Integrin-Alpha IIb Identifies Murine Lymph Node Lymphatic Endothelial Cells Responsive to RANKL

Microenvironment and activation signals likely imprint heterogeneity in the lymphatic endothelial cell (LEC) population. Particularly LECs of secondary lymphoid organs are exposed to different cell types and immune stimuli. However, our understanding of the nature of LEC activation signals and their cell source within the secondary lymphoid organ in the steady state remains incomplete. Here we show that integrin alpha 2b (ITGA2b), known to be carried by platelets, megakaryocytes and hematopoietic progenitors, is expressed by a lymph node subset of LECs, residing in medullary, cortical and subcapsular sinuses. In the subcapsular sinus, the floor but not the ceiling layer expresses the integrin, being excluded from ACKR4⁺ LECs but overlapping with MAdCAM-1 expression. ITGA2b expression increases in response to immunization, raising the possibility that heterogeneous ITGA2b levels reflect variation in exposure to activation signals. We show that alterations of the level of receptor activator of NF-κB ligand (RANKL), by overexpression, neutralization or deletion from stromal marginal reticular cells, affected the proportion of ITGA2b⁺ LECs. Lymph node LECs but not peripheral LECs express RANK. In addition, we found that lymphotoxin-β receptor signaling likewise regulated the proportion of ITGA2b⁺ LECs. These findings demonstrate that stromal reticular cells activate LECs via RANKL and support the action of hematopoietic cell-derived lymphotoxin.     

Interactions of surfactin,a biosurfactant fromBacillus subtilis,with inorganic cations

Summary The properties of surfactin, a biosurfactant lipopeptide, were highly modified in the presence of inorganic cations. The micellization of surfactin was favoured by monovalent and, especially by divalent cations with a modification of the molecular area at the air-water interface. Haemolysis of erythrocytes by surfactin was enhanced by low concentrations of divalent cations with an increase of the binding of the lipopeptide to membrane. Inorganic ions induced conformational rearrangements probably due to ion-surfactin associations which modify the surface-active properties.     

Sodium butyrate inhibits the phosphorylation of the retinoblastoma gene product in mouse fibroblasts by a transcription-dependent mechanism

In the chemically transformed mouse fibroblasts BP-A31, the retinoblastoma protein (pRb) is hypophosphorylated at quiescence and becomes hyperphosphorylated after approximately 6 h of serum stimulation. Phosphorylation of pRb was blocked if sodium butyrate was added together with serum or within 3 h afterwards. Actinomycin D added 3 h after serum stimulation did not prevent pRb phosphorylation, but it reversed the inhibitory effect of butyrate. These observations indicate that sodium butyrate acts by turning on the expression of gene(s) coding for proteins which prevent the accumulation of hyperphosphorylated pRb. Such butyrate-induced inhibitor(s) may interfere with the phosphorylation of pRb by cyclin-dependent kinases. Treatment of quiescent BP-A31 cells with serum in the presence of sodium butyrate has led to an increased cell content of the Waf1/CIP1 mRNA (coding for a cyclin-dependent kinase inhibitory protein) compared with serum alone, suggesting a possible role of p21Waf1/CIP1. In contrast, the mitogen activated protein kinase (enzyme which has been shown to phosphorylate pRb) was constitutively active in BP-A31 cells, and its activity was not significantly affected by a ≤ 3 h incubation with sodium butyrate. © 1996 Wiley-Liss, Inc.     

Modified absorptive and secretory processes in the rat distal colon after neutron irradiation: in vivo and in vitro studies

Impaired fluid and electrolyte transport in the intestine is a well-recognized characteristic of radiation-induced pathologies in the gastrointestinal tract. The aim of this study was to investigate the responsiveness of the epithelium of the colon of the rat to electrical and pharmacological (serotonin, carbachol) stimulation concomitantly with in vivo assessment of the absorptive capacity of the colon at 1, 3, 5 and 7 days after 3.8 Gy whole-body exposure to neutrons. The responsiveness of rat colon in vitro to electrical stimulation and the number of mast cells were measured to examine the role of neuroimmune networks in radiation-induced dysfunction. Animals showed an impaired capacity of the colon to absorb water and sodium from 3 to 5 days after irradiation together with decreased responsiveness to electrical and pharmacological stimulation. The time course of decreased responsiveness to neural stimulation was similar to that of impaired absorption observed in vivo, but it was not correlated with variations in mast cell numbers. Histological (mast cells) and biochemical analyses (myeloperoxidase and NO synthase activities) did not find evidence of a marked infiltration and/or activation of inflammatory cells. Thus the impaired absorptive capacity of the colon observed after irradiation occurs concomitantly with decreased neural influence, and is possibly related to reduced epithelial functional capacity but not to decreased mast cell numbers.     

Effects of alcohol on psycho-technical tests and social communication in a festive situation: a chronopsychological approach

The aim of this study was to determine the effect of consuming alcoholic vs. nonalcoholic beverages on performance of psycho-technical tasks (attentional and general nonverbal intelligence tasks) and social behavior at different times of day. Both alcoholic and nonalcoholic consumption took place in a largely festive situation. The experiment was conducted on 184 degree-level and postgraduate students (94 female and 90 male) divided into eight independent groups for study at different times: 8:00 to 11:00, 11:00 to 14:00, 14:00 to 17:00, 17:00 to 20:00h. The main result obtained, by analysis of variance (ANOVA), showed that time of day had no effect on the performance of psycho-technical tasks nor on social communication, except for the retest situation in the attentional task. Alcohol (equal to approximately 0.5 g/L of blood) facilitated communication, but basically it had no effect on any of the psycho-technical performance tests. For the latter, an interaction was observed between when the test was done and type of beverage consumed. Alcohol appears to alter the expected change in performance in the retest situation. The results suggest that the body's sensitivity to a measured quantity of alcohol differs according to the cognitive processes involved.     

Does clinical research provide any "direct individual benefit"?

The European Commission and Parliament have promulgated a directive on clinical research (2001/20/CE) in April 2001. Its provisions have to be incorporated in all national laws by May 2004. Accordingly, the French " loi Huriet " (a law passed in 1988 organizing clinical research in France) had to be revised. During the process, it appeared that a key issue was the suppression of a distinction made by this law between research with and without " direct individual benefit ", a French specificity, as the directive recommends rather the assessment of the risk/benefit ratio. In order to harmonize the French legislation with the other European laws, and to suppress a set of provisions which have been repeatedly attacked during the last ten years, the French members of parliament have voted on October 2003 a new law which, among other important modifications, suppress that distinction.     

Origin of resistance to Imatinib mesylate: lessons learned from this experience

For drug development and pharmaceutical research, targeting the molecular abnormalities is considered as a new challenge. A number of diseases including cancer are linked to perturbation of tyrosine kinase (TK). Imatinib (Glivec or Gleevec, Novartis), the most potent inhibitor of c-abl TK, was recently developed. This molecule has been approved in the treatment of chronic myeloid leukemia (CML). However, emergence of clinical resistance regarding a low rate of CML patients leads to intensive research. In the current article, we discuss the data and the mechanism of the resistance phenomenon. This review illustrates the important requirement to transfer back the information from patient to laboratory in order to improve future drug design.