Physiological role of mucins in the colonic barrier integrity

Colonic mucus is a key element of colonic barrier as it is located at the frontier between luminal microflora and colonic mucosa itself. Colonic mucus is mainly composed of high molecular weight glycoproteins called mucins that can be either secreted or membrane-linked. The expression of various colonic mucins is altered in colorectal cancers or inflammations. The aim of this review is to highlight the crucial role played by colonic mucins in the maintenance of colonic barrier integrity, both because they are part of the protective mucus layer, and because they individually exert specific functions involved in epithelial barrier, like cell growth and differentiation, immunomodulation, signal transduction or cell adhesion.     

Retirees' social identity and satisfaction with retirement

The purpose of this study was to examine the structure of retirees' social identity and its impact on satisfaction with retirement. From social identity theory formulations, we assumed that (1) retiree-identity was comprised of three distinct components (cognitive, evaluative, and affective), and (2) only the affective component would play a role in satisfaction with retirement. Results of the present study conducted with 154 retired people in France revealed only two components of social identity: a cognitive identity which refers to self-categorization as "retired people", and an affective identity which refers to evaluation of the group and affective involvement. As expected, regression analyses results indicated that only affective identity was a predictor of satisfaction with retirement. These results will be discussed in the framework of social identity theory literature.     

Arthritogenic antibodies specific for a major type II collagen triple-helical epitope bind and destabilize cartilage independent of inflammation

OBJECTIVE: To investigate the significance and pathogenic potential of a highly conserved major type II collagen triple-helical epitope-specific antibody (U1; amino acids 494-504) in vivo and in vitro in patients with early rheumatoid arthritis (RA) and in experimental animal models of collagen-induced arthritis (CIA). METHODS: U1-specific antibodies in sera from patients with early RA (with or without joint erosions) were analyzed. Disease progression in the CIA models in mice and rats with anti-U1 antibodies was compared. The pathogenicity of binding of monoclonal antibodies (mAb) UL1 and CIIF4 to the U1 epitope and the F4 epitope (aa 926-936), respectively, was compared in vivo and on chondrocyte cultures and preformed cartilage in vitro, using Fourier transform infrared microspectroscopy analysis. In addition, UL1-induced proteoglycan depletion in vivo in the presence and absence of the complement factor C5 was analyzed. RESULTS: Increased levels of U1 antibodies were observed in patients with early RA, especially in association with joint erosions. A significant correlation of U1-specific antibodies with disease progression was found in rats and mice with CIA. UL1 mAb induced, whereas CIIF4 mAb inhibited, the progression of arthritis. Similarly, UL1, but not CIIF4, impaired matrix synthesis on chondrocyte cultures and adversely affected preformed cartilage. Furthermore, UL1 induced significant proteoglycan depletion in vivo 3 days after injection, even in the absence of C5. CONCLUSION: Antibody epitope specificity contributes significantly to the development of arthritis, and the early pathogenic events operate independent of inflammation both in vitro and in vivo.     

MiR-29a down-regulation in ALK-positive anaplastic large cell lymphomas contributes to apoptosis blockade through MCL-1 overexpression

Although deregulated expression of specific microRNAs (miRNAs) has been described in solid cancers and leukemias, little evidence of miRNA deregulation has been reported in ALK-positive (ALK(+)) anaplastic large cell lymphomas (ALCL). These tumors overexpress the major antiapoptotic protein myeloid cell leukemia 1 (MCL-1), a situation that could compensate for the lack of BCL-2. We report that ALK(+) ALCL cell lines and biopsy specimens (n = 20) express a low level of miR-29a and that this down-modulation requires an active NPM-ALK kinase. Murine models (transgenic mice and mouse embryonic fibroblast [MEF] cells), which allow conditional NPM-ALK fusion protein expression, showed an increase of miR-29a expression in the absence of NPM-ALK. Concordant results were observed after the abolition of NPM-ALK kinase activity (siALK or PF-2341066) in NPM-ALK(+) ALCL cell lines. In addition, we showed that low expression of miR-29a, probably through methylation repression, plays an important regulatory role in MCL-1 overexpression that could promote tumor cell survival by inhibiting apoptosis. Enforced miR-29a expression was found to modulate apoptosis through inhibition of MCL-1 expression in ALCL cell lines and in a xenografted model, with a concomitant tumor growth reduction. Thus, synthetic miR-29a represents a potential new tool to affect tumorigenesis in these lymphomas.     

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-β, one of the pathological hallmarks of Alzheimer disease (AD). Acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear. Here we show that ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1−) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1− causes a 32% content increase in 24-hydroxycholesterol (24SOH), the major oxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1− causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1− causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP and HMGR protein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.     

Impact of yeast-bacteria coinfection on the detection of Candida sp. in an automated blood culture system

Invasive candidiasis remains a major cause of morbidity and mortality. It is now well known that an early diagnosis contributes to the patients' outcome. Blood cultures, which are the first-line test in case of bloodstream infection suspicion, can be carried out using fungus-selective medium (containing antibiotics) or standard microorganism medium allowing both bacterial and fungal growth. Some patients can suffer from polymicrobial sepsis involving bacteria and yeasts, so we decided to investigate in blood cultures the influence of the presence of bacteria on fungal development. Simulated blood cultures were performed using Candida albicans or C. glabrata coincubated with Escherichia coli or Staphylococcus aureus at different concentrations. The results showed that, in a standard microorganism medium, bacterial growth could hide the fungal development. Thus, in patients at risk of invasive candidiasis, the use of a specific fungal medium could improve the diagnosis and allow an earlier efficient antifungal treatment.