A novel selective 11b-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis.

Glucocorticoid excess increases fat mass, preferentially within omental depots; yet circulating cortisol concentrations are normal in most patients with metabolic syndrome (MS). At a pre-receptor level, 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) activates cortisol from cortisone locally within adipose tissue, and inhibition of 11b-HSD1 in liver and adipose tissue has been proposed as a novel therapy to treat MS by reducing hepatic glucose output and adiposity. Using a transformed human subcutaneous preadipocyte cell line (Chub-S7) and human primary preadipocytes, we have defined the role of glucocorticoids and 11b-HSD1 in regulating adipose tissue differentiation. Human cells were differentiated with 1.0 mM cortisol (F), or cortisone (E) with or without 100 nM of a highly selective 11b-HSD1 inhibitor PF-877423. 11b-HSD1 mRNA expression increased across adipocyte differentiation (P!0.001, nZ4), which was paralleled by an increase in 11b-HSD1 oxo-reductase activity (from nil on day 0 to 5.9G1.9 pmol/mg per h on day 16,P!0.01, nZ7). Cortisone enhanced adipocyte differentiation; fatty acid-binding protein 4 expression increased 312-fold (P!0.001) and glycerol-3-phosphate dehydrogenase 47-fold (P!0.001) versus controls. This was abolished by co-incubation with PF-877423. In addition, cellular lipid content decreased significantly. These findings were confirmed in the primary cultures of human subcutaneous preadipocytes. The increase in 11b-HSD1 mRNA expression and activity is essential for the induction of human adipogenesis. Blocking adipogenesis with a novel and specific 11b-HSD1 inhibitor may represent a novel approach to treat obesity in patients with MS

Mathematical modeling of cell population dynamics in the colonic crypt and in colorectal cancer

Colorectal cancer is initiated in colonic crypts. A succession of genetic mutations or epigenetic changes can lead to homeostasis in the crypt being overcome, and subsequent unbounded growth. We consider the dynamics of a single colorectal crypt by using a compartmental approach [Tomlinson IPM, Bodmer WF (1995) Proc Natl Acad Sci USA 92: 11130-11134], which accounts for populations of stem cells, differential cells, and transit cells. That original model made the simplifying assumptions that each cell popuation divides synchronously, but we relax these assumptions by adopting an age-structured approach that models asynchronous cell division, and by using a continuum model. We discuss two mechanims that could regulate the growth of cell numbers and maintain the equilibrium that is normally observed in the crypt. The first will always maintain an equilibrium for all parameter values, whereas the second can allow unbounded proliferation if the net per capita growth rates are large enough. Results show that an increase in cell renewal, which is equivalent to a failure of programmed cell death or of differentiation, can lead to the growth of cancers. The second model can be used to explain the long lag phases in tumor growth, during which news, higher equilibria are reached, before unlimited growth in cell number ensues

HIV infection significantly reduces lipoprotein lipase which remains low after 6 months of antiretroviral therapy

Purpose of the study Fractional clearance rate of apolipoprotein B100-containing lipoproteins is reduced in HIV infection before and after antiretroviral (ARV) treatment [1]. We compared lipoprotein lipase (LPL) activity and gene expression in HIV-positive subjects before and 6 months after ARV with HIV-negative controls. Methods Fasting blood post heparin total and hepatic lipase activity,adiponectin, leptin, insulin, glucose, and lipid measurementswere made in 32 HIV-infected and 15 HIVnegative controls. LPL was estimated by subtractinghepatic lipase from total lipase. Adiponectin, LPL andhormone sensitive lipase (HSL) gene expression weremeasured from iliac crest subcutaneous fat biopsies.Patients were tested before, and 6 months after randomisation to AZT/3TC (n = 15) or TDF/FTC (n = 17) with EFV.Between-group comparison was by Mann-Whitney andpaired samples by the Wilcoxon signed rank tests. Summary of results There were no differences in gender, ethnicity, baseline BMI, regional fat distribution (whole body DEXA) and visceral (VAT) and subcutaneous fat (SAT) measured by abdominal CT scans between controls and patients. Trunk fat/BMI ratio, VAT and VAT:SAT ratio significantly increased after 6-month ARV therapy (p = 0.01). There were no differences between groups in serum NEFA,HOMA and leptin levels. Selected other results are shown in Table 1. Conclusion Post heparin lipoprotein lipase activity is reduced in HIV and does not return to control levels after 6 months of ARV therapy. AZT-containing regimens are associated with a greater increase in LPL, LPL gene expression and plasma adiponectin than TDF

The Stokes-Einstein Relation in Supercooled Aqueous Solutions of Glycerol

The diffusion of glycerol molecules decreases with decreasing temperature as its viscosity increases in a manner simply described by the Stokes-Einstein(SE) relation. Approaching the glass transition, this relation breaks down as it does with a number of other pure liquid glass formers. We have measured the diffusion coefficient for binary mixtures of glycerol and water and find that the Stokes-Einstein relation is restored with increasing water concentration. Our comparison with theory suggests that addition of water postpones the formation of frustration domainsComment: 4 Pages and 3 Figure

Stereolithography for 3D photoelasticity

Recently, the use of photoelasticity has become more widespread due to the development of digital methods of fringe analysis [1] that allow a significant reduction in the time taken to achieve a stress map for any given model, particularly when only fractional fringe orders are displayed. However, in order for the full potential of the photoelastic method to be realised, a technique for rapidly producing complex 3-dimensional photoelastic models must be developed. Stereolithography is one so-called ‘rapid-prototype’ method that works by building a laminar model from a tank of photo-curing resin. A perforated metal plate is submerged in the liquid resin to a depth of typically around 0.1mm. A laser then traces the shape of the first layer of the component onto the plate, curing a thin layer of the resin. The plate is lowered by 0.1mm, and a further layer of resin cured by the laser. By this method, complex structures may be ‘laid-up’ in a matter of hours. Previous studies concerned with the use of stereolithography for the production of photoelastic models [2] have noted that unacceptable levels of residual birefringence and stress have remained in the photoelastic model even after conventional annealing methods. Thus the use of such methods has been limited. If the stereolithographic method were developed for photoelasticity, one possible area of interest would be the design and analysis of orthopedic implants. This paper outlines a series of studies looking at the requirements of photoelastic materials for three-dimensional stress analysis

Static and Dry Friction due to Multiscale Surface Roughness

It is shown on the basis of scaling arguments that a disordered interface between two elastic solids will quite generally exhibit static and "dry friction" (i.e., kinetic friction which does not vanish as the sliding velocity approaches zero), because of Tomlinson model instabilities that occur for small length scale asperities. This provides a possible explanation for why static and "dry" friction are virtually always observed, and superlubricity almost never occurs

Airborne multiwavelength High Spectral Resolution Lidar (HSRL-2) observations during TCAP 2012 : Vertical profiles of optical and microphysical properties of a smoke/urban haze plume over the northeastern coast of the US

© Author(s) 2014. This work is distributed under the Creative Commons Attribution 3.0 License.We present measurements acquired by the world's first airborne 3 backscatter (β) + 2 extinction (α) High Spectral Resolution Lidar (HSRL-2). HSRL-2 measures particle backscatter coefficients at 355, 532, and 1064 nm, and particle extinction coefficients at 355 and 532 nm. The instrument has been developed by the NASA Langley Research Center. The instrument was operated during Phase 1 of the Department of Energy (DOE) Two-Column Aerosol Project (TCAP) in July 2012. We observed pollution outflow from the northeastern coast of the US out over the western Atlantic Ocean. Lidar ratios were 50-60 sr at 355 nm and 60-70 sr at 532 nm. Extinction-related Ångström exponents were on average 1.2-1.7, indicating comparably small particles. Our novel automated, unsupervised data inversion algorithm retrieved particle effective radii of approximately 0.2 μm, which is in agreement with the large Ångström exponents. We find good agreement with particle size parameters obtained from coincident in situ measurements carried out with the DOE Gulfstream-1 aircraft.Peer reviewedFinal Published versio

An investigation into CLIL-related sections of EFL coursebooks : issues of CLIL inclusion in the publishing market

The current ELT global coursebook market has embraced CLIL as a weak form of bilingual education and an innovative component to include in General English coursebooks for EFL contexts. In this paper I investigate how CLIL is included in ELT coursebooks aimed at teenaged learners, available to teachers in Argentina. My study is based on the content analysis of four series which include a section advertised as CLIL-oriented. Results suggest that such sections are characterised by (1) little correlation between featured subject specific content and school curricula in L1, (2) oversimplification of contents, and (3) dominance of reading skills development and lower-order thinking tasks. Through this study, I argue that CLIL components become superficial supplements rather than a meaningful attempt to promote weak forms of bilingual education

Nuclear Magnetic Resonance and Hyperfine Structure

Contains reports on six research projects