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  • 1.
    Akhras, Michael
    et al.
    KTH, School of Biotechnology (BIO).
    Thiyagarajan, Sreedevi
    Stanford Univ, Stanford Genome Technol Ctr.
    Villablanca, Andrea C.
    Stanford Univ, Stanford Genome Technol Ctr.
    Davis, Ronald W.
    Stanford Univ, Stanford Genome Technol Ctr.
    Nyrén, Pål
    KTH, School of Biotechnology (BIO).
    Pourmand, Nader
    Stanford Univ, Stanford Genome Technol Ctr.
    PathogenMip Assay: A Multiplex Pathogen Detection Assay2007In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 2, no 2, p. e223-Article in journal (Refereed)
    Abstract [en]

    The Molecular Inversion Probe (MIP) assay has been previously applied to a large-scale human SNP detection. Here we describe the PathogenMip Assay, a complete protocol for probe production and applied approaches to pathogen detection. We have demonstrated the utility of this assay with an initial set of 24 probes targeting the most clinically relevant HPV genotypes associated with cervical cancer progression. Probe construction was based on a novel, cost-effective, ligase-based protocol. The assay was validated by performing pyrosequencing and Microarray chip detection in parallel experiments. HPV plasmids were used to validate sensitivity and selectivity of the assay. In addition, 20 genomic DNA extracts from primary tumors were genotyped with the PathogenMip Assay results and were in 100% agreement with conventional sequencing using an L1-based HPV genotyping protocol. The PathogenMip Assay is a widely accessible protocol for producing and using highly discriminating probes, with experimentally validated results in pathogen genotyping, which could potentially be applied to the detection and characterization of any microbe.

  • 2. Al-Sabahi, Jamal
    et al.
    Bora, Tanujjal
    Al-Abri, Mohammed
    Dutta, Joydeep
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Efficient visible light photocatalysis of benzene, toluene, ethylbenzene and xylene (BTEX) in aqueous solutions using supported zinc oxide nanorods2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0189276Article in journal (Refereed)
    Abstract [en]

    Benzene, toluene, ethylbenzene and xylenes (BTEX) are some of the common environmental pollutants originating mainly from oil and gas industries, which are toxic to human as well as other living organisms in the ecosystem. Here we investigate photocatalytic degradation of BTEX under visible light irradiation using supported zinc oxide (ZnO) nanorods grown on glass substrates using a microwave assisted hydrothermal method. ZnO nanorods were characterized by electron microscopy, X-ray diffraction (XRD), specific surface area, UV/visible absorption and photoluminescence spectroscopy. Visible light photocatalytic degradation products of BTEX are studied for individual components using gas chromatograph/mass spectrometer (GC/MS). ZnO nanorods with significant amount of electronic defect states, due to the fast crystallization of the nanorods under microwave irradiation, exhibited efficient degradation of BTEX under visible light, degrading more than 80% of the individual BTEX components in 180 minutes. Effect of initial concentration of BTEX as individual components is also probed and the photocatalytic activity of the ZnO nanorods in different conditions is explored. Formation of intermediate byproducts such as phenol, benzyl alcohol, benzaldehyde and benzoic acid were confirmed by our HPLC analysis which could be due to the photocatalytic degradation of BTEX. Carbon dioxide was evaluated and showed an increasing pattern over time indicating the mineralization process confirming the conversion of toxic organic compounds into benign products.

  • 3. Andersson, Anders F.
    et al.
    Lindberg, Mathilda
    Jakobsson, Hedvig
    Bäckhed, Fredrik
    Nyrén, Pål
    KTH, School of Biotechnology (BIO).
    Engstrand, Lars
    Comparative Analysis of Human Gut Microbiota by Barcoded Pyrosequencing2008In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 3, no 7, p. e2836-Article in journal (Refereed)
    Abstract [en]

    Humans host complex microbial communities believed to contribute to health maintenance and, when in imbalance, to the development of diseases. Determining the microbial composition in patients and healthy controls may thus provide novel therapeutic targets. For this purpose, high-throughput, cost-effective methods for microbiota characterization are needed. We have employed 454-pyrosequencing of a hyper-variable region of the 16S rRNA gene in combination with sample-specific barcode sequences which enables parallel in-depth analysis of hundreds of samples with limited sample processing. In silico modeling demonstrated that the method correctly describes microbial communities down to phylotypes below the genus level. Here we applied the technique to analyze microbial communities in throat, stomach and fecal samples. Our results demonstrate the applicability of barcoded pyrosequencing as a high-throughput method for comparative microbial ecology.

  • 4. Andersson, Sandra
    et al.
    Nilsson, Kenneth
    Fagerberg, Linn
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hallström, Björn M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sundström, Christer
    Danielsson, Angelika
    Edlund, Karolina
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Asplund, Anna
    The Transcriptomic and Proteomic Landscapes of Bone Marrow and Secondary Lymphoid Tissues2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, p. e115911-Article in journal (Refereed)
    Abstract [en]

    Background: The sequencing of the human genome has opened doors for global gene expression profiling, and the immense amount of data will lay an important ground for future studies of normal and diseased tissues. The Human Protein Atlas project aims to systematically map the human gene and protein expression landscape in a multitude of normal healthy tissues as well as cancers, enabling the characterization of both housekeeping genes and genes that display a tissue-specific expression pattern. This article focuses on identifying and describing genes with an elevated expression in four lymphohematopoietic tissue types (bone marrow, lymph node, spleen and appendix), based on the Human Protein Atlas-strategy that combines high throughput transcriptomics with affinity-based proteomics. Results: An enriched or enhanced expression in one or more of the lymphohematopoietic tissues, compared to other tissue-types, was seen for 693 out of 20,050 genes, and the highest levels of expression were found in bone marrow for neutrophilic and erythrocytic genes. A majority of these genes were found to constitute well-characterized genes with known functions in lymphatic or hematopoietic cells, while others are not previously studied, as exemplified by C19ORF59. Conclusions: In this paper we present a strategy of combining next generation RNA-sequencing with in situ affinity-based proteomics in order to identify and describe new gene targets for further research on lymphatic or hematopoietic cells and tissues. The results constitute lists of genes with enriched or enhanced expression in the four lymphohematopoietic tissues, exemplified also on protein level with immunohistochemical images.

  • 5. Arner, P.
    et al.
    Henjes, Frauke
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Darmanis, Spyros N.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Dahlman, I.
    Iresjö, B. -M
    Naredi, P.
    Agustsson, T.
    Lundholm, K.
    Nilsson, Peter M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Rydén, M.
    Circulating Carnosine Dipeptidase 1 associates with weight loss and poor prognosis in gastrointestinal cancer2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4, article id e0123566Article in journal (Refereed)
    Abstract [en]

    Background: Cancer cachexia (CC) is linked to poor prognosis. Although the mechanisms promoting this condition are not known, several circulating proteins have been proposed to contribute. We analyzed the plasma proteome in cancer subjects in order to identify factors associated with cachexia. Design/Subjects: Plasma was obtained from a screening cohort of 59 patients, newly diagnosed with suspected gastrointestinal cancer, with (n = 32) or without (n = 27) cachexia. Samples were subjected to proteomic profiling using 760 antibodies (targeting 698 individual proteins) from the Human Protein Atlas project. The main findings were validated in a cohort of 93 patients with verified and advanced pancreas cancer. Results: Only six proteins displayed differential plasma levels in the screening cohort. Among these, Carnosine Dipeptidase 1 (CNDP1) was confirmed by sandwich immunoassay to be lower in CC (p = 0.008). In both cohorts, low CNDP1 levels were associated with markers of poor prognosis including weight loss, malnutrition, lipid breakdown, low circulating albumin/IGF1 levels and poor quality of life. Eleven of the subjects in the discovery cohort were finally diagnosed with non-malignant disease but omitting these subjects from the analyses did not have any major influence on the results. Conclusions: In gastrointestinal cancer, reduced plasma levels of CNDP1 associate with signs of catabolism and poor outcome. These results, together with recently published data demonstrating lower circulating CNDP1 in subjects with glioblastoma and metastatic prostate cancer, suggest that CNDP1 may constitute a marker of aggressive cancer and CC.

  • 6. Ayllnon, David
    et al.
    Gil-Pita, Roberto
    Seoane, Fernando
    KTH, School of Technology and Health (STH), Medical Engineering, Medical sensors, signals and systems.
    Detection and Classification of Measurement Errors in Bioimpedance Spectroscopy2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, article id e0156522Article in journal (Refereed)
    Abstract [en]

    Bioimpedance spectroscopy (BIS) measurement errors may be caused by parasitic stray capacitance, impedance mismatch, cross-talking or their very likely combination. An accurate detection and identification is of extreme importance for further analysis because in some cases and for some applications, certain measurement artifacts can be corrected, minimized or even avoided. In this paper we present a robust method to detect the presence of measurement artifacts and identify what kind of measurement error is present in BIS measurements. The method is based on supervised machine learning and uses a novel set of generalist features for measurement characterization in different immittance planes. Experimental validation has been carried out using a database of complex spectra BIS measurements obtained from different BIS applications and containing six different types of errors, as well as error-free measurements. The method obtained a low classification error (0.33%) and has shown good generalization. Since both the features and the classification schema are relatively simple, the implementation of this pre-processing task in the current hardware of bioimpedance spectrometers is possible.

  • 7.
    Ayoglu, Burcu
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Szarka, Eszter
    Huber, Krisztina
    Orosz, Anita
    Babos, Fruzsina
    Magyar, Anna
    Hudecz, Ferenc
    Rojkovich, Bernadette
    Gati, Tamas
    Nagy, Gyoergy
    Schwenk, Jochen M.
    Sarmay, Gabriella
    Prechl, Jozsef
    Nilsson, Peter
    Papp, Krisztian
    Bead Arrays for Antibody and Complement Profiling Reveal Joint Contribution of Antibody Isotypes to C3 Deposition2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, p. e96403-Article in journal (Refereed)
    Abstract [en]

    The development of antigen arrays has provided researchers with great tools to identify reactivities against self or foreign antigens from body fluids. Yet, these approaches mostly do not address antibody isotypes and their effector functions even though these are key points for a more detailed understanding of disease processes. Here, we present a bead array-based assay for a multiplexed determination of antigen-specific antibody levels in parallel with their properties for complement activation. We measured the deposition of C3 fragments from serum samples to reflect the degree of complement activation via all three complement activation pathways. We utilized the assay on a bead array containing native and citrullinated peptide antigens to investigate the levels of IgG, IgM and IgA autoantibodies along with their complement activating properties in serum samples of 41 rheumatoid arthritis patients and 40 controls. Our analysis revealed significantly higher IgG reactivity against the citrullinated fibrinogen beta and filaggrin peptides as well as an IgA reactivity that was exclusive for citrullinated fibrinogen b peptide and C3 deposition in rheumatoid arthritis patients. In addition, we characterized the humoral immune response against the viral EBNA-1 antigen to demonstrate the applicability of this assay beyond autoimmune conditions. We observed that particular buffer compositions were demanded for separate measurement of antibody reactivity and complement activation, as detection of antigen-antibody complexes appeared to be masked due to C3 deposition. We also found that rheumatoid factors of IgM isotype altered C3 deposition and introduced false-positive reactivities against EBNA-1 antigen. In conclusion, the presented bead-based assay setup can be utilized to profile antibody reactivities and immune-complex induced complement activation in a high-throughput manner and could facilitate the understanding and diagnosis of several diseases where complement activation plays role in the pathomechanism.

  • 8. Bachelet, Delphine
    et al.
    Hassler, Signe
    Mbogning, Cyprien
    Link, Jenny
    Ryner, Malin
    Ramanujam, Ryan
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Auer, Michael
    Jensen, Poul Erik Hyldgaard
    Koch-Henriksen, Nils
    Warnke, Clemens
    Ingenhoven, Kathleen
    Buck, Dorothea
    Grummel, Verena
    Lawton, Andy
    Donnellan, Naoimh
    Hincelin-Mery, Agnes
    Sikkema, Dan
    Pallardy, Marc
    Kieseier, Bernd
    Hemmer, Bernard
    Hartung, Hans Peter
    Sorensen, Per Soelberg
    Deisenhammer, Florian
    Donnes, Pierre
    Davidson, Julie
    Fogdell-Hahn, Anna
    Broet, Philippe
    Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0162752Article in journal (Refereed)
    Abstract [en]

    Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFN beta)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFN beta-1a subcutaneous and IFN beta-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFN beta-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). Patients older than 50 years at start of IFN beta therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). Interestingly we observed that in Sweden and Germany, patients who started IFN beta in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). We confirmed previously reported differences in immunogenicity of the different types of IFN beta. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.

  • 9.
    Balakrishnan Kumar, Ramakrishnan
    et al.
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology. Department of Biosciences and Nutrition, Karolinska Institutet, Sweden.
    Zhu, Lin
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology. Department of Biosciences and Nutrition, Karolinska Institutet,.
    Idborg, Helena
    Radmark, Olof
    Jakobsson, Per-Johan
    Rinaldo-Matthis, Agnes
    Hebert, Hans
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology. Department of Biosciences and Nutrition, Karolinska Institutet,.
    Jegerschöld, Caroline
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology. Department of Biosciences and Nutrition, Karolinska Institutet,.
    Structural and Functional Analysis of Calcium Ion Mediated Binding of 5-Lipoxygenase to Nanodiscs2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0152116Article in journal (Refereed)
    Abstract [en]

    An important step in the production of inflammatory mediators of the leukotriene family is the Ca2+ mediated recruitment of 5 Lipoxygenase (5LO) to nuclear membranes. To study this reaction in vitro, the natural membrane mimicking environment of nanodiscs was used. Nanodiscs with 10.5 nm inner diameter were made with the lipid POPC and membrane scaffolding protein MSP1E3D1. Monomeric and dimeric 5LO were investigated. Monomeric 5LO mixed with Ca2+ and nanodiscs are shown to form stable complexes that 1) produce the expected leukotriene products from arachidonic acid and 2) can be, for the first time, visualised by native gel electrophoresis and negative stain transmission electron micros-copy and 3) show a highest ratio of two 5LO per nanodisc. We interpret this as one 5LO on each side of the disc. The dimer of 5LO is visualised by negative stain transmission electron microscopy and is shown to not bind to nanodiscs. This study shows the advantages of nanodiscs to obtain basic structural information as well as functional information of a complex between a monotopic membrane protein and the membrane.

  • 10. Bauso, Dario
    et al.
    Dia, Ben Mansour
    Djehiche, Boualem
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematical Statistics.
    Tembine, Hamidou
    Tempone, Raul
    Mean-Field Games for Marriage2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, p. e94933-Article in journal (Refereed)
    Abstract [en]

    This article examines mean-field games for marriage. The results support the argument that optimizing the long-term wellbeing through effort and social feeling state distribution (mean-field) will help to stabilize marriage. However, if the cost of effort is very high, the couple fluctuates in a bad feeling state or the marriage breaks down. We then examine the influence of society on a couple using mean-field sentimental games. We show that, in mean-field equilibrium, the optimal effort is always higher than the one-shot optimal effort. We illustrate numerically the influence of the couple's network on their feeling states and their well-being.

  • 11.
    Belić, Jovana
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Kumar, Arvind
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Hellgren Kotaleski, Jeanette
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Interplay between periodic stimulation and GABAergic inhibition in striatal network oscillations2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, p. 1-17Article in journal (Refereed)
    Abstract [en]

    Network oscillations are ubiquitous across many brain regions. In the basal ganglia, oscillations are also present at many levels and a wide range of characteristic frequencies have been reported to occur during both health and disease. The striatum, the main input nucleus of the basal ganglia, receives massive glutamatergic inputs from the cortex and is highly susceptible to external oscillations. However, there is limited knowledge about the exact nature of this routing process and therefore, it is of key importance to understand how time-dependent, external stimuli propagate through the striatal circuitry. Using a network model of the striatum and corticostriatal projections, we try to elucidate the importance of specific GABAergic neurons and their interactions in shaping striatal oscillatory activity. Here, we propose that fast-spiking interneurons can perform an important role in transferring cortical oscillations to the striatum especially to those medium spiny neurons that are not directly driven by the cortical oscillations. We show how the activity levels of different populations, the strengths of different inhibitory synapses, degree of outgoing projections of striatal cells, ongoing activity and synchronicity of inputs can influence network activity. These results suggest that the propagation of oscillatory inputs into the medium spiny neuron population is most efficient, if conveyed via the fast-spiking interneurons. Therefore, pharmaceuticals that target fast-spiking interneurons may provide a novel treatment for regaining the spectral characteristics of striatal activity that correspond to the healthy state.

  • 12. Bergquist, Helen
    et al.
    Rocha, Cristina S. J.
    Alvarez-Asencio, Ruben
    KTH, School of Chemical Science and Engineering (CHE), Chemistry. Universitario de Cantoblanco, Spain.
    Nguyen, Chi-Hung
    Rutland, Mark W.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry.
    Smith, C. I. Edvard
    Good, Liam
    Nielsen, Peter E.
    Zain, Rula
    Disruption of Higher Order DNA Structures in Friedreich's Ataxia (GAA)(n) Repeats by PNA or LNA Targeting2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0165788Article in journal (Refereed)
    Abstract [en]

    Expansion of (GAA)(n) repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich's ataxia. (GAA)(n) expansions form non-canonical structures, including intramolecular triplex (H-DNA), and Rloops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)(n) expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)(n) repeats of different lengths (short: n= 9, medium: n= 75 or long: n= 115) by chemical probing of triple helical and single stranded regions. We found that a triplex structure (H-DNA) forms at GAA repeats of different lengths; however, single stranded regions were not detected within the medium size pathological repeat, suggesting the presence of a more complex structure. Furthermore, (GAA) 4-PNA binding of the repeat abolished all detectable triplex DNA structures, whereas (CTT) 5-PNA did not. We present evidence that (GAA) 4-PNA can invade the DNA at the repeat region by binding the DNA CTT strand, thereby preventing non-canonical-DNA formation, and that triplex invasion complexes by (CTT) 5-PNA form at the GAA repeats. Locked nucleic acid (LNA) oligonucleotides also inhibited triplex formation at GAA repeat expansions, and atomic force microscopy analysis showed significant relaxation of plasmid morphology in the presence of GAA-LNA. Thus, by inhibiting disease related higher order DNA structures in the Frataxin gene, such PNA and LNA oligomers may have potential for discovery of drugs aiming at recovering Frataxin expression.

  • 13.
    Bergström, Ilias
    et al.
    KTH, School of Computer Science and Communication (CSC), Media Technology and Interaction Design, MID. University of Barcelona, Spain.
    Kilteni, Konstantina
    Slater, Mel
    First-Person Perspective Virtual Body Posture Influences Stress: A Virtual Reality Body Ownership Study2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 2, article id e0148060Article in journal (Refereed)
    Abstract [en]

    In immersive virtual reality (IVR) it is possible to replace a person's real body by a life-sized virtual body that is seen from first person perspective to visually substitute their own. Multisensory feedback from the virtual to the real body (such as the correspondence of touch and also movement) can also be present. Under these conditions participants typically experience a subjective body ownership illusion (BOI) over the virtual body, even though they know that it is not their real one. In most studies and applications the posture of the real and virtual bodies are as similar as possible. Here we were interested in whether the BOI is diminished when there are gross discrepancies between the real and virtual body postures. We also explored whether a comfortable or uncomfortable virtual body posture would induce feelings and physiological responses commensurate with the posture. We carried out an experiment with 31 participants in IVR realized with a wide field-of-view head-mounted display. All participants were comfortably seated. Sixteen of them were embodied in a virtual body designed to be in a comfortable posture, and the remainder in an uncomfortable posture. The results suggest that the uncomfortable body posture led to lesser subjective BOI than the comfortable one, but that participants in the uncomfortable posture experienced greater awareness of their autonomic physiological responses. Moreover their heart rate, heart rate variability, and the number of mistakes in a cognitive task were associated with the strength of their BOI in the uncomfortable posture: greater heart rate, lower heart rate variability and more mistakes were associated with higher levels of the BOI. These findings point in a consistent direction-that the BOI over a body that is in an uncomfortable posture can lead to subjective, physiological and cognitive effects consistent with discomfort that do not occur with the BOI over a body in a comfortable posture.

  • 14.
    Bernhem, Kristoffer
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Blom, H.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Brismar, Hjalmar
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics.
    Quantification of endogenous and exogenous protein expressions of Na,K-ATPase with super-resolution PALM/STORM imaging2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0195825Article in journal (Refereed)
    Abstract [en]

    Transient transfection of fluorescent fusion proteins is a key enabling technology in fluorescent microscopy to spatio-temporally map cellular protein distributions. Transient transfection of proteins may however bypass normal regulation of expression, leading to overexpression artefacts like misallocations and excess amounts. In this study we investigate the use of STORM and PALM microscopy to quantitatively monitor endogenous and exogenous protein expression. Through incorporation of an N-terminal hemagglutinin epitope to a mMaple3 fused Na,K-ATPase (α1 isoform), we analyze the spatial and quantitative changes of plasma membrane Na,K-ATPase localization during competitive transient expression. Quantification of plasma membrane protein density revealed a time dependent increase of Na,K-ATPase, but no increase in size of protein clusters. Results show that after 41h transfection, the total plasma membrane density of Na,K-ATPase increased by 63% while the endogenous contribution was reduced by 16%. © 2018 Bernhem et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

  • 15.
    Berthet, Pierre
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Lansner, Anders
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Optogenetic Stimulation in a Computational Model of the Basal Ganglia Biases Action Selection and Reward Prediction Error2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, p. e90578-Article in journal (Refereed)
    Abstract [en]

    Optogenetic stimulation of specific types of medium spiny neurons (MSNs) in the striatum has been shown to bias the selection of mice in a two choices task. This shift is dependent on the localisation and on the intensity of the stimulation but also on the recent reward history. We have implemented a way to simulate this increased activity produced by the optical flash in our computational model of the basal ganglia (BG). This abstract model features the direct and indirect pathways commonly described in biology, and a reward prediction pathway (RP). The framework is similar to Actor-Critic methods and to the ventral/ dorsal distinction in the striatum. We thus investigated the impact on the selection caused by an added stimulation in each of the three pathways. We were able to reproduce in our model the bias in action selection observed in mice. Our results also showed that biasing the reward prediction is sufficient to create a modification in the action selection. However, we had to increase the percentage of trials with stimulation relative to that in experiments in order to impact the selection. We found that increasing only the reward prediction had a different effect if the stimulation in RP was action dependent (only for a specific action) or not. We further looked at the evolution of the change in the weights depending on the stage of learning within a block. A bias in RP impacts the plasticity differently depending on that stage but also on the outcome. It remains to experimentally test how the dopaminergic neurons are affected by specific stimulations of neurons in the striatum and to relate data to predictions of our model.

  • 16.
    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.

  • 17.
    Blom, Hans
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Rönnlund, Daniel
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Scott, L.
    Westin, L.
    Widengren, Jerker
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Aperia, A.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Spatial Distribution of DARPP-32 in Dendritic Spines2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e75155-Article in journal (Refereed)
    Abstract [en]

    The phosphoprotein DARPP-32 (dopamine and cyclic adenosine 3́, 5́-monophosphate-regulated phosphoprotein, 32 kDa) is an important component in the molecular regulation of postsynaptic signaling in neostriatum. Despite the importance of this phosphoprotein, there is as yet little known about the nanoscale distribution of DARPP-32. In this study we applied superresolution stimulated emission depletion microscopy (STED) to assess the expression and distribution of DARPP-32 in striatal neurons. Primary culture of striatal neurons were immunofluorescently labeled for DARPP-32 with Alexa-594 and for the dopamine D1 receptor (D1R) with atto-647N. Dual-color STED microscopy revealed discrete localizations of DARPP-32 and D1R in the spine structure, with clustered distributions in both head and neck. Dissected spine structures reveal that the DARPP-32 signal rarely overlapped with the D1R signal. The D1R receptor is positioned in an "aggregated" manner primarily in the spine head and to some extent in the neck, while DARPP-32 forms several neighboring small nanoclusters spanning the whole spine structure. The DARPP-32 clusters have a mean size of 52 +/- 6 nm, which is close to the resolution limit of the microscope and corresponds to the physical size of a few individual phosphoprotein immunocomplexes. Dissection of synaptic proteins using superresolution microscopy gives possibilities to reveal in better detail biologically relevant information, as compared to diffraction-limited microscopy. In this work, the dissected postsynaptic topology of the DARPP-32 phosphoprotein provides strong evidence for a compartmentalized and confined distribution in dendritic spines. The protein topology and the relatively low copy number of phosphoprotein provides a conception of DARPP-32's possibilities to fine-tune the regulation of synaptic signaling, which should have an impact on the performance of the neuronal circuits in which it is expressed.

  • 18. Blystad, Ida
    et al.
    Warntjes, J. B. Marcel
    Smedby, Örjan
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Image Processing and Visualization. Linköping University, Sweden.
    Lundberg, Peter
    Larsson, Elna-Marie
    Tisell, Anders
    Quantitative MRI for analysis of peritumoral edema in malignant gliomas2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0177135Article in journal (Refereed)
    Abstract [en]

    Background and purpose Damage to the blood-brain barrier with subsequent contrast enhancement is a hallmark of glioblastoma. Non-enhancing tumor invasion into the peritumoral edema is, however, not usually visible on conventional magnetic resonance imaging. New quantitative techniques using relaxometry offer additional information about tissue properties. The aim of this study was to evaluate longitudinal relaxation R-1, transverse relaxation R-2, and proton density in the peritumoral edema in a group of patients with malignant glioma before surgery to assess whether relaxometry can detect changes not visible on conventional images. Methods In a prospective study, 24 patients with suspected malignant glioma were examined before surgery. A standard MRI protocol was used with the addition of a quantitative MR method (MAGIC), which measured R-1, R-2, and proton density. The diagnosis of malignant glioma was confirmed after biopsy/surgery. In 19 patients synthetic MR images were then created from the MAGIC scan, and ROIs were placed in the peritumoral edema to obtain the quantitative values. Dynamic susceptibility contrast perfusion was used to obtain cerebral blood volume (rCBV) data of the peritumoral edema. Voxel-based statistical analysis was performed using a mixed linear model. Results R-1, R-2, and rCBV decrease with increasing distance from the contrast-enhancing part of the tumor. There is a significant increase in R1 gradient after contrast agent injection (P<.0001). There is a heterogeneous pattern of relaxation values in the peritumoral edema adjacent to the contrast-enhancing part of the tumor. Conclusion Quantitative analysis with relaxometry of peritumoral edema in malignant gliomas detects tissue changes not visualized on conventional MR images. The finding of decreasing R-1 and R-2 means shorter relaxation times closer to the tumor, which could reflect tumor invasion into the peritumoral edema. However, these findings need to be validated in the future.

  • 19.
    Borgström, Erik
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Lundin, Sverker
    KTH, School of Biotechnology (BIO), Gene Technology.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Large Scale Library Generation for High Throughput Sequencing Authors and Affiliations2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 4, p. e19119-Article in journal (Refereed)
    Abstract [en]

    Background: Large efforts have recently been made to automatethe sample preparation protocols for massively parallel sequencing in order to match the increasing instrument throughput. Still, the size selection through agarose gel electrophoresis separation is a labor-intensive bottleneck of these protocols. Methodology/Principal Findings: In this study a method for automatic library preparation and size selection on a liquid handling robot is presented. The method utilizes selective precipitation of certain sizes of DNA molecules on to paramagnetic beads for cleanup and selection after standard enzymatic reactions. Conclusions/Significance: The method is used to generate libraries for de novo and re-sequencing on the Illumina HiSeq 2000 instrument with a throughput of 12 samples per instrument in approximately 4 hours. The resulting output data show quality scores and pass filter rates comparable to manually prepared samples. The sample size distribution can be adjusted for each application, and are suitable for all high throughput DNA processing protocols seeking to control size intervals.

  • 20.
    Borgström, Erik
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Paterlini, Marta
    Mold, Jeff E.
    Frisen, Jonas
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Comparison of whole genome amplification techniques for human single cell exome sequencing2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0171566Article in journal (Refereed)
    Abstract [en]

    Background Whole genome amplification (WGA) is currently a prerequisite for single cell whole genome or exome sequencing. Depending on the method used the rate of artifact formation, allelic dropout and sequence coverage over the genome may differ significantly. Results The largest difference between the evaluated protocols was observed when analyzing the target coverage and read depth distribution. These differences also had impact on the downstream variant calling. Conclusively, the products from the AMPLI1 and MALBAC kits were shown to be most similar to the bulk samples and are therefore recommended for WGA of single cells. Discussion In this study four commercial kits for WGA (AMPLI1, MALBAC, Repli-G and PicoPlex) were used to amplify human single cells. The WGA products were exome sequenced together with non-amplified bulk samples from the same source. The resulting data was evaluated in terms of genomic coverage, allelic dropout and SNP calling.

  • 21.
    Borysov, Stanislav S.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Nanostructure Physics. KTH, Centres, Nordic Institute for Theoretical Physics NORDITA. Stockholm University, Sweden.
    Balatsky, Alexander V.
    KTH, Centres, Nordic Institute for Theoretical Physics NORDITA. Stockholm University, Sweden.
    Cross-Correlation Asymmetries and Causal Relationships between Stock and Market Risk2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e105874-Article in journal (Refereed)
    Abstract [en]

    We study historical correlations and lead-lag relationships between individual stock risk (volatility of daily stock returns) and market risk (volatility of daily returns of a market-representative portfolio) in the US stock market. We consider the cross-correlation functions averaged over all stocks, using 71 stock prices from the Standard & Poor's 500 index for 1994-2013. We focus on the behavior of the cross-correlations at the times of financial crises with significant jumps of market volatility. The observed historical dynamics showed that the dependence between the risks was almost linear during the US stock market downturn of 2002 and after the US housing bubble in 2007, remaining at that level until 2013. Moreover, the averaged cross-correlation function often had an asymmetric shape with respect to zero lag in the periods of high correlation. We develop the analysis by the application of the linear response formalism to study underlying causal relations. The calculated response functions suggest the presence of characteristic regimes near financial crashes, when the volatility of an individual stock follows the market volatility and vice versa.

  • 22.
    Borysov, Stanislav S.
    et al.
    KTH, Centres, Nordic Institute for Theoretical Physics NORDITA.
    Geilhufe, R. Matthias
    KTH, Centres, Nordic Institute for Theoretical Physics NORDITA.
    Balatsky, Alexander V.
    KTH, Centres, Nordic Institute for Theoretical Physics NORDITA.
    Organic materials database: An open-access online database for data mining2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0171501Article in journal (Refereed)
    Abstract [en]

    We present an organic materials database (OMDB) hosting thousands of Kohn-Sham electronic band structures, which is freely accessible online at http://omdb.diracmaterials.org. The OMDB focus lies on electronic structure, density of states and other properties for purely organic and organometallic compounds that are known to date. The electronic band structures are calculated using density functional theory for the crystal structures contained in the Crystallography Open Database. The OMDB web interface allows users to retrieve materials with specified target properties using non-trivial queries about their electronic structure. We illustrate the use of the OMDB and how it can become an organic part of search and prediction of novel functional materials via data mining techniques. As a specific example, we provide data mining results for metals and semiconductors, which are known to be rare in the class of organic materials.

  • 23. Boström, Johan
    et al.
    Sramkova, Zuzana
    Salasova, Alena
    Johard, Helena
    Mahdessian, Diana
    Fedr, Radek
    Marks, Carolyn
    Medalova, Jirina
    Soucek, Karel
    Lundberg, Emma
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Linnarsson, Sten
    Bryja, Vitezslav
    Sekyrova, Petra
    Altun, Mikael
    Andang, Michael
    Comparative cell cycle transcriptomics reveals synchronization of developmental transcription factor networks in cancer cells2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0188772Article in journal (Refereed)
    Abstract [en]

    The cell cycle coordinates core functions such as replication and cell division. However, cell-cycle-regulated transcription in the control of non-core functions, such as cell identity maintenance through specific transcription factors (TFs) and signalling pathways remains unclear. Here, we provide a resource consisting of mapped transcriptomes in unsynchro-nized HeLa and U2OS cancer cells sorted for cell cycle phase by Fucci reporter expression. We developed a novel algorithm for data analysis that enables efficient visualization and data comparisons and identified cell cycle synchronization of Notch signalling and TFs associated with development. Furthermore, the cell cycle synchronizes with the circadian clock, providing a possible link between developmental transcriptional networks and the cell cycle. In conclusion we find that cell cycle synchronized transcriptional patterns are temporally compartmentalized and more complex than previously anticipated, involving genes, which control cell identity and development.

  • 24. Cai, Tingting
    et al.
    Zhu, Huilin
    Xu, Jie
    Wu, Shijing
    Li, Xinge
    He, Sailing
    KTH, School of Electrical Engineering (EES), Electromagnetic Engineering.
    Human cortical neural correlates of visual fatigue during binocular depth perception: An fNIRS study2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0172426Article in journal (Refereed)
    Abstract [en]

    Functional near-infrared spectroscopy (fNIRS) was adopted to investigate the cortical neural correlates of visual fatigue during binocular depth perception for different disparities (from 0.1 degrees to 1.5 degrees). By using a slow event-related paradigm, the oxyhaemoglobin (HbO) responses to fused binocular stimuli presented by the random-dot stereogram (RDS) were recorded over the whole visual dorsal area. To extract from an HbO curve the characteristics that are correlated with subjective experiences of stereopsis and visual fatigue, we proposed a novel method to fit the time-course HbO curve with various response functions which could reflect various processes of binocular depth perception. Our results indicate that the parietal-occipital cortices are spatially correlated with binocular depth perception and that the process of depth perception includes two steps, associated with generating and sustaining stereovision. Visual fatigue is caused mainly by generating stereovision, while the amplitude of the haemodynamic response corresponding to sustaining stereovision is correlated with stereopsis. Combining statistical parameter analysis and the fitted time-course analysis, fNIRS could be a promising method to study visual fatigue and possibly other multi-process neural bases.

  • 25. Carlsson, Mikael A.
    et al.
    Bisch-Knaden, Sonja
    Schaepers, Alexander
    Mozuraitis, Raimondas
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Hansson, Bill S.
    Janz, Niklas
    Odour Maps in the Brain of Butterflies with Divergent Host-Plant Preferences2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e24025-Article in journal (Refereed)
    Abstract [en]

    Butterflies are believed to use mainly visual cues when searching for food and oviposition sites despite that their olfactory system is morphologically similar to their nocturnal relatives, the moths. The olfactory ability in butterflies has, however, not been thoroughly investigated. Therefore, we performed the first study of odour representation in the primary olfactory centre, the antennal lobes, of butterflies. Host plant range is highly variable within the butterfly family Nymphalidae, with extreme specialists and wide generalists found even among closely related species. Here we measured odour evoked Ca(2+) activity in the antennal lobes of two nymphalid species with diverging host plant preferences, the specialist Aglais urticae and the generalist Polygonia c-album. The butterflies responded with stimulus-specific combinations of activated glomeruli to single plant-related compounds and to extracts of host and non-host plants. In general, responses were similar between the species. However, the specialist A. urticae responded more specifically to its preferred host plant, stinging nettle, than P. c-album. In addition, we found a species-specific difference both in correlation between responses to two common green leaf volatiles and the sensitivity to these compounds. Our results indicate that these butterflies have the ability to detect and to discriminate between different plant-related odorants.

  • 26. Chen, Kevin
    et al.
    Maaskola, Jonas
    Max Delbrück Centrum für Molekulare Medizin, Berlin-Buch, Germany.
    Siegal, Mark L
    Rajewsky, Nikolaus
    Reexamining microRNA site accessibility in Drosophila: a population genomics study.2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 5Article in journal (Refereed)
    Abstract [en]

    Kertesz et al. (Nature Genetics 2008) described PITA, a miRNA target prediction algorithm based on hybridization energy and site accessibility. In this note, we used a population genomics approach to reexamine their data and found that the PITA algorithm had lower specificity than methods based on evolutionary conservation at comparable levels of sensitivity.We also showed that deeply conserved miRNAs tend to have stronger hybridization energies to their targets than do other miRNAs. Although PITA had higher specificity in predicting targets than a naïve seed-match method, this signal was primarily due to the use of a single cutoff score for all miRNAs and to the observed correlation between conservation and hybridization energy. Overall, our results clarify the accuracy of different miRNA target prediction algorithms in Drosophila and the role of site accessibility in miRNA target prediction.

  • 27. Chen, Yun
    et al.
    Molnar, Mátyás
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Li, Li
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Friberg, Peter
    Gan, Li-Ming
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fu, Ying
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Characterization of VCAM-1-Binding Peptide-Functionalized Quantum Dots for Molecular Imaging of Inflamed Endothelium2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e83805-Article in journal (Refereed)
    Abstract [en]

    Inflammation-induced activation of endothelium constitutes one of the earliest changes during atherogenesis. New imaging techniques that allow detecting activated endothelial cells can improve the identification of persons at high cardiovascular risk in early stages. Quantum dots (QDs) have attractive optical properties such as bright fluorescence and high photostability, and have been increasingly studied and developed for bio-imaging and bio-targeting applications. We report here the development of vascular cell adhesion molecule-1 binding peptide (VCAM-1 binding peptide) functionalized QDs (VQDs) from amino QDs. It was found that the QD fluorescence signal in tumor necrosis factor alpha (TNF-alpha) treated endothelial cells in vitro was significantly higher when these cells were labeled with VQDs than amino QDs. The VQD labeling of TNF-alpha-treated endothelial cells was VCAM-1 specific since pre-incubation with recombinant VCAM-1 blocked cells' uptake of VQDs. Our ex vivo and in vivo experiments showed that in the inflamed endothelium, QD fluorescence signal from VQDs was also much stronger than that of amino QDs. Moreover, we observed that the QD fluorescence peak was significantly blue-shifted after VQDs interacted with aortic endothelial cells in vivo and in vitro. A similar blue-shift was observed after VQDs were incubated with recombinant VCAM-1 in tube. We anticipate that the specific interaction between VQDs and VCAM-1 and the blue-shift of the QD fluorescence peak can be very useful for VCAM-1 detection in vivo.

  • 28. Cheng, Qing
    et al.
    Lu, Li
    Grafström, Jonas
    Olofsson, Maria Hägg
    Thorell, Jan-Olov
    Samén, Erik
    Johansson, Katarina
    Ahlzén, Hanna-Stina
    Stone-Elander, Sharon
    Linder, Stig
    Arnér, Elias S J
    Combining [11C]-AnxA5 PET imaging with serum biomarkers for improved detection in live mice of modest cell death in human solid tumor xenografts.2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 8, p. e42151-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In vivo imaging using Annexin A5-based radioligands is a powerful technique for visualizing massive cell death, but has been less successful in monitoring the modest cell death typically seen in solid tumors after chemotherapy. Here we combined dynamic positron emission tomography (PET) imaging using Annexin A5 with a serum-based apoptosis marker, for improved sensitivity and specificity in assessment of chemotherapy-induced cell death in a solid tumor model.

    METHODOLOGY/PRINCIPAL FINDINGS: Modest cell death was induced by doxorubicin in a mouse xenograft model with human FaDu head and neck cancer cells. PET imaging was based on (11)C-labeled Sel-tagged Annexin A5 ([(11)C]-AnxA5-ST) and a size-matched control. 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]-FDG) was utilized as a tracer of tissue metabolism. Serum biomarkers for cell death were ccK18 and K18 (M30 Apoptosense® and M65). Apoptosis in tissue sections was verified ex vivo for validation. Both PET imaging using [(11)C]-AnxA5-ST and serum ccK18/K18 levels revealed treatment-induced cell death, with ccK18 displaying the highest detection sensitivity. [(18)F]-FDG uptake was not affected by this treatment in this tumor model. [(11)C]-AnxA5-ST gave robust imaging readouts at one hour and its short half-life made it possible to perform paired scans in the same animal in one imaging session.

    CONCLUSIONS/SIGNIFICANCE: The combined use of dynamic PET with [(11)C]-AnxA5-ST, showing specific increases in tumor binding potential upon therapy, with ccK18/K18 serum measurements, as highly sensitive markers for cell death, enabled effective assessment of modest therapy-induced cell death in this mouse xenograft model of solid human tumors.

  • 29.
    Costea, Paul Igor
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Akan, Pelin
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    TagGD: Fast and Accurate Software for DNA Tag Generation and Demultiplexing2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, p. e57521-Article in journal (Refereed)
    Abstract [en]

    Multiplexing is of vital importance for utilizing the full potential of next generation sequencing technologies. We here report TagGD (DNA-based Tag Generator and Demultiplexor), a fully-customisable, fast and accurate software package that can generate thousands of barcodes satisfying user-defined constraints and can guarantee full demultiplexing accuracy. The barcodes are designed to minimise their interference with the experiment. Insertion, deletion and substitution events are considered when designing and demultiplexing barcodes. 20,000 barcodes of length 18 were designed in 5 minutes and 2 million barcoded Illumina HiSeq-like reads generated with an error rate of 2% were demultiplexed with full accuracy in 5 minutes. We believe that our software meets a central demand in the current high-throughput biology and can be utilised in any field with ample sample abundance. The software is available on GitHub (https://github.com/pelinakan/UBD.git).

  • 30. Crommert, M. E.
    et al.
    Halvorsen, Kjartan
    KTH, School of Technology and Health (STH).
    Ekblom, M. M.
    Trunk muscle activation at the initiation and braking of bilateral shoulder flexion movements of different amplitudes2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0141777Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate if trunk muscle activation patterns during rapid bilateral shoulder flexions are affected by movement amplitude. Eleven healthy males performed shoulder flexion movements starting from a position with arms along sides (0°) to either 45°, 90° or 180°. EMG was measured bilaterally from transversus abdominis (TrA), obliquus internus (OI) with intra-muscular electrodes, and from rectus abdominis (RA), erector spinae (ES) and deltoideus with surface electrodes. 3D kinematics was recorded and inverse dynamics was used to calculate the reactive linear forces and torque about the shoulders and the linear and angular impulses. The sequencing of trunk muscle onsets at the initiation of arm movements was the same across movement amplitudes with ES as the first muscle activated, followed by TrA, RA and OI. All arm movements induced a flexion angular impulse about the shoulders during acceleration that was reversed during deceleration. Increased movement amplitude led to shortened onset latencies of the abdominal muscles and increased level of activation in TrA and ES. The activation magnitude of TrA was similar in acceleration and deceleration where the other muscles were specific to acceleration or deceleration. The findings show that arm movements need to be standardized when used as a method to evaluate trunk muscle activation patterns and that inclusion of the deceleration of the arms in the analysis allow the study of the relationship between trunk muscle activation and direction of perturbing torque during one and the same arm movement © 2015 Eriksson Crommert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

  • 31.
    Dahlin, Paul
    et al.
    KTH, School of Biotechnology (BIO), Glycoscience.
    Srivastava, Vaibhav
    KTH, School of Biotechnology (BIO), Glycoscience.
    Ekengren, Sophia
    KTH, School of Biotechnology (BIO), Glycoscience.
    McKee, Lauren S.
    KTH, School of Biotechnology (BIO), Glycoscience.
    Bulone, Vincent
    KTH, School of Biotechnology (BIO), Glycoscience.
    Comparative analysis of sterol acquisition in the oomycetes Saprolegnia parasitica and Phytophthora infestans2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0170873Article in journal (Refereed)
    Abstract [en]

    The oomycete class includes pathogens of animals and plants which are responsible for some of the most significant global losses in agriculture and aquaculture. There is a need to replace traditional chemical means of controlling oomycete growth with more targeted approaches, and the inhibition of sterol synthesis is one promising area. To better direct these efforts, we have studied sterol acquisition in two model organisms: the sterol-autotrophic Saprolegnia parasitica, and the sterol-heterotrophic Phytophthora infestans. We first present a comprehensive reconstruction of a likely sterol synthesis pathway for S. parasitica, causative agent of the disease saprolegniasis in fish. This pathway shows multiple potential routes of sterol synthesis, and draws on several avenues of new evidence: bioinformatic mining for genes with sterol-related functions, expression analysis of these genes, and analysis of the sterol profiles in mycelium grown in different media. Additionally, we explore the extent to which P. infestans, which causes the late blight in potato, can modify exogenously provided sterols. We consider whether the two very different approaches to sterol acquisition taken by these pathogens represent any specific survival advantages or potential drug targets.

  • 32. Danielsson, Angelika
    et al.
    Pontén, Fredrik
    Fagerberg, Linn
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hallström, Björn M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Korsgren, Olle
    Lindskog, Cecilia
    The Human Pancreas Proteome Defined by Transcriptomics and Antibody-Based Profiling2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, p. e115421-Article in journal (Refereed)
    Abstract [en]

    The pancreas is composed of both exocrine glands and intermingled endocrine cells to execute its diverse functions, including enzyme production for digestion of nutrients and hormone secretion for regulation of blood glucose levels. To define the molecular constituents with elevated expression in the human pancreas, we employed a genome-wide RNA sequencing analysis of the human transcriptome to identify genes with elevated expression in the human pancreas. This quantitative transcriptomics data was combined with immunohistochemistry-based protein profiling to allow mapping of the corresponding proteins to different compartments and specific cell types within the pancreas down to the single cell level. Analysis of whole pancreas identified 146 genes with elevated expression levels, of which 47 revealed a particular higher expression as compared to the other analyzed tissue types, thus termed pancreas enriched. Extended analysis of in vitro isolated endocrine islets identified an additional set of 42 genes with elevated expression in these specialized cells. Although only 0.7% of all genes showed an elevated expression level in the pancreas, this fraction of transcripts, in most cases encoding secreted proteins, constituted 68% of the total mRNA in pancreas. This demonstrates the extreme specialization of the pancreas for production of secreted proteins. Among the elevated expression profiles, several previously not described proteins were identified, both in endocrine cells (CFC1, FAM159B, RBPJL and RGS9) and exocrine glandular cells (AQP12A, DPEP1, GATM and ERP27). In summary, we provide a global analysis of the pancreas transcriptome and proteome with a comprehensive list of genes and proteins with elevated expression in pancreas. This list represents an important starting point for further studies of the molecular repertoire of pancreatic cells and their relation to disease states or treatment effects.

  • 33. Darmanis, Spyros
    et al.
    Cui, Tao
    Drobin, Kimi
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Li, Su-Chen
    Öberg, Kjell
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Identification of Candidate Serum Proteins for Classifying Well-Differentiated Small Intestinal Neuroendocrine Tumors2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e81712-Article in journal (Refereed)
    Abstract [en]

    Background: Patients with well-differentiated small intestine neuroendocrine tumors (WD-SI-NETs) are most often diagnosed at a metastatic stage of disease, which reduces possibilities for a curative treatment. Thus new approaches for earlier detection and improved monitoring of the disease are required. Materials and Methods: Suspension bead arrays targeting 124 unique proteins with antibodies from the Human Protein Atlas were used to profile biotinylated serum samples. Discoveries from a cohort of 77 individuals were followed up in a cohort of 132 individuals both including healthy controls as well as patients with untreated primary WD-SI-NETs, lymph node metastases and liver metastases. Results: A set of 20 antibodies suggested promising proteins for further verification based on technically verified statistical significance. Proceeding, we assessed the classification performance in an independent cohort of patient serum, achieving, classification accuracy of up to 85% with different subsets of antibodies in respective pairwise group comparisons. The protein profiles of nine targets, namely IGFBP2, IGF1, SHKBP1, ETS1, IL1 alpha, STX2, MAML3, EGR3 and XIAP were verified as significant contributors to tumor classification. Conclusions: We propose new potential protein biomarker candidates for classifying WD-SI-NETs at different stage of disease. Further evaluation of these proteins in larger sample sets and with alternative approaches is needed in order to further improve our understanding of their functional relation to WD-SI-NETs and their eventual use in diagnostics.

  • 34. Davanian, H.
    et al.
    Stranneheim, Henrik
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Båge, T.
    Lagervall, M.
    Jansson, L.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Yucel-Lindberg, T.
    Gene Expression Profiles in Paired Gingival Biopsies from Periodontitis-Affected and Healthy Tissues Revealed by Massively Parallel Sequencing2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e46440-Article in journal (Refereed)
    Abstract [en]

    Periodontitis is a chronic inflammatory disease affecting the soft tissue and bone that surrounds the teeth. Despite extensive research, distinctive genes responsible for the disease have not been identified. The objective of this study was to elucidate transcriptome changes in periodontitis, by investigating gene expression profiles in gingival tissue obtained from periodontitis-affected and healthy gingiva from the same patient, using RNA-sequencing. Gingival biopsies were obtained from a disease-affected and a healthy site from each of 10 individuals diagnosed with periodontitis. Enrichment analysis performed among uniquely expressed genes for the periodontitis-affected and healthy tissues revealed several regulated pathways indicative of inflammation for the periodontitis-affected condition. Hierarchical clustering of the sequenced biopsies demonstrated clustering according to the degree of inflammation, as observed histologically in the biopsies, rather than clustering at the individual level. Among the top 50 upregulated genes in periodontitis-affected tissues, we investigated two genes which have not previously been demonstrated to be involved in periodontitis. These included interferon regulatory factor 4 and chemokine (C-C motif) ligand 18, which were also expressed at the protein level in gingival biopsies from patients with periodontitis. In conclusion, this study provides a first step towards a quantitative comprehensive insight into the transcriptome changes in periodontitis. We demonstrate for the first time site-specific local variation in gene expression profiles of periodontitis-affected and healthy tissues obtained from patients with periodontitis, using RNA-seq. Further, we have identified novel genes expressed in periodontitis tissues, which may constitute potential therapeutic targets for future treatment strategies of periodontitis.

  • 35. Debevec, Tadej
    et al.
    Simpson, Elizabeth J.
    Macdonald, Ian A.
    Eiken, Ola
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Environmental Physiology.
    Mekjavic, Igor B.
    Exercise Training during Normobaric Hypoxic Confinement Does Not Alter Hormonal Appetite Regulation2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e98874-Article in journal (Refereed)
    Abstract [en]

    Background: Both exposure to hypoxia and exercise training have the potential to modulate appetite and induce beneficial metabolic adaptations. The purpose of this study was to determine whether daily moderate exercise training performed during a 10-day exposure to normobaric hypoxia alters hormonal appetite regulation and augments metabolic health. Methods: Fourteen healthy, male participants underwent a 10-day hypoxic confinement at,4000 m simulated altitude (FIO2 = 0.139 +/- 0.003%) either combined with daily moderate intensity exercise (Exercise group; N = 8, Age = 25.8 +/- 2.4 yrs, BMI = 22.9 +/- 1.2 kg.m(-2)) or without any exercise (Sedentary group; N = 6 Age = 24.8 +/- 3.1 yrs, BMI = 22.3 +/- 2.5 kg.m(-2)). A meal tolerance test was performed before (Pre) and after the confinement (Post) to quantify fasting and postprandial concentrations of selected appetite-related hormones and metabolic risk markers. C-13-Glucose was dissolved in the test meal and (CO2)-C-13 determined in breath samples. Perceived appetite ratings were obtained throughout the meal tolerance tests. Results: While body mass decreased in both groups (-1.4 kg; p = 0.01) following the confinement, whole body fat mass was only reduced in the Exercise group (-1.5 kg; p = 0.01). At Post, postprandial serum insulin was reduced in the Sedentary group (-49%; p = 0.01) and postprandial plasma glucose in the Exercise group (-19%; p = 0.03). Fasting serum total cholesterol levels were reduced (-12%; p = 0.01) at Post in the Exercise group only, secondary to low-density lipoprotein cholesterol reduction (-16%; p = 0.01). No differences between groups or testing periods were noted in fasting and/or postprandial concentrations of total ghrelin, peptide YY, and glucagon-like peptide-1, leptin, adiponectin, expired (CO2)-C-13 as well as perceived appetite ratings (p>0.05). Conclusion: These findings suggest that performing daily moderate intensity exercise training during continuous hypoxic exposure does not alter hormonal appetite regulation but can improve the lipid profile in healthy young males.

  • 36. Delhomme, Nicolas
    et al.
    Sundstrom, Gorel
    Zamani, Neda
    Lantz, Henrik
    Lin, Yao-Cheng
    Hvidsten, Torgeir R.
    Hoppner, Marc P.
    Jern, Patric
    Van de Peer, Yves
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Grabherr, Manfred G.
    Street, Nathaniel R.
    Serendipitous Meta-Transcriptomics: The Fungal Community of Norway Spruce (Picea abies)2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0139080Article in journal (Refereed)
    Abstract [en]

    After performing de novo transcript assembly of >1 billion RNA-Sequencing reads obtained from 22 samples of different Norway spruce (Picea abies) tissues that were not surface sterilized, we found that assembled sequences captured a mix of plant, lichen, and fungal transcripts. The latter were likely expressed by endophytic and epiphytic symbionts, indicating that these organisms were present, alive, and metabolically active. Here, we show that these serendipitously sequenced transcripts need not be considered merely as contamination, as is common, but that they provide insight into the plant's phyllosphere. Notably, we could classify these transcripts as originating predominantly from Dothideomycetes and Leotiomycetes species, with functional annotation of gene families indicating active growth and metabolism, with particular regards to glucose intake and processing, as well as gene regulation.

  • 37. Dey, Prasenjit
    et al.
    Velazquez-Villegas, Laura A.
    Faria, Michelle
    Turner, Anthony
    Jonsson, Philp
    Webb, Paul
    Williams, Cecilia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. University of Houston, United States.
    Gustafsson, Jan-Åke
    Ström, Anders M.
    Estrogen Receptor beta 2 Induces Hypoxia Signature of Gene Expression by Stabilizing HIF-1 alpha in Prostate Cancer2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0128239Article in journal (Refereed)
    Abstract [en]

    The estrogen receptor (ER) beta variant ER beta 2 is expressed in aggressive castration-resistant prostate cancer and has been shown to correlate with decreased overall survival. Genome-wide expression analysis after ER beta 2 expression in prostate cancer cells revealed that hypoxia was an overrepresented theme. Here we show that ER beta 2 interacts with and stabilizes HIF-1 alpha protein in normoxia, thereby inducing a hypoxic gene expression signature. HIF-1 alpha is known to stimulate metastasis by increasing expression of Twist1 and increasing vascularization by directly activating VEGF expression. We found that ER beta 2 interacts with HIF-1 alpha and piggybacks to the HIF-1 alpha response element present on the proximal Twist1 and VEGF promoters. These findings suggest that at least part of the oncogenic effects of ER beta 2 is mediated by HIF-1 alpha and that targeting of this ER beta 2 -HIF-1 alpha interaction may be a strategy to treat prostate cancer.

  • 38.
    Dinér, Peter
    et al.
    University of Gothenburg.
    Veide Vilg, Jenny
    Kjellén, Jimmy
    Migdal, Iwona
    Andersson, Terese
    Gebbia, Marinella
    Giaever, Guri
    Nislow, Corey
    Hohmann, Stefan
    Wysocki, Robert
    Tamás, Markus J.
    Grøtli, Morten
    Design, synthesis, and characterization of a highly effective Hog1 inhibitor: a powerful tool for analyzing MAP kinase signaling in yeast2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 5Article in journal (Refereed)
  • 39. Dreij, Kristian
    et al.
    Chaudhry, Qasim Ali
    KTH, School of Computer Science and Communication (CSC), Numerical Analysis, NA.
    Jernstrom, Bengt
    Morgenstern, Ralf
    Hanke, Michael
    KTH, School of Computer Science and Communication (CSC), Numerical Analysis, NA.
    A Method for Efficient Calculation of Diffusion and Reactions of Lipophilic Compounds in Complex Cell Geometry2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e23128-Article in journal (Refereed)
    Abstract [en]

    A general description of effects of toxic compounds in mammalian cells is facing several problems. Firstly, most toxic compounds are hydrophobic and partition phenomena strongly influence their behaviour. Secondly, cells display considerable heterogeneity regarding the presence, activity and distribution of enzymes participating in the metabolism of foreign compounds i.e. bioactivation/biotransformation. Thirdly, cellular architecture varies greatly. Taken together, complexity at several levels has to be addressed to arrive at efficient in silico modelling based on physicochemical properties, metabolic preferences and cell characteristics. In order to understand the cellular behaviour of toxic foreign compounds we have developed a mathematical model that addresses these issues. In order to make the system numerically treatable, methods motivated by homogenization techniques have been applied. These tools reduce the complexity of mathematical models of cell dynamics considerably thus allowing to solve efficiently the partial differential equations in the model numerically on a personal computer. Compared to a compartment model with well-stirred compartments, our model affords a more realistic representation. Numerical results concerning metabolism and chemical solvolysis of a polycyclic aromatic hydrocarbon carcinogen show good agreement with results from measurements in V79 cell culture. The model can easily be extended and refined to include more reactants, and/or more complex reaction chains, enzyme distribution etc, and is therefore suitable for modelling cellular metabolism involving membrane partitioning also at higher levels of complexity.

  • 40. Dubnovitsky, Anatoly
    et al.
    Sandberg, Anders
    Rahman, M Mahafuzur
    Benilova, Iryna
    Lendel, Christofer
    Härd, Torleif
    Amyloid-β protofibrils: size, morphology and synaptotoxicity of an engineered mimic.2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, article id e66101Article in journal (Refereed)
    Abstract [en]

    Structural and biochemical studies of the aggregation of the amyloid-β peptide (Aβ) are important to understand the mechanisms of Alzheimer's disease, but research is complicated by aggregate inhomogeneity and instability. We previously engineered a hairpin form of Aβ called Aβcc, which forms stable protofibrils that do not convert into amyloid fibrils. Here we provide a detailed characterization of Aβ42cc protofibrils. Like wild type Aβ they appear as smooth rod-like particles with a diameter of 3.1 (±0.2) nm and typical lengths in the range 60 to 220 nm when observed by atomic force microscopy. Non-perturbing analytical ultracentrifugation and nanoparticle tracking analyses are consistent with such rod-like protofibrils. Aβ42cc protofibrils bind the ANS dye indicating that they, like other toxic protein aggregates, expose hydrophobic surface. Assays with the OC/A11 pair of oligomer specific antibodies put Aβ42cc protofibrils into the same class of species as fibrillar oligomers of wild type Aβ. Aβ42cc protofibrils may be used to extract binding proteins in biological fluids and apolipoprotein E is readily detected as a binder in human serum. Finally, Aβ42cc protofibrils act to attenuate spontaneous synaptic activity in mouse hippocampal neurons. The experiments indicate considerable structural and chemical similarities between protofibrils formed by Aβ42cc and aggregates of wild type Aβ42. We suggest that Aβ42cc protofibrils may be used in research and applications that require stable preparations of protofibrillar Aβ.

  • 41.
    Dubus, Gaël
    et al.
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH, Music Acoustics.
    Bresin, Roberto
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH, Music Acoustics.
    A Systematic Review of Mapping Strategies for the Sonification of Physical Quantities2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e82491-Article in journal (Refereed)
    Abstract [en]

    The field of sonification has progressed greatly over the past twenty years and currently constitutes an established area of research. This article aims at exploiting and organizing the knowledge accumulated in previous experimental studies to build a foundation for future sonification works. A systematic review of these studies may reveal trends in sonification design, and therefore support the development of design guidelines. To this end, we have reviewed and analyzed 179 scientific publications related to sonification of physical quantities. Using a bottom-up approach, we set up a list of conceptual dimensions belonging to both physical and auditory domains. Mappings used in the reviewed works were identified, forming a database of 495 entries. Frequency of use was analyzed among these conceptual dimensions as well as higher-level categories. Results confirm two hypotheses formulated in a preliminary study: pitch is by far the most used auditory dimension in sonification applications, and spatial auditory dimensions are almost exclusively used to sonify kinematic quantities. To detect successful as well as unsuccessful sonification strategies, assessment of mapping efficiency conducted in the reviewed works was considered. Results show that a proper evaluation of sonification mappings is performed only in a marginal proportion of publications. Additional aspects of the publication database were investigated: historical distribution of sonification works is presented, projects are classified according to their primary function, and the sonic material used in the auditory display is discussed. Finally, a mapping-based approach for characterizing sonification is proposed.

  • 42. Dugassa, Sisay
    et al.
    Lindh, Jenny M.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Oyieke, Florence
    Mukabana, Wolfgang R.
    Lindsay, Steven W.
    Fillinger, Ulrike
    Development of a Gravid Trap for Collecting Live Malaria Vectors Anopheles gambiae s.l.2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e68948-Article in journal (Refereed)
    Abstract [en]

    Background: Effective malaria vector control targeting indoor host-seeking mosquitoes has resulted in fewer vectors entering houses in many areas of sub-Saharan Africa, with the proportion of vectors outdoors becoming more important in the transmission of this disease. This study aimed to develop a gravid trap for the outdoor collection of the malaria vector Anopheles gambiae s.l. based on evaluation and modification of commercially available gravid traps. Methods: Experiments were implemented in an 80 m(2) semi-field system where 200 gravid Anopheles gambiae s.s. were released nightly. The efficacy of the Box, CDC and Frommer updraft gravid traps was compared. The Box gravid trap was tested to determine if the presence of the trap over water and the trap's sound affected catch size. Mosquitoes approaching the treatment were evaluated using electrocuting nets or detergents added to the water in the trap. Based on the results, a new gravid trap (OviART trap) that provided an open, unobstructed oviposition site was developed and evaluated. Results: Box and CDC gravid traps collected similar numbers (relative rate (RR) 0.8, 95% confidence interval (CI) 0.6-1.2; p = 0.284), whereas the Frommer trap caught 70% fewer mosquitoes (RR 0.3, 95% CI 0.2-0.5; p < 0.001). The number of mosquitoes approaching the Box trap was significantly reduced when the trap was positioned over a water-filled basin compared to an open pond (RR 0.7 95% CI 0.6-0.7; p < 0.001). This effect was not due to the sound of the trap. Catch size increased by 60% (RR 1.6, 1.2-2.2; p = 0.001) with the new OviART trap. Conclusion: Gravid An. Gambiae s.s. females were visually deterred by the presence of the trapping device directly over the oviposition medium. Based on these investigations, an effective gravid trap was developed that provides open landing space for egg-laying Anopheles.

  • 43. Dupont, Chris L.
    et al.
    Larsson, John
    Yooseph, Shibu
    Ininbergs, Karolina
    Goll, Johannes
    Asplund-Samuelsson, Johannes
    McCrow, John P.
    Celepli, Narin
    Allen, Lisa Zeigler
    Ekman, Martin
    Lucas, Andrew J.
    Hagström, Åke
    Thiagarajan, Mathangi
    Brindefalk, Björn
    Richter, Alexander R.
    Andersson, Anders F.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Tenney, Aaron
    Lundin, Daniel
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Tovchigrechko, Andrey
    Nylander, Johan A. A.
    Brami, Daniel
    Badger, Jonathan H.
    Allen, Andrew E.
    Rusch, Douglas B.
    Hoffman, Jeff
    Norrby, Erling
    Friedman, Robert
    Pinhassi, Jarone
    Venter, J. Craig
    Bergman, Birgitta
    Functional Tradeoffs Underpin Salinity-Driven Divergence in Microbial Community Composition2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e89549-Article in journal (Refereed)
    Abstract [en]

    Bacterial community composition and functional potential change subtly across gradients in the surface ocean. In contrast, while there are significant phylogenetic divergences between communities from freshwater and marine habitats, the underlying mechanisms to this phylogenetic structuring yet remain unknown. We hypothesized that the functional potential of natural bacterial communities is linked to this striking divide between microbiomes. To test this hypothesis, metagenomic sequencing of microbial communities along a 1,800 km transect in the Baltic Sea area, encompassing a continuous natural salinity gradient from limnic to fully marine conditions, was explored. Multivariate statistical analyses showed that salinity is the main determinant of dramatic changes in microbial community composition, but also of large scale changes in core metabolic functions of bacteria. Strikingly, genetically and metabolically different pathways for key metabolic processes, such as respiration, biosynthesis of quinones and isoprenoids, glycolysis and osmolyte transport, were differentially abundant at high and low salinities. These shifts in functional capacities were observed at multiple taxonomic levels and within dominant bacterial phyla, while bacteria, such as SAR11, were able to adapt to the entire salinity gradient. We propose that the large differences in central metabolism required at high and low salinities dictate the striking divide between freshwater and marine microbiomes, and that the ability to inhabit different salinity regimes evolved early during bacterial phylogenetic differentiation. These findings significantly advance our understanding of microbial distributions and stress the need to incorporate salinity in future climate change models that predict increased levels of precipitation and a reduction in salinity.

  • 44. Dückers, Michel L. A.
    et al.
    Thormar, Sigridur B.
    Juen, Barbara
    Ajdukovic, Dean
    Newlove-Eriksson, Lindy
    KTH. Swedish Defence University, Sweden.
    Olff, Miranda
    Measuring and modelling the quality of 40 post-disaster mental health and psychosocial support programmes2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 2, article id e0193285Article in journal (Refereed)
    Abstract [en]

    Disasters can have an enormous impact on the health and well-being of those affected. Internationally, governments and service providers are often challenged to address complex psychosocial problems. Ideally, the potentially broad range of support activities include a coherent, high-quality mental health and psychosocial support (MHPSS) programme. We present a theory-driven quantitative analysis of the quality of 40 MHPSS programmes, mostly implemented in European disaster settings. The objective is to measure quality domains recognized as relevant in the literature and to empirically test associations. During the EU project "Operationalizing Psychosocial Support in Crisis" (OPSIC) an evaluation survey was designed and developed for this purpose and completed by 40 MHPSS programme coordinators involved in different mass emergencies and disasters. We analysed the survey data in two steps. Firstly, we used the data to operationalize quality domains of a MHPSS programme, tested constructs and assessed their internal consistency reliability. A total of 26 out of 44 survey items clustered into three of the four domains identified within the theoretical framework: "planning and delivery system" (Cronbach's alpha 0.82); "general evaluation criteria" (Cronbach's alpha 0.82); and "essential psychosocial principles" (Cronbach's alpha 0.75). "Measures and interventions applied", theoretically a potential fourth domain, could not be confirmed to empirically cluster together. Secondly, several models with associations between domains and measures and interventions were tested and compared. The model with the best fit suggests that in MHPSS programmes with a higher planning and delivery systems score, a larger number of measures and interventions from evidence informed guidelines are applied. In such programmes, coordinators are more positive about general evaluation criteria and the realization of essential psychosocial principles. Moreover, the analyses showed that some measures and interventions are more likely to be applied in programmes with more evolved planning and delivery systems, yet for most measures and interventions the likelihood of being applied is not linked to planning and delivery system status, nor to coordinator perceptions concerning psychosocial principles and evaluation criteria. Further research is necessary to validate and expand the findings and to learn more about success factors and obstacles for MHPSS programme implementation.

  • 45. Echternach, Matthias
    et al.
    Burk, Fabian
    Koeberlein, Marie
    Selamtzis, Andreas
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH.
    Doellinger, Michael
    Burdumy, Michael
    Richter, Bernhard
    Herbst, Christian Thomas
    Laryngeal evidence for the first and second passaggio in professionally trained sopranos2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0175865Article in journal (Refereed)
    Abstract [en]

    Introduction Due to a lack of empirical data, the current understanding of the laryngeal mechanics in the passaggio regions (i.e., the fundamental frequency ranges where vocal registration events usually occur) of the female singing voice is still limited. Material and methods In this study the first and second passaggio regions of 10 professionally trained female classical soprano singers were analyzed. The sopranos performed pitch glides from A3 (f(o) = 220 Hz) to A4 (f(o) = 440 Hz) and from A4 (f(o) = 440 Hz) to A5 (f(o) = 880 Hz) on the vowel [i:]. Vocal fold vibration was assessed with trans-nasal high speed videoendoscopy at 20,000 fps, complemented by simultaneous electroglottographic (EGG) and acoustic recordings. Register breaks were perceptually rated by 12 voice experts. Voice stability was documented with the EGG-based sample entropy. Glottal opening and closing patterns during the passaggi were analyzed, supplemented with open quotient data extracted from the glottal area waveform. Results In both the first and the second passaggio, variations of vocal fold vibration patterns were found. Four distinct patterns emerged: smooth transitions with either increasing or decreasing durations of glottal closure, abrupt register transitions, and intermediate loss of vocal fold contact. Audible register transitions (in both the first and second passaggi) generally coincided with higher sample entropy values and higher open quotient variance through the respective passaggi. Conclusions Noteworthy vocal fold oscillatory registration events occur in both the first and the second passaggio even in professional sopranos. The respective transitions are hypothesized to be caused by either (a) a change of laryngeal biomechanical properties; or by (b) vocal tract resonance effects, constituting level 2 source-filter interactions.

  • 46.
    Fasterius, Erik
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Raso, Cinzia
    Kennedy, Susan
    Rauch, Nora
    Lundin, Par
    Kolch, Walter
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Al-Khalili Szigyarto, Cristina
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    A novel RNA sequencing data analysis method for cell line authentication2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0171435Article in journal (Refereed)
    Abstract [en]

    We have developed a novel analysis method that can interrogate the authenticity of biological samples used for generation of transcriptome profiles in public data repositories. The method uses RNA sequencing information to reveal mutations in expressed transcripts and subsequently confirms the identity of analysed cells by comparison with publicly available cell-specific mutational profiles. Cell lines constitute key model systems widely used within cancer research, but their identity needs to be confirmed in order to minimise the influence of cell contaminations and genetic drift on the analysis. Using both public and novel data, we demonstrate the use of RNA-sequencing data analysis for cell line authentication by examining the validity of COLO205, DLD1, HCT15, HCT116, HKE3, HT29 and RKO colorectal cancer cell lines. We successfully authenticate the studied cell lines and validate previous reports indicating that DLD1 and HCT15 are synonymous. We also show that the analysed HKE3 cells harbour an unexpected KRAS-G13D mutation and confirm that this cell line is a genuine KRAS dosage mutant, rather than a true isogenic derivative of HCT116 expressing only the wild type KRAS. This authentication method could be used to revisit the numerous cell line based RNA sequencing experiments available in public data repositories, analyse new experiments where whole genome sequencing is not available, as well as facilitate comparisons of data from different experiments, platforms and laboratories.

  • 47.
    Forsström, Björn
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Axnäs, Barbara Bislawska
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Rockberg, Johan
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Danielsson, Hanna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Bohlin, Anna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Dissecting Antibodies with Regards to Linear and Conformational Epitopes2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0121673Article in journal (Refereed)
    Abstract [en]

    An important issue for the performance and specificity of an antibody is the nature of the binding to its protein target, including if the recognition involves linear or conformational epitopes. Here, we dissect polyclonal sera by creating epitope-specific antibody fractions using a combination of epitope mapping and an affinity capture approach involving both synthesized peptides and recombinant protein fragments. This allowed us to study the relative amounts of antibodies to linear and conformational epitopes in the polyclonal sera as well as the ability of each antibody-fraction to detect its target protein in Western blot assays. The majority of the analyzed polyclonal sera were found to have most of the target-specific antibodies directed towards linear epitopes and these were in many cases giving Western blot bands of correct molecular weight. In contrast, many of the antibodies towards conformational epitopes did not bind their target proteins in the Western blot assays. The results from this work have given us insights regarding the nature of the antibody response generated by immunization with recombinant protein fragments and has demonstrated the advantage of using antibodies recognizing linear epitopes for immunoassay involving wholly or partially denatured protein targets.

  • 48. Fristedt, Richard
    et al.
    Elebro, Jacob
    Gaber, Alexander
    Jonsson, Liv
    Heby, Margareta
    Yudina, Yulyana
    Nodin, Bjorn
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. AlbaNova University, Sweden.
    Eberhard, Jakob
    Jirstrom, Karin
    Reduced Expression of the Polymeric Immunoglobulin Receptor in Pancreatic and Periampullary Adenocarcinoma Signifies Tumour Progression and Poor Prognosis2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112728-Article in journal (Refereed)
    Abstract [en]

    The polymeric immunoglobulin receptor (pIgR) is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically treated with pancreaticoduodenectomy for pancreatic and periampullary adenocarcinoma in Malmo and Lund University Hospitals, Sweden, between 2001-2011. Tissue microarrays were constructed from primary tumours (n = 175) and paired lymph node metastases (n = 105). A multiplied score was calculated from the fraction and intensity of pIgR staining. Classification and regression tree analysis was used to select the prognostic cut-off. Unadjusted and adjusted hazard ratios (HR) for death and recurrence within 5 years were calculated. pIgR expression could be evaluated in 172/175 (98.3%) primary tumours and in 96/105 (91.4%) lymph node metastases. pIgR expression was significantly down-regulated in lymph node metastases as compared with primary tumours (p = 0.018). Low pIgR expression was significantly associated with poor differentiation grade (p<0.001), perineural growth (p = 0.027), lymphatic invasion (p = 0.016), vascular invasion (p = 0.033) and infiltration of the peripancreatic fat (p = 0.039). In the entire cohort, low pIgR expression was significantly associated with an impaired 5-year survival (HR = 2.99, 95% confidence interval (CI) 1.71-5.25) and early recurrence (HR = 2.89, 95% CI 1.67-4.98). This association remained significant for survival after adjustment for conventional clinicopathological factors, tumour origin and adjuvant treatment (HR = 1.98, 95% CI 1.10-3.57). These results demonstrate, for the first time, that high tumour-specific pIgR expression signifies a more favourable tumour phenotype and that low expression independently predicts a shorter survival in patients with pancreatic and periampullary cancer. The mechanistic basis for the putative tumour suppressing properties of pIgR in these cancers merits further study.

  • 49. Gardberg, M.
    et al.
    Kaipio, K.
    Lehtinen, L.
    Mikkonen, P.
    Heuser, V. D.
    Talvinen, K.
    Iljin, K.
    Kampf, C.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Grénman, R.
    Koivisto, M.
    Carpén, O.
    FHOD1, a Formin Upregulated in Epithelial-Mesenchymal Transition, Participates in Cancer Cell Migration and Invasion2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e74923-Article in journal (Refereed)
    Abstract [en]

    Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.

  • 50. Giordano, B.L.
    et al.
    Egermann, H.
    Bresin, Roberto
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH, Music Acoustics. KTH, School of Computer Science and Communication (CSC), Media Technology and Interaction Design, MID. KTH.
    The production and perception of emotionally expressive walking sounds: Similarities between musical performance and everyday motor activity2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, p. e115587-Article in journal (Refereed)
    Abstract [en]

    Several studies have investigated the encoding and perception of emotional expressivity in music performance. A relevant question concerns how the ability to communicate emotions in music performance is acquired. In accordance with recent theories on the embodiment of emotion, we suggest here that both the expression and recognition of emotion in music might at least in part rely on knowledge about the sounds of expressive body movements. We test this hypothesis by drawing parallels between musical expression of emotions and expression of emotions in sounds associated with a non-musical motor activity: walking. In a combined production-perception design, two experiments were conducted, and expressive acoustical features were compared across modalities. An initial performance experiment tested for similar feature use in walking sounds and music performance, and revealed that strong similarities exist. Features related to sound intensity, tempo and tempo regularity were identified as been used similarly in both domains. Participants in a subsequent perception experiment were able to recognize both non-emotional and emotional properties of the sound-generating walkers. An analysis of the acoustical correlates of behavioral data revealed that variations in sound intensity, tempo, and tempo regularity were likely used to recognize expressed emotions. Taken together, these results lend support the motor origin hypothesis for the musical expression of emotions.

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