Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) controls adipogenesis in obesity in mice and in humans

Aims/hypothesis: Extracellular matrix reorganisation is a crucial step of adipocyte differentiation and is controlled by the matrix metalloproteinase-tissue inhibitor of matrix metalloproteinase (TIMP) enzyme system. We therefore sought to define the role of TIMP1 in adipogenesis and to elucidate whether upregulation of TIMP1 in obesity has direct effects on adipocyte formation. Methods: TIMP1 protein levels and mRNA were measured in lean and obese mice with a focus on levels in adipose tissue. We also analysed the effect of recombinant murine TIMP1 on adipogenesis, adipocyte size and metabolic control in vitro and in vivo. Results: TIMP1 levels were increased in the serum and adipose tissue of obese mouse models. Recombinant murine TIMP1 inhibited adipocyte differentiation in 3T3-L1 as well as in subcutaneous primary pre-adipocytes. Conversely, neutralising TIMP1 with a specific antibody enhanced adipocyte differentiation. In vivo, injection of recombinant TIMP1 in mice challenged with a high-fat diet led to enlarged adipocytes. TIMP1-treated mice developed an impaired metabolic profile with increased circulating NEFA levels, hepatic triacylglycerol accumulation and accelerated insulin resistance. Altered glucose clearance in TIMP1-injected mice was due to changes in adipose tissue glucose uptake, whereas muscle glucose clearance remained unaffected. Conclusions/interpretation: TIMP1 is a negative regulator of adipogenesis. In vivo, TIMP1 leads to enlarged adipocytes in the state of overnutrition. This might contribute to the detrimental metabolic consequences seen in TIMP1-injected mice, such as systemic fatty acid overload, hepatic lipid accumulation and insulin resistanc

I-mode studies at ASDEX Upgrade: L-I and I-H transitions, pedestal and confinement properties

The I-mode is a plasma regime obtained when the usual L-H power threshold is high, e.g. with unfavourable ion B ∇ direction. It is characterised by the development of a temperature pedestal while the density remains roughly as in the L-mode. This leads to a confinement improvement above the L-mode level which can sometimes reach H-mode values. This regime, already obtained in the ASDEX Upgrade tokamak about two decades ago, has been studied again since 2009 taking advantage of the development of new diagnostics and heating possibilities. The I-mode in ASDEX Upgrade has been achieved with different heating methods such as NBI, ECRH and ICRF. The I-mode properties, power threshold, pedestal characteristics and confinement, are independent of the heating method. The power required at the L-I transition exhibits an offset linear density dependence but, in contrast to the L-H threshold, depends weakly on the magnetic field. The L-I transition seems to be mainly determined by the edge pressure gradient and the comparison between ECRH and NBI induced L-I transitions suggests that the ion channel plays a key role. The I-mode often evolves gradually over a few confinement times until the transition to H-mode which offers a very interesting situation to study the transport reduction and its link with the pedestal formation. Exploratory discharges in which n = 2 magnetic perturbations have been applied indicate that these can lead to an increase of the I-mode power threshold by flattening the edge pressure at fixed heating input power: more heating power is necessary to restore the required edge pressure gradient. Finally, the confinement properties of the I-mode are discussed in detail.European Commission (EUROfusion 633053

Fast-ion redistribution and loss due to edge perturbations in the ASDEX Upgrade, DIII-D and KSTAR tokamaks

The impact of edge localized modes (ELMs) and externally applied resonant and non-resonant magnetic perturbations (MPs) on fast-ion confinement/transport have been investigated in the ASDEX Upgrade (AUG), DIII-D and KSTAR tokamaks. Two phases with respect to the ELM cycle can be clearly distinguished in ELM-induced fast-ion losses. Inter-ELM losses are characterized by a coherent modulation of the plasma density around the separatrix while intra-ELM losses appear as well-defined bursts. In high collisionality plasmas with mitigated ELMs, externally applied MPs have little effect on kinetic profiles, including fast-ions, while a strong impact on kinetic profiles is observed in low-collisionality, low q 95 plasmas with resonant and non-resonant MPs. In low-collisionality H-mode plasmas, the large fast-ion filaments observed during ELMs are replaced by a loss of fast-ions with a broad-band frequency and an amplitude of up to an order of magnitude higher than the neutral beam injection prompt loss signal without MPs. A clear synergy in the overall fast-ion transport is observed between MPs and neoclassical tearing modes. Measured fast-ion losses are typically on banana orbits that explore the entire pedestal/scrape-off layer. The fast-ion response to externally applied MPs presented here may be of general interest for the community to better understand the MP field penetration and overall plasma response.Ministerio de Economía y Empresa ((RYC-2011-09152 y ENE2012-31087)Marie Curie (Grant PCIG11-GA-2012-321455)US Department of Energy (DE-FC02-04ER54698, SC-G903402, DE-FG02-04ER54761, DE-AC02-09CH11466 and DE-FG02- 08ER54984)NRF Korea contract 2009-0082012MEST under the KSTAR projec

A striking correspondence between the dynamics generated by the vector fields and by the scalar parabolic equations

The purpose of this paper is to enhance a correspondence between the dynamics of the differential equations $\dot y(t)=g(y(t))$ on $\mathbb{R}^d$ and those of the parabolic equations $\dot u=\Delta u +f(x,u,\nabla u)$ on a bounded domain $\Omega$. We give details on the similarities of these dynamics in the cases $d=1$, $d=2$ and $d\geq 3$ and in the corresponding cases $\Omega=(0,1)$, $\Omega=\mathbb{T}^1$ and dim($\Omega$)$\geq 2$ respectively. In addition to the beauty of such a correspondence, this could serve as a guideline for future research on the dynamics of parabolic equations

Macropinocytotic uptake and infection of human epithelial cells with species B2 adenovirus type 35

The human adenovirus serotype 35 (HAdV-35, short Ad35) causes kidney and urinary tract infections, and infects respiratory organs of immunocompromised individuals. Unlike other adenoviruses, Ad35 has a low seroprevalence which makes Ad35-based vectors promising candidates for gene therapy. Ad35 utilizes CD46 and integrins as receptors for infection of epithelial and hematopoietic cells. Here, we show that infectious entry of Ad35 into HeLa, human kidney HK-2 cells and normal human lung fibroblasts strongly depended on CD46 and integrins but not heparan sulfate, and variably required the large GTPase dynamin. Ad35 infections were independent of expression of the carboxy-terminal domain of AP180 which effectively blocks clathrin-mediated uptake. Ad35 infections were inhibited by small chemicals against the serine/threonine kinase Pak1 (p21-activated kinase), protein kinase C (PKC), sodium-proton exchangers, actin and acidic organelles. Remarkably, the F-actin inhibitor jasplakinolide, the Pak1 inhibitor IPA-3 or the sodium-proton exchange inhibitor EIPA blocked the endocytic uptake of Ad35. Dominant-negative proteins or small interfering RNAs against factors driving macropinocytosis, including the small GTPase Rac1, Pak1 or the Pak1 effector C-terminal binding protein 1 (CtBP1) potently inhibited Ad35 infection. Confocal laser scanning microscopy, electron microscopy and live cell imaging showed that Ad35 colocalized with fluid phase markers in large endocytic structures that were positive for CD46, alpha v integrins and also CtBP1. Our results extend earlier observations with HAdV-3 (Ad3), and establish macropinocytosis as an infectious pathway for species B human adenoviruses in epithelial and hematopoietic cells