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Cell Reports

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https://www.readbyqxmd.com/read/29456100/the-coding-regions-of-germline-mrnas-confer-sensitivity-to-argonaute-regulation-in-c-elegans
#1
Meetu Seth, Masaki Shirayama, Wen Tang, En-Zhi Shen, Shikui Tu, Heng-Chi Lee, Zhiping Weng, Craig C Mello
Protein-coding genes undergo a wide array of regulatory interactions with factors that engage non-coding regions. Open reading frames (ORFs), in contrast, are thought to be constrained by coding function, precluding a major role in gene regulation. Here, we explore Piwi-interacting (pi)RNA-mediated transgene silencing in C. elegans and show that marked differences in the sensitivity to piRNA silencing map to the endogenous sequences within transgene ORFs. Artificially increasing piRNA targeting within the ORF of a resistant transgene can lead to a partial yet stable reduction in expression, revealing that piRNAs not only silence but can also "tune" gene expression...
February 14, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444443/kinetics-and-mechanism-of-mammalian-mitochondrial-ribosome-assembly
#2
Daniel F Bogenhagen, Anne G Ostermeyer-Fay, John D Haley, Miguel Garcia-Diaz
Mammalian mtDNA encodes only 13 proteins, all essential components of respiratory complexes, synthesized by mitochondrial ribosomes. Mitoribosomes contain greatly truncated RNAs transcribed from mtDNA, including a structural tRNA in place of 5S RNA as a scaffold for binding 82 nucleus-encoded proteins, mitoribosomal proteins (MRPs). Cryoelectron microscopy (cryo-EM) studies have determined the structure of the mitoribosome, but its mechanism of assembly is unknown. Our SILAC pulse-labeling experiments determine the rates of mitochondrial import of MRPs and their assembly into intact mitoribosomes, providing a basis for distinguishing MRPs that bind at early and late stages in mitoribosome assembly to generate a working model for mitoribosome assembly...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444442/diverse-regulators-of-human-ribosome-biogenesis-discovered-by-changes-in-nucleolar-number
#3
Katherine I Farley-Barnes, Kathleen L McCann, Lisa M Ogawa, Janie Merkel, Yulia V Surovtseva, Susan J Baserga
Ribosome biogenesis is a highly regulated, essential cellular process. Although studies in yeast have established some of the biological principles of ribosome biogenesis, many of the intricacies of its regulation in higher eukaryotes remain unknown. To understand how ribosome biogenesis is globally integrated in human cells, we conducted a genome-wide siRNA screen for regulators of nucleolar number. We found 139 proteins whose depletion changed the number of nucleoli per nucleus from 2-3 to only 1 in human MCF10A cells...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444441/initiating-events-in-direct-cardiomyocyte-reprogramming
#4
Kimberly Sauls, Todd M Greco, Li Wang, Meng Zou, Michelle Villasmil, Li Qian, Ileana M Cristea, Frank L Conlon
Direct reprogramming of fibroblasts into cardiomyocyte-like cells (iCM) holds great potential for heart regeneration and disease modeling and may lead to future therapeutic applications. Currently, application of this technology is limited by our lack of understanding of the molecular mechanisms that drive direct iCM reprogramming. Using a quantitative mass spectrometry-based proteomic approach, we identified the temporal global changes in protein abundance that occur during initial phases of iCM reprogramming...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444440/measuring-integrin-conformational-change-on-the-cell-surface-with-super-resolution-microscopy
#5
Travis I Moore, Jesse Aaron, Teng-Leong Chew, Timothy A Springer
We use super-resolution interferometric photoactivation and localization microscopy (iPALM) and a constrained photoactivatable fluorescent protein integrin fusion to measure the displacement of the head of integrin lymphocyte function-associated 1 (LFA-1) resulting from integrin conformational change on the cell surface. We demonstrate that the distance of the LFA-1 head increases substantially between basal and ligand-engaged conformations, which can only be explained at the molecular level by integrin extension...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444439/differential-effector-engagement-by-oncogenic-kras
#6
Tina L Yuan, Arnaud Amzallag, Rachel Bagni, Ming Yi, Shervin Afghani, William Burgan, Nicole Fer, Leslie A Strathern, Katie Powell, Brian Smith, Andrew M Waters, David Drubin, Ty Thomson, Rosy Liao, Patricia Greninger, Giovanna T Stein, Ellen Murchie, Eliane Cortez, Regina K Egan, Lauren Procter, Matthew Bess, Kwong Tai Cheng, Chih-Shia Lee, Liam Changwoo Lee, Christof Fellmann, Robert Stephens, Ji Luo, Scott W Lowe, Cyril H Benes, Frank McCormick
KRAS can bind numerous effector proteins, which activate different downstream signaling events. The best known are RAF, phosphatidylinositide (PI)-3' kinase, and RalGDS families, but many additional direct and indirect effectors have been reported. We have assessed how these effectors contribute to several major phenotypes in a quantitative way, using an arrayed combinatorial siRNA screen in which we knocked down 41 KRAS effectors nodes in 92 cell lines. We show that every cell line has a unique combination of effector dependencies, but in spite of this heterogeneity, we were able to identify two major subtypes of KRAS mutant cancers of the lung, pancreas, and large intestine, which reflect different KRAS effector engagement and opportunities for therapeutic intervention...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444438/commonly-occurring-cell-subsets-in-high-grade-serous-ovarian-tumors-identified-by-single-cell-mass-cytometry
#7
Veronica D Gonzalez, Nikolay Samusik, Tiffany J Chen, Erica S Savig, Nima Aghaeepour, David A Quigley, Ying-Wen Huang, Valeria Giangarrà, Alexander D Borowsky, Neil E Hubbard, Shih-Yu Chen, Guojun Han, Alan Ashworth, Thomas J Kipps, Jonathan S Berek, Garry P Nolan, Wendy J Fantl
We have performed an in-depth single-cell phenotypic characterization of high-grade serous ovarian cancer (HGSOC) by multiparametric mass cytometry (CyTOF). Using a CyTOF antibody panel to interrogate features of HGSOC biology, combined with unsupervised computational analysis, we identified noteworthy cell types co-occurring across the tumors. In addition to a dominant cell subset, each tumor harbored rarer cell phenotypes. One such group co-expressed E-cadherin and vimentin (EV), suggesting their potential role in epithelial mesenchymal transition, which was substantiated by pairwise correlation analyses...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444437/mutations-in-cytosine-5-trna-methyltransferases-impact-mobile-element-expression-and-genome-stability-at-specific-dna-repeats
#8
Bianca Genenncher, Zeljko Durdevic, Katharina Hanna, Daniela Zinkl, Mehrpouya Balaghy Mobin, Nevcin Senturk, Bruno Da Silva, Carine Legrand, Clément Carré, Frank Lyko, Matthias Schaefer
The maintenance of eukaryotic genome stability is ensured by the interplay of transcriptional as well as post-transcriptional mechanisms that control recombination of repeat regions and the expression and mobility of transposable elements. We report here that mutations in two (cytosine-5) RNA methyltransferases, Dnmt2 and NSun2, impact the accumulation of mobile element-derived sequences and DNA repeat integrity in Drosophila. Loss of Dnmt2 function caused moderate effects under standard conditions, while heat shock exacerbated these effects...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444436/shwachman-diamond-syndrome-protein-sbds-maintains-human-telomeres-by-regulating-telomerase-recruitment
#9
Yi Liu, Feng Liu, Yizhao Cao, Huimin Xu, Yangxiu Wu, Su Wu, Dan Liu, Yong Zhao, Zhou Songyang, Wenbin Ma
Shwachman-Diamond syndrome (SDS) is a rare pediatric disease characterized by various systemic disorders, including hematopoietic dysfunction. The mutation of Shwachman-Bodian-Diamond syndrome (SBDS) gene has been proposed to be a major causative reason for SDS. Although SBDS patients were reported to have shorter telomere length in granulocytes, the underlying mechanism is still unclear. Here we provide data to elucidate the role of SBDS in telomere protection. We demonstrate that SBDS deficiency leads to telomere shortening...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444435/ptpn2-regulates-inflammasome-activation-and-controls-onset-of-intestinal-inflammation-and-colon-cancer
#10
Marianne R Spalinger, Roberto Manzini, Larissa Hering, Julianne B Riggs, Claudia Gottier, Silvia Lang, Kirstin Atrott, Antonia Fettelschoss, Florian Olomski, Thomas M Kündig, Michael Fried, Declan F McCole, Gerhard Rogler, Michael Scharl
Variants in the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with inflammatory disorders, including inflammatory bowel diseases, rheumatoid arthritis, and type 1 diabetes. The anti-inflammatory role of PTPN2 is highlighted by the fact that PTPN2-deficient mice die a few weeks after birth because of systemic inflammation and severe colitis. However, the tissues, cells, and molecular mechanisms that contribute to this phenotype remain unclear. Here, we demonstrate that myeloid cell-specific deletion of PTPN2 in mice (PTPN2-LysMCre) promotes intestinal inflammation but protects from colitis-associated tumor formation in an IL-1β-dependent manner...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444434/b1-cell-ige-impedes-mast-cell-mediated-enhancement-of-parasite-expulsion-through-b2-ige-blockade
#11
Rebecca K Martin, Sheela R Damle, Yolander A Valentine, Matthew P Zellner, Briana N James, Joseph C Lownik, Andrea J Luker, Elijah H Davis, Martha M DeMeules, Laura M Khandjian, Fred D Finkelman, Joseph F Urban, Daniel H Conrad
Helminth infection is known for generating large amounts of poly-specific IgE. Here we demonstrate that innate-like B1 cells are responsible for this IgE production during infection with the nematode parasites Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. In vitro analysis of B1 cell immunoglobulin class switch recombination to IgE demonstrated a requirement for anti-CD40 and IL-4 that was further enhanced when IL-5 was added or when the B1 source was helminth infected mice. An IL-25-induced upregulation of IgE in B1 cells was also demonstrated...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444433/microrna-223-suppresses-the-canonical-nf-%C3%AE%C2%BAb-pathway-in-basal-keratinocytes-to-dampen-neutrophilic-inflammation
#12
Wenqing Zhou, Arpita S Pal, Alan Yi-Hui Hsu, Theodore Gurol, Xiaoguang Zhu, Sara E Wirbisky-Hershberger, Jennifer L Freeman, Andrea L Kasinski, Qing Deng
MicroRNA-223 is known as a myeloid-enriched anti-inflammatory microRNA that is dysregulated in numerous inflammatory conditions. Here, we report that neutrophilic inflammation (wound response) is augmented in miR-223-deficient zebrafish, due primarily to elevated activation of the canonical nuclear factor κB (NF-κB) pathway. NF-κB over-activation is restricted to the basal layer of the surface epithelium, although miR-223 is detected throughout the epithelium and in phagocytes. Not only phagocytes but also epithelial cells are involved in miR-223-mediated regulation of neutrophils' wound response and NF-κB activation...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444432/surface-matrix-screening-identifies-semi-specific-interactions-that-improve-potency-of-a-near-pan-reactive-hiv-1-neutralizing-antibody
#13
Young D Kwon, Gwo-Yu Chuang, Baoshan Zhang, Robert T Bailer, Nicole A Doria-Rose, Tatyana S Gindin, Bob Lin, Mark K Louder, Krisha McKee, Sijy O'Dell, Amarendra Pegu, Stephen D Schmidt, Mangaiarkarasi Asokan, Xuejun Chen, Misook Choe, Ivelin S Georgiev, Vivian Jin, Marie Pancera, Reda Rawi, Keyun Wang, Rajoshi Chaudhuri, Lisa A Kueltzo, Slobodanka D Manceva, John-Paul Todd, Diana G Scorpio, Mikyung Kim, Ellis L Reinherz, Kshitij Wagh, Bette M Korber, Mark Connors, Lawrence Shapiro, John R Mascola, Peter D Kwong
Highly effective HIV-1-neutralizing antibodies could have utility in the prevention or treatment of HIV-1 infection. To improve the potency of 10E8, an antibody capable of near pan-HIV-1 neutralization, we engineered 10E8-surface mutants and screened for improved neutralization. Variants with the largest functional enhancements involved the addition of hydrophobic or positively charged residues, which were positioned to interact with viral membrane lipids or viral glycan-sialic acids, respectively. In both cases, the site of improvement was spatially separated from the region of antibody mediating molecular contact with the protein component of the antigen, thereby improving peripheral semi-specific interactions while maintaining unmodified dominant contacts responsible for broad recognition...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444431/mechanisms-to-evade-the-phagocyte-respiratory-burst-arose-by-convergent-evolution-in-typhoidal-salmonella-serovars
#14
Hirotaka Hiyoshi, Tamding Wangdi, Gabriel Lock, Cheng Saechao, Manuela Raffatellu, Brian A Cobb, Andreas J Bäumler
Typhoid fever caused by Salmonella enterica serovar (S.) Typhi differs in its clinical presentation from gastroenteritis caused by S. Typhimurium and other non-typhoidal Salmonella serovars. The different clinical presentations are attributed in part to the virulence-associated capsular polysaccharide (Vi antigen) of S. Typhi, which prevents phagocytes from triggering a respiratory burst by preventing antibody-mediated complement activation. Paradoxically, the Vi antigen is absent from S. Paratyphi A, which causes a disease that is indistinguishable from typhoid fever...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444430/%C3%AE-cell-specific-deletion-of-the-il-1-receptor-antagonist-impairs-%C3%AE-cell-proliferation-and-insulin-secretion
#15
Marianne Böni-Schnetzler, Stéphanie P Häuselmann, Elise Dalmas, Daniel T Meier, Constanze Thienel, Shuyang Traub, Friederike Schulze, Laura Steiger, Erez Dror, Praxedis Martin, Pedro L Herrera, Cem Gabay, Marc Y Donath
Interleukin-1 receptor antagonist (IL-1Ra) is elevated in the circulation during obesity and type 2 diabetes (T2D) but is decreased in islets from patients with T2D. The protective role of local IL-1Ra was investigated in pancreatic islet β cell (βIL-1Ra)-specific versus myeloid-cell (myeloIL-1Ra)-specific IL-1Ra knockout (KO) mice. Deletion of IL-1Ra in β cells, but not in myeloid cells, resulted in diminished islet IL-1Ra expression. Myeloid cells were not the main source of circulating IL-1Ra in obesity...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444429/glucagon-receptor-antagonism-improves-glucose-metabolism-and-cardiac-function-by-promoting-amp-mediated-protein-kinase-in-diabetic-mice
#16
Ankit X Sharma, Ezekiel B Quittner-Strom, Young Lee, Joshua A Johnson, Sarah A Martin, Xinxin Yu, Jianping Li, John Lu, Zheqing Cai, Shiuhwei Chen, May-Yun Wang, Yiyi Zhang, Mackenzie J Pearson, Andie C Dorn, Jeffrey G McDonald, Ruth Gordillo, Hai Yan, Dung Thai, Zhao V Wang, Roger H Unger, William L Holland
The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in an insulin-centric clinical environment. To investigate the metabolic effects of glucagon receptor antagonism in type 2 diabetes, we treated Lepr db/db and Lep ob/ob mice with REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor. As expected, REMD 2.59 suppresses hepatic glucose production and improves glycemia. Surprisingly, it also enhances insulin action in both liver and skeletal muscle, coinciding with an increase in AMP-activated protein kinase (AMPK)-mediated lipid oxidation...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444428/agrp-neurons-require-carnitine-acetyltransferase-to-regulate-metabolic-flexibility-and-peripheral-nutrient-partitioning
#17
Alex Reichenbach, Romana Stark, Mathieu Mequinion, Raphael R G Denis, Jeferson F Goularte, Rachel E Clarke, Sarah H Lockie, Moyra B Lemus, Greg M Kowalski, Clinton R Bruce, Cheng Huang, Ralf B Schittenhelm, Randall L Mynatt, Brian J Oldfield, Matthew J Watt, Serge Luquet, Zane B Andrews
AgRP neurons control peripheral substrate utilization and nutrient partitioning during conditions of energy deficit and nutrient replenishment, although the molecular mechanism is unknown. We examined whether carnitine acetyltransferase (Crat) in AgRP neurons affects peripheral nutrient partitioning. Crat deletion in AgRP neurons reduced food intake and feeding behavior and increased glycerol supply to the liver during fasting, as a gluconeogenic substrate, which was mediated by changes to sympathetic output and peripheral fatty acid metabolism in the liver...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444427/an-excitatory-neural-assembly-encodes-short-term-memory-in-the-prefrontal-cortex
#18
Yonglu Tian, Chaojuan Yang, Yaxuan Cui, Feng Su, Yongjie Wang, Yangzhen Wang, Peijiang Yuan, Shujiang Shang, Hao Li, Jizong Zhao, Desheng Zhu, Shiming Tang, Peng Cao, Yunbo Liu, Xunli Wang, Liecheng Wang, Wenbo Zeng, Haifei Jiang, Fei Zhao, Minhua Luo, Wei Xiong, Zilong Qiu, Xiang-Yao Li, Chen Zhang
Short-term memory (STM) is crucial for animals to hold information for a small period of time. Persistent or recurrent neural activity, together with neural oscillations, is known to encode the STM at the cellular level. However, the coding mechanisms at the microcircuitry level remain a mystery. Here, we performed two-photon imaging on behaving mice to monitor the activity of neuronal microcircuitry. We discovered a neuronal subpopulation in the medial prefrontal cortex (mPFC) that exhibited emergent properties in a context-dependent manner underlying a STM-like behavior paradigm...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444426/inferior-olive-hcn1-channels-coordinate-synaptic-integration-and-complex-spike-timing
#19
Derek L F Garden, Marlies Oostland, Marta Jelitai, Arianna Rinaldi, Ian Duguid, Matthew F Nolan
Cerebellar climbing-fiber-mediated complex spikes originate from neurons in the inferior olive (IO), are critical for motor coordination, and are central to theories of cerebellar learning. Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels expressed by IO neurons have been considered as pacemaker currents important for oscillatory and resonant dynamics. Here, we demonstrate that in vitro, network actions of HCN1 channels enable bidirectional glutamatergic synaptic responses, while local actions of HCN1 channels determine the timing and waveform of synaptically driven action potentials...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444425/modulation-of-apoptosis-controls-inhibitory-interneuron-number-in-the-cortex
#20
Myrto Denaxa, Guilherme Neves, Adam Rabinowitz, Sarah Kemlo, Petros Liodis, Juan Burrone, Vassilis Pachnis
Cortical networks are composed of excitatory projection neurons and inhibitory interneurons. Finding the right balance between the two is important for controlling overall cortical excitation and network dynamics. However, it is unclear how the correct number of cortical interneurons (CIs) is established in the mammalian forebrain. CIs are generated in excess from basal forebrain progenitors, and their final numbers are adjusted via an intrinsically determined program of apoptosis that takes place during an early postnatal window...
February 13, 2018: Cell Reports
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