Two novel human NUMB isoforms provide a potential link between development and cancer

We previously identified four functionally distinct human NUMB isoforms. Here, we report the identification of two additional isoforms and propose a link between the expression of these isoforms and cancer. These novel isoforms, NUMB5 and NUMB6, lack exon 10 and are expressed in cells known for polarity and migratory behavior, such as human amniotic fluid cells, glioblastoma and metastatic tumor cells. RT-PCR and luciferase assays demonstrate that NUMB5 and NUMB6 are less antagonistic to NOTCH signaling than other NUMB isoforms. Immunocytochemistry analyses show that NUMB5 and NUMB6 interact and complex with CDC42, vimentin and the CDC42 regulator IQGAP1 (IQ (motif) GTPase activating protein 1). Furthermore, the ectopic expression of NUMB5 and NUMB6 induces the formation of lamellipodia (NUMB5) and filopodia (NUMB6) in a CDC42- and RAC1-dependent manner. These results are complemented by in vitro and in vivo studies, demonstrating that NUMB5 and NUMB6 alter the migratory behavior of cells. Together, these novel isoforms may play a role in further understanding the NUMB function in development and cancer

Developmental Changes in Notch1 and Numb Expression Mediated by Local Cell–Cell Interactions Underlie Progressively Increasing Delta Sensitivity in Neural Crest Stem Cells

Neural stem cells become progressively less neurogenic and more gliogenic with development. Here, we show that between E10.5 and E14.5, neural crest stem cells (NCSCs) become increasingly sensitive to the Notch ligand Delta-Fc, a progliogenic and anti-neurogenic signal. This transition is correlated with a 20- to 30-fold increase in the relative ratio of expression of Notch and Numb (a putative inhibitor of Notch signaling). Misexpression experiments suggest that these changes contribute causally to increased Delta sensitivity. Moreover, such changes can occur in NCSCs cultured at clonal density in the absence of other cell types. However, they require local cell–cell interactions within developing clones. Delta-Fc mimics the effect of such cell–cell interactions to increase Notch and decrease Numb expression in isolated NCSCs. Thus, Delta-mediated feedback interactions between NCSCs, coupled with positive feedback control of Notch sensitivity within individual cells, may underlie developmental changes in the ligand-sensitivity of these cells

Neural Crest Stem Cells Undergo Cell-Intrinsic Developmental Changes in Sensitivity to Instructive Differentiation Signals

Rat neural crest stem cells (NCSCs) prospectively isolated from uncultured E14.5 sciatic nerve and transplanted into chick embryos generate fewer neurons than do NCSCs isolated from E10.5 neural tube explants. In addition, they differentiate primarily to cholinergic parasympathetic neurons, although in culture they can also generate noradrenergic sympathetic neurons. This in vivo behavior can be explained, at least in part, by a reduced sensitivity of sciatic nerve-derived NCSCs to the neurogenic signal BMP2 and by the observation that cholinergic neurons differentiate at a lower BMP2 concentration than do noradrenergic neurons in vitro. These results demonstrate that neural stem cells can undergo cell-intrinsic changes in their sensitivity to instructive signals, while maintaining multipotency and self-renewal capacity. They also suggest that the choice between sympathetic and parasympathetic fates may be determined by the local concentration of BMP2

Distinct human NUMB isoforms regulate differentiation vs. proliferation in the neuronal lineage

Neuronal cell fate decisions are directed in Drosophila by NUMB, a signaling adapter protein with two protein–protein interaction domains: a phosphotyrosine-binding domain and a proline-rich region (PRR) that functions as an SH3-binding domain. Here we show that there are at least four human NUMB isoforms and that these serve two distinct developmental functions in the neuronal lineage: differentiation (but not proliferation) is promoted by human NUMB protein isoforms with a type I (short) PRR. In contrast, proliferation (but not differentiation) is directed by isoforms that have a type II (long) PRR. The two types of PRR may promote distinct intracellular signaling pathways downstream of the NOTCH receptor during mammalian neurogenesis

NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis. Neuron

Trk receptor ligand specificity by reducing binding of nonpreferred ligands (Bibel et al., 1999; Brennan et al., 1999) and by attenuating TrkA activity through intracellular signaling paths (MacPhee and Barker, 1997). The precise physical arrangement of p75NTR with the Trk receptors is not known, but p75NTR and TrkA codistribute on cell surfaces (Ross et al., 1996), and p75NTR can be immunoprecipitated with each of the three Trk receptors when both are overexpressed (Gargano et al., 1997; Bibel et al., 1999). p75NTR is widely distributed within cells that lack catalytically active Trk receptors and is capable of autonomous signaling. Numerous studies have shown that p75NTR can mediate cell death both in vitro and in vivo (Barrett and Bartlett, 1994; Casaccia-Bonnefil et al.

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on $10^3$ pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype