Inactivation of hypoxia inducible factor (HIF) 1 alpha induces obesity-associated metabolic disorders through brown adipose tissue dysfunction

published_or_final_versionThe 14th Medical Research Conference, Hong Kong, 10 January 2009. In Hong Kong Medical Journal, 2009, v. 15, suppl. 1, p. 40, article no. 6

Hot embossing for fabrication of a microfluidic 3D cell culture

Clinically relevant studies of cell function in vitro require a physiologically-representative microenvironment possessing aspects such as a 3D extracellular matrix (ECM) and controlled biochemical and biophysical parameters. A polydimethylsiloxane (PDMS) microfluidic system with a 3D collagen gel has previously served for analysis of factors inducing different responses of cells in a 3D microenvironment under controlled biochemical and biophysical parameters. In the present study, applying the known commercially-viable manufacturing methods to a cyclic olefin copolymer (COC) material resulted in a microfluidic device with enhanced 3D gel capabilities, controlled surface properties, and improved potential to serve high-volume applications. Hot embossing and roller lamination molded and sealed the microfluidic device. A combination of oxygen plasma and thermal treatments enhanced the sealing, ensured proper placement of the 3D gel, and created controlled and stable surface properties within the device. Culture of cells in the new device indicated no adverse effects of the COC material or processing as compared to previous PDMS devices. The results demonstrate a methodology to transition microfludic devices for 3D cell culture from scientific research to high-volume applications with broad clinical impact.National Cancer Institute (U.S.) (award R21CA140096)Charles Stark Draper Laboratory (IR&D Grant

Goldstini

Supersymmetric phenomenology has been largely bound to the hypothesis that supersymmetry breaking originates from a single source. In this paper, we relax this underlying assumption and consider a multiplicity of sectors which independently break supersymmetry, thus yielding a corresponding multiplicity of goldstini. While one linear combination of goldstini is eaten via the super-Higgs mechanism, the orthogonal combinations remain in the spectrum as physical degrees of freedom. Interestingly, supergravity effects induce a universal tree-level mass for the goldstini which is exactly twice the gravitino mass. Since visible sector fields can couple dominantly to the goldstini rather than the gravitino, this framework allows for substantial departures from conventional supersymmetric phenomenology. In fact, this even occurs when a conventional mediation scheme is augmented by additional supersymmetry breaking sectors which are fully sequestered. We discuss a number of striking collider signatures, including various novel decay modes for the lightest observable-sector supersymmetric particle, gravitinoless gauge-mediated spectra, and events with multiple displaced vertices. We also describe goldstini cosmology and the possibility of goldstini dark matter.Comment: 14 pages, 7 figures; references adde

Bino Dark Matter and Big Bang Nucleosynthesis in the Constrained E6SSM with Massless Inert Singlinos

We discuss a new variant of the E6 inspired supersymmetric standard model (E6SSM) in which the two inert singlinos are exactly massless and the dark matter candidate has a dominant bino component. A successful relic density is achieved via a novel mechanism in which the bino scatters inelastically into heavier inert Higgsinos during the time of thermal freeze-out. The two massless inert singlinos contribute to the effective number of neutrino species at the time of Big Bang Nucleosynthesis, where the precise contribution depends on the mass of the Z' which keeps them in equilibrium. For example for mZ' > 1300 GeV we find Neff \approx 3.2, where the smallness of the additional contribution is due to entropy dilution. We study a few benchmark points in the constrained E6SSM with massless inert singlinos to illustrate this new scenario.Comment: 24 pages, revised for publication in JHE

Z' signals in polarised top-antitop final states

We study the sensitivity of top-antitop samples produced at all energy stages of the Large Hadron Collider (LHC) to the nature of an underlying Z' boson, in presence of full tree level standard model (SM) background effects and relative interferences. We concentrate on differential mass spectra as well as both spatial and spin asymmetries thereby demonstrating that exploiting combinations of these observables will enable one to distinguish between sequential Z's and those pertaining to Left-Right symmetric models as well as E6 inspired ones, assuming realistic final state reconstruction efficiencies and error estimates.Comment: 21 pages, 6 colour figures, 10 table

Transactivation of EGFR by LPS induces COX-2 expression in enterocytes

Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity and mortality in preterm infants. NEC is characterized by an exaggerated inflammatory response to bacterial flora leading to bowel necrosis. Bacterial lipopolysaccharide (LPS) mediates inflammation through TLR4 activation and is a key molecule in the pathogenesis of NEC. However, LPS also induces cyclooxygenase-2 (COX-2), which promotes intestinal barrier restitution through stimulation of intestinal cell survival, proliferation, and migration. Epidermal growth factor receptor (EGFR) activation prevents experimental NEC and may play a critical role in LPS-stimulated COX-2 production. We hypothesized that EGFR is required for LPS induction of COX-2 expression. Our data show that inhibiting EGFR kinase activity blocks LPS-induced COX-2 expression in small intestinal epithelial cells. LPS induction of COX-2 requires Src-family kinase signaling while LPS transactivation of EGFR requires matrix metalloprotease (MMP) activity. EGFR tyrosine kinase inhibitors block LPS stimulation of mitogen-activated protein kinase ERK, suggesting an important role of the MAPK/ERK pathway in EGFR-mediated COX-2 expression. LPS stimulates proliferation of IEC-6 cells, but this stimulation is inhibited with either the EGFR kinase inhibitor AG1478, or the selective COX-2 inhibitor Celecoxib. Taken together, these data show that EGFR plays an important role in LPS-induction of COX-2 expression in enterocytes, which may be one mechanism for EGF in inhibition of NEC

Peroxisome Proliferator-Activated Receptor alpha (PPAR alpha) down-regulation in cystic fibrosis lymphocytes

Background: PPARs exhibit anti-inflammatory capacities and are potential modulators of the inflammatory response. We hypothesized that their expression and/or function may be altered in cystic fibrosis (CF), a disorder characterized by an excessive host inflammatory response. Methods: PPARα, β and γ mRNA levels were measured in peripheral blood cells of CF patients and healthy subjects via RT-PCR. PPARα protein expression and subcellular localization was determined via western blot and immunofluorescence, respectively. The activity of PPARα was analyzed by gel shift assay. Results: In lymphocytes, the expression of PPARα mRNA, but not of PPARβ, was reduced (-37%; p < 0.002) in CF patients compared with healthy persons and was therefore further analyzed. A similar reduction of PPARα was observed at protein level (-26%; p < 0.05). The transcription factor was mainly expressed in the cytosol of lymphocytes, with low expression in the nucleus. Moreover, DNA binding activity of the transcription factor was 36% less in lymphocytes of patients (p < 0.01). For PPARα and PPARβ mRNA expression in monocytes and neutrophils, no significant differences were observed between CF patients and healthy persons. In all cells, PPARγ mRNA levels were below the detection limit. Conclusion: Lymphocytes are important regulators of the inflammatory response by releasing cytokines and antibodies. The diminished lymphocytic expression and activity of PPARα may therefore contribute to the inflammatory processes that are observed in CF