journal
MENU ▼
Read by QxMD icon Read
search

ELife

journal
https://www.readbyqxmd.com/read/29143738/bladder-cancer-associated-mutations-in-rxra-activate-peroxisome-proliferator-activated-receptors-to-drive-urothelial-proliferation
#1
Angela M Halstead, Chiraag D Kapadia, Jennifer Bolzenius, Clarence E Chu, Andrew Schriefer, Lukas D Wartman, Gregory R Bowman, Vivek K Arora
RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from the TCGA raised the possibility that hyperactive PPAR signaling, either due to PPAR gamma gene amplification or RXRA hot-spot mutation (S427F/Y) drives 20-25% of human bladder cancers. Here we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers in human bladder cancer cells. Structure-function studies indicate that the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs...
November 16, 2017: ELife
https://www.readbyqxmd.com/read/29140251/vg1-nodal-heterodimers-are-the-endogenous-inducers-of-mesendoderm
#2
Tessa Grace Montague, Alexander F Schier
Nodal is considered the key inducer of mesendoderm in vertebrate embryos and embryonic stem cells. Other TGF-beta-related signals, such as Vg1/Dvr1/Gdf3, have also been implicated in this process but their roles have been unclear or controversial. Here we report that zebrafish embryos without maternally provided vg1 fail to form endoderm and head and trunk mesoderm, and closely resemble nodal loss-of-function mutants. Although Nodal is processed and secreted without Vg1, it requires Vg1 for its endogenous activity...
November 15, 2017: ELife
https://www.readbyqxmd.com/read/29140250/gdf3-is-required-for-robust-nodal-signaling-during-germ-layer-formation-and-left-right-patterning
#3
Jose L Pelliccia, Granton A Jindal, Rebecca D Burdine
Vertebrate embryonic patterning depends on signaling from Nodal, a TGFβ superfamily member. There are three Nodal orthologs in zebrafish; southpaw directs left-right asymmetries, while squint and cyclops function earlier to pattern mesendoderm. TGFβ member Vg1 is implicated in mesoderm formation but the role of the zebrafish ortholog, Growth differentiation factor 3 (Gdf3), has not been fully explored. We show that zygotic expression of gdf3 is dispensable for embryonic development, while maternally deposited gdf3 is required for mesendoderm formation and dorsal-ventral patterning...
November 15, 2017: ELife
https://www.readbyqxmd.com/read/29140249/maternal-gdf3-is-an-obligatory-cofactor-in-nodal-signaling-for-embryonic-axis-formation-in-zebrafish
#4
Brent W Bisgrove, Yi-Chu Su, H Joseph Yost
Zebrafish Gdf3 (Dvr1) is a member of the TGFb superfamily of cell signaling ligands that includes Xenopus Vg1 and mammalian Gdf1/3. Surprisingly, engineered homozygous mutants in zebrafish have no apparent phenotype. Elimination of Gdf3 in oocytes of maternal-zygotic mutants results in embryonic lethality that can be fully rescued with gdf3 RNA, demonstrating that Gdf3 is required only early in development, beyond which mutants are viable and fertile. Gdf3 mutants are refractory to Nodal ligands and Nodal repressor Lefty1...
November 15, 2017: ELife
https://www.readbyqxmd.com/read/29140248/glutamate-is-required-for-depression-but-not-potentiation-of-long-term-presynaptic-function
#5
Zahid Padamsey, Rudi Tong, Nigel Emptage
Hebbian plasticity is thought to require glutamate signalling. We show this is not the case for hippocampal presynaptic long-term potentiation (LTPpre), which is expressed as an increase in transmitter release probability (Pr). We find that LTPpre can be induced by pairing pre- and postsynaptic spiking in the absence of glutamate signalling. LTPpre induction involves a non-canonical mechanism of retrograde nitric oxide signalling, which is triggered by Ca(2+) influx from L-type voltage-gated Ca(2+) channels, not postsynaptic NMDA receptors (NMDARs), and does not require glutamate release...
November 15, 2017: ELife
https://www.readbyqxmd.com/read/29140247/ddm1-and-lsh-remodelers-allow-methylation-of-dna-wrapped-in-nucleosomes
#6
David B Lyons, Daniel Zilberman
Cytosine methylation regulates essential genome functions across eukaryotes, but the fundamental question of whether nucleosomal or naked DNA is the preferred substrate of plant and animal methyltransferases remains unresolved. Here, we show that genetic inactivation of a single DDM1/Lsh family nucleosome remodeler biases methylation toward inter-nucleosomal linker DNA in Arabidopsis thaliana and mouse. We find that DDM1 enables methylation of DNA bound to the nucleosome, suggesting that nucleosome-free DNA is the preferred substrate of eukaryotic methyltransferases in vivo...
November 15, 2017: ELife
https://www.readbyqxmd.com/read/29140246/an-eya1-notch-axis-specifies-bipotential-epibranchial-differentiation-in-mammalian-craniofacial-morphogenesis
#7
Haoran Zhang, Li Wang, Elaine Yee Man Wong, Sze Lan Tsang, Pin-Xian Xu, Urban Lendahl, Mai Har Sham
Craniofacial morphogenesis requires proper development of pharyngeal arches and epibranchial placodes. We show that the epibranchial placodes, in addition to giving rise to cranial sensory neurons, generate a novel lineage-related non-neuronal cell population for mouse pharyngeal arch development. Eya1 is essential for the development of epibranchial placodes and proximal pharyngeal arches. We identify an Eya1-Notch regulatory axis that specifies both the neuronal and non-neuronal commitment of the epibranchial placode, where Notch acts downstream of Eya1 and promotes the non-neuronal cell fate...
November 15, 2017: ELife
https://www.readbyqxmd.com/read/29140245/bacterial-fumarase-and-l-malic-acid-are-evolutionary-ancient-components-of-the-dna-damage-response
#8
Esti Singer, Yardena Bh Silas, Sigal Ben-Yehuda, Ophry Pines
Fumarase is distributed between two compartments of the eukaryotic cell. The enzyme catalyses the reversible conversion of fumaric to L-malic acid in mitochondria as part of the tricarboxylic acid (TCA) cycle, and in the cytosol/nucleus as part of the DNA damage response (DDR). Here we show that fumarase of the model prokaryote Bacillus subtilis (Fum-bc) is induced upon DNA damage, co-localized with the bacterial DNA and is required for the DDR. Fum-bc can substitute for both eukaryotic functions in yeast. Furthermore, we found that the fumarase dependent intracellular signaling of the B...
November 15, 2017: ELife
https://www.readbyqxmd.com/read/29140244/subcellular-analysis-of-pigeon-hair-cells-implicates-vesicular-trafficking-in-cuticulosome-formation-and-maintenance
#9
Simon Nimpf, Erich Pascal Malkemper, Mattias Lauwers, Lyubov Ushakova, Gregory Nordmann, Andrea Wenninger-Weinzierl, Thomas R Burkard, Sonja Jacob, Thomas Heuser, Guenter P Resch, David A Keays
Hair cells are specialized sensors located in the inner ear that enable the transduction of sound, motion, and gravity into neuronal impulses. In birds some hair cells contain an iron-rich organelle, the cuticulosome, that has been implicated in the magnetic sense. Here, we exploit histological, transcriptomic and tomographic methods to investigate the development of cuticulosomes, as well as the molecular and subcellular architecture of cuticulosome positive hair cells. We show that this organelle forms rapidly after hatching in a process that involves vesicle fusion and nucleation of ferritin nanoparticles...
November 15, 2017: ELife
https://www.readbyqxmd.com/read/29140243/a-versatile-genetic-tool-for-post-translational-control-of-gene-expression-in-drosophila-melanogaster
#10
Sachin Sethi, Jing W Wang
Several techniques have been developed to manipulate gene expression temporally in intact neural circuits. However, the applicability of current tools developed for in vivo studies in Drosophila is limited by their incompatibility with existing GAL4 lines and side effects on physiology and behavior. To circumvent these limitations, we adopted a strategy to reversibly regulate protein degradation with a small molecule by using a destabilizing domain (DD). We show that this system is effective across different tissues and developmental stages...
November 15, 2017: ELife
https://www.readbyqxmd.com/read/29135437/an-adaptation-of-astronomical-image-processing-enables-characterization-and-functional-3d-mapping-of-individual-sites-of-excitation-contraction-coupling-in-rat-cardiac-muscle
#11
Qinghai Tian, Lars Kaestner, Laura Schröder, Jia Guo, Peter Lipp
In beating cardiomyocytes, synchronized localized Ca(2+) transients from thousands of active excitation-contraction coupling sites (ECC couplons) comprising plasma and sarcoplasmic reticulum membrane calcium channels are important determinants of the heart's performance. Nevertheless, our knowledge about their properties is limited by the lack of appropriate experimental and analysis strategies. We designed CaCLEAN to untangle fundamental characteristics of ECC couplons by combining the astronomer's CLEAN algorithm with known properties of calcium diffusion...
November 14, 2017: ELife
https://www.readbyqxmd.com/read/29135436/defective-synaptic-transmission-causes-disease-signs-in-a-mouse-model-of-juvenile-neuronal-ceroid-lipofuscinosis
#12
Benedikt Grünewald, Maren D Lange, Christian Werner, Aet O'Leary, Andreas Weishaupt, Sandy Popp, David A Pearce, Heinz Wiendl, Andreas Reif, Hans C Pape, Klaus V Toyka, Claudia Sommer, Christian Geis
Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3(Δex7/8)) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination...
November 14, 2017: ELife
https://www.readbyqxmd.com/read/29132502/transcriptomic-and-proteomic-landscape-of-mitochondrial-dysfunction-reveals-secondary-coenzyme-q-deficiency-in-mammals
#13
Inge Kühl, Maria Miranda, Ilian Atanassov, Irina Kuznetsova, Yvonne Hinze, Arnaud Mourier, Aleksandra Filipovska, Nils-Göran Larsson
Dysfunction of the oxidative phosphorylation (OXPHOS) system is a major cause of human disease and the cellular consequences are highly complex. Here, we present comparative analyses of mitochondrial proteomes, cellular transcriptomes and targeted metabolomics of five knockout mouse strains deficient in essential factors required for mitochondrial DNA gene expression, leading to OXPHOS dysfunction. Moreover, we describe sequential protein changes during post-natal development and progressive OXPHOS dysfunction in time course analyses in control mice and a middle lifespan knockout, respectively...
November 14, 2017: ELife
https://www.readbyqxmd.com/read/29130884/ubiquitin-turnover-and-endocytic-trafficking-in-yeast-are-regulated-by-ser57-phosphorylation-of-ubiquitin
#14
Sora Lee, Jessica M Tumolo, Aaron C Ehlinger, Kristin K Jernigan, Susan J Qualls-Histed, Pi-Chiang Hsu, W Hayes McDonald, Walter J Chazin, Jason A MacGurn
Despite its central role in protein degradation little is known about the molecular mechanisms that sense, maintain, and regulate steady state concentration of ubiquitin in the cell. Here, we describe a novel mechanism for regulation of ubiquitin homeostasis that is mediated by phosphorylation of ubiquitin at the Ser57 position. We find that loss of Ppz phosphatase activity leads to defects in ubiquitin homeostasis that are at least partially attributable to elevated levels of Ser57 phosphorylated ubiquitin...
November 13, 2017: ELife
https://www.readbyqxmd.com/read/29130883/regulatory-network-structure-determines-patterns-of-intermolecular-epistasis
#15
Mato Lagator, Srdjan Sarikas, Hande Acar, Jonathan P Bollback, Călin C Guet
Most phenotypes are determined by molecular systems composed of specifically interacting molecules. However, unlike for individual components, little is known about the distributions of mutational effects of molecular systems as a whole. We ask how the distribution of mutational effects of a transcriptional regulatory system differs from the distributions of its components, by first independently, and then simultaneously, mutating a transcription factor and the associated promoter it represses. We find that the system distribution exhibits increased phenotypic variation compared to individual component distributions - an effect arising from intermolecular epistasis between the transcription factor and its DNA-binding site...
November 13, 2017: ELife
https://www.readbyqxmd.com/read/29130882/simultaneous-enumeration-of-cancer-and-immune-cell-types-from-bulk-tumor-gene-expression-data
#16
Julien Racle, Kaat de Jonge, Petra Baumgaertner, Daniel E Speiser, David Gfeller
Immune cells infiltrating tumors can have important impact on tumor progression and response to therapy. We present an efficient algorithm to simultaneously estimate the fraction of cancer and immune cell types from bulk tumor gene expression data. Our method integrates novel gene expression profiles from each major non-malignant cell type found in tumors, renormalization based on cell-type specific mRNA content, and the ability to consider uncharacterized and possibly highly variable cell types. Feasibility is demonstrated by validation with flow cytometry, immunohistochemistry and single-cell RNA-Seq analyses of human melanoma and colorectal tumor specimens...
November 13, 2017: ELife
https://www.readbyqxmd.com/read/29125463/pharmacological-augmentation-of-nicotinamide-phosphoribosyltransferase-nampt-protects-against-paclitaxel-induced-peripheral-neuropathy
#17
Peter M LoCoco, April L Risinger, Hudson R Smith, Teresa S Chavera, Kelly A Berg, William P Clarke
Chemotherapy-induced peripheral neuropathy (CIPN) arises from collateral damage to peripheral afferent sensory neurons by anticancer pharmacotherapy, leading to debilitating neuropathic pain. No effective treatment for CIPN exists, short of dose-reduction which worsens cancer prognosis. Here we report that stimulation of nicotinamide phosphoribosyltransferase (NAMPT) produced robust neuroprotection in an aggressive CIPN model utilizing the frontline anticancer drug, paclitaxel (PTX). Daily treatment of rats with the first-in-class NAMPT stimulator, P7C3-A20, prevented behavioral and histologic indicators of peripheral neuropathy, stimulated tissue NAD recovery, improved general health, and abolished attrition produced by a near maximum-tolerated dose of PTX...
November 10, 2017: ELife
https://www.readbyqxmd.com/read/29125462/systematic-proteomic-analysis-of-lrrk2-mediated-rab-gtpase-phosphorylation-establishes-a-connection-to-ciliogenesis
#18
Martin Steger, Federico Diez, Herschel S Dhekne, Pawel Lis, Raja S Nirujogi, Ozge Karayel, Francesca Tonelli, Terina N Martinez, Esben Lorentzen, Suzanne R Pfeffer, Dario R Alessi, Matthias Mann
We previously reported that Parkinson's disease (PD) kinase LRRK2 phosphorylates a subset of Rab GTPases on a conserved residue in their switch-II domains (Steger, Tonelli et al., 2016) (PMID: 26824392). Here, we systematically analyzed the Rab protein family and found 14 of them (Rab3A/B/C/D, Rab5A/B/C, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) to be specifically phosphorylated by LRRK2, with evidence for endogenous phosphorylation for ten of them (Rab3A/B/C/D, Rab8A/B, Rab10, Rab12, Rab35 and Rab43)...
November 10, 2017: ELife
https://www.readbyqxmd.com/read/29125121/structural-basis-of-host-recognition-and-biofilm-formation-by-salmonella-saf-pili
#19
Longhui Zeng, Li Zhang, Pengran Wang, Guoyu Meng
Pili are critical in host recognition, colonization and biofilm formation during bacterial infection. Here, we report the crystal structures of SafD-dsc and SafD-SafA-SafA (SafDAA-dsc) in Saf pili. Cell adherence assays show that SafD and SafA are both required for host recognition, suggesting a poly-adhesive mechanism for Saf pili. Moreover, the SafDAA-dsc structure, as well as SAXS characterization, reveals an unexpected inter-molecular oligomerization, prompting the investigation of Saf-driven self-association in biofilm formation...
November 10, 2017: ELife
https://www.readbyqxmd.com/read/29120327/capillary-pericytes-mediate-coronary-no-reflow-after-myocardial-ischaemia
#20
Fergus M O'Farrell, Svetlana Mastitskaya, Matthew Hammond-Haley, Felipe Freitas, Wen Rui Wah, David Attwell
After cardiac ischaemia, a prolonged decrease of coronary microvascular perfusion often occurs even after flow is restored in an upstream artery. This 'no-reflow' phenomenon worsens patient prognosis. In the brain, after stroke, a similar post-ischaemic 'no-reflow' has been attributed to capillary constriction by contractile pericytes. We now show that occlusion of a rat coronary artery, followed by reperfusion, blocks 40% of cardiac capillaries and halves perfused blood volume within the affected region. Capillary blockages colocalised strongly with pericytes, where capillary diameter was reduced by 37%...
November 9, 2017: ELife
journal
journal
43971
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"