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Cell Reports

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https://www.readbyqxmd.com/read/29212041/soluble-prefusion-closed-ds-sosip-664-env-trimers-of-diverse-hiv-1-strains
#1
M Gordon Joyce, Ivelin S Georgiev, Yongping Yang, Aliaksandr Druz, Hui Geng, Gwo-Yu Chuang, Young Do Kwon, Marie Pancera, Reda Rawi, Mallika Sastry, Guillaume B E Stewart-Jones, Angela Zheng, Tongqing Zhou, Misook Choe, Joseph G Van Galen, Rita E Chen, Christopher R Lees, Sandeep Narpala, Michael Chambers, Yaroslav Tsybovsky, Ulrich Baxa, Adrian B McDermott, John R Mascola, Peter D Kwong
The elicitation of autologous neutralizing responses by immunization with HIV-1 envelope (Env) trimers conformationally stabilized in a prefusion closed state has generated considerable interest in the HIV-1 vaccine field. However, soluble prefusion closed Env trimers have been produced from only a handful of HIV-1 strains, limiting their utility as vaccine antigens and B cell probes. Here, we report the engineering from 81 HIV-1 strains of soluble, fully cleaved, prefusion Env trimers with appropriate antigenicity...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212040/molecular-and-cellular-organization-of-taste-neurons-in-adult-drosophila-pharynx
#2
Yu-Chieh David Chen, Anupama Dahanukar
The Drosophila pharyngeal taste organs are poorly characterized despite their location at important sites for monitoring food quality. Functional analysis of pharyngeal neurons has been hindered by the paucity of molecular tools to manipulate them, as well as their relative inaccessibility for neurophysiological investigations. Here, we generate receptor-to-neuron maps of all three pharyngeal taste organs by performing a comprehensive chemoreceptor-GAL4/LexA expression analysis. The organization of pharyngeal neurons reveals similarities and distinctions in receptor repertoires and neuronal groupings compared to external taste neurons...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212039/comprehensive-mapping-of-pluripotent-stem-cell-metabolism-using-dynamic-genome-scale-network-modeling
#3
Sriram Chandrasekaran, Jin Zhang, Zhen Sun, Li Zhang, Christian A Ross, Yu-Chung Huang, John M Asara, Hu Li, George Q Daley, James J Collins
Metabolism is an emerging stem cell hallmark tied to cell fate, pluripotency, and self-renewal, yet systems-level understanding of stem cell metabolism has been limited by the lack of genome-scale network models. Here, we develop a systems approach to integrate time-course metabolomics data with a computational model of metabolism to analyze the metabolic state of naive and primed murine pluripotent stem cells. Using this approach, we find that one-carbon metabolism involving phosphoglycerate dehydrogenase, folate synthesis, and nucleotide synthesis is a key pathway that differs between the two states, resulting in differential sensitivity to anti-folates...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212038/co-chaperone-bag2-determines-the-pro-oncogenic-role-of-cathepsin-b-in-triple-negative-breast-cancer-cells
#4
Kyung-Min Yang, Eunjin Bae, Sung Gwe Ahn, Kyoungwha Pang, Yuna Park, Jinah Park, Jihee Lee, Akira Ooshima, Bora Park, Junil Kim, Yunshin Jung, Satoru Takahashi, Joon Jeong, Seok Hee Park, Seong-Jin Kim
Triple-negative breast cancer (TNBC) is considered incurable with currently available treatments, highlighting the need for therapeutic targets and predictive biomarkers. Here, we report a unique role for Bcl-2-associated athanogene 2 (BAG2), which is significantly overexpressed in TNBC, in regulating the dual functions of cathepsin B as either a pro- or anti-oncogenic enzyme. Silencing BAG2 suppresses tumorigenesis and lung metastasis and induces apoptosis by increasing the intracellular mature form of cathepsin B, whereas BAG2 expression induces metastasis by blocking the auto-cleavage processing of pro-cathepsin B via interaction with the propeptide region...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212037/a-bacterial-receptor-pcrk-senses-the-plant-hormone-cytokinin-to-promote-adaptation-to-oxidative-stress
#5
Fang-Fang Wang, Shou-Ting Cheng, Yao Wu, Bao-Zhen Ren, Wei Qian
Recognition of the host plant is a prerequisite for infection by pathogenic bacteria. However, how bacterial cells sense plant-derived stimuli, especially chemicals that function in regulating plant development, remains completely unknown. Here, we have identified a membrane-bound histidine kinase of the phytopathogenic bacterium Xanthomonas campestris, PcrK, as a bacterial receptor that specifically detects the plant cytokinin 2-isopentenyladenine (2iP). 2iP binds to the extracytoplasmic region of PcrK to decrease its autokinase activity...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212036/%C3%AE-np63-inhibits-oxidative-stress-induced-cell-death-including-ferroptosis-and-cooperates-with-the-bcl-2-family-to-promote-clonogenic-survival
#6
Gary X Wang, Ho-Chou Tu, Yiyu Dong, Anders Jacobsen Skanderup, Yufeng Wang, Shugaku Takeda, Yogesh Tengarai Ganesan, Song Han, Han Liu, James J Hsieh, Emily H Cheng
The BCL-2 family proteins are central regulators of apoptosis. However, cells deficient for BAX and BAK or overexpressing BCL-2 still succumb to oxidative stress upon DNA damage or matrix detachment. Here, we show that ΔNp63α overexpression protects cells from oxidative stress induced by oxidants, DNA damage, anoikis, or ferroptosis-inducing agents. Conversely, ΔNp63α deficiency increases oxidative stress. Mechanistically, ΔNp63α orchestrates redox homeostasis through transcriptional control of glutathione biogenesis, utilization, and regeneration...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212035/comprehensive-characterization-of-the-complex-lola-locus-reveals-a-novel-role-in-the-octopaminergic-pathway-via-tyramine-beta-hydroxylase-regulation
#7
Nadja Dinges, Violeta Morin, Nastasja Kreim, Tony D Southall, Jean-Yves Roignant
Longitudinals lacking (lola) is one of the most complex genes in Drosophila melanogaster, encoding up to 20 protein isoforms that include key transcription factors involved in axonal pathfinding and neural reprogramming. Most previous studies have employed loss-of-function alleles that disrupt lola common exons, making it difficult to delineate isoform-specific functions. To overcome this issue, we have generated isoform-specific mutants for all isoforms using CRISPR/Cas9. This enabled us to study specific isoforms with respect to previously characterized roles for Lola and to demonstrate a specific function for one variant in axon guidance via activation of the microtubule-associated factor Futsch...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212034/gadd34-function-in-protein-trafficking-promotes-adaptation-to-hyperosmotic-stress-in-human-corneal-cells
#8
Dawid Krokowski, Bo-Jhih Guan, Jing Wu, Yuke Zheng, Padmanabhan P Pattabiraman, Raul Jobava, Xing-Huang Gao, Xiao-Jing Di, Martin D Snider, Ting-Wei Mu, Shijie Liu, Brian Storrie, Eric Pearlman, Anna Blumental-Perry, Maria Hatzoglou
GADD34, a stress-induced regulatory subunit of the phosphatase PP1, is known to function in hyperosmotic stress through its well-known role in the integrated stress response (ISR) pathway. Adaptation to hyperosmotic stress is important for the health of corneal epithelial cells exposed to changes in extracellular osmolarity, with maladaptation leading to dry eye syndrome. This adaptation includes induction of SNAT2, an endoplasmic reticulum (ER)-Golgi-processed protein, which helps to reverse the stress-induced loss of cell volume and promote homeostasis through amino acid uptake...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212033/enhancer-sines-link-pol-iii-to-pol-ii-transcription-in-neurons
#9
Cristina Policarpi, Luca Crepaldi, Emily Brookes, Justyna Nitarska, Sarah M French, Alessandro Coatti, Antonella Riccio
Spatiotemporal regulation of gene expression depends on the cooperation of multiple mechanisms, including the functional interaction of promoters with distally located enhancers. Here, we show that, in cortical neurons, a subset of short interspersed nuclear elements (SINEs) located in the proximity of activity-regulated genes bears features of enhancers. Enhancer SINEs (eSINEs) recruit the Pol III cofactor complex TFIIIC in a stimulus-dependent manner and are transcribed by Pol III in response to neuronal depolarization...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212032/targeting-the-conserved-fusion-loop-of-hap2-inhibits-the-transmission-of-plasmodium-berghei-and-falciparum
#10
Fiona Angrisano, Katarzyna A Sala, Dari F Da, Yanjie Liu, Jimin Pei, Nick V Grishin, William J Snell, Andrew M Blagborough
Inhibiting transmission of Plasmodium is a central strategy in malarial eradication, and the biological process of gamete fusion during fertilization is a proven target for this approach. The lack of a structure or known molecular function of current anti-malarial vaccine targets has previously been a hindrance in the development of transmission-blocking vaccines. Structure/function studies have indicated that the conserved gamete membrane fusion protein HAP2 is a class II viral fusion protein. Here, we demonstrate that targeting a function-critical site of the fusion/cd loop with species-specific antibodies reduces Plasmodium berghei transmission in vivo by 58...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212031/integration-of-gpcr-signaling-and-sorting-from-very-early-endosomes-via-opposing-appl1-mechanisms
#11
Silvia Sposini, Frederic G Jean-Alphonse, Mohammed A Ayoub, Affiong Oqua, Camilla West, Stuart Lavery, Jan J Brosens, Eric Reiter, Aylin C Hanyaloglu
Endocytic trafficking is a critical mechanism for cells to decode complex signaling pathways, including those activated by G-protein-coupled receptors (GPCRs). Heterogeneity in the endosomal network enables GPCR activity to be spatially restricted between early endosomes (EEs) and the recently discovered endosomal compartment, the very early endosome (VEE). However, the molecular machinery driving GPCR activity from the VEE is unknown. Using luteinizing hormone receptor (LHR) as a prototype GPCR for this compartment, along with additional VEE-localized GPCRs, we identify a role for the adaptor protein APPL1 in rapid recycling and endosomal cAMP signaling without impacting the EE-localized β2-adrenergic receptor...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212030/loss-of-caveolin-1-in-metastasis-associated-macrophages-drives-lung-metastatic-growth-through-increased-angiogenesis
#12
Ward Celus, Giusy Di Conza, Ana Isabel Oliveira, Manuel Ehling, Bruno M Costa, Mathias Wenes, Massimiliano Mazzone
Although it is well established that tumor-associated macrophages take part in each step of cancer progression, less is known about the distinct role of the so-called metastasis-associated macrophages (MAMs) at the metastatic site. Previous studies reported that Caveolin-1 (Cav1) has both tumor-promoting and tumor-suppressive functions. However, the role of Cav1 in bone-marrow-derived cells is unknown. Here, we describe Cav1 as an anti-metastatic regulator in mouse models of lung and breast cancer pulmonary metastasis...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212029/melk-promotes-melanoma-growth-by-stimulating-the-nf-%C3%AE%C2%BAb-pathway
#13
Radoslav Janostiak, Navin Rauniyar, TuKiet T Lam, Jianhong Ou, Lihua J Zhu, Michael R Green, Narendra Wajapeyee
Melanoma accounts for more than 80% of skin cancer-related deaths, and current therapies provide only short-term benefit to patients. Here, we show in melanoma cells that maternal embryonic leucine zipper kinase (MELK) is transcriptionally upregulated by the MAPK pathway via transcription factor E2F1. MELK knockdown or pharmacological inhibition blocked melanoma growth and enhanced the effectiveness of BRAFV600E inhibitor against melanoma cells. To identify mediators of MELK function, we performed stable isotope labeling with amino acids in cell culture (SILAC) and identified 469 proteins that had downregulated phosphorylation after MELK inhibition...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212028/non-canonical-hedgehog-signaling-is-a-positive-regulator-of-the-wnt-pathway-and-is-required-for-the-survival-of-colon-cancer-stem-cells
#14
Joseph L Regan, Dirk Schumacher, Stephanie Staudte, Andreas Steffen, Johannes Haybaeck, Ulrich Keilholz, Caroline Schweiger, Nicole Golob-Schwarzl, Dominik Mumberg, David Henderson, Hans Lehrach, Christian R A Regenbrecht, Reinhold Schäfer, Martin Lange
Colon cancer is a heterogeneous tumor driven by a subpopulation of cancer stem cells (CSCs). To study CSCs in colon cancer, we used limiting dilution spheroid and serial xenotransplantation assays to functionally define the frequency of CSCs in a panel of patient-derived cancer organoids. These studies demonstrated cancer organoids to be enriched for CSCs, which varied in frequency between tumors. Whole-transcriptome analysis identified WNT and Hedgehog signaling components to be enhanced in CSC-enriched tumors and in aldehyde dehydrogenase (ALDH)-positive CSCs...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212027/melanoma-therapeutic-strategies-that-select-against-resistance-by-exploiting-myc-driven-evolutionary-convergence
#15
Katherine R Singleton, Lorin Crawford, Elizabeth Tsui, Haley E Manchester, Ophelia Maertens, Xiaojing Liu, Maria V Liberti, Anniefer N Magpusao, Elizabeth M Stein, Jennifer P Tingley, Dennie T Frederick, Genevieve M Boland, Keith T Flaherty, Shannon J McCall, Clemens Krepler, Katrin Sproesser, Meenhard Herlyn, Drew J Adams, Jason W Locasale, Karen Cichowski, Sayan Mukherjee, Kris C Wood
Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212026/differential-effects-of-egfl6-on-tumor-versus-wound-angiogenesis
#16
Kyunghee Noh, Lingegowda S Mangala, Hee-Dong Han, Ningyan Zhang, Sunila Pradeep, Sherry Y Wu, Shaolin Ma, Edna Mora, Rajesha Rupaimoole, Dahai Jiang, Yunfei Wen, Mian M K Shahzad, Yasmin Lyons, MinSoon Cho, Wei Hu, Archana S Nagaraja, Monika Haemmerle, Celia S L Mak, Xiuhui Chen, Kshipra M Gharpure, Hui Deng, Wei Xiong, Charles V Kingsley, Jinsong Liu, Nicholas Jennings, Michael J Birrer, Richard R Bouchard, Gabriel Lopez-Berestein, Robert L Coleman, Zhiqiang An, Anil K Sood
Angiogenesis inhibitors are important for cancer therapy, but clinically approved anti-angiogenic agents have shown only modest efficacy and can compromise wound healing. This necessitates the development of novel anti-angiogenesis therapies. Here, we show significantly increased EGFL6 expression in tumor versus wound or normal endothelial cells. Using a series of in vitro and in vivo studies with orthotopic and genetically engineered mouse models, we demonstrate the mechanisms by which EGFL6 stimulates tumor angiogenesis...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212025/convergence-of-bmi1-and-chd7-on-erk-signaling-in-medulloblastoma
#17
Sara Badodi, Adrian Dubuc, Xinyu Zhang, Gabriel Rosser, Mariane Da Cunha Jaeger, Michelle M Kameda-Smith, Anca Sorana Morrissy, Paul Guilhamon, Philipp Suetterlin, Xiao-Nan Li, Loredana Guglielmi, Ashirwad Merve, Hamza Farooq, Mathieu Lupien, Sheila K Singh, M Albert Basson, Michael D Taylor, Silvia Marino
We describe molecular convergence between BMI1 and CHD7 in the initiation of medulloblastoma. Identified in a functional genomic screen in mouse models, a BMI1High;CHD7Low expression signature within medulloblastoma characterizes patients with poor overall survival. We show that BMI1-mediated repression of the ERK1/2 pathway leads to increased proliferation and tumor burden in primary human MB cells and in a xenograft model, respectively. We provide evidence that repression of the ERK inhibitor DUSP4 by BMI1 is dependent on a more accessible chromatin configuration in G4 MB cells with low CHD7 expression...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212024/cell-type-specific-splicing-of-piezo2-regulates-mechanotransduction
#18
Marcin Szczot, Leah A Pogorzala, Hans Jürgen Solinski, Lynn Young, Philina Yee, Claire E Le Pichon, Alexander T Chesler, Mark A Hoon
Piezo2 is a mechanically activated ion channel required for touch discrimination, vibration detection, and proprioception. Here, we discovered that Piezo2 is extensively spliced, producing different Piezo2 isoforms with distinct properties. Sensory neurons from both mice and humans express a large repertoire of Piezo2 variants, whereas non-neuronal tissues express predominantly a single isoform. Notably, even within sensory ganglia, we demonstrate the splicing of Piezo2 to be cell type specific. Biophysical characterization revealed substantial differences in ion permeability, sensitivity to calcium modulation, and inactivation kinetics among Piezo2 splice variants...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212023/disc1-modulates-neuronal-stress-responses-by-gate-keeping-er-mitochondria-ca2-transfer-through-the-mam
#19
Sung Jin Park, Su Been Lee, Yeongjun Suh, Su-Jeong Kim, Namgyu Lee, Ji-Ho Hong, Cana Park, Youngsik Woo, Koko Ishizuka, Joung-Hun Kim, Per-Olof Berggren, Akira Sawa, Sang Ki Park
A wide range of Ca2+-mediated functions are enabled by the dynamic properties of Ca2+, all of which are dependent on the endoplasmic reticulum (ER) and mitochondria. Disrupted-in-schizophrenia 1 (DISC1) is a scaffold protein that is involved in the function of intracellular organelles and is linked to cognitive and emotional deficits. Here, we demonstrate that DISC1 localizes to the mitochondria-associated ER membrane (MAM). At the MAM, DISC1 interacts with IP3R1 and downregulates its ligand binding, modulating ER-mitochondria Ca2+ transfer through the MAM...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212022/alpha2delta-1-in-sf1-neurons-of-the-ventromedial-hypothalamus-is-an-essential-regulator-of-glucose-and-lipid-homeostasis
#20
Jennifer A Felsted, Cheng-Hao Chien, Dongqing Wang, Micaella Panessiti, Dominique Ameroso, Andrew Greenberg, Guoping Feng, Dong Kong, Maribel Rios
The central mechanisms controlling glucose and lipid homeostasis are inadequately understood. We show that α2δ-1 is an essential regulator of glucose and lipid balance, acting in steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus (VMH). These effects are body weight independent and involve regulation of SF1+ neuronal activity and sympathetic output to metabolic tissues. Accordingly, mice with α2δ-1 deletion in SF1 neurons exhibit glucose intolerance, altered lipolysis, and decreased cholesterol content in adipose tissue despite normal energy balance regulation...
December 5, 2017: Cell Reports
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