Zebrafish SPI-1 marks a site of myeloid development independent of primitive erythropoiesis: implications for axial patterning.

The mammalian transcription factor SPI-1 (synonyms: SPI1, PU.1, or Sfpi1) plays a critical role in myeloid development. To examine early myeloid commitment in the zebrafish embryo, we isolated a gene from zebrafish that is a SPI-1 orthologue on the basis of homology and phylogenetic considerations. The zebrafish spi1 (pu1) gene was first expressed at 12 h postfertilization in rostral lateral plate mesoderm (LPM), anatomically isolated from erythroid development in caudal lateral plate mesoderm. Fate-mapping traced rostral LPM cells from the region of initial spi1 expression to a myeloid fate. spi1 expression was lost in the bloodless mutant cloche, but rostral spi1 expression and myeloid development were preserved in the mutant spadetail, despite its complete erythropoietic failure. This dissociation of myeloid and erythroid development was further explored in studies of embryos overexpressing BMP-4, or chordin, in bmp-deficient swirl and snailhouse mutants, and chordin-deficient chordino mutants. These studies demonstrate that, in zebrafish, spi1 marks a rostral population of LPM cells committed to a myeloid fate anatomically separated from and developmentally independent of erythroid commitment in the caudal LPM. Such complete anatomical and developmental dissociation of two hematopoietic lineages adds an interesting complexity to the understanding of vertebrate hematopoietic development and presents significant implications for the mechanisms regulating axial patterning

Modeling the Impact of Tuberculosis Control Strategies in Highly Endemic Overcrowded Prisons

International audienceBACKGROUND: Tuberculosis (TB) in prisons is a major health problem in countries of high and intermediate TB endemicity such as Brazil. For operational reasons, TB control strategies in prisons cannot be compared through population based intervention studies. METHODOLOGY/PRINCIPAL FINDINGS: A mathematical model is proposed to simulate the TB dynamics in prison and evaluate the potential impact on active TB prevalence of several intervention strategies. The TB dynamics with the ongoing program was simulated over a 10 year period in a Rio de Janeiro prison (TB prevalence 4.6 %). Then, a simulation of the DOTS strategy reaching the objective of 70 % of bacteriologically-positive cases detected and 85 % of detected cases cured was performed; this strategy reduced only to 2.8% the average predicted TB prevalence after 5 years. Adding TB detection at entry point to DOTS strategy had no major effect on the predicted active TB prevalence. But, adding further a yearly X-ray mass screening of inmates reduced the predicted active TB prevalence below 1%. Furthermore, according to this model, after applying this strategy during 2 years (three annual screenings), the TB burden would be reduced and the active TB prevalence could be kept at a low level by associating X-ray screening at entry point and DOTS. CONCLUSIONS/SIGNIFICANCE: We have shown that X-ray mass screenings should be considered to control TB in highly endemic prison. Prisons with different levels of TB prevalence could be examined thanks to this model which provides a rational tool for public health deciders

Mediator Subunit 12 Is Required for Neutrophil Development in Zebrafish

Hematopoiesis requires the spatiotemporal organization of regulatory factors to successfully orchestrate diverse lineage specificity from stem and progenitor cells. Med12 is a regulatory component of the large Mediator complex that enables contact between the general RNA polymerase II transcriptional machinery and enhancer bound regulatory factors. We have identified a new zebrafish med12 allele, syr, with a single missense mutation causing a valine to aspartic acid change at position 1046. Syr shows defects in hematopoiesis, which predominantly affect the myeloid lineage. Syr has identified a hematopoietic cell-specific requirement for Med12, suggesting a new role for this transcriptional regulator

Antigen-induced aggregation and modulation of receptors on hapten-specific B lymphocytes

Since the discovery of the high density of immunoglobulin (Ig) present at the surface of mouse B lymphocytes (1), the changes in the distribution of these Ig receptors after attachment of divalent antiglobulin have been extensively studied (2-4). The formation by metabolism-independent diffusion of receptor patches, and the subsequent metabolism-dependent emergence of a "cap " of aggregated receptors over one pole of the cell is well known. In contrast, there have been few studies of a parallel nature on the movement of B-lymphocyte receptors induced by specific antigens. This is because only a small minority of a random population of B lymphocytes react with a given antigen, and thus the investigator must search amongst many negative cells before finding suitable objects for study. It has been observed that polymeric antigens can, as expected, cap B-lymphocyte receptors (5-8); that immunogenic concentrations of antigen can be quickly eliminated (9) and can cause emergence of a denser receptor coat within about 6 h (5, 9); that tolerogenic antigens can cause failure of capping (5) or prolonged surface persistence of antigen (10); and that the totality of the surface Ig on a B lymphocyte can be brought into a cap by a given antigen (6, 8), suggesting homogeneity of the receptor population (6)

vitro model for natural tolerance to self-antigens. Inhibition of the development of surface-immunoglobulin-negative lymphocytes into T-dependent responsive B cells by antigen.J. Exp. Med

One explanation for natural tolerance to self-antigens is the clonal-deletion model proposed by Burnet (1), or the elimination of self-reactive lymphocytes upon contact with self-antigens. This was later expanded by Nossal (2) into the clonal abortion theory that states that as a lymphocyte acquires immunological competence, there is a particular differentiation stage at which contact with self-antigen results in elimination of potential self-reactive clones. The obvious prediction from this theory is that if one starts with an immunologically incompetent population of B lymphocytes, i.e., those lacking surface-immunoglobulin (s-Ig) 1 receptors, and allows them to mature in the presence of specific antigen, then the developing antigen-specific lymphocytes should be eliminated. Experiments designed to study tolerance induction using the T-dependent splenic focus assay, which examines tolerance at the level of the individual B cells without the complication of T-cell tolerance, have indicated that the developing B cell is highly susceptible to tolerance induction (3-5). This is consistent with the clonal abortion theory but with one important stipulation: that the developing B cell i

Antibodies which bind the G-CSF receptor extracelluar domain and methods of treatment

PCT No. PCT/US95/01696 Sec. 371 Date Jan. 21, 1997 Sec. 102(e) Date Jan. 21, 1997 PCT Filed Feb. 8, 1995 PCT Pub. No. WO95/21864 PCT Pub. Date Aug. 17, 1995The invention relates to a composition comprising antibodies or binding portions thereof which bind to a naturally occurring or recombinant G-CSF receptor extracellular domain, and reduce tyrosine phosphorylation of a JAK molecule. The invention also relates to methods of using this composition for inhibiting or decreasing tyrosine phosphorylation of a JAK kinase and for inhibiting or decreasing G-CSF interaction with its receptor. Also described are antibodies which bind to a G-CSF receptor extracellular domain and which are produced by immunizing an animal with cells transfected with DNA encoding a G-CSF receptor