Patterns of Pathogenesis: Discrimination of Pathogenic and Nonpathogenic Microbes by the Innate Immune System

The dominant conceptual framework for understanding innate immunity has been that host cells respond to evolutionarily conserved molecular features of pathogens called pathogen-associated molecular patterns (PAMPs). Here, we propose that PAMPs should be understood in the context of how they are naturally presented by pathogens. This can be experimentally challenging, since pathogens, almost by definition, bypass host defense. Nevertheless, in this review, we explore the idea that the immune system responds to PAMPs in the context of additional signals that derive from common “patterns of pathogenesis” employed by pathogens to infect, multiply within, and spread among their hosts

Null Branes in Curved Backgrounds

We consider null bosonic p-branes in curved space-times. Some exact solutions of the classical equations of motion and of the constraints for the null membrane in general stationary, axially symmetrical, four dimensional, gravity background are found.Comment: 19 pages, LaTeX, no figures. Extended version. To appear in Phys. Rev.

Prospectus, November 3, 1999

https://spark.parkland.edu/prospectus_1999/1028/thumbnail.jp

Prospectus, February 16, 2000

https://spark.parkland.edu/prospectus_2000/1005/thumbnail.jp

Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-ht2 receptors

Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT(2) receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9–11, and describe their synthetic routes. Ligand docking in the 5-HT(2B) crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9–11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT(2A) subtype, for which 9–11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT(2) receptor subtype-selective ligands

Prospectus, November 17, 1999

https://spark.parkland.edu/prospectus_1999/1030/thumbnail.jp

Prospectus, February 23, 2000

https://spark.parkland.edu/prospectus_2000/1006/thumbnail.jp

Tree-Level Unitarity Constraints on the Gravitational Couplings of Higher-Spin Massive Fields

We analyse the high-energy behavior of tree-level graviton Compton amplitudes for particles of mass m and arbitrary spin, concentrating on a combination of forward amplitudes that will be unaffected by eventual cross- couplings to other, higher spins. We first show that for any spin larger than 2, tree-level unitarity is already violated at energies well below the Planck scale M, if m << M. We then restore unitarity to this amplitude up to M by adding non-minimal couplings that depend on the curvature and its derivatives, and modify the minimal description - including particle gravitational quadrupole moments - at scales O(1/m).Comment: 12 pages (Latex file, needs FEYNMAN macros), IASSNS-HEP-94/63, NYU-TH-94/05/01, CERN-TH.7388/9

Hemophagocytic Macrophages Harbor Salmonella enterica during Persistent Infection

Salmonella enterica subspecies can establish persistent, systemic infections in mammals, including human typhoid fever. Persistent S. enterica disease is characterized by an initial acute infection that develops into an asymptomatic chronic infection. During both the acute and persistent stages, the bacteria generally reside within professional phagocytes, usually macrophages. It is unclear how salmonellae can survive within macrophages, cells that evolved, in part, to destroy pathogens. Evidence is presented that during the establishment of persistent murine infection, macrophages that contain S. enterica serotype Typhimurium are hemophagocytic. Hemophagocytic macrophages are characterized by the ingestion of non-apoptotic cells of the hematopoietic lineage and are a clinical marker of typhoid fever as well as certain other infectious and genetic diseases. Cell culture assays were developed to evaluate bacterial survival in hemophagocytic macrophages. S. Typhimurium preferentially replicated in macrophages that pre-phagocytosed viable cells, but the bacteria were killed in macrophages that pre-phagocytosed beads or dead cells. These data suggest that during persistent infection hemophagocytic macrophages may provide S. Typhimurium with a survival niche

Prospectus, October 27, 1999

https://spark.parkland.edu/prospectus_1999/1027/thumbnail.jp