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  • 1. Bergmann, Olaf
    et al.
    Zdunek, Sofia
    Felker, Anastasia
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Alkass, Kanar
    Bernard, Samuel
    Sjostrom, Staffan L.
    Szewczykowska, Mirosawa
    Jackowska, Teresa
    dos Remedios, Cris
    Malm, Torsten
    Andrae, Michaela
    Jashari, Ramadan
    Nyengaard, Jens R.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Jovinge, Stefan
    Druid, Henrik
    Frisen, Jonas
    Dynamics of Cell Generation and Turnover in the Human Heart2015In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 161, no 7, p. 1566-1575Article in journal (Refereed)
    Abstract [en]

    The contribution of cell generation to physiological heart growth and maintenance in humans has been difficult to establish and has remained controversial. We report that the full complement of cardiomyocytes is established perinataly and remains stable over the human lifespan, whereas the numbers of both endothelial and mesenchymal cells increase substantially from birth to early adulthood. Analysis of the integration of nuclear bomb test-derived C-14 revealed a high turnover rate of endothelial cells throughout life (>15% per year) and more limited renewal of mesenchymal cells (<4% per year in adulthood). Cardiomyocyte exchange is highest in early childhood and decreases gradually throughout life to <1% per year in adulthood, with similar turnover rates in the major subdivisions of the myocardium. We provide an integrated model of cell generation and turnover in the human heart.

  • 2. Bertram, Lars
    et al.
    Schjeide, Brit-Maren M.
    Hooli, Basavaraj
    Mullin, Kristina
    Hiltunen, Mikko
    Soininen, Hilkka
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Blacker, Deborah
    Tanzi, Rudolph E.
    No association between CALHM1 and Alzheimer's disease risk2008In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 135, no 6, p. 993-994Article in journal (Refereed)
  • 3. Bowman, John L
    et al.
    Kohchi, Takayuki
    Yamato, Katsuyuki T
    Jenkins, Jerry
    Shu, Shengqiang
    Ishizaki, Kimitsune
    Yamaoka, Shohei
    Nishihama, Ryuichi
    Nakamura, Yasukazu
    Berger, Frédéric
    Adam, Catherine
    Aki, Shiori Sugamata
    Althoff, Felix
    Araki, Takashi
    Arteaga-Vazquez, Mario A
    Balasubrmanian, Sureshkumar
    Barry, Kerrie
    Bauer, Diane
    Boehm, Christian R
    Briginshaw, Liam
    Caballero-Perez, Juan
    Catarino, Bruno
    Chen, Feng
    Chiyoda, Shota
    Chovatia, Mansi
    Davies, Kevin M
    Delmans, Mihails
    Demura, Taku
    Dierschke, Tom
    Dolan, Liam
    Dorantes-Acosta, Ana E
    Eklund, D. Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution. Monash Univ, Sch Biol Sci, Melbourne, Vic 3800, Australia.
    Florent, Stevie N
    Flores-Sandoval, Eduardo
    Fujiyama, Asao
    Fukuzawa, Hideya
    Galik, Bence
    Grimanelli, Daniel
    Grimwood, Jane
    Grossniklaus, Ueli
    Hamada, Takahiro
    Haseloff, Jim
    Hetherington, Alexander J
    Higo, Asuka
    Hirakawa, Yuki
    Hundley, Hope N
    Ikeda, Yoko
    Inoue, Keisuke
    Inoue, Shin-Ichiro
    Ishida, Sakiko
    Jia, Qidong
    Kakita, Mitsuru
    Kanazawa, Takehiko
    Kawai, Yosuke
    Kawashima, Tomokazu
    Kennedy, Megan
    Kinose, Keita
    Kinoshita, Toshinori
    Kohara, Yuji
    Koide, Eri
    Komatsu, Kenji
    Kopischke, Sarah
    Kubo, Minoru
    Kyozuka, Junko
    Lagercrantz, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Lin, Shih-Shun
    Lindquist, Erika
    Lipzen, Anna M
    Lu, Chia-Wei
    De Luna, Efraín
    Martienssen, Robert A
    Minamino, Naoki
    Mizutani, Masaharu
    Mizutani, Miya
    Mochizuki, Nobuyoshi
    Monte, Isabel
    Mosher, Rebecca
    Nagasaki, Hideki
    Nakagami, Hirofumi
    Naramoto, Satoshi
    Nishitani, Kazuhiko
    Ohtani, Misato
    Okamoto, Takashi
    Okumura, Masaki
    Phillips, Jeremy
    Pollak, Bernardo
    Reinders, Anke
    Rövekamp, Moritz
    Sano, Ryosuke
    Sawa, Shinichiro
    Schmid, Marc W
    Shirakawa, Makoto
    Solano, Roberto
    Spunde, Alexander
    Suetsugu, Noriyuki
    Sugano, Sumio
    Sugiyama, Akifumi
    Sun, Rui
    Suzuki, Yutaka
    Takenaka, Mizuki
    Takezawa, Daisuke
    Tomogane, Hirokazu
    Tsuzuki, Masayuki
    Ueda, Takashi
    Umeda, Masaaki
    Ward, John M
    Watanabe, Yuichiro
    Yazaki, Kazufumi
    Yokoyama, Ryusuke
    Yoshitake, Yoshihiro
    Yotsui, Izumi
    Zachgo, Sabine
    Schmutz, Jeremy
    Insights into Land Plant Evolution Garnered from the Marchantia polymorpha Genome2017In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 171, no 2, p. 287-304.15Article in journal (Refereed)
    Abstract [en]

    The evolution of land flora transformed the terrestrial environment. Land plants evolved from an ancestral charophycean alga from which they inherited developmental, biochemical, and cell biological attributes. Additional biochemical and physiological adaptations to land, and a life cycle with an alternation between multicellular haploid and diploid generations that facilitated efficient dispersal of desiccation tolerant spores, evolved in the ancestral land plant. We analyzed the genome of the liverwort Marchantia polymorpha, a member of a basal land plant lineage. Relative to charophycean algae, land plant genomes are characterized by genes encoding novel biochemical pathways, new phytohormone signaling pathways (notably auxin), expanded repertoires of signaling pathways, and increased diversity in some transcription factor families. Compared with other sequenced land plants, M. polymorpha exhibits low genetic redundancy in most regulatory pathways, with this portion of its genome resembling that predicted for the ancestral land plant. PAPERCLIP.

  • 4. Enge, Martin
    et al.
    Arda, H. Efsun
    Mignardi, Marco
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Bioengn & Appl Phys, Stanford, CA 94305 USA.
    Beausang, John
    Bottino, Rita
    Kim, Seung K.
    Quake, Stephen R.
    Single-cell analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns2017In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 171, no 2, p. 321-330.e14Article in journal (Refereed)
    Abstract [en]

    As organisms age, cells accumulate genetic and epigenetic errors that eventually lead to impaired organ function or catastrophic transformation such as cancer. Because aging reflects a stochastic process of increasing disorder, cells in an organ will be individually affected in different ways, thus rendering bulk analyses of postmitotic adult cells difficult to interpret. Here, we directly measure the effects of aging in human tissue by performing single-cell transcriptome analysis of 2,544 human pancreas cells from eight donors spanning six decades of life. We find that islet endocrine cells from older donors display increased levels of transcriptional noise and potential fate drift. By determining the mutational history of individual cells, we uncover a novel mutational signature in healthy aging endocrine cells. Our results demonstrate the feasibility of using single-cell RNA sequencing (RNA-seq) data from primary cells to derive insights into genetic and transcriptional processes that operate on aging human tissue.

  • 5.
    Ernst, Aurélie
    et al.
    Karolinska Institut.
    Alkass, Kanar
    Karolinska Institut.
    Bernard, Samuel
    University of Lyon, Villeurbanne, France.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Perl, Shira
    NHLBI, NIH, Bethesda, Maryland, USA.
    Tisdale, John
    NHLBI, NIH, Bethesda, Maryland, USA.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Druid, Henrik
    Karolinska Institut.
    Frisén, Jonas
    Karolinska Institut.
    Neurogenesis in the Striatum of the Adult Human Brain2014In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 156, no 5, p. 1072-1083Article in journal (Refereed)
    Abstract [en]

    Neurons are added throughout life in the hippocampus and olfactory bulb in most mammals, although humans represent an exception without detectable olfactory bulb neurogenesis. Nevertheless, neuroblasts are generated in the lateral ventricle wall in humans, the neurogenic niche for olfactory bulb neurons in other mammals. We show that, in humans, new neurons integrate adjacent to this neurogenic niche, in the striatum. The neuronal turnover in the striatum appears restricted to interneurons and we show that postnatally generated striatal neurons are preferentially depleted in Huntington’s disease. This demonstrates a unique pattern of neurogenesis in the adult human brain.  

  • 6. Gao, Haixiao
    et al.
    Zhou, Zhihong
    Rawat, Urmila
    Huang, Chenhui
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Bouakaz, Lamine
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Wang, Chernhoe
    Cheng, Zhihong
    Liu, Yuying
    Zavialov, Andrey
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Gursky, Richard
    Sanyal, Suparna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Ehrenberg, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Frank, Joachim
    Song, Haiwei
    RF3 induces ribosomal conformational changes responsible for dissociation of class I release factors2007In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 129, no 5, p. 929-941Article in journal (Refereed)
    Abstract [en]

    During translation termination, class II release factor RF3 binds to the ribosome to promote rapid dissociation of a class I release factor (RF) in a GTP-dependent manner. We present the crystal structure of E. coli RF3•GDP, which has a three-domain architecture strikingly similar to the structure of EF-Tu•GTP. Biochemical data on RF3 mutants show that a surface region involving domains II and III is important for distinct steps in the action cycle of RF3. Furthermore, we present a cryo-electron microscopy (cryo-EM) structure of the posttermination ribosome bound with RF3 in the GTP form. Our data show that RF3•GTP binding induces large conformational changes in the ribosome, which break the interactions of the class I RF with both the decoding center and the GTPase-associated center of the ribosome, apparently leading to the release of the class I RF.

  • 7.
    Hart, Traver
    et al.
    Donnelly Ctr, Toronto, ON M5S 3E1, Canada..
    Chandrashekhar, Megha
    Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada..
    Aregger, Michael
    Donnelly Ctr, Toronto, ON M5S 3E1, Canada..
    Steinhart, Zachary
    Univ Toronto, Dept Pharmaceut Sci, Toronto, ON M5S 1A1, Canada.;Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON M5S 1A1, Canada..
    Brown, Kevin R.
    Donnelly Ctr, Toronto, ON M5S 3E1, Canada..
    MacLeod, Graham
    Univ Toronto, Dept Pharmaceut Sci, Toronto, ON M5S 1A1, Canada.;Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON M5S 1A1, Canada..
    Mis, Monika
    Univ Toronto, Dept Pharmaceut Sci, Toronto, ON M5S 1A1, Canada.;Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON M5S 1A1, Canada..
    Zimmermann, Michal
    Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada..
    Fradet-Turcotte, Amelie
    Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada..
    Sun, Song
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada.;Univ Toronto, Dept Comp Sci, Toronto, ON M5G 1X8, Canada..
    Mero, Patricia
    Donnelly Ctr, Toronto, ON M5S 3E1, Canada..
    Dirks, Peter
    Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada.;Hosp Sick Children, Div Neurosurg, Program Dev & Stem Cell Biol, Toronto, ON M5G 1X8, Canada..
    Sidhu, Sachdev
    Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada..
    Roth, Frederick P.
    Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada.;Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada.;Univ Toronto, Dept Comp Sci, Toronto, ON M5G 1X8, Canada.;Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada.;Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA..
    Rissland, Olivia S.
    Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada.;Hosp Sick Children, Res Inst, Mol Struct & Funct Program, Toronto, ON M5G 0A4, Canada..
    Durocher, Daniel
    Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada.;Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada..
    Angers, Stephane
    Univ Toronto, Dept Pharmaceut Sci, Toronto, ON M5S 1A1, Canada.;Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON M5S 1A1, Canada.;Univ Toronto, Dept Biochem, Toronto, ON M5S 1A1, Canada..
    Moffat, Jason
    Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada.;Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada..
    High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities2015In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 163, no 6Article in journal (Refereed)
    Abstract [en]

    The ability to perturb genes in human cells is crucial for elucidating gene function and holds great potential for finding therapeutic targets for diseases such as cancer. To extend the catalog of human core and context-dependent fitness genes, we have developed a high-complexity second-generation genome-scale CRISPR-Cas9 gRNA library and applied it to fitness screens in five human cell lines. Using an improved Bayesian analytical approach, we consistently discover 5-fold more fitness genes than were previously observed. We present a list of 1,580 human core fitness genes and describe their general properties. Moreover, we demonstrate that context-dependent fitness genes accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and reveal cell-type-specific dependencies for specific receptor tyrosine kinases, even in oncogenic KRAS backgrounds. Thus, rigorous identification of human cell line fitness genes using a high-complexity CRISPR-Cas9 library affords a high-resolution view of the genetic vulnerabilities of a cell.

  • 8.
    Holmberg, Johan
    et al.
    Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute.
    Genander, Maria
    Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute.
    Halford, Michael M
    Annerén, Cecilia
    Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute.
    Sondell, Mariann
    Chumley, Michael J
    Silvany, Robert E
    Henkemeyer, Mark
    Frisén, Jonas
    Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute.
    EphB receptors coordinate migration and proliferation in the intestinal stem cell niche.2006In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 125, no 6, p. 1151-63Article in journal (Refereed)
    Abstract [en]

    More than 10(10) cells are generated every day in the human intestine. Wnt proteins are key regulators of proliferation and are known endogenous mitogens for intestinal progenitor cells. The positioning of cells within the stem cell niche in the intestinal epithelium is controlled by B subclass ephrins through their interaction with EphB receptors. We report that EphB receptors, in addition to directing cell migration, regulate proliferation in the intestine. EphB signaling promotes cell-cycle reentry of progenitor cells and accounts for approximately 50% of the mitogenic activity in the adult mouse small intestine and colon. These data establish EphB receptors as key coordinators of migration and proliferation in the intestinal stem cell niche.

  • 9. Jin, Jing
    et al.
    Sison, Karen
    Li, Chengjin
    Tian, Ruijun
    Wnuk, Monika
    Sung, Hoon-Ki
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Zhang, Cunjie
    Tucholska, Monika
    Jones, Nina
    Kerjaschki, Dontscho
    Shibuya, Masabumi
    Fantus, I George
    Nagy, Andras
    Gerber, Hans-Peter
    Ferrara, Napoleone
    Pawson, Tony
    Quaggin, Susan E
    Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function2012In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 151, no 2, p. 384-399Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor and its receptors, FLK1/KDR and FLT1, are key regulators of angiogenesis. Unlike FLK1/KDR, the role of FLT1 has remained elusive. FLT1 is produced as soluble (sFLT1) and full-length isoforms. Here, we show that pericytes from multiple tissues produce sFLT1. To define the biologic role of sFLT1, we chose the glomerular microvasculature as a model system. Deletion of Flt1 from specialized glomerular pericytes, known as podocytes, causes reorganization of their cytoskeleton with massive proteinuria and kidney failure, characteristic features of nephrotic syndrome in humans. The kinase-deficient allele of Flt1 rescues this phenotype, demonstrating dispensability of the full-length isoform. Using cell imaging, proteomics, and lipidomics, we show that sFLT1 binds to the glycosphingolipid GM3 in lipid rafts on the surface of podocytes, promoting adhesion and rapid actin reorganization. sFLT1 also regulates pericyte function in vessels outside of the kidney. Our findings demonstrate an autocrine function for sFLT1 to control pericyte behavior.

  • 10. Kitambi, Satish Srinivas
    et al.
    Toledo, Enrique M.
    Usoskin, Dmitry
    Wee, Shimei
    Harisankar, Aditya
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sigmundsson, Kristmundur
    Kalderen, Christina
    Niklasson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kundu, Soumi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Aranda, Sergi
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Andang, Michael
    Damberg, Peter
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arenas, Ernest
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Walfridsson, Julian
    Nilsson, Karin Forsberg
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Hammarstrom, Lars G. J.
    Ernfors, Patrik
    Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule2014In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 157, no 2, p. 313-328Article in journal (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with marginal life expectancy. Based on the assumption that GBM cells gain functions not necessarily involved in the cancerous process, patient-derived glioblastoma cells (GCs) were screened to identify cellular processes amenable for development of targeted treatments. The quinine-derivative NSC13316 reliably and selectively compromised viability. Synthetic chemical expansion reveals delicate structure-activity relationship and analogs with increased potency, termed Vacquinols. Vacquinols stimulate death by membrane ruffling, cell rounding, massive macropinocytic vacuole accumulation, ATP depletion, and cytoplasmic membrane rupture of GCs. The MAP kinase MKK4, identified by a shRNA screen, represents a critical signaling node. Vacquinol-1 displays excellent in vivo pharmacokinetics and brain exposure, attenuates disease progression, and prolongs survival in a GBM animal model. These results identify a vulnerability to massive vacuolization that can be targeted by small molecules and point to the possible exploitation of this process in the design of anticancer therapies.

  • 11.
    Pedersen, K
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. MOLEKYLÄRBIOLOGI.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    The bacterial toxin RelE displays codon specific cleavage of mRNAs in the ribosomal A-site2003In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 112, no 1, p. 131-140Article in journal (Refereed)
  • 12. Raval, Aparna
    et al.
    Tanner, Stephan M.
    Byrd, John C.
    Angerman, Elizabeth B.
    Perko, James D.
    Chen, Shih-Shih
    Hackanson, Björn
    Grever, Michael R.
    Lucas, David M.
    Matkovic, Jennifer J.
    Lin, Thomas S.
    Kipps, Thomas J.
    Murray, Fiona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Weisenburger, Dennis
    Sanger, Warren
    Lynch, Jane
    Watson, Patrice
    Jansen, Mary
    Yoshinaga, Yuko
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    de Jong, Pieter J.
    Coggill, Penny
    Beck, Stephan
    Lynch, Henry
    de la Chapelle, Albert
    Plass, Christoph
    Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia2007In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 129, no 5, p. 879-890Article in journal (Refereed)
    Abstract [en]

    The heritability of B cell chronic lymphocytic leukemia (CLL) is relatively high; however, no predisposing mutation has been convincingly identified. We show that loss or reduced expression of death-associated protein kinase 1 (DAPK1) underlies cases of heritable predisposition to CLL and the majority of sporadic CLL. Epigenetic silencing of DAPK1 by promoter methylation occurs in almost all sporadic CLL cases. Furthermore, we defined a disease haplotype, which segregates with the CLL phenotype in a large family. DAPK1 expression of the CLL allele is downregulated by 75% in germline cells due to increased HOXB7 binding. In the blood cells from affected family members, promoter methylation results in additional loss of DAPK1 expression. Thus, reduced expression of DAPK1 can result from germline predisposition, as well as epigenetic or somatic events causing or contributing to the CLL phenotype.

  • 13. Robinson, Nicholas P.
    et al.
    Dionne, Isabelle
    Lundgren, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Marsh, Victoria L.
    Bernander, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Bell, Stephen D.
    Identification of two origins of replication in the single chromosome of the archaeon Sulfolobus solfataricus2004In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 116, no 1, p. 25-38Article in journal (Refereed)
    Abstract [en]

    Eukaryotic chromosomes possess multiple origins of replication, whereas bacterial chromosomes are replicated from a single origin. The archaeon Pyrococcus abyssi also appears to have a single origin, suggesting a common rule for prokaryotes. However, in the current work, we describe the identification of two active origins of replication in the single chromosome of the hyperthermophilic archaeon Sulfolobus solfataricus. Further, we identify conserved sequence motifs within the origins that are recognized by a family of three Sulfolobus proteins that are homologous to the eukaryotic initiator proteins Orc1 and Cdc6. We demonstrate that the two origins are recognized by distinct subsets of these Orc1/Cdc6 homologs. These data, in conjunction with an analysis of the levels of the three Orc1/Cdc6 proteins in different growth phases and cell cycle stages, lead us to propose a model for the roles for these proteins in modulating origin activity.

  • 14. Roth, John R.
    et al.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Poxvirus Use a "Gene Accordion" to Tune Out Host Defenses2012In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 150, no 4, p. 671-672Article in journal (Other academic)
    Abstract [en]

    A multistep process of gene amplification, mutation, and reduction allows poxvirus to overcome host antiviral defenses. The mechanism speeds genetic adaptation and promises to be broadly applicable in many biological settings.

  • 15. Spaulding, Kirsty
    et al.
    Bergmann, Olaf
    Alkass, Kanar
    Bernard, Samuel
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Huttner, Hagen
    Boström, Emil
    Westerlund, Isabelle
    Vial, Céline
    Buchholz, Bruce
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Mash, Deborah
    Druid, Henrik
    Frisén, Jonas
    Dynamics of Hippocampal Neurogenesis in Adult Humans2013In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 153, no 6, p. 1219-1227Article in journal (Refereed)
    Abstract [en]

    Adult-born hippocampal neurons are important for cognitive plasticity in rodents. There is evidence for hippocampal neurogenesis in adult humans, although whether its extent is sufficient to have func- tional significance has been questioned. We have assessed the generation of hippocampal cells in humans by measuring the concentration of nuclear- bomb-test-derived 14C in genomic DNA, and we present an integrated model of the cell turnover dy- namics. We found that a large subpopulation of hip- pocampal neurons constituting one-third of the neu- rons is subject to exchange. In adult humans, 700 new neurons are added in each hippocampus per day, corresponding to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging. We conclude that neu- rons are generated throughout adulthood and that the rates are comparable in middle-aged humans and mice, suggesting that adult hippocampal neuro- genesis may contribute to human brain function.

  • 16. Van de Veire, Sara
    et al.
    Stalmans, Ingeborg
    Heindryckx, Femke
    Oura, Hajimu
    Tijeras-Raballand, Annemilaï
    Schmidt, Thomas
    Loges, Sonja
    Albrecht, Imke
    Jonckx, Bart
    Vinckier, Stefan
    Van Steenkiste, Christophe
    Tugues, Sònia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rolny, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    De Mol, Maria
    Dettori, Daniela
    Hainaud, Patricia
    Coenegrachts, Lieve
    Contreres, Jean-Olivier
    Van Bergen, Tine
    Cuervo, Henar
    Xiao, Wei-Hong
    Le Henaff, Carole
    Buysschaert, Ian
    Kharabi Masouleh, Behzad
    Geerts, Anja
    Schomber, Tibor
    Bonnin, Philippe
    Lambert, Vincent
    Haustraete, Jurgen
    Zacchigna, Serena
    Rakic, Jean-Marie
    Jiménez, Wladimiro
    Noël, Agnes
    Giacca, Mauro
    Colle, Isabelle
    Foidart, Jean-Michel
    Tobelem, Gerard
    Morales-Ruiz, Manuel
    Vilar, José
    Maxwell, Patrick
    Vinores, Stanley A.
    Carmeliet, Geert
    Dewerchin, Mieke
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dupuy, Evelyne
    Van Vlierberghe, Hans
    Christofori, Gerhard
    Mazzone, Massimiliano
    Detmar, Michael
    Collen, Désiré
    Carmeliet, Peter
    Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease2010In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 141, no 1, p. 178-190Article in journal (Refereed)
    Abstract [en]

    Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.

  • 17.
    Vieira, Natassia M.
    et al.
    Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA.;Univ Sao Paulo, Biosci Inst, Human Genome & Stem Cell Ctr, BR-05508090 Sao Paulo, Brazil..
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA..
    Alexander, Matthew S.
    Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA..
    Moreira, Yuri B.
    Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, Brazil..
    Eran, Alal
    Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA..
    Gomes, Juliana P.
    Univ Sao Paulo, Biosci Inst, Human Genome & Stem Cell Ctr, BR-05508090 Sao Paulo, Brazil..
    Marshall, Jamie L.
    Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA..
    Karlsson, Elinor K.
    Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA.;Univ Massachusetts, Sch Med, Program Bioinformat & Integrat Biol, Worcester, MA 01605 USA..
    Verjovski-Almeida, Sergio
    Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, Brazil.;Inst Butantan, BR-05508050 Sao Paulo, Brazil..
    Lindblad-Toh, Kerstin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA..
    Kunkel, Louis M.
    Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Pediat & Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA..
    Zatz, Mayana
    Univ Sao Paulo, Biosci Inst, Human Genome & Stem Cell Ctr, BR-05508090 Sao Paulo, Brazil..
    Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype2015In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 163, no 5, p. 1204-1213Article in journal (Refereed)
    Abstract [en]

    Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner.

  • 18.
    Walldén, Mats
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fange, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundius, Ebba Gregorsson
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Baltekin, Özden
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The Synchronization of Replication and Division Cycles in Individual E. coli Cells2016In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 166, no 3, p. 729-739Article in journal (Refereed)
    Abstract [en]

    Isogenic E. coli cells growing in a constant environment display significant variability in growth rates, division sizes, and generation times. The guiding principle appears to be that each cell, during one generation, adds a size increment that is uncorrelated to its birth size. Here, we investigate the mechanisms underlying this "adder'' behavior by mapping the chromosome replication cycle to the division cycle of individual cells using fluorescence microscopy. We have found that initiation of chromosome replication is triggered at a fixed volume per chromosome independent of a cell's birth volume and growth rate. Each initiation event is coupled to a division event after a growth-rate-dependent time. We formalize our findings in a model showing that cell-to-cell variation in division timing and cell size is mainly driven by variations in growth rate. The model also explains why fast-growing cells display adder behavior and correctly predict deviations from the adder behavior at slow growth.

  • 19.
    Yang, Xinping
    et al.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Southern Med Univ, Nanfang Hosp, Dept Obstet & Gynecol, Guangzhou 510515, Guangdong, Peoples R China..
    Coulombe-Huntington, Jasmin
    McGill Univ, Dept Bioengn, Montreal, PQ H3A 0C3, Canada.;Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada..
    Kang, Shuli
    Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA.;Univ So Calif, Dept Biol Sci, Mol & Computat Biol Program, Los Angeles, CA 90089 USA..
    Sheynkman, Gloria M.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Hao, Tong
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Richardson, Aaron
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Sun, Song
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada.;Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada..
    Yang, Fan
    Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada.;Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada..
    Shen, Yun A.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Murray, Ryan R.
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Univ Helsinki, Biomedicum Helsinki 1, FIN-00290 Helsinki, Finland..
    Spirohn, Kerstin
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Begg, Bridget E.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;MIT, Dept Biol, Cambridge, MA 02139 USA..
    Duran-Frigola, Miquel
    Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona 08028, Spain..
    MacWilliams, Andrew
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Tecan US Inc, Morrisville, NC 27560 USA..
    Pevzner, Samuel J.
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA.;Boston Univ, Sch Med, Boston, MA 02118 USA..
    Zhong, Quan
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Wright State Univ, Dept Biol Sci, Dayton, OH 45435 USA..
    Trigg, Shelly A.
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Univ Calif San Diego, Dept Biol Sci, La Jolla, CA 92093 USA..
    Tam, Stanley
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA..
    Ghamsari, Lila
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Genocea Biosci Inc, Cambridge, MA 02140 USA..
    Sahni, Nidhi
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Yi, Song
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Rodriguez, Maria D.
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Cedars Sinai Med Ctr, Biomed Sci & Translat Med, Los Angeles, CA 90048 USA..
    Balcha, Dawit
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Tan, Guihong
    Costanzo, Michael
    Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada..
    Andrews, Brenda
    Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada..
    Boone, Charles
    Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada..
    Zhou, Xianghong J.
    Univ So Calif, Dept Biol Sci, Mol & Computat Biol Program, Los Angeles, CA 90089 USA..
    Salehi-Ashtiani, Kourosh
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;New York Univ Abu Dhabi, Div Sci & Math, Abu Dhabi, U Arab Emirates.;New York Univ Abu Dhabi, Ctr Genom & Syst Biol CGSB, Abu Dhabi, U Arab Emirates..
    Charloteaux, Benoit
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Univ Liege, Unit Anim Genom, GIGA R, B-4000 Liege, Belgium.;Univ Liege, Fac Vet Med, B-4000 Liege, Belgium..
    Chen, Alyce A.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Calderwood, Michael A.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Aloy, Patrick
    Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona 08028, Spain.;ICREA, Barcelona 08010, Catalonia, Spain..
    Roth, Frederick P.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada.;Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada.;Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada..
    Hill, David E.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Iakoucheva, Lilia M.
    Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA..
    Xia, Yu
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;McGill Univ, Dept Bioengn, Montreal, PQ H3A 0C3, Canada..
    Vidal, Marc
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing2016In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 164, no 4, p. 805-817Article in journal (Refereed)
    Abstract [en]

    While alternative splicing is known to diversify the functional characteristics of some genes, the extent to which protein isoforms globally contribute to functional complexity on a proteomic scale remains unknown. To address this systematically, we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling to functionally compare hundreds of protein isoform pairs. The majority of isoform pairs share less than 50% of their interactions. In the global context of interactome network maps, alternative isoforms tend to behave like distinct proteins rather than minor variants of each other. Interaction partners specific to alternative isoforms tend to be expressed in a highly tissue-specific manner and belong to distinct functional modules. Our strategy, applicable to other functional characteristics, reveals a widespread expansion of protein interaction capabilities through alternative splicing and suggests that many alternative "isoforms'' are functionally divergent (i.e., "functional alloforms'').

  • 20.
    Yeung, Maggie
    et al.
    Karolinska Insitutet, CMB.
    Sofia, Zdunek
    Karolinska Insitutet, CMB.
    Bergmann, Olaf
    Karolinska Insitutet, CMB.
    Bernard, Samuel
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Alkass, Kanar
    Perl, Shira
    Tisdale, John
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Ion Physics.
    Brundin, Lou
    Druid, Henrik
    Karolinska Insitutet, CMB.
    Frisén, Jonas
    Karolinska Insitutet, CMB.
    Dynamics of Oligodendrocyte Generation and Myelination in the Human Brain2014In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 159, no 4, p. 766-774Article in journal (Refereed)
    Abstract [en]

    The myelination of axons by oligodendrocytes has been suggested to be modulated by experience, which could mediate neural plasticity by optimizing the performance of the circuitry. We have assessed the dynamics of oligodendrocyte generation and myelination in the human brain. The number of oligodendrocytes in the corpus callosum is established in childhood and remains stable after that. Analysis of the integration of nuclear bomb test-derived 14C revealed that myelin is exchanged at a high rate, whereas the oligodendrocyte population in white matter is remarkably stable in humans, with an annual exchange of 1/300 oligodendrocytes. We conclude that oligodendrocyte turnover contributes minimally to myelin remodeling in human white matter and that this instead may be carried out by mature oligodendrocytes, which may facilitate rapid neural plasticity.

  • 21.
    Zhao, Zhen
    et al.
    Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90089 USA.;Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Los Angeles, CA 90089 USA..
    Nelson, Amy R.
    Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90089 USA.;Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Los Angeles, CA 90089 USA..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Zlokovic, Berislav V.
    Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90089 USA.;Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Los Angeles, CA 90089 USA..
    Establishment and Dysfunction of the Blood-Brain Barrier2015In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 163, no 5, p. 1064-1078Article in journal (Other academic)
    Abstract [en]

    Structural and functional brain connectivity, synaptic activity, and information processing require highly coordinated signal transduction between different cell types within the neurovascular unit and intact blood-brain barrier (BBB) functions. Here, we examine the mechanisms regulating the formation and maintenance of the BBB and functions of BBB-associated cell types. Furthermore, we discuss the growing evidence associating BBB breakdown with the pathogenesis of inherited monogenic neurological disorders and complex multifactorial diseases, including Alzheimer's disease.

1 - 21 of 21
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