A Toggle-Switch and a Feed-Forward Loop Engage in the Control of the Drosophila Retinal Determination Gene Network

Dipterans show a striking range of eye sizes, shapes, and functional specializations. Their eye is of the compound type, the most frequent eye architecture in nature. The development of this compound eye has been most studied in Drosophila melanogaster. The early development of the Drosophila eye is under the control of a gene regulatory network of transcription factors and signaling molecules called the retinal determination gene network (RDGN). Nodes in this network have been found to be involved not only in the development of different eye types in invertebrates and vertebrates, but also of other organs. Here we have analyzed the network properties in detail. First, we have generated quantitative expression profiles for a number of the key RDGN transcription factors, at a single-cell resolution. With these profiles, and applying a correlation analysis, we revisited several of the links in the RDGN. Our study uncovers a new link, that we confirm experimentally, between the transcription factors Hth/Meis1 and Optix/Six3 and indicates that, at least during the period of eye differentiation, positive feedback regulation from Eya and Dac on the Pax6 gene Ey is not operating. From this revised RDGN we derive a simplified gene network that we model mathematically. This network integrates three basic motifs: a coherent feedforward loop, a toggle-switch and a positive autoregulation which, together with the input from the Dpp/BMP2 signaling molecule, recapitulate the gene expression profiles obtained experimentally, while ensuring a robust transition from progenitor cells into retinal precursors.MINECOFEDER (BFU2012-34324, BFU2015-66040-P)Agencia Estatal de Investigacion (AEI) of Spai

A toggle-switch and a feed-forward loop engage in the control of the Drosophila retinal determination gene network

© 2019 Sánchez-Aragón, Cantisán-Gómez, Luque, Brás-Pereira, Lopes, Lemos and CasaresDipterans show a striking range of eye sizes, shapes, and functional specializations. Their eye is of the compound type, the most frequent eye architecture in nature. The development of this compound eye has been most studied in Drosophila melanogaster. The early development of the Drosophila eye is under the control of a gene regulatory network of transcription factors and signaling molecules called the retinal determination gene network (RDGN). Nodes in this network have been found to be involved not only in the development of different eye types in invertebrates and vertebrates, but also of other organs. Here we have analyzed the network properties in detail. First, we have generated quantitative expression profiles for a number of the key RDGN transcription factors, at a single-cell resolution. With these profiles, and applying a correlation analysis, we revisited several of the links in the RDGN. Our study uncovers a new link, that we confirm experimentally, between the transcription factors Hth/Meis1 and Optix/Six3 and indicates that, at least during the period of eye differentiation, positive feedback regulation from Eya and Dac on the Pax6 gene Ey is not operating. From this revised RDGN we derive a simplified gene network that we model mathematically. This network integrates three basic motifs: a coherent feedforward loop, a toggle-switch and a positive autoregulation which, together with the input from the Dpp/BMP2 signaling molecule, recapitulate the gene expression profiles obtained experimentally, while ensuring a robust transition from progenitor cells into retinal precursors.This work was funded by MINECO and the Agencia Estatal de Investigacion (AEI) of Spain, co-financed by FEDER funds (EU) through grants BFU2012-34324 and BFU2015-66040-P to FC, MDM-2016-0687 in which FC is participant researcher, and TIN2017-89842 P in which MCL is participant researcher

Evaluación preliminar de una versión pictórica y abreviada del Free and Cued Selective Reminding Test.

A picture version of the Free and Cued Selective Reminding Test (FCSRT) would assist in the assessment of memory function in patients with low levels of schooling. A shortened version would improve the test's applicability. To analyse the diagnostic usefulness of a shortened picture version of the FCSRT for distinguishing patients with amnestic mild cognitive impairment (aMCI) from controls, without excluding participants with a low level of schooling. Phase I study of a diagnostic evaluation (convenience sampling; pre-test prevalence 50%). A blinded researcher independently administered the FCSRT to 30 patients with aMCI and 30 controls matched for age, sex, level of schooling and literacy, using images and omitting the usual 30-minute delayed recall item. Three variables were recorded: free recall, total recall, and cue efficiency. Diagnostic accuracy was calculated using receiver operating characteristic curves and the area under the curve. The Youden index was used to identify optimal cut-off points. Of all participants, 41.7% had not completed primary education. There were no differences between groups as regards sociodemographic variables. Area under the curve was excellent for free recall (0.99), total recall (0.95), and cue efficiecy (0.93). The optimal cut-off points were 21/22, 43/44, and This preliminary analysis shows that a shortened picture version of the FCSRT may be useful and applicable for the diagnosis of aMCI without excluding individuals with a low level of schooling

Regular monitoring of cytomegalovirus-specific cell-mediated immunity in intermediate-risk kidney transplant recipients: predictive value of the immediate post-transplant assessment.

Previous studies on monitoring of post-transplant cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) are limited by single-centre designs and disparate risk categories. We aimed to assess the clinical value of a regular monitoring strategy in a large multicentre cohort of intermediate-risk kidney transplant (KT) recipients. We recruited 124 CMV-seropositive KT recipients with no T-cell-depleting induction pre-emptively managed at four Spanish institutions. CMV-specific interferon-γ-producing CD4+ and CD8+ T cells were counted through the first post-transplant year by intracellular cytokine staining after stimulation with pp65 and immediate early-1 peptides (mean of six measurements per patient). The primary outcome was the occurrence of any CMV event (asymptomatic infection and/or disease). Optimal cut-off values for CMV-specific T cells were calculated at baseline and day 15. Twelve-month cumulative incidence of CMV infection and/or disease was 47.6%. Patients with pre-transplant CMV-specific CD8+ T-cell count Monitoring for CMV-specific CMI in intermediate-risk KT recipients must be regular to reflect dynamic changes in overall immunosuppression and individual susceptibility. The early assessment at post-transplant day 15 remains particularly informative