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https://www.readbyqxmd.com/read/28823561/molecular-and-circuit-dynamical-identification-of-top-down-neural-mechanisms-for-restraint-of-reward-seeking
#1
Christina K Kim, Li Ye, Joshua H Jennings, Nandini Pichamoorthy, Daniel D Tang, Ai-Chi W Yoo, Charu Ramakrishnan, Karl Deisseroth
Reward-seeking behavior is fundamental to survival, but suppression of this behavior can be essential as well, even for rewards of high value. In humans and rodents, the medial prefrontal cortex (mPFC) has been implicated in suppressing reward seeking; however, despite vital significance in health and disease, the neural circuitry through which mPFC regulates reward seeking remains incompletely understood. Here, we show that a specific subset of superficial mPFC projections to a subfield of nucleus accumbens (NAc) neurons naturally encodes the decision to initiate or suppress reward seeking when faced with risk of punishment...
August 16, 2017: Cell
https://www.readbyqxmd.com/read/28823560/activation-and-desensitization-mechanism-of-ampa-receptor-tarp-complex-by-cryo-em
#2
Shanshuang Chen, Yan Zhao, Yuhang Wang, Mrinal Shekhar, Emad Tajkhorshid, Eric Gouaux
AMPA receptors mediate fast excitatory neurotransmission in the mammalian brain and transduce the binding of presynaptically released glutamate to the opening of a transmembrane cation channel. Within the postsynaptic density, however, AMPA receptors coassemble with transmembrane AMPA receptor regulatory proteins (TARPs), yielding a receptor complex with altered gating kinetics, pharmacology, and pore properties. Here, we elucidate structures of the GluA2-TARP γ2 complex in the presence of the partial agonist kainate or the full agonist quisqualate together with a positive allosteric modulator or with quisqualate alone...
August 16, 2017: Cell
https://www.readbyqxmd.com/read/28823559/dynamic-reorganization-of-neuronal-activity-patterns-in-parietal-cortex
#3
Laura N Driscoll, Noah L Pettit, Matthias Minderer, Selmaan N Chettih, Christopher D Harvey
Neuronal representations change as associations are learned between sensory stimuli and behavioral actions. However, it is poorly understood whether representations for learned associations stabilize in cortical association areas or continue to change following learning. We tracked the activity of posterior parietal cortex neurons for a month as mice stably performed a virtual-navigation task. The relationship between cells' activity and task features was mostly stable on single days but underwent major reorganization over weeks...
August 16, 2017: Cell
https://www.readbyqxmd.com/read/28823558/restoration-of-tet2-function-blocks-aberrant-self-renewal-and-leukemia-progression
#4
Luisa Cimmino, Igor Dolgalev, Yubao Wang, Akihide Yoshimi, Gaëlle H Martin, Jingjing Wang, Victor Ng, Bo Xia, Matthew T Witkowski, Marisa Mitchell-Flack, Isabella Grillo, Sofia Bakogianni, Delphine Ndiaye-Lobry, Miguel Torres Martín, Maria Guillamot, Robert S Banh, Mingjiang Xu, Maria E Figueroa, Ross A Dickins, Omar Abdel-Wahab, Christopher Y Park, Aristotelis Tsirigos, Benjamin G Neel, Iannis Aifantis
Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2(+) and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs...
August 16, 2017: Cell
https://www.readbyqxmd.com/read/28823557/neural-precursor-derived-pleiotrophin-mediates-subventricular-zone-invasion-by-glioma
#5
Elizabeth Y Qin, Dominique D Cooper, Keene L Abbott, James Lennon, Surya Nagaraja, Alan Mackay, Chris Jones, Hannes Vogel, Peter K Jackson, Michelle Monje
The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular mechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC):glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect...
August 12, 2017: Cell
https://www.readbyqxmd.com/read/28823556/excess-translation-of-epigenetic-regulators-contributes-to-fragile-x-syndrome-and-is-alleviated-by-brd4-inhibition
#6
Erica Korb, Margaret Herre, Ilana Zucker-Scharff, Jodi Gresack, C David Allis, Robert B Darnell
Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability and autism. FXS results from the loss of function of fragile X mental retardation protein (FMRP), which represses translation of target transcripts. Most of the well-characterized target transcripts of FMRP are synaptic proteins, yet targeting these proteins has not provided effective treatments. We examined a group of FMRP targets that encode transcriptional regulators, particularly chromatin-associated proteins. Loss of FMRP in mice results in widespread changes in chromatin regulation and aberrant gene expression...
August 12, 2017: Cell
https://www.readbyqxmd.com/read/28803729/the-ground-state-and-evolution-of-promoter-region-directionality
#7
Yi Jin, Umut Eser, Kevin Struhl, L Stirling Churchman
Eukaryotic promoter regions are frequently divergently transcribed in vivo, but it is unknown whether the resultant antisense RNAs are a mechanistic by-product of RNA polymerase II (Pol II) transcription or biologically meaningful. Here, we use a functional evolutionary approach that involves nascent transcript mapping in S. cerevisiae strains containing foreign yeast DNA. Promoter regions in foreign environments lose the directionality they have in their native species. Strikingly, fortuitous promoter regions arising in foreign DNA produce equal transcription in both directions, indicating that divergent transcription is a mechanistic feature that does not imply a function for these transcripts...
August 9, 2017: Cell
https://www.readbyqxmd.com/read/28803728/distinct-cellular-mechanisms-underlie-anti-ctla-4-and-anti-pd-1-checkpoint-blockade
#8
Spencer C Wei, Jacob H Levine, Alexandria P Cogdill, Yang Zhao, Nana-Ama A S Anang, Miles C Andrews, Padmanee Sharma, Jing Wang, Jennifer A Wargo, Dana Pe'er, James P Allison
Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations...
August 9, 2017: Cell
https://www.readbyqxmd.com/read/28803730/renal-sodium-gradient-orchestrates-a-dynamic-antibacterial-defense-zone
#9
Miriam R Berry, Rebeccah J Mathews, John R Ferdinand, Chenzhi Jing, Kevin W Loudon, Elizabeth Wlodek, Thomas W Dennison, Christoph Kuper, Wolfgang Neuhofer, Menna R Clatworthy
Lower urinary tract infections are among the most common human bacterial infections, but extension to the kidneys is rare. This has been attributed to mechanical forces, such as urine flow, that prevent the ascent of bladder microbes. Here, we show that the regional hypersalinity, required for the kidney's urine-concentrating function, instructs epithelial cells to produce chemokines that localize monocyte-derived mononuclear phagocytes (MNPs) to the medulla. This hypersaline environment also increases the intrinsic bactericidal and neutrophil chemotactic activities of MNPs to generate a zone of defense...
August 8, 2017: Cell
https://www.readbyqxmd.com/read/28803727/elimination-of-toxic-microsatellite-repeat-expansion-rna-by-rna-targeting-cas9
#10
Ranjan Batra, David A Nelles, Elaine Pirie, Steven M Blue, Ryan J Marina, Harrison Wang, Isaac A Chaim, James D Thomas, Nigel Zhang, Vu Nguyen, Stefan Aigner, Sebastian Markmiller, Guangbin Xia, Kevin D Corbett, Maurice S Swanson, Gene W Yeo
Microsatellite repeat expansions in DNA produce pathogenic RNA species that cause dominantly inherited diseases such as myotonic dystrophy type 1 and 2 (DM1/2), Huntington's disease, and C9orf72-linked amyotrophic lateral sclerosis (C9-ALS). Means to target these repetitive RNAs are required for diagnostic and therapeutic purposes. Here, we describe the development of a programmable CRISPR system capable of specifically visualizing and eliminating these toxic RNAs. We observe specific targeting and efficient elimination of microsatellite repeat expansion RNAs both when exogenously expressed and in patient cells...
August 8, 2017: Cell
https://www.readbyqxmd.com/read/28803726/golgi-resident-g%C3%AE-o-promotes-protrusive-membrane-dynamics
#11
Gonzalo P Solis, Oleksii Bilousov, Alexey Koval, Anne-Marie Lüchtenborg, Chen Lin, Vladimir L Katanaev
To form protrusions like neurites, cells must coordinate their induction and growth. The first requires cytoskeletal rearrangements at the plasma membrane (PM), the second requires directed material delivery from cell's insides. We find that the Gαo-subunit of heterotrimeric G proteins localizes dually to PM and Golgi across phyla and cell types. The PM pool of Gαo induces, and the Golgi pool feeds, the growing protrusions by stimulated trafficking. Golgi-residing KDELR binds and activates monomeric Gαo, atypically for G protein-coupled receptors that normally act on heterotrimeric G proteins...
August 7, 2017: Cell
https://www.readbyqxmd.com/read/28823555/distinct-neural-circuits-for-the-formation-and-retrieval-of-episodic-memories
#12
Dheeraj S Roy, Takashi Kitamura, Teruhiro Okuyama, Sachie K Ogawa, Chen Sun, Yuichi Obata, Atsushi Yoshiki, Susumu Tonegawa
The formation and retrieval of a memory is thought to be accomplished by activation and reactivation, respectively, of the memory-holding cells (engram cells) by a common set of neural circuits, but this hypothesis has not been established. The medial temporal-lobe system is essential for the formation and retrieval of episodic memory for which individual hippocampal subfields and entorhinal cortex layers contribute by carrying out specific functions. One subfield whose function is poorly known is the subiculum...
July 29, 2017: Cell
https://www.readbyqxmd.com/read/28757253/enhancer-reprogramming-promotes-pancreatic-cancer-metastasis
#13
Jae-Seok Roe, Chang-Il Hwang, Tim D D Somerville, Joseph P Milazzo, Eun Jung Lee, Brandon Da Silva, Laura Maiorino, Hervé Tiriac, C Megan Young, Koji Miyabayashi, Dea Filippini, Brianna Creighton, Richard A Burkhart, Jonathan M Buscaglia, Edward J Kim, Jean L Grem, Audrey J Lazenby, James A Grunkemeyer, Michael A Hollingsworth, Paul M Grandgenett, Mikala Egeblad, Youngkyu Park, David A Tuveson, Christopher R Vakoc
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo...
July 25, 2017: Cell
https://www.readbyqxmd.com/read/28802049/snapshot-cellular-senescence-pathways
#14
Ricardo Iván Martínez-Zamudio, Lucas Robinson, Pierre-Francois Roux, Oliver Bischof
Cellular senescence is a fundamental cell fate, playing important physiological and pathophysiological roles. This SnapShot focuses on major signaling pathways and transcriptional control mechanisms that consolidate the senescence phenotype.
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28802048/biology-gone-wild
#15
Diana Crow
No abstract text is available yet for this article.
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28802047/dual-ifgmosaic-a-versatile-method-for-multispectral-and-combinatorial-mosaic-gene-function-analysis
#16
Samuel Pontes-Quero, Luis Heredia, Verónica Casquero-García, Macarena Fernández-Chacón, Wen Luo, Ana Hermoso, Mayank Bansal, Irene Garcia-Gonzalez, Maria S Sanchez-Muñoz, Juan R Perea, Adrian Galiana-Simal, Iker Rodriguez-Arabaolaza, Sergio Del Olmo-Cabrera, Susana F Rocha, Luis M Criado-Rodriguez, Giovanna Giovinazzo, Rui Benedito
Improved methods for manipulating and analyzing gene function have provided a better understanding of how genes work during organ development and disease. Inducible functional genetic mosaics can be extraordinarily useful in the study of biological systems; however, this experimental approach is still rarely used in vertebrates. This is mainly due to technical difficulties in the assembly of large DNA constructs carrying multiple genes and regulatory elements and their targeting to the genome. In addition, mosaic phenotypic analysis, unlike classical single gene-function analysis, requires clear labeling and detection of multiple cell clones in the same tissue...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28802046/replication-transcription-conflicts-generate-r-loops-that-orchestrate-bacterial-stress-survival-and-pathogenesis
#17
Kevin S Lang, Ashley N Hall, Christopher N Merrikh, Mark Ragheb, Hannah Tabakh, Alex J Pollock, Joshua J Woodward, Julia E Dreifus, Houra Merrikh
Replication-transcription collisions shape genomes, influence evolution, and promote genetic diseases. Although unclear why, head-on transcription (lagging strand genes) is especially disruptive to replication and promotes genomic instability. Here, we find that head-on collisions promote R-loop formation in Bacillus subtilis. We show that pervasive R-loop formation at head-on collision regions completely blocks replication, elevates mutagenesis, and inhibits gene expression. Accordingly, the activity of the R-loop processing enzyme RNase HIII at collision regions is crucial for stress survival in B...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28802045/transcription-replication-conflict-orientation-modulates-r-loop-levels-and-activates-distinct-dna-damage-responses
#18
Stephan Hamperl, Michael J Bocek, Joshua C Saldivar, Tomek Swigut, Karlene A Cimprich
Conflicts between transcription and replication are a potent source of DNA damage. Co-transcriptional R-loops could aggravate such conflicts by creating an additional barrier to replication fork progression. Here, we use a defined episomal system to investigate how conflict orientation and R-loop formation influence genome stability in human cells. R-loops, but not normal transcription complexes, induce DNA breaks and orientation-specific DNA damage responses during conflicts with replication forks. Unexpectedly, the replisome acts as an orientation-dependent regulator of R-loop levels, reducing R-loops in the co-directional (CD) orientation but promoting their formation in the head-on (HO) orientation...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28802044/the-neuropeptide-corazonin-controls-social-behavior-and-caste-identity-in-ants
#19
Janko Gospocic, Emily J Shields, Karl M Glastad, Yanping Lin, Clint A Penick, Hua Yan, Alexander S Mikheyev, Timothy A Linksvayer, Benjamin A Garcia, Shelley L Berger, Jürgen Liebig, Danny Reinberg, Roberto Bonasio
Social insects are emerging models to study how gene regulation affects behavior because their colonies comprise individuals with the same genomes but greatly different behavioral repertoires. To investigate the molecular mechanisms that activate distinct behaviors in different castes, we exploit a natural behavioral plasticity in Harpegnathos saltator, where adult workers can transition to a reproductive, queen-like state called gamergate. Analysis of brain transcriptomes during the transition reveals that corazonin, a neuropeptide homologous to the vertebrate gonadotropin-releasing hormone, is downregulated as workers become gamergates...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28802043/an-engineered-orco-mutation-produces-aberrant-social-behavior-and-defective-neural-development-in-ants
#20
Hua Yan, Comzit Opachaloemphan, Giacomo Mancini, Huan Yang, Matthew Gallitto, Jakub Mlejnek, Alexandra Leibholz, Kevin Haight, Majid Ghaninia, Lucy Huo, Michael Perry, Jesse Slone, Xiaofan Zhou, Maria Traficante, Clint A Penick, Kelly Dolezal, Kaustubh Gokhale, Kelsey Stevens, Ingrid Fetter-Pruneda, Roberto Bonasio, Laurence J Zwiebel, Shelley L Berger, Jürgen Liebig, Danny Reinberg, Claude Desplan
Ants exhibit cooperative behaviors and advanced forms of sociality that depend on pheromone-mediated communication. Odorant receptor neurons (ORNs) express specific odorant receptors (ORs) encoded by a dramatically expanded gene family in ants. In most eusocial insects, only the queen can transmit genetic information, restricting genetic studies. In contrast, workers in Harpegnathos saltator ants can be converted into gamergates (pseudoqueens) that can found entire colonies. This feature facilitated CRISPR-Cas9 generation of germline mutations in orco, the gene that encodes the obligate co-receptor of all ORs...
August 10, 2017: Cell
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