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https://www.readbyqxmd.com/read/29681455/the-structure-of-the-necrosome-ripk1-ripk3-core-a-human-hetero-amyloid-signaling-complex
#1
Miguel Mompeán, Wenbo Li, Jixi Li, Ségolène Laage, Ansgar B Siemer, Gunes Bozkurt, Hao Wu, Ann E McDermott
The RIPK1-RIPK3 necrosome is an amyloid signaling complex that initiates TNF-induced necroptosis, serving in human immune defense, cancer, and neurodegenerative diseases. RIPK1 and RIPK3 associate through their RIP homotypic interaction motifs with consensus sequences IQIG (RIPK1) and VQVG (RIPK3). Using solid-state nuclear magnetic resonance, we determined the high-resolution structure of the RIPK1-RIPK3 core. RIPK1 and RIPK3 alternately stack (RIPK1, RIPK3, RIPK1, RIPK3, etc.) to form heterotypic β sheets...
April 16, 2018: Cell
https://www.readbyqxmd.com/read/29681457/the-evolutionary-landscape-of-localized-prostate-cancers-drives-clinical-aggression
#2
Shadrielle Melijah G Espiritu, Lydia Y Liu, Yulia Rubanova, Vinayak Bhandari, Erle M Holgersen, Lesia M Szyca, Natalie S Fox, Melvin L K Chua, Takafumi N Yamaguchi, Lawrence E Heisler, Julie Livingstone, Jeff Wintersinger, Fouad Yousif, Emilie Lalonde, Alexandre Rouette, Adriana Salcedo, Kathleen E Houlahan, Constance H Li, Vincent Huang, Michael Fraser, Theodorus van der Kwast, Quaid D Morris, Robert G Bristow, Paul C Boutros
The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localized prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features. Early tumor development is characterized by point mutations and deletions followed by later subclonal amplifications and changes in trinucleotide mutational signatures...
April 14, 2018: Cell
https://www.readbyqxmd.com/read/29681456/chemoresistance-evolution-in-triple-negative-breast-cancer-delineated-by-single-cell-sequencing
#3
Charissa Kim, Ruli Gao, Emi Sei, Rachel Brandt, Johan Hartman, Thomas Hatschek, Nicola Crosetto, Theodoros Foukakis, Nicholas E Navin
Triple-negative breast cancer (TNBC) is an aggressive subtype that frequently develops resistance to chemotherapy. An unresolved question is whether resistance is caused by the selection of rare pre-existing clones or alternatively through the acquisition of new genomic aberrations. To investigate this question, we applied single-cell DNA and RNA sequencing in addition to bulk exome sequencing to profile longitudinal samples from 20 TNBC patients during neoadjuvant chemotherapy (NAC). Deep-exome sequencing identified 10 patients in which NAC led to clonal extinction and 10 patients in which clones persisted after treatment...
April 13, 2018: Cell
https://www.readbyqxmd.com/read/29681454/chemistry-first-approach-for-nomination-of-personalized-treatment-in-lung-cancer
#4
Elizabeth A McMillan, Myung-Jeom Ryu, Caroline H Diep, Saurabh Mendiratta, Jean R Clemenceau, Rachel M Vaden, Ju-Hwa Kim, Takashi Motoyaji, Kyle R Covington, Michael Peyton, Kenneth Huffman, Xiaofeng Wu, Luc Girard, Yeojin Sung, Pei-Hsaun Chen, Prema L Mallipeddi, Joo Young Lee, Jordan Hanson, Sukesh Voruganti, Yunku Yu, Sunho Park, Jessica Sudderth, Christopher DeSevo, Donna M Muzny, HarshaVardhan Doddapaneni, Adi Gazdar, Richard A Gibbs, Tae-Hyun Hwang, John V Heymach, Ignacio Wistuba, Kevin R Coombes, Noelle S Williams, David A Wheeler, John B MacMillan, Ralph J Deberardinis, Michael G Roth, Bruce A Posner, John D Minna, Hyun Seok Kim, Michael A White
Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer...
April 11, 2018: Cell
https://www.readbyqxmd.com/read/29656896/opposite-roles-of-salicylic-acid-receptors-npr1-and-npr3-npr4-in-transcriptional-regulation-of-plant-immunity
#5
Yuli Ding, Tongjun Sun, Kevin Ao, Yujun Peng, Yaxi Zhang, Xin Li, Yuelin Zhang
Salicylic acid (SA) is a plant defense hormone required for immunity. Arabidopsis NPR1 and NPR3/NPR4 were previously shown to bind SA and all three proteins were proposed as SA receptors. NPR1 functions as a transcriptional co-activator, whereas NPR3/NPR4 were suggested to function as E3 ligases that promote NPR1 degradation. Here we report that NPR3/NPR4 function as transcriptional co-repressors and SA inhibits their activities to promote the expression of downstream immune regulators. npr4-4D, a gain-of-function npr4 allele that renders NPR4 unable to bind SA, constitutively represses SA-induced immune responses...
April 11, 2018: Cell
https://www.readbyqxmd.com/read/29656894/deterministic-evolutionary-trajectories-influence-primary-tumor-growth-tracerx-renal
#6
Samra Turajlic, Hang Xu, Kevin Litchfield, Andrew Rowan, Stuart Horswell, Tim Chambers, Tim O'Brien, Jose I Lopez, Thomas B K Watkins, David Nicol, Mark Stares, Ben Challacombe, Steve Hazell, Ashish Chandra, Thomas J Mitchell, Lewis Au, Claudia Eichler-Jonsson, Faiz Jabbar, Aspasia Soultati, Simon Chowdhury, Sarah Rudman, Joanna Lynch, Archana Fernando, Gordon Stamp, Emma Nye, Aengus Stewart, Wei Xing, Jonathan C Smith, Mickael Escudero, Adam Huffman, Nik Matthews, Greg Elgar, Ben Phillimore, Marta Costa, Sharmin Begum, Sophia Ward, Max Salm, Stefan Boeing, Rosalie Fisher, Lavinia Spain, Carolina Navas, Eva Grönroos, Sebastijan Hobor, Sarkhara Sharma, Ismaeel Aurangzeb, Sharanpreet Lall, Alexander Polson, Mary Varia, Catherine Horsfield, Nicos Fotiadis, Lisa Pickering, Roland F Schwarz, Bruno Silva, Javier Herrero, Nick M Luscombe, Mariam Jamal-Hanjani, Rachel Rosenthal, Nicolai J Birkbak, Gareth A Wilson, Orsolya Pipek, Dezso Ribli, Marcin Krzystanek, Istvan Csabai, Zoltan Szallasi, Martin Gore, Nicholas McGranahan, Peter Van Loo, Peter Campbell, James Larkin, Charles Swanton
The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution...
April 11, 2018: Cell
https://www.readbyqxmd.com/read/29681453/dissociable-structural-and-functional-hippocampal-outputs-via-distinct-subiculum-cell-classes
#7
Mark S Cembrowski, Matthew G Phillips, Salvatore F DiLisio, Brenda C Shields, Johan Winnubst, Jayaram Chandrashekar, Erhan Bas, Nelson Spruston
The mammalian hippocampus, comprised of serially connected subfields, participates in diverse behavioral and cognitive functions. It has been postulated that parallel circuitry embedded within hippocampal subfields may underlie such functional diversity. We sought to identify, delineate, and manipulate this putatively parallel architecture in the dorsal subiculum, the primary output subfield of the dorsal hippocampus. Population and single-cell RNA-seq revealed that the subiculum can be divided into two spatially adjacent subregions associated with prominent differences in pyramidal cell gene expression...
April 10, 2018: Cell
https://www.readbyqxmd.com/read/29656897/in-silico-labeling-predicting-fluorescent-labels-in-unlabeled-images
#8
Eric M Christiansen, Samuel J Yang, D Michael Ando, Ashkan Javaherian, Gaia Skibinski, Scott Lipnick, Elliot Mount, Alison O'Neil, Kevan Shah, Alicia K Lee, Piyush Goyal, William Fedus, Ryan Poplin, Andre Esteva, Marc Berndl, Lee L Rubin, Philip Nelson, Steven Finkbeiner
Microscopy is a central method in life sciences. Many popular methods, such as antibody labeling, are used to add physical fluorescent labels to specific cellular constituents. However, these approaches have significant drawbacks, including inconsistency; limitations in the number of simultaneous labels because of spectral overlap; and necessary perturbations of the experiment, such as fixing the cells, to generate the measurement. Here, we show that a computational machine-learning approach, which we call "in silico labeling" (ISL), reliably predicts some fluorescent labels from transmitted-light images of unlabeled fixed or live biological samples...
April 9, 2018: Cell
https://www.readbyqxmd.com/read/29656895/tracking-cancer-evolution-reveals-constrained-routes-to-metastases-tracerx-renal
#9
Samra Turajlic, Hang Xu, Kevin Litchfield, Andrew Rowan, Tim Chambers, Jose I Lopez, David Nicol, Tim O'Brien, James Larkin, Stuart Horswell, Mark Stares, Lewis Au, Mariam Jamal-Hanjani, Ben Challacombe, Ashish Chandra, Steve Hazell, Claudia Eichler-Jonsson, Aspasia Soultati, Simon Chowdhury, Sarah Rudman, Joanna Lynch, Archana Fernando, Gordon Stamp, Emma Nye, Faiz Jabbar, Lavinia Spain, Sharanpreet Lall, Rosa Guarch, Mary Falzon, Ian Proctor, Lisa Pickering, Martin Gore, Thomas B K Watkins, Sophia Ward, Aengus Stewart, Renzo DiNatale, Maria F Becerra, Ed Reznik, James J Hsieh, Todd A Richmond, George F Mayhew, Samantha M Hill, Catherine D McNally, Carol Jones, Heidi Rosenbaum, Stacey Stanislaw, Daniel L Burgess, Nelson R Alexander, Charles Swanton
Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure...
April 9, 2018: Cell
https://www.readbyqxmd.com/read/29656893/dna-repair-network-analysis-reveals-shieldin-as-a-key-regulator-of-nhej-and-parp-inhibitor-sensitivity
#10
Rajat Gupta, Kumar Somyajit, Takeo Narita, Elina Maskey, Andre Stanlie, Magdalena Kremer, Dimitris Typas, Michael Lammers, Niels Mailand, Andre Nussenzweig, Jiri Lukas, Chunaram Choudhary
Repair of damaged DNA is essential for maintaining genome integrity and for preventing genome-instability-associated diseases, such as cancer. By combining proximity labeling with quantitative mass spectrometry, we generated high-resolution interaction neighborhood maps of the endogenously expressed DNA repair factors 53BP1, BRCA1, and MDC1. Our spatially resolved interaction maps reveal rich network intricacies, identify shared and bait-specific interaction modules, and implicate previously concealed regulators in this process...
April 7, 2018: Cell
https://www.readbyqxmd.com/read/29656892/cancer-germline-antigen-expression-discriminates-clinical-outcome-to-ctla-4-blockade
#11
Sachet A Shukla, Pavan Bachireddy, Bastian Schilling, Christina Galonska, Qian Zhan, Clyde Bango, Rupert Langer, Patrick C Lee, Daniel Gusenleitner, Derin B Keskin, Mehrtash Babadi, Arman Mohammad, Andreas Gnirke, Kendell Clement, Zachary J Cartun, Eliezer M Van Allen, Diana Miao, Ying Huang, Alexandra Snyder, Taha Merghoub, Jedd D Wolchok, Levi A Garraway, Alexander Meissner, Jeffrey S Weber, Nir Hacohen, Donna Neuberg, Patrick R Potts, George F Murphy, Christine G Lian, Dirk Schadendorf, F Stephen Hodi, Catherine J Wu
CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro...
April 6, 2018: Cell
https://www.readbyqxmd.com/read/29656891/timing-the-landmark-events-in-the-evolution-of-clear-cell-renal-cell-cancer-tracerx-renal
#12
Thomas J Mitchell, Samra Turajlic, Andrew Rowan, David Nicol, James H R Farmery, Tim O'Brien, Inigo Martincorena, Patrick Tarpey, Nicos Angelopoulos, Lucy R Yates, Adam P Butler, Keiran Raine, Grant D Stewart, Ben Challacombe, Archana Fernando, Jose I Lopez, Steve Hazell, Ashish Chandra, Simon Chowdhury, Sarah Rudman, Aspasia Soultati, Gordon Stamp, Nicos Fotiadis, Lisa Pickering, Lewis Au, Lavinia Spain, Joanna Lynch, Mark Stares, Jon Teague, Francesco Maura, David C Wedge, Stuart Horswell, Tim Chambers, Kevin Litchfield, Hang Xu, Aengus Stewart, Reza Elaidi, Stéphane Oudard, Nicholas McGranahan, Istvan Csabai, Martin Gore, P Andrew Futreal, James Larkin, Andy G Lynch, Zoltan Szallasi, Charles Swanton, Peter J Campbell
Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis...
April 4, 2018: Cell
https://www.readbyqxmd.com/read/29628141/pseudouridylation-of-trna-derived-fragments-steers-translational-control-in-stem-cells
#13
Nicola Guzzi, Maciej Cieśla, Phuong Cao Thi Ngoc, Stefan Lang, Sonali Arora, Marios Dimitriou, Kristyna Pimková, Mikael N E Sommarin, Roberto Munita, Michal Lubas, Yiting Lim, Kazuki Okuyama, Shamit Soneji, Göran Karlsson, Jenny Hansson, Göran Jönsson, Anders H Lund, Mikael Sigvardsson, Eva Hellström-Lindberg, Andrew C Hsieh, Cristian Bellodi
Pseudouridylation (Ψ) is the most abundant and widespread type of RNA epigenetic modification in living organisms; however, the biological role of Ψ remains poorly understood. Here, we show that a Ψ-driven posttranscriptional program steers translation control to impact stem cell commitment during early embryogenesis. Mechanistically, the Ψ "writer" PUS7 modifies and activates a novel network of tRNA-derived small fragments (tRFs) targeting the translation initiation complex. PUS7 inactivation in embryonic stem cells impairs tRF-mediated translation regulation, leading to increased protein biosynthesis and defective germ layer specification...
April 4, 2018: Cell
https://www.readbyqxmd.com/read/29628143/stress-granule-assembly-disrupts-nucleocytoplasmic-transport
#14
Ke Zhang, J Gavin Daigle, Kathleen M Cunningham, Alyssa N Coyne, Kai Ruan, Jonathan C Grima, Kelly E Bowen, Harsh Wadhwa, Peiguo Yang, Frank Rigo, J Paul Taylor, Aaron D Gitler, Jeffrey D Rothstein, Thomas E Lloyd
Defects in nucleocytoplasmic transport have been identified as a key pathogenic event in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mediated by a GGGGCC hexanucleotide repeat expansion in C9ORF72, the most common genetic cause of ALS/FTD. Furthermore, nucleocytoplasmic transport disruption has also been implicated in other neurodegenerative diseases with protein aggregation, suggesting a shared mechanism by which protein stress disrupts nucleocytoplasmic transport. Here, we show that cellular stress disrupts nucleocytoplasmic transport by localizing critical nucleocytoplasmic transport factors into stress granules, RNA/protein complexes that play a crucial role in ALS pathogenesis...
April 2, 2018: Cell
https://www.readbyqxmd.com/read/29628142/a-kinesin-14-motor-activates-neocentromeres-to-promote-meiotic-drive-in-maize
#15
R Kelly Dawe, Elizabeth G Lowry, Jonathan I Gent, Michelle C Stitzer, Kyle W Swentowsky, David M Higgins, Jeffrey Ross-Ibarra, Jason G Wallace, Lisa B Kanizay, Magdy Alabady, Weihong Qiu, Kuo-Fu Tseng, Na Wang, Zhi Gao, James A Birchler, Alex E Harkess, Amy L Hodges, Evelyn N Hiatt
Maize abnormal chromosome 10 (Ab10) encodes a classic example of true meiotic drive that converts heterochromatic regions called knobs into motile neocentromeres that are preferentially transmitted to egg cells. Here, we identify a cluster of eight genes on Ab10, called the Kinesin driver (Kindr) complex, that are required for both neocentromere motility and preferential transmission. Two meiotic drive mutants that lack neocentromere activity proved to be kindr epimutants with increased DNA methylation across the entire gene cluster...
April 2, 2018: Cell
https://www.readbyqxmd.com/read/29628140/disease-causing-mutations-in-the-g-protein-g%C3%AE-s-subvert-the-roles-of-gdp-and-gtp
#16
Qi Hu, Kevan M Shokat
The single most frequent cancer-causing mutation across all heterotrimeric G proteins is R201C in Gαs. The current model explaining the gain-of-function activity of the R201 mutations is through the loss of GTPase activity and resulting inability to switch off to the GDP state. Here, we find that the R201C mutation can bypass the need for GTP binding by directly activating GDP-bound Gαs through stabilization of an intramolecular hydrogen bond network. Having found that a gain-of-function mutation can convert GDP into an activator, we postulated that a reciprocal mutation might disrupt the normal role of GTP...
April 1, 2018: Cell
https://www.readbyqxmd.com/read/29606356/tumor-induced-generation-of-splenic-erythroblast-like-ter-cells-promotes-tumor-progression
#17
Yanmei Han, Qiuyan Liu, Jin Hou, Yan Gu, Yi Zhang, Zhubo Chen, Jia Fan, Weiping Zhou, Shuangjian Qiu, Yonghong Zhang, Tao Dong, Ning Li, Zhengping Jiang, Ha Zhu, Qian Zhang, Yuanwu Ma, Lianfeng Zhang, Qingqing Wang, Yizhi Yu, Nan Li, Xuetao Cao
Identifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119+ CD45- CD71+ phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood...
March 28, 2018: Cell
https://www.readbyqxmd.com/read/29606355/fetal-neuropathology-in-zika-virus-infected-pregnant-female-rhesus-monkeys
#18
Amanda J Martinot, Peter Abbink, Onur Afacan, Anna K Prohl, Roderick Bronson, Jonathan L Hecht, Erica N Borducchi, Rafael A Larocca, Rebecca L Peterson, William Rinaldi, Melissa Ferguson, Peter J Didier, Deborah Weiss, Mark G Lewis, Rafael A De La Barrera, Edward Yang, Simon K Warfield, Dan H Barouch
The development of interventions to prevent congenital Zika syndrome (CZS) has been limited by the lack of an established nonhuman primate model. Here we show that infection of female rhesus monkeys early in pregnancy with Zika virus (ZIKV) recapitulates many features of CZS in humans. We infected 9 pregnant monkeys with ZIKV, 6 early in pregnancy (weeks 6-7 of gestation) and 3 later in pregnancy (weeks 12-14 of gestation), and compared findings with uninfected controls. 100% (6 of 6) of monkeys infected early in pregnancy exhibited prolonged maternal viremia and fetal neuropathology, including fetal loss, smaller brain size, and histopathologic brain lesions, including microcalcifications, hemorrhage, necrosis, vasculitis, gliosis, and apoptosis of neuroprogenitor cells...
March 28, 2018: Cell
https://www.readbyqxmd.com/read/29606354/visualization-of-membrane-pore-in-live-cells-reveals-a-dynamic-pore-theory-governing-fusion-and-endocytosis
#19
Wonchul Shin, Lihao Ge, Gianvito Arpino, Seth A Villarreal, Edaeni Hamid, Huisheng Liu, Wei-Dong Zhao, Peter J Wen, Hsueh-Cheng Chiang, Ling-Gang Wu
Fusion is thought to open a pore to release vesicular cargoes vital for many biological processes, including exocytosis, intracellular trafficking, fertilization, and viral entry. However, fusion pores have not been observed and thus proved in live cells. Its regulatory mechanisms and functions remain poorly understood. With super-resolution STED microscopy, we observed dynamic fusion pore behaviors in live (neuroendocrine) cells, including opening, expansion, constriction, and closure, where pore size may vary between 0 and 490 nm within 26 milliseconds to seconds (vesicle size: 180-720 nm)...
March 28, 2018: Cell
https://www.readbyqxmd.com/read/29606353/direct-promoter-repression-by-bcl11a-controls-the-fetal-to-adult-hemoglobin-switch
#20
Nan Liu, Victoria V Hargreaves, Qian Zhu, Jesse V Kurland, Jiyoung Hong, Woojin Kim, Falak Sher, Claudio Macias-Trevino, Julia M Rogers, Ryo Kurita, Yukio Nakamura, Guo-Cheng Yuan, Daniel E Bauer, Jian Xu, Martha L Bulyk, Stuart H Orkin
Fetal hemoglobin (HbF, α2 γ2 ) level is genetically controlled and modifies severity of adult hemoglobin (HbA, α2 β2 ) disorders, sickle cell disease, and β-thalassemia. Common genetic variation affects expression of BCL11A, a regulator of HbF silencing. To uncover how BCL11A supports the developmental switch from γ- to β- globin, we use a functional assay and protein binding microarray to establish a requirement for a zinc-finger cluster in BCL11A in repression and identify a preferred DNA recognition sequence...
March 28, 2018: Cell
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