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1.  Comparative mapping in the Fagaceae and beyond with EST-SSRs 
BMC Plant Biology  2012;12:153.
Genetic markers and linkage mapping are basic prerequisites for comparative genetic analyses, QTL detection and map-based cloning. A large number of mapping populations have been developed for oak, but few gene-based markers are available for constructing integrated genetic linkage maps and comparing gene order and QTL location across related species.
We developed a set of 573 expressed sequence tag-derived simple sequence repeats (EST-SSRs) and located 397 markers (EST-SSRs and genomic SSRs) on the 12 oak chromosomes (2n = 2x = 24) on the basis of Mendelian segregation patterns in 5 full-sib mapping pedigrees of two species: Quercus robur (pedunculate oak) and Quercus petraea (sessile oak). Consensus maps for the two species were constructed and aligned. They showed a high degree of macrosynteny between these two sympatric European oaks. We assessed the transferability of EST-SSRs to other Fagaceae genera and a subset of these markers was mapped in Castanea sativa, the European chestnut. Reasonably high levels of macrosynteny were observed between oak and chestnut. We also obtained diversity statistics for a subset of EST-SSRs, to support further population genetic analyses with gene-based markers. Finally, based on the orthologous relationships between the oak, Arabidopsis, grape, poplar, Medicago, and soybean genomes and the paralogous relationships between the 12 oak chromosomes, we propose an evolutionary scenario of the 12 oak chromosomes from the eudicot ancestral karyotype.
This study provides map locations for a large set of EST-SSRs in two oak species of recognized biological importance in natural ecosystems. This first step toward the construction of a gene-based linkage map will facilitate the assignment of future genome scaffolds to pseudo-chromosomes. This study also provides an indication of the potential utility of new gene-based markers for population genetics and comparative mapping within and beyond the Fagaceae.
PMCID: PMC3493355  PMID: 22931513
2.  Family physicians’ completion of scoring criteria in virtual patient encounters 
AMIA Annual Symposium Proceedings  2011;2011:1355-1360.
The American Board of Family Medicine (ABFM) has used a 60-item Multiple Choice Question (MCQ) section followed by a Virtual Patient (VP) exercise in Maintenance Of Certification (MOC) since 2004, and has had an asthma module since 2005. The original asthma VP criteria anticipated some Expert Panel Report-3 recommendations, such as home peak flow monitoring and a written plan, that were added to the MCQ section only when the guideline was updated in 2007. VP completion rates for these criteria improved markedly with the MCQ update, while other criteria completion rates were stable. Asthma criteria completion rates are not predicted by the strength of evidence for the criteria. User interface details influence criteria completion rates, but did not affect the changes observed in 2007. Asthma MCQ content affects Diplomate performance on asthma VP: this translational step suggests that MOC exercises could result in improved care for real patients.
PMCID: PMC3243160  PMID: 22195197
3.  Neuropilin-2 acts as a modulator of Sema3A-dependent glioma cell migration 
Cell Adhesion & Migration  2009;3(4):383-389.
Semaphorin 3A (Sema3A) is a secreted guidance molecule initially described in the nervous system. This protein is able to control axon growth but also effects on endothelial cells migration. Here, we report that Sema3A acts as a chemorepellent factor for the rat C6 glioma cells and three different human glioma cell lines. Interestingly, Sema3A triggered a chemoattractive response in a fourth human glioma cell line. The nature of the receptor complex ensuring the appropriate signaling was dissected in C6 cells by using function blocking antibodies and gain- or loss-of function experiments using recombinant receptors. Our results demonstrate that neuropilin-1, neuropilin-2 and PlexinA1 are necessary to trigger cell repulsion. The selective blockade of neuropilin-1 or Plexin-A1 switched the chemorepulsive effect of Sema3A into a chemoattractive one. Strikingly, blocking Neuropilin-2 suppressed Sema3A-induced cell migration while overexpression of neuropilin-2 was able to convert the chemorepulsive effect of Sema3A into a chemoattractive one. Our results not only provide additional evidence for a biological function of Sema3A in glioma migration but also reveal part of the receptor complex involved. Hence, our study describes a receptor-based plasticity in cancer cells leading to opposite migration behavior in response to the same extracellular signal.
PMCID: PMC2802752  PMID: 19855168
semaphorin; neuropilin; glioma; cell migration; signalling; cancer
4.  A PKC-Dependent Recruitment of MMP-2 Controls Semaphorin-3A Growth-Promoting Effect in Cortical Dendrites 
PLoS ONE  2009;4(4):e5099.
There is increasing evidence for a crucial role of proteases and metalloproteinases during axon growth and guidance. In this context, we recently described a functional link between the chemoattractive Sema3C and Matrix metalloproteinase 3 (MMP3). Here, we provide data demonstrating the involvement of MMP-2 to trigger the growth-promoting effect of Sema3A in cortical dendrites. The in situ analysis of MMP-2 expression and activity is consistent with a functional growth assay demonstrating in vitro that the pharmacological inhibition of MMP-2 reduces the growth of cortical dendrites in response to Sema3A. Hence, our results suggest that the selective recruitment and activation of MMP-2 in response to Sema3A requires a PKC alpha dependent mechanism. Altogether, we provide a second set of data supporting MMPs as effectors of the growth-promoting effects of semaphorins, and we identify the potential signalling pathway involved.
PMCID: PMC2663036  PMID: 19352510
5.  Endogenous Morphine in SH-SY5Y Cells and the Mouse Cerebellum 
PLoS ONE  2008;3(2):e1641.
Morphine, the principal active agent in opium, is not restricted to plants, but is also present in different animal tissues and cell types, including the mammalian brain. In fact, its biosynthetic pathway has been elucidated in a human neural cell line. These data suggest a role for morphine in brain physiology (e.g., neurotransmission), but this hypothesis remains a matter of debate. Recently, using the adrenal neuroendocrine chromaffin cell model, we have shown the presence of morphine-6-glucuronide (M6G) in secretory granules and their secretion products, leading us to propose that these endogenous alkaloids might represent new neuroendocrine factors. Here, we investigate the potential function of endogenous alkaloids in the central nervous system.
Methodology and Principal Findings
Microscopy, molecular biology, electrophysiology, and proteomic tools were applied to human neuroblastoma SH-SY5Y cells (i) to characterize morphine and M6G, and (ii) to demonstrate the presence of the UDP-glucuronyltransferase 2B7 enzyme, which is responsible for the formation of M6G from morphine. We show that morphine is secreted in response to nicotine stimulation via a Ca2+-dependent mechanism involving specific storage and release mechanisms. We also show that morphine and M6G at concentrations as low as 10−10 M are able to evoke specific naloxone-reversible membrane currents, indicating possible autocrine/paracrine regulation in SH-SY5Y cells. Microscopy and proteomic approaches were employed to detect and quantify endogenous morphine in the mouse brain. Morphine is present in the hippocampus, cortex, olfactory bulb, and cerebellum at concentration ranging from 1.45 to 7.5 pmol/g. In the cerebellum, morphine immunoreactivity is localized to GABA basket cells and their termini, which form close contacts on Purkinje cell bodies.
The presence of morphine in the brain and its localization in particular areas lead us to conclude that it has a specific function in neuromodulation and/or neurotransmission. Furthermore, its presence in cerebellar basket cell termini suggests that morphine has signaling functions in Purkinje cells that remain to be discovered.
PMCID: PMC2265639  PMID: 18327293
6.  Modeling Relief 
The American Board of Family Medicine deployed virtual patient simulations in 2004 to evaluate Diplomates’ diagnostic and management skills. A previously reported dynamic process generates general symptom histories from time series data representing baseline values and reactions to medications. The simulator also must answer queries about details such as palliation and provocation. These responses often describe some recurring pattern, such as, “this medicine relieves my symptoms in a few minutes.” The simulator can provide a detail stored as text, or it can evaluate a reference to a second query object. The second query object can generate details using a single Bayesian network to evaluate the effect of each drug in a virtual patient’s medication list. A new medication option may not require redesign of the second query object if its implementation is consistent with related drugs. We expect this mechanism to maintain realistic responses to detail questions in complex simulations.
PMCID: PMC2655778  PMID: 18693928
7.  Myelin/oligodendrocyte glycoprotein–deficient (MOG-deficient) mice reveal lack of immune tolerance to MOG in wild-type mice 
Journal of Clinical Investigation  2003;112(4):544-553.
We studied the immunological basis for the very potent encephalitogenicity of myelin/oligodendrocyte glycoprotein (MOG), a minor component of myelin in the CNS that is widely used to induce experimental autoimmune encephalomyelitis (EAE). For this purpose, we generated a mutant mouse lacking a functional mog gene. This MOG-deficient mouse presents no clinical or histological abnormalities, permitting us to directly assess the role of MOG as a target autoantigen in EAE. In contrast to WT mice, which developed severe EAE following immunization with whole myelin, MOG-deficient mice had a mild phenotype, demonstrating that the anti-MOG response is a major pathogenic component of the autoimmune response directed against myelin. Moreover, while MOG transcripts are expressed in lymphoid organs in minute amounts, both MOG-deficient and WT mice show similar T and B cell responses against the extracellular domain of MOG, including the immunodominant MOG 35–55 T cell epitope. Furthermore, no differences in the fine specificity of the T cell responses to overlapping peptides covering the complete mouse MOG sequence were observed between MOG+/+ and MOG–/– mice. In addition, upon adoptive transfer, MOG-specific T cells from WT mice and those from MOG-deficient mice are equally pathogenic. This total lack of immune tolerance to MOG in WT C57BL/6 mice may be responsible for the high pathogenicity of the anti-MOG immune response as well as the high susceptibility of most animal strains to MOG-induced EAE.
PMCID: PMC171383  PMID: 12925695
8.  A Modular Coding Engine Based on the National Library of Medicine's Knowledge Source Server 
This project involved the construction of a multitiered modular application for querying clinical vocabularies using local databases and the UMLS Knowledge Source Server (KSS), and the development of a mechanism for evaluating the contribution of remote access to the KSS.
PMCID: PMC2232281

Results 1-8 (8)