Faculty Bibliography

Cochleates are a novel lipid-based delivery vehicle consisting of crystalline phospholipid-cation structures that form spiral lipid sheets. They represent a new technology platform for oral delivery of clinically important drugs that possess poor oral bioavailability. Orally administered cochleates containing amphotericin B (CAMB) showed broad-spectrum activity in murine infection models of candidiasis, aspergillosis and cryptococcosis. Initial biodistribution studies of CAMB administered orally in mice demonstrated that cochleates delivered significant levels of AMB to target organs. The lipid particulate nature of cochleates also imparted reduced toxicity that mimics other lipid-amphotericin B complexes. Cochleates are a promising new vehicle for oral delivery of amphotericin B at therapeutic levels.

Members of the EGF-CFC family play essential roles in embryonic development and have been implicated in tumorigenesis. The TGFbeta signals Nodal and Vg1/GDF1, but not Activin, require EGF-CFC coreceptors to activate Activin receptors. We report that the TGFbeta signaling antagonist Lefty also acts through an EGF-CFC-dependent mechanism. Lefty inhibits Nodal and Vg1 signaling, but not Activin signaling. Lefty genetically interacts with EGF-CFC proteins and competes with Nodal for binding to these coreceptors. Chimeras between Activin and Nodal or Vg1 identify a 14 amino acid region that confers independence from EGF-CFC coreceptors and resistance to Lefty. These results indicate that coreceptors are targets for both TGFbeta agonists and antagonists and suggest that subtle sequence variations in TGFbeta signals result in greater ligand diversity

Recent preliminary data suggest that vaccination with Alzheimer's Abeta might reduce senile plaque load and stabilize cognitive decline in human Alzheimer's disease. To examine the mechanisms and consequences of anti-Abeta-antibody formation in a species more closely related to humans, rhesus monkeys (Macaca mulatta) were vaccinated with aggregated Abeta(1-42). Immunized monkeys developed anti-Abeta titers exceeding 1:1000, and their plasma Abeta levels were 5-10-fold higher than the plasma Abeta levels observed in monkeys vaccinated with aggregated amylin. These data support the use of non-human primates to model certain phenomena associated with vaccination of humans with aggregated Alzheimer's Abeta

Infantile systemic hyaloinosis is a rare, progressive, and fatal disease that is inherited in an autosomal recessive fashion. We describe 2 patients in whom thickened skin; small nodules of the perianal region, face, and neck; joint contractures; growth failure; diarrhea; and frequent infections developed within the first few weeks of life. Both patients died before 2 years of age

The present study was designed to examine the effects of overheating on meiotic spindle morphology within in vitro matured human oocytes using a polarized light microscope (Polscope). Immature human oocytes at either germinal vesicle or metaphase I stage were cultured in vitro for 24-36 h until they reached metaphase II (M-II) stage. After maturation, oocytes at M-II stage were imaged in the living state with the Polscope at 37, 38, 39 and 40 degrees C for up to 20 min. After heating, oocytes were returned to 37 degrees C and then imaged for another 20 min at 37 degrees C. The microtubules in the spindles were quantified by their maximum retardance, which represents the amount of microtubules. Spindles were intact at 37 degrees C during 40 min of examination and their maximum retardance (1.72-1.79) did not change significantly during imaging. More microtubules were formed in the spindles heated to 38 degrees C and the maximum retardance was increased from 1.77 before heating to 1.95 at 20 min after heating. By contrast, spindles started to disassemble when the temperature was increased to 39 degrees C for 10 min (maximum retardance was reduced from 1.76 to 1.65) or 40 degrees C for 1 min (maximum retardance was reduced from 1.75 to 1.5). At the end of heating (20 min), fewer microtubules were present in the spindles and the maximum retardance was reduced to 0.8 and 0.78 in the oocytes heated to 39 degrees C and 40 degrees C, respectively. Heating to 40 degrees C also induced spindles to relocate in the cytoplasm in some oocytes. After the temperature was returned to 37 degrees C, microtubules were repolymerized to form spindles, but the spindles were not reconstituted completely compared with the spindles imaged before heating. These results indicate that spindles in human eggs are sensitive to high temperature. Moreover, maintenance of an in vitro manipulation temperature of 37 degrees C is crucial for normal spindle morphology

RNA interference provides a new approach for elucidation of gene function. It holds the advantages of quickness, convenience, high effect and high specificity. In spite of these, the application of RNA interference technique in studying the mammalian cells and human disease is still in the beginning. In this paper, a review of the development of RNA interference in mammalian cells and human disease is presented

Successful cell migration depends on the careful regulation of the timing of movement, the guidance of motile cells, and cytoskeletal and adhesive changes within the cells. This review focuses on genes that act cell-autonomously to promote these aspects of cell migration in Drosophila. We discuss recent advances in understanding the migration of the ovarian border cells, embryonic blood cells, primordial germ cells, somatic gonadal precursors, and tracheal cells. Comparison of genes that regulate these processes to those that promote tumorigenesis and metastasis in mammals demonstrates that studies in fruit flies are uncovering new genes highly relevant to cancer biology.

Neutrophils provide an essential defense against bacterial and fungal infection and play a major role in tissue damage during inflammation. Using oligonucleotide microarrays, we have examined the time course of changes in gene expression induced by stimulation with live, opsonized Escherichia coli, soluble lipopolysaccharide, and the chemoattractant formyl-methionyl-leucyl-phenylalanine. The results indicate that activated neutrophils generate a broad and vigorous set of alterations in gene expression. The responses included changes in the levels of transcripts encoding 148 transcription factors and chromatin-remodeling genes and 95 regulators of protein synthesis or stability. Clustering analysis showed distinct temporal patterns with many rapid changes in gene expression within the first hour of exposure. In addition to the temporal clustering of genes, we also observed rather different profiles associated with each stimulus, suggesting that even a nonvirulent organism such as E. coli is able to play a dynamic role in shaping the inflammatory response. Principal component analysis of transcription factor genes demonstrated clear separation of the neutrophil-response clusters from those of resting and stimulated human monocytes. The present study indicates that combinatorial transcriptional regulation including alterations of chromatin structure may play a role in the rapid changes in gene expression that occur in these terminally differentiated cells

Atopic diseases are characterized by Th2 and IgE responses to common environmental and food antigens. In vivo, IgE production depends on interactions between allergen-specific B lymphocytes and Th2 lymphocytes. IgE levels are extremely low in normal individuals, suggesting that IgE production is under strong regulation. One of the reasons behind the lack of atopy in healthy individuals is the activity of regulatory T cells, which prevent naive T helper cell precursors from acquiring a differentiated Th2 phenotype. In addition to naturally occurring regulatory T cells, atopy can be prevented by allergen-specific tolerant/regulatory cells induced through mucosal stimulation, and by mechanisms that directly suppress Iepsilon sterile transcript production on activated B lymphocytes. This article reviews the recent progress on thymic-derived as well as peripherally induced regulatory T cells as they relate to atopy. The latter discussion also includes regulatory T cells that arise through immunotherapy