The mathematical theory of group selection. I. Full solution of a nonlinear Levins E = E(x) model

The first complete overtime solution is obtained for a group selection model of Levins E = E(x) type with recolonization but no other gene flow between islands. Assuming a subdivided population at carrying capacity, the model describes selection at a biallelic locus (A, a) where a is opposed by Mendelian selection but is favored by a lower rate of extinction of demes having high a frequency. By contrast to the linear diffusion equations encountered in classical mathematical genetics, the PDE governing the dynamics is now nonlinear in the metapopulation gene frequency distribution φ(x, t); furthermore, the initial conditions now heavily influence the equilibrium distribution φ_∞(x). A fully explicit formula (20) expressing this dependence is derived. The results indicate that a fixation is never reached, but (A, a) polymorphism in the metapopulation will result if , where s 1 parametrizes the strength of Mendelian selection, E(x) is the Levins extinction operator, h (typically in the open interval (0, 1)) is the dominance of a, and B is a parameter measuring the flatness of the initial distribution f(x) in the x → 1 limit.     

Chlamydia trachomatis (L2 serovar) can be bound, ingested and destroyed by differentiated but not by undifferentiated human promyelocyte cell line HL-60

As a model system for analysing interactions between chlamydiae and myeloid cells and their precursors, we have studied binding, ingestion and destruction of Chlamydia trachomatis (L2 serovar) by the human promyelocytic cell line HL-60. HL-60 cells were induced by phorbol myristate acetate (PMA) and dimethyl sulphoxide (DMSO) to differentiate along either the macrophage or the granulocyte pathway, respectively. Using an immunofluorescence assay and electron microscopy, we have shown that induced (differentiated) HL-60 cells, but not uninduced (undifferentiated) HL-60 or other cell lines treated with PMA or DMSO, exhibit increased binding, ingestion and elimination of C. trachomatis; these activities are associated with specific histochemical and antigenic markers of myeloid differentiation. These results suggest that myeloid cells acquire the ability to interact with and kill chlamydiae during cell development.     

Combining efficient conformational sampling with a deformable elastic network model facilitates structure refinement at low resolution

Structural studies of large proteins and protein assemblies are a difficult and pressing challenge in molecular biology. Experiments often yield only low-resolution or sparse data that are not sufficient to fully determine atomistic structures. We have developed a general geometry-based algorithm that efficiently samples conformational space under constraints imposed by low-resolution density maps obtained from electron microscopy or X-ray crystallography experiments. A deformable elastic network (DEN) is used to restrain the sampling to prior knowledge of an approximate structure. The DEN restraints dramatically reduce over-fitting, especially at low resolution. Cross-validation is used to optimally weight the structural information and experimental data. Our algorithm is robust even for noise-added density maps and has a large radius of convergence for our test case. The DEN restraints can also be used to enhance reciprocal space simulated annealing refinement.     

Physiology of sulfide in the rat colon: use of bismuth to assess colonic sulfide production.

Colonic bacteria produce hydrogen sulfide, a toxic compound postulated to play a pathogenetic role in ulcerative colitis. Colonic sulfide exposure has previously been assessed via measurements of fecal sulfide concentration. However, we found that <1% of fecal sulfide of rats was free, the remainder being bound in soluble and insoluble complexes. Thus fecal sulfide concentrations may reflect sulfide binding capacity rather than the toxic potential of feces. We utilized bismuth subnitrate to quantitate intracolonic sulfide release based on observations that bismuth 1) avidly binds sulfide; 2) quantitatively releases bound sulfide when acidified; and 3) does not influence fecal sulfide production by fecal homogenates. Rats ingesting bismuth subnitrate excreted 350 +/- 18 micromol/day of fecal sulfide compared with 9 +/- 1 micromol/day in control rats. Thus the colon normally absorbs approximately 340 micromol of sulfide daily, a quantity that would produce local and systemic injury if not efficiently detoxified by the colonic mucosa. Studies utilizing bismuth should help to clarify the factors influencing sulfide production in the human colon.     

Isolation and partial characterization of endothelial cell extracellular complexes

Human endothelial cells release components into the growth medium that stimulate cell-substratum adhesion. Several macromolecular components were isolated by ultracentrifugation of the endothelial cell conditioned medium. The components were heterogeneous, consisting of several sizes when examined by sedimentation velocity and gel filtration. When the extracellular components were evaluated by electron microscopy, structurally discrete particles were observed. The extracellular components and the complexes mediated cell-substratum adhesion to both human umbilical and arterial endothelial cells. The majority of the extracellular components that promote endothelial cell adhesion were pelleted by ultracentrifugation. Although the complexes contained fibronectin, antibodies to fibronectin did not inhibit cell adhesion to the complexes. Significant inhibition of endothelial cell adhesion was observed in the presence of heparin and heparan sulfate. The supernatant fraction following ultracentrifugation of the growth medium contained a component that suppressed endothelial cell adhesion to culture dishes coated with fibronectin, type I collagen, and endothelial cell complexes. SDS-polyacrylamide gel electrophoresis indicated that the complexes contained several components, and the majority of the large-molecular-weight components were pelleted by ultracentrifugation. The conditioned medium from human endothelial cells contains specific complexes that promote cell-substratum adhesion and components that suppress cell-substratum adhesion.