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  • 101.
    Dourado, Daniel F. A. R.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Flores, Samuel Coulbourn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Modeling and fitting protein-protein complexes to predict change of binding energy2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 25406Article in journal (Refereed)
    Abstract [en]

    It is possible to accurately and economically predict change in protein-protein interaction energy upon mutation (Delta Delta G), when a high-resolution structure of the complex is available. This is of growing usefulness for design of high-affinity or otherwise modified binding proteins for therapeutic, diagnostic, industrial, and basic science applications. Recently the field has begun to pursue Delta Delta G prediction for homology modeled complexes, but so far this has worked mostly for cases of high sequence identity. If the interacting proteins have been crystallized in free (uncomplexed) form, in a majority of cases it is possible to find a structurally similar complex which can be used as the basis for template-based modeling. We describe how to use MMB to create such models, and then use them to predict Delta Delta G, using a dataset consisting of free target structures, co-crystallized template complexes with sequence identify with respect to the targets as low as 44%, and experimental Delta Delta G measurements. We obtain similar results by fitting to a low-resolution Cryo-EM density map. Results suggest that other structural constraints may lead to a similar outcome, making the method even more broadly applicable.

  • 102.
    Duong, Dinh Thuy
    et al.
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore.
    Singh, Shalini
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bagheri, Mojtaba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Tehran, Inst Biochem & Biophys, Peptide Chem Lab, Tehran 1417614335, Iran..
    Verma, Navin Kumar
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore..
    Schmidtchen, Artur
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore.;Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden..
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Pronounced peptide selectivity for melanoma through tryptophan end-tagging2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 24952Article in journal (Refereed)
    Abstract [en]

    Effects of oligotryptophan end-tagging on the uptake of arginine-rich peptides into melanoma cells was investigated under various conditions and compared to that into non-malignant keratinocytes, fibroblasts, and erythrocytes, also monitoring resulting cell toxicity. In parallel, biophysical studies on peptide binding to, and destabilization of, model lipid membranes provided mechanistic insight into the origin of the selectivity between melanoma and non-malignant cells. Collectively, the results demonstrate that W-tagging represents a powerful way to increase selective peptide internalization in melanoma cells, resulting in toxicity against these, but not against the non-malignant cells. These effects were shown to be due to increased peptide adsorption to the outer membrane in melanoma cells, caused by the presence of anionic lipids such as phosphatidylserine and ganglioside GM1, and to peptide effects on mitochondria membranes and resulting apoptosis. In addition, the possibility of using W-tagged peptides for targeted uptake of nanoparticles/drug carriers in melanoma was demonstrated, as was the possibility to open up the outer membrane of melanoma cells in order to facilitate uptake of low Mw anticancer drugs, here demonstrated for doxorubicin.

  • 103.
    Dörk, Thilo
    et al.
    Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany.
    Peterlongo, Paolo
    IFOM FIRC Inst Mol Oncol, Genome Diagnost Program, Milan, Italy.
    Mannermaa, Arto
    Univ Eastern Finland, Translat Canc Res Area, Kuopio, Finland;Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland;Kuopio Univ Hosp, Imaging Ctr, Dept Clin Pathol, Kuopio, Finland.
    Bolla, Manjeet K.
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England.
    Wang, Qin
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England.
    Dennis, Joe
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England.
    Ahearn, Thomas
    NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA.
    Andrulis, Irene L.
    Lunenfeld Tanenbaum Res Inst Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Toronto, ON, Canada;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.
    Anton-Culver, Hoda
    Univ Calif Irvine, Dept Epidemiol, Genet Epidemiol Res Inst, Irvine, CA USA.
    Arndt, Volker
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, C070, Heidelberg, Germany.
    Aronson, Kristan J.
    Queens Univ, Dept Publ Hlth Sci, Kingston, ON, Canada;Queens Univ, Canc Res Inst, Kingston, ON, Canada.
    Augustinsson, Annelie
    Lund Univ, Dept Canc Epidemiol, Clin Sci, Lund, Sweden.
    Freeman, Laura E. Beane
    NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA.
    Beckmann, Matthias W.
    Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr ER EMN, Dept Gynecol & Obstet, Erlangen, Germany.
    Beeghly-Fadiel, Alicia
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA.
    Behrens, Sabine
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany.
    Bermisheva, Marina
    Russian Acad Sci, Ufa Fed Res Ctr, Inst Biochem & Genet, Ufa, Russia.
    Blomqvist, Carl
    Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland;Orebro Univ Hosp, Dept Oncol, Orebro, Sweden.
    Bogdanova, Natalia, V
    Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany;Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany;NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, BELARUS.
    Bojesen, Stig E.
    Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark;Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany;German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany;Univ Tubingen, iFIT Cluster Excellence, Tubingen, Germany.
    Brenner, Hermann
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, C070, Heidelberg, Germany;German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany;German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany;Natl Ctr Tumor Dis NCT, Heidelberg, Germany.
    Burwinkel, Barbara
    German Canc Res Ctr, Mol Epidemiol Grp, C080, Heidelberg, Germany;Heidelberg Univ, Univ Womens Clin Heidelberg, Mol Biol Breast Canc, Heidelberg, Germany.
    Canzian, Federico
    German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany.
    Chan, Tsun L.
    Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Happy Valley, Hong Kong, Peoples R China;Hong Kong Sanat & Hosp, Dept Pathol, Happy Valley, Hong Kong, Peoples R China.
    Chang-Claude, Jenny
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany;Univ Med Ctr Hamburg Eppendorf, UCCH, Canc Epidemiol Grp, Hamburg, Germany.
    Chanock, Stephen J.
    NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA.
    Choi, Ji-Yeob
    Seoul Natl Univ, Dept Biomed Sci, Grad Sch, Seoul, South Korea;Seoul Natl Univ, Canc Res Inst, Seoul, South Korea.
    Christiansen, Hans
    Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany.
    Clarke, Christine L.
    Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia.
    Couch, Fergus J.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA.
    Czene, Kamila
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Daly, Mary B.
    Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA.
    dos-Santos-Silva, Isabel
    London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England.
    Dwek, Miriam
    Univ Westminster, Fac Sci & Technol, Dept Biomed Sci, London, England.
    Eccles, Diana M.
    Univ Southampton, Canc SciencesAcad Unit, Fac Med, Southampton, Hants, England.
    Ekici, Arif B.
    Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, Inst Human Genet, Erlangen, Germany.
    Eriksson, Mikael
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Evans, D. Gareth
    Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol, Sch Biol Sci,Div Evolut & Genom Sci, Manchester, Lancs, England;Manchester Univ Hosp NHS Fdn Trust, St Marys Hosp, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, Manchester, Lancs, England.
    Fasching, Peter A.
    Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr ER EMN, Dept Gynecol & Obstet, Erlangen, Germany;Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Div Hematol & Oncol, Los Angeles, CA 90024 USA.
    Figueroa, Jonine
    NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA;Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Med Sch, Edinburgh, Midlothian, Scotland;Canc Res UK Edinburgh Ctr, Edinburgh, Midlothian, Scotland.
    Flyger, Henrik
    Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Breast Surg, Herlev, Denmark.
    Fritschisl, Lin
    Curtin Univ, Sch Publ Hlth, Perth, WA, Australia.
    Gabrielson, Marike
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Gago-Dominguez, Manuela
    Complejo Hosp Univ Santiago, SERGAS, Inst Invest Sanitaria Santiago de Compostela IDIS, Genom Med Grp,Galician Fdn Genom Med, Santiago De Compostela, Spain;Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA.
    Gao, Chi
    Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
    Gapstur, Susan M.
    Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30329 USA.
    Garcia-Closas, Montserrat
    NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA;Inst Canc Res, Div Genet & Epidemiol, London, England.
    Garcia-Saenz, Jose A.
    Ctr Invest Biomed Red Canc CIBERONC, Inst Invest Sanitaria San Carlos IdISSC, Hosp Clin San Carlos, Med Oncol Dept, Madrid, Spain.
    Gaudet, Mia M.
    Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30329 USA.
    Giles, Graham G.
    Canc Council Victoria, Canc Epidemiol Div, Melbourne, Vic, Australia;Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia;Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia.
    Goldberg, Mark S.
    McGill Univ, Dept Med, Montreal, PQ, Canada;McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ, Canada.
    Goldgar, David E.
    Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT USA.
    Guenel, Pascal
    Univ Paris Sud, Univ Paris Saclay, INSERM, Canc & Environm Grp,Ctr Res Epidemiol & Populat H, Villejuif, France.
    Haeberle, Lothar
    Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynaecol & Obstet, Erlangen, Germany.
    Haiman, Christopher A.
    Univ Southern Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA USA.
    Hakansson, Niclas
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Hall, Per
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Soder Sjukhuset, Dept Oncol, Stockholm, Sweden.
    Hamann, Ute
    German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany.
    Hartman, Mikael
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore;Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore.
    Hauke, Jan
    Univ Cologne, Fac Med, Ctr Familial Breast & Ovarian Canc, Cologne, Germany;Univ Cologne, Univ Hosp Cologne, Cologne, Germany;Univ Cologne, Fac Med, CMMC, Cologne, Germany;Univ Cologne, Fac Med, CIO, Cologne, Germany.
    Hein, Alexander
    Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr ER EMN, Dept Gynecol & Obstet, Erlangen, Germany.
    Hillemanns, Peter
    Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany.
    Hogervorst, Frans B. L.
    Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands.
    Hooning, Maartje J.
    Erasmus MC Canc Inst, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands.
    Hopper, John L.
    Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia.
    Howell, Tony
    Univ Manchester, Div Canc Sci, Manchester, Lancs, England.
    Huo, Dezheng
    Univ Chicago, Ctr Clin Canc Genet, Chicago, IL 60637 USA.
    Ito, Hidemi
    Aichi Canc Ctr Res Inst, Div Canc Epidemiol & Prevent, Nagoya, Aichi, Japan;Nagoya Univ, Div Canc Epidemiol, Grad Sch Med, Nagoya, Aichi, Japan.
    Iwasaki, Motoki
    Natl Canc Ctr, Ctr Publ Hlth Sci, Div Epidemiol, Tokyo, Japan.
    Jakubowska, Anna
    Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland;Pomeranian Med Univ, Lab Mol Biol & Genet Diagnost, Szczecin, Poland.
    Janni, Wolfgang
    Univ Hosp Ulm, Dept Gynaecol & Obstet, Ulm, Germany.
    John, Esther M.
    Stanford Univ, Sch Med, Stanford Canc Inst, Div Oncol,Dept Med, Stanford, CA USA.
    Jung, Audrey
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany.
    Kaaks, Rudolf
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany.
    Kang, Daehee
    Seoul Natl Univ, Dept Biomed Sci, Grad Sch, Seoul, South Korea;Seoul Natl Univ, Canc Res Inst, Seoul, South Korea;Seoul Natl Univ, Dept Prevent Med, Coll Med, Seoul, South Korea.
    Kapoor, Pooja Middha
    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany;Heidelberg Univ, Fac Med, Heidelberg, Germany.
    Khusnutdinova, Elza
    Russian Acad Sci, Ufa Fed Res Ctr, Inst Biochem & Genet, Ufa, Russia;Bashkir State Univ, Dept Genet & Fundamental Med, Ufa, Russia.
    Kim, Sung-Won
    Daer St Marys Hosp, Dept Surg, Seoul, South Korea.
    Kitahara, Cari M.
    NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Koutros, Stella
    NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA.
    Kraft, Peter
    Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
    Kristensen, Vessela N.
    Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway;Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway.
    Kwon, Ava
    Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Happy Valley, Hong Kong, Peoples R China;Univ Hong Kong, Dept Surg, Pok Fu Lam, Hong Kong, Peoples R China;Hong Kong Sanat & Hosp, Dept Surg, Happy Valley, Hong Kong, Peoples R China.
    Lambrechts, Diether
    VIB, VIB Ctr Canc Biol, Leuven, Belgium;Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium.
    Le Marchand, Loic
    Univ Hawaii, Epidemiol Program, Canc Ctr, Honolulu, HI 96822 USA.
    Li, Jingmei
    Genome Inst Singapore, Human Genet Div, Singapore, Singapore.
    Lindstrom, Sara
    Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.
    Linet, Martha
    NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Lo, Wing-Yee
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany;Univ Tubingen, Tubingen, Germany.
    Long, Jirong
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA.
    Lophatananon, Artitaya
    Univ Manchester, Fac Biol Med & Hlth, Sch Hlth Sci, Div Populat Hlth,Hlth Serv Res & Primary Care, Manchester, Lancs, England.
    Lubinski, Jan
    Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland.
    Manoochehri, Mehdi
    German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori Milano, Dept Med Oncol & Hematol, Unit Med Genet, Milan, Italy.
    Margolin, Sara
    Soder Sjukhuset, Dept Oncol, Stockholm, Sweden;Karolinska Inst, Sodersjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Martinez, Elena
    Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA;Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA.
    Matsuo, Keitaro
    Aichi Canc Ctr Res Inst, Div Canc Epidemiol & Prevent, Nagoya, Aichi, Japan;Nagoya Univ, Div Canc Epidemiol, Grad Sch Med, Nagoya, Aichi, Japan.
    Mavroudis, Dimitris
    Univ Hosp Heraklion, Dept Med Oncol, Iraklion, Greece.
    Meindl, Alfons
    Ludwig Maximilian Univ Munich, Dept Gynecol & Obstet, Munich, Germany.
    Menon, Usha
    UCL, Inst Clin Trials & Methodol, MRC Clin Trials Unit, London, England.
    Milne, Roger L.
    Canc Council Victoria, Canc Epidemiol Div, Melbourne, Vic, Australia;Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia;Monash Univ, Sch Clin Sci, Precis Med, Monash Hlth, Clayton, Vic, Australia.
    Taib, Nur Aishah Mohd
    Univ Malaya, UM Canc Res Inst, Breast Canc Res Unit, Med Ctr, Kuala Lumpur, Malaysia.
    Muir, Kenneth
    Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry, W Midlands, England;Univ Manchester, Fac Biol Med & Hlth, Sch Hlth Sci, Div Populat Hlth,Hlth Serv Res & Primary Care, Manchester, Lancs, England.
    Mulligan, Anna Marie
    Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada;Univ Hlth Network, Lab Med Program, Toronto, ON, Canada.
    Neuhausen, Susan L.
    City Hope Natl Med Ctr, Dept Populat Sci, Beckman Res Inst, Duarte, CA USA.
    Nevanlinna, Heli
    Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland.
    Neven, Patrick
    Univ Hosp Leuven, Leuven Multidisciplinary Breast Ctr, Leuven Canc Inst, Dept OfOncol, Leuven, Belgium.
    Newman, William G.
    Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol, Sch Biol Sci,Div Evolut & Genom Sci, Manchester, Lancs, England;Manchester Univ Hosp NHS Fdn Trust, St Marys Hosp, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, Manchester, Lancs, England.
    Offit, Kenneth
    Mem Sloan Kettering Canc Ctr, Clin Genet Res Lab, Dept Canc Biol & Genet, 1275 York Ave, New York, NY 10021 USA;Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, 1275 York Ave, New York, NY 10021 USA.
    Olopade, Olufunmilayo, I
    Univ Chicago, Ctr Clin Canc Genet, Chicago, IL 60637 USA.
    Olshan, Andrew F.
    Univ North Carolina Chapel Hill, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA;Univ North Carolina Chapel Hill, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA.
    Olson, Janet E.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA.
    Olsson, Hakan
    Lund Univ, Dept Canc Epidemiol, Clin Sci, Lund, Sweden.
    Park, Sue K.
    Seoul Natl Univ, Dept Biomed Sci, Grad Sch, Seoul, South Korea;Seoul Natl Univ, Canc Res Inst, Seoul, South Korea;Seoul Natl Univ, Dept Prevent Med, Coll Med, Seoul, South Korea.
    Park-Simon, Tjoung-Won
    Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany.
    Peto, Julian
    London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England.
    Plaseska-Karanfilska, Dijana
    Macedonian Acad Sci & Arts, Res Ctr Genet Engn & Biotechnol Georgi D Efremov, Skopje, Macedonia.
    Pohl-Rescigno, Esther
    Univ Cologne, Fac Med, Ctr Familial Breast & Ovarian Canc, Cologne, Germany;Univ Cologne, Univ Hosp Cologne, Cologne, Germany;Univ Cologne, Fac Med, CMMC, Cologne, Germany;Univ Cologne, Fac Med, CIO, Cologne, Germany.
    Presneau, Nadege
    Univ Westminster, Fac Sci & Technol, Dept Biomed Sci, London, England.
    Rack, Brigitte
    Univ Hosp Ulm, Dept Gynaecol & Obstet, Ulm, Germany.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Dept Res, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy.
    Rashid, Muhammad U.
    German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany;Shaukat Khanum Mem Canc Hosp & Res Ctr SKMCH & RC, Dept Basic Sci, Lahore, Pakistan.
    Rennert, Gad
    Carmel Hosp, Clalit Natl Canc Control Ctr, Haifa, Israel;Technion Fac Med, Haifa, Israel.
    Rennert, Hedy S.
    Carmel Hosp, Clalit Natl Canc Control Ctr, Haifa, Israel;Technion Fac Med, Haifa, Israel.
    Romero, Atocha
    Hosp Univ Puerta Hierro, Med Oncol Dept, Madrid, Spain.
    Ruebner, Matthias
    Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynaecol & Obstet, Erlangen, Germany.
    Saloustros, Emmanouil
    Univ Hosp Larissa, Dept Oncol, Larisa, Greece.
    Schmidt, Marjanka K.
    Antoni von Leeuwenhoek Hosp, Div Mol Pathol, Netherlands Canc Inst, Amsterdam, Netherlands;Antoni von Leeuwenhoek Hosp, Div Psychosocial Res & Epidemiol, Netherlands Canc Inst, Amsterdam, Netherlands.
    Schmutzler, Rita K.
    Univ Cologne, Fac Med, Ctr Familial Breast & Ovarian Canc, Cologne, Germany;Univ Cologne, Univ Hosp Cologne, Cologne, Germany;Univ Cologne, Fac Med, CMMC, Cologne, Germany;Univ Cologne, Fac Med, CIO, Cologne, Germany.
    Schneider, Michael O.
    Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynaecol & Obstet, Erlangen, Germany.
    Schoemaker, Minouk J.
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Scott, Christopher
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA.
    Shen, Chen-Yang
    Acad Sinica, Inst Biomed Sci, Taipei, Taiwan;China Med Univ, Sch Publ Hlth, Taichung, Taiwan.
    Shu, Xiao-Ou
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA.
    Simard, Jacques
    Univ Laval, CHU Quebec, Res Ctr, Genom Ctr, Quebec City, PQ, Canada.
    Slager, Susan
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA.
    Smichkoska, Snezhana
    Ss Cyril & Methodius Univ Skopje, Med Fac, Univ Clin Radiotherapy & Oncol, Skopje, Macedonia.
    Southey, Melissa C.
    Monash Univ, Sch Clin Sci, Precis Med, Monash Hlth, Clayton, Vic, Australia;Univ Melbourne, Dept Clin Pathol, Melbourne, Vic, Australia.
    Spinelli, John J.
    BC Canc, Populat Oncol, Vancouver, BC, Canada;Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada.
    Stone, Jennifer
    Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia;Curtin Univ, Curtin UWA Ctr Genet Origins Hlth & Dis, Perth, WA, Australia;Univ Western Australia, Perth, WA, Australia.
    Surowy, Harald
    German Canc Res Ctr, Mol Epidemiol Grp, C080, Heidelberg, Germany;Heidelberg Univ, Univ Womens Clin Heidelberg, Mol Biol Breast Canc, Heidelberg, Germany.
    Swerdlow, Anthony J.
    Inst Canc Res, Div Genet & Epidemiol, London, England;Inst Canc Res, Div Breast Canc Res, London, England.
    Tamimi, Rulla M.
    Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Tapper, William J.
    Univ Southampton, Fac Med, Southampton, Hants, England.
    Teo, Soo H.
    Univ Malaya, UM Canc Res Inst, Breast Canc Res Unit, Med Ctr, Kuala Lumpur, Malaysia;Canc Res Malaysia, Subang Jaya, Selangor, Malaysia.
    Terry, Mary Beth
    Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA.
    Toland, Amanda E.
    Ohio State Univ, Dept Canc Biol & Genet, Columbus, OH 43210 USA.
    Tollenaar, Rob A. E. M.
    Leiden Univ, Dept Surg, Med Ctr, Leiden, Netherlands.
    Torres, Diana
    German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany;Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia.
    Torres-Mejia, Gabriela
    Natl Inst Publ Hlth, Ctr Populat Hlth Res, Mexico City, DF, Mexico.
    Troester, Melissa A.
    Univ North Carolina Chapel Hill, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA;Univ North Carolina Chapel Hill, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA.
    Truong, Therese
    Univ Paris Sud, Univ Paris Saclay, INSERM, Canc & Environm Grp,Ctr Res Epidemiol & Populat H, Villejuif, France.
    Tsugane, Shoichiro
    Natl Canc Ctr, Ctr Publ Hlth Sci, Tokyo, Japan.
    Untch, Michael
    Helios Clin Berlin Buch, Dept Gynecol & Obstet, Berlin, Germany.
    Vachon, Celine M.
    Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA.
    van den Ouweland, Ans M. W.
    Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands.
    van Veen, Elke M.
    Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol, Sch Biol Sci,Div Evolut & Genom Sci, Manchester, Lancs, England;Manchester Univ Hosp NHS Fdn Trust, St Marys Hosp, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, Manchester, Lancs, England.
    Vijai, Joseph
    Mem Sloan Kettering Canc Ctr, Clin Genet Res Lab, Dept Canc Biol & Genet, 1275 York Ave, New York, NY 10021 USA;Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, 1275 York Ave, New York, NY 10021 USA.
    Wendt, Camilla
    Karolinska Inst, Sodersjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Yu, Jyh-Cherng
    Triserv Gen Hosp, Natl Def Med Ctr, Dept Surg, Taipei, Taiwan.
    Zheng, Wei
    Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA.
    Ziogas, Argyrios
    Univ Calif Irvine, Dept Epidemiol, Genet Epidemiol Res Inst, Irvine, CA USA.
    Ziv, Elad
    Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, Inst Human Genet, Dept Med, San Francisco, CA 94143 USA.
    Dunning, Alison M.
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England.
    Pharoah, Paul D. P.
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England;Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England.
    Schindler, Detlev
    Univ Wurzburg, Bioctr, Inst Human Genet, Wurzburg, Germany.
    Devilee, Peter
    Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands;Leiden Univ, Dept Human Genet, Med Ctr, Leiden, Netherlands.
    Easton, Douglas F.
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England;Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England.
    Balleine, Rosemary
    Pathol West ICPMR, Sydney, NSW, Australia.
    Baxter, Robert
    Univ Sydney, Royal North Shore Hosp, Kollig Inst Med Res, Sydney, NSW, Australia.
    Braye, Stephen
    John Hunter Hosp, Pathol North, Newcastle, NSW, Australia.
    Carpenter, Jane
    Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia.
    Dahlstrom, Jane
    Canberra Hosp, Dept Anat Pathol, ACT Pathol, Canberra, ACT, Australia;Australian Natl Univ, ANU Med Sch, Canberra, ACT, Australia.
    Forbes, John
    Univ Newcastle, Dept Surg Oncol, Calvary Mater Newcastle Hosp, Australian New Zealand Breast Canc Trials Grp, Newcastle, NSW, Australia;Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW, Australia.
    Lee, C. Soon
    Univ Western Sydney, Sch Sci & Hlth, Sydney, NSW, Australia.
    Marsh, Deborah
    Univ Sydney, Royal North Shore Hosp, Kolling Inst Med Res, Hormones & Canc Grp, Sydney, NSW, Australia.
    Morey, Adrienne
    Syd Path St Vincents Hosp, Sydney, NSW, Australia.
    Pathmanathan, Nirmala
    Westmead Hosp, Westmead Breast Canc Inst, Dept Tissue Pathol & Diagnost Oncol, Pathol West, Sydney, NSW, Australia.
    Scott, Rodney
    Hunter Med Res Inst, Ctr Informat Based Med, Newcastle, NSW, Australia;Univ Newcastle, Fac Hlth, Prior Res Ctr Canc, Sch Biomed Sci & Pharm, Newcastle, NSW, Australia.
    Simpson, Peter
    Univ Queensland, UQ Ctr Clin Res & Sch Med, Brisbane, Qld, Australia.
    Spigelman, Allan
    St Vincents Hosp, Kinghorn Canc Ctr, Hereditary Canc Clin, Sydney, NSW, Australia.
    Wilcken, Nicholas
    Westmead Hosp, Crown Princess Mary Canc Ctr, Sydney, NSW, Australia;Univ Sydney, Sydney Med Sch Westmead, Sydney, NSW, Australia.
    Yip, Desmond
    Australian Natl Univ, ANU Med Sch, Canberra, ACT, Australia;Canberra Hosp, Dept Med Oncol, Canberra, ACT, Australia.
    Zeps, Nikolajs
    St John God Perth Northern Hosp, Perth, WA, Australia.
    Borresen-Dale, Anne-Lise
    Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway;Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway.
    Alnaes, Grethe I. Grenaker
    Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.
    Sahlberg, Kristine K.
    Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway;Vestre Viken Hosp, Dept Res, Drammen, Norway;Oslo Univ Hosp, Breast Canc Res Consortium, Oslo, Norway.
    Ottestad, Lars
    Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.
    Karesen, Rolf
    Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway;Oslo Univ Hosp Ulleval, Div Surg Canc & Transplantat Med, Dept Canc, Sect Breast & Endocrine Surg, Oslo, Norway.
    Schlichting, Ellen
    Oslo Univ Hosp Ulleval, Div Surg Canc & Transplantat Med, Dept Canc, Sect Breast & Endocrine Surg, Oslo, Norway.
    Holmen, Marit Muri
    Oslo Univ Hosp, Dept Radiol & Nucl Med, Oslo, Norway.
    Sauer, Toril
    Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway;Akershus Univ Hosp, Dept Pathol, Lorenskog, Norway.
    Haakensen, Vilde
    Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.
    Engebraten, Olav
    Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway;Oslo Univ Hosp, Inst Canc Res, Dept Tumor Biol, Oslo, Norway;Oslo Univ Hosp, Dept Oncol, Div Surg Canc & Transplantat Med, Radiumhosp, Oslo, Norway.
    Naume, Bjorn
    Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway;Oslo Univ Hosp, Dept Oncol, Div Surg Canc & Transplantat Med, Radiumhosp, Oslo, Norway.
    Fossa, Alexander
    Oslo Univ Hosp, Dept Oncol, Div Surg Canc & Transplantat Med, Radiumhosp, Oslo, Norway;Oslo Univ Hosp, Natl Advisory Unit Late Effects Canc Treatment, Radiumhosp, Oslo, Norway.
    Kiserud, Cecile E.
    Oslo Univ Hosp, Dept Oncol, Div Surg Canc & Transplantat Med, Radiumhosp, Oslo, Norway;Oslo Univ Hosp, Natl Advisory Unit Late Effects Canc Treatment, Radiumhosp, Oslo, Norway.
    Reinertsen, Kristin, V
    Oslo Univ Hosp, Dept Oncol, Div Surg Canc & Transplantat Med, Radiumhosp, Oslo, Norway;Oslo Univ Hosp, Natl Advisory Unit Late Effects Canc Treatment, Radiumhosp, Oslo, Norway.
    Helland, Aslaug
    Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway;Oslo Univ Hosp, Dept Oncol, Div Surg Canc & Transplantat Med, Radiumhosp, Oslo, Norway.
    Riis, Margit
    Oslo Univ Hosp Ulleval, Div Surg Canc & Transplantat Med, Dept Canc, Sect Breast & Endocrine Surg, Oslo, Norway.
    Geisler, Juergen
    Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway;Akershus Univ Hosp, Dept Oncol, Lorenskog, Norway.
    Two truncating variants in FANCC and breast cancer risk2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 12524Article in journal (Refereed)
    Abstract [en]

    Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95% CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

  • 104.
    Egaña, Isabel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kaito, Hiroshi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nitzsche, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Becker, Lore
    German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.; Department of Neurology, Friedrich-Baur-Institut, Ludwig-Maximilians-Universität München, Munich, Germany.
    Ballester-Lopez, Carolina
    German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Expt Genet, German Mouse Clin, Neuherberg, Germany.; German Ctr Lung Res DZL, Comprehens Pneumol Ctr, Helmholtz Zentrum Munchen, Inst Lung Biol & Dis,German Res Ctr Environm Hlth, Munich, Germany.
    Niaudet, Colin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Petkova, Milena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Vernaleken, Alexandra
    German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Expt Genet, German Mouse Clin, Neuherberg, Germany.; Ludwig Maximilians Univ Munchen, Friedrich Baur Inst, Dept Neurol, Munich, Germany.
    Klopstock, Thomas
    Department of Neurology, Friedrich-Baur-Institut, Ludwig-Maximilians-Universität München, Munich, Germany.; German Center for Vertigo and Balance Disorders, Munich, Germany.; Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), Munich, Germany.; German Network for Mitochondrial Disorders (mitoNET), Munich, Germany.
    Fuchs, Helmut
    German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
    Gailus-Durner, Valerie
    German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
    Hrabe de Angelis, Martin
    German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.; Tech Univ Munich, Ctr Life & Food Sci Weihenstephan, Expt Genet, Neuherberg, Germany.; German Ctr Diabet Res DZD, Neuherberg, Germany.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Johansson, Henrik J.
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Canc Prote Mass Spectrometry, Stockholm, Sweden.
    Lehtiö, Janne
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Canc Prote Mass Spectrometry, Stockholm, Sweden.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yildirim, Ali Ö.
    German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.; Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), The German Center for Lung Research (DZL), Munich, Germany.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 15453Article in journal (Refereed)
    Abstract [en]

    Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.

  • 105. Einarsdottir, Elisabet
    et al.
    Peyrard-Janvid, Myriam
    Darki, Fahimeh
    Tuulari, Jetro J
    Merisaari, Harri
    Karlsson, Linnea
    Scheinin, Noora M
    Saunavaara, Jani
    Parkkola, Riitta
    Kantojärvi, Katri
    Ämmälä, Antti-Jussi
    Yiu-Lin Yu, Nancy
    Matsson, Hans
    Nopola-Hemmi, Jaana
    Karlsson, Hasse
    Paunio, Tiina
    Klingberg, Torkel
    Leinonen, Eira
    Kere, Juha
    Identification of NCAN as a candidate gene for developmental dyslexia.2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 9294Article in journal (Refereed)
    Abstract [en]

    A whole-genome linkage analysis in a Finnish pedigree of eight cases with developmental dyslexia (DD) revealed several regions shared by the affected individuals. Analysis of coding variants from two affected individuals identified rs146011974G > A (Ala1039Thr), a rare variant within the NCAN gene co-segregating with DD in the pedigree. This variant prompted us to consider this gene as a putative candidate for DD. The RNA expression pattern of the NCAN gene in human tissues was highly correlated (R > 0.8) with that of the previously suggested DD susceptibility genes KIAA0319, CTNND2, CNTNAP2 and GRIN2B. We investigated the association of common variation in NCAN to brain structures in two data sets: young adults (Brainchild study, Sweden) and infants (FinnBrain study, Finland). In young adults, we found associations between a common genetic variant in NCAN, rs1064395, and white matter volume in the left and right temporoparietal as well as the left inferior frontal brain regions. In infants, this same variant was found to be associated with cingulate and prefrontal grey matter volumes. Our results suggest NCAN as a new candidate gene for DD and indicate that NCAN variants affect brain structure.

  • 106. El-Sayed, Ramy
    et al.
    Bhattacharya, Kunal
    Gu, Zhonglin
    Yang, Zaixing
    Weber, Jeffrey K.
    Li, Hu
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Leifer, Klaus
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Zhao, Yichen
    Toprak, Muhammet S.
    Zhou, Ruhong
    Fadeel, Bengt
    Single-Walled Carbon Nanotubes Inhibit the Cytochrome P450 Enzyme, CYP3A42016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 21316Article in journal (Refereed)
    Abstract [en]

    We report a detailed computational and experimental study of the interaction of single-walled carbon nanotubes (SWCNTs) with the drug-metabolizing cytochrome P450 enzyme, CYP3A4. Dose-dependent inhibition of CYP3A4-mediated conversion of the model compound, testosterone, to its major metabolite, 6β-hydroxy testosterone was noted. Evidence for a direct interaction between SWCNTs and CYP3A4 was also provided. The inhibition of enzyme activity was alleviated when SWCNTs were pre-coated with bovine serum albumin. Furthermore, covalent functionalization of SWCNTs with polyethylene glycol (PEG) chains mitigated the inhibition of CYP3A4 enzymatic activity. Molecular dynamics simulations suggested that inhibition of the catalytic activity of CYP3A4 is mainly due to blocking of the exit channel for substrates/products through a complex binding mechanism. This work suggests that SWCNTs could interfere with metabolism of drugs and other xenobiotics and provides a molecular mechanism for this toxicity. Our study also suggests means to reduce this toxicity, eg., by surface modification.

  • 107.
    Engel, Fabian
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Attermeyer, Katrin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Ayala, Ana I
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Fischer, Helmut
    Kirchesch, Volker
    Pierson, Don
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Weyhenmeyer, Gesa A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Phytoplankton gross primary production increases along cascading impoundments in a temperate, low-discharge river: Insights from high frequency water quality monitoring2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 6701Article in journal (Refereed)
    Abstract [en]

    Damming alters carbon processing along river continua. Estimating carbon transport along rivers intersected by multiple dams requires an understanding of the effects of cascading impoundments on the riverine metabolism. We analyzed patterns of riverine metabolism and phytoplankton biomass (chlorophyll a; Chla) along a 74.4-km river reach intersected by six low-head navigation dams. Calculating gross primary production (GPP) from continuous measurements of dissolved oxygen concentration, we found a maximum increase in the mean GPP by a factor of 3.5 (absolute difference of 0.45 g C m−3 d−1) along the first 26.5 km of the study reach, while Chla increased over the entire reach by a factor of 2.9 (8.7 µg l−1). In the intermittently stratified section of the deepest impoundment the mean GPP between the 1 and 4 m water layer differed by a factor of 1.4 (0.31 g C m−3 d−1). Due to the strong increase in GPP, the river featured a wide range of conditions characteristic of low- to medium-production rivers. We suggest that cascading impoundments have the potential to stimulate riverine GPP, and conclude that phytoplankton CO2 uptake is an important carbon flux in the river Saar, where a considerable amount of organic matter is of autochthonous origin.

  • 108.
    Englund, Elias
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Liang, Feiyan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Lindberg, Pia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Evaluation of promoters and ribosome binding sites for biotechnological applications in the unicellular cyanobacterium Synechocystis sp. PCC 68032016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 36640Article in journal (Refereed)
    Abstract [en]

    For effective metabolic engineering, a toolbox of genetic components that enables predictable control of gene expression is needed. Here we present a systematic study of promoters and ribosome binding sites in the unicellular cyanobacterium Synechocystis sp. PCC 6803. A set of metal ion inducible promoters from Synechocystis were compared to commonly used constitutive promoters, by measuring fluorescence of a reporter protein in a standardized setting to allow for accurate comparisons of promoter activity. The most versatile and useful promoter was found to be PnrsB, which from a relatively silent expression could be induced almost 40-fold, nearly up to the activity of the strong psbA2 promoter. By varying the concentrations of the two metal ion inducers Ni(2+) and Co(2+), expression from the promoter was highly tunable, results that were reproduced with PnrsB driving ethanol production. The activities of several ribosomal binding sites were also measured, and tested in parallel in Synechocystis and Escherichia coli. The results of the study add useful information to the Synechocystis genetic toolbox for biotechnological applications.

  • 109.
    Enroth, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Enroth, Sofia Bosdotter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Protein profiling reveals consequences of lifestyle choices on predicted biological aging2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 17282Article in journal (Refereed)
    Abstract [en]

    Ageing is linked to a number of changes in how the body and its organs function. On a molecular level, ageing is associated with a reduction of telomere length, changes in metabolic and gene-transcription profiles and an altered DNA-methylation pattern. Lifestyle factors such as smoking or stress can impact some of these molecular processes and thereby affect the ageing of an individual. Here we demonstrate by analysis of 77 plasma proteins in 976 individuals, that the abundance of circulating proteins accurately predicts chronological age, as well as anthropometrical measurements such as weight, height and hip circumference. The plasma protein profile can also be used to identify lifestyle factors that accelerate and decelerate ageing. We found smoking, high BMI and consumption of sugar-sweetened beverages to increase the predicted chronological age by 2-6 years, while consumption of fatty fish, drinking moderate amounts of coffee and exercising reduced the predicted age by approximately the same amount. This method can be applied to dried blood spots and may thus be useful in forensic medicine to provide basic anthropometrical measures for an individual based on a biological evidence sample.

  • 110.
    Enroth, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Enroth, Sofia Bosdotter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Protein profiling reveals consequences of lifestyle choices on predicted biological aging2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 17282Article in journal (Refereed)
    Abstract [en]

    Ageing is linked to a number of changes in how the body and its organs function. On a molecular level, ageing is associated with a reduction of telomere length, changes in metabolic and gene-transcription profiles and an altered DNA-methylation pattern. Lifestyle factors such as smoking or stress can impact some of these molecular processes and thereby affect the ageing of an individual. Here we demonstrate by analysis of 77 plasma proteins in 976 individuals, that the abundance of circulating proteins accurately predicts chronological age, as well as anthropometrical measurements such as weight, height and hip circumference. The plasma protein profile can also be used to identify lifestyle factors that accelerate and decelerate ageing. We found smoking, high BMI and consumption of sugar-sweetened beverages to increase the predicted chronological age by 2-6 years, while consumption of fatty fish, drinking moderate amounts of coffee and exercising reduced the predicted age by approximately the same amount. This method can be applied to dried blood spots and may thus be useful in forensic medicine to provide basic anthropometrical measures for an individual based on a biological evidence sample.

  • 111.
    Enroth, Stefan
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Maturi, Varun
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Berggrund, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bosdotter Enroth, Sofia
    Med Prod Agcy, POB 26, SE-75103 Uppsala, Sweden..
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Gyllensten, Ulf B.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Systemic and specific effects of antihypertensive and lipid-lowering medication on plasma protein biomarkers for cardiovascular diseases2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 5531Article in journal (Refereed)
    Abstract [en]

    A large fraction of the adult population is on lifelong medication for cardiovascular disorders, but the metabolic consequences are largely unknown. This study determines the effects of common anti-hypertensive and lipid lowering drugs on circulating plasma protein biomarkers. We studied 425 proteins in plasma together with anthropometric and lifestyle variables, and the genetic profile in a cross-sectional cohort. We found 8406 covariate-protein associations, and a two-stage GWAS identified 17253 SNPs to be associated with 109 proteins. By computationally removing variation due to lifestyle and genetic factors, we could determine that medication, per se, affected the abundance levels of 35.7% of the plasma proteins. Medication either affected a single, a few, or a large number of protein, and were found to have a negative or positive influence on known disease pathways and biomarkers. Anti-hypertensive or lipid lowering drugs affected 33.1% of the proteins. Angiotensin-converting enzyme inhibitors showed the strongest lowering effect by decreasing plasma levels of myostatin. Cell-culture experiments showed that angiotensin-converting enzyme inhibitors reducted myostatin RNA levels. Thus, understanding the effects of lifelong medication on the plasma proteome is important both for sharpening the diagnostic precision of protein biomarkers and in disease management.

  • 112.
    Eriksson, Daniel
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    Bianchi, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Dalin, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Skov, Jakob
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Hultin-Rosenberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mathioudaki, Argyri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordin, Jessika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallgren, Asa
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Andersson, Goran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlqvist, Solbritt Rantapaa
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Soderkvist, Peter
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hulting, Anna-Lena
    Wahlberg, Jeanette
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Linkoping Univ, Dept Endocrinol, Linkoping, Sweden;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Dahlqvist, Per
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Ekwall, Olov
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden.
    Meadows, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindblad-Toh, Kerstin
    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 MIT & Harvard, Cambridge, MA USA.
    Bensing, Sophie
    Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kampe, Olle
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden;KG Jebsen Ctr Autoimmune Dis, Bergen, Norway.
    Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8395Article in journal (Refereed)
    Abstract [en]

    Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

  • 113.
    Eriksson, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Engholm, Ebbe
    Univ Copenhagen, Chem Biol, Dept Chem, DK-1871 Frederiksberg C, Denmark.
    Blixt, Ola
    Univ Copenhagen, Chem Biol, Dept Chem, DK-1871 Frederiksberg C, Denmark.
    Waldenstrom, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, SE-39231 Kalmar, Sweden.
    Munster, Vincent
    NIAID, Lab Virol, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsen, Bjorn
    Uppsala Univ, Zoonosis Sci Ctr, Dept Med Sci, SE-75123 Uppsala, Sweden.
    Jourdain, Elsa
    INRA, EPIA, VetAgro Sup, UMR0346, FR-63122 St Genes Champanelle, France.
    Ellstrom, Patrik
    Uppsala Univ, Zoonosis Sci Ctr, Dept Med Sci, SE-75123 Uppsala, Sweden.
    Characterization of avian influenza virus attachment patterns to human and pig tissues2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12215Article in journal (Refereed)
    Abstract [en]

    Wild birds of Anseriformes and Charadriiformes are natural reservoirs of influenza A viruses (IAVs). Occasionally, IAVs transmit and adapt to mammalian hosts, and are maintained as epidemic strains in their new hosts. Viral adaptions to mammalian hosts include altered receptor preference of host epithelial sialylated oligosaccharides from terminal alpha 2,3-linked sialic acid (SA) towards alpha 2,6-linked SA. However, alpha 2,3-linked SA has been found in human respiratory tract epithelium, and human infections by avian IAVs (AIVs) have been reported. To further explore the attachment properties of AIVs, four AIVs of different subtypes were investigated on human and pig tissues using virus histochemistry. Additionally, glycan array analysis was performed for further characterization of IAVs' receptor structure tropism. Generally, AIV attachment was more abundant to human tissues than to pig tissues. The attachment pattern was very strong to human conjunctiva and upper respiratory tract, but variable to the lower respiratory tract. AIVs mainly attached to alpha 2,3-linked SA, but also to combinations of alpha 2,3-and alpha 2,6-linked SA. The low attachment of these AIV isolates to pig tissues, but high attachment to human tissues, addresses the question whether AIVs in general require passage through pigs to obtain adaptions towards mammalian receptor structures.

  • 114.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Falk Delgado, Anna
    Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.
    Outcome switching in randomized controlled oncology trials reporting on surrogate endpoints: a cross-sectional analysis2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 9206Article in journal (Refereed)
    Abstract [en]

    Inconsistent reporting of clinical trials is well-known in the literature. Despite this, factors associated with poor practice such as outcome switching in clinical trials are poorly understood. We performed a cross-sectional analysis to evaluate the prevalence of, and the factors associated with outcome switching. PubMed and Embase were searched for pharmaceutical randomized controlled trials (RCTs) in oncology reporting on a surrogate primary outcome published in 2015. Outcome switching was present in 18% (39/216). First-author male sex was significantly more likely associated with outcome switching compared to female sex with an OR of 3.05 (95% CI 1.07-8.64, p = 0.04) after multivariable adjustment. For-profit funded RCTs were less likely associated with outcome switching compared to non-profit funded research with an OR of 0.22 (95% CI 0.07-0.74, p = 0.01). First author male sex was more likely associated with outcome switching compared to female sex in drug oncology RCTs reporting on a primary surrogate endpoint. For-profit funded research was less likely associated with outcome switching compared to research funded by non-profit organizations. Furthermore, 18 percent of drug oncology trials reporting on a surrogate endpoint could have a higher risk of false positive results due to primary outcome switching.

  • 115.
    Fall, Tove
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ekberg, Sara
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Lundholm, Cecilia
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Fang, Fang
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Almqvist, Catarina
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Unit Pediat Allergy & Pulmonol, Stockholm, Sweden.
    Dog characteristics and future risk of asthma in children growing up with dogs2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 16899Article in journal (Refereed)
    Abstract [en]

    There is observational evidence that children exposed to dogs in early life are at lower risk of asthma. It is unknown whether this association is modified by dog characteristics such as sex, breed, number of dogs, and dog size. The aim of this study was to determine whether different dog characteristics modify the risk of asthma among children exposed to dogs during their first year of life. In the main analysis, we used national register data for all children born in Sweden from Jan 1st 2001 to Dec 31st 2004 with a registered dog in the household during their first year of life (n = 23,585). We used logistic regression models to study the association between dog characteristics and the risk of asthma or allergy diagnosis and medication at age six. The prevalence of asthma at age six was 5.4%. Children exposed to female dogs had lower risk of asthma compared to those exposed to male dogs, odds ratio, OR= 0.84 (95% confidence interval, CI 0.74 to 0.95). Children with two dogs or more had lower risk of asthma than those with one dog only, OR= 0.79 (95%Cl 0.65 to 0.95). Children whose parents had asthma and allergy had a higher frequency of exposure to dog breeds anecdotally described as "hypoallergenic" compared to those parents without asthma or allergy (11.7% vs 7.6%, p < 0.001). Exposure to these breeds were associated with higher risk of allergy OR= 1.27 (95% CI 1.02 to 1.59) but not asthma. In conclusion, we found evidence of an association between the sex of dog and the number of dogs with a lower risk of childhood asthma in dog-exposed children.

  • 116.
    Fall, Tove
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kuja-Halkola, Ralf
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Dobney, Keith
    Univ Liverpool, Dept Archaeol Class & Egyptol, Liverpool, Merseyside, England.
    Westgarth, Carri
    Univ Liverpool, Inst Infect & Global Hlth, Liverpool, Merseyside, England;Univ Liverpool, Inst Vet Sci, Liverpool, Merseyside, England.
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Evidence of large genetic influences on dog ownership in the Swedish Twin Registry has implications for understanding domestication and health associations2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 7554Article in journal (Refereed)
    Abstract [en]

    Dogs were the first domesticated animal and, according to the archaeological evidence, have had a close relationship with humans for at least 15,000 years. Today, dogs are common pets in our society and have been linked to increased well-being and improved health outcomes in their owners. A dog in the family during childhood is associated with ownership in adult life. The underlying factors behind this association could be related to experiences or to genetic influences. We aimed to investigate the heritability of dog ownership in a large twin sample including all twins in the Swedish Twin Registry born between 1926 and 1996 and alive in 2006. Information about dog ownership was available from 2001 to 2016 from national dog registers. The final data set included 85,542 twins from 50,507 twin pairs with known zygosity, where information on both twins were available in 35,035 pairs. Structural equation modeling was performed to estimate additive genetic effects (the heritability), common/shared environmental, and unique/non-shared environmental effects. We found that additive genetic factors largely contributed to dog ownership, with heritability estimated at 57% for females and 51% for males. An effect of shared environmental factors was only observed in early adulthood. In conclusion, we show a strong genetic contribution to dog ownership in adulthood in a large twin study. We see two main implications of this finding: (1) genetic variation may have contributed to our ability to domesticate dogs and other animals and (2) potential pleiotropic effects of genetic variation affecting dog ownership should be considered in studies examining health impacts of dog ownership.

  • 117.
    Fallahsharoudi, Amir
    et al.
    AVIAN Behavioural Genomics and Physiology Group, IFMBiology, Linköping University.
    de Kock, Neil
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Johnsson, Martin
    AVIAN Behavioural Genomics and Physiology Group, IFMBiology, Linköping University.
    Ubhayasekera, Sarojini J.K.A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Wright, Dominic
    AVIAN Behavioural Genomics and Physiology Group, IFMBiology, Linköping University.
    Jensen, Per
    AVIAN Behavioural Genomics and Physiology Group, IFMBiology, Linköping University.
    Domestication Effects on Stress Induced Steroid Secretion and Adrenal Gene Expression in Chickens2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15345Article in journal (Refereed)
    Abstract [en]

    Understanding the genetic basis of phenotypic diversity is a challenge in contemporary biology. Domestication provides a model for unravelling aspects of the genetic basis of stress sensitivity. The ancestral Red Junglefowl (RJF) exhibits greater fear-related behaviour and a more pronounced HPA-axis reactivity than its domesticated counterpart, the White Leghorn (WL). By comparing hormones (plasmatic) and adrenal global gene transcription profiles between WL and RJF in response to an acute stress event, we investigated the molecular basis for the altered physiological stress responsiveness in domesticated chickens. Basal levels of pregnenolone and dehydroepiandrosterone as well as corticosterone response were lower in WL. Microarray analysis of gene expression in adrenal glands showed a significant breed effect in a large number of transcripts with over-representation of genes in the channel activity pathway. The expression of the best-known steroidogenesis genes were similar across the breeds used. Transcription levels of acute stress response genes such as StAR, CH25 and POMC were upregulated in response to acute stress. Dampened HPA reactivity in domesticated chickens was associated with changes in the expression of several genes that presents potentially minor regulatory effects rather than by means of change in expression of critical steroidogenic genes in the adrenal.

  • 118.
    Fallaize, Rosalind
    et al.
    Univ Reading, Hugh Sinclair Unit Human Nutr, Reading RG6 6AP, Berks, England.;Univ Reading, Inst Cardiovasc & Metab Res, Reading RG6 6AP, Berks, England.;Univ Hertfordshire, Sch Life & Med Sci, Coll Lane, Hatfield AL10 9AB, Herts, England..
    Carvalho-Wells, Andrew L.
    Univ Reading, Hugh Sinclair Unit Human Nutr, Reading RG6 6AP, Berks, England.;Univ Reading, Inst Cardiovasc & Metab Res, Reading RG6 6AP, Berks, England..
    Tierney, Audrey C.
    Univ Coll Dublin, Conway Inst, Nutrigen Res Grp, Dublin, Ireland..
    Marin, Carmen
    Univ Cordoba, IMIBIC, Reina Sofia Univ Hosp, Lipids & Atherosclerosis Unit, Cordoba, Spain..
    Kiec-Wilk, Beata
    Univ Med Coll, Dept Metab Dis, Krakow, Poland..
    Dembinska-Kiec, Aldona
    Jagiellonian Univ, Dept Clin Biochem, Coll Med, Krakow, Poland..
    Drevon, Christian A.
    Univ Oslo, Dept Nutr, Inst Basic Med Sci, Fac Med, Oslo, Norway..
    DeFoort, Catherine
    INSERM, Human Nutr & Lipids 476, Marseille, France..
    Lopez-Miranda, Jose
    Univ Cordoba, IMIBIC, Reina Sofia Univ Hosp, Lipids & Atherosclerosis Unit, Cordoba, Spain..
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Saris, Wim H.
    MUMC, Dept Human Biol, NUTRIM Sch Nutr & Translat Res Metab, Maastricht, Netherlands..
    Blaak, Ellen E.
    MUMC, Dept Human Biol, NUTRIM Sch Nutr & Translat Res Metab, Maastricht, Netherlands..
    Roche, Helen M.
    Univ Coll Dublin, Conway Inst, Nutrigen Res Grp, Dublin, Ireland..
    Lovegrove, Julie A.
    Univ Reading, Hugh Sinclair Unit Human Nutr, Reading RG6 6AP, Berks, England.;Univ Reading, Inst Cardiovasc & Metab Res, Reading RG6 6AP, Berks, England..
    APOE genotype influences insulin resistance, apolipoprotein CII and CIII according to plasma fatty acid profile in the Metabolic Syndrome2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6274Article in journal (Refereed)
    Abstract [en]

    Metabolic markers associated with the Metabolic Syndrome (MetS) may be affected by interactions between the APOE genotype and plasma fatty acids (FA). In this study, we explored FA-gene interactions between the missense APOE polymorphisms and FA status on metabolic markers in MetS. Plasma FA, blood pressure, insulin sensitivity and lipid concentrations were determined at baseline and following a 12-week randomized, controlled, parallel, dietary FA intervention in 442 adults with MetS (LIPGENE study). FA-APOE gene interactions at baseline and following change in plasma FA were assessed using adjusted general linear models. At baseline E4 carriers had higher plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) compared with E2 carriers; and higher TC, LDL-C and apo B compared with E3/E3. Whilst elevated plasma n-3 polyunsaturated FA (PUFA) was associated with a beneficially lower concentration of apo CIII in E2 carriers, a high proportion of plasma C16:0 was associated with insulin resistance in E4 carriers. Following FA intervention, a reduction in plasma long-chain n-3 PUFA was associated with a reduction in apo CII concentration in E2 carriers. Our novel data suggest that individuals with MetS may benefit from personalized dietary interventions based on APOE genotype.

  • 119.
    Fang, Hailiang
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Cedervall, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Hedlund, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Shafeie, Samrand
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Deledda, Stefano
    Olsson, Fredrik
    von Fieandt, Linus
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Bednarcik, Jozef
    Svedlindh, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Gunnarsson, Klas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Sahlberg, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Structural, microstructural and magnetic evolution in cryo milled carbon doped MnAl2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 2525Article in journal (Refereed)
    Abstract [en]

    The low cost, rare earth free τ-phase of MnAl has high potential to partially replace bonded Nd2Fe14B rare earth permanent magnets. However, the τ-phase is metastable and it is experimentally difficult to obtain powders suitable for the permanent magnet alignment process, which requires the fine powders to have an appropriate microstructure and high τ-phase purity. In this work, a new method to make high purity τ-phase fne powders is presented. A high purity τ-phase Mn0.55Al0.45C0.02 alloy was synthesized by the drop synthesis method. The drop synthesized material was subjected to cryo milling and followed by a fash heating process. The crystal structure and microstructure of the drop synthesized, cryo milled and flash heated samples were studied by X-ray in situ powder diffraction, scanning electron microscopy, X-ray energy dispersive spectroscopy and electron backscatter diffraction. Magnetic properties and magnetic structure of the drop synthesized, cryo milled, flash heated samples were characterized by magnetometry and neutron powder diffraction, respectively. The results reveal that the 2 and 4hours cryo milled and flash heated samples both exhibit high τ-phase purity and micron-sized round particle shapes. Moreover, the fash heated samples display high saturation magnetization as well as increased coercivity.

  • 120.
    Fang, Jianping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Song, Tianyi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Enzyme overexpression - an exercise toward understanding regulation of heparan sulfate biosynthesis2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 31242Article in journal (Refereed)
    Abstract [en]

    Biosynthesis of heparan sulfate (HS) involves conversion of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA) units catalyzed by glucuronyl C5-epimerase (Hsepi). IdoA units are the favored substrate for 2-O-sulfotransferase (2OST). We used HEK293 cells as a model to investigate the effects of overexpression of these enzymes on HS structure. Overexpression of Hsepi alone resulted in an unexpected increase in HS chain length. A Hsepi point-mutant (Y168A), devoid of catalytic activity, failed to affect chain length. Moreover, the effect of Hsepi overexpression on HS chain length was abolished by simultaneous overexpression of 2OST. These findings raise novel aspects on regulation of HS biosynthesis. We propose a hypothetical enzyme-binding protein (EBP) with distinct, specific and partly overlapping binding sites, the interactions of which will determine levels of enzymes available to the biosynthetic process.

  • 121.
    Fawcett, Christine
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala Univ, Uppsala, Sweden..
    Arslan, Melda
    Univ Ghent, Ghent, Belgium.
    Falck-Ytter, Terje
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Solna, Sweden; Ctr Psychiat Res, Stockholm, Sweden.
    Roeyers, Herbert
    Univ Ghent, Ghent, Belgium.
    Gredebäck, Gustaf
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Author Correction: Human eyes with dilated pupils induce pupillary contagion in infants2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 4157Article in journal (Other academic)
  • 122.
    Fawcett, Christine
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Arslan, Melda
    Univ Ghent, Ghent, Belgium.
    Falck-Ytter, Terje
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Solna, Sweden; Stockholm Cty, Ctr Psychiat Res, Stockholm, Sweden.
    Roeyers, Herbert
    Univ Ghent, Ghent, Belgium.
    Gredebäck, Gustaf
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Human eyes with dilated pupils induce pupillary contagion in infants2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 9601Article in journal (Refereed)
    Abstract [en]

    Being sensitive and responsive to others’ internal states is critical for social life. One reliable cue to what others might be feeling is pupil dilation because it is linked to increases in arousal. When adults view an individual with dilated pupils, their pupils dilate in response, suggesting not only sensitivity to pupil size, but a corresponding response as well. However, little is known about the origins or mechanism underlying this phenomenon of pupillary contagion. Here we show that 4- to 6-month-old infants show pupillary contagion when viewing photographs of eyes with varying pupil sizes: their pupils dilate in response to others’ large, but not small or medium pupils. The results suggest that pupillary contagion is likely driven by a transfer of arousal and that it is present very early in life in human infants, supporting the view that it could be an adaptation fundamental for social and emotional development.

  • 123.
    Feifel, R.
    et al.
    Univ Gothenburg, Dept Phys, Origovagen 6B, SE-41296 Gothenburg, Sweden..
    Eland, J. H. D.
    Univ Gothenburg, Dept Phys, Origovagen 6B, SE-41296 Gothenburg, Sweden.;Univ Oxford, Phys & Theoret Chem Lab, Dept Chem, South Parks Rd, Oxford OX1 3QZ, England..
    Carniato, S.
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France..
    Selles, P.
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France..
    Puettner, R.
    Free Univ Berlin, Fachbereich Phys, Arnimallee 14, D-14195 Berlin, Germany..
    Koulentianos, D.
    Univ Gothenburg, Dept Phys, Origovagen 6B, SE-41296 Gothenburg, Sweden.;UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France..
    Marchenko, T.
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France.;Synchrotron SOLEIL, Orme Merisiers, BP 48, F-91192 Gif sur Yvette, France..
    Journel, L.
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France.;Synchrotron SOLEIL, Orme Merisiers, BP 48, F-91192 Gif sur Yvette, France..
    Guillemin, R.
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France.;Synchrotron SOLEIL, Orme Merisiers, BP 48, F-91192 Gif sur Yvette, France..
    Goldsztejn, G.
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France.;Max Born Inst, Max Born Str 2A, D-12489 Berlin, Germany..
    Travnikova, O.
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France.;Synchrotron SOLEIL, Orme Merisiers, BP 48, F-91192 Gif sur Yvette, France..
    Ismail, I.
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France..
    de Miranda, B. Cunha
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France..
    Lago, A. F.
    Univ Fed Abc, Ctr Ciencias Nat & Humanas, Ave Estados,5001, BR-09210580 Santo Andre, SP, Brazil..
    Ceolin, D.
    Synchrotron SOLEIL, Orme Merisiers, BP 48, F-91192 Gif sur Yvette, France..
    Lablanquie, P.
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France..
    Penent, F.
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France..
    Piancastelli, Maria Novella
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics. UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France..
    Simon, M.
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7614,Lab Chim Phys Mat & Rayonnment, F-75005 Paris 05, France.;Synchrotron SOLEIL, Orme Merisiers, BP 48, F-91192 Gif sur Yvette, France..
    Cationic double K-hole pre-edge states of CS2 and SF62017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 13317Article in journal (Refereed)
    Abstract [en]

    Recent advances in X-ray instrumentation have made it possible to measure the spectra of an essentially unexplored class of electronic states associated with double inner-shell vacancies. Using the technique of single electron spectroscopy, spectra of states in CS2 and SF6 with a double hole in the K-shell and one electron exited to a normally unoccupied orbital have been obtained. The spectra are interpreted with the aid of a high-level theoretical model giving excellent agreement with the experiment. The results shed new light on the important distinction between direct and conjugate shake-up in a molecular context. In particular, systematic similarities and differences between pre-edge states near single core holes investigated in X-ray absorption spectra and the corresponding states near double core holes studied here are brought out.

  • 124.
    Felkel, Sabine
    et al.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria;Vienna Grad Sch Populat Genet, Vienna, Austria.
    Vogl, Claus
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria.
    Rigler, Doris
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria.
    Dobretsberger, Viktoria
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria.
    Chowdhary, Bhanu P.
    United Arab Emirates Univ, Al Ain 15551, U Arab Emirates.
    Distl, Ottmar
    Univ Vet Med Hannover, Inst Anim Breeding & Genet, D-30559 Hannover, Germany.
    Fries, Ruedi
    Tech Univ Muenchen, Lehrstuhl Tierzucht, D-85354 Freising Weihenstephan, Germany.
    Jagannathan, Vidhya
    Univ Bern, Vetsuisse Fac, Inst Genet, CH-3001 Bern, Switzerland.
    Janecka, Jan E.
    Duquesne Univ, Dept Biol Sci, Pittsburgh, PA 15282 USA.
    Leeb, Tosso
    Univ Bern, Vetsuisse Fac, Inst Genet, CH-3001 Bern, Switzerland.
    Lindgren, Gabriella
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden;Katholieke Univ Leuven, Dept Biosyst, B-3001 Leuven, Belgium.
    McCue, Molly
    Univ Minnesota, Vet Populat Med Dept, St Paul, MN 55108 USA.
    Metzger, Julia
    Univ Vet Med Hannover, Inst Anim Breeding & Genet, D-30559 Hannover, Germany.
    Neuditschko, Markus
    Agroscope, Swiss Natl Stud Farm, CH-1580 Avenches, Switzerland.
    Rattei, Thomas
    Univ Vienna, Dept Microbiol & Ecosyst Sci, Div Computat Syst Biol, Althanstr 14, A-1090 Vienna, Austria.
    Raudsepp, Terje
    Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.
    Rieder, Stefan
    Agroscope, Swiss Natl Stud Farm, CH-1580 Avenches, Switzerland.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schaefer, Robert
    Agroscope, Swiss Natl Stud Farm, CH-1580 Avenches, Switzerland.
    Schloetterer, Christian
    Univ Vet Med Vienna, Inst Populat Genet, A-1210 Vienna, Austria.
    Thaller, Georg
    Univ Kiel, Inst Anim Breeding & Husb, D-24098 Kiel, Germany.
    Tetens, Jens
    Univ Kiel, Inst Anim Breeding & Husb, D-24098 Kiel, Germany;Georg August Univ Gottingen, Dept Anim Sci, Funct Breeding Grp, D-37077 Gottingen, Germany.
    Velie, Brandon
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden;Univ Sydney, Sch Life & Environm Sci, Sydney, NSW 2006, Australia.
    Brem, Gottfried
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria.
    Wallner, Barbara
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria.
    The horse Y chromosome as an informative marker for tracing sire lines2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 6095Article in journal (Refereed)
    Abstract [en]

    Analysis of the Y chromosome is the best-established way to reconstruct paternal family history in humans. Here, we applied fine-scaled Y-chromosomal haplotyping in horses with biallelic markers and demonstrate the potential of our approach to address the ancestry of sire lines. We de novo assembled a draft reference of the male-specific region of the Y chromosome from Illumina short reads and then screened 5.8 million basepairs for variants in 130 specimens from intensively selected and rural breeds and nine Przewalski's horses. Among domestic horses we confirmed the predominance of a young'crown haplogroup' in Central European and North American breeds. Within the crown, we distinguished 58 haplotypes based on 211 variants, forming three major haplogroups. In addition to two previously characterised haplogroups, one observed in Arabian/Coldblooded and the other in Turkoman/Thoroughbred horses, we uncovered a third haplogroup containing Iberian lines and a North African Barb Horse. In a genealogical showcase, we distinguished the patrilines of the three English Thoroughbred founder stallions and resolved a historic controversy over the parentage of the horse 'Galopin', born in 1872. We observed two nearly instantaneous radiations in the history of Central and Northern European Y-chromosomal lineages that both occurred after domestication 5,500 years ago.

  • 125.
    Filppula, Anne M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Parvizi, Rezvan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mateus, André
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Baranczewski, Pawel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Pharmacy and SciLifeLab Drug Discovery and Development Platform, ADME of Therapeutics facility, Department of Pharmacy, Uppsala University, BMC, Box 580, SE-75123, Uppsala, Sweden..
    Improved predictions of time-dependent drug-drug interactions by determination of cytosolic drug concentrations2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 5850Article in journal (Refereed)
    Abstract [en]

    The clinical impact of drug-drug interactions based on time-dependent inhibition of cytochrome P450 (CYP) 3A4 has often been overpredicted, likely due to use of improper inhibitor concentration estimates at the enzyme. Here, we investigated if use of cytosolic unbound inhibitor concentrations could improve predictions of time-dependent drug-drug interactions. First, we assessed the inhibitory effects of ten time-dependent CYP3A inhibitors on midazolam 1′-hydroxylation in human liver microsomes. Then, using a novel method, we determined the cytosolic bioavailability of the inhibitors in human hepatocytes, and used the obtained values to calculate their concentrations at the active site of the enzyme, i.e. the cytosolic unbound concentrations. Finally, we combined the data in mechanistic static predictions, by considering different combinations of inhibitor concentrations in intestine and liver, including hepatic concentrations corrected for cytosolic bioavailability. The results were then compared to clinical data. Compared to no correction, correction for cytosolic bioavailability resulted in higher accuracy and precision, generally in line with those obtained by more demanding modelling. The best predictions were obtained when the inhibition of hepatic CYP3A was based on unbound maximal inhibitor concentrations corrected for cytosolic bioavailability. Our findings suggest that cytosolic unbound inhibitor concentrations improves predictions of time-dependent drug-drug interactions for CYP3A.

  • 126.
    Fisher, Matthew C.
    et al.
    Imperial Coll London, Sch Publ Hlth, Fac Med, Dept Infect Dis Epidemiol, St Marys Campus, London W2 1PG, England.
    Ghosh, Pria
    Imperial Coll London, Sch Publ Hlth, Fac Med, Dept Infect Dis Epidemiol, St Marys Campus, London W2 1PG, England;North West Univ, Unit Environm Sci & Management, Private Bag x6001, ZA-2520 Potchefstroom, South Africa.
    Shelton, Jennifer M. G.
    Imperial Coll London, Sch Publ Hlth, Fac Med, Dept Infect Dis Epidemiol, St Marys Campus, London W2 1PG, England.
    Bates, Kieran
    Imperial Coll London, Sch Publ Hlth, Fac Med, Dept Infect Dis Epidemiol, St Marys Campus, London W2 1PG, England.
    Brookes, Lola
    Inst Zool, Regents Pk, London NW1 4RY, England.
    Wierzbicki, Claudia
    Imperial Coll London, Sch Publ Hlth, Fac Med, Dept Infect Dis Epidemiol, St Marys Campus, London W2 1PG, England.
    Rosa, Goncalo M.
    Inst Zool, Regents Pk, London NW1 4RY, England;Univ Lisbon, Fac Ciencias, Ctr Ecol Evolut & Environm Changes CE3C, Lisbon, Portugal.
    Farrer, Rhys A.
    Imperial Coll London, Sch Publ Hlth, Fac Med, Dept Infect Dis Epidemiol, St Marys Campus, London W2 1PG, England.
    Aanensen, David M.
    Imperial Coll London, Sch Publ Hlth, Fac Med, Dept Infect Dis Epidemiol, St Marys Campus, London W2 1PG, England;Ctr Genom Pathogen Surveillance, Wellcome Genome Campus, Hinxton, Cambs, England.
    Alvarado-Rybak, Mario
    Univ Andres Bello, Fac Ecol & Recursos Nat, Ctr Invest Sustentabilidad, Republ 440, Santiago, Chile.
    Bataille, Arnaud
    Seoul Natl Univ, Sch Biol Sci, Lab Behav & Populat Ecol, Seoul 08826, South Korea;CIRAD, UMR ASTRE, F-34398 Montpellier, France;Univ Montpellier, ASTRE, CIRAD, INRA, Montpellier, France.
    Berger, Lee
    James Cook Univ, Coll Publ Hlth Med & Vet Sci, Hlth Res Grp 1, Townsville, Qld 4811, Australia.
    Böll, Susanne
    Agcy Populat Ecol & Nat Conservancy, Gerbrunn, Germany.
    Bosch, Jaime
    CSIC, Museo Nacl Ciencias Nat, C Jose Gutierrez Abascal 2, E-28006 Madrid, Spain.
    Clare, Frances C.
    Imperial Coll London, Sch Publ Hlth, Fac Med, Dept Infect Dis Epidemiol, St Marys Campus, London W2 1PG, England.
    Courtois, Elodie A.
    Univ Guyane, CNRS, IFREMER, LEEISA, Cayenne 97300, French Guiana.
    Crottini, Angelica
    Univ Porto, InBIO, CIBIO Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Cunningham, Andrew A.
    Inst Zool, Regents Pk, London NW1 4RY, England.
    Doherty-Bone, Thomas M.
    Royal Zool Soc Scotland, Conservat Programmes, Edinburgh, Midlothian, Scotland.
    Gebresenbet, Fikirte
    Oklahoma State Univ, Dept Integrat Biol, Life Sci West 113, Stillwater, OK 74078 USA.
    Gower, David J.
    Nat Hist Museum, Life Sci, London SW7 5BD, England.
    Höglund, Jacob
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    James, Timothy Y.
    Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA.
    Jenkinson, Thomas S.
    Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA.
    Kosch, Tiffany A.
    Seoul Natl Univ, Sch Biol Sci, Lab Behav & Populat Ecol, Seoul 08826, South Korea;James Cook Univ, Coll Publ Hlth Med & Vet Sci, Hlth Res Grp 1, Townsville, Qld 4811, Australia.
    Lambertini, Carolina
    Univ Estadual Campinas, Inst Biol, Dept Biol Anim, Lab Hist Nat Anfibios Brasileiros, BR-13083862 Campinas, SP, Brazil.
    Laurila, Anssi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Lin, Chun-Fu
    Endem Species Res Inst, Zool Div, 1 Ming Shen East Rd, Nantou 552, Taiwan.
    Loyau, Adeline
    UFZ Helmholtz Ctr Environm Res, Dept Conservat Biol, Permoserstr 15, D-04318 Leipzig, Germany;Univ Toulouse, CNRS, ECOLAB, INPT,UPS, Toulouse, France.
    Martel, An
    Univ Ghent, Dept Pathol Bacteriol & Avian Dis, Fac Vet Med, Salisburylaan 133, B-9820 Merelbeke, Belgium.
    Meurling, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Miaud, Claude
    Univ Paul Valery Montpellier, Univ Montpellier, PSL Res Univ, CEFE,UMR 5175,CNRS,EPHE,Biogeog & Ecol Vertebres, Montpellier, France.
    Minting, Pete
    Amphibian & Reptile Conservat ARC Trust, 655A Christchurch Rd, Bournemouth BH1 4AP, Dorset, England.
    Ndriantsoa, Serge
    Durrell Wildlife Conservat Trust, Madagascar Programme, Antananarivo, Madagascar.
    O'Hanlon, Simon J.
    Imperial Coll London, Sch Publ Hlth, Fac Med, Dept Infect Dis Epidemiol, St Marys Campus, London W2 1PG, England;Inst Zool, Regents Pk, London NW1 4RY, England.
    Pasmans, Frank
    Univ Ghent, Dept Pathol Bacteriol & Avian Dis, Fac Vet Med, Salisburylaan 133, B-9820 Merelbeke, Belgium.
    Rakotonanahary, Tsanta
    Durrell Wildlife Conservat Trust, Madagascar Programme, Antananarivo, Madagascar.
    Rabemananjara, Falitiana C. E.
    Durrell Wildlife Conservat Trust, Madagascar Programme, Antananarivo, Madagascar;IUCN SSC Amphibian Specialist Grp Madagascar, Antananarivo 101, Madagascar.
    Ribeiro, Luisa P.
    Univ Estadual Campinas, Inst Biol, Dept Biol Anim, Lab Hist Nat Anfibios Brasileiros, BR-13083862 Campinas, SP, Brazil.
    Schmeller, Dirk S.
    UFZ Helmholtz Ctr Environm Res, Dept Conservat Biol, Permoserstr 15, D-04318 Leipzig, Germany;Univ Toulouse, CNRS, ECOLAB, INPT,UPS, Toulouse, France.
    Schmidt, Benedikt R.
    Univ Zurich, Dept Evolutionary Biol & Environm Studies, Winterthurerstr 190, CH-8057 Zurich, Switzerland;Univ Neuchatel, Info Fauna Karch, Bellevaux 51,UniMail Batiment 6, CH-2000 Neuchatel, Switzerland.
    Skerratt, Lee
    James Cook Univ, Coll Publ Hlth Med & Vet Sci, Hlth Res Grp 1, Townsville, Qld 4811, Australia.
    Smith, Freya
    APHA, Natl Wildlife Management Ctr, Woodchester Pk GL10 3UJ, Glos, England.
    Soto-Azat, Claudio
    Univ Andres Bello, Fac Ecol & Recursos Nat, Ctr Invest Sustentabilidad, Republ 440, Santiago, Chile.
    Tessa, Giulia
    Nonprofit Assoc Zirichiltaggi Sardinia Wildlife C, Str Vicinale Filigheddu 62-C, I-07100 Sassari, Italy.
    Toledo, Luis Felipe
    Univ Estadual Campinas, Inst Biol, Dept Biol Anim, Lab Hist Nat Anfibios Brasileiros, BR-13083862 Campinas, SP, Brazil.
    Valenzuela-Sanchez, Andres
    Univ Andres Bello, Fac Ecol & Recursos Nat, Ctr Invest Sustentabilidad, Republ 440, Santiago, Chile;ONG Ranita Darwin, Nataniel Cox 152, Santiago, Chile.
    Verster, Ruhan
    North West Univ, Unit Environm Sci & Management, Private Bag x6001, ZA-2520 Potchefstroom, South Africa.
    Vörös, Judit
    Hungarian Nat Hist Museum, Dept Zool, Collect Amphibians & Reptiles, Baross U 13, H-1088 Budapest, Hungary.
    Waldman, Bruce
    Seoul Natl Univ, Sch Biol Sci, Lab Behav & Populat Ecol, Seoul 08826, South Korea.
    Webb, Rebecca J.
    James Cook Univ, Coll Publ Hlth Med & Vet Sci, Hlth Res Grp 1, Townsville, Qld 4811, Australia.
    Weldon, Che
    North West Univ, Unit Environm Sci & Management, Private Bag x6001, ZA-2520 Potchefstroom, South Africa.
    Wombwell, Emma
    Inst Zool, Regents Pk, London NW1 4RY, England.
    Zamudio, Kelly R.
    Cornell Univ, Dept Ecol & Evolutionary Biol, Ithaca, NY 14853 USA.
    Longcore, Joyce E.
    Univ Maine, Sch Biol & Ecol, Orono, ME 04469 USA.
    Garner, Trenton W. J.
    Inst Zool, Regents Pk, London NW1 4RY, England;Nonprofit Assoc Zirichiltaggi Sardinia Wildlife C, Str Vicinale Filigheddu 62-C, I-07100 Sassari, Italy;North West Univ, Unit Environm Sci & Management, Private Bag x6001, ZA-2520 Potchefstroom, South Africa.
    Development and worldwide use of non-lethal, and minimal population-level impact, protocols for the isolation of amphibian chytrid fungi2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 7772Article in journal (Refereed)
    Abstract [en]

    Parasitic chytrid fungi have emerged as a significant threat to amphibian species worldwide, necessitating the development of techniques to isolate these pathogens into culture for research purposes. However, early methods of isolating chytrids from their hosts relied on killing amphibians. We modified a pre-existing protocol for isolating chytrids from infected animals to use toe clips and biopsies from toe webbing rather than euthanizing hosts, and distributed the protocol to researchers as part of the BiodivERsA project RACE; here called the RML protocol. In tandem, we developed a lethal procedure for isolating chytrids from tadpole mouthparts. Reviewing a database of use a decade after their inception, we find that these methods have been applied across 5 continents, 23 countries and in 62 amphibian species. Isolation of chytrids by the non-lethal RML protocol occured in 18% of attempts with 207 fungal isolates and three species of chytrid being recovered. Isolation of chytrids from tadpoles occured in 43% of attempts with 334 fungal isolates of one species (Batrachochytrium dendrobatidis) being recovered. Together, these methods have resulted in a significant reduction and refinement of our use of threatened amphibian species and have improved our ability to work with this group of emerging pathogens.

  • 127. Fleetwood, Filippa
    et al.
    Klint, Susanne
    Hanze, Martin
    Gunneriusson, Elin
    Frejd, Fredrik Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Stah, Stefan
    Lofblom, John
    Simultaneous targeting of two ligand-binding sites on VEGFR2 using biparatopic Affibody molecules results in dramatically improved affinity2014In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 4, p. 7518-Article in journal (Refereed)
    Abstract [en]

    Angiogenesis plays an important role in cancer and ophthalmic disorders such as age-related macular degeneration and diabetic retinopathy. The vascular endothelial growth factor (VEGF) family and corresponding receptors are regulators of angiogenesis and have been much investigated as therapeutic targets. The aim of this work was to generate antagonistic VEGFR2-specific affinity proteins having adjustable pharmacokinetic properties allowing for either therapy or molecular imaging. Two antagonistic Affibody molecules that were cross-reactive for human and murine VEGFR2 were selected by phage and bacterial display. Surprisingly, although both binders independently blocked VEGF-A binding, competition assays revealed interaction with non-overlapping epitopes on the receptor. Biparatopic molecules, comprising the two Affibody domains, were hence engineered to potentially increase affinity even further through avidity. Moreover, an albumin-binding domain was included for half-life extension in future in vivo experiments. The best-performing of the biparatopic constructs demonstrated up to 180-fold slower dissociation than the monomers. The new Affibody constructs were also able to specifically target VEGFR2 on human cells, while simultaneously binding to albumin, as well as inhibit VEGF-induced signaling. In summary, we have generated small antagonistic biparatopic Affibody molecules with high affinity for VEGFR2, which have potential for both future therapeutic and diagnostic purposes in angiogenesis-related diseases.

  • 128.
    Flowers, Sarah A.
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Med Biochem & Cell Biol, Gothenburg, Sweden..
    Zieba, Agata
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Örnros, Jessica
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Med Biochem & Cell Biol, Gothenburg, Sweden..
    Jin, Chunsheng
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Med Biochem & Cell Biol, Gothenburg, Sweden..
    Rolfson, Ola
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Orthopaed, Gothenburg, Sweden..
    Björkman, Lena I.
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden..
    Eisler, Thomas
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden..
    Kalamajski, Sebastian
    Lund Univ, Dept Mol Skeletal Biol, Lund, Sweden..
    Kamali-Moghaddam, Masood
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Karlsson, Niclas G.
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Med Biochem & Cell Biol, Gothenburg, Sweden..
    Lubricin binds cartilage proteins, cartilage oligomeric matrix protein, fibronectin and collagen II at the cartilage surface2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 13149Article in journal (Refereed)
    Abstract [en]

    Lubricin, a heavily O-glycosylated protein, is essential for boundary lubrication of articular cartilage. Strong surface adherence of lubricin is required given the extreme force it must withstand. Disulfide bound complexes of lubricin and cartilage oligomeric matrix protein (COMP) have recently been identified in arthritic synovial fluid suggesting they may be lost from the cartilage surface in osteoarthritis and inflammatory arthritis. This investigation was undertaken to localise COMP-lubricin complexes within cartilage and investigate if other cartilage proteins are involved in anchoring lubricin to the joint. Immunohistochemical analysis of human cartilage biopsies showed lubricin and COMP co-localise to the cartilage surface. COMP knockout mice, however, presented with a lubricin layer on the articular cartilage leading to the further investigation of additional lubricin binding mechanisms. Proximity ligation assays (PLA) on human cartilage biopsies was used to localise additional lubricin binding partners and demonstrated that lubricin bound COMP, but also fibronectin and collagen II on the cartilage surface. Fibronectin and collagen II binding to lubricin was confirmed and characterised by solid phase binding assays with recombinant lubricin fragments. Overall, COMP, fibronectin and collagen II bind lubricin, exposed on the articular cartilage surface suggesting they may be involved in maintaining essential boundary lubrication.

  • 129. Formenti, Federico
    et al.
    Bommakanti, Nikhil
    Chen, Rongsheng
    Cronin, John N
    McPeak, Hanne
    Holopherne-Doran, Delphine
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Hahn, Clive E W
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Farmery, Andrew D
    Respiratory oscillations in alveolar oxygen tension measured in arterial blood.2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 7499Article in journal (Refereed)
    Abstract [en]

    Arterial oxygen partial pressure can increase during inspiration and decrease during expiration in the presence of a variable shunt fraction, such as with cyclical atelectasis, but it is generally presumed to remain constant within a respiratory cycle in the healthy lung. We measured arterial oxygen partial pressure continuously with a fast intra-vascular sensor in the carotid artery of anaesthetized, mechanically ventilated pigs, without lung injury. Here we demonstrate that arterial oxygen partial pressure shows respiratory oscillations in the uninjured pig lung, in the absence of cyclical atelectasis (as determined with dynamic computed tomography), with oscillation amplitudes that exceeded 50 mmHg, depending on the conditions of mechanical ventilation. These arterial oxygen partial pressure respiratory oscillations can be modelled from a single alveolar compartment and a constant oxygen uptake, without the requirement for an increased shunt fraction during expiration. Our results are likely to contribute to the interpretation of arterial oxygen respiratory oscillations observed during mechanical ventilation in the acute respiratory distress syndrome.

  • 130.
    Forslund, Ola Kenji
    et al.
    KTH Royal Inst Technol, Dept Appl Phys, Elect 229, SE-16440 Kista, Sweden.
    Andreica, Daniel
    Babes Bolyai Univ, Fac Phys, Cluj Napoca, Romania.
    Sassa, Yasmine
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Nozaki, Hiroshi
    Toyota Cent Res & Dev Labs Inc, 41-1 Yokomichi, Nagakute, Aichi 4801192, Japan.
    Umegaki, Izumi
    Toyota Cent Res & Dev Labs Inc, 41-1 Yokomichi, Nagakute, Aichi 4801192, Japan.
    Nocerino, Elisabetta
    KTH Royal Inst Technol, Dept Appl Phys, Elect 229, SE-16440 Kista, Sweden.
    Jonsson, Viktor
    KTH Royal Inst Technol, Dept Appl Phys, Elect 229, SE-16440 Kista, Sweden.
    Tjernberg, Oscar
    KTH Royal Inst Technol, Dept Appl Phys, Elect 229, SE-16440 Kista, Sweden.
    Guguchia, Zurab
    Paul Scherrer Inst, Lab Muon Spin Spect, CH-5232 Villigen, PSI, Switzerland.
    Shermadini, Zurab
    Paul Scherrer Inst, Lab Muon Spin Spect, CH-5232 Villigen, PSI, Switzerland.
    Khasanov, Rustem
    Paul Scherrer Inst, Lab Muon Spin Spect, CH-5232 Villigen, PSI, Switzerland.
    Isobe, Masahiko
    Max Planck Inst Solid State Res, Heisenbergstr 1, D-70569 Stuttgart, Germany.
    Takagi, Hidenori
    Max Planck Inst Solid State Res, Heisenbergstr 1, D-70569 Stuttgart, Germany.
    Ueda, Yutaka
    Toyota Phys & Chem Res Inst, 41-1 Yokomichi, Nagakute, Aichi 4801192, Japan.
    Sugiyama, Jun
    Toyota Cent Res & Dev Labs Inc, 41-1 Yokomichi, Nagakute, Aichi 4801192, Japan.
    Mansson, Martin
    KTH Royal Inst Technol, Dept Appl Phys, Elect 229, SE-16440 Kista, Sweden.
    Magnetic phase diagram of K2Cr8O16 clarified by high-pressure muon spin spectroscopy2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 1141Article in journal (Refereed)
    Abstract [en]

    The K2Cr8O16 compound belongs to a series of quasi-1D compounds with intriguing magnetic properties that are stabilized through a high-pressure synthesis technique. In this study, a muon spin rotation, relaxation and resonance (mu+SR) technique is used to investigate the pressure dependent magnetic properties up to 25 kbar. mu+SR allows for measurements in true zero applied field and hereby access the true intrinsic material properties. As a result, a refined temperature/pressure phase diagram is presented revealing a novel low temperature/high pressure (p(C1) = 21 kbar) transition from a ferromagnetic insulating to a high-pressure antiferromagnetic insulator. Finally, the current study also indicates the possible presence of a quantum critical point at p(C2) similar to 33 kbar where the magnetic order in K2Cr8O16 is expected to be fully suppressed even at T = 0 K.

  • 131.
    Fredolini, Claudia
    et al.
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, Sci Life Lab, S-17121 Solna, Sweden.
    Byström, Sanna
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, Sci Life Lab, S-17121 Solna, Sweden.
    Sanchez-Rivera, Laura
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, Sci Life Lab, S-17121 Solna, Sweden.
    Ioannou, Marina
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, Sci Life Lab, S-17121 Solna, Sweden.
    Tamburro, Davide
    Karolinska Inst, Sci Life Lab, Dept Oncol Pathol, Canc Prote, S-17121 Solna, Sweden.
    Pontén, Fredrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Branca, Rui M.
    Karolinska Inst, Sci Life Lab, Dept Oncol Pathol, Canc Prote, S-17121 Solna, Sweden.
    Nilsson, Peter
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, Sci Life Lab, S-17121 Solna, Sweden.
    Lehtiö, Janne
    Karolinska Inst, Sci Life Lab, Dept Oncol Pathol, Canc Prote, S-17121 Solna, Sweden.
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, Sci Life Lab, S-17121 Solna, Sweden.
    Systematic assessment of antibody selectivity in plasma based on a resource of enrichment profiles2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 8324Article in journal (Refereed)
    Abstract [en]

    There is a strong need for procedures that enable context and application dependent validation of antibodies. Here, we applied a magnetic bead assisted workflow and immunoprecipitation mass spectrometry (IP-MS/MS) to assess antibody selectivity for the detection of proteins in human plasma. A resource was built on 414 IP experiments using 157 antibodies (targeting 120 unique proteins) in assays with heat-treated or untreated EDTA plasma. For each protein we determined their antibody related degrees of enrichment using z-scores and their frequencies of identification across all IP assays. Out of 1,313 unique endogenous proteins, 426 proteins (33%) were detected in >20% of IPs, and these background components were mainly comprised of proteins from the complement system. For 45% (70/157) of the tested antibodies, the expected target proteins were enriched (z-score >= 3). Among these 70 antibodies, 59 (84%) co-enriched other proteins beside the intended target and mainly due to sequence homology or protein abundance. We also detected protein interactions in plasma, and for IGFBP2 confirmed these using several antibodies and sandwich immunoassays. The protein enrichment data with plasma provide a very useful and yet lacking resource for the assessment of antibody selectivity. Our insights will contribute to a more informed use of affinity reagents for plasma proteomics assays.

  • 132. Freedman, Kevin J.
    et al.
    Haq, S. Raza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Edel, Joshua B.
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kim, Min Jun
    Single molecule unfolding and stretching of protein domains inside a solid-state nanopore by electric field2013In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 3, p. 1638-Article in journal (Refereed)
    Abstract [en]

    Single molecule methods have provided a significantly new look at the behavior of biomolecules in both equilibrium and non-equilibrium conditions. Most notable are the stretching experiments performed by atomic force microscopes and laser tweezers. Here we present an alternative single molecule method that can unfold a protein domain, observed at electric fields greater than 106 V/m, and is fully controllable by the application of increasing voltages across the membrane of the pore. Furthermore this unfolding mechanism is characterized by measuring both the residence time of the protein within the nanopore and the current blockade. The unfolding data supports a gradual unfolding mechanism rather than the cooperative transition observed by classical urea denaturation experiments. Lastly it is shown that the voltage-mediated unfolding is a function of the stability of the protein by comparing two mutationally destabilized variants of the protein.

  • 133.
    Fritze, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Malinovskis, Paulius
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Riekehr, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    von Fieandt, Linus
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Lewin, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Jansson, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Hard and crack resistant carbon supersaturated refractory nanostructured multicomponent coatings2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 14508Article in journal (Refereed)
    Abstract [en]

    The combination of ceramic hardness with high crack resistance is a major challenge in the design of protective thin films. High entropy alloys have shown in earlier studies promising mechanical properties with a potential use as thin film materials. In this study, we show that small amounts of carbon in magnetron-sputtered multicomponent CrNbTaTiW films can lead to a significant increase in hardness. The film properties were strongly dependent on the metal composition and the most promising results were observed for TaW-rich films. They crystallised in a bcc structure with a strong (110) texture and coherent grain boundaries. It was possible to deposit films with 8 at.% C in a supersaturated solid-solution into the bcc structure without carbide formation. A major effect of carbon was a significant grain refinement, reducing the column diameter from approximately 35 to 10 nm. This resulted in an increase in hardness from 14.7 to 19.1 GPa while the reduced E-modulus stayed constant at 322 GPa. The carbon-containing films exhibited extremely little plastic deformation around the indent and no cracks were observed. These results show that supersaturation of carbon into high entropy films can be a promising concept to combine superior hardness with high crack resistance.

  • 134.
    Fryknäs, Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Zhang, Xiaonan
    Linkping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden.;Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, SE-17176 Stockholm, Sweden..
    Bremberg, Ulf
    Beactica, SE-75450 Uppsala, Sweden..
    Senkowski, Wojciech
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Olofsson, Maria Hägg
    Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, SE-17176 Stockholm, Sweden..
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Persson, Ingmar
    Swedish Univ Agr Sci, Dept Chem & Biotechnol, POB 7015, SE-75651 Uppsala, Sweden..
    D'Arcy, Padraig
    Linkping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden..
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Schughart, Leoni Kunz
    Tech Univ Dresden, OncoRay Natl Ctr Radiat Res Oncol, D-01307 Dresden, Germany..
    Linder, Stig
    Linkping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden.;Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, SE-17176 Stockholm, Sweden..
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Iron chelators target both proliferating and quiescent cancer cells2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 38343Article in journal (Refereed)
    Abstract [en]

    Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells.

  • 135.
    Galant, Natalie J.
    et al.
    Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Bugyei-Twum, Antoinette
    Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Rakhit, Rishi
    Stanford Univ, Dept Chem & Syst Biol, Stanford, CA 94305 USA..
    Walsh, Patrick
    Univ Toronto, Dept Biochem, Hosp Sick Children, Mol Struct & Funct Program, 1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada..
    Sharpe, Simon
    Univ Toronto, Dept Biochem, Hosp Sick Children, Mol Struct & Funct Program, 1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada..
    Arslan, Pharhad Eli
    Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Higaki, Jeffrey N.
    Prothena Biosci Inc, Dept Biochem, San Francisco, CA 94080 USA.;Prothena Biosci Inc, Dept Histopathol, San Francisco, CA 94080 USA..
    Torres, Ronald
    Prothena Biosci Inc, Dept Biochem, San Francisco, CA 94080 USA.;Prothena Biosci Inc, Dept Histopathol, San Francisco, CA 94080 USA..
    Tapia, Jose
    Prothena Biosci Inc, Dept Biochem, San Francisco, CA 94080 USA.;Prothena Biosci Inc, Dept Histopathol, San Francisco, CA 94080 USA..
    Chakrabartty, Avijit
    Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 25080Article in journal (Refereed)
    Abstract [en]

    Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis (R) and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89-97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential.

  • 136.
    Garousi, Javad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Andersson, Ken G.
    KTH Royal Inst Technol, Dept Prot Technol.
    Dam, Johan H.
    Odense Univ Hosp, Dept Nucl Med.
    Olsen, Birgitte B.
    Odense Univ Hosp, Dept Nucl Med..
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Buijs, Jos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Ståhl, Stefan
    KTH Royal Inst Technol, Dept Prot Technol.
    Löfblom, John
    KTH Royal Inst Technol, Dept Prot Technol.
    Thisgaard, Helge
    Odense Univ Hosp, Dept Nucl Med.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    The use of radiocobalt as a label improves imaging of EGFR using DOTA-conjugated Affibody molecule2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 5961Article in journal (Refereed)
    Abstract [en]

    Several anti-cancer therapies target the epidermal growth factor receptor (EGFR). Radionuclide imaging of EGFR expression in tumours may aid in selection of optimal cancer therapy. The In-111-labelled DOTA-conjugated Z(EGFR:2377) Affibody molecule was successfully used for imaging of EGFR-expressing xenografts in mice. An optimal combination of radionuclide, chelator and targeting protein may further improve the contrast of radionuclide imaging. The aim of this study was to evaluate the targeting properties of radiocobalt-labelled DOTA-Z(EGFR:2377). DOTA-Z(EGFR:2377) was labelled with Co-57 (T-1/2 = 271.8 d), Co-55 (T-1/2 = 17.5 h), and, for comparison, with the positron-emitting radionuclide Ga-68 (T-1/2 = 67.6 min) with preserved specificity of binding to EGFR-expressing A431 cells. The long-lived cobalt radioisotope Co-57 was used in animal studies. Both Co-57-DOTA-Z(EGFR:2377) and Ga-68-DOTA-Z(EGFR:2377) demonstrated EGFR-specific accumulation in A431 xenografts and EGFR-expressing tissues in mice. Tumour-to-organ ratios for the radiocobalt-labelled DOTA-Z(EGFR:2377) were significantly higher than for the gallium-labelled counterpart already at 3 h after injection. Importantly, Co-57-DOTA-Z(EGFR:2377) demonstrated a tumour-to-liver ratio of 3, which is 7-fold higher than the tumour-to-liver ratio for (68)GaDOTA-Z(EGFR:2377). The results of this study suggest that the positron-emitting cobalt isotope 55Co would be an optimal label for DOTA-Z(EGFR:2377) and further development should concentrate on this radionuclide as a label.

  • 137.
    Garousi, Javad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Lindbo, Sarah
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, Stockholm, Sweden..
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Buijs, Jos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Hober, Sophia
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, Stockholm, Sweden..
    Comparative evaluation of tumor targeting using the anti-HER2 ADAPT scaffold protein labeled at the C-terminus with indium-111 or technetium-99m2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 14780Article in journal (Refereed)
    Abstract [en]

    ABD-Derived Affinity Proteins (ADAPTs) is a novel class of engineered scaffold proteins derived from an albumin-binding domain of protein G. The use of ADAPT6 derivatives as targeting moiety have provided excellent preclinical radionuclide imaging of human epidermal growth factor 2 (HER2) tumor xenografts. Previous studies have demonstrated that selection of nuclide and chelator for its conjugation has an appreciable effect on imaging properties of scaffold proteins. In this study we performed a comparative evaluation of the anti-HER2 ADAPT having an aspartate-glutamate-alanine-valine-aspartate-alanine-asparagine-serine (DEAVDANS) N-terminal sequence and labeled at C-terminus with (99)mTc using a cysteine-containing peptide based chelator, glycine-serine-serine-cysteine (GSSC), and a similar variant labeled with In-111 using a maleimido derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. Both (99)mTc-DEAVDANS-ADAPT6-GSSC and In-111-DEAVDANS-ADAPT6-GSSC-DOTA accumulated specifically in HER2-expressing SKOV3 xenografts. The tumor uptake of both variants did not differ significantly and average values were in the range of 19-21% ID/g. However, there was an appreciable variation in uptake of conjugates in normal tissues that resulted in a notable difference in the tumor-to-organ ratios. The In-111-DOTA label provided 2-6 fold higher tumor-to-organ ratios than (99)mTc-GSSC and is therefore the preferable label for ADAPTs.

  • 138.
    Gautier, Candice
    et al.
    Sapienza Univ Roma, Dipartimento Sci Biochim A Rossi Fanelli, Ist Pasteur, Fdn Cenci Bolognetti, I-00185 Rome, Italy.;Sapienza Univ Roma, Ist Biol & Patol Mol, CNR, I-00185 Rome, Italy..
    Visconti, Lorenzo
    Sapienza Univ Roma, Dipartimento Sci Biochim A Rossi Fanelli, Ist Pasteur, Fdn Cenci Bolognetti, I-00185 Rome, Italy.;Sapienza Univ Roma, Ist Biol & Patol Mol, CNR, I-00185 Rome, Italy..
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gianni, Stefano
    Sapienza Univ Roma, Dipartimento Sci Biochim A Rossi Fanelli, Ist Pasteur, Fdn Cenci Bolognetti, I-00185 Rome, Italy.;Sapienza Univ Roma, Ist Biol & Patol Mol, CNR, I-00185 Rome, Italy..
    Addressing the role of the alpha-helical extension in the folding of the third PDZ domain from PSD-952017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 12593Article in journal (Refereed)
    Abstract [en]

    PDZ domains are one of the most important protein-protein interaction domains in human. While presenting a conserved three dimensional structure, a substantial number of PDZ domains display structural extensions suggested to be involved in their folding and binding mechanisms. The C-terminal a-helix extension (alpha 3) of the third PDZ domain from PSD-95 (PDZ3) has been reported to have a role in function of the domain as well as in the stabilization of the native fold. Here we report an evaluation of the effect of the truncation of this additional helix on the folding and unfolding kinetics of PDZ3. Fluorescent variants of full length and truncated PDZ3 were produced and stopped-flow fluorescence measurements were made under different experimental conditions (pH, ionic strength and temperature) to investigate the folding kinetics of the respective variant. The results show that folding of PDZ3 is robust and that the mechanism is only marginally affected by the truncation, which contributes to a destabilization of the native state, but otherwise do not change the overall observed kinetics. Furthermore, the increase in the unfolding rate constants, but not the folding rate constant upon deletion of alpha 3 suggests that the a-helical extension is largely unstructured in the folding transition state.

  • 139.
    Geiger, Harri
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Barker, Abigail K.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Troll, Valentin R.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics. Univ Las Palmas Gran Canaria, Dept Phys GEOVOL, La Palmas Gran Canaria, Spain.
    Locating the depth of magma supply for volcanic eruptions, insights from Mt. Cameroon2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 33629Article in journal (Refereed)
    Abstract [en]

    Mt. Cameroon is one of the most active volcanoes in Africa and poses a possible threat to about half a million people in the area, yet knowledge of the volcano’s underlying magma supply system is sparse. To characterize Mt. Cameroon’s magma plumbing system, we employed mineral-melt equilibrium thermobarometry on the products of the volcano’s two most recent eruptions of 1999 and 2000. Our results suggest pre-eruptive magma storage between 20 and 39 km beneath Mt. Cameroon, which corresponds to the Moho level and below. Additionally, the 1999 eruption products reveal several shallow magma pockets between 3 and 12 km depth, which are not detected in the 2000 lavas. This implies that small-volume magma batches actively migrate through the plumbing system during repose intervals. Evolving and migrating magma parcels potentially cause temporary unrest and short-lived explosive outbursts, and may be remobilized during major eruptions that are fed from sub-Moho magma reservoirs.

  • 140.
    Geiger, Harri
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Troll, Valentin R.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics. Univ Padjajaran UNPAD, Fac Geol Engn, Bandung, Indonesia;Ist Nazl Geofis & Vulcanol, Rome, Italy.
    Jolis, Ester M.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics. Geomar Helmholtz Ctr Ocean Res, Kiel, Germany.
    Deegan, Frances M.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics. Ist Nazl Geofis & Vulcanol, Rome, Italy.
    Harris, Chris
    Univ Cape Town, Dept Geol Sci, Cape Town, South Africa.
    Hilton, David R.
    Scripps Inst Oceanog, Geosci Res Div, La Jolla, CA USA.
    Freda, Carmela
    Ist Nazl Geofis & Vulcanol, Rome, Italy.
    Multi-level magma plumbing at Agung and Batur volcanoes increases risk of hazardous eruptions2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 10547Article in journal (Refereed)
    Abstract [en]

    The island of Bali in Indonesia is home to two active stratovolcanoes, Agung and Batur, but relatively little is known of their underlying magma plumbing systems. Here we define magma storage depths and isotopic evolution of the 1963 and 1974 eruptions using mineral-melt equilibrium thermobarometry and oxygen and helium isotopes in mineral separates. Olivine crystallised from a primitive magma and has average delta O-18 values of 4.8%. Clinopyroxene records magma storage at the crust-mantle boundary, and displays mantle-like isotope values for Helium (8.62 R-A) and delta O-18 (5.0-5.8%). Plagioclase reveals crystallisation in upper crustal storage reservoirs and shows delta O-18 values of 5.5-6.4%. Our new thermobarometry and isotope data thus corroborate earlier seismic and InSAR studies that inferred upper crustal magma storage in the region. This type of multi-level plumbing architecture could drive replenishing magma to rapid volatile saturation, thus increasing the likelihood of explosive eruptions and the consequent hazard potential for the population of Bali.

  • 141.
    Geilhufe, R. Matthias
    et al.
    KTH Royal Inst Technol, Ctr Quantum Mat, Nordita, Roslagstullsbacken 23, S-10691 Stockholm, Sweden.;Stockholm Univ, Roslagstullsbacken 23, S-10691 Stockholm, Sweden..
    Borysov, Stanislav S.
    KTH Royal Inst Technol, Ctr Quantum Mat, Nordita, Roslagstullsbacken 23, S-10691 Stockholm, Sweden.;Stockholm Univ, Roslagstullsbacken 23, S-10691 Stockholm, Sweden..
    Bouhon, Adrien
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Balatsky, Alexander V.
    KTH Royal Inst Technol, Ctr Quantum Mat, Nordita, Roslagstullsbacken 23, S-10691 Stockholm, Sweden.;Stockholm Univ, Roslagstullsbacken 23, S-10691 Stockholm, Sweden.;Los Alamos Natl Lab, Inst Mat Sci, Los Alamos, NM 87545 USA.;ETH, ETH Inst Theoret Studies, CH-8092 Zurich, Switzerland..
    Data Mining for Three-Dimensional Organic Dirac Materials: Focus on Space Group 192017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 7298Article in journal (Refereed)
    Abstract [en]

    We combined the group theory and data mining approach within the Organic Materials Database that leads to the prediction of stable Dirac-point nodes within the electronic band structure of three-dimensional organic crystals. We find a particular space group P2(1)2(1)2(1) (#19) that is conducive to the Dirac nodes formation. We prove that nodes are a consequence of the orthorhombic crystal structure. Within the electronic band structure, two different kinds of nodes can be distinguished: 8-fold degenerate Dirac nodes protected by the crystalline symmetry and 4-fold degenerate Dirac nodes protected by band topology. Mining the Organic Materials Database, we present band structure calculations and symmetry analysis for 6 previously synthesized organic materials. In all these materials, the Dirac nodes are well separated within the energy and located near the Fermi surface, which opens up a possibility for their direct experimental observation.

  • 142. Ghaffari, Pouyan
    et al.
    Mardinoglu, Adil
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shoaie, Saeed
    Kampf, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhlen, Mathias
    Nielsen, Jens
    Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 8183-Article in journal (Refereed)
    Abstract [en]

    Human cancer cell lines are used as important model systems to study molecular mechanisms associated with tumor growth, hereunder how genomic and biological heterogeneity found in primary tumors affect cellular phenotypes. We reconstructed Genome scale metabolic models (GEMs) for eleven cell lines based on RNA-Seq data and validated the functionality of these models with data from metabolite profiling. We used cell line-specific GEMs to analyze the differences in the metabolism of cancer cell lines, and to explore the heterogeneous expression of the metabolic subsystems. Furthermore, we predicted 85 antimetabolites that can inhibit growth of, or even kill, any of the cell lines, while at the same time not being toxic for 83 different healthy human cell types. 60 of these antimetabolites were found to inhibit growth in all cell lines. Finally, we experimentally validated one of the predicted antimetabolites using two cell lines with different phenotypic origins, and found that it is effective in inhibiting the growth of these cell lines. Using immunohistochemistry, we also showed high or moderate expression levels of proteins targeted by the validated antimetabolite. Identified anti-growth factors for inhibition of cell growth may provide leads for the development of efficient cancer treatment strategies.

  • 143.
    Ghariblou, Saeed
    et al.
    Univ Tehran, Fac New Sci & Technol, Tehran, Iran; Inst Res Fundamental Sci IPM, Sch Comp Sci, Tehran, Iran.
    Salehi, Mostafa
    Univ Tehran, Fac New Sci & Technol, Tehran, Iran; Inst Res Fundamental Sci IPM, Sch Comp Sci, Tehran, Iran.
    Magnani, Matteo
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computing Science.
    Jalili, Mahdi
    RMIT Univ, Sch Engn, Melbourne, Vic, Australia.
    Shortest Paths in Multiplex Networks2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 2142Article in journal (Refereed)
    Abstract [en]

    The shortest path problem is one of the most fundamental networks optimization problems. Nowadays, individuals interact in extraordinarily numerous ways through their offline and online life (e.g., co-authorship, co-workership, or retweet relation in Twitter). These interactions have two key features. First, they have a heterogeneous nature, and second, they have different strengths that are weighted based on their degree of intimacy, trustworthiness, service exchange or influence among individuals. These networks are known as multiplex networks. To our knowledge, none of the previous shortest path definitions on social interactions have properly reflected these features. In this work, we introduce a new distance measure in multiplex networks based on the concept of Pareto efficiency taking both heterogeneity and weighted nature of relations into account. We then model the problem of finding the whole set of paths as a form of multiple objective decision making and propose an exact algorithm for that. The method is evaluated on five real-world datasets to test the impact of considering weights and multiplexity in the resulting shortest paths. As an application to find the most influential nodes, we redefine the concept of betweenness centrality based on the proposed shortest paths and evaluate it on a real-world dataset from two-layer trade relation among countries between years 2000 and 2015.

  • 144.
    Ghindilis, Andrey L.
    et al.
    TORCATECH LLC, 5210,104th St SW, Mukilteo, WA 98275 USA.
    Chesnokov, Olga
    Florida Atlantic Univ, Charles E Schmidt Coll Med, Dept Biomed Sci, 777 Glades Rd, Boca Raton, FL 33428 USA.
    Ngasala, Billy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania.
    Smith, Maria W.
    TORCATECH LLC, 5210,104th St SW, Mukilteo, WA 98275 USA.
    Smith, Kenneth
    TORCATECH LLC, 5210,104th St SW, Mukilteo, WA 98275 USA.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Oleinikov, Andrew V.
    Florida Atlantic Univ, Charles E Schmidt Coll Med, Dept Biomed Sci, 777 Glades Rd, Boca Raton, FL 33428 USA.
    Detection of sub-microscopic blood levels of Plasmodium falciparum using Tandem Oligonucleotide Repeat Cascade Amplification (TORCA) assay with an attomolar detection limit2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 2901Article in journal (Refereed)
    Abstract [en]

    Tandem Oligonucleotide Repeat Cascade Amplification (TORCA) based on signal rather than target amplification under isothermal conditions was developed for nucleic acid assays. The initial signal was generated by hybridization of single stranded DNA targets to immobilized recognition probes followed by hybrid cleavage with specific restriction endonuclease (REase), and release of trigger oligonucleotides (Tr1). The signal amplification chamber contained two bead types carrying single-stranded amplification probes and two amplification REases. The probes consisted of multiple tandem repeats of either Tr1 or another trigger Tr2, with the tandem-Tr1 anchored to the beads through the antisense Tr2 linker and vice versa. Addition of the recognition reaction solution and Tr1 hybridization to the anti-Tr1 linkers started cleavage and release of additional Tr1 and Tr2, resulting in exponential signal amplification. The cleavage cascade also released horseradish peroxidase (HRP) pre-attached to the amplification probes, and the resultant signal was measured colorimetrically. A TORCA assay was developed for detection of Plasmodium falciparum parasites in blood. It had the detection limit in the attomolar concentration range, successfully detecting sub-microscopic P. falciparum infections at less than 0.75 infected erythrocytes per microliter. Further TORCA optimization will likely produce the quantitative isothermal alternative to PCR at a fraction of its cost.

  • 145.
    Gingnell, Malin
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Toffoletto, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Bannbers, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Emotional anticipation after delivery - a longitudinal neuroimaging study of the postpartum period2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 114Article in journal (Refereed)
    Abstract [en]

    Neuroimaging research has begun to unveil the mechanisms behind emotion processing during the postpartum period, which, in turn, may be of relevance for the development of postpartum depression. The present study sought to longitudinally investigate the neural correlates of emotion anticipation during the postpartum period in healthy women. Functional magnetic resonance imaging was employed to measure the blood oxygen level-dependent signal in the brain in response to anticipation of negative emotional stimuli and during processing of images with positive or negative valence. The participating women were scanned twice: the first scan occurred during the first 48 hours after delivery, and the second was performed 4-6 weeks after delivery. The early postpartum period was characterized by higher anterior cingulate cortex reactivity during anticipation of negative emotional stimuli than the late postpartum period. This was accompanied by a negative relationship with insular reactivity during the early postpartum period and a trend towards an increase in insular reactivity in the late postpartum period. Thus, during the first four weeks of the postpartum period, a diminished top-down regulatory feedback on emotion-related areas of the brain was noted. This finding suggests a physiologically important adaptation during the healthy postpartum period.

  • 146.
    Glechner, T.
    et al.
    TU Wien, Inst Mat Sci & Technol, A-1060 Vienna, Austria.
    Mayrhofer, P. H.
    TU Wien, Inst Mat Sci & Technol, A-1060 Vienna, Austria.
    Holec, D.
    Univ Leoben, Dept Mat Sci, A-8700 Leoben, Austria.
    Fritze, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Lewin, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Paneta, Valentina
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Primetzhofer, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Kolozsvari, S.
    Plansee Composite Mat GmbH, D-86983 Lechbruck, Germany.
    Riedl, H.
    TU Wien, Inst Mat Sci & Technol, A-1060 Vienna, Austria.
    Tuning structure and mechanical properties of Ta-C coatings by N-alloying and vacancy population2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 17669Article in journal (Refereed)
    Abstract [en]

    Tailoring mechanical properties of transition metal carbides by substituting carbon with nitrogen atoms is a highly interesting approach, as thereby the bonding state changes towards a more metallic like character and thus ductility can be increased. Based on ab initio calculations we could prove experimentally, that up to a nitrogen content of about 68% on the non-metallic sublattice, Ta-C-N crystals prevail a face centered cubic structure for sputter deposited thin films. The cubic structure is partly stabilized by non-metallic as well as Ta vacancies-the latter are decisive for nitrogen rich compositions. With increasing nitrogen content, the originally super-hard fcc-TaC0.71 thin films soften from 40 GPa to 26 GPa for TaC0.33N0.67, accompanied by a decrease of the indentation modulus. With increasing nitrogen on the non-metallic sublattice (hence, decreasing C) the damage tolerance of Ta-C based coatings increases, when characterized after the Pugh and Pettifor criteria. Consequently, varying the non-metallic sublattice population allows for an effective tuning and designing of intrinsic coating properties.

  • 147.
    Gliga, Anda R.
    et al.
    Karolinska Inst, Div Mol Toxicol, Stockholm, Sweden.;Karolinska Inst, Inst Environm Med, Div Biochem Toxicol, Stockholm, Sweden..
    Edoff, Karin
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Caputo, Fanny
    Univ Roma Tor Vergata, Dept Biol, Rome, Italy.;Univ Roma Tor Vergata, Dept Chem Sci & Technol, Rome, Italy..
    Källman, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Blom, Hans
    Royal Inst Technol, Sci Life Lab, Solna, Sweden..
    Karlsson, Hanna L.
    Karolinska Inst, Inst Environm Med, Div Biochem Toxicol, Stockholm, Sweden..
    Ghibelli, Lina
    Univ Roma Tor Vergata, Dept Biol, Rome, Italy..
    Traversa, Enrico
    Univ Roma Tor Vergata, Dept Chem Sci & Technol, Rome, Italy.;Xi An Jiao Tong Univ, Int Res Ctr Renewable Energy, Xian, Shaanxi, Peoples R China..
    Ceccatelli, Sandra
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Fadeel, Bengt
    Karolinska Inst, Div Mol Toxicol, Stockholm, Sweden..
    Cerium oxide nanoparticles inhibit differentiation of neural stem cells2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 9284Article in journal (Refereed)
    Abstract [en]

    Cerium oxide nanoparticles (nanoceria) display antioxidant properties and have shown cytoprotective effects both in vitro and in vivo. Here, we explored the effects of nanoceria on neural progenitor cells using the C17.2 murine cell line as a model. First, we assessed the effects of nanoceria versus samarium (Sm) doped nanoceria on cell viability in the presence of the prooxidant, DMNQ. Both particles were taken up by cells and nanoceria, but not Sm-doped nanoceria, elicited a temporary cytoprotective effect upon exposure to DMNQ. Next, we employed RNA sequencing to explore the transcriptional responses induced by nanoceria or Sm-doped nanoceria during neuronal differentiation. Detailed computational analyses showed that nanoceria altered pathways and networks relevant for neuronal development, leading us to hypothesize that nanoceria inhibits neuronal differentiation, and that nanoceria and Sm-doped nanoceria both interfere with cytoskeletal organization. We confirmed that nanoceria reduced neuron specific beta 3-tubulin expression, a marker of neuronal differentiation, and GFAP, a neuroglial marker. Furthermore, using super-resolution microscopy approaches, we could show that both particles interfered with cytoskeletal organization and altered the structure of neural growth cones. Taken together, these results reveal that nanoceria may impact on neuronal differentiation, suggesting that nanoceria could pose a developmental neurotoxicity hazard.

  • 148. Golkaram, Mahdi
    et al.
    Jang, Jiwon
    Hellander, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Kosik, Kenneth S.
    Petzold, Linda R.
    The role of chromatin density in cell population heterogeneity during stem cell differentiation2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, p. 13307:1-11, article id 13307Article in journal (Refereed)
  • 149. Gorski, Mathias
    et al.
    van der Most, Peter J
    Teumer, Alexander
    Chu, Audrey Y
    Li, Man
    Mijatovic, Vladan
    Nolte, Ilja M
    Cocca, Massimiliano
    Taliun, Daniel
    Gomez, Felicia
    Li, Yong
    Tayo, Bamidele
    Tin, Adrienne
    Feitosa, Mary F
    Aspelund, Thor
    Attia, John
    Biffar, Reiner
    Bochud, Murielle
    Boerwinkle, Eric
    Borecki, Ingrid
    Bottinger, Erwin P
    Chen, Ming-Huei
    Chouraki, Vincent
    Ciullo, Marina
    Coresh, Josef
    Cornelis, Marilyn C
    Curhan, Gary C
    d'Adamo, Adamo Pio
    Dehghan, Abbas
    Dengler, Laura
    Ding, Jingzhong
    Eiriksdottir, Gudny
    Endlich, Karlhans
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Esko, Tõnu
    Franco, Oscar H
    Gasparini, Paolo
    Gieger, Christian
    Girotto, Giorgia
    Gottesman, Omri
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Hancock, Stephen J
    Harris, Tamara B
    Helmer, Catherine
    Höllerer, Simon
    Hofer, Edith
    Hofman, Albert
    Holliday, Elizabeth G
    Homuth, Georg
    Hu, Frank B
    Huth, Cornelia
    Hutri-Kähönen, Nina
    Hwang, Shih-Jen
    Imboden, Medea
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kähönen, Mika
    König, Wolfgang
    Kramer, Holly
    Krämer, Bernhard K
    Kumar, Ashish
    Kutalik, Zoltan
    Lambert, Jean-Charles
    Launer, Lenore J
    Lehtimäki, Terho
    de Borst, Martin
    Navis, Gerjan
    Swertz, Morris
    Liu, Yongmei
    Lohman, Kurt
    Loos, Ruth J F
    Lu, Yingchang
    Lyytikäinen, Leo-Pekka
    McEvoy, Mark A
    Meisinger, Christa
    Meitinger, Thomas
    Metspalu, Andres
    Metzger, Marie
    Mihailov, Evelin
    Mitchell, Paul
    Nauck, Matthias
    Oldehinkel, Albertine J
    Olden, Matthias
    Wjh Penninx, Brenda
    Pistis, Giorgio
    Pramstaller, Peter P
    Probst-Hensch, Nicole
    Raitakari, Olli T
    Rettig, Rainer
    Ridker, Paul M
    Rivadeneira, Fernando
    Robino, Antonietta
    Rosas, Sylvia E
    Ruderfer, Douglas
    Ruggiero, Daniela
    Saba, Yasaman
    Sala, Cinzia
    Schmidt, Helena
    Schmidt, Reinhold
    Scott, Rodney J
    Sedaghat, Sanaz
    Smith, Albert V
    Sorice, Rossella
    Stengel, Benedicte
    Stracke, Sylvia
    Strauch, Konstantin
    Toniolo, Daniela
    Uitterlinden, Andre G
    Ulivi, Sheila
    Viikari, Jorma S
    Völker, Uwe
    Vollenweider, Peter
    Völzke, Henry
    Vuckovic, Dragana
    Waldenberger, Melanie
    Jin Wang, Jie
    Yang, Qiong
    Chasman, Daniel I
    Tromp, Gerard
    Snieder, Harold
    Heid, Iris M
    Fox, Caroline S
    Köttgen, Anna
    Pattaro, Cristian
    Böger, Carsten A
    Fuchsberger, Christian
    1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 45040Article in journal (Refereed)
    Abstract [en]

    HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

  • 150.
    Gramolelli, Silvia
    et al.
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Cheng, Jianpin
    CHU Vaudois, Dept Oncol, Lausanne, Switzerland;Univ Lausanne, Lausanne, Switzerland;Ludwig Inst Canc Res, Lausanne, Switzerland.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vaha-Koskela, Markus
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Elbasani, Endrit
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Kaivanto, Elisa
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Rantanen, Ville
    Univ Helsinki, Genome Scale Biol, Res Programs Unit, Helsinki, Finland.
    Tuohinto, Krista
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Hautaniemi, Sampsa
    Univ Helsinki, Genome Scale Biol, Res Programs Unit, Helsinki, Finland.
    Bower, Mark
    Chelsea & Westminster Hosp, London, England;Imperial Coll London, London, England.
    Haglund, Caj
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland;Univ Helsinki, Dept Surg, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland;Univ Helsinki, Dept Pathol, Helsinki, Finland.
    Alitalo, Kari
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Petrova, Tatiana V.
    CHU Vaudois, Dept Oncol, Lausanne, Switzerland;Univ Lausanne, Lausanne, Switzerland;Ludwig Inst Canc Res, Lausanne, Switzerland.
    Lehti, Kaisa
    Univ Helsinki, Genome Scale Biol, Res Programs Unit, Helsinki, Finland;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Ojala, Paivi M.
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland;Imperial Coll London, Dept Med, Div Infect Dis, Sect Virol, London, England;Fdn Finnish Canc Inst, Helsinki, Finland.
    PROX1 is a transcriptional regulator of MMP142018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 9531Article in journal (Refereed)
    Abstract [en]

    The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.

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