertilization (hpf), and de novo transcription of zygotic pparγ commences at ~48 hpf. Since maternal pparγ transcripts are elevated during a critical window of cell fate specification, the objective of this study was to test the hypothesis that PPARγ regulates gastrulation and dorsoventral patterning during zebrafish embryogenesis. To accomplish this objective, we relied on (1) ciglitazone as a potent PPARγ agonist and (2) a splice-blocking, pparγ-specific morpholino to knockdown pparγ. We found that initiation of ciglitazone-a potent human PPARγ agonist-exposure by 4 hpf resulted in concentration-dependent effects on dorsoventral patterning in the absence of epiboly defects during gastrulation, leading to ventralized embryos by 24 hpf. Interestingly, ciglitazone-induced ventralization was reversed by co-exposure with dorsomorphin, a bone morphogenetic protein signaling inhibitor that induces strong dorsalization within zebrafish embryos. Moreover, mRNA-sequencing revealed that lipid- and cholesterol-related processes were affected by exposure to ciglitazone. However, pparγ knockdown did not block ciglitazone-induced ventralization, suggesting that PPARγ is not required for dorsoventral patterning nor involved in ciglitazone-induced toxicity within zebrafish embryos. Our findings point to a novel, PPARγ-independent mechanism of action and phenotype following ciglitazone exposure during early embryonic development

Metabolomic study of the LDL receptor null mouse fed a high-fat diet reveals profound perturbations in choline metabolism that are shared with ApoE null mice

Failure to express or expression of dysfunctional low-density lipoprotein receptors (LDLR) causes familial hypercholesterolemia in humans, a disease characterized by elevated blood cholesterol concentrations, xanthomas, and coronary heart disease, providing compelling evidence that high blood cholesterol concentrations cause atherosclerosis. In this study, we used 1H nuclear magnetic resonance spectroscopy to examine the metabolic profiles of plasma and urine from the LDLR knockout mice. Consistent with previous studies, these mice developed hypercholesterolemia and atherosclerosis when fed a high-fat/cholesterol/cholate-containing diet. In addition, multivariate statistical analysis of the metabolomic data highlighted significant differences in tricarboxylic acid cycle and fatty acid metabolism, as a result of high-fat/cholesterol diet feeding. Our metabolomic study also demonstrates that the effect of high-fat/cholesterol/cholate diet, LDLR gene deficiency, and the diet-genotype interaction caused a significant perturbation in choline metabolism, notably the choline oxidation pathway. Specifically, the loss in the LDLR caused a marked reduction in the urinary excretion of betaine and dimethylglycine, especially when the mice are fed a high-fat/cholesterol/cholate diet. Furthermore, as we demonstrate that these metabolic changes are comparable with those detected in ApoE knockout mice fed the same high-fat/cholesterol/cholate diet they may be useful for monitoring the onset of atherosclerosis across animal models

A tool to aid redesign of flexible transport services to increase efficiency in rural transport service provision

This research was supported by the Research Councils UK Digital Economy programme award (reference: EP/G066051/1) to the dot.rural Digital Economy Hub, at the University of Aberdeen.Peer reviewedPublisher PD

Some Properties of the Exchange Operator with respect to Structured Matrices defined by Indefinite Scalar Product Spaces

The properties of the exchange operator on some types of matrices are explored in this paper. In particular, the properties of exc(A,p,q), where A is a given structured matrix of size (p+q)Ã(p+q) and exc : M ÃNÃN â M is the exchange operator are studied. This paper is a generalization of one of the results in [N.J. Higham. J-orthogonal matrices: Properties and generation. SIAM Review, 45:504â519, 2003.]

Kinematical Analogy for Marginal Dyon Decay

We describe a kinematical analogy for the marginal decay of 1/4-BPS dyons in 4-dimensional N=4 string compactifications. In this analogy, the electric and magnetic charges play the role of spatial momenta, the BPS mass plays the role of energy, and 1/2-BPS dyons correspond to massless particles. Using SO(12,1) "Lorentz" invariance and standard kinematical formulae in particle physics, we provide simple derivations of the curves of marginal stability. We also show how these curves map into the momentum ellipsoid, and propose some applications of this analogy.Comment: 10 pages, minor revision

Location Management in Mobile Ad Hoc Wireless Networks Using Quorums and Clusters

Position-based reactive routing is a scalable solution for routing in mobile ad hoc networks. The route discovery algorithm in position-based routing can be efficiently implemented only if the source knows the current address of the destination. In this paper, a quorum-based location management scheme is proposed. Location servers are selected using the minimum dominating set (MDS) approach, and are further organized into quorums for location update and location query. when a mobile node moves, it updates its location servers in the update quorum; when a node requests the location information of another node, it will send a query message to the location servers in the query quorum. We propose to use the position-based quorum system, which is easy to construct and guarantees that the update quorums always intersect with the query quorums so that at least one location server in the query quorum is aware of the most recent location of the mobile node. Clusters are introduced for large scale ad hoc networks for scalability. Experiment results show that the proposed scheme provides good scalability when network size increases