Mitochondrial DNA segregation in hematopoietic lineages does not depend on MHC presentation of mitochondrially encoded peptides

Mutations in mitochondrial DNA (mtDNA) are associated with a broad spectrum of clinical disorders. The segregation pattern of pathogenic mtDNAs is an important determinant of both the onset and the severity of the disease phenotype, but the mechanisms controlling mtDNA segregation remain poorly understood. To investigate this, we previously generated heteroplasmic mice containing two different mtDNA haplotypes and showed that BALB/c mtDNA was invariably selected over NZB mtDNA in blood and spleen. Here, we have characterized this process in hematopoietic tissues and tested whether it involves the presentation of mtDNA-encoded peptides by MHC class Ib molecules. Selection against NZB mtDNA was widespread across different hematopoietic cell lineages and proportional to heteroplasmy levels. Backcrossing heteroplasmic mice with CAST/Ei, a strain in which the MHC class Ib molecule H2-M3 is silent, completely abolished selection against NZB mtDNA in the spleen. To test whether this effect depended on an intact immune system, we generated heteroplasmic mice missing functional copies of Tap1, beta2m or Rag1 to impair presentation or recognition of mtDNA-encoded peptides. The kinetics of selection against NZB mtDNA were unaltered in these mice compared with their wild-type littermates. We conclude that mtDNA selection in hematopoietic tissues is not based on an immune mechanism, but likely involves metabolic signaling.     

The effects of leukotrienes,thromboxane A2 and phospholipase A2 on human,porcine and guinea pig lung parenchyma

A comparison was made of the contractions, induced by LTD₄, histamine and phospholipase A₂ in parenchymal strips of guinea pig (GPLP), porcine and human lung in a cascade superfusion system. The effects of LTD₄ and phospholipase A₂ on the release of TxA₂ in these tissues and of TxA₂, 5-HT and acetylcholine on the GPLP were also determined.In the GPLP strip, the LTC₄-induced contractions are due for±80% to the release of TxA₂ and for±20% to the direct effect of LTC₄.The guinea pig tissue displayed the highest sentivity towards all substances, except to the contraction induced by histamine, which was most effective in the porcine tissue. Low activities wer found in the human tissue in all tests. The reason for these effects may be a difference in activities or number of cell types which participate in the reactions leading to the contractions.     

Contrasting roles of DAP10 and KARAP/DAP12 signaling adaptors in activation of the RBL-2H3 leukemic mast cell line

A common feature of hematopoietic activating immunoreceptors resides in their association at the cell surface with transmembrane signaling adaptors. Several adaptors, such as the CD3 molecules, FcRgamma and KARAP/DAP12, harbor intracytoplasmic immunoreceptor tyrosine-based activation motifs (ITAM) that activate Syk-family protein tyrosine kinases. In contrast, another transmembrane adaptor, DAP10, bears a YxxM motif that delivers signals by activation of lipid kinase pathways. We show here that the human signal-regulatory protein SIRPbeta1 can associate with both DAP10 and KARAP/DAP12 in a model of RBL-2H3 cell transfectants. In association with KARAP/DAP12, SIRPbeta1 complexes are capable of inducing serotonin release and tumor necrosis factor (TNF) secretion. By contrast,in the absence of KARAP/DAP12, engagement of SIRPbeta1:DAP10 complexes does not lead to detectable serotonin release or TNF secretion by RBL-2H3 transfectants. However, triggering of SIRPbeta1:DAP10 complexes co-stimulates RBL-2H3 effector function induced by sub-optimal stimulation of the endogenous FcepsilonRI complex. Therefore, we report here a cellular model in which the association of a cell surface receptor with various signaling adaptors dictates the co-stimulatory or the direct stimulatory properties of the complex.     

Physiological Correlates of Mental Activity: Eye Movements, Alpha, and Heart Rate During Imagining, Suppression, Concentration, Search, and Choice

Rapid eye movements (REMs), EEG alpha, and tonic heart rate (HR) were measured during 6 types of cognitive tasks—imagining a liked person, suppressing thoughts of the person, searching one's mind for alternative solutions, arithmetic involving little concentration, problems involving high concentration, and choosing a preferred activity. The latter 3 required verbalization, the former 3 did not. Only suppression and search did not differ significantly from each other on at least one physiological variable. Imagining, suppression, and search yielded few REMs, high alpha, and low HR. High concentration yielded many REMs, low alpha, and high HR. Choice yielded many REMs, low alpha, and intermediate HR. Low concentration yielded few REMs, low alpha, and high HR. Suppression produced somewhat less alpha than imagining but did not differ significantly in REMs.     

Frequent spontaneous deletions at a shuttle vector locus in transgenic mice

Transgenic mice carrying multiple copies of a recoverable lambdaphage shuttle vector (     

P-selectin glycoprotein ligand-1 mediates rolling of mouse bone marrow-derived mast cells on P-selectin but not efficiently on E-selectin

It has been shown recently that mast cells play an essential role as a source of tumor necrosis factor-α production during neutrophil recruitment to sites of bacterial infection. Increased numbers of mast cells are indeed noted at sites of wound healing and inflammation. These cells are either recruited from the bone marrow or proliferate locally under cytokine stimulation. Little is known about how mast cell progenitors extravasate into tissue. Using antibody-like fusion proteins of mouse E-selectin and P-selectin, we have analyzed the ability of immature mouse bone marrow-derived mast cells (BMMC) to interact with the endothelial selectins. The P-selectin glycoprotein ligand-1 (PSGL-1) was affinity-isolated from detergent extracts of surface biotinylated BMMC with both selectin-IgG fusion proteins. However, only P-selectin-IgG, but not E-selectin-IgG showed significant interaction with intact BMMC as tested by flow cytometry and cell attachment assays with the immobilized fusion proteins under flow and non-flow conditions at physiological shear stress. Thus, in spite of carrying the necessary carbohydrate modifications which enable solubilized PSGL-1 to bind avidly to E-selectin, PSGL-1 on the surface of BMMC is presented in a way that prevents it from interacting efficiently with E-selectin. Affinity-purified rabbit antibodies against mouse PSGL-1 almost completely blocked the interaction of BMMC with P-selectin-IgG in flow cytometry as well as in cell adhesion assays under static and under flow conditions. Our data reveal that PSGL-1 is the major binding site for P-selectin on mouse BMMC progenitors, but does not support efficient interactions with E-selectin.     

Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection

Understanding the regulation of immune responses is central for control of autoimmune and infectious disease. In murine models of autoimmunity and chronic inflammatory disease, potent regulatory T lymphocytes have recently been characterized. Despite an explosion of interest in these cells, their relevance to human disease has been uncertain. In a longitudinal study of malaria sporozoite infection via the natural route, we provide evidence that regulatory T cells have modifying effects on blood-stage infection in vivo in humans. Cells with the characteristics of regulatory T cells are rapidly induced following blood-stage infection and are associated with a burst of TGF-beta production, decreased proinflammatory cytokine production, and decreased antigen-specific immune responses. Both the production of TGF-beta and the presence of CD4+CD25+FOXP3+ regulatory T cells are associated with higher rates of parasite growth in vivo. P. falciparum-mediated induction of regulatory T cells may represent a parasite-specific virulence factor.     

Linear performance characteristics of latissimus dorsi muscle: potential for cardiac assistance

Knowledge of the quantitative performance capabilities of skeletal muscle in a linear geometry is necessary to predict the performance and to optimize the design of linearly configured, skeletal muscle powered cardiac assist devices (MCADs). This study determined the performance characteristics of goat latissimus dorsi muscle (LDM) using a linear, ex vivo experimental apparatus. In five goats, the LDM (130.6 +/- 18.8 g) was dissected free of its distal attachments, connected to a series of weights (500 to 2250 g), and maximal tetanic contractions were elicited via thoracodorsal nerve stimulation. Second order polynomial equations were derived to represent each of the following variables versus load: muscle prestretch (range 1.5 to 5.4 cm), contraction duration (220 to 360 milliseconds), contraction shortening distance (13.5 to 10.9 cm), contraction velocity (60 to 31 cm/s), generated stroke power (3 to 7 W), and stroke work (0.7 to 2.4 J). Analysis of the potential stroke volumes obtained with a linearly configured, cylindrically shaped MCAD directly coupled to the circulation indicate that a feasible MCAD operating region exists based on the LDM performance data across a range of device geometries and mean ejection pressures.     

Evaluation of the professional practices of physicians in transfusion technology and medicine]

The evaluation of the professional practices (EPP) is obligatory for all the physicians since July 1, 2005 for a first five-year period. It represents one of the components of the continuous medical training (CMT). The French Society of Blood Transfusion and National Institute of Blood Transfusion are the promoters of the EPP in transfusion technology and medicine. Initially, the programs of EPP will be conceived and controlled by experts and will relate to their basic activities. During a five years cycle, the physician taking part in a program must validate a specific action and take part in a rolling programme. At the end of the programme, the physician will receive a certificate issued by National Institute of Blood Transfusion and will have to submit it to a committee placed under the responsibility of the regional physicians' committee.