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  • 1101.
    Zhang, Cheng
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Aldrees, Mohammed
    Arif, Muhammad
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Li, Xiangyu
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Aziz, Mohammad Azhar
    Elucidating the Reprograming of Colorectal Cancer Metabolism Using Genome-Scale Metabolic Modeling2019In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 9, article id 681Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer is the third most incidental cancer worldwide, and the response rate of current treatment for colorectal cancer is very low. Genome-scale metabolic models (GEMs) are systems biology platforms, and they had been used to assist researchers in understanding the metabolic alterations in different types of cancer. Here, we reconstructed a generic colorectal cancer GEM by merging 374 personalized GEMs from the Human Pathology Atlas and used it as a platform for systematic investigation of the difference between tumor and normal samples. The reconstructed model revealed the metabolic reprogramming in glutathione as well as the arginine and proline metabolism in response to tumor occurrence. In addition, six genes including ODC1, SMS, SRM, RRM2, SMOX, and SAT1 associated with arginine and proline metabolism were found to be key players in this metabolic alteration. We also investigated these genes in independent colorectal cancer patients and cell lines and found that many of these genes showed elevated level in colorectal cancer and exhibited adverse effect in patients. Therefore, these genes could be promising therapeutic targets for treatment of a specific colon cancer patient group.

  • 1102.
    Zhang, Cheng
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bidkhori, Gholamreza
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Benfeitas, Rui
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lee, Sunjae
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Arif, Muhammad
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Uhlen, Mathias
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    ESS: A Tool for Genome-Scale Quantification of Essentiality Score for Reaction/Genes in Constraint-Based Modeling2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 1355Article in journal (Refereed)
    Abstract [en]

    Genome-scale metabolic models (GEMs) are comprehensive descriptions of cell metabolism and have been extensively used to understand biological responses in health and disease. One such application is in determining metabolic adaptation to the absence of a gene or reaction, i.e., essentiality analysis. However, current methods do not permit efficiently and accurately quantifying reaction/gene essentiality. Here, we present Essentiality Score Simulator (ESS), a tool for quantification of gene/reaction essentialities in GEMs. ESS quantifies and scores essentiality of each reaction/gene and their combinations based on the stoichiometric balance using synthetic lethal analysis. This method provides an option to weight metabolic models which currently rely mostly on topologic parameters, and is potentially useful to investigate the metabolic pathway differences between different organisms, cells, tissues, and/or diseases. We benchmarked the proposed method against multiple network topology parameters, and observed that our method displayed higher accuracy based on experimental evidence. In addition, we demonstrated its application in the wild-type and ldh knock-out E. coli core model, as well as two human cell lines, and revealed the changes of essentiality in metabolic pathways based on the reactions essentiality score. ESS is available without any limitation at https://sourceforge.net/projects/essentiality-score-simulator.

  • 1103.
    Zhang, Cheng
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lee, Sunjae
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mardinoglu, Adil
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers, Dept Biol & Biol Engn, Sweden.
    Hua, Qiang
    Investigating the Combinatory Effects of Biological Networks on Gene Co-expression2016In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, article id 160Article in journal (Refereed)
    Abstract [en]

    Co-expressed genes often share similar functions, and gene co-expression networks have been widely used in studying the functionality of gene modules. Previous analysis indicated that genes are more likely to be co-expressed if they are either regulated by the same transcription factors, forming protein complexes or sharing similar topological properties in protein-protein interaction networks. Here, we reconstructed transcriptional regulatory and protein-protein networks for Saccharornyces cerevisiae using well-established databases, and we evaluated their co-expression activities using publically available gene expression data. Based on our network-dependent analysis, we found that genes that were co-regulated in the transcription regulatory networks and shared similar neighbors in the protein-protein networks were more likely to be co-expressed. Moreover, their biological functions were closely related.

  • 1104.
    Zhang, Miao
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Materials and Nanophysics. KTH.
    Ngampeerapong, Chonmanart
    Redin, David
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ahmadian, Afshin
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sychugov, Ilya
    KTH, School of Engineering Sciences (SCI), Applied Physics, Materials and Nanophysics.
    Linnros, Jan
    KTH, School of Engineering Sciences (SCI), Applied Physics, Materials and Nanophysics.
    Thermophoresis-Controlled Size-Dependent DNA Translocation through an Array of Nanopores2018In: ACS Nano, ISSN 1936-0851, E-ISSN 1936-086X, Vol. 12, no 5, p. 4574-4582Article in journal (Refereed)
    Abstract [en]

    Large arrays of nanopores can be used for high-throughput biomolecule translocation with applications toward size discrimination and sorting at the single-molecule level. In this paper, we propose to discriminate DNA length by the capture rate of the molecules to an array of relatively large nanopores (50–130 nm) by introducing a thermal gradient by laser illumination in front of the pores balancing the force from an external electric field. Nanopore arrays defined by photolithography were batch processed using standard silicon technology in combination with electrochemical etching. Parallel translocation of single, fluorophore-labeled dsDNA strands is recorded by imaging the array with a fast CMOS camera. The experimental data show that the capture rates of DNA molecules decrease with increasing DNA length due to the thermophoretic effect of the molecules. It is shown that the translocation can be completely turned off for the longer molecule using an appropriate bias, thus allowing a size discrimination of the DNA translocation through the nanopores. A derived analytical model correctly predicts the observed capture rate. Our results demonstrate that by combining a thermal and a potential gradient at the nanopores, such large nanopore arrays can potentially be used as a low-cost, high-throughput platform for molecule sensing and sorting.

  • 1105.
    Zhang, Miao
    et al.
    KTH, School of Information and Communication Technology (ICT), Materials- and Nano Physics, Material Physics, MF.
    Schmidt, Torsten
    KTH, School of Information and Communication Technology (ICT), Materials- and Nano Physics, Material Physics, MF.
    Jemt, Anders
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sahlén, Pelin
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sychugov, Ilya
    KTH, School of Information and Communication Technology (ICT), Materials- and Nano Physics, Material Physics, MF.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Linnros, Jan
    KTH, School of Information and Communication Technology (ICT), Materials- and Nano Physics, Material Physics, MF.
    Nanopore arrays in a silicon membrane for parallel single-molecule detection: DNA translocation2015In: Nanotechnology, ISSN 0957-4484, E-ISSN 1361-6528, Vol. 26, no 31, article id 314002Article in journal (Refereed)
    Abstract [en]

    Optical nanopore sensing offers great potential in single-molecule detection, genotyping, or DNA sequencing for high-throughput applications. However, one of the bottle-necks for fluorophore-based biomolecule sensing is the lack of an optically optimized membrane with a large array of nanopores, which has large pore-to-pore distance, small variation in pore size and low background photoluminescence (PL). Here, we demonstrate parallel detection of single-fluorophore-labeled DNA strands (450 bps) translocating through an array of silicon nanopores that fulfills the above-mentioned requirements for optical sensing. The nanopore array was fabricated using electron beam lithography and anisotropic etching followed by electrochemical etching resulting in pore diameters down to similar to 7 nm. The DNA translocation measurements were performed in a conventional wide-field microscope tailored for effective background PL control. The individual nanopore diameter was found to have a substantial effect on the translocation velocity, where smaller openings slow the translocation enough for the event to be clearly detectable in the fluorescence. Our results demonstrate that a uniform silicon nanopore array combined with wide-field optical detection is a promising alternative with which to realize massively-parallel single-molecule detection.

  • 1106. Zhang, Ming-Dong
    et al.
    Barde, Swapnali
    Szodorai, Edit
    Josephson, Anna
    Mitsios, Nicholas
    Watanabe, Masahiko
    Attems, Johannes
    Lubec, Gert
    Kovacs, Gabor G.
    Uhlen, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mulder, Jan
    Harkany, Tibor
    Hokfelt, Tomas
    Erratum to: Comparative anatomical distribution of neuronal calcium-binding protein (NECAB) 1 and -2 in rodent and human spinal cord2016In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 221, no 7, p. 3843-3843Article in journal (Refereed)
  • 1107. Zhang, Ming-Dong
    et al.
    Tortoriello, Giuseppe
    Hsueh, Brian
    Tomer, Raju
    Ye, Li
    Mitsios, Nicholas
    Borgius, Lotta
    Grant, Gunnar
    Kiehn, Ole
    Watanabe, Masahiko
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mulder, Jan
    Deisseroth, Karl
    Harkany, Tibor
    Hökfelt, Tomas G. M.
    Neuronal calcium-binding proteins 1/2 localize to dorsal root ganglia and excitatory spinal neurons and are regulated by nerve injury2014In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 12, p. E1149-E1158Article in journal (Refereed)
    Abstract [en]

    Neuronal calcium (Ca2+)-binding proteins 1 and 2 (NECAB1/2) are members of the phylogenetically conserved EF-hand Ca2+-binding protein superfamily. To date, NECABs have been explored only to a limited extent and, so far, not at all at the spinal level. Here, we describe the distribution, phenotype, and nerve injury-induced regulation of NECAB1/NECAB2 in mouse dorsal root ganglia (DRGs) and spinal cord. In DRGs, NECAB1/2 are expressed in around 70% of mainly small-and medium-sized neurons. Many colocalize with calcitonin gene-related peptide and isolectin B4, and thus represent nociceptors. NECAB1/2 neurons are much more abundant in DRGs than the Ca2+-binding proteins (parvalbumin, calbindin, calretinin, and secretagogin) studied to date. In the spinal cord, the NECAB1/2 distribution is mainly complementary. NECAB1 labels interneurons and a plexus of processes in superficial layers of the dorsal horn, commissural neurons in the intermediate area, and motor neurons in the ventral horn. Using CLARITY, a novel, bilaterally connected neuronal system with dendrites that embrace the dorsal columns like palisades is observed. NECAB2 is present in cell bodies and presynaptic boutons across the spinal cord. In the dorsal horn, most NECAB1/2 neurons are glutamatergic. Both NECAB1/2 are transported into dorsal roots and peripheral nerves. Peripheral nerve injury reduces NECAB2, but not NECAB1, expression in DRG neurons. Our study identifies NECAB1/2 as abundant Ca2+-binding proteins in pain-related DRG neurons and a variety of spinal systems, providing molecular markers for known and unknown neuron populations of mechanosensory and pain circuits in the spinal cord.

  • 1108.
    Zhang, Wang
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Akusjarvi, Sara Svensson
    Karolinska Inst, Div Clin Microbiol, Dept Lab Med, Solna, Sweden..
    Sonnerborg, Anders
    Karolinska Inst, Div Clin Microbiol, Dept Lab Med, Solna, Sweden.;Karolinska Univ Hosp, Karolinska Inst, Unit Infect Dis, Dept Med Huddinge, Solna, Sweden..
    Neogi, Ujjwal
    Karolinska Inst, Div Clin Microbiol, Dept Lab Med, Solna, Sweden..
    Characterization of Inducible Transcription and Translation-Competent HIV-1 Using the RNAscope ISH Technology at a Single-Cell Resolution2018In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 9, article id 2358Article in journal (Refereed)
    Abstract [en]

    Identifying the source and dynamics of persistent HIV-1 at single-cell resolution during cART is crucial for the design of strategies to eliminate the latent HIV-1 reservoir. An assay to measure latent HIV-1 that can distinguish inducible from defective proviruses with high precision is essential to evaluate the efficacy of HIV-1 cure efforts but is presently lacking. The primary aim of this study was therefore to identify transcription and translation competent latently infected cells through detection of biomolecules that are dependent on transcriptional activation of the provirus. We investigated the applicability of two commercially available assays; PrimeFlow (TM) RNA Assay (RNAflow) and RNAscope (R) ISH (RNAscope) for evaluation of the efficacy of latency reversal agents (LRAs) to reactivate the HIV-1 latent reservoir. The J-Lat cell model (clones 6.3, 9.3, and 10.6) and four LRAs was used to evaluate the sensitivity, specificity, and lower detection limit of the RNAflow and RNAscope assays for the detection and description of the translation-competent HIV-1 reservoir. We also checked for HIV-1 subtype specificity of the RNAscope assay using patient-derived subtype A1, B, C, and CRFOLAE recombinant plasmids following transfection in 293T cells and the applicability of the method in patient-derived peripheral blood mononuclear cells (PBMCs). The lower detection limit of RNAflow was 575 HIV-1 infected cells/million and 45 cells/million for RNAscope. The RNAscope probes, designed for HIV-1B, also detected other subtypes (A1, B, C, and CRF<b>01 _AE). RNAscope was applicable for the detection of in patient-derived PBMCs following LRA activation. In conclusion, our study showed that RNAscope can be used to quantify the number of directly observed individual cells expressing HIV-1 mRNA following LRA activation. Therefore, it can be a useful tool for characterization of translation-competent HIV-1 in latently infected cell at single-cell resolution in the fields of HIV-1 pathogenesis and viral persistence.

  • 1109.
    Zhang, Wang
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Ambikan, Anoop T.
    Sperk, Maike
    van Domselaar, Robert
    Nowak, Piotr
    Noyan, Kajsa
    Russom, Aman
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Sonnerborg, Anders
    Neogi, Ujjwal
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Transcriptomics and Targeted Proteomics Analysis to Gain Insights Into the Immune-control Mechanisms of HIV-1 Infected Elite Controllers2018In: EBioMedicine, E-ISSN 2352-3964, Vol. 27, p. 40-50Article in journal (Refereed)
    Abstract [en]

    A small subset of HIV-1 infected individuals, the "Elite Controllers" (EC), can control viral replication and restrain progression to immunodeficiency without antiretroviral therapy (ART). In this study, a cross-sectional transcriptomics and targeted proteomics analysis were performed in a well-defined Swedish cohort of untreated EC (n = 19), treatment naive patients with viremia (VP, n = 32) and HIV-1-negative healthy controls (HC, n = 23). The blood transcriptome identified 151 protein-coding genes that were differentially expressed (DE) in VP compared to EC. Genes like CXCR6 and SIGLEC1were downregulated in EC compared to VP. A definite distinction in gene expression between males and females among all patient-groups were observed. The gene expression profile between female EC and the healthy females was similar but did differ between male EC and healthy males. At targeted proteomics analysis, 90% (29/32) of VPs clustered together while EC and HC clustered separately from VP. Among the soluble factors, 33 were distinctive to be statistically significant (False discovery rate = 0.02). Cell surface receptor signaling pathway, programmed cell death, response to cytokine and cytokine-mediated signaling seem to synergistically play an essential role in HIV-1 control in EC.

  • 1110.
    Zhang, Wang
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Sweden.
    Morshed, Mohammed M.
    Noyan, Kajsa
    Russom, Aman
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sonnerborg, Anders
    Neogi, Ujjwal
    Quantitative humoral profiling of the HIV-1 proteome in elite controllers and patients with very long-term efficient antiretroviral therapy2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 666Article in journal (Refereed)
    Abstract [en]

    A major challenge in evaluating the success of HIV eradication approaches is the need for accurate measurement of persistent HIV during effective antiretroviral therapy (ART). Previous studies have reported that the anti-HIV antibody assay "luciferase immuno-precipitation systems (LIPS)"can distinguish HIV-infected individuals harboring different sizes of the viral reservoirs. We performed antibody profiling of HIV-1 proteomes using LIPS in viremic progressors (n = 38), elite controllers (ECs; n = 19) and patients with fully suppressive long-term antiretroviral therapy (ART) (n = 19) (mean 17 years). IgG was quantified against six HIV-1 fusion proteins: p24, gp41, RT, Tat, integrase and protease. Lower antibody levels to all six-fusion proteins were observed in long-term ART patients compared to viremics (p < 0.05). In contrast ECs had lower antibody levels only against Tat and Integrase (p < 0.05). Principal component analysis and cluster-network analysis identified that 68% (13/19) of the long-term ART patients clustered together with 26% (5/19) ECs. The remaining ECs clustered together with the viremics indicating non-homogeneity among the ECs. The low anti-HIV levels in the long-term treated patients may indicate a restricted remaining viral replication. In contrast, the higher levels in ECs suggest a continuous viral expression with a limited concomitant release of extracellular virus.

  • 1111.
    Zhang, Wensheng
    et al.
    Soochow Univ, Cam Su Genom Resource Ctr, Suzhou 215123, Peoples R China.;Wellcome Sanger Inst, Hinxton CB10 1SA, England..
    Chronis, Constantinos
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol & Chem, Los Angeles, CA 90095 USA.;Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA USA.;Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Bioinformat Program, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA..
    Chen, Xi
    Wellcome Sanger Inst, Hinxton CB10 1SA, England..
    Zhang, Heyao
    Soochow Univ, Cam Su Genom Resource Ctr, Suzhou 215123, Peoples R China..
    Spalinskas, Rapolas
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Pardo, Mercedes
    Chester Beatty Labs, Inst Canc Res, London, England..
    Chen, Liangliang
    Soochow Univ, Cam Su Genom Resource Ctr, Suzhou 215123, Peoples R China..
    Wu, Guangming
    Max Planck Inst Mol Biomed, Dept Cell & Dev Biol, Rontgenstr 20, D-48149 Munster, Germany..
    Zhu, Zhexin
    Wellcome Sanger Inst, Hinxton CB10 1SA, England..
    Yu, Yong
    Wellcome Sanger Inst, Hinxton CB10 1SA, England..
    Yu, Lu
    Chester Beatty Labs, Inst Canc Res, London, England..
    Choudhary, Jyoti
    Chester Beatty Labs, Inst Canc Res, London, England..
    Nichols, Jennifer
    Univ Cambridge, Wellcome Trust Med Res Council, Stem Cell Inst, Tennis Court Rd, Cambridge CB2 1QR, England..
    Parast, Mana M.
    Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA.;Univ Calif San Diego, Sanford Consortium Regenerat Med, La Jolla, CA 92093 USA..
    Greber, Boris
    Max Planck Inst Mol Biomed, Dept Cell & Dev Biol, Rontgenstr 20, D-48149 Munster, Germany..
    Sahlén, Pelin
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Plath, Kathrin
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol & Chem, Los Angeles, CA 90095 USA.;Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA USA.;Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Bioinformat Program, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA..
    The BAF and PRC2 Complex Subunits Dpf2 and Eed Antagonistically Converge on Tbx3 to Control ESC Differentiation2019In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 24, no 1, p. 138-+Article in journal (Refereed)
    Abstract [en]

    BAF complexes are composed of different subunits with varying functional and developmental roles, although many subunits have not been examined in depth. Here we show that the Baf45 subunit Dpf2 maintains pluripotency and ESC differentiation potential. Dpf2 co-occupies enhancers with Oct4, Sox2, p300, and the BAF subunit Brg1, and deleting Dpf2 perturbs ESC self-renewal, induces repression of Tbx3, and impairs mesendodermal differentiation without dramatically altering Brg1 localization. Mesendodermal differentiation can be rescued by restoring Tbx3 expression, whose distal enhancer is positively regulated by Dpf2-dependent H3K27ac maintenance and recruitment of pluripotency TFs and Brg1. In contrast, the PRC2 subunit Eed binds an intragenic Tbx3 enhancer to oppose Dpf2-dependent Tbx3 expression and mesendodermal differentiation. The PRC2 subunit Ezh2 likewise opposes Dpf2-dependent differentiation through a distinct mechanism involving Nanog repression. Together, these findings delineate distinct mechanistic roles for specific BAF and PRC2 subunits during ESC differentiation.

  • 1112. Zhang, Xiang
    et al.
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Joosten, Leo A. B.
    Kuivenhoven, Jan A.
    Li, Yang
    Netea, Mihai G.
    Groen, Albert K.
    Identification of Discriminating Metabolic Pathways and Metabolites in Human PBMCs Stimulated by Various Pathogenic Agents2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 139Article in journal (Refereed)
    Abstract [en]

    Immunity and cellular metabolism are tightly interconnected but it is not clear whether different pathogens elicit specific metabolic responses. To address this issue, we studied differential metabolic regulation in peripheral blood mononuclear cells (PBMCs) of healthy volunteers challenged by Candida albicans, Borrelia burgdorferi, lipopolysaccharide, and Mycobacterium tuberculosis in vitro. By integrating gene expression data of stimulated PBMCs of healthy individuals with the KEGG pathways, we identified both common and pathogen-specific regulated pathways depending on the time of incubation. At 4 h of incubation, pathogenic agents inhibited expression of genes involved in both the glycolysis and oxidative phosphorylation pathways. In contrast, at 24 h of incubation, particularly glycolysis was enhanced while genes involved in oxidative phosphorylation remained unaltered in the PBMCs. In general, differential gene expression was less pronounced at 4 h compared to 24 h of incubation. KEGG pathway analysis allowed differentiation between effects induced by Candida and bacterial stimuli. Application of genome-scale metabolic model further generated a Candida-specific set of 103 reporter metabolites (e.g., desmosterol) that might serve as biomarkers discriminating Candida stimulated PBMCs from bacteria-stimuated PBMCs. Our analysis also identified a set of 49 metabolites that allowed discrimination between the effects of Borrelia burgdorferi, lipopolysaccharide and Mycobacterium tuberculosis. We conclude that analysis of pathogen-induced effects on PBMCs by a combination of KEGG pathways and genome-scale metabolic model provides deep insight in the metabolic changes coupled to host defense.

  • 1113. Zhang, Yiming
    et al.
    Liu, Guodong
    Engqvist, Martin K. M.
    Krivoruchko, Anastasia
    Hallström, Björn M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Chen, Yun
    Siewers, Verena
    Nielsen, Jens
    Adaptive mutations in sugar metabolism restore growth on glucose in a pyruvate decarboxylase negative yeast strain2015In: Microbial Cell Factories, ISSN 1475-2859, E-ISSN 1475-2859, Vol. 14, article id 116Article in journal (Refereed)
    Abstract [en]

    Background: A Saccharomyces cerevisiae strain carrying deletions in all three pyruvate decarboxylase (PDC) genes (also called Pdc negative yeast) represents a non-ethanol producing platform strain for the production of pyruvate derived biochemicals. However, it cannot grow on glucose as the sole carbon source, and requires supplementation of C2 compounds to the medium in order to meet the requirement for cytosolic acetyl-CoA for biosynthesis of fatty acids and ergosterol. Results: In this study, a Pdc negative strain was adaptively evolved for improved growth in glucose medium via serial transfer, resulting in three independently evolved strains, which were able to grow in minimal medium containing glucose as the sole carbon source at the maximum specific rates of 0.138, 0.148, 0.141 h(-1), respectively. Several genetic changes were identified in the evolved Pdc negative strains by genomic DNA sequencing. Among these genetic changes, 4 genes were found to carry point mutations in at least two of the evolved strains: MTH1 encoding a negative regulator of the glucose-sensing signal transduction pathway, HXT2 encoding a hexose transporter, CIT1 encoding a mitochondrial citrate synthase, and RPD3 encoding a histone deacetylase. Reverse engineering of the non-evolved Pdc negative strain through introduction of the MTH1(81D) allele restored its growth on glucose at a maximum specific rate of 0.053 h(-1) in minimal medium with 2% glucose, and the CIT1 deletion in the reverse engineered strain further increased the maximum specific growth rate to 0.069 h(-1). Conclusions: In this study, possible evolving mechanisms of Pdc negative strains on glucose were investigated by genome sequencing and reverse engineering. The non-synonymous mutations in MTH1 alleviated the glucose repression by repressing expression of several hexose transporter genes. The non-synonymous mutations in HXT2 and CIT1 may function in the presence of mutated MTH1 alleles and could be related to an altered central carbon metabolism in order to ensure production of cytosolic acetyl-CoA in the Pdc negative strain.

  • 1114.
    Zheng, Daoshan
    et al.
    Mayo Clin, Dept Canc Biol, 4500 San Pablo Rd,Griffin 210, Jacksonville, FL 32224 USA..
    Trynda, Justyna
    Mayo Clin, Dept Canc Biol, 4500 San Pablo Rd,Griffin 210, Jacksonville, FL 32224 USA..
    Williams, Cecilia
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Vold, Jeremy A.
    Mayo Clin, Mayo Canc Registry, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Nguyen, Justin H.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Ctr Canc, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Harnois, Denise M.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Ctr Canc, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Bagaria, Sanjay P.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Ctr Canc, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    McLaughlin, Sarah A.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Ctr Canc, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Li, Zhaoyu
    Mayo Clin, Dept Canc Biol, 4500 San Pablo Rd,Griffin 210, Jacksonville, FL 32224 USA..
    Sexual dimorphism in the incidence of human cancers2019In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, no 1, article id 684Article in journal (Refereed)
    Abstract [en]

    BackgroundSex differences in the incidences of cancers become a critical issue in both cancer research and the development of precision medicine. However, details in these differences have not been well reported. We provide a comprehensive analysis of sexual dimorphism in human cancers.MethodsWe analyzed four sets of cancer incidence data from the SEER (USA, 1975-2015), from the Cancer Registry at Mayo Clinic (1970-2015), from Sweden (1970-2015), and from the World Cancer Report in 2012.ResultsWe found that all human cancers had statistically significant sexual dimorphism with male dominance in the United States and mostly significant in the Mayo Clinic, Sweden, and the world data, except for thyroid cancer, which is female-dominant.ConclusionsSexual dimorphism is a clear but mostly neglected phenotype for most human cancers regarding the clinical practice of cancer. We expect that our study will facilitate the mechanistic studies of sexual dimorphism in human cancers. We believe that fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of individualized precision medicine beginning from the sex-specific diagnosis, prognosis, and treatment.

  • 1115.
    Zheng, Daoshan
    et al.
    Dept Canc Biol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Williams, Cecilia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Cellular and Clinical Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Institute.
    Vold, Jeremy A.
    Mayo Canc Registry, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Nguyen, Justin H.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Mayo Clin Canc Ctr, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Harnois, Denise M.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Mayo Clin Canc Ctr, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Bagaria, Sanjay P.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Mayo Clin Canc Ctr, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    McLaughlin, Sarah A.
    Mayo Clin, Dept Surg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA.;Mayo Clin, Mayo Clin Canc Ctr, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Li, Zhaoyu
    Dept Canc Biol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA..
    Regulation of sex hormone receptors in sexual dimorphism of human cancers2018In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 438, p. 24-31Article, review/survey (Refereed)
    Abstract [en]

    Gender differences in the incidences of cancers have been found in almost all human cancers. However, the mechanisms that underlie gender disparities in most human cancer types have been under-investigated. Here, we provide a comprehensive overview of potential mechanisms underlying sexual dimorphism of each cancer regarding sex hormone signaling. Fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of precision medicine. Our discussions of potential mechanisms underlying sexual dimorphism in each cancer will be instructive for future cancer research on gender disparities.

  • 1116. Zheng, Zongli
    et al.
    Advani, Abdolreza
    Melefors, Öjar
    Glavas, Steve
    Nordström, Henrik
    Ye, Weimin
    Engstrand, Lars
    Andersson, Anders F.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Titration-free 454 sequencing using Y adapters2011In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 6, no 9, p. 1367-1376Article in journal (Refereed)
    Abstract [en]

    We describe a protocol for construction and quantification of libraries for emulsion PCR (emPCR)-based sequencing platforms such as Roche 454 or Ion Torrent PGM. The protocol involves library construction using customized Y adapters, quantification using TaqMan-MGB (minor groove binder) probe-based quantitative PCR (qPCR) and calculation of an optimal template-to-bead ratio based on Poisson statistics, thereby avoiding the need for a laborious titration assay. Unlike other qPCR methods, the TaqMan-MGB probe specifically quantifies effective libraries in molar concentration and does not require specialized equipment. A single quality control step prior to emulsion PCR ensures that libraries contain no adapter dimers and have an optimal length distribution. The presented protocol takes similar to 7 h to prepare eight barcoded libraries from genomic DNA into libraries that are ready to use for full-scale emPCR. It will be useful, for example, to allow analyses of precious clinical samples and amplification-free metatranscriptomics.

  • 1117. Zheng, Zongli
    et al.
    Andersson, Anders F.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ye, Weimin
    Nyrén, Olof
    Normark, Staffan
    Engstrand, Lars
    A Method for Metagenomics of Helicobacter pylori from Archived Formalin-Fixed Gastric Biopsies Permitting Longitudinal Studies of Carcinogenic Risk2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 10, p. e26442-Article in journal (Refereed)
    Abstract [en]

    The human microbiota has come into focus in the search for component causes of chronic diseases, such as gastrointestinal cancers. Presumably long induction periods and altered local environments after disease onset call for the development of methods for characterization of microorganisms colonizing the host decades before disease onset. Sequencing of microbial genomes in old formalin-fixed and paraffin-embedded (FFPE) gastrointestinal biopsies provides a means for such studies but is still challenging. Here we report a method based on laser capture micro-dissection and modified Roche 454 high-throughput pyrosequencing to obtain metagenomic profiles of Helicobacter pylori. We applied this method to two 15 year old FFPE biopsies from two patients. Frozen homogenized biopsies from the same gastroscopy sessions were also available for comparison after re-culture of H. pylori. For both patients, H. pylori DNA dissected from FFPE sections had similar to 96.4% identity with culture DNA from the same patients, while only similar to 92.5% identity with GenBank reference genomes, and with culture DNA from the other patient. About 82% and 60% of the predicted genes in the two genomes were captured by at least a single sequencing read. Along with sequences displaying high similarity to known H. pylori genes, novel and highly variant H. pylori sequences were identified in the FFPE sections by our physical enrichment approach, which would likely not have been detected by a sequence capture approach. The study demonstrates the feasibility of longitudinal metagenomic studies of H. pylori using decade-preserved FFPE biopsies.

  • 1118.
    Zhou, Xiamo
    et al.
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Sjöberg, Ronald
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Druet, Amaury
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    van der Wijngaart, Wouter
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Haraldsson, Tommy
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Carlborg, Carl Fredrik
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems.
    Thiol–ene–epoxy thermoset for low-temperature bonding to biofunctionalized microarray surfaces2017In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 17, no 21, p. 3672-3681Article in journal (Refereed)
    Abstract [en]

    One way to improve the sensitivity and throughput of miniaturized biomolecular assays is to integrate microfluidics to enhance the transport efficiency of biomolecules to the reaction sites. Such microfluidic integration requires bonding of a prefabricated microfluidic gasket to an assay surface without destroying its biological activity. In this paper we address the largely unmet challenge to accomplish a proper seal between a microfluidic gasket and a protein surface, with maintained biological activity and without contaminating the surface or blocking the microfluidic channels. We introduce a novel dual cure polymer resin for the formation of microfluidic gaskets that can be room-temperature bonded to a range of substrates using only UVA light. This polymer is the first polymer that features over a month of shelf life between the structure formation and the bonding, moreover the fully cured polymer gaskets feature the following set of properties suitable for microfluidics: high stiffness, which prevents microfluidic channel collapse during handling; very limited absorption of biomolecules; and no significant leaching of uncured monomers. We describe the novel polymer resin and its characteristics, study through FT-IR, and demonstrate its use as microfluidic well-arrays bonded onto protein array slides at room temperature followed by multiplexed immunoassays. The results confirm maintained biological activity and show high repeatability between protein arrays. This new approach for integrating microfluidic gaskets to biofunctionalised surfaces has the potential to improve sample throughput and decrease manufacturing costs for miniaturized biomolecular systems.

  • 1119. Zhow, Yongjin J.
    et al.
    Buijs, Nicolaas A.
    Zhu, Zhiwei
    Gomez, Diego Orol
    Boonsombuti, Akarin
    Siewers, Verena
    Nielsen, Jens
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden; Technical University of Denmark, Denmark.
    Harnessing Yeast Peroxisomes for Biosynthesis of Fatty-Acid-Derived Biofuels and Chemicals with Relieved Side-Pathway Competition2016In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 47, p. 15368-15377Article in journal (Refereed)
    Abstract [en]

    Establishing efficient synthetic pathways for microbial production of biochemicals is often hampered by competing pathways and/or insufficient precursor supply. Compartmentalization in cellular organelles can isolate synthetic pathways from competing pathways, and provide a compact and suitable environment for biosynthesis. Peroxisomes are cellular organelles where fatty acids are degraded, a process that is inhibited under typical fermentation conditions making them an interesting workhouse for production of fatty-acid-derived molecules. Here, we show that targeting synthetic pathways to peroxisomes can increase the production of fatty-acid-derived fatty alcohols, alkanes and olefins up to 700%. In addition, we demonstrate that biosynthesis of these chemicals in the peroxisomes results in significantly decreased accumulation of byproducts formed by competing enzymes. We further demonstrate that production can be enhanced up to 3-fold by increasing the peroxisome population. The strategies described here could be used for production of other chemicals, especially acyl-CoA-derived molecules.

  • 1120. Zhu, J.
    et al.
    Zhao, C.
    Zhuang, T.
    Jonsson, P.
    Sinha, I.
    Williams, Cecilia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Strömblad, S.
    Dahlman-Wright, K.
    RING finger protein 31 promotes p53 degradation in breast cancer cells2016In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, no 15, p. 1955-1964Article in journal (Refereed)
    Abstract [en]

    The atypical E3 ubiquitin ligase RNF31 is highly expressed in human breast cancer, the most frequent neoplastic lethality among women. Here, RNF31 depletion in breast cancer cells in combination with global gene expression profiling revealed p53 (TP53) signaling as a potential RNF31 target. Interestingly, RNF31 decreased p53 stability, whereas depletion of RNF31 in breast cancer cells caused cell cycle arrest and cisplatin-induced apoptosis in a p53-dependent manner. Furthermore, RNF31 associated with the p53/MDM2 complex and facilitated p53 polyubiquitination and degradation by stabilizing MDM2, suggesting a molecular mechanism by which RNF31 regulates cell death. Analysis of publically available clinical data sets displayed a negative correlation between RNF31 and p53 target genes, including IGFBP3 and BTG1, consistent with RNF31 regulating p53 function in vivo as well. Together, our findings suggest RNF31 as a potential therapeutic target to restore p53 function in breast cancer.

  • 1121. Zhu, X.
    et al.
    Shen, Y.
    Chen, X.
    Hu, Yue O. O.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Xiang, H.
    Tao, J.
    Ling, Y.
    Biodegradation mechanism of microcystin-LR by a novel isolate of Rhizobium sp. TH and the evolutionary origin of the mlrA gene2016In: International Biodeterioration & Biodegradation, ISSN 0964-8305, E-ISSN 1879-0208, Vol. 115, p. 17-25Article in journal (Refereed)
    Abstract [en]

    The frequent presence of microcystin (MC) in eutrophic water bodies worldwide poses a serious threat to ecosystems. Biodegradation has been extensively investigated as a main pathway for MC attenuation, and an mlr-dependent mechanism of MC degradation have been elucidated in detail. However, the evolutionary origin and the distribution of mlr genes in MC-degrading bacteria is poorly understood. In this study, a novel Rhizobium sp. TH, which is the first α-proteobacterial MC-degrading bacterium other than Sphingomonadales, was isolated. Strain TH degraded MC via the mlr-dependent mechanism with a first-order rate constant of 0.18–0.29 h−1 under near-natural conditions. The partial length mlr gene cluster was sequenced, and the function of its key gene, mlrA, was verified by heterologous expression in Escherichia coli. Phylogenetic analyses show that the mlrA gene initially arose in α-proteobacteria by vertical evolution, and the two strains from β- and γ-proteobacteria acquired it by horizontal gene transfer. Therefore, the mlrA gene mainly exists in α-proteobacteria but is seldom present in other bacteria. A pair of primers matching well with mlrA sequences reported so far were designed and could be used to determine the MC-degrading mechanism for novel isolates or to screen for MC-degrading ability among environmental samples.

  • 1122. Zhu, Y.
    et al.
    Engström, P. G.
    Tellgren-Roth, C.
    Baudo, C. D.
    Kennell, J. C.
    Sun, S.
    Billmyre, R. B.
    Schröder, M. S.
    Andersson, A.
    Holm, T.
    Sigurgeirsson, Benjamin
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Wu, G.
    Sankaranarayanan, S. R.
    Siddharthan, R.
    Sanyal, K.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nystedt, B.
    Boekhout, T.
    Dawson, T.L., Jr.
    Heitman, J.
    Scheynius, A.
    Lehtiö, J.
    Proteogenomics produces comprehensive and highly accurate protein-coding gene annotation in a complete genome assembly of Malassezia sympodialis2017In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 5, p. 2629-2643Article in journal (Refereed)
    Abstract [en]

    Complete and accurate genome assembly and annotation is a crucial foundation for comparative and functional genomics. Despite this, few complete eukaryotic genomes are available, and genome annotation remains a major challenge. Here, we present a complete genome assembly of the skin commensal yeast Malassezia sympodialis and demonstrate how proteogenomics can substantially improve gene annotation. Through long-read DNA sequencing, we obtained a gap-free genome assembly for M. sympodialis (ATCC 42132), comprising eight nuclear and one mitochondrial chromosome. We also sequenced and assembled four M. sympodialis clinical isolates, and showed their value for understanding Malassezia reproduction by confirming four alternative allele combinations at the two mating-type loci. Importantly, we demonstrated how proteomics data could be readily integrated with transcriptomics data in standard annotation tools. This increased the number of annotated protein-coding genes by 14% (from 3612 to 4113), compared to using transcriptomics evidence alone. Manual curation further increased the number of protein-coding genes by 9% (to 4493). All of these genes have RNA-seq evidence and 87% were confirmed by proteomics. The M. sympodialis genome assembly and annotation presented here is at a quality yet achieved only for a few eukaryotic organisms, and constitutes an important reference for future host-microbe interaction studies.

  • 1123. Zhu, Z.
    et al.
    Zhou, Y. J.
    Kang, M. -K
    Krivoruchko, A.
    Buijs, N. A.
    Nielsen, Jens
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Technical University of Denmark.
    Enabling the synthesis of medium chain alkanes and 1-alkenes in yeast2017In: Metabolic engineering, ISSN 1096-7176, E-ISSN 1096-7184, Vol. 44, p. 81-88Article in journal (Refereed)
    Abstract [en]

    Microbial synthesis of medium chain aliphatic hydrocarbons, attractive drop-in molecules to gasoline and jet fuels, is a promising way to reduce our reliance on petroleum-based fuels. In this study, we enabled the synthesis of straight chain hydrocarbons (C7–C13) by yeast Saccharomyces cerevisiae through engineering fatty acid synthases to control the chain length of fatty acids and introducing heterologous pathways for alkane or 1-alkene synthesis. We carried out enzyme engineering/screening of the fatty aldehyde deformylating oxygenase (ADO), and compartmentalization of the alkane biosynthesis pathway into peroxisomes to improve alkane production. The two-step synthesis of alkanes was found to be inefficient due to the formation of alcohols derived from aldehyde intermediates. Alternatively, the drain of aldehyde intermediates could be circumvented by introducing a one-step decarboxylation of fatty acids to 1-alkenes, which could be synthesized at a level of 3 mg/L, 25-fold higher than that of alkanes produced via aldehydes.

  • 1124. Zieba, A.
    et al.
    Ponten, F.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Landegren, U.
    In situ protein detection with enhanced specificity using DNA-conjugated antibodies and proximity ligation2018In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 31, no 2, p. 253-263Article in journal (Refereed)
    Abstract [en]

    Antibodies are important tools in anatomical pathology and research, but the quality of in situ protein detection by immunohistochemistry greatly depends on the choice of antibodies and the abundance of the targeted proteins. Many antibodies used in scientific research do not meet requirements for specificity and sensitivity. Accordingly, methods that improve antibody performance and produce quantitative data can greatly advance both scientific investigations and clinical diagnostics based on protein expression and in situ localization. We demonstrate here protocols for antibody labeling that allow specific protein detection in tissues via bright-field in situ proximity ligation assays, where each protein molecule must be recognized by two antibodies. We further demonstrate that single polyclonal antibodies or purified serum preparations can be used for these dual recognition assays. The requirement for protein recognition by pairs of antibody conjugates can significantly improve specificity of protein detection over single-binder assays.

  • 1125.
    Zieba, Agata
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Sjöstedt, Evelina
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Olovsson, Matts
    Uppsala Univ, Dept Womens & Childrens Hlth, S-75185 Uppsala, Sweden..
    Fagerberg, Linn
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hallström, Björn M.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Oskarsson, Linda
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Edlund, Karolina
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Tolf, Anna
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ponten, Fredrik
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    The Human Endometrium-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling2015In: Omics, ISSN 1536-2310, E-ISSN 1557-8100, Vol. 19, no 11, p. 659-668Article in journal (Refereed)
    Abstract [en]

    The human uterus includes the complex endometrial mucosa, the endometrium that undergoes dynamic, hormone-dependent alterations throughout the life of fertile females. Here we have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to analyze gene expression patterns in the normal endometrium. Human endometrial tissues from five women were used for deep sequencing (RNA-Seq). The mRNA and protein expression data from the endometrium were compared to 31 (RNA) and 44 (protein) other normal tissue types, to identify genes with elevated expression in the endometrium and to localize the expression of corresponding proteins at a cellular resolution. Based on the expression levels of transcripts, we could classify all putative human protein coding genes into categories defined by expression patterns and found altogether 101 genes that showed an elevated pattern of expression in the endometrium, with only four genes showing more than five-fold higher expression levels in the endometrium compared to other tissues. In conclusion, our analysis based on transcriptomics and antibody-based protein profiling reports here comprehensive lists of genes with elevated expression levels in the endometrium, providing important starting points for a better molecular understanding of human reproductive biology and disease.

  • 1126.
    Zivanov, Jasenko
    et al.
    MRC, Lab Mol Biol, Cambridge, England..
    Nakane, Takanori
    MRC, Lab Mol Biol, Cambridge, England..
    Forsberg, Björn O.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Kimanius, Dari
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Hagen, Wim J. H.
    European Mol Biol Lab, Struct & Computat Biol Unit, Heidelberg, Germany.;European Mol Biol Lab, Cryoelectron Microscopy Serv Platform, Heidelberg, Germany..
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Scheres, Sjors H. W.
    MRC, Lab Mol Biol, Cambridge, England..
    New tools for automated high-resolution cryo-EM structure determination in RELION-32018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e42166Article in journal (Refereed)
    Abstract [en]

    Here, we describe the third major release of RELION. CPU-based vector acceleration has been added in addition to GPU support, which provides flexibility in use of resources and avoids memory limitations. Reference-free autopicking with Laplacian-of-Gaussian filtering and execution of jobs from python allows non-interactive processing during acquisition, including 2D-classification, de novo model generation and 3D-classification. Per-particle refinement of CTF parameters and correction of estimated beam tilt provides higher resolution reconstructions when particles are at different heights in the ice, and/or coma-free alignment has not been optimal. Ewald sphere curvature correction improves resolution for large particles. We illustrate these developments with publicly available data sets: together with a Bayesian approach to beam-induced motion correction it leads to resolution improvements of 0.2-0.7 angstrom compared to previous RELION versions.

  • 1127. Zong, N. C.
    et al.
    Li, H.
    Lam, M. P. Y.
    Jimenez, R. C.
    Kim, C. S.
    Deng, N.
    Kim, A. K.
    Choi, J. H.
    Zelaya, I.
    Liem, D.
    Meyer, D.
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fang, C.
    Lu, H. -J
    Xu, T.
    Weiss, J.
    Duan, H.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Yates III, J. R.
    Apweiler, R.
    Ge, J.
    Hermjakob, H.
    Ping, P.
    Integration of cardiac proteome biology and medicine by a specialized knowledgebase2013In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 113, no 9, p. 1043-1053Article in journal (Refereed)
    Abstract [en]

    Rationale: Omics sciences enable a systems-level perspective in characterizing cardiovascular biology. Integration of diverse proteomics data via a computational strategy will catalyze the assembly of contextualized knowledge, foster discoveries through multidisciplinary investigations, and minimize unnecessary redundancy in research efforts. Objective: The goal of this project is to develop a consolidated cardiac proteome knowledgebase with novel bioinformatics pipeline and Web portals, thereby serving as a new resource to advance cardiovascular biology and medicine. Methods and results: We created Cardiac Organellar Protein Atlas Knowledgebase (COPaKB; www.HeartProteome.org), a centralized platform of high-quality cardiac proteomic data, bioinformatics tools, and relevant cardiovascular phenotypes. Currently, COPaKB features 8 organellar modules, comprising 4203 LC-MS/MS experiments from human, mouse, drosophila, and Caenorhabditis elegans, as well as expression images of 10 924 proteins in human myocardium. In addition, the Java-coded bioinformatics tools provided by COPaKB enable cardiovascular investigators in all disciplines to retrieve and analyze pertinent organellar protein properties of interest. Conclusions: COPaKB provides an innovative and interactive resource that connects research interests with the new biological discoveries in protein sciences. With an array of intuitive tools in this unified Web server, nonproteomics investigators can conveniently collaborate with proteomics specialists to dissect the molecular signatures of cardiovascular phenotypes.

  • 1128.
    Älgenäs, Cajsa
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Agaton, Charlotta
    Fagerberg, Linn
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Asplund, Anna
    Björling, Lisa
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Björling, Erik
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Kampf, Caroline
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Persson, Anja
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Wester, Kenneth
    Pontén, Fredrik
    Wernerus, Henrik
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ottosson Takanen, Jenny
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Hober, Sophia
    KTH, School of Biotechnology (BIO), Protein Technology.
    Antibody performance in western blot applications is context- dependent2014In: Biotechnology Journal, ISSN 1860-6768, E-ISSN 1860-7314, Vol. 9, no 3, p. 435-445Article in journal (Refereed)
    Abstract [en]

    An important concern for the use of antibodies in various applications, such as western blot (WB) or immunohistochemistry (IHC), is specificity. This calls for systematic validations using well-designed conditions. Here, we have analyzed 13000 antibodies using western blot with lysates from human cell lines, tissues, and plasma. Standardized stratification showed that 45% of the antibodies yielded supportive staining, and the rest either no staining (12%) or protein bands of wrong size (43%). A comparative study of WB and IHC showed that the performance of antibodies is application-specific, although a correlation between no WB staining and weak IHC staining could be seen. To investigate the influence of protein abundance on the apparent specificity of the antibody, new WB analyses were performed for 1369 genes that gave unsupportive WBs in the initial screening using cell lysates with overexpressed full-length proteins. Then, more than 82% of the antibodies yielded a specific band corresponding to the full-length protein. Hence, the vast majority of the antibodies (90%) used in this study specifically recognize the target protein when present at sufficiently high levels. This demonstrates the context- and application-dependence of antibody validation and emphasizes that caution is needed when annotating binding reagents as specific or cross-reactive. WB is one of the most commonly used methods for validation of antibodies. Our data implicate that solely using one platform for antibody validation might give misleading information and therefore at least one additional method should be used to verify the achieved data.

  • 1129. Ågren, Rasmus
    et al.
    Mardinoglu, Adil
    Asplund, Anna
    Kampf, Caroline
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Identification of anticancer drugs for hepatocellular carcinoma through personalized genome-scale metabolic modeling2014In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 10, no 3, p. A721-Article in journal (Refereed)
    Abstract [en]

    Synopsis image Personalized GEMs for six hepatocellular carcinoma patients are reconstructed using proteomics data and a task-driven model reconstruction algorithm. These GEMs are used to predict antimetabolites preventing tumor growth in all patients or in individual patients. The presence of proteins encoded by 15,841 genes in tumors from 27 HCC patients is evaluated by immunohistochemistry. Personalized GEMs for six HCC patients and GEMs for 83 healthy cell types are reconstructed based on HMR 2.0 and the tINIT algorithm for task-driven model reconstruction. 101 antimetabolites are predicted to inhibit tumor growth in all patients. Antimetabolite toxicity is tested using the 83 cell type-specific GEMs. An l-carnitine analog inhibits the proliferation of HepG2 cells. Abstract Genome-scale metabolic models (GEMs) have proven useful as scaffolds for the integration of omics data for understanding the genotype-phenotype relationship in a mechanistic manner. Here, we evaluated the presence/absence of proteins encoded by 15,841 genes in 27 hepatocellular carcinoma (HCC) patients using immunohistochemistry. We used this information to reconstruct personalized GEMs for six HCC patients based on the proteomics data, HMR 2.0, and a task-driven model reconstruction algorithm (tINIT). The personalized GEMs were employed to identify anticancer drugs using the concept of antimetabolites; i.e., drugs that are structural analogs to metabolites. The toxicity of each antimetabolite was predicted by assessing the in silico functionality of 83 healthy cell type-specific GEMs, which were also reconstructed with the tINIT algorithm. We predicted 101 antimetabolites that could be effective in preventing tumor growth in all HCC patients, and 46 antimetabolites which were specific to individual patients. Twenty-two of the 101 predicted antimetabolites have already been used in different cancer treatment strategies, while the remaining antimetabolites represent new potential drugs. Finally, one of the identified targets was validated experimentally, and it was confirmed to attenuate growth of the HepG2 cell line.

  • 1130.
    Åkerborg, Örjan
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Spalinskas, Rapolas
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Pradhananga, Sailendra
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Anil, Anandashankar
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Höjer, Pontus
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Poujade, Flore-Anne
    Karolinska Inst, Cardiovasc Med Unit, Dept Med, Ctr Mol Med, Stockholm, Sweden..
    Folkersen, Lasse
    Tech Univ Denmark, Dept Bioinformat, Copenhagen, Denmark..
    Sahlén, Pelin
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Eriksson, Per
    Karolinska Inst, Cardiovasc Med Unit, Dept Med, Ctr Mol Med, Stockholm, Sweden..
    High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways2019In: Circulation. Genomic and precision medicine, ISSN 2574-8300, Vol. 12, no 3, article id e002353Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Genetic variant landscape of coronary artery disease is dominated by noncoding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct genes both to gain insights into perturbed functions and better assess the risk of disease. METHODS: In this study, we generated high-resolution genomic interaction maps (similar to 750 bases) in aortic endothelial, smooth muscle cells and THP-1 (human leukemia monocytic cell line) macrophages stimulated with lipopolysaccharide using Hi-C coupled with sequence capture targeting 25 429 features, including variants associated with coronary artery disease. We also sequenced their transcriptomes and mapped putative enhancers using chromatin immunoprecipitation with an antibody against H3K27Ac. RESULTS: The regions interacting with promoters showed strong enrichment for enhancer elements and validated several previously known interactions and enhancers. We detected interactions for 727 risk variants obtained by genome-wide association studies and identified novel, as well as established genes and functions associated with cardiovascular diseases. We were able to assign potential target genes for additional 398 genome-wide association studies variants using haplotype information, thereby identifying additional relevant genes and functions. Importantly, we discovered that a subset of risk variants interact with multiple promoters and their expression levels were strongly correlated. CONCLUSIONS: In summary, we present a catalog of candidate genes regulated by coronary artery disease-related variants and think that it will be an invaluable resource to further the investigation of cardiovascular pathologies and disease.

  • 1131.
    Åkesson, Lovisa
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Cellular and Clinical Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mahdessian, Diana
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Cellular and Clinical Proteomics.
    Gnann, Christian
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Cellular and Clinical Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Thul, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Cellular and Clinical Proteomics.
    Lundberg, Emma
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Cellular and Clinical Proteomics.
    Spatial organization of the nucleolar proteome during mitosisManuscript (preprint) (Other academic)
    Abstract [en]

    In the interphase cell, the membrane-less nucleoli are the sites of ribosome biogenesis. As part of the Human Protein Atlas we created an image catalogue comprising 1,314 nucleolar proteins using antibody-based proteomics. We show experimental evidence for 1,027 proteins localizing to the whole nucleoli and 287 to the fibrillar center or dense fibrillar component. We also propose a new sub-compartment located in the nucleoplasmic border denoted as nucleoli rim, comprising at least 131 proteins. As a step toward better understanding of nucleolar protein function during cell division, we additionally generated confocal images of 68 nucleolar proteins being recruited to the chromosomal periphery in mitosis. Thanks to the single cell resolution we were able to define three expression phenotypes among the mitotic chromosome proteins; early, intermediate and late recruitment suggesting phase specific functions. We also for the first time provide a proteome-wide confirmation that the nucleoli in general, but mitotic chromosome proteins in particular have a higher predicted intrinsic disorder level compared to cytoplasmic proteins, indicating that the perichromosomal layer indeed is a liquid-like layer.

  • 1132. Åström, J.A.
    et al.
    Carter, A.
    Hetherington, J.
    Ioakimidis, K.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mozdzynski, G.
    Nash, R. W.
    Schlatter, Philipp
    KTH, School of Engineering Sciences (SCI), Mechanics.
    Signell, A.
    Westerholm, J.
    Preparing scientific application software for exascale computing2013In: Applied Parallel and Scientific Computing: 11th International Conference, PARA 2012, Helsinki, Finland, June 10-13, 2012, Revised Selected Papers / [ed] Pekka Manninen, Per Öster, Springer, 2013, p. 27-42Conference paper (Refereed)
    Abstract [en]

    Many of the most widely used scientifc application software of today were developed largely during a time when the typical amount of compute cores was calculated in tens or hundreds. Within a not too distant future the number of cores will be calculated in at least hundreds of thousands or even millions. A European collaboration group CRESTA has recently been working on a set of renowned scientific software to investigate and develop these codes towards the realm of exascale computing. The codes are ELMFIRE, GROMACS, IFS, HemeLB, NEK5000, and OpenFOAM. This paper contains a summary of the strategies for their development towards exascale and results achieved during the first year of the collaboration project.

20212223 1101 - 1132 of 1132
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