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  • 1. Acero Sanchez, Josep Ll.
    et al.
    Joda, Hamdi
    Henry, Olivier Y. F.
    Solnestam, Beata W.
    Kvastad, Linda
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sahlén, Pelin
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Laddach, Nadja
    Ramakrishnan, Dheeraj
    Riley, Ian
    Schwind, Carmen
    Latta, Daniel
    O'Sullivan, Ciara K.
    Electrochemical Genetic Profiling of Single Cancer Cells2017In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 89, no 6, p. 3378-3385Article in journal (Refereed)
    Abstract [en]

    Recent understandings in the development and spread of cancer have led to the realization of novel single cell analysis platforms focused on circulating tumor cells (CTCs). A simple, rapid, and inexpensive analytical platform capable of providing genetic information on these rare cells is highly desirable to support clinicians and researchers alike to either support the selection or adjustment of therapy or provide fundamental insights into cell function and cancer progression mechanisms. We report on the genetic profiling of single cancer cells, exploiting a combination of multiplex ligation-dependent probe amplification (MLPA) and electrochemical detection. Cells were isolated using laser capture and lysed, and the mRNA was extracted and transcribed into DNA. Seven markers were amplified by MLPA, which allows for the simultaneous amplification of multiple targets with a single primer pair, using MLPA probes containing unique barcode sequences. Capture probes complementary to each of these barcode sequences were immobilized on a printed circuit board (PCB) manufactured electrode array and exposed to single-stranded MLPA products and subsequently to a single stranded DNA reporter probe bearing a HRP molecule, followed by substrate addition and fast electrochemical pulse amperometric detection. We present asimple, rapid, flexible, and inexpensive approach for the simultaneous quantification of multiple breast cancer related mRNA markers, with single tumor cell sensitivity.

  • 2. Ahmad, Yasmeen
    et al.
    Boisvert, Francois-Michel
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lamond, Angus I.
    Systematic Analysis of Protein Pools, Isoforms, and Modifications Affecting Turnover and Subcellular Localization2012In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 11, no 3Article in journal (Refereed)
    Abstract [en]

    In higher eukaryotes many genes encode protein isoforms whose properties and biological roles are often poorly characterized. Here we describe systematic approaches for detection of either distinct isoforms, or separate pools of the same isoform, with differential biological properties. Using information from ion intensities we have estimated protein abundance levels and using rates of change in stable isotope labeling with amino acids in cell culture isotope ratios we measured turnover rates and subcellular distribution for the HeLa cell proteome. Protein isoforms were detected using three data analysis strategies that evaluate differences between stable isotope labeling with amino acids in cell culture isotope ratios for specific groups of peptides within the total set of peptides assigned to a protein. The candidate approach compares stable isotope labeling with amino acids in cell culture isotope ratios for predicted isoform- specific peptides, with ratio values for peptides shared by all the isoforms. The rule of thirds approach compares the mean isotope ratio values for all peptides in each of three equal segments along the linear length of the protein, assessing differences between segment values. The three in a row approach compares mean isotope ratio values for each sequential group of three adjacent peptides, assessing differences with the mean value for all peptides assigned to the protein. Protein isoforms were also detected and their properties evaluated by fractionating cell extracts on one- dimensional SDS- PAGE prior to trypsin digestion and MS analysis and independently evaluating isotope ratio values for the same peptides isolated from different gel slices. The effect of protein phosphorylation on turnover rates was analyzed by comparing mean turnover values calculated for all peptides assigned to a protein, either including, or excluding, values for cognate phosphopeptides. Collectively, these experimental and analytical approaches provide a framework for expanding the func- tional annotation of the genome.

  • 3. Ahmed, Mona
    et al.
    Cerroni, Barbara
    Razuvaev, Anton
    Härmark, Johan
    KTH, School of Technology and Health (STH).
    Paradossi, Gaio
    Caidahl, Kenneth
    Gustafsson, Bjorn
    Cellular Uptake of Plain and SPION-Modified Microbubbles for Potential Use in Molecular Imaging2017In: Cellular and Molecular Bioengineering, ISSN 1865-5025, E-ISSN 1865-5033, Vol. 10, no 6, p. 537-548Article in journal (Refereed)
    Abstract [en]

    Both diagnostic ultrasound (US) and magnetic resonance imaging (MRI) accuracy can be improved by using contrast enhancement. For US gas-filled microbubbles (MBs) or silica nanoparticles (SiNPs), and for MRI superparamagnetic or paramagnetic agents, contribute to this. However, interactions of MBs with the vascular wall and cells are not fully known for all contrast media. We studied the in vitro interactions between three types of non-targeted air-filled MBs with a polyvinyl-alcohol shell and murine macrophages or endothelial cells. The three MB types were plain MBs and two types that were labelled (internally and externally) with superparamagnetic iron oxide nanoparticles (SPIONs) for US/MRI bimodality. Cells were incubated with MBs and imaged by microscopy to evaluate uptake and adhesion. Interactions were quantified and the MB internalization was confirmed by fluorescence quenching of non-internalized MBs. Macrophages internalized each MB type within different time frames: plain MBs 6 h, externally labelled MBs 25 min and internally labelled MBs 2 h. An average of 0.14 externally labelled MBs per cell were internalized after 30 min and 1.34 after 2 h; which was 113% more MBs than the number of internalized internally labelled MBs. The macrophages engulfed these three differently modified new MBs at various rate, whereas endothelial cells did not engulf MBs. Polyvinyl-alcohol MBs are not taken up by endothelial cells. The MB uptake by macrophages is promoted by SPION labelling, in particular external such, which may be important for macrophage targeting.

  • 4.
    Ahrenstedt, Lage
    et al.
    KTH, School of Biotechnology (BIO). KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Olksanen, Antti
    VTT Technical Research Centre of Finland.
    Salmien, Kristian
    VTT Technical Research Centre of Finland.
    Brumer, Harry
    KTH, School of Biotechnology (BIO), Glycoscience. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Paper dry strength improvement by xyloglucan addition: Wet-end application, spray coating and synergism with borate2008In: Holzforschung, ISSN 0018-3830, E-ISSN 1437-434X, Vol. 62, no 1, p. 8-14Article in journal (Refereed)
    Abstract [en]

    The polysaccharide xyloglucan as a wet-end additive improves paper properties. In the present study, paper strength improvement was analysed for dry handsheets made from chemical, mechanical and recycled pulps coated with xyloglucan in a spray application. Results are compared with sheets made from the same pulps treated with xyloglucan in the wet-end. Kraft pulp handsheets of bleached hardwood and softwood showed significant improvements of tensile, tear and Z-strength by xyloglucan spray treatment versus wet-end application, whereas handsheets of de-inked and thermomechanical pulp were improved only slightly. In both wet-end and spray applications, the effect of xyloglucan addition was intimately related to the presence of non-cellulosic components on the fibre surface. Further strength improvements were obtained for chemical pulps by addition of borax to the spray solution, which were likely to be due to the formation of borate-mediated xyloglucan cross-links. Spray coating of xyloglucan, with or without borax, thus represents a potential new application of this polysaccharide to increase paper dry strength.

  • 5. Albèr, C.
    et al.
    Brandner, B. D.
    Björklund, S.
    Billsten, P.
    Corkery, Robert
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Applied Physical Chemistry.
    Engblom, J.
    Effects of water gradients and use of urea on skin ultrastructure evaluated by confocal Raman microspectroscopy2013In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1828, no 11, p. 2470-2478Article in journal (Refereed)
    Abstract [en]

    The rather thin outermost layer of the mammalian skin, stratum corneum (SC), is a complex biomembrane which separates the water rich inside of the body from the dry outside. The skin surface can be exposed to rather extreme variations in ambient conditions (e.g. water activity, temperature and pH), with potential effects on the barrier function. Increased understanding of how the barrier is affected by such changes is highly relevant for regulation of transdermal uptake of exogenous chemicals. In the present study we investigate the effect of hydration and the use of a well-known humectant, urea, on skin barrier ultrastructure by means of confocal Raman microspectroscopy. We also perform dynamic vapor sorption (DVS) microbalance measurements to examine the water uptake capacity of SC pretreated with urea. Based on novel Raman images, constructed from 2D spectral maps, we can distinguish large water inclusions within the skin membrane exceeding the size of fully hydrated corneocytes. We show that these inclusions contain water with spectral properties similar to that of bulk water. The results furthermore show that the ambient water activity has an important impact on the formation of these water inclusions as well as on the hydration profile across the membrane. Urea significantly increases the water uptake when present in skin, as compared to skin without urea, and it promotes formation of larger water inclusions in the tissue. The results confirm that urea can be used as a humectant to increase skin hydration.

  • 6.
    Al-Khalili, Lubna
    et al.
    KTH, School of Biotechnology (BIO), Industrial Biotechnology.
    de Castro Barbosa, T.
    Östling, J.
    Massart, J.
    Katayama, M.
    Nyström, A. -C
    Oscarsson, J.
    Zierath, J. R.
    Profiling of human myotubes reveals an intrinsic proteomic signature associated with type 2 diabetes2014In: Translational Proteomics, ISSN 2212-9634, Vol. 2, no 1, p. 25-38Article in journal (Refereed)
    Abstract [en]

    The development of insulin resistance and type 2 diabetes (T2D) involves a complex array of metabolic defects in skeletal muscle. An in vitro cell culture system excludes the acute effects of external systemic factors existing in vivo. Thus, we aimed to determine whether intrinsic differences in the protein profile exist in cultured myotubes derived from T2D versus normal glucose tolerant (NGT) healthy people. Applying two dimensional difference gel electrophoresis technology (2-D DIGE), the abundance of 47 proteins differed in myotubes derived from T2D patients versus NGT donors. Proteins involved in fatty acid and amino acid metabolism, TCA cycle, mitochondrial function, mRNA processing, DNA repair and cell survival showed higher abundance, while proteins associated with redox signaling (PARK7; Parkinson disease 7), glutathione metabolism (glutathione S-transferase, GST, isoforms T1, P1 and M2), and protein dynamics (heat shock protein, HSP, isoform B1 and 90A) showed reduced abundance in myotubes derived from T2D versus NGT donors. Consistent with our proteome analysis results, the level of total glutathione was reduced in myotubes obtained from T2D versus NGT donors. Taken together, our data provide evidence for intrinsic differences in the profile of proteins involved in energy metabolism, cellular oxidative stress, protein dynamics and gene regulation in myotubes derived from T2D patients. These differences thereby suggest a genetic or epigenetic influence on protein content level, which can be further investigated to understand the molecular underpinnings of T2D progression and lead to new therapeutic approaches.

  • 7. Altai, M.
    et al.
    Westerlund, Kristina
    KTH, School of Biotechnology (BIO), Protein Technology.
    Velletta, J.
    Honarvar, H.
    Orlova, A.
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, V.
    Comparative evaluation of Lu-177-HP2 and In-111-HP2, secondary agents for affibody-based PNA-mediated radionuclide pretargeting2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S237-S237Article in journal (Refereed)
  • 8. Alvarez, Francisco J.
    et al.
    Ryman, Kicki
    Hooijmaijers, Cornelis
    KTH, School of Biotechnology (BIO), Glycoscience.
    Bulone, Vincent
    KTH, School of Biotechnology (BIO), Glycoscience.
    Ljungdahl, Per O.
    Diverse Nitrogen Sources in Seminal Fluid Act in Synergy To Induce Filamentous Growth of Candida albicans2015In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 81, no 8, p. 2770-2780Article in journal (Refereed)
    Abstract [en]

    The pathogenic fungus Candida albicans is the leading cause of vulvovaginal candidiasis (VVC). VVC represents a major quality- of-life issue for women during their reproductive years, a stage of life where the vaginal epithelium is subject to periodic hormonally induced changes associated with menstruation and concomitant exposure to serum as well as potential intermittent contact with seminal fluid. Seminal fluid potently triggers Candida albicans to switch from yeastlike to filamentous modes of growth, a developmental response tightly linked to virulence. Conversely, vaginal fluid inhibits filamentation. Here, we used artificial formulations of seminal and vaginal fluids that faithfully mimic genuine fluids to assess the contribution of individual components within these fluids to filamentation. The high levels of albumin, amino acids, and N-acetylglucosamine in seminal fluid act synergistically as potent inducers of filamentous growth, even at atmospheric levels of CO2 and reduced temperatures (30 degrees C). Using a simplified in vitro model that mimics the natural introduction of seminal fluid into the vulvovaginal environment, a pulse of artificial seminal fluid (ASF) was found to exert an enduring potential to overcome the inhibitory efficacy of artificial vaginal fluid (AVF) on filamentation. These findings suggest that a transient but substantial change in the nutrient levels within the vulvovaginal environment during unprotected coitus can induce resident C. albicans cells to engage developmental programs associated with virulent growth.

  • 9.
    Aminlashgari, Nina
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Höglund, Odd V
    Borg, Niklas
    Hakkarainen, Minna
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Degradation profile and preliminary clinical testing of a resorbable device for ligation of blood vessels2013In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 9, no 6, p. 6898-904Article in journal (Refereed)
    Abstract [en]

    A resorbable device for ligation of blood vessels was developed and tested in vitro to reveal the degradation profile of the device and to predict the clinical performance in terms of adequate mechanical support during a healing period of I week. In addition, preliminary clinical testing was performed that showed complete hemostasis and good tissue grip of renal arteries in five pigs. The device was made by injection molding of poly(glycolide-co-trimethylene carbonate) triblock copolymer, and it consisted of a case with a locking mechanism connected to a partly perforated flexible band. A hydrolytic degradation study was carried out for 7, 30 and 60 days in water and buffer medium, following the changes in mass, water absorption, pH and mechanical properties. A new rapid matrix-free laser desorption ionization-mass spectrometry (LDI-MS) method was developed for direct screening of degradation products released into the degradation medium. The combination of LDI-MS and electrospray ionization-mass spectrometry analyses enabled the comparison of the degradation product patterns in water and buffer medium. The identified degradation products were rich in trimethylene carbonate units, indicating preferential hydrolysis of amorphous regions where trimethylene units are located. The crystallinity of the material was doubled after 60 days of hydrolysis, additionally confirming the preferential hydrolysis of trimethylene carbonate units and the enrichment of glycolide units in the remaining solid matrix. The mechanical performance of the perforated band was followed for the first week of hydrolysis and the results suggest that sufficient strength is retained during the healing time of the blood vessels.

  • 10.
    Andersson, Helene
    et al.
    KTH. University of Twente, Netherlands.
    Van Berg, A. D.
    From lab-on-a-chip to lab-in-a-cell2005In: Microfluidics, BioMEMS, and Medical Microsystems III, SPIE - International Society for Optical Engineering, 2005, p. 1-12Conference paper (Refereed)
    Abstract [en]

    There are many efforts today trying to mimic the properties of single cells in order to design chips that are as efficient as cells. However, cells are nature's nanotechnology engineering at the scale of atoms and molecules. Therefore, it might be better to vision a microchip that utilizes a single cell as experimentation platform. A novel, so-called Lab-in-a-Cell (LIC) concept is described, where advantage is taken of micro/nanotechnological tools to enable precise control of the biochemical cellular environment and possibility to analyze the composition of single cells. This is followed by a review on the present chip solutions for single cell handling and analysis.

  • 11.
    Ayoglu, Burcu
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Affinity Arrays for Profiling Proteins and Autoantibody Repertoires2014Doctoral thesis, comprehensive summary (Other academic)
  • 12.
    Ayoglu, Burcu
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Chaouch, Amina
    Lochmüller, Hanns
    Politano, Luisa
    Bertini, Enrico
    Spitali, Pietro
    Hiller, Monika
    Niks, Eric H.
    Gualandi, Francesca
    Pontén, Fredrik
    Bushby, Kate
    Aartsma-Rus, Annemieke
    Schwartz, Elena
    Le Priol, Yannick
    Straub, Volker
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Cirak, Sebahattin
    't Hoen, Peter A. C.
    Muntoni, Francesco
    Ferlini, Alessandra
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Szigyarto, Cristina Al-Khalili
    Affinity proteomics within rare diseases: a BIO-NMD study for blood biomarkers of muscular dystrophies2014In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 6, no 7, p. 918-936Article in journal (Refereed)
    Abstract [en]

    Despite the recent progress in the broad-scaled analysis of proteins in body fluids, there is still a lack in protein profiling approaches for biomarkers of rare diseases. Scarcity of samples is the main obstacle hindering attempts to apply discovery driven protein profiling in rare diseases. We addressed this challenge by combining samples collected within the BIO-NMD consortium from four geographically dispersed clinical sites to identify protein markers associated with muscular dystrophy using an antibody bead array platform with 384 antibodies. Based on concordance in statistical significance and confirmatory results obtained from analysis of both serum and plasma, we identified eleven proteins associated with muscular dystrophy, among which four proteins were elevated in blood from muscular dystrophy patients: carbonic anhydrase III (CA3) and myosin light chain 3 (MYL3), both specifically expressed in slow-twitch muscle fibers and mitochondrial malate dehydrogenase 2 (MDH2) and electron transfer flavo-protein A (ETFA). Using age-matched sub-cohorts, 9 protein profiles correlating with disease progression and severity were identified, which hold promise for the development of new clinical tools for management of dystrophinopathies.

  • 13.
    Ayoglu, Burcu
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Mitsios, Nicholas
    Kockum, Ingrid
    Khademi, Mohsen
    Zandian, Arash
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sjoberg, Ronald
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Forsstrom, Bjorn
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bredenberg, Johan
    Bomfim, Izaura Lima
    Holmgren, Erik
    Gronlund, Hans
    Guerreiro-Cacais, Andre Ortlieb
    Abdelmagid, Nada
    Uhlen, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Waterboer, Tim
    Alfredsson, Lars
    Mulder, Jan
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Olsson, Tomas
    Nilsson, Peter
    Anoctamin 2 identified as an autoimmune target in multiple sclerosis2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 8, p. 2188-2193Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.

  • 14. Azimi, A.
    et al.
    Caramuta, S.
    Seashore-Ludlow, B.
    Boström, J.
    Robinson, J. L.
    Edfors, Fredrik
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Tuominen, R.
    Kemper, K.
    Krijgsman, O.
    Peeper, D. S.
    Nielsen, J.
    Hansson, J.
    Egyhazi Brage, S.
    Altun, M.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO).
    Maddalo, G.
    Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors2018In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 14, no 3, article id e7858Article in journal (Refereed)
    Abstract [en]

    Novel therapies are undergoing clinical trials, for example, the Hsp90 inhibitor, XL888, in combination with BRAF inhibitors for the treatment of therapy-resistant melanomas. Unfortunately, our data show that this combination elicits a heterogeneous response in a panel of melanoma cell lines including PDX-derived models. We sought to understand the mechanisms underlying the differential responses and suggest a patient stratification strategy. Thermal proteome profiling (TPP) identified the protein targets of XL888 in a pair of sensitive and unresponsive cell lines. Unbiased proteomics and phosphoproteomics analyses identified CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors and its expression is regulated by the transcription factor MITF upon XL888 treatment. The CDK2 inhibitor, dinaciclib, attenuated resistance to both classes of inhibitors and combinations thereof. Notably, we found that MITF expression correlates with CDK2 upregulation in patients; thus, dinaciclib would warrant consideration for treatment of patients unresponsive to BRAF-MEK and/or Hsp90 inhibitors and/or harboring MITF amplification/overexpression. 

  • 15. Backvall, H.
    et al.
    Stromberg, S.
    Gustafsson, Anna
    KTH, Superseded Departments, Biotechnology.
    Asplund, A.
    Sivertsson, Åsa
    KTH, Superseded Departments, Biotechnology.
    Lundeberg, Joakim
    KTH, Superseded Departments, Biotechnology.
    Ponten, F.
    Mutation spectra of epidermal p53 clones adjacent to basal cell carcinoma and squamous cell carcinoma2004In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 13, no 10, p. 643-650Article in journal (Refereed)
    Abstract [en]

    Foci of normal keratinocytes overexpressing p53 protein are frequently found in normal human skin. Such epidermal p53 clones are common in chronically sun-exposed skin and have been suggested to play a role in skin cancer development. In the present study, we have analyzed the prevalence of p53 mutations in epidermal p53 clones from normal skin surrounding basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Using laser-assisted microdissection, 37 epidermal p53 clones adjacent to BCC (21) and SCC (16) were collected. Genetic analysis was performed using a multiplex/nested polymerase chain reaction followed by direct DNA sequencing of p53 exons 2-11. In total, 21 of 37 analyzed p53 clones consisted of p53-mutated keratinocytes. The identified mutations were located in p53 exons 4-8, corresponding to the sequence-specific DNA-binding domain. All mutations were missense, and 78% displayed a typical ultraviolet signature. The frequency of p53 mutations was similar in skin adjacent to BCC compared to SCC. The presented data confirm and extend previous knowledge on the genetic background of epidermal p53 clones. The mutation spectra found in epidermal p53 clones resemble that of non-melanoma skin cancer. Approximately, 40% of the epidermal p53 clones lacked an underlying p53 mutation, suggesting that other genetic events in genes up- or downstream of the p53 gene can generate foci of normal keratinocytes overexpressing p53 protein.

  • 16.
    Bai, Yunpeng
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Weibull, Emilie
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Jönsson, Håkan
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Andersson Svahn, Helene
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Interfacing picoliter droplet microfluidics with addressable microliter compartments using fluorescence activated cell sorting2014In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 194, p. 249-254Article in journal (Refereed)
    Abstract [en]

    Droplet microfluidic platforms have, while enabling high-throughput manipulations and the assaying of single cell scale compartments, been lacking interfacing to allow macro scale access to the output from droplet microfluidic operations. Here, we present a simple and high-throughput method for individually directing cell containing droplets to an addressable and macro scale accessible microwell slide for downstream analysis. Picoliter aqueous droplets containing low gelling point agarose and eGFP expressing Escherichia coli (E. coli) are created in a microfluidic device, solidified to agarose beads and transferred into an aqueous buffer. A Fluorescence activated cell sorter (FACS) is used to sort agarose beads containing cells into microwells in which the growth and expansion of cell colonies is monitored. We demonstrate fast sorting and high accuracy positioning of sorted 15 μm gelled droplet agarose beads into microwells (14 × 48) on a 25 mm × 75 mm microscope slide format using a FACS with a 100 μm nozzle and an xy-stage. The interfacing method presented here enables the products of high-throughput or single cell scale droplet microfluidics assays to be output to a wide range of microtiter plate formats familiar to biological researchers lowering the barriers for utilization of these microfluidic platforms.

  • 17. Bao, D.
    et al.
    Zou, Zhuo
    KTH, School of Information and Communication Technology (ICT), Industrial and Medical Electronics. KTH, School of Information and Communication Technology (ICT), Centres, VinnExcellence Center for Intelligence in Paper and Packaging, iPACK.
    Huan, Y.
    Zhai, Chuanying
    KTH, School of Information and Communication Technology (ICT), Industrial and Medical Electronics. KTH, School of Information and Communication Technology (ICT), Centres, VinnExcellence Center for Intelligence in Paper and Packaging, iPACK.
    Bagaian, T.
    Tenhunen, Hannu
    KTH, School of Information and Communication Technology (ICT), Industrial and Medical Electronics. KTH, School of Information and Communication Technology (ICT), Centres, VinnExcellence Center for Intelligence in Paper and Packaging, iPACK.
    Källbäck, B.
    Zheng, Lirong
    KTH, School of Information and Communication Technology (ICT), Industrial and Medical Electronics. KTH, School of Information and Communication Technology (ICT), Centres, VinnExcellence Center for Intelligence in Paper and Packaging, iPACK. State Key Laboratory of ASIC and System, Fudan University, Shanghai, China .
    A smart catheter system for minimally invasive brain monitoring2015In: Proceedings of the International Conference on Biomedical Electronics and Devices, SciTePress, 2015, p. 198-203Conference paper (Refereed)
    Abstract [en]

    This paper demonstrates a smart catheter system with intracranial pressure (ICP) and temperature sensing capability which is designed for real-time monitoring in traumatic brain injury (TBI) therapy. It uses a single flexible catheter with a 1 mm (3 Fr) diameter that integrates electrodes and sophisticated silicon chip on flexible substrates, enabling multimodality monitoring of physiological signals. A micro-electromechanical-system (MEMS) catheter pressure sensor is mounted on the distal end. It can be used for detecting both pressure and temperature by different switch configurations, which minimizes the size of catheter and reduces the cost. The interconnects (signalling conductors) are printed on a bio-compatible flexible substrate, and the sensor is interfaced with an embedded electronic system at the far-end. The electronic system consists of analog front end with analog-to-digital converter (ADC), a microcontroller, and data interface to the hospital infrastructure with a graphical user interface (GUI). The overall smart catheter system achieves a pressure sensing root mean square error (RMSE) of ±1.5 mmHg measured from 20 mmHg to 300 mmHg above 1 atm and a temperature sensing RMSE of ±0.08°C measured from 32°C to 42°C. The sampling rate can be up to 10S/s. The in vivo performance is demonstrated in laboratory animals.

  • 18.
    Barnkob, Rune
    et al.
    Tech Univ Denmark, Lyngby, Denmark .
    Iranmanesh, Ida
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Wiklund, Martin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Bruus, Henrik
    Tech Univ Denmark, Lyngby, Denmark .
    Measuring acoustic energy density in microchannel acoustophoresis using a simple and rapid light-intensity method2012In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 12, no 13, p. 2337-2344Article in journal (Refereed)
    Abstract [en]

    We present a simple and rapid method for measuring the acoustic energy density in microchannel acoustophoresis based on light-intensity measurements of a suspension of particles. The method relies on the assumption that each particle in the suspension undergoes single-particle acoustophoresis. It is validated by the single-particle tracking method, and we show by proper re-scaling that the re-scaled light intensity plotted versus re-scaled time falls on a universal curve. The method allows for analysis of moderate-resolution images in the concentration range encountered in typical experiments, and it is an attractive alternative to particle tracking and particle image velocimetry for quantifying acoustophoretic performance in microchannels.

  • 19. Basile, Walter
    et al.
    Sachenkova, Oxana
    Light, Sara
    Elofsson, Arne
    KTH, Centres, SeRC - Swedish e-Science Research Centre.
    High GC content causes orphan proteins to be intrinsically disordered2017In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 13, no 3, article id e1005375Article in journal (Refereed)
    Abstract [en]

    De novo creation of protein coding genes involves the formation of short ORFs from noncoding regions; some of these ORFs might then become fixed in the population These orphan proteins need to, at the bare minimum, not cause serious harm to the organism, meaning that they should for instance not aggregate. Therefore, although the creation of short ORFs could be truly random, the fixation should be subjected to some selective pressure. The selective forces acting on orphan proteins have been elusive, and contradictory results have been reported. In Drosophila young proteins are more disordered than ancient ones, while the opposite trend is present in yeast. To the best of our knowledge no valid explanation for this difference has been proposed. To solve this riddle we studied structural properties and age of proteins in 187 eukaryotic organisms. We find that, with the exception of length, there are only small differences in the properties between proteins of different ages. However, when we take the GC content into account we noted that it could explain the opposite trends observed for orphans in yeast (low GC) and Drosophila (high GC). GC content is correlated with codons coding for disorder promoting amino acids. This leads us to propose that intrinsic disorder is not a strong determining factor for fixation of orphan proteins. Instead these proteins largely resemble random proteins given a particular GC level. During evolution the properties of a protein change faster than the GC level causing the relationship between disorder and GC to gradually weaken.

  • 20.
    Bass, Tarek
    KTH, School of Biotechnology (BIO), Protein Technology.
    Affibody molecules targeting HER3 for cancer therapy2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The development of targeted therapy has contributed tremendously to the treatment of patients with cancer. The use of highly specific affinity proteins to target cancer cells has become a standard in treatment strategies for several different cancers. In light of this, many cancer cell markers are investigated for their potential use in diagnostics and therapy. One such marker is the human epidermal growth factor receptor 3, HER3. It has been established as an important contributor to many cancer types. The function of HER3 is to relay cell growth signals from outside of the cell to the inside. Interfering with- and inhibit- ing the function of HER3 has emerged as an interesting strategy for cancer therapeutics. The studies presented in this thesis aim to target HER3 with small, engineered affinity domain proteins for therapeutic purposes. Monomeric affibody molecules have previously been engineered to bind and inhibit HER3 in vitro. Due to the relatively low expression of HER3, an increase in valency appears promising to strengthen the therapeutic potential. Affibody molecules targeting the receptor were thus linked to form bivalent and bispecific constructs and evaluated both in vitro and in vivo. In the first study of this thesis affibody molecules specific for HER3 and HER2 were fused to an albumin binding domain to form bivalent and bispecific construct. The constructs inhibited ligand-induced receptor phos- phorylation of both HER2 and HER3 more efficiently than monomeric affibody molecules. A second approach to enhance the potential of affibody molecules in tumor targeting is described in the second study, where monomeric HER3-binding affibody molecules were engineered to increase their affinity for HER3. The resulting variants showed a 20-fold in- creased affinity and higher capacity to inhibit cancer cell growth. Combining the findings of the first two studies, the third study describes the evaluation of a HER3-targeting bivalent affibody construct for potential application as a therapeutic. Here, the bivalent construct inhibited cancer cell growth in vitro and was found to slow down tumor growth in mice, while being well tolerated and showing no visible toxicity. The fourth study built upon these findings and compares a very similar bivalent construct to the clinically-investigated HER3-specific monoclonal antibody seribantumab. The affibody construct showed very comparable efficacy with the antibody in terms of decreasing tumor growth rate and ex- tending mouse survival. Collectively, these works describe for the first time the use of alternative affinity protein constructs with therapeutic potential targeting HER3.

  • 21.
    Bass, Tarek
    KTH, School of Biotechnology (BIO), Protein Technology.
    Evaluating the therapeutic potential of a dimeric HER3-binding affibody construct in comparison with a monoclonal antibody, seribantumab.Manuscript (preprint) (Other academic)
    Abstract [en]

    A number of monoclonal antibodies targeting HER3 are currently under clinical investigation as potential cancer therapeutics. We have earlier generated high affinity (low picomolar) affibody molecules targeting HER3. These are small, 58 amino acid, non-immunoglobulin based scaffold proteins that have proved suitable for tumor targeting applications, previously primarily for molecular imaging purposes. Our high affinity HER3-binding affibody molecule has demonstrated to have anti-proliferative capacity on HER3-positive tumor cells. When formatted as a bivalent construct, in which the two affibody moieties are flanking a small albumin-binding domain (ABD), we have recently demonstrated that tumor growth could be delayed in mice for HER3-positive xenografts. In this study, we have modified the construct further and reduced the size. In a comparative study, we evaluated safety, the capacity to delay tumor growth in mice with BxPC-3 xenografts, and mouse survival. Our novel construct was compared to the HER3-specific monoclonal antibody seribantumab (MM-121), presently in clinical development. They were found to be equally potent in their therapeutic effects and in their safety profile. We conclude that this format of bivalent HER3-binding affibody molecules seems promising for further evaluation as candidate therapeutics for treatment of HER3-overexpressing tumors.

  • 22.
    Baumann, Martin J.
    KTH, School of Biotechnology (BIO).
    Xyloglucan-active enzymes: properties, structures and applications2007Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    Cellulosic materials are the most abundant renewable resource in the world; plant cell walls are natural composite materials containing crystalline cellulose embedded in a matrix of hemicelluloses, structural proteins, and lignin. Xyloglucans are an important group of hemicelluloses, which coat and cross-link crystalline cellulose in the plant cell wall. In this thesis, structure-function relationships of a range of xyloglucan-active enzymes were examined.

    A paradigm for efficient enzymatic biomass utilization is the cellulosome of the anaerobic bacterium Clostridium thermocellum. The cellulosome is a high molecular weight complex of proteins with diverse enzyme activities, including the inverting xyloglucan endo-hydrolase CtXGH74A. The protein structure of CtXGH74A was solved in complex with xyloglucan oligosaccharides (XGOs) which stabilized disordered loops of the apo-structure. Further detailed kinetic and product analyses were used to conclusively demonstrate that CtXGH74A is an endo-xyloglucase that produces Glc4-based XGOs as limit digestion products.

    In comparison, the retaining glycoside hydrolase family 16 (GH16) contains hydrolytic endo-xyloglucanases as well as xyloglucan transglycosylases (XETs) from plants. To elucidate the determinants of the transglycosylase/hydrolysis ratio in GH16 xyloglucan-active enzymes, a strict transglycosylase, PttXET16-34 from hybrid aspen, was compared structurally and kinetically with the closely related hydrolytic enzyme NXG1 from nasturtium. A key loop extension was identified in NXG1, truncation of which yielded a mutant enzyme that exhibited an increased transglycosylase rate and reduced hydrolytic activity. Kinetic studies were facilitated by the development of new, sensitive assays using well-defined XGOs and a series of chromogenic XGO aryl-glycosides.

    A detailed understanding of GH16 xyloglucan enzymology has paved the way for the development of a novel chemo-enzymatic approach for biomimetic fiber surface modification, in which the transglycosylating activity of PttXET16-34 was employed. Aminoalditol derivates of XGOs were used as key intermediates to incorporate novel chemical functionality into xyloglucan, including chromophores, reactive groups, protein ligands, and initiators for polymerization reactions. The resulting modified xyloglucans were subsequently bound to a range of cellulose materials to radically alter surface properties. As such, the technology provides a novel, versatile toolkit for fiber surface modification.

  • 23.
    Beaussant Törne, Karin
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Khan, Fareed Ashraf
    Örnberg, A.
    Weissenrieder, Jonas
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Zn-Mg and Zn-Ag degradation mechanism under biologically relevant conditionsManuscript (preprint) (Other academic)
    Abstract [en]

    Zinc alloys form a promising new class of biodegradable metals that combine suitable mechanical properties with the favorable degradation properties of pure zinc. However, the current understanding of the influence of alloying elements on the corrosion of zinc alloys, in biologically relevant media, is limited. We studied the degradation of three alloys, Zn 4 wt% Ag, Zn 0.5 wt% Mg and Zn 3 wt% Mg by in situ electrochemical impedance spectroscopy (EIS). After exposure for 1h or 30 days the samples were characterized by infrared spectroscopy and scanning electron microscopy (SEM). The presence of secondary phases in the alloy microstructure induced selective corrosion and increased degradation rate. An increase in surface inhomogeneity was evident by EIS analysis both at short (hours) as well as long immersion times (days). The microgalvanic corrosion of the Zn-Ag alloy resulted in enrichment of the AgZn3 phase at the sample surface. The enrichment of Ag and potential release of AgZn3 particles may result in complications during the tissue regeneration. The Zn-Mg alloy surface was depleted of the Mg-rich phase after 8-12 days. The selective dissolution caused local precipitation of2corrosion products and a thicker corrosion layer with larger pore size consistent with increased corrosion rate.

    The full text will be freely available from 2018-10-01 14:30
  • 24.
    Beaussant Törne, Karin
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Örnberg, A.
    Weissenrieder, Jonas
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Characterization of the Protective Layer Formed on Zinc in Whole BloodManuscript (preprint) (Other academic)
    Abstract [en]

    The advantageous degradation properties of zinc in a biological environment are related to the presence of a protective corrosion layer composed of both organic and inorganic components. However, the mechanisms governing its formation and how the organic species influence its properties have not been established. Here we study the protective layer formation during anodic polarization in whole blood by in situ electrochemical impedance spectroscopy (EIS) as well as infrared spectroscopy and scanning electron microscopy. Simulated body fluid (m-SBF) was used as a reference media to discern the influence of the organic species present in whole blood. Protective zinc phosphate layers form on the Zn surface in both solutions, but of different nature and through diverse mechanisms. In m-SBF the passivating thin film formation occur already at open circuit potential, reducing the corrosion current compared to exposure in whole blood by a factor of 103. The high corrosion current in whole blood can be explained by a process including rapid protein adsorption preventing the initial formation of a protective phosphate layer. EIS analysis detected an inductive arc in whole blood at low overpotentials, before the onset of protective film formation, indicating the presence of adsorbed Zn2ions. The coverage of Zn ions approach 100% of the active surface at 110 mV. At this critical surface coverage a reaction between the adsorbed Zn ions and PO42- takes place which results in formation of a protective, porous, film of ~1 μm thickness. The inorganic component of the protective film formed in whole blood was characterized as Zn(PO4)2(OH)2·3H2O.

    The full text will be freely available from 2018-10-01 14:26
  • 25. Bello, M. A.
    et al.
    Ruiz-León, Y.
    Sandoval-Sierra, J. V.
    Rezinciuc, Svetlana
    KTH, School of Biotechnology (BIO), Glycoscience.
    Diéguez-Uribeondo, J.
    Scanning electron microscopy (SEM) protocols for problematic plant, oomycete, and fungal samples2017In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, Vol. 2017, no 120, article id e55031Article in journal (Refereed)
    Abstract [en]

    Common problems in the processing of biological samples for observations with the scanning electron microscope (SEM) include cell collapse, treatment of samples from wet microenvironments and cell destruction. Using young floral tissues, oomycete cysts, and fungi spores (Agaricalesas examples, specific protocols to process delicate samples are described here that overcome some of the main challenges in sample treatment for image capture under the SEM. Floral meristems fixed with FAA (Formalin-Acetic-Alcohol) and processed with the Critical Point Dryer (CPD) did not display collapsed cellular walls or distorted organs. These results are crucial for the reconstruction of floral development. A similar CPD-based treatment of samples from wet microenvironments, such as the glutaraldehyde-fixed oomycete cysts, is optimal to test the differential growth of diagnostic characteristics (e.g., the cyst spines) on different types of substrates. Destruction of nurse cells attached to fungi spores was avoided after rehydration, dehydration, and the CPD treatment, an important step for further functional studies of these cells. The protocols detailed here represent low-cost and rapid alternatives for the acquisition of good-quality images to reconstruct growth processes and to study diagnostic characteristics.

  • 26. Bengtsson, Erik
    et al.
    Nerjovaj, Pashtrik
    Wangefjord, Sakarias
    Nodin, Björn
    Eberhard, Jakob
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Borgquist, Signe
    Jirström, Karin
    HMG-CoA reductase expression in primary colorectal cancer correlates with favourable clinicopathological characteristics and an improved clinical outcome2014In: Diagnostic Pathology, ISSN 1746-1596, E-ISSN 1746-1596, Vol. 9, no 1, p. 78-Article in journal (Refereed)
    Abstract [en]

    Background: An association between tumor-specific HMG-CoA reductase (HMGCR) expression and good prognosis has previously been demonstrated in breast and ovarian cancer. In this study, the expression, clinicopathological correlates and prognostic value of HMGCR expression in colorectal cancer was examined. Findings: Immunohistochemical expression of HMGCR was assessed in tissue microarrays with primary tumours from 557 incident cases of colorectal cancer in the Malmo Diet and Cancer Study. Pearson's Chi Square test was applied to explore the associations between HMGCR expression and clinicopathological factors and other investigative biomarkers. Kaplan Meier analysis and Cox proportional hazards modeling were used to assess the relationship between HMGCR expression and cancer-specific survival (CSS) according to negative vs positive HMGCR expression. A total number of 535 (96.0%) tumours were suitable for analysis, of which 61 (11.4%) were HMGCR negative. Positive cytoplasmic HMGCR expression was associated with distant metastasis-free disease at diagnosis (p = 0.002), lack of vascular invasion (p = 0.043), microsatellite-instability (p = 0.033), expression of cyclin D1 (p = <0.001) and p21 (p = <0.001). Positive HMGCR expression was significantly associated with a prolonged CSS in unadjusted Cox regression analysis in the entire cohort (HR = 1.79; 95% CI 1.20-2.66) and in Stage III-IV disease (HR = 1.71; 95% CI 1.09-2.68), but not after adjustment for established clinicopathological parameters. Conclusions: Findings from this prospective cohort study demonstrate that HMGCR is differentially expressed in colorectal cancer and that positive expression is associated with favourable tumour characteristics and a prolonged survival in unadjusted analysis. The utility of HMGCR as a predictor of response to neoadjuvant or adjuvant statin treatment in colorectal cancer merits further study. Virtual slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2115647072103464.

  • 27. Bengtsson-Palme, Johan
    et al.
    Hammaren, Rickard
    Pal, Chandan
    Ostman, Marcus
    Björlenius, Berndt
    KTH, School of Biotechnology (BIO), Industrial Biotechnology.
    Flach, Carl-Fredrik
    Fick, Jerker
    Kristiansson, Erik
    Tysklind, Mats
    Larsson, D. G. Joakim
    Elucidating selection processes for antibiotic resisitance in sewage treatment plants using metagenomics2016In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 572, p. 697-712Article in journal (Refereed)
    Abstract [en]

    Sewage treatment plants (STPs) have repeatedly been suggested as hotspots for the emergence and dissemination of antibiotic-resistant bacteria. A critical question still unanswered is if selection pressures within STPs, caused by residual antibiotics or other co-selective agents, are sufficient to specifically promote resistance. To address this, we employed shotgun metagenomic sequencing of samples from different steps of the treatment process in three Swedish STPs. In parallel, concentrations of selected antibiotics, biocides and metals were analyzed. We found that concentrations of tetracycline and ciprofloxacin in the influent were above predicted concentrations for resistance selection, however, there was no consistent enrichment of resistance genes to any particular class of antibiotics in the STPs, neither for biocide and metal resistance genes. The most substantial change of the bacterial communities compared to human feces occurred already in the sewage pipes, manifested by a strong shift from obligate to facultative anaerobes. Through the treatment process, resistance genes against antibiotics, biocides and metals were not reduced to the same extent as fecal bacteria. The OXA-48 gene was consistently enriched in surplus and digested sludge. We find this worrying as OXA-48, still rare in Swedish clinical isolates, provides resistance to carbapenems, one of our most critically important classes of antibiotics. Taken together, metagenomics analyses did not provide clear support for specific antibiotic resistance selection. However, stronger selective forces affecting gross taxonomic composition, and with that resistance gene abundances, limit interpretability. Comprehensive analyses of resistant/non-resistant strains within relevant species are therefore warranted. 

  • 28.
    Berg, Cecilia
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Hedrum, A
    Holmberg, A
    Pontén, F
    Uhlén, M
    Lundeberg, J
    Direct solid-phase sequence analysis of the human p53 gene by use of multiplex polymerase chain reaction and alpha-thiotriphosphate nucleotides.1995In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 41, no 10, p. 1461-6Article in journal (Refereed)
    Abstract [en]

    Among the candidate cancer-prognostic genes is the p53 tumor suppressor gene, which, when mutated, plays an important role in the development of many types of cancers. To facilitate robust large-scale DNA analysis of microdissected tumor biopsies, we describe a multiplex/nested PCR approach for a simultaneous outer amplification of exons 4-9 of the human p53 gene with parallel amplification of the HLA-DQB1 locus, involving a total of 14 primers. This approach reduces the required number of cells for analysis and avoids any variation in the amplifications of the individual p53 exons during the common outer amplification step. The HLA sequencing allows sample identification because the DQB1 locus is highly polymorphic and is thereby patient-specific. The p53 and HLA amplicons are analyzed by solid-phase sequencing in a semiautomated format. To improve the DNA sequence quality, we used 2'-deoxyribonucleoside 5'-O-1-thiotriphosphates in the sequencing reactions.

  • 29.
    Berglund, Sofia
    et al.
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Gaballa, Ahmed
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Sawaisorn, Piamsiri
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.;Mahidol Univ, Fac Med Technol, Ctr Res & Innovat, Bangkok, Thailand..
    Sundberg, Berit
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Uhlin, Michael
    KTH, School of Engineering Sciences (SCI), Applied Physics. Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.; Karolinska Univ Hosp, Dept Immunol & Transfus Med, Stockholm, Sweden..
    Expansion of Gammadelta T Cells from Cord Blood: A Therapeutical Possibility2018In: STEM CELLS INTERNATIONAL, ISSN 1687-966X, article id 8529104Article in journal (Refereed)
    Abstract [en]

    Gammadelta (gamma delta) T cells are found in both blood and tissues and have antiviral and antitumor properties. The frequency of gamma delta T cells in umbilical cord blood (UCB) is low, and the majority express delta 1, in contrast to blood, whereas the main subset is delta 2 gamma 9 T cells. UCB gamma delta T cells are functionally immature, which together with their scarcity complicates the development of UCB gamma delta T cell therapies. We aimed to develop an effective expansion protocol for UCB gamma delta T cells based on zoledronate and IL-2. We found that culture with 5 mu M zoledronate and 200 IU IL-2/ml medium for 14 days promoted extensive proliferation. The majority of the cultured cells were gamma 9 delta 2 T cells. The fold expansion of this, originally infrequent, subset was impressive (median and maximum fold change 253 and 1085, resp.). After culture, the cells had a polyclonal gamma delta T cell repertoire and the main memory subset was central memory (CD45RO(+) CD27(+)). The cells produced cytokines such as IL-1B, IL-2, and IL-8 and displayed significant tumor-killing capacity. These results show that development of in vitro expanded UCB gamma delta T cell therapies is feasible. It could prove a valuable treatment modality for patients after umbilical cord blood transplantation.

  • 30.
    Beven, Laure
    et al.
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Charenton, Claire
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Dautant, Alain
    Univ Bordeaux, Bordeaux, France ; IBMC, CNRS, Bordeaux, France.
    Bouyssou, Guillaume
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Labroussaa, Fabien
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Sköllermo, Anna
    KTH, School of Biotechnology (BIO), Proteomics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Persson, Anja
    KTH, School of Biotechnology (BIO), Proteomics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Blanchard, Alain
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Sirand-Pugnet, Pascal
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Specific Evolution of F-1-Like ATPases in Mycoplasmas2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e38793-Article in journal (Refereed)
    Abstract [en]

    F1F0 ATPases have been identified in most bacteria, including mycoplasmas which have very small genomes associated with a host-dependent lifestyle. In addition to the typical operon of eight genes encoding genuine F1F0 ATPase (Type 1), we identified related clusters of seven genes in many mycoplasma species. Four of the encoded proteins have predicted structures similar to the alpha, beta, gamma and e subunits of F-1 ATPases and could form an F-1-like ATPase. The other three proteins display no similarity to any other known proteins. Two of these proteins are probably located in the membrane, as they have three and twelve predicted transmembrane helices. Phylogenomic studies identified two types of F-1-like ATPase clusters, Type 2 and Type 3, characterized by a rapid evolution of sequences with the conservation of structural features. Clusters encoding Type 2 and Type 3 ATPases were assumed to originate from the Hominis group of mycoplasmas. We suggest that Type 3 ATPase clusters may spread to other phylogenetic groups by horizontal gene transfer between mycoplasmas in the same host, based on phylogeny and genomic context. Functional analyses in the ruminant pathogen Mycoplasma mycoides subsp. mycoides showed that the Type 3 cluster genes were organized into an operon. Proteomic analyses demonstrated that the seven encoded proteins were produced during growth in axenic media. Mutagenesis and complementation studies demonstrated an association of the Type 3 cluster with a major ATPase activity of membrane fractions. Thus, despite their tendency toward genome reduction, mycoplasmas have evolved and exchanged specific F-1-like ATPases with no known equivalent in other bacteria. We propose a model, in which the F-1-like structure is associated with a hypothetical X-0 sector located in the membrane of mycoplasma cells.

  • 31.
    Bjurhager, Ingela
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Gamstedt, E. Kristofer
    Keunecke, Daniel
    Niemz, Peter
    Berglund, Lars A.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Biocomposites. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Mechanical performance of yew (Taxus baccata L.) from a longbow perspective2013In: Holzforschung, ISSN 0018-3830, E-ISSN 1437-434X, Vol. 67, no 7, p. 763-770Article in journal (Refereed)
    Abstract [en]

    Yew (Taxus baccata L.) longbow was the preferred weapon in the Middle Ages until the emergence of guns. In this study, the tensile, compression, and bending properties of yew were investigated. The advantage of yew over the other species in the study was also confirmed by a simple beam model. The superior toughness of yew has the effect that a yew longbow has a higher range compared with bows made from other species. Unexpectedly, the mechanical performance of a bow made from yew is influenced by the juvenile-to-mature wood ratio rather than by the heartwood-to-sapwood ratio. A yew bow is predicted to have maximized performance at a juvenile wood content of 30-50%, and located at the concave side (the compressive side facing the bowyer). Here, the stiffness and yield stress in compression should be as high as possible.

  • 32.
    Bjällmark, Anna
    KTH, School of Technology and Health (STH), Medical Engineering.
    New ultrasonographic approaches to monitoring cardiac and vascular function2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Atherosclerotic cardiovascular disease is the leading cause of death worldwide. To decrease mortality and morbidity in cardiovascular disease, the development of accurate, non-invasive methods for early diagnosis of atherosclerotic cardiac and vascular engagement is of considerable clinical interest. Cardiovascular ultrasound imaging is today the cornerstone in the routine evaluation of cardiovascular function and recent development has resulted in two new techniques, tissue velocity imaging (TVI) and speckle tracking, which allow objective quantification of cardiovascular function. TVI and speckle tracking are the basis for three new approaches to cardiac and vascular monitoring presented in this thesis: wave intensity wall analysis (WIWA), two-dimensional strain imaging in the common carotid artery, and the state diagram of the heart.

     

    WIWA uses longitudinal and radial strain rate as input for calculations of wave intensity in the arterial wall. In this thesis, WIWA was validated against a commercially available wave intensity system, showing that speckle tracking-derived strain variables can be useful in wave intensity analysis. WIWA was further tested in patients with end stage renal disease and documented high mortality in cardiovascular disease. The latter study evaluated the effects of a single session of hemodialysis using WIWA and TVI variables and showed improved systolic function after hemodialysis. The results also indicated that preload-adjusted early systolic wave intensity obtained by the WIWA system may contribute in the assessment of left ventricular contractility in this patient category. Two-dimensional strain imaging in the common carotid artery is a new approach showing great potential to detect age-dependent differences in mechanical properties of the common carotid artery. Among the measured strain variables, global circumferential strain had the best discriminating performance and appeared to be superior to conventional measures of arterial stiffness such as elastic modulus and β stiffness index. The state diagram is a visualisation tool that provides a quantitative overview of the temporal interrelationship of mechanical events in the left and right ventricles. Case examples and a small clinical study showed that state diagrams clearly visualize cardiac function and can be useful in the detection of non ST-elevation myocardial infarction (NSTEMI).

     

    Even though WIWA, two-dimensional strain imaging in the common carotid artery and the state diagram show potential to be useful in the evaluation of cardiovascular function, there still remains a considerable amount of work to be done before they can be used in the daily clinical practice.

  • 33.
    Blom, Hans
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Rönnlund, Daniel
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Scott, Lena
    Spicarova, Zuzana
    Rantanen, Ville
    Widengren, Jerker
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Aperia, Anita
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Nearest neighbor analysis of dopamine D1 receptors and Na plus -K plus -ATPases in dendritic spines dissected by STED microscopy2012In: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 75, no 2, p. 220-228Article in journal (Refereed)
    Abstract [en]

    Protein localization in dendritic spines is the focus of intense investigations within neuroscience. Applications of super-resolution microscopy to dissect nanoscale protein distributions, as shown in this work with dual-color STED, generate spatial correlation coefficients having quite small values. This means that colocalization analysis to some extent looses part of its correlative impact. In this study we thus introduced nearest neighbor analysis to quantify the spatial relations between two important proteins in neurons, the dopamine D1 receptor and Na+,K+-ATPase. The analysis gave new information on how dense the D1 receptor and Na+,K+-ATPase constituting nanoclusters are located both with respect to the homogenous (self to same) and the heterogeneous (same to other) topology. The STED dissected nanoscale topologies provide evidence for both a joint as well as a separated confinement of the D1 receptor and the Na+,K+-ATPase in the postsynaptic areas of dendritic spines. This confined topology may have implications for generation of local sodium gradients and for structural and functional interactions modulating slow synaptic transmission processes. Microsc. Res. Tech., 2011.

  • 34.
    Blomfeldt, Thomas O. J.
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Kuktaite, Ramune
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Johansson, Eva
    Hedenqvist, Mikael S.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Mechanical Properties and Network Structure of Wheat Gluten Foams2011In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 12, no 5, p. 1707-1715Article in journal (Refereed)
    Abstract [en]

    This Article reports the influence of the protein network structure on the mechanical properties of foams produced from commercial wheat gluten using freeze-drying. Foams were produced from alkaline aqueous solutions at various gluten concentrations with or without glycerol, modified with bacterial cellulose nanosized fibers, or both. The results showed that 20 wt % glycerol was sufficient for plasticization, yielding foams with low modulus and high strain recovery. It was found that when fibers were mixed into the foams, a small but insignificant increase in elastic modulus was achieved, and the foam structure became more homogeneous. SEM indicated that the compatibility between the fibers and the matrix was good, with fibers acting as bridges in the cell walls. IR spectroscopy and SE-HPLC revealed a relatively low degree of aggregation, which was highest in the presence of glycerol. Confocal laser scanning microscopy revealed distinct differences in HMW-glutenin subunits and gliadin distributions for all of the different samples.

  • 35. Bolander, Å.
    et al.
    Agnarsdóttir, M.
    Strömberg, S.
    Ponten, F.
    Hesselius, P.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101).
    Bergqvist, M.
    The protein expression of TRP-1 and galectin-1 in cutaneous malignant melanomas2008In: Cancer Genomics & Proteomics, ISSN 1109-6535, E-ISSN 1790-6245, Vol. 5, no 6, p. 293-300Article in journal (Refereed)
    Abstract [en]

    Background: Patients with metastazing malignant melanoma have a poor outcome and determination of thickness of the primary tumor remains as the most important prognostic predictor. The aim of this study was to use an antibody-based proteomics strategy to search for new molecular markers associated with melanoma progression. Two proteins, TRP-1 and galectin-1, were identified as proteins with enhanced expression in cells from the melanocytic lineage. Patients and Methods: Protein profiling of TRP-1 and galectin-1 together with proliferation marker Ki-67 and melanocyte marker Melan-A was performed in normal tissues from 144 individuals and in 216 different tumors using tissue microarrays and immunohistochemistry. The protein expression pattern was further analyzed in a defined cohort of 157 patients diagnosed with invasive cutaneous malignant melanoma. Results: Both TRP-1 and galectin-1 were highly expressed in normal melanocytes and melanoma. The expression of TRP-1 was inversely correlated with tumor stage (p=0.002, (R=-0.28)). Neither TRP-1 or galectin-1 was associated with overall or disease free survival (p>0.14, p>0.46 respectively). Ki-67 was associated with tumor stage and survival (p<0.001). Conclusion: TRP-1 and galectin-1 protein expression patterns were determined in normal and cancer tissues and both proteins were expressed in the majority of the malignant melanomas. There was no correlation between TRP-1 or galectin-1 expression and survival.

  • 36. Bollampalli, V. P.
    et al.
    Harumi Yamashiro, L.
    Feng, X.
    Bierschenk, D.
    Gao, Y.
    Blom, Hans
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Henriques-Normark, B.
    Nylén, S.
    Rothfuchs, A. G.
    BCG Skin Infection Triggers IL-1R-MyD88-Dependent Migration of EpCAMlow CD11bhigh Skin Dendritic cells to Draining Lymph Node During CD4+ T-Cell Priming2015In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, no 10, article id e1005206Article in journal (Refereed)
    Abstract [en]

    The transport of antigen from the periphery to the draining lymph node (DLN) is critical for T-cell priming but remains poorly studied during infection with Mycobacterium bovis Bacille Calmette-Guérin (BCG). To address this we employed a mouse model to track the traffic of Dendritic cells (DCs) and mycobacteria from the BCG inoculation site in the skin to the DLN. Detection of BCG in the DLN was concomitant with the priming of antigen-specific CD4+ T cells at that site. We found EpCAMlow CD11bhigh migratory skin DCs to be mobilized during the transport of BCG to the DLN. Migratory skin DCs distributed to the T-cell area of the LN, co-localized with BCG and were found in close apposition to antigen-specific CD4+ T cells. Consequently, blockade of skin DC traffic into DLN dramatically reduced mycobacterial entry into DLN and muted T-cell priming. Interestingly, DC and mycobacterial entry into the DLN was dependent on IL-1R-I, MyD88, TNFR-I and IL-12p40. In addition, we found using DC adoptive transfers that the requirement for MyD88 in BCG-triggered migration was not restricted to the migrating DC itself and that hematopoietic expression of MyD88 was needed in part for full-fledged migration. Our observations thus identify a population of DCs that contribute towards the priming of CD4+ T cells to BCG infection by transporting bacilli into the DLN in an IL-1R-MyD88-dependent manner and reveal both DC-intrinsic and -extrinsic requirements for MyD88 in DC migration.

  • 37. Bora, Kangkana
    et al.
    Chowdhury, Manish
    KTH, School of Technology and Health (STH).
    Mahanta, Lipi B.
    Kundu, Malay Kumar
    Das, Anup Kumar
    Automated classification of Pap smear images to detect cervical dysplasia2017In: Computer Methods and Programs in Biomedicine, ISSN 0169-2607, E-ISSN 1872-7565, Vol. 138, p. 31-47Article in journal (Refereed)
    Abstract [en]

    Background and objectives: The present study proposes an intelligent system for automatic categorization of Pap smear images to detect cervical dysplasia, which has been an open problem ongoing for last five decades. Methods: The classification technique is based on shape, texture and color features. It classifies the cervical dysplasia into two-level (normal and abnormal) and three-level (Negative for Intraepithelial Lesion or Malignancy, Low-grade Squamous Intraepithelial Lesion and High-grade Squamous Intraepithelial Lesion) classes reflecting the established Bethesda system of classification used for diagnosis of cancerous or precancerous lesion of cervix. The system is evaluated on two generated databases obtained from two diagnostic centers, one containing 1610 single cervical cells and the other 1320 complete smear level images. The main objective of this database generation is to categorize the images according to the Bethesda system of classification both of which require lots of training and expertise. The system is also trained and tested on the benchmark Herlev University database which is publicly available. In this contribution a new segmentation technique has also been proposed for extracting shape features. Ripplet Type I transform, Histogram first order statistics and Gray Level Co-occurrence Matrix have been used for color and texture features respectively. To improve classification results, ensemble method is used, which integrates the decision of three classifiers. Assessments are performed using 5 fold cross validation. Results: Extended experiments reveal that the proposed system can successfully classify Pap smear images performing significantly better when compared with other existing methods. Conclusion: This type of automated cancer classifier will be of particular help in early detection of cancer.

  • 38. Bose, Indranil
    et al.
    Ohlander, Anna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kutter, Christoph
    Russom, Aman
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    DNA Analysis on integrated all foil based microdevicesManuscript (preprint) (Other academic)
  • 39. Boutajangout, Allal
    et al.
    Lindberg, Hanna
    KTH, School of Biotechnology (BIO), Protein Technology.
    Awwad, Abdulaziz
    Paul, Arun
    Wahlberg, Elisabet
    Gudmundsdotter, Hanna
    Härd, Torleif
    Löfblom, John
    KTH, School of Biotechnology (BIO), Protein Technology.
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Wisniewski, Thomas
    Affibody-mediated Reduction of Amyloid Burden and Improvement of Cognitive Decline in an Animal Model of Alzheimer’s diseaseManuscript (preprint) (Other academic)
  • 40. Bouzenzana, Jamel
    et al.
    Pelosi, Ludovic
    Briolay, Anne
    Briolay, Jerome
    Bulone, Vincent
    KTH, School of Biotechnology (BIO), Glycoscience.
    Identification of the first Oomycete annexin as a (1 -> 3)-beta-D-glucan synthase activator2006In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 62, no 2, p. 552-565Article in journal (Refereed)
    Abstract [en]

    (1 -> 3)-beta-D-Glucans are major components of the cell walls of Oomycetes and as such they play an essential role in the morphogenesis and growth of these microorganisms. Despite the biological importance of (1 -> 3)-beta-D-glucans, their mechanisms of biosynthesis are poorly understood. Previous studies on (1 -> 3)-beta-D-glucan synthases from Saprolegnia monoica have shown that three protein bands of an apparent molecular weight of 34, 48 and 50 kDa co-purify with enzyme activity. However, none of the corresponding proteins have been identified. Here we have identified, purified, sequenced and characterized a protein from the 34 kDa band and clearly shown that it has all the biochemical properties of proteins from the annexin family. In addition, we have unequivocally demonstrated that the purified protein is an activator of (1 -> 3)-beta-D-glucan synthase. This represents a new type of function for proteins belonging to the annexin family. Two other proteins from the 48 and 50 kDa bands were identified as ATP synthase subunits, which most likely arise from contaminations by mitochondria during membrane preparation. The results, which are discussed in relation with the possible regulation mechanisms of (1 -> 3)-beta-D-glucan synthases, represent a first step towards a better understanding of cell wall polysaccharide biosynthesis in Oomycetes.

  • 41.
    Brandt, Ludwig
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics.
    Pfefferle, Aline
    Goodridge, Jodie
    Malmberg, Karl-Johan
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Cytotoxicity and killing kinetics of KIR educated NK cells2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 301-301Article in journal (Other academic)
  • 42.
    Branneby, Cecilia
    KTH, School of Biotechnology (BIO), Biochemistry.
    Exploiting enzyme promiscuity for rational design2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Enzymes are today well recognized in various industrial applications, being an important component in detergents, and catalysts in the production of agrochemicals, foods, pharmaceuticals, and fine chemicals. Their large use is mainly due to their high selectivity and environmental advantage, compared to traditional catalysts. Tools and techniques in molecular biology offer the possibility to screen the natural sources and engineer new enzyme activities which further increases their usefulness as catalysts, in a broader area.

    Although enzymes show high substrate and reaction selectivity many enzymes are today known to catalyze other reactions than their natural ones. This is called enzyme promiscuity. It has been suggested that enzyme promiscuity is Nature’s way to create diversity. Small changes in the protein sequence can give the enzyme new reaction specificity.

    In this thesis I will present how rational design, based on molecular modeling, can be used to explore enzyme promiscuity and to change the enzyme reaction specificity. The first part of this work describes how Candida antarctica lipase B (CALB), by a single point mutation, was mutated to give increased activity for aldol additions, Michael additions and epoxidations. The activities of these reactions were predicted by quantum chemical calculations, which suggested that a single-point mutant of CALB would catalyze these reactions. Hence, the active site of CALB, which consists of a catalytic triad (Ser, His, Asp) and an oxyanion hole, was targeted by site-directed mutagenesis and the nucleophilic serine was mutated for either glycine or alanine. Enzymes were expressed in Pichia pastoris and analyzed for activity of the different reactions. In the case of the aldol additions the best mutant showed a four-fold initial rate over the wild type enzyme, for hexanal. Also Michael additions and epoxidations were successfully catalyzed by this mutant.

    In the last part of this thesis, rational design of alanine racemase from Geobacillus stearothermophilus was performed in order to alter the enzyme specificity. Active protein was expressed in Escherichia coli and analyzed. The explored reaction was the conversion of alanine to pyruvate and 2-butanone to 2-butylamine. One of the mutants showed increased activity for transamination, compared to the wild type.

  • 43. Brasko, Csilla
    et al.
    Smith, Kevin
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Molnar, Csaba
    Farago, Nora
    Hegedus, Lili
    Balind, Arpad
    Balassa, Tamas
    Szkalisity, Abel
    Sukosd, Farkas
    Kocsis, Katalin
    Balint, Balazs
    Paavolainen, Lassi
    Enyedi, Marton Z.
    Nagy, Istvan
    Puskas, Laszlo G.
    Haracska, Lajos
    Tamas, Gabor
    Horvath, Peter
    Intelligent image-based in situ single-cell isolation2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 226Article in journal (Refereed)
    Abstract [en]

    Quantifying heterogeneities within cell populations is important for many fields including cancer research and neurobiology; however, techniques to isolate individual cells are limited. Here, we describe a high-throughput, non-disruptive, and cost-effective isolation method that is capable of capturing individually targeted cells using widely available techniques. Using high-resolution microscopy, laser microcapture microscopy, image analysis, and machine learning, our technology enables scalable molecular genetic analysis of single cells, targetable by morphology or location within the sample.

  • 44. Brazalez, Astrid Algaba
    et al.
    Manholm, Lars
    Johansson, Martin
    Quevedo-Teruel, Oscar
    Miao, Jingwei
    KTH, School of Electrical Engineering and Computer Science (EECS), Electromagnetic Engineering.
    Investigation of a Ka-band Luneburg Lens Made of a Glide-Symmetric Holey Structure2017In: 2017 INTERNATIONAL SYMPOSIUM ON ANTENNAS AND PROPAGATION (ISAP 2017), IEEE , 2017Conference paper (Refereed)
    Abstract [en]

    A Ka-hand 2D flat-profiled Luneburg lens antenna implemented with a glide-symmetric holey structure is presented. The required refractive index for the lens design has been investigated via an analysis of the hole depth and the gap between the two metallic layers constituting the lens. The final unit cell is described and applied to create the complete metasurface Luneburg lens showing that a plane wave is obtained when feeding at an opposite arbitrary point with a discrete source.

  • 45. Broström, Eva
    et al.
    Örtqvist, Maria
    Haglund-Åkerlind, Yvonne
    Hagelberg, Stefan
    Gutierrez-Farewik, Elena M.
    KTH, School of Engineering Sciences (SCI), Mechanics.
    Trunk and center of mass movements during gait in children with juvenile idiopathic arthritis2007In: Human Movement Science, ISSN 0167-9457, E-ISSN 1872-7646, Vol. 26, no 2, p. 296-305Article in journal (Refereed)
    Abstract [en]

    Motion of the body center of mass (CoM) can often indicate the overall effect of the strategy of forward progression used. In the present study, focus is placed on trunk movements in the sagittal, coronal, and transverse/rotation plane, as well as placement of the CoM, during gait in children with juvenile idiopathic arthritis (JIA). Seventeen children with JIA, all with polyarticular lower extremity involvement were examined before and approximately two weeks after treatment with intra-articular cortico-steroid injections. Movement was recorded with a 6-camera 3D motion analysis system in both the children with JIA and in 21 healthy controls. Trunk and center of mass movements were compared between JIA and controls, and effects of intra-articular cortico-steroid treatment were evaluated. Children with JIA were more posteriorly tilted in the trunk, contrary to the common clinical impression, and had their CoM placed more posterior and off-centred, which may have been a result of pain. With such knowledge, it might be possible to better understand the effects of their pain and involvement, and ultimately to plan a treatment strategy for improving their gait patterns.

  • 46.
    Byström, Sanna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Affinity assays for profiling disease-associated proteins in human plasma2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Affinity-based proteomics offers opportunities for the discovery and validation of disease-associated proteins in human body fluids. This thesis describes the use of antibody-based immunoassays for multiplexed analysis of proteins in human plasma, serum and cerebrospinal fluid (CSF). This high-throughput method was applied with the objective to identify proteins associated to clinical variables. The main work in this thesis was conducted within the diseases of multiple sclerosis and malignant melanoma, as well as mammographic density, a risk factor for breast cancer.

    The suspension bead array (SBA) technology has been the main method for the work presented in this thesis (Paper I-IV). SBA assays and other affinity proteomic technologies were introduced for protein profiling of sample material obtained from clinical collaborators and biobanks. Perspectives on the validation of antibody selectivity by means of e.g. immuno-capture mass spectrometry are also provided.

    Paper I describes the development and application of a protocol for multiplexed pro- tein profiling of CSF. The analysis of 340 CSF samples from patients with multiple sclerosis and other neurological disease revealed proteins with potential association to disease progression (GAP43) and inflammation (SERPINA3). Paper II continued on this work with an extended investigation of more than 1,000 clinical samples and included both plasma and CSF collected from the same patients. Comparison of disease subtypes and controls revealed five plasma proteins of potential diagnostic relevance, such as IRF8 and GAP43. The previously reported associations for GAP43 and SERPINA3 in CSF was confirmed. Subsequent immunohistochemical analysis of post-mortem brain tissue revealed differential protein expression in disease affected areas. In Paper III, 150 serum samples from patients with cutaneous malignant melanoma were analyzed. Protein profiles from antibody bead arrays suggested three proteins (RGN, MTHFD1L, STX7) of differential abundance between patients with no disease recurrence and low tumor thickness (T-stage 1 and 2) compared to patients with high tumor thickness (T-stage 3 and 4) and disease recurrence. We observed MTHFD1L expression in tissue of a majority of patients, while expression of STX7 in melanoma tissue had been reported previously. Paper IV describes the analysis of protein in plasma in relation to mammographic breast density (MD), one of the strongest risk factors for the development of breast cancers. More than 1,300 women without prior history of breast cancer were screened. Linear associations to MD in two independent sample sets were found for 11 proteins, which are expressed in the breast and involved in tissue homeostasis, DNA repair, cancer development and/or progression in MD.

    In conclusion, this thesis describes the use of multiplexed antibody bead arrays for protein profiling of serum, plasma and CSF, and it shortlists disease associated proteins for further validation studies. 

  • 47.
    Byström, Sanna
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Eklund, Martin
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Hong, Mun-Gwan
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Fredolini, Claudia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Eriksson, Mikael
    Czene, Kamila
    Hall, Per
    Schwenk, Jochen. M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Gabrielson, Marike
    Affinity proteomic profiling of plasma for proteins associated to mammographic breast densityManuscript (preprint) (Other academic)
  • 48.
    Byström, Sanna
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Fredolini, Claudia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Edqvist, Per-Henrik
    Nyaiesh, Etienne-Nicholas
    Drobin, Kimi
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Matthias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Bergqvist, Michael
    Pontén, Fredrik
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Affinity proteomics exploration of melanoma identifies proteins in serum with associations to T-stage and recurrenceManuscript (preprint) (Other academic)
  • 49.
    Cakici, Baki
    et al.
    KTH, School of Information and Communication Technology (ICT), Communication: Services and Infrastucture, Software and Computer Systems, SCS.
    Hebing, Kenneth
    Swedish Institute for Infectious Control (SMI), Solna, Sweden.
    Grünewald, Maria
    Swedish Institute for Infectious Control (SMI), Solna, Sweden.
    Saretok, Paul
    Swedish Institute for Infectious Control (SMI), Solna, Sweden.
    Hulth, Anette
    Swedish Institute for Infectious Control (SMI), Solna, Sweden.
    CASE: a framework for computer supported outbreak detection2010In: BMC Medical Informatics and Decision Making, ISSN 1472-6947, E-ISSN 1472-6947, Vol. 10, p. 14-Article in journal (Refereed)
    Abstract [en]

    Background: In computer supported outbreak detection, a statistical method is applied to a collection of cases to detect any excess cases for a particular disease. Whether a detected aberration is a true outbreak is decided by a human expert. We present a technical framework designed and implemented at the Swedish Institute for Infectious Disease Control for computer supported outbreak detection, where a database of case reports for a large number of infectious diseases can be processed using one or more statistical methods selected by the user. Results: Based on case information, such as diagnosis and date, different statistical algorithms for detecting outbreaks can be applied, both on the disease level and the subtype level. The parameter settings for the algorithms can be configured independently for different diagnoses using the provided graphical interface. Input generators and output parsers are also provided for all supported algorithms. If an outbreak signal is detected, an email notification is sent to the persons listed as receivers for that particular disease. Conclusions: The framework is available as open source software, licensed under GNU General Public License Version 3. By making the code open source, we wish to encourage others to contribute to the future development of computer supported outbreak detection systems, and in particular to the development of the CASE framework.

  • 50.
    Caraballo, Rémi
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Sakulsombat, Morakot
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Ramström, Olof
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Towards Dynamic Drug Design: Identification and Optimization of β-Galactosidase Inhibitors from a Dynamic Hemithioacetal System2010In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 11, no 11, p. 1600-1606Article in journal (Refereed)
    Abstract [en]

    A discovery strategy relying on the identification of fragments through resolution of a constitutional dynamic system, coupled to subsequent static ligand design and optimization, is demonstrated. The strategic design and synthesis of the best molecular fragments identified from a dynamic hemithioacetal system into static ligand structures yielded a range of -galactosidase inhibitors. Two series of structures mimicking the hemithioacetal motif were envisaged: thioglycosides and C-glycosides. Inhibition studies provided important structural information for the two groups, and 1-thiobenzyl--D-galactopyranoside demonstrated the best inhibitory effects.

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