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  • 1501. Wucher, Valentin
    et al.
    Legeai, Fabrice
    Hédan, Benoît
    Rizk, Guillaume
    Lagoutte, Lætitia
    Leeb, Tosso
    Jagannathan, Vidhya
    Cadieu, Edouard
    David, Audrey
    Lohi, Hannes
    Cirera, Susanna
    Fredholm, Merete
    Botherel, Nadine
    Leegwater, Peter A J
    Le Béguec, Céline
    Fieten, Hille
    Johnson, Jeremy
    Alföldi, Jessica
    André, Catherine
    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 Institute of MIT and Harvard, Cambridge, MA, USA.
    Hitte, Christophe
    Derrien, Thomas
    FEELnc: a tool for long non-coding RNA annotation and its application to the dog transcriptome2017Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, nr 8, artikkel-id e57Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Whole transcriptome sequencing (RNA-seq) has become a standard for cataloguing and monitoring RNA populations. One of the main bottlenecks, however, is to correctly identify the different classes of RNAs among the plethora of reconstructed transcripts, particularly those that will be translated (mRNAs) from the class of long non-coding RNAs (lncRNAs). Here, we present FEELnc (FlExible Extraction of LncRNAs), an alignment-free program that accurately annotates lncRNAs based on a Random Forest model trained with general features such as multi k-mer frequencies and relaxed open reading frames. Benchmarking versus five state-of-the-art tools shows that FEELnc achieves similar or better classification performance on GENCODE and NONCODE data sets. The program also provides specific modules that enable the user to fine-tune classification accuracy, to formalize the annotation of lncRNA classes and to identify lncRNAs even in the absence of a training set of non-coding RNAs. We used FEELnc on a real data set comprising 20 canine RNA-seq samples produced by the European LUPA consortium to substantially expand the canine genome annotation to include 10 374 novel lncRNAs and 58 640 mRNA transcripts. FEELnc moves beyond conventional coding potential classifiers by providing a standardized and complete solution for annotating lncRNAs and is freely available at https://github.com/tderrien/FEELnc.

  • 1502. Wulff, Ragna Peterson
    et al.
    Lundqvist, Joakim
    Rutsdottir, Gudrun
    Hansson, Andreas
    Stenbaek, Anne
    Elmlund, Dominika
    KTH, Skolan för teknik och hälsa (STH), Strukturell bioteknik.
    Elmlund, Hans
    Jensen, Poul Erik
    Hansson, Mats
    The Activity of Barley NADPH-Dependent Thioredoxin Reductase C Is Independent of the Oligomeric State of the Protein: Tetrameric Structure Determined by Cryo-Electron Microscopy2011Inngår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 50, nr 18, s. 3713-3723Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Thioredoxin and thioredoxin reductase can regulate cell metabolism through redox regulation of disulfide bridges or through removal of H2O2. These two enzymatic functions are combined in NADPH-dependent thioredoxin reductase C (NTRC), which contains an N-terminal thioredoxin reductase domain fused with a C-terminal thioredoxin domain. Rice NTRC exists in different oligomeric states, depending on the absence or presence of its NADPH cofactor. It has been suggested that the different oligomeric states may have diverse activity. Thus, the redox status of the chloroplast could influence the oligomeric state of NTRC and thereby its activity. We have characterized the oligomeric states of NTRC from barley (Hard rum vulgare L.). This also includes a structural model of the tetrameric NTRC derived from cryo-electron microscopy and single-particle reconstruction. We conclude that the tetrameric NTRC is a dimeric arrangement of two NTRC homodimers. Unlike that of rice NTRC, the quaternary structure of barley NTRC complexes is unaffected by addition of NADPH. The activity of NTRC was tested with two different enzyme assays. The N-terminal part of NTRC was tested in a thioredoxin reductase assay. A peroxide sensitive Mg-protoporphyrin IX monomethyl ester (MPE) cyclase enzyme system of the chlorophyll biosynthetic pathway was used to test the catalytic ability of both the N- and C-terminal parts of NTRC. The different oligomeric assembly states do not exhibit significantly different activities. Thus, it appears that the activities are independent of the oligomeric state of barley NTRC.

  • 1503.
    Wullimann, David
    Högskolan i Skövde, Institutionen för hälsa och lärande.
    Discovery of candidate biomarkers for purification of atrial and ventricular cardiomyocytes derived from human pluripotent stemcells: Version 22017Independent thesis Basic level (degree of Bachelor), 20 poäng / 30 hpOppgave
  • 1504.
    Wuolikainen, Anna
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ahnlund, Maria
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Moritz, Thomas
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Trupp, Miles
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Multi-platform mass spectrometry analysis of the CSF and plasma metabolomes of rigorously matched amyotrophic lateral sclerosis, Parkinson's disease and control subjects2016Inngår i: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 12, nr 4, s. 1287-1298Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) are protein-aggregation diseases that lack clear molecular etiologies. Biomarkers could aid in diagnosis, prognosis, planning of care, drug target identification and stratification of patients into clinical trials. We sought to characterize shared and unique metabolite perturbations between ALS and PD and matched controls selected from patients with other diagnoses, including differential diagnoses to ALS or PD that visited our clinic for a lumbar puncture. Cerebrospinal fluid (CSF) and plasma from rigorously age-, sex- and sampling-date matched patients were analyzed on multiple platforms using gas chromatography (GC) and liquid chromatography (LC)-mass spectrometry (MS). We applied constrained randomization of run orders and orthogonal partial least squares projection to latent structure-effect projections (OPLS-EP) to capitalize upon the study design. The combined platforms identified 144 CSF and 196 plasma metabolites with diverse molecular properties. Creatine was found to be increased and creatinine decreased in CSF of ALS patients compared to matched controls. Glucose was increased in CSF of ALS patients and alpha-hydroxybutyrate was increased in CSF and plasma of ALS patients compared to matched controls. Leucine, isoleucine and ketoleucine were increased in CSF of both ALS and PD. Together, these studies, in conjunction with earlier studies, suggest alterations in energy utilization pathways and have identified and further validated perturbed metabolites to be used in panels of biomarkers for the diagnosis of ALS and PD.

  • 1505.
    Wuttke, Anne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Yu, Qian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tengholm, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Autocrine Signaling Underlies Fast Repetitive Plasma Membrane Translocation of Conventional and Novel Protein Kinase C Isoforms in beta Cells2016Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, nr 29, s. 14986-14995Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PKC signaling has been implicated in the regulation of many cell functions, including metabolism, cell death, proliferation, and secretion. Activation of conventional and novel PKC isoforms is associated with their Ca2+- and/or diacylglycerol (DAG)-dependent translocation to the plasma membrane. In 13 cells, exocytosis of insulin granules evokes brief (<10 s) local DAG elevations ("spiking") at the plasma membrane because of autocrine activation of P2Y(1), purinoceptors by ATP co-released with insulin. Using total internal reflection microscopy, fluorescent protein -tagged PKCs, and signaling biosensors, we investigated whether DAG spiking causes membrane recruitment of PKCs and whether different classes of PKCs show characteristic responses. Glucose stimulation of MINE cells triggered DAG spiking with concomitant repetitive translocation of the novel isoforms PKCI, PKCE, and PKCirp The conventional PKCa, PKCI3I, and PKC beta II isoforms showed a more complex pattern with both rapid and slow translocation. K+ depolarization-induced PKCE translocation entirely mirrored DAG spiking, whereas PKC beta 1 translocation showed a sustained component, reflecting the subplasma membrane Ca2+ concentration ([Ca2+)pm), with additional effect during DAG spikes. Interference with DAG spiking by purinoceptor inhibition prevented intermittent translocation of PKCs and reduced insulin secretion but did not affect [Ca2+]{,1 elevation or sustained PKCAI translocation. The muscarinic agonist carbachol induced pronounced transient PKCi3I translocation and sustained recruitment of PKCE. When rise of [Ca2+](p), was prevented, the carbachol-induced DAG and PKCE responses were somewhat reduced, but PKCI3I translocation was completely abolished. We conclude that exocytosis-induced DAG spikes efficiently recruit both conventional and novel PKCs to the beta cell plasma membrane. PKC signaling is thus implicated in autocrine regulation of beta cell function.

  • 1506.
    Wählby, Carolina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    The quest for multiplexed spatially resolved transcriptional profiling2016Inngår i: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 13, nr 8, s. 623-624Artikkel i tidsskrift (Annet vitenskapelig)
  • 1507.
    Wåhlin-Larsson, Britta
    et al.
    Örebro universitet, Institutionen för hälsovetenskaper.
    Wilkinson, Daniel J.
    MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Division of Medical Sciences and Graduate Entry Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom.
    Strandberg, Emelie
    Örebro universitet, Institutionen för hälsovetenskaper.
    Hosford-Donovan, Adrian
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Atherton, Philip J.
    MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Division of Medical Sciences and Graduate Entry Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom.
    Kadi, Fawzi
    Örebro universitet, Institutionen för hälsovetenskaper.
    Mechanistic Links Underlying the Impact of C-Reactive Protein on Muscle Mass in Elderly2017Inngår i: Cellular Physiology and Biochemistry, ISSN 1015-8987, E-ISSN 1421-9778, Vol. 44, nr 1, s. 267-278Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND/AIMS: Mechanisms underlying the relationship between systemic inflammation and age-related decline in muscle mass are poorly defined. The purpose of this work was to investigate the relationship between the systemic inflammatory marker CRP and muscle mass in elderly and to identify mechanisms by which CRP mediates its effects on skeletal muscle, in-vitro.

    METHODS: Muscle mass and serum CRP level were determined in a cohort of 118 older women (67±1.7 years). Human muscle cells were differentiated into myotubes and were exposed to CRP. The size of myotubes was determined after immunofluorescent staining using troponin. Muscle protein synthesis was assessed using stable isotope tracers and key signalling pathways controlling protein synthesis were determined using western-blotting.

    RESULTS: We observed an inverse relationship between circulating CRP level and muscle mass (β= -0.646 (95% CI: -0.888, -0.405) p<0.05) and demonstrated a reduction (p < 0.05) in the size of human myotubes exposed to CRP for 72 h. We next showed that this morphological change was accompanied by a CRP-mediated reduction (p < 0.05) in muscle protein fractional synthetic rate of human myotubes exposed to CRP for 24 h. We also identified a CRP-mediated increased phosphorylation (p<0.05) of regulators of cellular energy stress including AMPK and downstream targets, raptor and ACC-β, together with decreased phosphorylation of Akt and rpS6, which are important factors controlling protein synthesis.

    CONCLUSION: This work established for the first time mechanistic links by which chronic elevation of CRP can contribute to age-related decline in muscle function.

  • 1508.
    Xiao, Yi
    et al.
    Bioinformatics Research Group School of Engineering and Information Technology The University of New South Wales Canberra, ACT 2600, Australia.
    Pham, Tuan D
    Bioinformatics Research Group School of Engineering and Information Technology The University of New South Wales Canberra, ACT 2600, Australia.
    Chang, Jeff
    Pathology Department Center for Biotechnology and Bioinformatics The Methodist Hospital Research Institute Weill Cornell Medical College Houston, TX 77030, USA.
    Zhou, Xiaobo
    Pathology Department Center for Biotechnology and Bioinformatics The Methodist Hospital Research Institute Weill Cornell Medical College Houston, TX 77030, USA.
    Symmetry-based presentation for stem-cell image segmentation2011Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Cancer stem cells have been isolated from many tumors, including breast, brain, colon, head and neck, lung, pancreas, and prostate tumors. Advances in stem cell biology and animal models help better characterization of cancer stem cells, including the cells of origin, molecular and cellular properties, functions in cancer initiation and development, treatment response, and drug resistance. An important and challenging task in image analysis of stem cells is the image segmentation. A difficulty is to segment aggregated cells that are deformed and occluded. Watershed transform and multiscale morphological operation are the common methods for this purpose, as they are robust against arbitrary shaping and the occlusion of cells. Notwithstanding their high robustness, the two methods are still limited in their applications in the cases with cells suffering perturbations and deformation during cell growth. In this paper, we propose a novel symmetry axis transformation for stem-cell image segmentation. Our algorithm was validated by its comparison with both watershed transform and multiscale morphological operation. Improved segmentation performance in terms of precision (up to 2.2% comparing to watershed; and up to 0.6% comparing to multiscale morphological operation) was achieved using 5197 cell images in which 291 cells are three mutually touching.

  • 1509.
    Xie, Beichen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Nguyen, Phuoc My
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Idevall-Hagren, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Feedback regulation of insulin secretion by extended synaptotagmin-12019Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, nr 4, s. 4716-4728Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Endoplasmic reticulum (ER)-plasma membrane (PM) contacts are dynamic structures with important roles in the regulation of calcium (Ca2+) and lipid homeostasis. The extended synaptotagmins (E-Syts) are ER-localized lipid transport proteins that interact with PM phosphatidylinositol 4,5-bisphosphate in a Ca2+-dependent manner. E-Syts bidirectionally transfer glycerolipids, including diacylglycerol (DAG), between the 2 juxtaposed membranes, but the biologic significance of this transport is still unclear. Using insulin-secreting cells and live-cell imaging, we now show that Ca2+-triggered exocytosis of insulin granules is followed, in sequence, by PM DAG formation and E-Syt1 recruitment. E-Syt1 counteracted the depolarization-induced DAG formation through a mechanism that required both voltage-dependent Ca2+ influx and Ca2+ release from the ER. E-Syt1 knockdown resulted in prolonged accumulation of DAG in the PM, resulting in increased glucose-stimulated insulin secretion. We conclude that Ca2+-triggered exocytosis is temporally coupled to Ca2+-triggered E-Syt1 PM recruitment and removal of DAG to negatively regulate the same process.

  • 1510.
    Xie, Yuan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Bergström, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Jiang, Yiwen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Johansson, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Marinescu, Voichita Dana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Lindberg, Nanna
    Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA..
    Segerman, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Wicher, Grzegorz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Niklasson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Baskaran, Sathishkumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Sreedharan, Smitha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Everlien, Isabelle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Kastemar, Marianne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Hermansson, Annika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Elfineh, Lioudmila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Libard, Sylwia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Holland, Eric Charles
    Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA..
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Forsberg-Nilsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Uhrbom, Lene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes2015Inngår i: EBioMedicine, E-ISSN 2352-3964, Vol. 2, nr 10, s. 1351-1363Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called gliomastem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional sub-types. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.

  • 1511.
    Xiong, Anqi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Kundu, Soumi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Forsberg, Maud
    Xiong, Yuyuan
    Bergström, Tobias
    Ilan, Neta
    Li, Jin-Ping
    Forsberg-Nilsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Heparanase confers a growth advantage to differentiating embryonic stem cells, and enhances their differentiation into oligodendrocytesManuskript (preprint) (Annet vitenskapelig)
  • 1512.
    Xiong, Anqi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Kundu, Soumi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Forsberg, Maud
    Xiong, Yuyuan
    Bergström, Tobias
    Ilan, Neta
    Li, Jin-Ping
    Forsberg-Nilsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Heparanase confers a growth advantage to differentiating embryonic stem cells, and enhances their differentiation into oligodendrocytesManuskript (preprint) (Annet vitenskapelig)
  • 1513.
    Xue-Franzen, Yongtao
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Karolinska Institutet.
    Johnsson, Anna
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Karolinska Intitutet.
    Brodin, David
    Karolinska Institutet.
    Henriksson, Johan
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Karolinska Institutet.
    Bürglin, Thomas R.
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Karolinska Institutet.
    Wright, Anthony P. H.
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Karolinska Institutet.
    Genome-wide characterisation of the Gcn5 histone acetyltransferase in budding yeast during stress adaptation reveals evolutionarily conserved and diverged roles2010Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, artikkel-id 200Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Gcn5 is a transcriptional coactivator with histone cetyltransferase activity that is conserved with regard to structure as ell as its histone substrates throughout the eukaryotes. Gene egulatory networks within cells are thought to be evolutionarily iverged. The use of evolutionarily divergent yeast species, such as S. erevisiae and S. pombe, which can be studied under similar nvironmental conditions, provides an opportunity to examine the nterface between conserved regulatory components and their cellular pplications in different organisms. esults: We show that Gcn5 is important for a common set of stress esponses in evolutionarily diverged yeast species and that the activity f the conserved histone acetyltransferase domain is required. We define group of KCl stress response genes in S. cerevisiae that are pecifically dependent on Gcn5. Gcn5 is localised to many Gcn5-dependent enes including Gcn5 repressed targets such as FLO8. Gcn5 regulates ivergent sets of KCl responsive genes in S. cerevisiae and S. pombe. enome-wide localization studies showed a tendency for redistribution of cn5 during KCl stress adaptation in S. cerevisiae from short genes to he transcribed regions of long genes. An analogous redistribution was ot observed in S. pombe. onclusions: Gcn5 is required for the regulation of divergent sets of Cl stress-response genes in S. cerevisiae and S. pombe even though it s required a common group of stress responses, including the response o KCl. Genes that are physically associated with Gcn5 require its ctivity for their repression or activation during stress adaptation, roviding support for a role of Gcn5 as a corepressor as well as a oactivator. The tendency of Gcn5 to re-localise to the transcribed egions of long genes during KCl stress adaptation suggests that Gcn5 lays a specific role in the expression of long genes under adaptive onditions, perhaps by regulating transcriptional elongation as has been een for Gcn5 in S. pombe. Interestingly an analogous redistribution of cn5 is not seen in S. pombe. The study thus provides important new nsights in relation to why coregulators like Gcn5 are required for the orrect expression of some genes but not others.

  • 1514.
    Xueli, Zhang
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Centre for Systems Biology, Soochow University, Suzhou, China.
    Zhang, Hong
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Shen, Bairong
    Centre for Systems Biology, Soochow University, Suzhou, China.
    Sun, Xiao-Feng
    Department of Oncology and Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Chromogranin-A Expression as a Novel Biomarker for Early Diagnosis of Colon Cancer Patients2019Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, nr 12, artikkel-id 2919Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Colon cancer is one of the major causes of cancer death worldwide. The five-year survival rate for the early-stage patients is more than 90%, and only around 10% for the later stages. Moreover, half of the colon cancer patients have been clinically diagnosed at the later stages. It is; therefore, of importance to enhance the ability for the early diagnosis of colon cancer. Taking advantages from our previous studies, there are several potential biomarkers which have been associated with the early diagnosis of the colon cancer. In order to investigate these early diagnostic biomarkers for colon cancer, human chromogranin-A (CHGA) was further analyzed among the most powerful diagnostic biomarkers. In this study, we used a logistic regression-based meta-analysis to clarify associations of CHGA expression with colon cancer diagnosis. Both healthy populations and the normal mucosa from the colon cancer patients were selected as the double normal controls. The results showed decreased expression of CHGA in the early stages of colon cancer as compared to the normal controls. The decline of CHGA expression in the early stages of colon cancer is probably a new diagnostic biomarker for colon cancer diagnosis with high predicting possibility and verification performance. We have also compared the diagnostic powers of CHGA expression with the typical oncogene KRAS, classic tumor suppressor TP53, and well-known cellular proliferation index MKI67, and the CHGA showed stronger ability to predict early diagnosis for colon cancer than these other cancer biomarkers. In the protein-protein interaction (PPI) network, CHGA was revealed to share some common pathways with KRAS and TP53. CHGA might be considered as a novel, promising, and powerful biomarker for early diagnosis of colon cancer.

  • 1515.
    Yakymovych, Ihor
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Yakymovych, Mariya
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Zang, Guangxiang
    Mu, Yabing
    Bergh, Anders
    Landström, Marene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Heldin, Carl-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    CIN85 modulates TGF beta signaling by promoting the presentation of TGF beta receptors on the cell surface2015Inngår i: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 210, nr 2, s. 319-332Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Members of the transforming growth factor beta (TGF beta) family initiate cellular responses by binding to TGF beta receptor type II (Tf3R11) and type I (TpRI) serine/threonine kinases, whereby Srnad2 and Smad3 are phosphorylated and activated, promoting their association with Smadzi. We report here that T beta RI interacts with the SH3 domains of the adaptor protein CIN85 in response to TGF beta stimulation in a TRAF6-dependent manner. Small interfering RNA mediated knockdown of CIN85 resulted in accumulation of T beta RI in intracellular compartments and diminished TGF beta-stimulated Sniad2 phosphorylation. Overexpression of CIN85 instead increased the amount of T beta RI at the cell surface. This effect was inhibited by a dominant-negative mutant of Rab11, suggesting that CIN85 promoted recycling of TGF beta receptors. CIN85 enhanced TGF beta-stimulated Smad2 phosphorylation, transcriptional responses, and cell migration. CIN85 expression correlated with the degree of malignancy of prostate cancers. Collectively, our results reveal that CIN85 promotes recycling of TGF beta receptors and thereby positively regulates TGF beta signaling.

  • 1516. Yamamoto, Shouji
    et al.
    Mitobe, Jiro
    Ishikawa, Takahiko
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Wai, Sun Nyunt
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Ohnishi, Makoto
    Watanabe, Haruo
    Izumiya, Hidemasa
    Regulation of natural competence by the orphan two-component system sensor kinase ChiS involves a non-canonical transmembrane regulator in Vibrio cholerae2014Inngår i: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 91, nr 2, s. 326-347Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In Vibrio cholerae, 41 chitin-inducible genes, including the genes involved in natural competence for DNA uptake, are governed by the orphan two-component system (TCS) sensor kinase ChiS. However, the mechanism by which ChiS controls the expression of these genes is currently unknown. Here, we report the involvement of a novel transcription factor termed TfoS' in this process. TfoS is a transmembrane protein that contains a large periplasmic domain and a cytoplasmic AraC-type DNA-binding domain, but lacks TCS signature domains. Inactivation of tfoS abolished natural competence as well as transcription of the tfoR gene encoding a chitin-induced small RNA essential for competence gene expression. A TfoS fragment containing the DNA-binding domain specifically bound to and activated transcription from the tfoR promoter. Intracellular TfoS levels were unaffected by disruption of chiS and coexpression of TfoS and ChiS in Escherichia coli recovered transcription of the chromosomally integrated tfoR::lacZ gene, suggesting that TfoS is post-translationally modulated by ChiS during transcriptional activation; however, this regulation persisted when the canonical phosphorelay residues of ChiS were mutated. The results presented here suggest that ChiS operates a chitin-induced non-canonical signal transduction cascade through TfoS, leading to transcriptional activation of tfoR.

  • 1517.
    Yan, Hongji
    et al.
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Div Glycosci,Dept Chem, S-10691 Stockholm, Sweden.
    Seignez, Cedric
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Hjorth, Morgan
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Div Glycosci,Dept Chem, S-10691 Stockholm, Sweden.
    Winkeljann, Benjamin
    Tech Univ Munich, Dept Mech Engn, Boltzmannstr 11, D-85748 Garching, Germany;Tech Univ Munich, Munich Sch Bioengn, Boltzmannstr 11, D-85748 Garching, Germany.
    Blakeley, Matthew
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Div Glycosci,Dept Chem, S-10691 Stockholm, Sweden.
    Lieleg, Oliver
    Tech Univ Munich, Dept Mech Engn, Boltzmannstr 11, D-85748 Garching, Germany;Tech Univ Munich, Munich Sch Bioengn, Boltzmannstr 11, D-85748 Garching, Germany.
    Phillipson, Mia
    Uppsala Univ, Dept Med Cell Biol, Div Integrat Physiol, S-75123 Uppsala, Sweden.
    Crouzier, Thomas
    AlbaNova Univ Ctr, KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Div Glycosci,Dept Chem, S-10691 Stockholm, Sweden.
    Immune-Informed Mucin Hydrogels Evade Fibrotic Foreign Body Response In Vivo2019Inngår i: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 29, nr 46, artikkel-id 1902581Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The immune-mediated foreign body response to biomaterial implants can trigger the formation of insulating fibrotic capsules that can compromise implant function. To address this challenge, the intrinsic bioactivity of the mucin biopolymer, a heavily glycosylated protein that forms the protective mucus gel covering mucosal epithelia, is leveraged. By using a bioorthogonal inverse electron demand Diels-Alder reaction, mucins are crosslinked into implantable hydrogels. It is shown that mucin hydrogels (Muc-gels) modulate the immune response driving biomaterial-induced fibrosis. Muc-gels do not elicit fibrosis 21 days after implantation in the peritoneal cavity of C57Bl/6 mice, whereas medical-grade alginate hydrogels are covered by fibrous tissues. Further, Muc-gels dampen the recruitment of innate and adaptive immune cells to the gel and trigger a pattern of very mild activation marked by a noticeably low expression of the fibrosis-stimulating transforming growth factor beta 1 cytokine. Macrophages recruited to Muc-gels upregulate the gene expression of the protein inhibitor of activated STAT 1 (PIAS1) and SH2-containing phosphatase 1 (SHP-1) cytokine regulatory proteins, which likely contributes to their low cytokine expression profiles. With this advance in mucin materials, an essential tool is provided to better understand mucin bioactivities and to initiate the development of new mucin-based and mucin-inspired "immune-informed" materials for implantable devices subject to fibrotic encapsulation.

  • 1518.
    Yan, Junhong
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    DNA-Assisted Immunoassays for High-Performance Protein Analyses2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Proteins play important roles in most cellular functions, such as, replication, transcription regulation, signal transduction, for catalyzing chemical reaction, etc. Technologies developed to identify proteins rely either on observing their own properties such as charge, size, mass to charge ratio or sequence composition; or on using affinity reagents that recognize specific protein targets. Immunoassays utilizing functionalized affinity reagents are powerful for targeted proteomics. Among them, DNA-assisted immunoassays in which affinity reagents are labeled with DNA molecules, offer some unique advantages.

    In this thesis, I will present works to improve current DNA-assisted immunoassays such as proximity ligation assays (PLA), as well as to take advantage of DNA reactions to adress other problems. In paper I, a new solid support (MBC-Ts) was functionalized with antibodies and used in the solid-phase PLA for detection of VEGF. The assay using MBC-Ts was compared among the commercially available solid supports in different matrices and it was shown to exhibit enhanced limit of detection in complex matrices. In paper II, a two-step protocol was described to prepare high-quality probes used in homogeneous and in situ PLA by purifying DNA-labeled affinity reagents from unconjugated affinity reagents and excess oligonucleotides. In paper III, PLA was applied on a capillary western blotting instrument so that both the sensitivity and specificity of the original assay were improved. In paper IV, a new method was introduced to profile protein components in individual protein complexes by DNA-barcoded antibodies. This method has been used to profile protein complexes such as surface proteins on individual secreted vesicles.

  • 1519.
    Yan, Junhong
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gu, Gucci Jijuan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Jost, Christian
    Hammond, Maria
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Plueckthun, Andreas
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kamali-Moghaddam, Masood
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    A Universal Approach to Prepare Reagents for DNA-Assisted Protein Analysis2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 9, s. e108061-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The quality of DNA-labeled affinity probes is critical in DNA-assisted protein analyses, such as proximity ligation and extension assays, immuno-PCR, and immuno-rolling circle amplification reactions. Efficient, high-performance methods are therefore required for isolation of pure conjugates from reactions where DNA strands have been coupled to antibodies or recombinant affinity reagents. Here we describe a universal, scalable approach for preparing high-quality oligonucleotide-protein conjugates by sequentially removing any unconjugated affinity reagents and remaining free oligonucleotides from conjugation reactions. We applied the approach to generate high-quality probes using either antibodies or recombinant affinity reagents. The purified high-grade probes were used in proximity ligation assays in solution and in situ, demonstrating both augmented assay sensitivity and improved signal-to-noise ratios.

  • 1520.
    Yanagisawa, Akihiro
    et al.
    Kumamoto Univ, Grad Sch Med Sci, Dept Orthopaed Surg, Chuo Ku, Kumamoto 8600811, Japan.;Kumamoto Univ, Grad Sch Med Sci, Dept Neurol, Chuo Ku, 1-1-1 Honjo, Kumamoto 8600811, Japan..
    Ueda, Mitsuharu
    Kumamoto Univ, Grad Sch Med Sci, Dept Neurol, Chuo Ku, 1-1-1 Honjo, Kumamoto 8600811, Japan..
    Sueyoshi, Takanao
    Kumamoto Univ, Grad Sch Med Sci, Dept Orthopaed Surg, Chuo Ku, Kumamoto 8600811, Japan..
    Nakamura, Eiichi
    Kumamoto Univ, Grad Sch Med Sci, Dept Orthopaed Surg, Chuo Ku, Kumamoto 8600811, Japan..
    Tasaki, Masayoshi
    Kumamoto Univ, Grad Sch Med Sci, Dept Neurol, Chuo Ku, 1-1-1 Honjo, Kumamoto 8600811, Japan..
    Suenaga, Genki
    Kumamoto Univ, Grad Sch Med Sci, Dept Neurol, Chuo Ku, 1-1-1 Honjo, Kumamoto 8600811, Japan..
    Motokawa, Hiroaki
    Kumamoto Univ, Grad Sch Med Sci, Dept Neurol, Chuo Ku, 1-1-1 Honjo, Kumamoto 8600811, Japan..
    Toyoshima, Risa
    Kumamoto Univ, Grad Sch Med Sci, Dept Neurol, Chuo Ku, 1-1-1 Honjo, Kumamoto 8600811, Japan..
    Kinoshita, Yumiko
    Kumamoto Univ, Grad Sch Med Sci, Dept Neurol, Chuo Ku, 1-1-1 Honjo, Kumamoto 8600811, Japan..
    Misumi, Yohei
    Kumamoto Univ, Grad Sch Med Sci, Dept Neurol, Chuo Ku, 1-1-1 Honjo, Kumamoto 8600811, Japan..
    Yamashita, Taro
    Kumamoto Univ, Grad Sch Med Sci, Dept Neurol, Chuo Ku, 1-1-1 Honjo, Kumamoto 8600811, Japan..
    Sakaguchi, Mitsuru
    Kumamoto Orthoped Hosp, Chuo Ku, Kumamoto, Japan..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mizuta, Hiroshi
    Kumamoto Univ, Grad Sch Med Sci, Dept Orthopaed Surg, Chuo Ku, Kumamoto 8600811, Japan..
    Ando, Yukio
    Kumamoto Univ, Grad Sch Med Sci, Dept Neurol, Chuo Ku, 1-1-1 Honjo, Kumamoto 8600811, Japan..
    Knee osteoarthritis associated with different kinds of amyloid deposits and the impact of aging on type of amyloid2016Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 23, nr 1, s. 26-32Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyloidosis is a protein conformational disorder in which amyloid fibrils accumulate in the extracellular space and induce organ dysfunction. Recently, two different amyloidogenic proteins, transthyretin (TTR) and apolipoprotein A-I (Apo A-I), were identified in amyloid deposits in knee joints in patients with knee osteoarthritis (OA). However, clinicopathological differences related to those two kinds of amyloid deposits in the knee joint remain to be clarified. Here, we investigated the clinicopathological features related to these knee amyloid deposits associated with knee OA and the biochemical characteristics of the amyloid deposits. We found that all of our patients with knee OA had amyloid deposits in the knee joints, especially in the meniscus, and those deposits were primarily derived from TTR and/or Apo A-I. Some patients with knee OA, however, had unclassified amyloid deposits. One of our interesting observations concerned the different effects of aging on each type of amyloid formed. The frequency of formation of ATTR deposits clearly increased with age, but that of AApo A-I deposits decreased. Furthermore, we found that similar to 16% of patients with knee OA developed ATTR/AApo A-I double deposits in the meniscus. Amyloid deposition may therefore be a common histopathological feature associated with knee OA. Also, aging may induce ATTR formation in the knee joint in elderly patients with knee OA, whereas AApo A-I formation may be inversely correlated with age.

  • 1521.
    Yanamandra, Kiran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Studies of in vivo prostate amyloidosis and autoimmune responses towards amyloid structures in neurodegeneration2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    By using multidisciplinary analysis of CA inclusions in prostate glands of patients diagnosed with prostate cancer, we have revealed that their major components are the amyloid forms of S100A8 and S100A9 proteins associated with numerous inflammatory conditions and types of cancer. We have demonstrated that material closely resembling CA can be produced from S100A8/A9 in vitro and shows the characters of amyloids. This process is facilitated by calcium or zinc, both of which are abundant in ex vivo inclusions. These observations were supported by computational analysis of the S100A8/A9 calcium-dependent aggregation propensity profiles. We have found DNA and proteins from Escherichia coli in CA bodies, suggesting that their formation is likely to be associated with bacterial infection. CA inclusions were also accompanied by the activation of macrophages and by an increase in the concentration of S100A8/A9 in the surrounding tissues, indicating inflammatory reactions. These findings, taken together, suggest a link between bacterial infection, inflammation and amyloid deposition of pro-inflammatory proteins S100A8/A9 in the prostate gland, such that a self-perpetuating cycle can be triggered and may increase the risk of malignancy in the ageing prostate.

    We evaluated the autoimmune reactions to endocrine (insulin) and astrocytical (S100B) biomarkers in the blood sera of PD patients compared with healthy controls. Peripheral immune responses can be sensitive indicators of disease pathology. We found a statistically significant increase of the autoimmune responses to both antigens in patients compared with controls. Heterogeneity of the immune responses observed in patients may reflect the modulating effect of multiple variables associated with neurodegeneration and also changes in the basic mechanisms of individual autoimmune reactivity. We did not detect any pronounced immune reactions towards insulin amyloid fibrils and oligomers in patients, indicating that an amyloid-specific conformational epitope is not involved in immune recognition of this amyloid type. Immune reactions towards S100B and insulin may reflect the neurodegenerative brain damaging processes and impaired insulin homeostasis occurring in PD.

    Generated auto-antibodies towards the major amyloidogenic protein involved in PD Lewy bodies - a-synuclein and its amyloid oligomers and fibrils were measured in the blood sera of early and late PD patients and controls by using ELISA, Western blot and Biacore surface plasmon resonance analyses. We found significantly higher antibody levels towards monomeric a-synuclein in the blood sera of PD patients compared to controls, though the responses decreased with PD progression. There were no noticeable immune responses towards amyloid oligomers, but substantially increased levels of IgGs towards a-synuclein amyloid fibrils both in PD patients and controls, which subsided with the disease progression. Pooled IgGs from PD patients and controls interacted also with amyloid fibrils of Ab (1-40) and hen lysozyme, however the latter were recognized with lower affinity. This suggests that IgGs bind to amyloid conformational epitope, though displaying higher specificity towards human amyloid species associated with neurodegeneration. The findings suggest the protective role of autoimmunity in PD and therefore immune reactions towards PD major amyloid protein - a-synuclein can be used in treatment strategies and in diagnostics, especially in identifying early disease.

  • 1522.
    Yang, Esther H.
    et al.
    Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton AB, Canada.
    Rode, Julia
    Örebro universitet, Institutionen för medicinska vetenskaper. Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton AB, Canada.
    Howlader, Amran
    Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton AB, Canada.
    Eckermann, Marina
    Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton AB, Canada; Ludwig-Maximilians-University, Munich, Germany.
    Santos, Jobette T.
    Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton AB, Canada; University of Toronto, Toronto ON, Canada.
    Armada, Daniel Hernandez
    Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton AB, Canada.
    Zheng, Ruixiang
    Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton AB, Canada.
    Zou, Chunxia
    Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton AB, Canada.
    Cairo, Christopher W.
    Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton AB, Canada.
    Galectin-3 alters the lateral mobility and clustering of β1-integrin receptors2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 10, artikkel-id e0184378Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glycoprotein receptors are influenced by myriad intermolecular interactions at the cell surface. Specific glycan structures may interact with endogenous lectins that enforce or disrupt receptor-receptor interactions. Glycoproteins bound by multivalent lectins may form extended oligomers or lattices, altering the lateral mobility of the receptor and influencing its function through endocytosis or changes in activation. In this study, we have examined the interaction of Galectin-3 (Gal-3), a human lectin, with adhesion receptors. We measured the effect of recombinant Gal-3 added exogenously on the lateral mobility of the alpha 5 beta 1 integrin on HeLa cells. Using single-particle tracking (SPT) we detected increased lateral mobility of the integrin in the presence of Gal-3, while its truncated C-terminal domain (Gal-3C) showed only minor reductions in lateral mobility. Treatment of cells with Gal-3 increased beta 1-integrin mediated migration with no apparent changes in viability. In contrast, Gal-3C decreased both cell migration and viability. Fluorescence microscopy allowed us to confirm that exogenous Gal-3 resulted in reorganization of the integrin into larger clusters. We used a proteomics analysis to confirm that cells expressed endogenous Gal-3, and found that addition of competitive oligosaccharide ligands for the lectin altered the lateral mobility of the integrin. Together, our results are consistent with a Gal-3-integrin lattice model of binding and confirm that the lateral mobility of integrins is natively regulated, in part, by galectins.

  • 1523.
    Yang, Hairu
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Hultmark, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    JAK/STAT and insulin signaling in Drosophila muscles regulate cellular immune responses against parasitoid wasp infectionManuskript (preprint) (Annet vitenskapelig)
  • 1524.
    Yang, Hairu
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Hultmark, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). BioMediTech, University of Tampere, Tampere, Finland.
    Tissue communication in a systemic immune response of Drosophila.2016Inngår i: Fly, ISSN 1933-6942, Vol. 10, nr 3, s. 115-122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several signaling pathways, including the JAK/STAT and Toll pathways, are known to activate blood cells (hemocytes) in Drosophila melanogaster larvae. They are believed to regulate the immune response against infections by parasitoid wasps, such as Leptopilina boulardi, but how these pathways control the hemocytes is not well understood. Here, we discuss the recent discovery that both muscles and fat body take an active part in this response. Parasitoid wasp infection induces Upd2 and Upd3 secretion from hemocytes, leading to JAK/STAT activation mainly in hemocytes and in skeletal muscles. JAK/STAT activation in muscles, but not in hemocytes, is required for an efficient encapsulation of wasp eggs. This suggests that Upd2 and Upd3 are important cytokines, coordinating different tissues for the cellular immune response in Drosophila. In the fat body, Toll signaling initiates a systemic response in which hemocytes are mobilized and activated hemocytes (lamellocytes) are generated. However, the contribution of Toll signaling to the defense against wasps is limited, probably because the wasps inject inhibitors that prevent the activation of the Toll pathway. In conclusion, parasite infection induces a systemic response in Drosophila larvae involving major organ systems and probably the physiology of the entire organism.

  • 1525.
    Yang, Hairu
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Kronhamn, Jesper
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Ekstrom, Jens-Ola
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Korkut, Gul Gizem
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Hultmark, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    JAK/STAT signaling in Drosophila muscles controls the cellular immune response against parasitoid infection2015Inngår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 16, nr 12, s. 1664-1672Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The role of JAK/STAT signaling in the cellular immune response of Drosophila is not well understood. Here, we show that parasitoid wasp infection activates JAK/STAT signaling in somatic muscles of the Drosophila larva, triggered by secretion of the cytokines Upd2 and Upd3 from circulating hemocytes. Deletion of upd2 or upd3, but not the related os (upd1) gene, reduced the cellular immune response, and suppression of the JAK/STAT pathway in muscle cells reduced the encapsulation of wasp eggs and the number of circulating lamellocyte effector cells. These results suggest that JAK/STAT signaling in muscles participates in a systemic immune defense against wasp infection.

  • 1526.
    Yang, Xinping
    et al.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Southern Med Univ, Nanfang Hosp, Dept Obstet & Gynecol, Guangzhou 510515, Guangdong, Peoples R China..
    Coulombe-Huntington, Jasmin
    McGill Univ, Dept Bioengn, Montreal, PQ H3A 0C3, Canada.;Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada..
    Kang, Shuli
    Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA.;Univ So Calif, Dept Biol Sci, Mol & Computat Biol Program, Los Angeles, CA 90089 USA..
    Sheynkman, Gloria M.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Hao, Tong
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Richardson, Aaron
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Sun, Song
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada.;Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada..
    Yang, Fan
    Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada.;Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada..
    Shen, Yun A.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Murray, Ryan R.
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Univ Helsinki, Biomedicum Helsinki 1, FIN-00290 Helsinki, Finland..
    Spirohn, Kerstin
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Begg, Bridget E.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;MIT, Dept Biol, Cambridge, MA 02139 USA..
    Duran-Frigola, Miquel
    Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona 08028, Spain..
    MacWilliams, Andrew
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Tecan US Inc, Morrisville, NC 27560 USA..
    Pevzner, Samuel J.
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA.;Boston Univ, Sch Med, Boston, MA 02118 USA..
    Zhong, Quan
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Wright State Univ, Dept Biol Sci, Dayton, OH 45435 USA..
    Trigg, Shelly A.
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Univ Calif San Diego, Dept Biol Sci, La Jolla, CA 92093 USA..
    Tam, Stanley
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA..
    Ghamsari, Lila
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Genocea Biosci Inc, Cambridge, MA 02140 USA..
    Sahni, Nidhi
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Yi, Song
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Rodriguez, Maria D.
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Cedars Sinai Med Ctr, Biomed Sci & Translat Med, Los Angeles, CA 90048 USA..
    Balcha, Dawit
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Tan, Guihong
    Costanzo, Michael
    Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada..
    Andrews, Brenda
    Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada..
    Boone, Charles
    Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada..
    Zhou, Xianghong J.
    Univ So Calif, Dept Biol Sci, Mol & Computat Biol Program, Los Angeles, CA 90089 USA..
    Salehi-Ashtiani, Kourosh
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;New York Univ Abu Dhabi, Div Sci & Math, Abu Dhabi, U Arab Emirates.;New York Univ Abu Dhabi, Ctr Genom & Syst Biol CGSB, Abu Dhabi, U Arab Emirates..
    Charloteaux, Benoit
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Univ Liege, Unit Anim Genom, GIGA R, B-4000 Liege, Belgium.;Univ Liege, Fac Vet Med, B-4000 Liege, Belgium..
    Chen, Alyce A.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Calderwood, Michael A.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Aloy, Patrick
    Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona 08028, Spain.;ICREA, Barcelona 08010, Catalonia, Spain..
    Roth, Frederick P.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada.;Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada.;Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada..
    Hill, David E.
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Iakoucheva, Lilia M.
    Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA..
    Xia, Yu
    Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;McGill Univ, Dept Bioengn, Montreal, PQ H3A 0C3, Canada..
    Vidal, Marc
    Dana Farber Canc Inst, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA.;Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA.;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing2016Inngår i: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 164, nr 4, s. 805-817Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 1527.
    Yau, Anthony C. Y.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Karolinska Inst, Div Med Inflammat Res, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden.
    Lönnblom, Erik
    Karolinska Inst, Div Med Inflammat Res, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden..
    Zhong, Jianghong
    Karolinska Inst, Div Med Inflammat Res, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden..
    Holmdahl, Rikard
    Karolinska Inst, Div Med Inflammat Res, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden..
    Influence of hydrocarbon oil structure on adjuvanticity and autoimmunity2017Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikkel-id 14998Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mineral oils are extensively used in our daily life, in food, cosmetics, biomedicine, vaccines and in different industrial applications. However, exposure to these mineral oils has been associated with immune adjuvant effects and the development of autoimmune diseases. Here we investigate the structural impacts of the hydrocarbon oil molecules on their adjuvanticity and autoimmunity. First, we showed that hydrocarbon oil molecules with small atomic differences could result in experimental arthritis in DA rats differing in disease severity, incidence, weight change and serum levels of acute phase proteins. Injection of these hydrocarbon oils resulted in the activation, proliferation and elevated expression of Th1 and especially Th17 cytokines by the T cells, which correlate with the arthritogenicity of the T cells. Furthermore, the more arthritogenic hydrocarbon oils resulted in an increased production of autoantibodies against cartilage joint specific, triple-helical type II collagen epitopes. When injected together with ovalbumin, the more arthritogenic hydrocarbon oils resulted in an increased production of alpha beta T cell-dependent anti-ovalbumin antibodies. This study shows the arthritogenicity of hydrocarbon oils is associated with their adjuvant properties with implications to not only arthritis research but also other diseases and medical applications such as vaccines in which oil adjuvants are involved.

  • 1528.
    Yazan, Alfalah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Campylobacter survival under stressconditions encountered between poultry farmand the human intestine2018Independent thesis Advanced level (degree of Master (Two Years)), 30 poäng / 45 hpOppgave
    Abstract [en]

    Campylobacter are probably the most important bacterial pathogen related to food-borne illnesses; specifically, gastroenteritis and diarrheal diseases. These bacteria can be isolated from various environments, but always originate from the intestine of warm blooded animals. Particularly, Campylobacter are found in the intestinal tract of poultry, and due to contamination of poultry meat and also further contamination of other food they can cause human infections. Sometimes this results in larger outbreaks, such as during 2016-2017 in Sweden where thousands of persons got infected by a single strain of Campylobacter jejuni sequence type 918 (ST-918). The same strain was also identified amongst a large number of poultry farms and suspicions were directed towards dirty transport cages for poultry as a main route for transmitting the strain between different farms. Similar scenarios with large outbreaks related to one or two single strains (ST-50 and ST-257) had also been observed in previous years and this raised questions about certain strains being especially adapted to survive outside the intestine. The aim here was to examine whether outbreak strains and other strains of C. jejuni have different potential to resist different stress conditions that may be encountered between the poultry farm and the human intestine.

  • 1529.
    Yeung, Maggie
    et al.
    Karolinska Insitutet, CMB.
    Sofia, Zdunek
    Karolinska Insitutet, CMB.
    Bergmann, Olaf
    Karolinska Insitutet, CMB.
    Bernard, Samuel
    Salehpour, Mehran
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Jonfysik.
    Alkass, Kanar
    Perl, Shira
    Tisdale, John
    Possnert, Göran
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Jonfysik.
    Brundin, Lou
    Druid, Henrik
    Karolinska Insitutet, CMB.
    Frisén, Jonas
    Karolinska Insitutet, CMB.
    Dynamics of Oligodendrocyte Generation and Myelination in the Human Brain2014Inngår i: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 159, nr 4, s. 766-774Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 1530.
    Yewale, Priti Prabhakar
    et al.
    Microbial Diversity Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
    Lokhande, Kiran Bharat
    Bioinformatics Research Laboratory, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
    Sridhar, Aishwarya
    Microbial Diversity Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
    Vaishnav, Monika
    Microbial Diversity Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
    Khan, Faisal Ahmad
    The Life Science Centre-Biology, School of Science and Technology, Örebro University, Sweden.
    Mandal, Abul
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Swamy, Kakumani Venkateswara
    Bioinformatics Research Laboratory, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
    Jass, Jana
    The Life Science Centre-Biology, School of Science and Technology, Örebro University, Sweden.
    Nawani, Neelu
    Microbial Diversity Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
    Molecular profiling of multidrug-resistant river water isolates: insights into resistance mechanism and potential inhibitors2019Inngår i: Environmental science and pollution research international, ISSN 0944-1344, E-ISSN 1614-7499Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Polluted waters are an important reservoir for antibiotic resistance genes and multidrug-resistant bacteria. This report describes the microbial community, antibiotic resistance genes, and the genetic profile of extended spectrum β-lactamase strains isolated from rivers at, Pune, India. ESBL-producing bacteria isolated from diverse river water catchments running through Pune City were characterized for their antibiotic resistance. The microbial community and types of genes which confer antibiotic resistance were identified followed by the isolation of antibiotic-resistant bacteria on selective media and their genome analysis. Four representative isolates were sequenced using next generation sequencing for genomic analysis. They were identified as Pseudomonas aeruginosa, Escherichia coli, and two isolates were Enterobacter cloacae. The genes associated with the multidrug efflux pumps, such as tolC, macA, macB, adeL, and rosB, were detected in the isolates. As MacAB-TolC is an ABC type efflux pump responsible for conferring resistance in bacteria to several antibiotics, potential efflux pump inhibitors were identified by molecular docking. The homology model of their MacB protein with that from Escherichia coli K12 demonstrated structural changes in different motifs of MacB. Molecular docking of reported efflux pump inhibitors revealed the highest binding affinity of compound MC207-110 against MacB. It also details the potential efflux pump inhibitors that can serve as possible drug targets in drug development and discovery. 

  • 1531.
    Ylärinne, Janne
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Production of neocartilage tissues using primary chondrocytes2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Hyaline cartilage is a highly specialized tissue, which plays an important role in the articulating joints of an individual. It provides the joints with a nearly frictionless, impact resisting surface to protect the ends of the articulating bones. Articular cartilage has a poor self-repair capacity and, therefore, it rarely heals back to normal after an injury. Overweight, injuries, overloading and genetic factors may initiate a degenerative disease of the joint called osteoarthritis.

    Osteoarthiritis is a major global public health issue. Currently, the most used treatment for large articular cartilage defects is joint replacement surgery. However, possibilities to replace this highly invasive operation with strategies based on tissue engineering are currently investigated. The idea of the tissue engineering is to optimize the use of the cells, biomaterials and culture conditions to regenerate a new functional tissue for the defect site.

    The goal of this thesis was to manufacture cartilage tissue in cell culture conditions in vitro. Bovine primary chondrocytes isolated from the femoral condyles were used in all the experiments for neocartilage production. The samples were collected for histology, gene expression level quantifications, and analyses of proteoglycan (PG) content and quality. The histological sections were stained for type II collagen and PGs, the quantitative RT-PCR was used to observe the relative expressions of aggrecan, Sox9, procollagen α2(I) and procollagen α1(II) genes. The PGs were quantified using a spectrophotometric method, and agarose gel electrophoresis was used to separate the PGs according to their size.

    In the two first studies, we optimized the culture conditions of in vitro scaffold-free culture technique to produce the native-type hyaline cartilage of a good quality. We found out that high glucose concentration and hypertonic medium at 20% oxygen tension promoted the best hyaline-like neocartilage tissue production. Glucosamine sulfate supplementation, low oxygen tension, 5 mM glucose concentration and a transient TGF-β3 supplementation were not beneficial for the neocartilage formation in the scaffold-free cell culture system.

    In the third study, we used these newly defined, optimized culture conditions to produce the neocartilage tissues in the HyStem™ and the HydroMatrix™ scaffold materials and we compared these tissues to the ones grown as scaffold-free control cultures. We noticed that there was no difference between the controls and the scaffolds, and occasionally the scaffold-free controls had produced better quality cartilage than the ones with the scaffolds. Overall, the neocartilage tissues were of good hyaline-like quality in the third study. Their extracellular matrix contents were close to the native cartilage, although the neotissues lacked the zonal organization typical to the normal articular cartilage. The tissues had the right components, but their ultrastructure differed from the native cartilage.

    In conclusion, we were able to optimize our in vitro neocartilage culture method further, and discovered a good combination of the culture conditions to produce hyaline-like cartilage of good quality. Surprisingly, the scaffold materials were not beneficial for the cartilage formation.

     

  • 1532.
    Ylärinne, Janne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Qu, Chengjuan
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Lammi, Mikko
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). School of Public Health, Health Science Center of Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi’an, P. R. China.
    Comparison of the neocartilages generated in scaffolds and scaffold-free agarose gel supported primary chondrocyte culture: Generation of neocartilage in vitro Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Objective: The present study was conducted to compare the neocartilages generated in scaffolds and scaffold-free, agarose gel-supported primary chondrocyte cultures.

    Design: Six million bovine primary chondrocytes were embedded in HyStem™ or HydroMatrix™ scaffolds, or scaffold-free in chondrocyte culture medium, and then loaded to agarose gel supported culture wells. Neocartilages were grown in the presence of hypertonic high glucose DMEM medium in 37 °C incubator at 20% O2 and 5% CO2 for one, three or six weeks. By the end of culture periods, the formed tissues were analyzed by histological staining for proteoglycans (PGs) and type II collagen, gene expression measurements of chondrocyte-specific genes aggrecan, Sox9 and procollagen α1(II), and procollagen α2(I) were performed using quantitative RT-PCR, and analyses of PG contents and structure were conducted by spectrophotometric and agarose gel electrophoretic methods, respectively.

    Results: The neocartilage generated in scaffold-free cultures appeared slightly bigger in size than in HyStem™- or HydroMatrix™-containing scaffolds. Histology visualized that the PGs and type II collagen were abundantly present in both in scaffold-free and scaffold-containing tissues. The PG content gradually increased following the culture period. However, the mRNA expression levels of the cartilage-specific genes of aggrecan, procollagen α1(II) and Sox9 gradually decreased following culture period, while procollagen α2(I) levels increased.

    Conclusions: After six weeks cultivations, the PG concentrations in neocartilage tissues manufactured with HyStem™ or HydroMatrix™ scaffolds, and in scaffold-free agarose gel-supported cell cultures, were similar to native cartilage. No obvious benefits could be seen on the extracellular matrix assembly in HyStem™ or HydroMatrix™ scaffolds cultures.

  • 1533.
    Ylärinne, Janne
    et al.
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Qu, Chengjuan
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Lammi, Mikko
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Hypertonic conditions enhance cartilage formation in scaffold-free primary chondrocyte cultures2014Inngår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, ISSN 1432-0878, Vol. 358, nr 2, s. 541-550Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The potential of hypertonic conditions at in vivo levels to promote cartilage extracellular matrix accumulation in scaffold-free primary chondrocyte cultures was investigated. Six million bovine primary chondrocytes were cultured in transwell inserts in low glucose (LG), high glucose (HG), or hypertonic high glucose (HHG) DMEM supplemented with fetal bovine serum, antibiotics, and ascorbate under 5 % or 20 % O2 tension with and without transforming growth factor (TGF)-β3 for 6 weeks. Samples were collected for histological staining of proteoglycans (PGs) and type II collagen, analysis by quantitative reverse transcription plus the polymerase chain reaction (RT-PCR) of mRNA expression of aggrecan and procollagen α1 (II) and of Sox9 and procollagen α2 (I), and quantitation of PGs and PG separation in agarose gels. Cartilage tissues produced at 20 % O2 tension were larger than those formed at 5 % O2 tension. Compared with LG, the tissues grew to larger sizes in HG or HHG medium. Histological staining showed the strongest PG and type II collagen staining in cartilage generated in HG or HHG medium at 20 % O2 tension. Quantitative RT-PCR results indicated significantly higher expression of procollagen α1 (II) mRNA in cartilage generated in HHG medium at 20 % O2 tension compared with that in the other samples. TGF-β3 supplements in the culture medium provided no advantage for cartilage formation. Thus, HHG medium used at 20 % O2 tension is the most beneficial combination of the tested culture conditions for scaffold-free cartilage production in vitro and should improve cell culture for research into cartilage repair or tissue engineering.

  • 1534.
    Ylärinne, Janne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Qu, Chengjuan
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Lammi, Mikko
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Xi’an Jiaotong Univ., Xi'an, China.
    HyStemTM and HydroMatrixTM scaffolds for articular cartilage tissue engineering2016Inngår i: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 24, s. S466-S466Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract
  • 1535.
    Yngve, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nordeman, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Estrada, Sergio
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Marklund, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Auberson, Yves
    Novartis Inst BioMed Res, Basel, Switzerland..
    Machauer, Rainer
    Novartis Inst BioMed Res, Basel, Switzerland..
    Briard, Emmanuelle
    Novartis Inst BioMed Res, Basel, Switzerland..
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Tracing BACE: Synthesis and evaluation of beta-secretase inhibitors as ligands for PET imaging2015Inngår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, s. S51-S51Artikkel i tidsskrift (Annet vitenskapelig)
  • 1536.
    Younis, Shady
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Ain Shams Univ, Dept Anim Prod, Cairo 11241, Egypt.
    Kamel, Wael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Falkeborn, Tina
    Linkoping Univ, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden.
    Wang, Hao
    Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden.
    Yu, Di
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Daniels, Robert
    Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden.
    Essand, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Hinkula, Jorma
    Linkoping Univ, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden.
    Akusjärvi, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77483 USA.
    Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth2018Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 16, s. E3808-E3816Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The zinc finger CCCH-type containing 11A (ZC3H11A) gene encodes a well-conserved zinc finger protein that may function in mRNA export as it has been shown to associate with the transcription export (TREX) complex in proteomic screens. Here, we report that ZC3H11A is a stress-induced nuclear protein with RNA-binding capacity that localizes to nuclear splicing speckles. During an adenovirus infection, the ZC3H11A protein and splicing factor SRSF2 relocalize to nuclear regions where viral DNA replication and transcription take place. Knockout (KO) of ZC3H11A in HeLa cells demonstrated that several nuclear-replicating viruses are dependent on ZC3H11A for efficient growth (HIV, influenza virus, herpes simplex virus, and adenovirus), whereas cytoplasmic replicating viruses are not (vaccinia virus and Semliki Forest virus). High-throughput sequencing of ZC3H11A-cross-linked RNA showed that ZC3H11A binds to short purine-rich ribonucleotide stretches in cellular and adenoviral transcripts. We show that the RNA-binding property of ZC3H11A is crucial for its function and localization. In ZC3H11A KO cells, the adenovirus fiber mRNA accumulates in the cell nucleus. Our results suggest that ZC3H11A is important for maintaining nuclear export of mRNAs during stress and that several nuclear-replicating viruses take advantage of this mechanism to facilitate their replication.

  • 1537. Yousefzadeh, Matthew J
    et al.
    Wyatt, David W
    Takata, Kei-Ichi
    Mu, Yunxiang
    Hensley, Sean C
    Tomida, Junya
    Bylund, Göran O
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doublié, Sylvie
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ramsden, Dale A
    McBride, Kevin M
    Wood, Richard D
    Mechanism of suppression of chromosomal instability by DNA polymerase POLQ2014Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, nr 10, s. e1004654-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although a defect in the DNA polymerase POLQ leads to ionizing radiation sensitivity in mammalian cells, the relevant enzymatic pathway has not been identified. Here we define the specific mechanism by which POLQ restricts harmful DNA instability. Our experiments show that Polq-null murine cells are selectively hypersensitive to DNA strand breaking agents, and that damage resistance requires the DNA polymerase activity of POLQ. Using a DNA break end joining assay in cells, we monitored repair of DNA ends with long 3' single-stranded overhangs. End joining events retaining much of the overhang were dependent on POLQ, and independent of Ku70. To analyze the repair function in more detail, we examined immunoglobulin class switch joining between DNA segments in antibody genes. POLQ participates in end joining of a DNA break during immunoglobulin class-switching, producing insertions of base pairs at the joins with homology to IgH switch-region sequences. Biochemical experiments with purified human POLQ protein revealed the mechanism generating the insertions during DNA end joining, relying on the unique ability of POLQ to extend DNA from minimally paired primers. DNA breaks at the IgH locus can sometimes join with breaks in Myc, creating a chromosome translocation. We found a marked increase in Myc/IgH translocations in Polq-defective mice, showing that POLQ suppresses genomic instability and genome rearrangements originating at DNA double-strand breaks. This work clearly defines a role and mechanism for mammalian POLQ in an alternative end joining pathway that suppresses the formation of chromosomal translocations. Our findings depart from the prevailing view that alternative end joining processes are generically translocation-prone.

  • 1538.
    Yu, Di
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Adenovirus for Cancer Therapy: With a Focus on its Surface Modification2013Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Adenovirus serotype 5 (Ad5) is widely used as an oncolytic agent for cancer therapy. However, its infectivity is highly dependent on the expression level of coxsackievirus-adenovirus receptor (CAR) on the surface of tumor cells. We engineered Ad5 virus with the protein transduction domain (PTD) from the HIV-1 Tat protein (Tat-PTD) inserted in the hypervariable region 5 (HVR5) of the hexon protein in the virus capsid. Tat-PTD-modified Ad5 shows a dramatically increased transduction level of CAR-negative cells and bypassed fiber-mediated transduction. It also overcomes the fiber-masking problem, which is caused by release of excess fiber proteins from infected cells. To achieve specific viral replication in neuroblastoma and neuroendocrine tumor cells, we identified the secretogranin III (SCG3) promoter and constructed an adenovirus Ad5PTD(ASH1-SCG3-E1A) wherein E1A gene expression is controlled by the SCG3 promoter and the achaete-scute complex homolog 1 (ASH1) enhancer. This virus shows selective and efficient killing of neuroblastoma cell lines in vitro, and delays human neuroblastoma xenograft tumor growth on nude mice. To further enhance the viral oncolytic efficacy, we also switched the fiber 5 to fiber 35 to generate Ad5PTDf35. This vector shows dramatically increased transduction capacity of primary human cell cultures including hematopoietic cells and their derivatives, pancreatic islets and exocrine cells, mesenchymal stem cells and primary tumor cells including primary cancer initiating cells. Ad5PTDf35-based adenovirus could be a useful platform for gene delivery and oncolytic virus development. Viral oncolysis alone cannot completely eradicate tumors. Therefore, we further armed the Ad5PTDf35-D24 virus with a secreted form of Helicobacter pylori Neutrophil Activating Protein (HP-NAP). Expression of HP-NAP recruits neutrophils to the site of infection, activates an innate immune response against tumor cells and provokes a Th1-type adaptive immune response. Established tumor on nude mice could be completely eradicated in some cases after treatment with this virus and the survival of mice was significantly prolonged.

  • 1539.
    Yue, Bai-Gong
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Regulation of adenovirus alternative pre-mRNA splicing: Functional characterization of exonic and intronic splicing enhancer elements2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Pre-mRNA splicing and alternative pre-mRNA splicing are key regulatory steps controlling geneexpression in higher eukaryotes. The work in this thesis was focused on a characterization of thesignificance of exonic and intronic splicing enhancer elements for pre-mRNA splicing.

    Previous studies have shown that removal of introns with weak and regulated splice sitesrequire a splicing enhancer for activity. Here we extended these studies by demonstrating thattwo "strong" constitutively active introns, the adenovirus 52,55K and the Drosophila Ftzintrons, are absolutely dependent on a downstream splicing enhancer for activity in vitro.

    Two types splicing enhancers were shown to perform redundant functions as activators ofSplicing. Thus, SR protein binding to an exonic splicing enhancer element or U1 snRNP bindingto a downstream 5'splice site independently stimulated upstream intron removal. The datafurther showed that a 5'splice site was more effective and more versatile in activating splicing.Collectively the data suggest that a U1 enhancer is the prototypical enhancer element activatingsplicing of constitutively active introns.

    Adenovirus IIIa pre-mRNA splicing is enhanced more than 200-fold in infected extracts. Themajor enhancer element responsible for this activation was shown to consist of the IIIa branchsite/polypyrimidne tract region. It functions as a Janus element and blocks splicing in extractsfrom uninfected cells while functioning as a splicing enhancer in the context of infected extracts.

    Phosphorylated SR proteins are essential for pre-mRNA splicing. Large amount recombinantSR proteins are needed in splicing studies. A novel expression system was developed to expressphosphorylated, soluble and functionally active ASF/SF2 in E. Coli.

  • 1540. Yuen, Pikkei
    Pushing the limits of antibioticsusceptibility testing: - an image analysis approach2015Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
  • 1541. Zabotina, Olga
    et al.
    Malm, Erik
    KTH, Skolan för bioteknologi (BIO), Glykovetenskap.
    Drakakaki, Georgia
    Bulone, Vincent
    KTH, Skolan för bioteknologi (BIO), Glykovetenskap.
    Raikhel, Natasha
    Identification and Preliminary Characterization of a New Chemical Affecting Glucosyltransferase Activities Involved in Plant Cell Wall Biosynthesis2008Inngår i: MOLECULAR PLANT, ISSN 1674-2052, Vol. 1, nr 6, s. 977-989Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chemical genetics as a part of chemical genomics is a powerful and fast developing approach to dissect biological processes that may be difficult to characterize using conventional genetics because of gene redundancy or lethality and, in the case of polysaccharide biosynthesis, plant flexibility. Polysaccharide synthetic enzymes are located in two main compartments-the Golgi apparatus and plasma membrane-and can be studied in vitro using membrane fractions. Here, we first developed a high-throughput assay that allowed the screening of a library of chemicals with a potential effect on glycosyltransferase activities. Out of the 4800 chemicals screened for their effect on Golgi glucosyltransferases, 66 compounds from the primary screen had an effect on carbohydrate biosynthesis. Ten of these compounds were confirmed to inhibit glucose incorporation after a second screen. One compound exhibiting a strong inhibition effect (ID 6240780 named chemical A) was selected and further studied. it reversibly inhibits the transfer of glucose from UDPglucose by Golgi membranes, but activates the plasma membrane-bound callose synthase. The inhibition effect is dependent on the chemical structure of the compound, which does not affect endomembrane morphology of the plant cells, but causes changes in cell wall composition. Chemical A represents a novel drug with a great potential for the study of the mechanisms of Golgi and plasma membrane-bound glucosyltransferases.

  • 1542. Zamani, Leila
    et al.
    Lundqvist, Magnus
    Zhang, Ye
    Åberg, Magnus
    Edfors, Fredrik
    Bidkhori, Gholamreza
    Lindahl, Anna
    Mie, Axel
    Mardinoglu, Adil
    Rockberg, Johan
    Chotteau, Veronique
    High cell density perfusion culture has a maintained exoproteome and metabolomeManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Chinese hamster ovary (CHO) cells are the workhorse to produce recombinant proteins in the biopharmaceutical industry using mammalian cells and are commonly cultured in either fed-batch or perfusion mode. The optimization of the complex biological systems used in such processes is extremely challenging. Multi-omics approaches can reveal otherwise unknown characteristics of these systems and identify culture parameters that can be manipulated to optimize the cultivation process. Here we have ap- plied both metabolomic and proteomic profiling to a monoclonal antibody (mAb) production operated in perfusion mode to explore how cell biology and reactor environment change as the cell density reaches ≥ 200 x 106 cells/mL. The extracellular metabolic composition obtained in perfusion mode was also com- pared to fed-batch, which showed a more stable profile for perfusion despite a far larger range of viable cell densities. The proteomics data showed an increase of structural proteins as the cell density increased, and both the proteomic and metabolic results showed signs of oxidative stress and changes in glutathione metabolism at very high cell densities. The methodology presented herein could be a powerful tool for optimizing cultivation processes and recombinant protein production.

  • 1543.
    Zamani, Neda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sundström, Görel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Meadows, Jennifer R. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Höppner, Marc P.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dainat, Jacques
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lantz, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Haas, Brian J.
    Grabherr, Manfred G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    A universal genomic coordinate translator for comparative genomics2014Inngår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 15, s. 227-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Genomic duplications constitute major events in the evolution of species, allowing paralogous copies of genes to take on fine-tuned biological roles. Unambiguously identifying the orthology relationship between copies across multiple genomes can be resolved by synteny, i.e. the conserved order of genomic sequences. However, a comprehensive analysis of duplication events and their contributions to evolution would require all-to-all genome alignments, which increases at N-2 with the number of available genomes, N. Results: Here, we introduce Kraken, software that omits the all-to-all requirement by recursively traversing a graph of pairwise alignments and dynamically re-computing orthology. Kraken scales linearly with the number of targeted genomes, N, which allows for including large numbers of genomes in analyses. We first evaluated the method on the set of 12 Drosophila genomes, finding that orthologous correspondence computed indirectly through a graph of multiple synteny maps comes at minimal cost in terms of sensitivity, but reduces overall computational runtime by an order of magnitude. We then used the method on three well-annotated mammalian genomes, human, mouse, and rat, and show that up to 93% of protein coding transcripts have unambiguous pairwise orthologous relationships across the genomes. On a nucleotide level, 70 to 83% of exons match exactly at both splice junctions, and up to 97% on at least one junction. We last applied Kraken to an RNA-sequencing dataset from multiple vertebrates and diverse tissues, where we confirmed that brain-specific gene family members, i.e. one-to-many or many-to-many homologs, are more highly correlated across species than single-copy (i.e. one-to-one homologous) genes. Not limited to protein coding genes, Kraken also identifies thousands of newly identified transcribed loci, likely non-coding RNAs that are consistently transcribed in human, chimpanzee and gorilla, and maintain significant correlation of expression levels across species. Conclusions: Kraken is a computational genome coordinate translator that facilitates cross-species comparisons, distinguishes orthologs from paralogs, and does not require costly all-to-all whole genome mappings. Kraken is freely available under LPGL from http://github.com/nedaz/kraken.

  • 1544.
    Zamotin, Vladimir
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gharibyan, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gibanova, NV
    Lavrikova, MA
    Dolgikh, DA
    Kirpichnikov, MP
    Kostanyan, IA
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Cytotoxicity of albebetin oligomers depends on cross-beta-sheet formation2006Inngår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 580, nr 10, s. 2451-2457Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Prefibrillar cytotoxicity was suggested as a common amyloid characteristic. We showed two types of albebetin prefibrillar oligomers are formed during incubation at pH 7.3. Initial round-shaped oligomers consist of 10–15 molecules determined by atomic force microscopy, do not bind thioflavin-T and do not affect viability of granular neurons and SH-SY5Y cells. They are converted into ca. 30–40-mers possessing cross-β-sheet and reducing viability of neuronal cells. Neither monomers nor fibrils possess cytotoxicity. We suggest that oligomeric size is important for stabilising cross-β-sheet core critical for cytotoxicity. As albebetin was used as a carrier-protein for drug delivery, examination of amyloidogenicity is required prior polypeptide biomedical applications.

  • 1545.
    Zanchi, Davide
    et al.
    Univ Hosp Geneva, Dept Imaging & Med Informat, Geneva, Switzerland.;Univ Geneva, Fac Med, CH-1211 Geneva 4, Switzerland..
    Brody, Arthur L.
    Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90024 USA.;VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA USA.;VA Greater Los Angeles Healthcare Syst, Dept Res, Los Angeles, CA USA..
    Montandon, Marie-Louise
    Univ Hosp Geneva, Dept Imaging & Med Informat, Geneva, Switzerland.;Univ Geneva, Fac Med, CH-1211 Geneva 4, Switzerland..
    Kopel, Rotem
    Univ Hosp Geneva, Dept Imaging & Med Informat, Geneva, Switzerland.;Univ Geneva, Fac Med, CH-1211 Geneva 4, Switzerland.;Ecole Polytech Fed Lausanne, Inst Bioengn, CH-1015 Lausanne, Switzerland..
    Emmert, Kirsten
    Univ Hosp Geneva, Dept Imaging & Med Informat, Geneva, Switzerland.;Univ Geneva, Fac Med, CH-1211 Geneva 4, Switzerland..
    Preti, Maria Giulia
    Univ Hosp Geneva, Dept Imaging & Med Informat, Geneva, Switzerland.;Univ Geneva, Fac Med, CH-1211 Geneva 4, Switzerland.;Ecole Polytech Fed Lausanne, Inst Bioengn, CH-1015 Lausanne, Switzerland..
    Van de Ville, Dimitri
    Univ Hosp Geneva, Dept Imaging & Med Informat, Geneva, Switzerland.;Univ Geneva, Fac Med, CH-1211 Geneva 4, Switzerland.;Ecole Polytech Fed Lausanne, Inst Bioengn, CH-1015 Lausanne, Switzerland..
    Haller, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Univ Geneva, Fac Med, CH-1211 Geneva 4, Switzerland.;Univ Hosp Freiburg, Dept Neuroradiol, Freiburg, Germany.;Affidea Ctr Diagnost Radiol Carouge CDRC, Geneva, Switzerland..
    Cigarette smoking leads to persistent and dose-dependent alterations of brain activity and connectivity in anterior insula and anterior cingulate2015Inngår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 20, nr 6, s. 1033-1041Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although many smokers try to quit smoking, only about 20-25 percent will achieve abstinence despite 6months or more of gold-standard treatment. This low success rate suggests long-term changes in the brain related to smoking, which remain poorly understood. We compared ex-smokers to both active smokers and non-smokers using functional magnetic resonance imaging (fMRI) to explore persistent modifications in brain activity and network organization. This prospective and consecutive study includes 18 non-smokers (29.5 +/- 6.7years of age, 11 women), 14 smokers (10 cigarettes a day >2years of smoking, 29.3 +/- 6.0years of age, 10 women) and 14 ex-smokers (>1year of quitting 30.5 +/- 5.7years of age, 10 women). Participants underwent a block-design fMRI study contrasting smoking cue with control (neutral cue) videos. Data analyses included task-related general linear model, seed-based functional connectivity, voxel-based morphometry (VBM) of gray matter and tract-based spatial statistics (TBSS) of white matter. Smoking cue videos versus control videos activated the right anterior insula in ex-smokers compared with smokers, an effect correlating with cumulative nicotine intake (pack-years). Moreover, ex-smokers had a persistent decrease in functional connectivity between right anterior insula and anterior cingulate cortex (ACC) compared with control participants, but similar to active smokers. Potentially confounding alterations in gray or white matter were excluded in VBM and TBSS analyses. In summary, ex-smokers with long-term nicotine abstinence have persistent and dose-dependent brain network changes notably in the right anterior insula and its connection to the ACC.

  • 1546.
    Zandian, Arash
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Forsström, Björn
    KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Häggmark-Månberg, Anna
    Schwenk, Jochen M.
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101). KTH, Skolan för bioteknologi (BIO), Nanobioteknologi (stängd 20130101). KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Nilsson, Peter
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Ayoglu, Burcu
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Whole-Proteome Peptide Microarrays for Profiling Autoantibody Repertoires within Multiple Sclerosis and Narcolepsy2017Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 16, nr 3, s. 1300-1314Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The underlying molecular mechanisms of autoimmune diseases are poorly understood. To unravel the autoimmune processes across diseases, comprehensive and unbiased analyses of proteins targets recognized by the adaptive immune system are needed. Here we present an approach starting from high-density peptide arrays to characterize autoantibody repertoires and to identify new autoantigens. A set of ten plasma and serum samples from subjects with multiple sclerosis, narcolepsy, and without any disease diagnosis were profiled on a peptide array representing the whole proteome, hosting 2.2 million 12-mer peptides with a six amino acid lateral shift. On the basis of the IgG reactivities found on these whole-proteome peptide micro arrays, a set of 23 samples was then studied on a targeted array with 174 000 12-mer peptides of single amino acid lateral shift. Finally, verification of IgG reactivities was conducted with a larger sample set (n = 448) using the bead-based peptide microarrays. The presented workflow employed three different peptide microarray formats to discover and resolve the epitopes of human autoantibodies and revealed two potentially new autoantigens: MAP3K7 in multiple sclerosis and NRXN1 in narcolepsy. The presented strategy provides insights into antibody repertoire reactivity at a peptide level and may accelerate the discovery and validation of autoantigens in human diseases.

  • 1547. Zeiai, S.
    et al.
    Zhao, J.
    Ekblad, A.
    Nordenskjold, A.
    Hilborn, Jöns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
    Gotherstrom, C.
    Fossum, M.
    From bone marrow to an autologous urothelium-PCL-collagen transplant2014Inngår i: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 8, s. 294-295Artikkel i tidsskrift (Annet vitenskapelig)
  • 1548.
    Zelenin, Sergey
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Hansson, Jonas
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Ardabili, Sahar
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Ramachandraiah, Harisha
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Brismar, Hjalmar
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Cellens fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Russom, Aman
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Microfluidic-based isolation of bacteria from whole blood for sepsis diagnostics2015Inngår i: Biotechnology letters, ISSN 0141-5492, E-ISSN 1573-6776, Vol. 37, nr 4, s. 825-830Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Blood-stream infections (BSI) remain a major health challenge, with an increasing incidence worldwide and a high mortality rate. Early treatment with appropriate antibiotics can reduce BSI-related morbidity and mortality, but success requires rapid identification of the infecting organisms. The rapid, culture-independent diagnosis of BSI could be significantly facilitated by straightforward isolation of highly purified bacteria from whole blood. We present a microfluidic-based, sample-preparation system that rapidly and selectively lyses all blood cells while it extracts intact bacteria for downstream analysis. Whole blood is exposed to a mild detergent, which lyses most blood cells, and then to osmotic shock using deionized water, which eliminates the remaining white blood cells. The recovered bacteria are 100 % viable, which opens up possibilities for performing drug susceptibility tests and for nucleic-acid-based molecular identification.

  • 1549. Zhang, Li-Fang
    et al.
    Yang, Hao-Meng
    Cui, Su-Xia
    Hu, Jia
    Wang, Jie
    Kuang, Ting-Yun
    Norling, Birgitta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Huang, Fang
    Proteomic analysis of plasma membranes of cyanobacterium Synechocystis sp. Strain PCC 6803 in response to high pH stress.2009Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 8, nr 6, s. 2892-902Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cyanobacteria are unique prokaryotes possessing plasma-, outer- and thylakoid membranes. The plasma membrane of a cyanobacterial cell serves as a crucial barrier against its environment and is essential for biogenesis of cyanobacterial photosystems. Previously, we have identified 79 different proteins in the plasma membrane of Synechocystis sp. Strain PCC 6803 based on 2D- and 1D- gels and MALDI-TOF MS. In this work, we have performed a proteomic study screening for high-pH-stress proteins in Synechocystis. 2-D gel profiles of plasma membranes isolated from both control and high pH-treated cells were constructed and compared quantitatively based on different protein staining methods including DIGE analysis. A total of 55 differentially expressed protein spots were identified using MALDI-TOF MS and MALDI-TOF/TOF MS, corresponding to 39 gene products. Twenty-five proteins were enhanced/induced and 14 reduced by high pH. One-third of the enhanced/induced proteins were transport and binding proteins of ABC transporters including 3 phosphate transport proteins. Other proteins include MinD involved in cell division, Cya2 in signaling and proteins involved in photosynthesis and respiration. Furthermore, among these proteins regulated by high pH, eight were found to be hypothetical proteins. Functional significance of the high-pH-stress proteins is discussed integrating current knowledge on cyanobacterial cell physiology.

  • 1550.
    Zhang, Lu
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ding, Zhoujie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Heyman, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    IgG3-antigen complexes are deposited on follicular dendritic cells in the presence of C1q and C32017Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikkel-id 5400Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    IgG3, passively administered together with small proteins, induces enhanced primary humoral responses against these proteins. We previously found that, within 2 h of immunization, marginal zone (MZ) B cells capture IgG3-antigen complexes and transport them into splenic follicles and that this requires the presence of complement receptors 1 and 2. We have here investigated the localization of IgG3 anti-2, 4, 6-trinitrophenyl (TNP)/biotin-ovalbumin-TNP immune complexes in the follicles and the involvement of classical versus total complement activation in this process. The majority (50-90%) of antigen inside the follicles of mice immunized with IgG3-antigen complexes co-localized with the follicular dendritic cell (FDC) network. Capture of antigen by MZ B cells as well as antigen deposition on FDC was severely impaired in mice lacking C1q or C3, and lack of either C1q or C3 also impaired the ability of IgG3 to enhance antibody responses. Finally, IgG3 efficiently primed for a memory response against small proteins as well as against the large protein keyhole limpet hemocyanine.

2829303132 1501 - 1550 of 1580
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