Intracellular mediators of transforming growth factor β superfamily signaling localize to endosomes in chicken embryo and mouse lenses in vivo

<p>Abstract</p> <p>Background</p> <p>Endocytosis is a key regulator of growth factor signaling pathways. Recent studies showed that the localization to endosomes of intracellular mediators of growth factor signaling may be required for their function. Although there is substantial evidence linking endocytosis and growth factor signaling in cultured cells, there has been little study of the endosomal localization of signaling components in intact tissues or organs.</p> <p>Results</p> <p>Proteins that are downstream of the transforming growth factor-β superfamily signaling pathway were found on endosomes in chicken embryo and postnatal mouse lenses, which depend on signaling by members of the TGFβ superfamily for their normal development. Phosphorylated Smad1 (pSmad1), pSmad2, Smad4, Smad7, the transcriptional repressors c-Ski and TGIF and the adapter molecules Smad anchor for receptor activation (SARA) and C184M, localized to EEA-1- and Rab5-positive vesicles in chicken embryo and/or postnatal mouse lenses. pSmad1 and pSmad2 also localized to Rab7-positive late endosomes. Smad7 was found associated with endosomes, but not caveolae. <it>Bmpr1a </it>conditional knock-out lenses showed decreased nuclear and endosomal localization of pSmad1. Many of the effectors in this pathway were distributed differently in vivo from their reported distribution in cultured cells.</p> <p>Conclusion</p> <p>Based on the findings reported here and data from other signaling systems, we suggest that the localization of activated intracellular mediators of the transforming growth factor-β superfamily to endosomes is important for the regulation of growth factor signaling.</p

Fabrication of submicron La2−x_{2-x}Srx_{x}CuO4_{4} intrinsic Josephson junction stacks

Intrinsic Josephson junction (IJJ) stacks of cuprate superconductors have potential to be implemented as intrinsic phase qubits working at relatively high temperatures. We report success in fabricating submicron La$_{2-x}$Sr$_{x}$CuO$_{4}$ (LSCO) IJJ stacks carved out of single crystals. We also show a new fabrication method in which argon ion etching is performed after focused ion beam etching. As a result, we obtained an LSCO IJJ stack in which resistive multi-branches appeared. It may be possible to control the number of stacked IJJs with an accuracy of a single IJJ by developing this method.Comment: 5 pages, 6 figure

Empirical Bayesian significance measure of neuronal spike response

Background: Functional connectivity analyses of multiple neurons provide a powerful bottom-up approach to reveal functions of local neuronal circuits by using simultaneous recording of neuronal activity. A statistical methodology, generalized linear modeling (GLM) of the spike response function, is one of the most promising methodologies to reduce false link discoveries arising from pseudo-correlation based on common inputs. Although recent advancement of fluorescent imaging techniques has increased the number of simultaneously recoded neurons up to the hundreds or thousands, the amount of information per pair of neurons has not correspondingly increased, partly because of the instruments' limitations, and partly because the number of neuron pairs increase in a quadratic manner. Consequently, the estimation of GLM suffers from large statistical uncertainty caused by the shortage in effective information. Results: In this study, we propose a new combination of GLM and empirical Bayesian testing for the estimation of spike response functions that enables both conservative false discovery control and powerful functional connectivity detection. We compared our proposed method's performance with those of sparse estimation of GLM and classical Granger causality testing. Our method achieved high detection performance of functional connectivity with conservative estimation of false discovery rate and q values in case of information shortage due to short observation time. We also showed that empirical Bayesian testing on arbitrary statistics in place of likelihood-ratio statistics reduce the computational cost without decreasing the detection performance. When our proposed method was applied to a functional multi-neuron calcium imaging dataset from the rat hippocampal region, we found significant functional connections that are possibly mediated by AMPA and NMDA receptors. Conclusions: The proposed empirical Bayesian testing framework with GLM is promising especially when the amount of information per a neuron pair is small because of growing size of observed network