Learning on tree architectures outperforms a convolutional feedforward network

Advanced deep learning architectures consist of tens of fully connected and convolutional hidden layers, which are already extended to hundreds, and are far from their biological realization. Their implausible biological dynamics is based on changing a weight in a non-local manner, as the number of routes between an output unit and a weight is typically large, using the backpropagation technique. Here, offline and online CIFAR-10 database learning on 3-layer tree architectures, inspired by experimental-based dendritic tree adaptations, outperforms the achievable success rates of the 5-layer convolutional LeNet. Its highly pruning tree backpropagation procedure, where a single route connects an output unit and a weight, represents an efficient dendritic deep learning.Comment: 20 pages, 4 figures, 1 table (improved figures resolution

Learning on tree architectures outperforms a convolutional feedforward network

Abstract Advanced deep learning architectures consist of tens of fully connected and convolutional hidden layers, currently extended to hundreds, are far from their biological realization. Their implausible biological dynamics relies on changing a weight in a non-local manner, as the number of routes between an output unit and a weight is typically large, using the backpropagation technique. Here, a 3-layer tree architecture inspired by experimental-based dendritic tree adaptations is developed and applied to the offline and online learning of the CIFAR-10 database. The proposed architecture outperforms the achievable success rates of the 5-layer convolutional LeNet. Moreover, the highly pruned tree backpropagation approach of the proposed architecture, where a single route connects an output unit and a weight, represents an efficient dendritic deep learning

Geometry of Gene Expression Space of Wilms' Tumors From Human Patients

Wilms' tumor is a pediatric malignancy that is thought to originate from faulty kidney development during the embryonic stage. However, there is a large variation between tumors from different patients in both histology and gene expression that is not well characterized. Here we use a meta-analysis of published microarray datasets to show that Favorable Histology Wilms' Tumors (FHWT's) fill a triangle-shaped continuum in gene expression space of which the vertices represent three idealized “archetypes”. We show that these archetypes have predominantly renal blastemal, stromal, and epithelial characteristics and that they correlate well with the three major lineages of the developing embryonic kidney. Moreover, we show that advanced stage tumors shift towards the renal blastemal archetype. These results illustrate the potential of this methodology for characterizing the cellular composition of Wilms' tumors and for assessing disease progression

Cellular Levels of Signaling Factors Are Sensed by β-actin Alleles to Modulate Transcriptional Pulse Intensity

The transcriptional response of β-actin to extra-cellular stimuli is a paradigm for transcription factor complex assembly and regulation. Serum induction leads to a precisely timed pulse of β-actin transcription in the cell population. Actin protein is proposed to be involved in this response, but it is not known whether cellular actin levels affect nuclear β-actin transcription. We perturbed the levels of key signaling factors and examined the effect on the induced transcriptional pulse by following endogenous β-actin alleles in single living cells. Lowering serum response factor (SRF) protein levels leads to loss of pulse integrity, whereas reducing actin protein levels reveals positive feedback regulation, resulting in elevated gene activation and a prolonged transcriptional response. Thus, transcriptional pulse fidelity requires regulated amounts of signaling proteins, and perturbations in factor levels eliminate the physiological response, resulting in either tuning down or exaggeration of the transcriptional pulse

Evidence of In Vitro Preservation of Human Nephrogenesis at the Single-Cell Level

During nephrogenesis, stem/progenitor cells differentiate and give rise to early nephron structures that segment to proximal and distal nephron cell types. Previously, we prospectively isolated progenitors from human fetal kidney (hFK) utilizing a combination of surface markers. However, upon culture nephron progenitors differentiated and could not be robustly maintained in vitro. Here, by culturing hFK in a modified medium used for in vitro growth of mouse nephron progenitors, and by dissection of NCAM+/CD133− progenitor cells according to EpCAM expression (NCAM+/CD133−/EpCAM−, NCAM+/CD133−/EpCAMdim, NCAM+/CD133−/EpCAMbright), we show at single-cell resolution a preservation of uninduced and induced cap mesenchyme as well as a transitioning mesenchymal-epithelial state. Concomitantly, differentiating and differentiated epithelial lineages are also maintained. In vitro expansion of discrete stages of early human nephrogenesis in nephron stem cell cultures may be used for drug screening on a full repertoire of developing kidney cells and for prospective isolation of mesenchymal or epithelial renal lineages for regenerative medicine

In Vivo Expansion of Cancer Stemness Affords Novel Cancer Stem Cell Targets: Malignant Rhabdoid Tumor as an Example

Summary: Cancer stem cell (CSC) identification relies on transplantation assays of cell subpopulations sorted from fresh tumor samples. Here, we attempt to bypass limitations of abundant tumor source and predetermined immune selection by in vivo propagating patient-derived xenografts (PDX) from human malignant rhabdoid tumor (MRT), a rare and lethal pediatric neoplasm, to an advanced state in which most cells behave as CSCs. Stemness is then probed by comparative transcriptomics of serial PDXs generating a gene signature of epithelial to mesenchymal transition, invasion/motility, metastasis, and self-renewal, pinpointing putative MRT CSC markers. The relevance of these putative CSC molecules is analyzed by sorting tumorigenic fractions from early-passaged PDX according to one such molecule, deciphering expression in archived primary tumors, and testing the effects of CSC molecule inhibition on MRT growth. Using this platform, we identify ALDH1 and lysyl oxidase (LOX) as relevant targets and provide a larger framework for target and drug discovery in rare pediatric cancers. : Golan et al. demonstrate that long-term propagation of human MRT xenografts robustly enriches for cancer stem cell frequency. This was exploited in turn for the identification of potential therapeutic targets in MRT such as lysyl oxidase and disclosed a platform to identify CSC targets in other rare pediatric tumors for which novel therapeutics are sought. Keywords: stem cells, cancer stem cells, PDX, MRT, targeted therapy, ALDH1, LOX inhibitio