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Identification of tissue-specific renal stem/progenitor cells with nephrogenic potential is a critical step in developing cell-based therapies for renal disease. In the human kidney, stem/progenitor cells are induced into the nephrogenic pathway to form nephrons until the 34 week of gestation, and no equivalent cell types can be traced in the adult kidney. Human nephron progenitor cells (hNPCs) have yet to be isolated. Here we show that growth of human foetal kidneys in serum-free defined conditions and prospective isolation of NCAM1+ cells selects for nephron lineage that includes the SIX2-positive cap mesenchyme cells identifying a mitotically active population with in vitro clonogenic and stem/progenitor properties. After transplantation in the chick embryo, these cells-but not differentiated counterparts-efficiently formed various nephron tubule types. hNPCs engrafted and integrated in diseased murine kidneys and treatment of renal failure in the 5/6 nephrectomy kidney injury model had beneficial effects on renal function halting disease progression. These findings constitute the first definition of an intrinsic nephron precursor population, with major potential for cell-based therapeutic strategies and modelling of kidney disease. [ABSTRACT FROM AUTHOR]

Motherhood is accompanied by alterations in numerous nonreproductive behaviors, including learning and memory, as well as anxiety and stress regulation. These functions have been linked to adult neurogenesis in the hippocampus, but the effect of maternal experience on this brain region has not been completely explored. To determine whether the production of new hippocampal granule cells is altered during the postpartum period, we examined the number of proliferating cells and their progeny in the dentate gyrus of primiparous female rats at various time points during the postpartum period while they were caring for their offspring, as well as after weaning. Additionally, we investigated whether cell proliferation in the postpartum female is affected by the presence of offspring and nursing-induced increases in glucocorticoids. Analysis of the number of BrdU-labeled cells revealed that cell proliferation in the dentate gyrus was suppressed in lactating postpartum females until the time of weaning. This effect was temporary; a difference was detectable at 1 week after BrdU-labeling, when the majority of cells expressed a marker of immature and mature granule neurons (TuJ1) but not at 2 weeks, when most cells expressed a marker of mature neurons (NeuN). The decrease in cell proliferation was dependent on elevated basal glucocorticoid levels associated with lactation; removal of nursing pups reduced basal corticosterone levels and prevented the decrease in the number of BrdU-labeled cells. Moreover, preventing increased basal corticosterone levels by means of adrenalectomy and low-dose corticosterone replacement eliminated the reduction in cell proliferation. These findings indicate that offspring interactions inhibit adult neurogenesis through changes in adrenal steroids, and further suggest a potential mechanism for alterations in hippocampal function during the postpartum period. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

G-protein coupled receptors (GPCRs) are a major group of drug targets for which only one x-ray structure is known (the nondrugable rhodopsin), limiting the application of structure-based drug discovery to GPCRs. In this paper we present the details of PREDICT, a new algorithmic approach for modeling the 3D structure of GPCRs without relying on homology to rhodopsin. PREDICT, which focuses on the transmembrane domain of GPCRs, starts from the primary sequence of the receptor, simultaneously optimizing multiple 'decoy' conformations of the protein in order to find its most stable structure, culminating in a virtual receptor-ligand complex. In this paper we present a comprehensive analysis of three PREDICT models for the dopamine D2, neurokinin NK1, and neuropeptide Y Y1 receptors. A shorter discussion of the CCR3 receptor model is also included. All models were found to be in good agreement with a large body of experimental data. The quality of the PREDICT models, at least for drug discovery purposes, was evaluated by their successful utilization in in-silico screening. Virtual screening using all three PREDICT models yielded enrichment factors 9-fold to 44-fold better than random screening. Namely, the PREDICT models can be used to identify active small-molecule ligands embedded in large compound libraries with an efficiency comparable to that obtained using crystal structures for non-GPCR targets. Proteins 2004. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

In an attempt to find a causative factor for the increased incidence of otitis media with effusion, a detailed study of 50 cases was conducted. This study included 50 cases of non-purulent otitis media with effusion requiring ventilating tubes without tonsilloadenoid pathology. A study of these cases revealed an interesting pattern which suggests that antihistamines and decongestants may be causative or precipitating factors in the etiology of otitis media with effusion. A pilot study on the effects of these drugs on mucociliary activity was conducted and revealed further evidence that antihistamines and decongestants interfere with normal mucociliary activity which probably is a factor in abnormal Eustachian tube physiology. [ABSTRACT FROM AUTHOR]