The c-Abl kinase shuttles between the nucleus and cytoplasm. In the nucleus, Abl is activated by DNA damage or TNF to induce apoptosis. To examine the mechanism by which Abl regulates apoptosis, we employed dimerization as a means to control Abl activity by fusing an FKBP domain to the N-terminus of Abl. We found mutational inactivation of the NLS abrogated cell death, whereas FKBP-Abl was more efficient than FKBP-AblNuk, a nuclear-exclusive Abl, in inducing apoptosis, suggesting that while the nuclear pool is required for apoptosis, the cytoplasmic pool cooperates once apoptosis program is initiated. To find out how cytoplasmic Abl regulates cell adhesion, we made an AbPP gene that encodes an Abl protein that is constitutively activated. We stably transfected this gene into HEK293 cells under the control of a TET-on promoter. AblPP induction caused the host cells to detach from the supporting matrix in the presence of serum. We found that this was due to phosphorylation of CrkII by AblPP, leading to dissociation of the complex CrkII-C3G and loss of the GEF activity of C3G, resulting in the inactivation of Rap1 GTPase. The inactivation of Rap1 caused a decrease of integrin affinity for fibronectin. We also found that the Rho-ROCK1 pathway activated by LPA or serum is required for the cell detachment. These two pathways function independently of each other, and also play a role in ephrin A1-induced PC3 cell detachment. To further analyze the mechanisms of cell detachment induced by Abl, we employed shRNA library screening. We developed a new analytical strategy that combined quantitative microarray data with previous biological knowledge, i.e. Gene Ontology and pathway information, to increase the power of this technique. Using this strategy we identified 16 candidate shRNA-target genes associated with cell detachment induced by AblPP. Included in this set of genes was IL6ST, a membrane protein that we have experimentally confirmed. We also found that the caspase-resistant Rb-MI protein caused type-1 cells defect in Bid cleavage despite caspase-8 activation. Inhibition of V-ATPase, which is essential in acidification of endosomes, specifically restored Bid cleavage in Rb-MI cells, thus sensitizing Rb- MI but not wild-type fibroblasts to TNF-induced apoptosis, and stimulated inflammation-associated colonic apoptosis in RbMI/MI but not wild-type mice

Potassium channels are pore-forming transmembrane proteins that regulate a multitude of biological processes by controlling potassium flow across cell membranes. Aberrant potassium channel functions contribute to diseases such as epilepsy, cardiac arrhythm

© 2019. The American Astronomical Society. All rights reserved.. We present a detailed high-resolution weak-lensing study of SPT-CL J2106-5844 at z = 1.132, claimed to be the most massive system discovered at z > 1 in the South Pole Telescope Sunyaev-Zel'dovich survey. Based on the deep imaging data from the Advanced Camera for Surveys and Wide Field Camera 3 on board the Hubble Space Telescope, we find that the cluster mass distribution is asymmetric, composed of a main clump and a subclump ∼640 kpc west thereof. The central clump is further resolved into two smaller northwestern and southeastern substructures separated by ∼150 kpc. We show that this rather complex mass distribution is more consistent with the cluster galaxy distribution than a unimodal distribution as previously presented. The northwestern substructure coincides with the brightest cluster galaxy and the X-ray peak while the southeastern one agrees with the location of the peak in number density. These morphological features and the comparison with the X-ray emission suggest that the cluster might be a merging system. We estimate the virial mass of the cluster to be M200c =(10.4-3.0+3.3 ± 1.0) × 1014 M⊙, where the second error bar is the systematic uncertainty. Our result confirms that the cluster SPT-CL J2106-5844 is indeed the most massive cluster at z > 1 known to date. We demonstrate the robustness of this mass estimate by performing a number of tests with different assumptions on the centroids, mass-concentration relations, and sample variance.

The time delay between multiple images of strongly lensed quasars is a powerful tool for measuring the Hubble constant (H 0). To achieve H 0 measurements with higher precision and accuracy using the time delay, it is crucial to expand the sample of lensed quasars. We conduct a search for strongly lensed quasars in the Dark Energy Spectroscopic Instrument (DESI) Legacy Imaging Surveys. The DESI Legacy Surveys comprise 19,000 deg2 of the extragalactic sky observed in three optical bands (g, r, and z), making it well suited for the discovery of new strongly lensed quasars. We apply an autocorrelation algorithm to ∼5 million objects classified as quasars in the DESI Quasar Sample. These systems are visually inspected and ranked. Here, we present 436 new multiply lensed and binary quasar candidates, 65 of which have redshifts from Sloan Digital Sky Survey Data Release 16. We provide redshifts for an additional 18 candidates from the SuperNova Integral Field Spectrograph.

Periodontal ligament derived stem cells (PDLSCs) are capable of differentiating into multiple cell types and inducing a promising immunomodulation for tissue regeneration and disease treatment. However, it is still challenging to develop a practical approach to activate endogenous stem cells for tissue self-healing and regeneration. In this study, transcriptome analysis reveals that resveratrol promotes PDLSC stemness through activation of stem cell, osteoprogenitor, and chondroprogenitor markers. Self-renewal and multipotent differentiation abilities are also improved in resveratrol-treated PDLSCs. In addition, immunomodulation of PDLSCs is dramatically increased after resveratrol treatment. Mechanistically, we show that resveratrol activates ERK/WNT crosstalk through elevation of olfactory and growth factor signaling pathways to upregulate the expression levels of RUNX2 and FASL for osteogenesis and immunomodulation, respectively. By using a periodontitis animal model, administration of resveratrol partially rescues bone loss through activation of endogenous somatic stem cells and inhibition of inflammatory T-cell infiltration. Taken together, our findings identify a novel pharmacological approach to achieve autotherapies for endogenous tissue regeneration.

Asthma pathogenesis is focused around conducting airways. The reasons for this focus have been unclear because it has not been possible to track the sites and timing of antigen uptake or subsequent antigen presentation to effector T cells. In this study, w

Mechanisms governing a neuron's regenerative ability are important but not well understood. We identify Rtca (RNA 3′-terminal phosphate cyclase) as an inhibitor of axon regeneration. Removal of Rtca cell-autonomously enhanced axon regrowth in the Drosophila CNS, whereas its overexpression reduced axon regeneration in the periphery. Rtca along with the RNA ligase Rtcb and its catalyst Archease operate in the RNA repair and splicing pathway important for stress-induced mRNA splicing, including that of Xbp1, a cellular stress sensor. Drosophila Rtca and Archease had opposing effects on Xbp1 splicing, and deficiency of Archease or Xbp1 impeded axon regeneration in Drosophila. Moreover, overexpressing mammalian Rtca in cultured rodent neurons reduced axonal complexity in vitro, whereas reducing its function promoted retinal ganglion cell axon regeneration after optic nerve crush in mice. Our study thus links axon regeneration to cellular stress and RNA metabolism, revealing new potential therapeutic targets for treating nervous system trauma.

© 2015 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Mechanisms governing a neuron's regenerative ability are important but not well understood. We identify Rtca (RNA 3′-terminal phosphate cyclase) as an inhibito

We present GIGA-Lens: a gradient-informed, GPU-accelerated Bayesian framework for modeling strong gravitational lensing systems, implemented in TensorFlow and JAX. The three components, optimization using multistart gradient descent, posterior covariance estimation with variational inference, and sampling via Hamiltonian Monte Carlo, all take advantage of gradient information through automatic differentiation and massive parallelization on graphics processing units (GPUs). We test our pipeline on a large set of simulated systems and demonstrate in detail its high level of performance. The average time to model a single system on four Nvidia A100 GPUs is 105 s. The robustness, speed, and scalability offered by this framework make it possible to model the large number of strong lenses found in current surveys and present a very promising prospect for the modeling of( 10 5 ) lensing systems expected to be discovered in the era of the Vera C. Rubin Observatory, Euclid, and the Nancy Grace Roman Space Telescope.