Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates.

Epidemiological and transgenic animal studies have implicated apo C-III as a major determinant of plasma triglyceride metabolism. Since fibrates are very efficient in lowering triglycerides, it was investigated whether fibrates regulate apo C-III gene expression. Different fibrates lowered rat liver apo C-III mRNA levels up to 90% in a dose- and time-dependent manner, whereas intestinal apo C-III mRNA remained constant. This decrease in liver apo C-III mRNA was rapid (1 d) and reversible, since it was restored to control levels within 1 wk after cessation of treatment. In addition, fenofibrate treatment abolished the developmental rise of hepatic apo C-III mRNA observed during the suckling-weaning period. Administration of fibrates to rats induced liver and intestinal expression of the acyl CoA oxidase gene, the rate-limiting enzyme for peroxisomal beta-oxidation of fatty acids. In primary cultures of rat and human hepatocytes, fenofibric acid lowered apo C-III mRNA in a time- and dose-dependent manner. This reduction in apo C-III mRNA levels was accompanied by a decreased secretion of apo C-III in the culture medium of human hepatocytes. In rat hepatocytes fenofibric acid induced acyl CoA oxidase gene expression, whereas acyl CoA oxidase mRNA remained unchanged in human hepatocytes. Nuclear run-on and transient transfection experiments of a reporter construct driven by the human apo C-III gene promoter indicated that fibrates downregulate apo C-III gene expression at the transcriptional level. In conclusion, these studies demonstrate that fibrates decrease rat and human liver apo C-III gene expression. In humans the mechanisms appears to be independent of the induction of peroxisomal enzymes. This downregulation of liver apo C-III gene expression by fibrates may contribute to the hypotriglyceridemic action of these drugs

Antagonistic interactions between filamentous heterotrophs and the cyanobacterium Nostoc muscorum

Background: Little is known about interactions between filamentous heterotrophs and filamentous cyanobacteria. Here, interactions between the filamentous heterotrophic bacteria Fibrella aestuarina (strain BUZ 2) and Fibrisoma limi (BUZ 3) with an axenic strain of the autotrophic filamentous cyanobacterium Nostoc muscorum (SAG 25.82) were studied in mixed cultures under nutrient rich (carbon source present in medium) and poor (carbon source absent in medium) conditions. Findings: F. aestuarina BUZ 2 significantly reduced the cyanobacterial population whereas F. limi BUZ 3 did not. Physical contact between heterotrophs and autotroph was observed and the cyanobacterial cells showed some level of damage and lysis. Therefore, either contact lysis or entrapment with production of extracellular compounds in close vicinity of host cells could be considered as potential modes of action. The supernatants from pure heterotrophic cultures did not have an effect on Nostoc cultures. However, supernatant from mixed cultures of BUZ 2 and Nostoc had a negative effect on cyanobacterial growth, indicating that the lytic compounds were only produced in the presence of Nostoc. The growth and survival of tested heterotrophs was enhanced by the presence of Nostoc or its metabolites, suggesting that the heterotrophs could utilize the autotrophs and its products as a nutrient source. However, the autotroph could withstand and out-compete the heterotrophs under nutrient poor conditions. Conclusions: Our results suggest that the nutrients in cultivation media, which boost or reduce the number of heterotrophs, were the important factor influencing the outcome of the interplay between filamentous heterotrophs and autotrophs. For better understanding of these interactions, additional research is needed. In particular, it is necessary to elucidate the mode of action for lysis by heterotrophs, and the possible defense mechanisms of the autotrophs

Climate change drives microevolution in a wild bird

To ensure long-term persistence, organisms must adapt to climate change, but an evolutionary response to a quantified selection pressure driven by climate change has not been empirically demonstrated in a wild population. Here, we show that pheomelanin-based plumage colouration in tawny owls is a highly heritable trait, consistent with a simple Mendelian pattern of brown (dark) dominance over grey (pale). We show that strong viability selection against the brown morph occurs, but only under snow-rich winters. As winter conditions became milder in the last decades, selection against the brown morph diminished. Concurrent with this reduced selection, the frequency of brown morphs increased rapidly in our study population during the last 28 years and nationwide during the last 48 years. Hence, we show the first evidence that recent climate change alters natural selection in a wild population leading to a microevolutionary response, which demonstrates the ability of wild populations to evolve in response to climate change

International Network for Comparison of HIV Neutralization Assays: The NeutNet Report

BACKGROUND: Neutralizing antibody assessments play a central role in human immunodeficiency virus type-1 (HIV-1) vaccine development but it is unclear which assay, or combination of assays, will provide reliable measures of correlates of protection. To address this, an international collaboration (NeutNet) involving 18 independent participants was organized to compare different assays. METHODS: Each laboratory evaluated four neutralizing reagents (TriMab, 447-52D, 4E10, sCD4) at a given range of concentrations against a panel of 11 viruses representing a wide range of genetic subtypes and phenotypes. A total of 16 different assays were compared. The assays utilized either uncloned virus produced in peripheral blood mononuclear cells (PBMCs) (virus infectivity assays, VI assays), or their Env-pseudotyped (gp160) derivatives produced in 293T cells (PSV assays) from molecular clones or uncloned virus. Target cells included PBMC and genetically-engineered cell lines in either a single- or multiple-cycle infection format. Infection was quantified by using a range of assay read-outs that included extracellular or intracellular p24 antigen detection, RNA quantification and luciferase and beta-galactosidase reporter gene expression. FINDINGS: PSV assays were generally more sensitive than VI assays, but there were important differences according to the virus and inhibitor used. For example, for TriMab, the mean IC50 was always lower in PSV than in VI assays. However, with 4E10 or sCD4 some viruses were neutralized with a lower IC50 in VI assays than in the PSV assays. Inter-laboratory concordance was slightly better for PSV than for VI assays with some viruses, but for other viruses agreement between laboratories was limited and depended on both the virus and the neutralizing reagent. CONCLUSIONS: The NeutNet project demonstrated clear differences in assay sensitivity that were dependent on both the neutralizing reagent and the virus. No single assay was capable of detecting the entire spectrum of neutralizing activities. Since it is not known which in vitro assay correlates with in vivo protection, a range of neutralization assays is recommended for vaccine evaluation

International Network for Comparison of HIV Neutralization Assays: The NeutNet Report II

BACKGROUND: Neutralizing antibodies provide markers for vaccine-induced protective immunity in many viral infections. By analogy, HIV-1 neutralizing antibodies induced by immunization may well predict vaccine effectiveness. Assessment of neutralizing antibodies is therefore of primary importance, but is hampered by the fact that we do not know which assay(s) can provide measures of protective immunity. An international collaboration (NeutNet) involving 18 different laboratories previously compared different assays using monoclonal antibodies (mAbs) and soluble CD4 (Phase I study). METHODS: In the present study (Phase II), polyclonal reagents were evaluated by 13 laboratories. Each laboratory evaluated nine plasmas against an 8 virus panel representing different genetic subtypes and phenotypes. TriMab, a mixture of three mAbs, was used as a positive control allowing comparison of the results with Phase I in a total of nine different assays. The assays used either uncloned virus produced in peripheral blood mononuclear cells (PBMCs) (Virus Infectivity Assays, VIA), or Env (gp160)-pseudotyped viruses (pseudoviruses, PSV) produced in HEK293T cells from molecular clones or from uncloned virus. Target cells included PBMC and genetically engineered cell lines in either single- or multiple-cycle infection format. Infection was quantified by using a range of assay read-outs including extra- or intra-cellular p24 antigen detection, luciferase, beta-galactosidase or green fluorescent protein (GFP) reporter gene expression. FINDINGS: Using TriMab, results of Phase I and Phase II were generally in agreement for six of the eight viruses tested and confirmed that the PSV assay is more sensitive than PBMC (p = 0.014). Comparisons with the polyclonal reagents showed that sensitivities were dependent on both virus and plasma. CONCLUSIONS: Here we further demonstrate clear differences in assay sensitivities that were dependent on both the neutralizing reagent and the virus. Consistent with the Phase I study, we recommend parallel use of PSV and VIA for vaccine evaluation

Involvement of cell surface TG2 in the aggregation of K562 cells triggered by gluten

Gluten-induced aggregation of K562 cells represents an in vitro model reproducing the early steps occurring in the small bowel of celiac patients exposed to gliadin. Despite the clear involvement of TG2 in the activation of the antigen-presenting cells, it is not yet clear in which compartment it occurs. Herein we study the calcium-dependent aggregation of these cells, using either cell-permeable or cell-impermeable TG2 inhibitors. Gluten induces efficient aggregation when calcium is absent in the extracellular environment, while TG2 inhibitors do not restore the full aggregating potential of gluten in the presence of calcium. These findings suggest that TG2 activity is not essential in the cellular aggregation mechanism. We demonstrate that gluten contacts the cells and provokes their aggregation through a mechanism involving the A-gliadin peptide 31-43. This peptide also activates the cell surface associated extracellular TG2 in the absence of calcium. Using a bioinformatics approach, we identify the possible docking sites of this peptide on the open and closed TG2 structures. Peptide docks with the closed TG2 structure near to the GTP/GDP site, by establishing molecular interactions with the same amino acids involved in stabilization of GTP binding. We suggest that it may occur through the displacement of GTP, switching the TG2 structure from the closed to the active open conformation. Furthermore, docking analysis shows peptide binding with the β-sandwich domain of the closed TG2 structure, suggesting that this region could be responsible for the different aggregating effects of gluten shown in the presence or absence of calcium. We deduce from these data a possible mechanism of action by which gluten makes contact with the cell surface, which could have possible implications in the celiac disease onset

Environmental justice and conceptions of the green economy

Green economy has become one of the most fashionable terms in global environmental public policy discussions and forums. Despite this popularity, and its being selected as one of the organizing themes of the United Nations Rio+20 Conference in Brazil, June 2012, its prospects as an effective mobilization tool for global environmental sustainability scholarship and practice remains unclear. A major reason for this is that much like its precursor concepts such as environmental sustainability and sustainable development, green economy is a woolly concept which lends itself to many interpretations. Hence, rather than resolve long-standing controversies, green economy merely reinvigorates existing debates over the visions, actors and policies best suited to secure a more sustainable future for all. In this review article, we aim to fill an important gap in scholarship by suggesting various ways in which green economy may be organized and synthesized as a concept, and especially in terms of its relationship with the idea of social and environmental justice. Accordingly, we offer a systemization of possible interpretations of green economy mapped onto a synthesis of existing typologies of environmental justice. This classification provides the context for future analysis of which, and how, various notions of green economy link with various conceptions of justice

Esophageal motor abnormalities in scleroderma and related diseases

Esophageal motor activity was measured by intra-esophageal pressure recordings in 53 patients with scleroderma and 29 patients with other collagen diseases. The purpose of the study was to determine the relationship of motor abnormalities to esophageal symptoms, to compare the abnormalities in scleroderma with those in other collagen diseases, and to try to increase understanding of the responsible mechanism. Methacholine was given to 36 of the 53 patients with scleroderma to confirm that the Mecholyl test is negative in scleroderma and to see whether intraluminal pressure changes accompany the resulting improvement in esophageal emptying.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44360/1/10620_2005_Article_BF02233564.pd

Scaffolds for cartilage regeneration: to use or not to use?

Joint cartilage has been a significant focus on the field of tissue engineering and regenerative medicine (TERM) since its inception in the 1980s. Represented by only one cell type, cartilage has been a simple tissue that is thought to be straightforward to deal with. After three decades, engineering cartilage has proven to be anything but easy. With the demographic shift in the distribution of world population towards ageing, it is expected that there is a growing need for more effective options for joint restoration and repair. Despite the increasing understanding of the factors governing cartilage development, there is still a lot to do to bridge the gap from bench to bedside. Dedicated methods to regenerate reliable articular cartilage that would be equivalent to the original tissue are still lacking. The use of cells, scaffolds and signalling factors has always been central to the TERM. However, without denying the importance of cells and signalling factors, the question posed in this chapter is whether the answer would come from the methods to use or not to use scaffold for cartilage TERM. This paper presents some efforts in TERM area and proposes a solution that will transpire from the ongoing attempts to understand certain aspects of cartilage development, degeneration and regeneration. While an ideal formulation for cartilage regeneration has yet to be resolved, it is felt that scaffold is still needed for cartilage TERM for years to come