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Deletion of α5 nicotine receptor subunits abolishes nicotinic aversive motivational effects in a manner that phenocopies dopamine receptor antagonism.

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Deletion of α5 nicotine receptor subunits abolishes nicotinic aversive motivational effects in a manner that phenocopies dopamine receptor antagonism.

Eur J Neurosci. 2017 May 12;:

Authors: Grieder TE, George O, Yee M, Bergamini MA, Chwalek M, Maal-Bared G, Vargas-Perez H, van der Kooy D

Abstract
Nicotine addiction is a worldwide epidemic that claims millions of lives each year. Genetic deletion of α5 nicotinic acetylcholine receptor (nAChR) subunits has been associated with increased nicotine intake, however, it remains unclear whether acute nicotine is less aversive or more rewarding, and whether mice lacking the α5 nAChR subunit can experience withdrawal from chronic nicotine. We used place conditioning and conditioned taste avoidance paradigms to examine the effect of α5 subunit-containing nAChR deletion (α5 -/-) on conditioned approach and avoidance behaviour in nondependent and nicotine-dependent and -withdrawn mice, and compared these motivational effects with those elicited after dopamine receptor antagonism. We show that nondependent α5 -/- mice find low, non-motivational doses of nicotine rewarding, and do not show an aversive conditioned response or taste avoidance to higher aversive doses of nicotine. Furthermore, nicotine-dependent α5 -/- mice do not show a conditioned aversive motivational response to withdrawal from chronic nicotine, although they continue to exhibit a somatic withdrawal syndrome. These effects phenocopy those observed after dopamine receptor antagonism, but are not additive, suggesting that α5 nAChR subunits act in the same pathway as dopamine and are critical for the experience of nicotine's aversive, but not rewarding motivational effects in both a nondependent and nicotine-dependent and -withdrawn motivational state. Genetic deletion of α5 nAChR subunits leads to a behavioural phenotype that exactly matches that observed after antagonizing dopamine receptors, thus we suggest that modulation of nicotinic receptors containing α5 subunits may modify dopaminergic signalling, suggesting novel therapeutic treatments for smoking cessation. This article is protected by copyright. All rights reserved.

PMID: 28498560 [PubMed - as supplied by publisher]



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P-Cadherin is necessary for retinal stem cell behavior in vitro, but not in vivo.

P-Cadherin is necessary for retinal stem cell behavior in vitro, but not in vivo.

Stem Cell Res. 2017 May 03;21:141-147

Authors: Coles BLK, van der Kooy D

Abstract
Adult retinal stem cells (RSCs) are rare quiescent cells within the ciliary epithelium of the eye, which is made up of non-pigmented N-Cadherin(+ve) inner and pigmented P-Cadherin(+ve) outer cell layers. Through FACs and single cell analyses, we have shown that RSCs arise from single cells from within the pigmented CE and express P-Cadherin. However, whether the expression of P-Cadherin is required for maintenance of the stem cell in vivo or in the formation of the clonal stem cell spheres in vitro is not known. Using cadherin functional blocking antibody experiments and a P-Cadherin (-/-) mouse to test whether the RSC population is affected by the loss of P-Cadherin expression, our experiments demonstrate that the RSCs reside in the pigmented CE layer and express P-Cadherin, which is important to the formation of adherent sphere colonies in vitro, however P-Cadherin is not required for maintenance of RSCs in vivo.

PMID: 28494434 [PubMed - as supplied by publisher]



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Progerin-Induced Replication Stress Facilitates Premature Senescence in Hutchinson Gilford Progeria Syndrome.

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Progerin-Induced Replication Stress Facilitates Premature Senescence in Hutchinson Gilford Progeria Syndrome.

Mol Cell Biol. 2017 May 08;:

Authors: Wheaton K, Campuzano D, Ma W, Sheinis M, Ho B, Brown GW, Benchimol S

Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation in LMNA that produces an aberrant lamin A protein, progerin. The accumulation of progerin in HGPS cells leads to an aberrant nuclear morphology, genetic instability and p53-dependent premature senescence. How p53 is activated in response to progerin production is unknown. Here, we show that young, cycling HGPS fibroblasts, exhibit chronic DNA damage primarily in S phase as well as delayed replication fork progression. We demonstrate that progerin binds to PCNA altering its distribution away from replicating DNA in HGPS cells leading to γH2AX formation, ATR activation and RPA Ser33 phosphorylation. Unlike normal human cells that can be immortalized by enforced expression of telomerase alone, immortalization of HGPS cells requires telomerase expression and p53 repression. In addition, we show that the DNA damage response in HGPS cells does not originate from eroded telomeres. Together, these results establish that progerin interferes with the coordination of essential DNA replication factors, causing replication stress and is the primary signal for p53 activation leading to premature senescence in HGPS. Furthermore, this damage response is shown to be independent of progerin farnesylation, implying that unprocessed lamin A alone causes replication stress.

PMID: 28483909 [PubMed - as supplied by publisher]



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The Relationship between Alternative Splicing and Proteomic Complexity.

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The Relationship between Alternative Splicing and Proteomic Complexity.

Trends Biochem Sci. 2017 May 05;:

Authors: Blencowe BJ

PMID: 28483376 [PubMed - as supplied by publisher]



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Transcription factors read epigenetics.

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Transcription factors read epigenetics.

Science. 2017 May 05;356(6337):489-490

Authors: Hughes TR, Lambert SA

PMID: 28473550 [PubMed - in process]



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Local delivery of chondroitinase ABC with or without stromal cell-derived factor 1α promotes functional repair in the injured rat spinal cord.

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Local delivery of chondroitinase ABC with or without stromal cell-derived factor 1α promotes functional repair in the injured rat spinal cord.

Biomaterials. 2017 Apr 18;134:13-21

Authors: Pakulska MM, Tator CH, Shoichet MS

Abstract
Traumatic spinal cord injury (SCI) is a devastating event for which functional recovery remains elusive. Due to the complex nature of SCI pathology, a combination treatment strategy will likely be required for success. We hypothesized that tissue and functional repair would be achieved in a rat model of impact-compression SCI by combining degradation of the glial scar, using chondroitinase ABC (ChABC), with recruitment of endogenous neural precursor cells (NPCs), using stromal cell-derived factor 1α (SDF). To test this hypothesis, we designed a crosslinked methylcellulose hydrogel (XMC) for minimally invasive, localized, and sustained intrathecal drug delivery. ChABC was released from XMC using protein-peptide affinity interactions while SDF was delivered by electrostatic affinity interactions from polymeric nanoparticles embedded in XMC. Rats with SCI were treated acutely with a combination of SDF and ChABC, SDF alone, ChABC alone, or vehicle alone, and compared to injury only. Treatment with ChABC, both alone and in combination with SDF, resulted in faster and more sustained behavioural improvement over time than other groups. The significantly reduced chondroitin sulfate proteoglycan levels and greater distribution of NPCs throughout the spinal cord tissue with ChABC delivery, both alone and in combination with SDF, may explain the improved locomotor function. Treatment with SDF alone had no apparent effect on NPC number or distribution nor synergistic effect with ChABC delivery. Thus, in this model of SCI, tissue and functional repair is attributed to ChABC.

PMID: 28453954 [PubMed - as supplied by publisher]



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Peptide-MHC-based nanomedicines for autoimmunity function as T-cell receptor microclustering devices.

Peptide-MHC-based nanomedicines for autoimmunity function as T-cell receptor microclustering devices.

Nat Nanotechnol. 2017 Apr 24;:

Authors: Singha S, Shao K, Yang Y, Clemente-Casares X, Solé P, Clemente A, Blanco J, Dai Q, Song F, Liu SW, Yamanouchi J, Umeshappa CS, Nanjundappa RH, Detampel P, Amrein M, Fandos C, Tanguay R, Newbigging S, Serra P, Khadra A, Chan WCW, Santamaria P

Abstract
We have shown that nanoparticles (NPs) can be used as ligand-multimerization platforms to activate specific cellular receptors in vivo. Nanoparticles coated with autoimmune disease-relevant peptide-major histocompatibility complexes (pMHC) blunted autoimmune responses by triggering the differentiation and expansion of antigen-specific regulatory T cells in vivo. Here, we define the engineering principles impacting biological activity, detail a synthesis process yielding safe and stable compounds, and visualize how these nanomedicines interact with cognate T cells. We find that the triggering properties of pMHC-NPs are a function of pMHC intermolecular distance and involve the sustained assembly of large antigen receptor microclusters on murine and human cognate T cells. These compounds show no off-target toxicity in zebrafish embryos, do not cause haematological, biochemical or histological abnormalities, and are rapidly captured by phagocytes or processed by the hepatobiliary system. This work lays the groundwork for the design of ligand-based NP formulations to re-program in vivo cellular responses using nanotechnology.

PMID: 28436959 [PubMed - as supplied by publisher]



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Automated analysis of high-content microscopy data with deep learning.

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Automated analysis of high-content microscopy data with deep learning.

Mol Syst Biol. 2017 Apr 18;13(4):924

Authors: Kraus OZ, Grys BT, Ba J, Chong Y, Frey BJ, Boone C, Andrews BJ

Abstract
Existing computational pipelines for quantitative analysis of high-content microscopy data rely on traditional machine learning approaches that fail to accurately classify more than a single dataset without substantial tuning and training, requiring extensive analysis. Here, we demonstrate that the application of deep learning to biological image data can overcome the pitfalls associated with conventional machine learning classifiers. Using a deep convolutional neural network (DeepLoc) to analyze yeast cell images, we show improved performance over traditional approaches in the automated classification of protein subcellular localization. We also demonstrate the ability of DeepLoc to classify highly divergent image sets, including images of pheromone-arrested cells with abnormal cellular morphology, as well as images generated in different genetic backgrounds and in different laboratories. We offer an open-source implementation that enables updating DeepLoc on new microscopy datasets. This study highlights deep learning as an important tool for the expedited analysis of high-content microscopy data.

PMID: 28420678 [PubMed - in process]



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Intratumoral Heterogeneity: Pathways to Treatment Resistance and Relapse in Human Glioblastoma.

Intratumoral Heterogeneity: Pathways to Treatment Resistance and Relapse in Human Glioblastoma.

Ann Oncol. 2017 Apr 12;:

Authors: Qazi MA, Vora P, Venugopal C, Sidhu SS, Moffat J, Swanton C, Singh SK

Abstract
Intratumoral heterogeneity (ITH) has increasingly being described for multiple cancers as the root cause of therapy resistance. Recent studies have started to explore the scope of ITH in glioblastoma (GBM), a highly aggressive and fatal form of brain tumor, to explain its inevitable therapy resistance and disease relapse. In this review, we detail the emerging data that explores the extensive genetic, cellular and functional ITH present in GBM. We discuss current experimental models of human GBM recurrence and suggest harnessing new technologies (CRISPR-Cas9 screening, CyTOF, cellular barcoding, single cell analysis) to delineate GBM ITH and identify treatment-refractory cell populations, thus opening new therapeutic windows. We will also explore why current therapeutics have failed in clinical trials and how ITH can inform us on developing empiric therapies for the treatment of recurrent GBM.

PMID: 28407030 [PubMed - as supplied by publisher]



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Spatial heterogeneity in medulloblastoma.

Spatial heterogeneity in medulloblastoma.

Nat Genet. 2017 Apr 10;:

Authors: Morrissy AS, Cavalli FM, Remke M, Ramaswamy V, Shih DJ, Holgado BL, Farooq H, Donovan LK, Garzia L, Agnihotri S, Kiehna EN, Mercier E, Mayoh C, Papillon-Cavanagh S, Nikbakht H, Gayden T, Torchia J, Picard D, Merino DM, Vladoiu M, Luu B, Wu X, Daniels C, Horswell S, Thompson YY, Hovestadt V, Northcott PA, Jones DT, Peacock J, Wang X, Mack SC, Reimand J, Albrecht S, Fontebasso AM, Thiessen N, Li Y, Schein JE, Lee D, Carlsen R, Mayo M, Tse K, Tam A, Dhalla N, Ally A, Chuah E, Cheng Y, Plettner P, Li HI, Corbett RD, Wong T, Long W, Loukides J, Buczkowicz P, Hawkins CE, Tabori U, Rood BR, Myseros JS, Packer RJ, Korshunov A, Lichter P, Kool M, Pfister SM, Schüller U, Dirks P, Huang A, Bouffet E, Rutka JT, Bader GD, Swanton C, Ma Y, Moore RA, Mungall AJ, Majewski J, Jones SJ, Das S, Malkin D, Jabado N, Marra MA, Taylor MD

Abstract
Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

PMID: 28394352 [PubMed - as supplied by publisher]



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