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  • 1.
    Palkopoulou, Eleftheria
    et al.
    Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Lipson, Mark
    Harvard Med Sch, Dept Genet, Boston, MA 02115 USA..
    Mallick, Swapan
    Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Nielsen, Svend
    Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark..
    Rohland, Nadin
    Harvard Med Sch, Dept Genet, Boston, MA 02115 USA..
    Baleka, Sina
    Univ Potsdam, Unit Gen Zool Evolutionary Adapt Genom, Inst Biochem & Biol, Fac Math & Life Sci, D-14476 Potsdam, Germany..
    Karpinski, Emil
    McMaster Univ, McMaster Ancient DNA Ctr, Dept Anthropol, Hamilton, ON L8S 4L9, Canada.;McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada.;McMaster Univ, Dept Biochem, Hamilton, ON L8S 4L8, Canada.;McMaster Univ, Michael G DeGroote Inst Infect Dis Res, Hamilton, ON L8S 4L8, Canada..
    Ivancevici, Atma M.
    Univ Adelaide, Sch Biol Sci, Dept Genet & Evolut, Adelaide, SA 5005, Australia..
    To, Thu-Hien
    Kortschak, Daniel
    Univ Adelaide, Sch Biol Sci, Dept Genet & Evolut, Adelaide, SA 5005, Australia..
    Raison, Joy M.
    Univ Adelaide, Sch Biol Sci, Dept Genet & Evolut, Adelaide, SA 5005, Australia..
    Qu, Zhipeng
    Univ Adelaide, Sch Biol Sci, Dept Genet & Evolut, Adelaide, SA 5005, Australia..
    Chin, Tat-Jun
    Univ Adelaide, Sch Comp Sci, Adelaide, SA 5005, Australia..
    Alt, Kurt W.
    Danube Private Univ, Ctr Nat & Cultural Human Hist, A-3500 Krems, Austria.;Univ Basel, Univ Basel Hosp, Dept Biomed Engn, CH-4123 Basel, Switzerland.;Univ Basel, Integrat Prehist & Archaeol Sci, CH-4051 Basel, Switzerland..
    Claesson, Stefan
    Inst Maritime Hist, Tall Timbers, MD 20690 USA..
    Dalen, Love
    Swedish Museum Nat Hist, Dept Bioinformat & Genet, SE-10405 Stockholm, Sweden..
    MacPhee, Ross D. E.
    Amer Museum Nat Hist, Div Vertebrate Zool Mammal, New York, NY 10024 USA..
    Meller, Harald
    State Off Heritage Management & Archaeol, D-06114 Halle, Saale, Germany..
    Rocar, Alfred L.
    Univ Illinois, Dept Anim Sci, Urbana, IL 61801 USA.;Univ Illinois, Inst Genom Biol, Urbana, IL 61801 USA..
    Ryder, Oliver A.
    San Diego Zoo, Inst Conservat Res, Escondido, CA 92027 USA..
    Heiman, David
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Young, Sarah
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Breen, Matthew
    North Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27607 USA..
    Williams, Christina
    North Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27607 USA..
    Aken, Bronwen L.
    European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Sanger Inst, Cambridge CB10 1SD, England..
    Ruffier, Magali
    European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Sanger Inst, Cambridge CB10 1SD, England..
    Karlsson, Elinor
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.;Univ Massachusetts, Sch Med, Program Bioinformat & Integrat Biol, Worcester, MA 01655 USA..
    Johnson, Jeremy
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Di Palma, Federica
    Earlham Inst, Norwich NR4 7UZ, Norfolk, England..
    Alfoldi, Jessica
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Adelsoni, David L.
    Univ Adelaide, Sch Biol Sci, Dept Genet & Evolut, Adelaide, SA 5005, Australia..
    Mailund, Thomas
    Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark..
    Munch, Kasper
    Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark..
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
    Hofreiter, Michael
    Univ Potsdam, Unit Gen Zool Evolutionary Adapt Genom, Inst Biochem & Biol, Fac Math & Life Sci, D-14476 Potsdam, Germany..
    Poinar, Hendrik
    McMaster Univ, McMaster Ancient DNA Ctr, Dept Anthropol, Hamilton, ON L8S 4L9, Canada.;McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada.;McMaster Univ, Dept Biochem, Hamilton, ON L8S 4L8, Canada.;McMaster Univ, Michael G DeGroote Inst Infect Dis Res, Hamilton, ON L8S 4L8, Canada..
    Reich, David
    Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.;Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA..
    A comprehensive genomic history of extinct and living elephants2018Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 11, s. E2566-E2574Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Elephantids are the world's most iconic megafaunal family, yet there is no comprehensive genomic assessment of their relationships. We report a total of 14 genomes, including 2 from the American mastodon, which is an extinct elephantid relative, and 12 spanning all three extant and three extinct elephantid species including an similar to 120,000-y-old straight-tusked elephant, a Columbian mammoth, and woolly mammoths. Earlier genetic studies modeled elephantid evolution via simple bifurcating trees, but here we show that interspecies hybridization has been a recurrent feature of elephantid evolution. We found that the genetic makeup of the straight-tusked elephant, previously placed as a sister group to African forest elephants based on lower coverage data, in fact comprises three major components. Most of the straight-tusked elephant's ancestry derives from a lineage related to the ancestor of African elephants while its remaining ancestry consists of a large contribution from a lineage related to forest elephants and another related to mammoths. Columbian and woolly mammoths also showed evidence of interbreeding, likely following a latitudinal cline across North America. While hybridization events have shaped elephantid history in profound ways, isolation also appears to have played an important role. Our data reveal nearly complete isolation between the ancestors of the African forest and savanna elephants for similar to 500,000 y, providing compelling justification for the conservation of forest and savanna elephants as separate species.

  • 2.
    Lapins, Maris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Arvidsson, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lampa, Samuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Berg, Arvid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Schaal, Wesley
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Alvarsson, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A confidence predictor for logD using conformal regression and a support-vector machine.2018Ingår i: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 10, nr 1, artikel-id 17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lipophilicity is a major determinant of ADMET properties and overall suitability of drug candidates. We have developed large-scale models to predict water-octanol distribution coefficient (logD) for chemical compounds, aiding drug discovery projects. Using ACD/logD data for 1.6 million compounds from the ChEMBL database, models are created and evaluated by a support-vector machine with a linear kernel using conformal prediction methodology, outputting prediction intervals at a specified confidence level. The resulting model shows a predictive ability of [Formula: see text] and with the best performing nonconformity measure having median prediction interval of [Formula: see text] log units at 80% confidence and [Formula: see text] log units at 90% confidence. The model is available as an online service via an OpenAPI interface, a web page with a molecular editor, and we also publish predictive values at 90% confidence level for 91 M PubChem structures in RDF format for download and as an URI resolver service.

  • 3.
    Wannberg, Johan
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Isaksson, Rebecka
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Bremberg, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Backlund, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes2018Ingår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, nr 3, s. 519-522Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A series of AT2R ligands have been synthesized applying a quick, simple, and safetransesterification-type reaction whereby the sulfonyl carbamate alkyl tail ofthe selective AT2R antagonist C38 was varied. Furthermore, a limited number ofcompounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acidbioisosteres were synthesized and evaluated. By reducing the size of the alkylchain of the sulfonyl carbamates, ligands 7a and 7b were identified withsignificantly improved in vitro metabolic stability in both human and mouse livermicrosomes as compared to C38 while retaining the AT2R binding affinity andAT2R/AT1R selectivity. Eight of the compounds synthesized exhibit an improvedstability in human microsomes as compared to C38.

  • 4. Liu, C
    et al.
    Marioni, R E
    Hedman, Åsa K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pfeiffer, L
    Tsai, P-C
    Reynolds, L M
    Just, A C
    Duan, Q
    Boer, C G
    Tanaka, T
    Elks, C E
    Aslibekyan, S
    Brody, J A
    Kühnel, B
    Herder, C
    Almli, L M
    Zhi, D
    Wang, Y
    Huan, T
    Yao, C
    Mendelson, M M
    Joehanes, R
    Liang, L
    Love, S-A
    Guan, W
    Shah, S
    McRae, A F
    Kretschmer, A
    Prokisch, H
    Strauch, K
    Peters, A
    Visscher, P M
    Wray, N R
    Guo, X
    Wiggins, K L
    Smith, A K
    Binder, E B
    Ressler, K J
    Irvin, M R
    Absher, D M
    Hernandez, D
    Ferrucci, L
    Bandinelli, S
    Lohman, K
    Ding, J
    Trevisi, L
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Stolk, L
    Uitterlinden, A G
    Yet, I
    Castillo-Fernandez, J E
    Spector, T D
    Schwartz, J D
    Vokonas, P
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Li, Y
    Fornage, M
    Arnett, D K
    Wareham, N J
    Sotoodehnia, N
    Ong, K K
    van Meurs, J B J
    Conneely, K N
    Baccarelli, A A
    Deary, I J
    Bell, J T
    North, K E
    Liu, Y
    Waldenberger, M
    London, S J
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
    Levy, D
    A DNA methylation biomarker of alcohol consumption.2018Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, s. 422-433Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10(-7). Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

  • 5.
    Kjellander, Marcus
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Billinger, Erika
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Ramachandraiah, Harisha
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Boman, Mats
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Oorganisk kemi.
    Bergström Lind, Sara
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Johansson, Gunnar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    A flow-through nanoporous alumina trypsin bioreactor for mass spectrometry peptide fingerprinting2018Ingår i: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 172, s. 165-172Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mass spectrometry-based proteomics benefits from efficient digestion of protein samples. In this study, trypsinwas immobilized on nanoporous anodized alumina membranes to create an enzyme reactor suitable for peptidemassfingerprinting. The membranes were derivatized with 3-aminopropyltriethoxysilane and the amino groupswere activated with carbonyldiimidazole to allow coupling of porcine trypsin viaε-amino groups. The functionwas assessed using the artificial substrate Nα-Benzoyl-L-arginine 4-nitroanilide hydrochloride, bovine ribonu-clease A and a human plasma sample. A 10-membraneflow-through reactor was used for fragmentation and MSanalysis after a single pass of substrate both by collection of product and subsequent off-line analysis, and bycoupling on-line to the instrument. The peptide pattern allowed correct identification of the single target proteinin both cases, and of > 70 plasma proteins in single pass mode followed by LC-MS analysis. The reactor retained76% of the initial activity after 14 days of storage and repeated use at room temperature.

    Significance:This manuscript describes the design of a stable enzyme reactor that allows efficient and fast di-gestion with negligible leakage of enzyme and enzyme fragments. The high stability facilitates the use in anonline-setup with MS detection since it allows the processing of multiple samples within an extended period of time without replacement.

  • 6. Stubleski, Jordan
    et al.
    Kukucka, Petr
    Salihovic, Samira
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Kärrman, Anna
    A method for analysis of marker persistent organic pollutants in low-volume plasma and serum samples using 96-well plate solid phase extraction.2018Ingår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1546, s. 18-27, artikel-id S0021-9673(18)30253-XArtikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objective of this study was to develop and validate a 96-well plate solid phase extraction method for analysis of 23 lipophilic persistent organic pollutants (POPs) in low-volume plasma and serum samples which is applicable for biomonitoring and epidemiological studies. The analysis of selected markers for internal exposure: 16 polychlorinated biphenyls (PCBs), 5 organochlorine pesticides (OCPs), octachlorinated dibenzo-p-dioxin (OCDD), and polybrominated diphenylether 47 (BDE 47) was evaluated by comparing two SPE sorbents and GC-HRMS or GC-MS/MS detection. The final method extracted 23 POPs from 150 μL of serum and plasma using a 96-well extraction plate containing 60 mg Oasis HLB sorbent per well prior to GC-HRMS magnetic sector analysis. The extraction method was applied to 40 plasma samples collected for an epidemiological study. The recovery of selected POPs ranged from 31% to 63% (n = 48), and detection limits ranged from 2.2 to 45 pg/mL for PCBs, 4.2 to 167 pg/mL for OCPs, 7.8 pg/mL for OCDD and 6.1 pg/mL for BDE 47. This method showed good precision with relative standard deviations of selected POP concentrations in quality control samples (n = 48) ranging from 11% to 25%. The trueness was determined with standard reference material serum (n = 48) and the deviation from certified values ranged from 1 to 27%. Of the 23 POPs analyzed, 18 were detected in 43% to 100% of plasma samples collected for the epidemiological study. The method showed good robustness with low inter-well plate variation (11-31%) determined by twelve 96-well plate extractions, and can extract 96 samples, including quality controls and procedural blanks in 2-3 days. Comparison with GC-MS/MS analysis showed that similar concentrations (within 0.5% to 30%) of most POPs could be obtained with GC-APCI-MS/MS. Larger deviations were observed for PCB 194 (60%) and trans-nonachlor (43%). The developed method produces accurate concentrations of low-level marker POPs in plasma and serum, providing a suitable high-throughput sample preparation procedure for biomonitoring and epidemiological studies involving large sample size and limited sample volume. GC-HRMS was chosen over GC-MS/MS, however the latter showed promising results, and could be used as an alternative to GC-HRMS analysis for most POPs.

  • 7.
    Manzetti, Sergio
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik. Fjordforsk A/S.
    An investigation into the physical, chemical and thermochemical properties of Niobium nanoclusters2018Ingår i: The 1st International Electronic Conference on Crystals: E. Nano- and Two-Dimensional Crystals / [ed] Prof. Dr. Alberto Girlando, 2018Konferensbidrag (Refereegranskat)
    Abstract [en]

    The search for spin-polarized metal clusters, energetic crystals and conductive materials is a paramount part of Nanotechnology. Adapting quantum chemistry and quantum mechanics methods to study and endeavor the electronic and lattice properties of groups of atoms in nanoclusters is a central approach, which aids in revealing crucial electronic properties that serve to develop and synthesize nanomaterials, nanometals and metal clusters. This project investigates the energy landscape of Niobium clusters (Nb n), in order to shed light on their electronic, dipole, and magnetic properties. The clusters are studied with the XTB Tight-binding software coupled with hybrid DFT functionals. The results show that Niobium clusters in nanosized particles (10-61 atoms) bear ultra-low orbital gaps, with promising properties for hyperconnects and nanoparticle-based electronics.

  • 8.
    Lombard, Marlize
    et al.
    University of Johannesburg, Centre for Anthropological Research, Johannesburg, South Africa; University of Johannesburg, Department of Anthropology and Development Studies, Johannesburg, South Africa.
    Jakobsson, Mattias
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Människans evolution. Uppsala universitet, Science for Life Laboratory, SciLifeLab. University of Johannesburg, Centre for Anthropological Research, Johannesburg, South Africa; University of Johannesburg, Department of Anthropology and Development Studies, Johannesburg, South Africa; .
    Schlebusch, Carina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Människans evolution. University of Johannesburg, Centre for Anthropological Research, Johannesburg, South Africa; University of Johannesburg, Department of Anthropology and Development Studies, Johannesburg, South Africa.
    Ancient human DNA: How sequencing the genome of a boy from Ballito Bay changed human history2018Ingår i: South African Journal of Science, ISSN 0038-2353, E-ISSN 1996-7489, Vol. 114, nr 1-2, artikel-id a0253Artikel i tidskrift (Övrigt vetenskapligt)
  • 9.
    Ma, Tao
    et al.
    Sichuan Univ, Coll Life Sci, Minist Educ, Key Lab Bioresource & Ecoenvironm, Chengdu 610065, Sichuan, Peoples R China..
    Wang, Kun
    Sichuan Univ, Coll Life Sci, Minist Educ, Key Lab Bioresource & Ecoenvironm, Chengdu 610065, Sichuan, Peoples R China..
    Hu, Quanjun
    Sichuan Univ, Coll Life Sci, Minist Educ, Key Lab Bioresource & Ecoenvironm, Chengdu 610065, Sichuan, Peoples R China..
    Xi, Zhenxiang
    Sichuan Univ, Coll Life Sci, Minist Educ, Key Lab Bioresource & Ecoenvironm, Chengdu 610065, Sichuan, Peoples R China..
    Wan, Dongshi
    Lanzhou Univ, Coll Life Sci, State Key Lab Grassland Agroecosyst, Lanzhou 730000, Gansu, Peoples R China..
    Wang, Qian
    Sichuan Univ, Coll Life Sci, Minist Educ, Key Lab Bioresource & Ecoenvironm, Chengdu 610065, Sichuan, Peoples R China..
    Feng, Jianju
    Lanzhou Univ, Coll Life Sci, State Key Lab Grassland Agroecosyst, Lanzhou 730000, Gansu, Peoples R China..
    Jiang, Dechun
    Lanzhou Univ, Coll Life Sci, State Key Lab Grassland Agroecosyst, Lanzhou 730000, Gansu, Peoples R China..
    Ahani, Hamid
    Nat Resources & Watershed Management Adm Khorasan, Khorasan 9177948974, Iran..
    Abbott, Richard J.
    Univ St Andrews, Sch Biol, St Andrews KY16 9TH, Fife, Scotland..
    Lascoux, Martin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Växtekologi och evolution. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nevo, Eviatar
    Univ Haifa, Inst Evolut, IL-3498838 Haifa, Israel..
    Liu, Jianquan
    Sichuan Univ, Coll Life Sci, Minist Educ, Key Lab Bioresource & Ecoenvironm, Chengdu 610065, Sichuan, Peoples R China..
    Ancient polymorphisms and divergence hitchhiking contribute to genomic islands of divergence within a poplar species complex2018Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 2, s. E236-E243Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    How genome divergence eventually leads to speciation is a topic of prime evolutionary interest. Genomic islands of elevated divergence are frequently reported between diverging lineages, and their size is expected to increase with time and gene flow under the speciation-with-gene-flow model. However, such islands can also result from divergent sorting of ancient polymorphisms, recent ecological selection regardless of gene flow, and/or recurrent background selection and selective sweeps in low-recombination regions. It is challenging to disentangle these nonexclusive alternatives, but here we attempt to do this in an analysis of what drove genomic divergence between four lineages comprising a species complex of desert poplar trees. Within this complex we found that two morphologically delimited species, Populus euphratica and Populus pruinosa, were paraphyletic while the four lineages exhibited contrasting levels of gene flow and divergence times, providing a good system for testing hypotheses on the origin of divergence islands. We show that the size and number of genomic islands that distinguish lineages are not associated with either rate of recent gene flow or time of divergence. Instead, they are most likely derived from divergent sorting of ancient polymorphisms and divergence hitchhiking. We found that highly diverged genes under lineage-specific selection and putatively involved in ecological and morphological divergence occur both within and outside these islands. Our results highlight the need to incorporate demography, absolute divergence measurement, and gene flow rate to explain the formation of genomic islands and to identify potential genomic regions involved in speciation.

  • 10.
    Islam, Md. Koushikul
    et al.
    Umea Univ, Dept Clin Microbiol, Infect Dis, Umea, Sweden..
    Strand, Mårten
    Umea Univ, Dept Clin Microbiol, Virol, Umea, Sweden..
    Saleeb, Michael
    Umea Univ, Dept Chem, Umea, Sweden..
    Svensson, Richard
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Baranczewski, Pawel
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Artursson, Per
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Wadell, Göran
    Umea Univ, Dept Clin Microbiol, Virol, Umea, Sweden..
    Ahlm, Clas
    Umea Univ, Dept Clin Microbiol, Infect Dis, Umea, Sweden..
    Elofsson, Mikael
    Umea Univ, Dept Chem, Umea, Sweden..
    Evander, Magnus
    Umea Univ, Dept Clin Microbiol, Virol, Umea, Sweden..
    Anti-Rift Valley fever virus activity in vitro, pre-clinical pharmacokinetics and oral bioavailability of benzavir-2, a broad-acting antiviral compound2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 1925Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rift Valley fever virus (RVFV) is a mosquito-borne hemorrhagic fever virus affecting both humans and animals with severe morbidity and mortality and is classified as a potential bioterror agent due to the possible aerosol transmission. At present there is no human vaccine or antiviral therapy available. Thus, there is a great need to develop new antivirals for treatment of RVFV infections. Benzavir-2 was previously identified as potent inhibitor of human adenovirus, herpes simplex virus type 1, and type 2. Here we assess the anti-RVFV activity of benzavir-2 together with four structural analogs and determine pre-clinical pharmacokinetic parameters of benzavir-2. In vitro, benzavir-2 efficiently inhibited RVFV infection, viral RNA production and production of progeny viruses. In vitro, benzavir-2 displayed satisfactory solubility, good permeability and metabolic stability. In mice, benzavir-2 displayed oral bioavailability with adequate maximum serum concentration. Oral administration of benzavir-2 formulated in peanut butter pellets gave high systemic exposure without any observed toxicity in mice. To summarize, our data demonstrated potent anti-RVFV activity of benzavir-2 in vitro together with a promising pre-clinical pharmacokinetic profile. This data support further exploration of the antiviral activity of benzavir-2 in in vivo efficacy models that may lead to further drug development for human use.

  • 11.
    Felkel, S.
    et al.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, Vienna, Austria.;Vienna Grad Sch Populat Genet, Vienna, Austria..
    Vogl, C.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, Vienna, Austria..
    Rigler, D.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, Vienna, Austria..
    Jagannathan, V.
    Univ Bern, Inst Genet, Vetsuisse Fac, Bern, Switzerland..
    Leeb, T.
    Univ Bern, Inst Genet, Vetsuisse Fac, Bern, Switzerland..
    Fries, R.
    Tech Univ Munich, Lehrstuhl Tierzucht, Freising Weihenstephan, Germany..
    Neuditschko, M.
    Agroscope, Swiss Natl Stud Farm, Avenches, Switzerland..
    Rieder, S.
    Agroscope, Swiss Natl Stud Farm, Avenches, Switzerland..
    Velie, B.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Lindgren, G.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Rubin, Carl-Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Schlötterer, C.
    Univ Vet Med Vienna, Inst Populat Genet, Vienna, Austria..
    Rattei, T.
    Univ Vienna, Dept Microbiol & Ecosyst Sci, Div Computat Syst Biol, Vienna, Austria..
    Brem, G.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, Vienna, Austria..
    Wallner, B.
    Univ Vet Med Vienna, Inst Anim Breeding & Genet, Vienna, Austria..
    Asian horses deepen the MSY phylogeny2018Ingår i: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 49, nr 1, s. 90-93Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Humans have shaped the population history of the horse ever since domestication about 5500years ago. Comparative analyses of the Y chromosome can illuminate the paternal origin of modern horse breeds. This may also reveal different breeding strategies that led to the formation of extant breeds. Recently, a horse Y-chromosomal phylogeny of modern horses based on 1.46Mb of the male-specific Y (MSY) was generated. We extended this dataset with 52 samples from five European, two American and seven Asian breeds. As in the previous study, almost all modern European horses fall into a crown group, connected via a few autochthonous Northern European lineages to the outgroup, the Przewalski's Horse. In total, we now distinguish 42 MSY haplotypes determined by 158 variants within domestic horses. Asian horses show much higher diversity than previously found in European breeds. The Asian breeds also introduce a deep split to the phylogeny, preliminarily dated to 5527 +/- 872years. We conclude that the deep splitting Asian Y haplotypes are remnants of a far more diverse ancient horse population, whose haplotypes were lost in other lineages.

  • 12.
    Fonnes, Tina
    et al.
    Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen; Haukeland Hosp, Dept Obstet & Gynecol, Bergen.
    Berg, Hege F.
    Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen; Haukeland Hosp, Dept Obstet & Gynecol, Bergen.
    Bredholt, Therese
    Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen; Haukeland Hosp, Dept Obstet & Gynecol, Bergen.
    Edqvist, Per-Henrik D.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sortland, Kristina
    Univ Bergen, Dept Biomed, Bergen.
    Berg, Anna
    Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen; Haukeland Hosp, Dept Obstet & Gynecol, Bergen.
    Salvesen, Helga B.
    Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen; Haukeland Hosp, Dept Obstet & Gynecol, Bergen.
    Akslen, Lars A.
    Haukeland Hosp, Dept Pathol, Bergen; Univ Bergen, Ctr Canc Biomarkers, Dept Clin Med, Sect Pathol, Bergen.
    Werner, Henrica M. J.
    Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen; Haukeland Hosp, Dept Obstet & Gynecol, Bergen.
    Trovik, Jone
    Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen; Haukeland Hosp, Dept Obstet & Gynecol, Bergen.
    Tangen, Ingvild L.
    Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen; Haukeland Hosp, Dept Obstet & Gynecol, Bergen.
    Krakstad, Camilla
    Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen; Haukeland Hosp, Dept Obstet & Gynecol, Bergen.
    Asparaginase-like protein 1 is an independent prognostic marker in primary endometrial cancer, and is frequently lost in metastatic lesions2018Ingår i: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 148, nr 1, s. 197-203Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective

    Loss of Asparaginase-like protein 1 (ASRGL1) has been suggested as a prognostic biomarker in endometrial carcinoma. Our objective was to validate this in a prospectively collected, independent patient cohort, and evaluate ASRGL1 expression in endometrial carcinoma precursor lesion and metastases.

    Methods

    782 primary endometrial carcinomas, 90 precursor lesions (complex atypical hyperplasia), and 179 metastases (from 87 patients) were evaluated for ASRGL1 expression by immunohistochemistry in relation to clinical and histopathological data. ASRGL1 mRNA level was investigated in 237 primary tumors and related to survival and ASRGL1 protein expression.

    Results

    Low expression of ASRGL1 protein and ASRGL1 mRNA predicted poor disease specific survival (P < 0.001). In multivariate survival analyses ASRGL1 had independent prognostic value both in the whole patient cohort (Hazard ratio (HR): 1.53, 95% confidence interval (CI): 1.04–2.26, P = 0.031) and within the endometrioid subgroup (HR: 2.64, CI: 1.47–4.74, P = 0.001). Low ASRGL1 expression was less frequent in patients with low grade endometrioid primary tumors compared to high grade endometrioid and non-endometrioid primary tumors, and ASRGL1 was lost in the majority of metastatic lesions.

    Conclusions

    In a prospective setting ASRGL1 validates as a strong prognostic biomarker in endometrial carcinoma. Loss of ASRGL1 is associated with aggressive disease and poor survival, and is demonstrated for the first time to have independent prognostic value in the entire endometrial carcinoma patient population.

  • 13.
    Fornell, Anna
    et al.
    Lund Univ, Dept Biomed Engn, Lund, Sweden..
    Cushing, Kevin
    Lund Univ, Dept Biomed Engn, Lund, Sweden..
    Nilsson, Johan
    Lund Univ, Dept Biomed Engn, Lund, Sweden..
    Tenje, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Biomed Engn, Lund, Sweden.
    Binary particle separation in droplet microfluidics using acoustophoresis2018Ingår i: Applied Physics Letters, ISSN 0003-6951, E-ISSN 1077-3118, Vol. 112, nr 6, artikel-id 063701Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We show a method for separation of two particle species with different acoustic contrasts originally encapsulated in the same droplet in a continuous two-phase system. This was realized by using bulk acoustic standing waves in a 380 mu m wide silicon-glass microfluidic channel. Polystyrene particles (positive acoustic contrast particles) and in-house synthesized polydimethylsiloxane (PDMS) particles (negative acoustic contrast particles) were encapsulated inside water-in-oil droplets either individually or in a mixture. At acoustic actuation of the system at the fundamental resonance frequency, the polystyrene particles were moved to the center of the droplet (pressure node), while the PDMS particles were moved to the sides of the droplet (pressure anti-nodes). The acoustic particle manipulation step was combined in series with a trifurcation droplet splitter, and as the original droplet passed through the splitter and was divided into three daughter droplets, the polystyrene particles were directed into the center daughter droplet, while the PDMS particles were directed into the two side daughter droplets. The presented method expands the droplet microfluidics tool-box and offers new possibilities to perform binary particle separation in droplet microfluidic systems.

    Publikationen är tillgänglig i fulltext från 2019-03-27 14:49
  • 14.
    Fotaki, Grammatiki
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Jin, Chuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kerzeli, Iliana Kyriaki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ramachandran, Mohanraj
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Martikainen, Minttu-Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Karlsson-Parra, Alex
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Immunicum AB, Gothenburg.
    Yu, Di
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cancer vaccine based on a combination of an infection-enhanced adenoviral vector and pro-inflammatory allogeneic DCs leads to sustained antigen-specific immune responses in three melanoma models2018Ingår i: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 7, nr 3, artikel-id e1397250Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Autologous patient-derived dendritic cells (DCs) modified ex vivo to present tumor-associated antigens (TAAs) are frequently used as cancer vaccines. However, apart from the stringent logistics in producing DCs on a patient basis, accumulating evidence indicate that ex vivo engineered DCs are poor in migration and in fact do not directly present TAA epitopes to naïve T cells in vivo. Instead, it is proposed that bystander host DCs take up material from vaccine-DCs, migrate and subsequently initiate antitumor T-cell responses. We used mouse models to examine the possibility of using pro-inflammatory allogeneic DCs (alloDCs) to activate host DCs and enable them to promote antigen-specific T-cell immunity. We found that alloDCs were able to initiate host DC activation and migration to draining lymph node leading to T-cell activation. The pro-inflammatory milieu created by alloDCs also led to recruitment of NK cells and neutrophils at the site of injection. Vaccination with alloDCs combined with Ad5M(gp100), an infection-enhanced adenovirus encoding the human melanoma-associated antigen gp100 resulted in generation of CD8+ T cells with a T-cell receptor (TCR) specific for the gp10025-33 epitope (gp100-TCR+). Ad5M(gp100)-alloDC vaccination in combination with transfer of gp100-specific pmel-1 T cells resulted in prolonged survival of B16-F10 melanoma-bearing mice and altered the composition of the tumor microenvironment (TME). We hereby propose that alloDCs together with TAA- or neoepitope-encoding Ad5M can become an “off-the-shelf” cancer vaccine, which can reverse the TME-induced immunosuppression and induce host cellular anti-tumor immune responses in patients without the need of a time-consuming preparation step of autologous DCs.

  • 15.
    Åslin, Matilda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Brandt, Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dahlberg, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    CheckQC: Quick quality control of Illumina sequencing runs2018Ingår i: The Journal of Open Source Software, ISSN 2475-9066, Vol. 3, nr 22, artikel-id 556Artikel i tidskrift (Refereegranskat)
  • 16.
    Goronzy, I. N.
    et al.
    Stanford Univ, Dept Chem, Stanford, CA 94305 USA..
    Rawle, R. J.
    Univ Virginia, Dept Mol Physiol & Biomed Engn, Box 800886, Charlottesville, VA 22908 USA..
    Boxer, S. G.
    Stanford Univ, Dept Chem, Stanford, CA 94305 USA..
    Kasson, Peter M.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylärbiologi. Univ Virginia, Dept Mol Physiol & Biomed Engn, Box 800886, Charlottesville, VA 22908 USA..
    Cholesterol enhances influenza binding avidity by controlling nanoscale receptor clustering2018Ingår i: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 9, nr 8, s. 2340-2347Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Influenza virus infects cells by binding to sialylated glycans on the cell surface. While the chemical structure of these glycans determines hemagglutinin-glycan binding affinity, bimolecular affinities are weak, so binding is avidity-dominated and driven by multivalent interactions. Here, we show that membrane spatial organization can control viral binding. Using single-virus fluorescence microscopy, we demonstrate that the sterol composition of the target membrane enhances viral binding avidity in a dose-dependent manner. Binding shows a cooperative dependence on concentration of receptors for influenza virus, as would be expected for a multivalent interaction. Surprisingly, the ability of sterols to promote viral binding is independent of their ability to support liquid-liquid phase separation in model systems. We develop a molecular explanation for this observation via molecular dynamics simulations, where we find that cholesterol promotes small-scale clusters of glycosphingolipid receptors. We propose a model whereby cholesterol orders the monomeric state of glycosphingolipid receptors, reducing the entropic penalty of receptor association and thus favoring multimeric complexes without phase separation. This model explains how cholesterol and other sterols control the spatial organization of membrane receptors for influenza and increase viral binding avidity. A natural consequence of this finding is that local cholesterol concentration in the plasma membrane of cells may alter the binding avidity of influenza virions. Furthermore, our results demonstrate a form of cholesterol-dependent membrane organization that does not involve lipid rafts, suggesting that cholesterol's effect on cell membrane heterogeneity is likely the interplay of several different factors.

  • 17.
    Mobacke, Ingrid
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Dunder, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Salihovic, Samira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Circulating levels of perfluoroalkyl substances and left ventricular geometry of the heart in the elderly.2018Ingår i: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 115, s. 295-300, artikel-id S0160-4120(17)32060-3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIMS: Some persistent organic pollutants (POPs) such as hexachlorobenzene (HCB) and some polychlorinated biphenyls (PCBs) have been shown to interfere with myocardial function and geometry. We therefore investigated if also another group of POPs: per- and polyfluoroalkyl substances (PFASs) were associated with alterations in left ventricular geometry.

    METHODS: 801 subjects aged 70 years were investigated in a cross-sectional study within the scope of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Eight PFASs were detected in >75% of participants´ plasma by ultra-performance liquid chromatograph/tandem mass spectrometry. Left ventricular geometry was determined by echocardiography. Multivariable linear regression was used to investigate the associations between PFASs and left ventricular geometry of the heart after exclusion of subjects with previous myocardial infarction (n = 72).

    RESULTS: When adjusting for multiple comparisons, none of the eight PFASs evaluated were significantly related to left ventricular mass. However, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) were related to relative wall thickness (RWT) in a negative fashion (p < 0.0021). Besides being inversely related to RWT, PFNA was also positively related to left ventricular end-diastolic volume (LVEDD) (p < 0.0021). These analyses were adjusted for traditional cardiovascular risk factors.

    CONCLUSION: In this cross-sectional study, several of the PFASs evaluated, especially PFNA, were related to myocardial geometry: a reduction in relative wall thickness and an increase in left ventricular diameter following adjustment for traditional cardiovascular risk factors, suggesting a role for PFASs in cardiac remodeling.

  • 18.
    Stenemo, Markus
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nowak, Christoph
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Byberg, Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford University School of Medicine, Department of Medicine, Division of Cardiovascular Medicine.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ärnlöv, Johan
    Dalarna University, School of Health and Social Studies, Falun; Karolinska Institutet, Care Science and Society, Department of Neurobiology, Division of Family Medicine and Primary Care .
    Circulating proteins as predictors of incident heart failure in the elderly2018Ingår i: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 20, nr 1, s. 55-62Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims

    To identify novel risk markers for incident heart failure using proteomic profiling of 80 proteins previously associated with cardiovascular pathology.

    Methods and results

    Proteomic profiling (proximity extension assay) was performed in two community‐based prospective cohorts of elderly individuals without heart failure at baseline: the Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS, n = 901, median age 70.2 (interquartile range 70.0–70.3) years, 80 events]; and the Uppsala Longitudinal Study of Adult Men [ULSAM, n = 685, median age 77.8 (interquartile range 76.9–78.1) years, 90 events]. Twenty‐nine proteins were associated with incident heart failure in the discovery cohort PIVUS after adjustment for age and sex, and correction for multiple testing. Eighteen associations replicated in ULSAM. In pooled analysis of both cohorts, higher levels of nine proteins were associated with incident heart failure after adjustment for established risk factors: growth differentiation factor 15 (GDF‐15), T‐cell immunoglobulin and mucin domain 1 (TIM‐1), tumour necrosis factor‐related apoptosis‐inducing ligand receptor 2 (TRAIL‐R2), spondin‐1 (SPON1), matrix metalloproteinase‐12 (MMP‐12), follistatin (FS), urokinase‐type plasminogen activator surface receptor (U‐PAR), osteoprotegerin (OPG), and suppression of tumorigenicity 2 (ST2). Of these, GDF‐15, U‐PAR, MMP‐12, TRAIL‐R2, SPON1 and FS were associated with worsened echocardiographic left ventricular systolic function at baseline, while only TIM‐1 was positively associated with worsened diastolic function (P < 0.02 for all).

    Conclusion

    Proteomic profiling identified several novel associations between proteins involved in apoptosis, inflammation, matrix remodelling, and fibrinolysis with incident heart failure in elderly individuals. Our results encourage additional studies investigating the underlying mechanisms and the clinical utility of our findings.

  • 19.
    Svensson, Fredrik
    et al.
    Cambridge University.
    Aniceto, Natalia
    Norinder, Ulf
    SweTox.
    Cortes-Ciriano, Isidro
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Carlsson, Lars
    AstraZeneca.
    Bender, Andreas
    Cambridge University.
    Conformal Regression for QSAR Modelling - Quantifying Prediction Uncertainty.2018Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960XArtikel i tidskrift (Refereegranskat)
    Abstract [en]

    Making predictions with an associated confidence is highly desirable as it facilitates decision making and resource prioritization. Conformal regression is a machine learning framework that allows the user to define the required confidence and delivers predictions that are guaranteed to be correct to the selected extent. In this study, we apply conformal regression to model molecular properties and bioactivity values and investigate different ways to scale the outputted prediction intervals to create as efficient (i.e. narrow) regressors as possible. Different algorithms to estimate the prediction uncertainty were used to normalize the prediction ranges and the different approaches were evaluated on 29 publicly available datasets. Our results show that the most efficient conformal regressors are obtained when using the natural exponential of the ensemble standard deviation from the underlying random forest to scale the prediction intervals. This approach afforded an average prediction range of 1.65 pIC50 units at the 80 % confidence level when applied to bioactivity modeling. The choice of nonconformity function has a pronounced impact on the average prediction range with a difference of close to one log unit in bioactivity between the tightest and widest prediction range. Overall, conformal regression is a robust approach to generate bioactivity predictions with associated confidence.

  • 20.
    Sellin, Mikael E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Müller, Anna A
    ETH Zürich, Institute of Microbiology, Zürich, Switzerland.
    Hardt, Wolf-Dietrich
    ETH Zürich, Institute of Microbiology, Zürich, Switzerland.
    Consequences of Epithelial Inflammasome Activation by Bacterial Pathogens2018Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, nr 2, s. 193-206, artikel-id S0022-2836(17)30183-3Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Inflammasome signaling impinges on the activation of inflammatory caspases (i.e., caspase-1 and caspase-4/5/11) and endows host cells with a sentinel system to sense microbial intrusion and thereby initiate appropriate immune responses. Lately, it has become evident that mammalian inflammasome-dependent responses to infection are not confined solely to cells of hematopoietic origin. Epithelial cells that line the body's mucosal surfaces use inflammasome signaling to sense and counteract pathogenic microorganisms that compromise barrier integrity. Many of the molecular mechanisms of epithelial inflammasome signaling remain unexplored. However, it now seems clear that epithelial inflammasome activation has a profound impact both on the infected cell itself and on its ability to communicate with other cell types of the mucosa. Here, we summarize current knowledge regarding the output of epithelial inflammasome activation during bacterial infection. Well-established downstream effects include epithelial cell death, release of soluble mediators, and subsequent recruitment of effector cell types, including NK cells, mast cells, and neutrophils, to sites of mucosal infection. We discuss the implications of recent findings for antibacterial defense in the mucosa and sketch out areas for future exploration.

  • 21.
    Eriksson, Daniel
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    Dalin, Frida
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Eriksson, Gabriel Nordling
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Landegren, Nils
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Bianchi, Matteo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hallgren, Åsa
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Dahlqvist, Per
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.
    Wahlberg, Jeanette
    Linköping Univ, Dept Endocrinol, Linköping, Sweden; Linköping Univ, Dept Med & Hlth Sci, Linköping, Sweden; Linköping Univ, Dept Clin & Expt Med, Linköping, Sweden.
    Ekwall, Olov
    Univ Gothenburg, Dept Pediat, Inst Clin Sci, Sahlgrenska Acad, Gothenburg, Sweden; Univ Gothenburg, Dept Rheumatol & Inflammat Res, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden.
    Winqvist, Ola
    Karolinska Inst, Dept Med Solna, Stockholm, Sweden.
    Catrina, Sergiu-Bogdan
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Hulting, Anna-Lena
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Alimohammad, Mohammad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Husebye, Eystein S
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; Univ Bergen, Dept Clin Sci, Bergen, Norway; Univ Bergen, Dept Med, Bergen, Norway; KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway.
    Knappskog, Per Morten
    Univ Bergen, Dept Clin Sci, Bergen, Norway; Haukeland Hosp, Ctr Med Genet & Mol Med, Bergen, Norway.
    Pielberg, Gerli Rosengren
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bensing, Sophie
    Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden; Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden .
    Kämpe, Olle
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden; KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway.
    Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS12018Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, nr 1, s. 179-186Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.

    Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.

    Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE.

    Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure.

    Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.

  • 22.
    Hoffmann, Jean-Marc