Dynamics of human adipose lipid turnover in health and metabolic disease

Adipose tissue mass is determined by the storage and removal of triglycerides in adipocytes. Little is known, however, about adipose lipid turnover in humans in health and pathology. To study this in vivo, here we determined lipid age by measuring (14)C derived from above ground nuclear bomb tests in adipocyte lipids. We report that during the average ten-year lifespan of human adipocytes, triglycerides are renewed six times. Lipid age is independent of adipocyte size, is very stable across a wide range of adult ages and does not differ between genders. Adipocyte lipid turnover, however, is strongly related to conditions with disturbed lipid metabolism. In obesity, triglyceride removal rate (lipolysis followed by oxidation) is decreased and the amount of triglycerides stored each year is increased. In contrast, both lipid removal and storage rates are decreased in non-obese patients diagnosed with the most common hereditary form of dyslipidaemia, familial combined hyperlipidaemia. Lipid removal rate is positively correlated with the capacity of adipocytes to break down triglycerides, as assessed through lipolysis, and is inversely related to insulin resistance. Our data support a mechanism in which adipocyte lipid storage and removal have different roles in health and pathology. High storage but low triglyceride removal promotes fat tissue accumulation and obesity. Reduction of both triglyceride storage and removal decreases lipid shunting through adipose tissue and thus promotes dyslipidaemia. We identify adipocyte lipid turnover as a novel target for prevention and treatment of metabolic disease.     

Action Research as Experimentation

This paper suggests that the metaphors of experimentation and the laboratory are applicable when positioning action research vis-à-vis more conventional business school research. Following on from three different action research projects in a large multinational pharmaceutical company, the paper argues that an action researcher can never construct a sheltered environment wherein certain qualities of nature can be isolated, purified, and enhanced, but must always undertake research activities in vivo, in real life organizational setting. Still, the metaphor of the laboratory is applicable because it enables for an understanding of how what Ian Hacking calls interventions in the hard sciences share certain characteristics with the action research activities. When action researchers intervene within organizations, the activities are always experimental in nature, i.e., they can never be fully predicted or anticipated, but are initial steps in an emergent process of organizational change.     

The complete genome sequence of Francisella tularensis, the causative agent of tularemia

Francisella tularensis is one of the most infectious human pathogens known. In the past, both the former Soviet Union and the US had programs to develop weapons containing the bacterium. We report the complete genome sequence of a highly virulent isolate of F. tularensis (1,892,819 bp). The sequence uncovers previously uncharacterized genes encoding type IV pili, a surface polysaccharide and iron-acquisition systems. Several virulence-associated genes were located in a putative pathogenicity island, which was duplicated in the genome. More than 10% of the putative coding sequences contained insertion-deletion or substitution mutations and seemed to be deteriorating. The genome is rich in IS elements, including IS630 Tc-1 mariner family transposons, which are not expected in a prokaryote. We used a computational method for predicting metabolic pathways and found an unexpectedly high proportion of disrupted pathways, explaining the fastidious nutritional requirements of the bacterium. The loss of biosynthetic pathways indicates that F. tularensis is an obligate host-dependent bacterium in its natural life cycle. Our results have implications for our understanding of how highly virulent human pathogens evolve and will expedite strategies to combat them.     

Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation

Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is a key process in several pathological conditions, including tumour growth and age-related macular degeneration. Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium. However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds. Here we demonstrate that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting of VEGFR-3 or blocking of VEGFR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR-3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR-2 (also known as KDR or FLK-1) inhibitors, whereas antibodies against VEGFR-3 and VEGFR-2 in combination resulted in additive inhibition of angiogenesis and tumour growth. Furthermore, genetic or pharmacological disruption of the Notch signalling pathway led to widespread endothelial VEGFR-3 expression and excessive sprouting, which was inhibited by blocking VEGFR-3 signals. Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors.     

Structural insights into the evolutionary paths of oxylipin biosynthetic enzymes

The oxylipin pathway generates not only prostaglandin-like jasmonates but also green leaf volatiles (GLVs), which confer characteristic aromas to fruits and vegetables. Although allene oxide synthase (AOS) and hydroperoxide lyase are atypical cytochrome P450 family members involved in the synthesis of jasmonates and GLVs, respectively, it is unknown how these enzymes rearrange their hydroperoxide substrates into different products. Here we present the crystal structures of Arabidopsis thaliana AOS, free and in complex with substrate or intermediate analogues. The structures reveal an unusual active site poised to control the reactivity of an epoxyallylic radical and its cation by means of interactions with an aromatic pi-system. Replacing the amino acid involved in these steps by a non-polar residue markedly reduces AOS activity and, unexpectedly, is both necessary and sufficient for converting AOS into a GLV biosynthetic enzyme. Furthermore, by combining our structural data with bioinformatic and biochemical analyses, we have discovered previously unknown hydroperoxide lyase in plant growth-promoting rhizobacteria, AOS in coral, and epoxyalcohol synthase in amphioxus. These results indicate that oxylipin biosynthetic genes were present in the last common ancestor of plants and animals, but were subsequently lost in all metazoan lineages except Placozoa, Cnidaria and Cephalochordata.     

Numerical taxonomy and the principle of maximum entropy

The standard procedure in numerical classification and identification of micro-organisms based on binary features is given a justification based on the principle of maximum entropy. This principle also strongly supports the assumption that all characteristics upon which the classification is based are equally important and the use of polythetic taxa. The relevance of the principle of maximum entropy in connection with taxonomic structures based on clustering and maximal predictivity is discussed. A result on asymptotic separateness of maximum entropy distributions has implications for minimizing identification errors.The work was partially supported by the Bank of Sweden Tercentenary Foundation, The Swedish Council for Forestry and Agricultural Research, The Carl Trygger Foundation, and the Swedish Cancer Foundation.     

Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis

In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A. VEGF-A is also essential for the induction of endothelial tip cells, but it is not known how single tip cells are selected to lead each vessel sprout, and how tip-cell numbers are determined. Here we present evidence that delta-like 4 (Dll4)-Notch1 signalling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in the mouse retina. We show that inhibition of Notch signalling using gamma-secretase inhibitors, genetic inactivation of one allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1, all promote increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 peptide leads to fewer tip cells and vessel branches. Dll4 and reporters of Notch signalling are distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assume tip-cell characteristics. Together, our results suggest that Dll4-Notch1 signalling between the endothelial cells within the angiogenic sprout serves to restrict tip-cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. This model offers an explanation for the dose-dependency and haploinsufficiency of the Dll4 gene, and indicates that modulators of Dll4 or Notch signalling, such as gamma-secretase inhibitors developed for Alzheimer's disease, might find usage as pharmacological regulators of angiogenesis.     

Structure of insect community in the fungus Inonotus radiatus in riparian boreal forests

Basidiomes of polypore fungi host many insects. Yet systematic information about insect assemblages from most fungal species is lacking. We studied the insect community associated with the wood-decaying fungus Inonotus radiatus (Sowerby: Fr.) P. Karst. (Hymenochaetales). More specifically, we studied the effect of successional stage and weight of basidiomes, as well as shore exposition (north or south), on species richness and composition, as well as occurrence and abundance of the most abundant fungivores. Basidiomes were collected from riparian forests at five lakes in Sweden. Insects were reared out from the basidiomes in the laboratory. A total of 5645 adult insect individuals of 117 taxa were obtained. Among these, 2782 specimens of 36 taxa use Inonotus radiatus basidiomes as breeding habitat. Eight species of parasitic wasps were new to Sweden. The most abundant fungivore was Ennearthron cornutum (Ciidae), which is a generalist breeding in many polypore species. Based on our material and literature, the melandryid beetles Abdera affinis and A. flexuosa seem to be specialists on the order Hymenochaetales. Other frequent fungivores were Dorcatoma dresdensis (Ptinidae), and the lepidopterans Archinemapogon yildizae, Nemapogon cloacellus and N. picarellus (Tineidae). The parasitoid community associated with the tineid moths was similar to the community associated with the other polypore species in the order Polyporales. In contrast, the parasitoids associated with Dorcatoma (and/or Abdera) were different from the other Polyporales species, suggesting that the fungal host species is more important for these parasitoid species than the beetle host species itself. The most abundant and frequent parasitoids were the braconids Diospilus dispar and Colastes fritzeni, which both parasitise Dorcatoma. Species richness was significantly smaller in fresh than in more decayed basidiomes, but species composition did not differ. There was no difference in species composition or richness between north and south shorelines.     

Alfvénic waves with sufficient energy to power the quiet solar corona and fast solar wind

Energy is required to heat the outer solar atmosphere to millions of degrees (refs 1, 2) and to accelerate the solar wind to hundreds of kilometres per second (refs 2-6). Alfvén waves (travelling oscillations of ions and magnetic field) have been invoked as a possible mechanism to transport magneto-convective energy upwards along the Sun's magnetic field lines into the corona. Previous observations of Alfvénic waves in the corona revealed amplitudes far too small (0.5?km?s(-1)) to supply the energy flux (100-200?W?m(-2)) required to drive the fast solar wind or balance the radiative losses of the quiet corona. Here we report observations of the transition region (between the chromosphere and the corona) and of the corona that reveal how Alfvénic motions permeate the dynamic and finely structured outer solar atmosphere. The ubiquitous outward-propagating Alfvénic motions observed have amplitudes of the order of 20?km?s(-1) and periods of the order of 100-500?s throughout the quiescent atmosphere (compatible with recent investigations), and are energetic enough to accelerate the fast solar wind and heat the quiet corona.