Faculty Bibliography

Stem cells have the remarkable ability to give rise to both self-renewing and differentiating daughter cells. Drosophila neural stem cells segregate cell-fate determinants from the self-renewing cell to the differentiating daughter at each division. Here, we show that one such determinant, the homeodomain transcription factor Prospero, regulates the choice between stem cell self-renewal and differentiation. We have identified the in vivo targets of Prospero throughout the entire genome. We show that Prospero represses genes required for self-renewal, such as stem cell fate genes and cell-cycle genes. Surprisingly, Prospero is also required to activate genes for terminal differentiation. We further show that in the absence of Prospero, differentiating daughters revert to a stem cell-like fate: they express markers of self-renewal, exhibit increased proliferation, and fail to differentiate. These results define a blueprint for the transition from stem cell self-renewal to terminal differentiation.

PURPOSE: To review the anatomy and histopathologic changes of the human main lacrimal gland. METHODS: Samples of lacrimal gland including palpebral lobes and orbital lobes were taken in autopsies, and the relationship between histopathologic changes and age and sex, as well as histopathologic differences between palpebral and orbital lobes of the lacrimal gland, were studied using light microscopy. RESULTS: Various histopathologic changes were observed in the human main lacrimal gland as follows: acinar atrophy; periacinar fibrosis; periductal fibrosis; interlobular ductal dilatation; interlobular ductal proliferation; lymphocytic infiltration; and fatty infiltration. Several histopathologic differences exist between the palpebral and orbital lobes. There were statistically significant correlations between age and diffuse fibrosis, diffuse atrophy, and periductal fibrosis in the orbital lobes of women. Diffuse fibrosis and diffuse atrophy in orbital lobes were more frequently observed in women than in men. CONCLUSION: It is speculated that periductal fibrosis is related to a decrease of tear flow with age and that interlobular ductal dilatation in palpebral lobes may be caused by stenosis of the excretory duct in conjunctival fornix. However, the mechanisms of these histopathologic changes in the human main lacrimal gland are not yet clear.

It has been well established that the tumor microenvironment can promote tumor cell adaptation and survival. However, the mechanisms that influence malignant progression have not been clearly elucidated. We have previously demonstrated that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR). Here, we show that tumors derived from K-Ras-transformed Perk(-/-) mouse embryonic fibroblasts (MEFs) are smaller and exhibit less angiogenesis than tumors with an intact ISR. Furthermore, Perk promotes a tumor microenvironment that favors the formation of functional microvessels. These observations were corroborated by a microarray analysis of polysome-bound RNA in aerobic and hypoxic Perk(+/+) and Perk(-/-) MEFs. This analysis revealed that a subset of proangiogenic transcripts is preferentially translated in a Perk-dependent manner; these transcripts include VCIP, an adhesion molecule that promotes cellular adhesion, integrin binding, and capillary morphogenesis. Taken with the concomitant Perk-dependent translational induction of additional proangiogenic genes identified by our microarray analysis, this study suggests that Perk plays a role in tumor cell adaptation to hypoxic stress by regulating the translation of angiogenic factors necessary for the development of functional microvessels and further supports the contention that the Perk pathway could be an attractive target for novel antitumor modalities

This study compared the analgesic efficacy of postoperative lavender oil aromatherapy in 50 patients undergoing breast biopsy surgery. Twenty-five patients received supplemental oxygen through a face mask with two drops of 2% lavender oil postoperatively. The remainder of the patients received supplemental oxygen through a face mask with no lavender oil. Outcome variables included pain scores (a numeric rating scale from 0 to 10) at 5, 30, and 60 minutes postoperatively, narcotic requirements in the postanesthesia care unit (PACU), patient satisfaction with pain control, as well as time to discharge from the PACU. There were no significant differences in narcotic requirements and recovery room discharge times between the two groups. Postoperative lavender oil aromatherapy did not significantly affect pain scores. However, patients in the lavender group reported a higher satisfaction rate with pain control than patients in the control group (P = 0.0001)

With pharmacological treatment, the lifespan of the patient with sickle cell disease can be extended to the sixth decade. Currently the only curative therapy for sickle cell disease is hemopoietic cell transplantation, which is still undergoing technical refinement. Most patients can be expected to undergo at least one orthopedic surgical procedure in their lifetime. Multidisciplinary management of orthopedic patients with sickle cell disease will decrease the overall complication rates and improve clinical outcomes

Hemodynamic responses that control blood pressure and the distribution of blood flow to different organs are essential for survival. Shear forces generated by blood flow regulate hemodynamic responses, but the molecular and genetic basis for such regulation is not known. The transcription factor KLF2 is activated by fluid shear stress in cultured endothelial cells, where it regulates a large number of vasoactive endothelial genes. Here, we show that Klf2 expression during development mirrors the rise of fluid shear forces, and that endothelial loss of Klf2 results in lethal embryonic heart failure due to a high-cardiac-output state. Klf2 deficiency does not result in anemia or structural vascular defects, and it can be rescued by administration of phenylephrine, a catecholamine that raises vessel tone. These findings identify Klf2 as an essential hemodynamic regulator in vivo and suggest that hemodynamic regulation in response to fluid shear stress is required for cardiovascular development and function

Lipopolysaccharide (LPS) induces matrix degradation and markedly stimulates the production of several cytokines, i.e., interleukin-1beta, -6, and -10, by disc cells and chondrocytes. We performed a series of experiments to compare cellular responses of cells from the bovine intervertebral disc (nucleus pulposus and annulus fibrosus) and from bovine articular cartilage to LPS. Alginate beads containing cells isolated from bovine intervertebral discs and articular cartilage were cultured with or without LPS in the presence of 10% fetal bovine serum. The DNA content and the rate of proteoglycan synthesis and degradation were determined. In articular chondrocytes, LPS strongly suppressed cell proliferation and proteoglycan synthesis in a dose-dependent manner and stimulated proteoglycan degradation. Compared with articular chondrocytes, nucleus pulposus cells responded in a similar, although less pronounced manner. However, treatment of annulus fibrosus cells with LPS showed no significant effects on proteoglycan synthesis or degradation. A slight, but statistically significant, inhibition of cell proliferation was observed at high concentrations of LPS in annulus fibrosus cells. Thus, LPS suppressed proteoglycan synthesis and stimulated proteoglycan degradation by articular chondrocytes and nucleus pulposus cells. The effects of LPS on annulus fibrosus cells were minor compared with those on the other two cell types. The dissimilar effects of LPS on the various cell types suggest metabolic differences between these cells and may further indicate a divergence in pathways of LPS signaling and a differential sensitivity to exogenous stimuli such as LPS.

The transcription factor ATF4 enhances bone formation by favoring amino acid import and collagen synthesis in osteoblasts, a function requiring its phosphorylation by RSK2, the kinase inactivated in Coffin-Lowry Syndrome. Here, we show that in contrast, RSK2 activity, ATF4-dependent collagen synthesis, and bone formation are increased in mice lacking neurofibromin in osteoblasts (Nf1(ob)(-/-) mice). Independently of RSK2, ATF4 phosphorylation by PKA is enhanced in Nf1(ob)(-/-) mice, thereby increasing Rankl expression, osteoclast differentiation, and bone resorption. In agreement with ATF4 function in amino acid transport, a low-protein diet decreased bone protein synthesis and normalized bone formation and bone mass in Nf1(ob)(-/-) mice without affecting other organ weight, while a high-protein diet overcame Atf4(-/-) and Rsk2(-/-) mice developmental defects, perinatal lethality, and low bone mass. By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development

Mechanisms that regulate oligodendrocyte survival and myelin formation are an intense focus of research into myelin repair in the lesions of multiple sclerosis (MS). Although demyelination and oligodendrocyte loss are pathological hallmarks of the disease, increased oligodendrocyte numbers and remyelination are frequently observed in early lesions, but these diminish as the disease course progresses. In the current study, we used a microarray-based approach to investigate genes regulating repair in MS lesions, and identified interleukin-11 (IL-11) as an astrocyte-derived factor that potentiates oligodendrocyte survival and maturation, and myelin formation. IL-11 was induced in human astrocyte cultures by the cytokines IL-1beta and TGFbeta1, which are both prominently expressed in MS plaques. In MS tissue samples, IL-11 was expressed by reactive astrocytes, with expression particularly localized at the myelinated border of both active and silent lesions. Its receptor, IL-11R alpha, was expressed by oligodendrocytes. In experiments in human cultures in vitro, IL-11R alpha localized to immature oligodendrocytes, and its expression decreased during maturation. In cultures treated with IL-11, we observed a significant increase in oligodendrocyte number, and this was associated with enhanced oligodendrocyte survival and maturation. Importantly, we also found that IL-11 treatment was associated with significantly increased myelin formation in rodent CNS cocultures. These data are the first to implicate IL-11 in oligodendrocyte viability, maturation, and myelination. We suggest that this pathway may represent a potential therapeutic target for oligodendrocyte protection and remyelination in MS