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  • 1.
    Aarestrup, F. M.
    et al.
    Tech Univ Denmark, Lyngby, Denmark..
    Auffray, C.
    EISBM, Vourles, France..
    Benhabiles, N.
    Univ Paris Saclay, CEA, French Atom Energy & Alternat Energy Commiss, Direct Rech Fondamentale, F-91191 Gif Sur Yvette, France..
    Blomberg, N.
    ELIXIR, Welcome Genome Campus, Cambridge CB10 1SD, England..
    Korbel, J. O.
    European Mol Biol Lab, Genome Biol Unit, Heidelberg, Germany..
    Oksvold, Per
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Van Oyen, H.
    Univ Sci & Technol, Dept Comp Sci, Krakow, Poland.;Univ Sci & Technol, Akad Gornizco Hutnizca, Acad Comp Ctr Cyfronet, Krakow, Poland.;Sciensano, Juliette Wystmanstr, B-1050 Brussels, Belgium..
    Towards a European health research and innovation cloud (HRIC)2020Ingår i: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 12, nr 1, artikel-id 18Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The European Union (EU) initiative on the Digital Transformation of Health and Care (Digicare) aims to provide the conditions necessary for building a secure, flexible, and decentralized digital health infrastructure. Creating a European Health Research and Innovation Cloud (HRIC) within this environment should enable data sharing and analysis for health research across the EU, in compliance with data protection legislation while preserving the full trust of the participants. Such a HRIC should learn from and build on existing data infrastructures, integrate best practices, and focus on the concrete needs of the community in terms of technologies, governance, management, regulation, and ethics requirements. Here, we describe the vision and expected benefits of digital data sharing in health research activities and present a roadmap that fosters the opportunities while answering the challenges of implementing a HRIC. For this, we put forward five specific recommendations and action points to ensure that a European HRIC: i) is built on established standards and guidelines, providing cloud technologies through an open and decentralized infrastructure; ii) is developed and certified to the highest standards of interoperability and data security that can be trusted by all stakeholders; iii) is supported by a robust ethical and legal framework that is compliant with the EU General Data Protection Regulation (GDPR); iv) establishes a proper environment for the training of new generations of data and medical scientists; and v) stimulates research and innovation in transnational collaborations through public and private initiatives and partnerships funded by the EU through Horizon 2020 and Horizon Europe.

  • 2.
    Abraham, Mark James
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Apostolov, Rossen
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Centra, Parallelldatorcentrum, PDC.
    Barnoud, Jonathan
    Univ Groningen, NL-9712 CP Groningen, Netherlands.;Univ Bristol, Intangible Real Lab, Bristol, Avon, England..
    Bauer, Paul
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Blau, Christian
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bonvin, Alexandre M. J. J.
    Univ Utrecht, Bijvoet Ctr, Fac Sci, Utrecht, Netherlands..
    Chavent, Matthieu
    Univ Paul Sabatier, IPBS, F-31062 Toulouse, France..
    Chodera, John
    Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Computat & Syst Biol Program, New York, NY 10065 USA..
    Condic-Jurkic, Karmen
    Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Computat & Syst Biol Program, New York, NY 10065 USA.;Open Force Field Consortium, La Jolla, CA USA..
    Delemotte, Lucie
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Grubmueller, Helmut
    Max Planck Inst Biophys Chem, D-37077 Gottingen, Germany..
    Howard, Rebecca
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Jordan, E. Joseph
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Box 1031, SE-17121 Solna, Sweden..
    Lindahl, Erik
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Ollila, O. H. Samuli
    Univ Helsinki, Inst Biotechnol, SF-00100 Helsinki, Finland..
    Selent, Jana
    Pompeu Fabra Univ, Hosp del Mar Med Res Inst IMIM, Res Programme Biomed Informat, Barcelona 08002, Spain.;Pompeu Fabra Univ, Dept Expt & Hlth Sci, Barcelona 08002, Spain..
    Smith, Daniel G. A.
    Mol Sci Software Inst, Blacksburg, VA 24060 USA..
    Stansfeld, Phillip J.
    Univ Oxford, Dept Biochem, Oxford OX1 2JD, England.;Univ Warwick, Sch Life Sci, Coventry CV4 7AL, W Midlands, England.;Univ Warwick, Dept Chem, Coventry CV4 7AL, W Midlands, England..
    Tiemann, Johanna K. S.
    Univ Leipzig, Fac Med, Inst Med Phys & Biophys, D-04107 Leipzig, Germany..
    Trellet, Mikael
    Univ Utrecht, Bijvoet Ctr, Fac Sci, Utrecht, Netherlands..
    Woods, Christopher
    Univ Bristol, Bristol BS8 1TH, Avon, England..
    Zhmurov, Artem
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sharing Data from Molecular Simulations2019Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 59, nr 10, s. 4093-4099Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Given the need for modern researchers to produce open, reproducible scientific output, the lack of standards and best practices for sharing data and workflows used to produce and analyze molecular dynamics (MD) simulations has become an important issue in the field. There are now multiple well-established packages to perform molecular dynamics simulations, often highly tuned for exploiting specific classes of hardware, each with strong communities surrounding them, but with very limited interoperability/transferability options. Thus, the choice of the software package often dictates the workflow for both simulation production and analysis. The level of detail in documenting the workflows and analysis code varies greatly in published work, hindering reproducibility of the reported results and the ability for other researchers to build on these studies. An increasing number of researchers are motivated to make their data available, but many challenges remain in order to effectively share and reuse simulation data. To discuss these and other issues related to best practices in the field in general, we organized a workshop in November 2018 (https://bioexcel.eu/events/workshop-on-sharing-data-from-molecular-simulations/). Here, we present a brief overview of this workshop and topics discussed. We hope this effort will spark further conversation in the MD community to pave the way toward more open, interoperable, and reproducible outputs coming from research studies using MD simulations.

  • 3.
    Abraham, Mark James
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Fysik, Teoretisk biologisk fysik.
    Murtola, Teemu
    Schulz, Roland
    Pall, Szilard
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Fysik, Teoretisk biologisk fysik.
    Smith, Jeremy C.
    Hess, Berk
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Fysik, Teoretisk biologisk fysik.
    Lindahl, Erik
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Fysik, Teoretisk biologisk fysik.
    GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers2015Ingår i: SoftwareX, E-ISSN 2352-7110, Vol. 1-2, s. 19-25Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    GROMACS is one of the most widely used open-source and free software codes in chemistry, used primarily for dynamical simulations of biomolecules. It provides a rich set of calculation types, preparation and analysis tools. Several advanced techniques for free-energy calculations are supported. In version 5, it reaches new performance heights, through several new and enhanced parallelization algorithms. These work on every level; SIMD registers inside cores, multithreading, heterogeneous CPU–GPU acceleration, state-of-the-art 3D domain decomposition, and ensemble-level parallelization through built-in replica exchange and the separate Copernicus framework. The latest best-in-class compressed trajectory storage format is supported.

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  • 4. Abrahamsson, T. R.
    et al.
    Jakobsson, H. E.
    Andersson, Anders F.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Björkstén, B.
    Engstrand, Lars
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Jenmalm, M. C.
    Low gut microbiota diversity in early infancy precedes asthma at school age2014Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 44, nr 6, s. 842-850Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Low total diversity of the gut microbiota during the first year of life is associated with allergic diseases in infancy, but little is known how early microbial diversity is related to allergic disease later in school age. Objective To assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to the prevalence of different allergic diseases in school age, such as asthma, allergic rhinoconjunctivitis (ARC) and eczema. Methods The microbial diversity and composition was analysed with barcoded 16S rDNA 454 pyrosequencing in stool samples at 1week, 1month and 12months of age in 47 infants which were subsequently assessed for allergic disease and skin prick test reactivity at 7years of age (ClinicalTrials.gov ID NCT01285830). Results Children developing asthma (n=8) had a lower diversity of the total microbiota than non-asthmatic children at 1week (P=0.04) and 1month (P=0.003) of age, whereas allergic rhinoconjunctivitis (n=13), eczema (n=12) and positive skin prick reactivity (n=14) at 7years of age did not associate with the gut microbiota diversity. Neither was asthma associated with the microbiota composition later in infancy (at 12months). Children having IgE-associated eczema in infancy and subsequently developing asthma had lower microbial diversity than those that did not. There were no significant differences, however, in relative abundance of bacterial phyla and genera between children with or without allergic disease. Conclusion and Clinical Relevance Low total diversity of the gut microbiota during the first month of life was associated with asthma but not ARC in children at 7years of age. Measures affecting microbial colonization of the infant during the first month of life may impact asthma development in childhood.

  • 5. Abrahamsson, Thomas R.
    et al.
    Jakobsson, Hedvig E.
    Andersson, Anders F.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Björksten, Bengt
    Engstrand, Lars
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Jenmalm, Maria C.
    Gut microbiota diversity and atopic disease: Does breast-feeding play a role? Reply2013Ingår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 131, nr 1, s. 248-249Artikel i tidskrift (Övrigt vetenskapligt)
  • 6. Abrahamsson, Thomas R.
    et al.
    Jakobsson, Hedvig E.
    Andersson, Anders F.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Björkstén, Bengt
    Engstrand, Lars
    Jenmalm, Maria C.
    Low diversity of the gut microbiota in infants with atopic eczema2012Ingår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 129, nr 2, s. 434-U244Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: It is debated whether a low total diversity of the gut microbiota in early childhood is more important than an altered prevalence of particular bacterial species for the increasing incidence of allergic disease. The advent of powerful, cultivation-free molecular methods makes it possible to characterize the total microbiome down to the genus level in large cohorts. OBJECTIVE: We sought to assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to atopic eczema development. METHODS: Microbial diversity and composition were analyzed with barcoded 16S rDNA 454-pyrosequencing in stool samples at 1 week, 1 month, and 12 months of age in 20 infants with IgE-associated eczema and 20 infants without any allergic manifestation until 2 years of age (ClinicalTrials.gov ID NCT01285830). RESULTS: Infants with IgE-associated eczema had a lower diversity of the total microbiota at 1 month (P= .004) and a lower diversity of the bacterial phylum Bacteroidetes and the genus Bacteroides at 1 month (P= .02 and P= .01) and the phylum Proteobacteria at 12 months of age (P= .02). The microbiota was less uniform at 1 month than at 12 months of age, with a high interindividual variability. At 12 months, when the microbiota had stabilized, Proteobacteria, comprising gram-negative organisms, were more abundant in infants without allergic manifestation (Empirical Analysis of Digital Gene Expression in R edgeR test: P= .008, q= 0.02). CONCLUSION: Low intestinal microbial diversity during the first month of life was associated with subsequent atopic eczema.

  • 7. Acero Sanchez, Josep Ll.
    et al.
    Joda, Hamdi
    Henry, Olivier Y. F.
    Solnestam, Beata W.
    Kvastad, Linda
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sahlén, Pelin
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Laddach, Nadja
    Ramakrishnan, Dheeraj
    Riley, Ian
    Schwind, Carmen
    Latta, Daniel
    O'Sullivan, Ciara K.
    Electrochemical Genetic Profiling of Single Cancer Cells2017Ingår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 89, nr 6, s. 3378-3385Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 8. Adiels, Martin
    et al.
    Mardinoglu, Adil
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Taskinen, Marja-Riitta
    Boren, Jan
    Kinetic Studies to Elucidate Impaired Metabolism of Triglyceride-rich Lipoproteins in Humans2015Ingår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 6, artikel-id 342Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    To develop novel strategies for prevention and treatment of dyslipidemia, it is essential to understand the pathophysiology of dyslipoproteinemia in humans. Lipoprotein metabolism is a complex system in which abnormal concentrations of various lipoprotein particles can result from alterations in their rates of production, conversion, and/or catabolism. Traditional methods that measure plasma lipoprotein concentrations only provide static estimates of lipoprotein metabolism and hence limited mechanistic information. By contrast, the use of tracers labeled with stable isotopes and mathematical modeling, provides us with a powerful tool for probing lipid and lipoprotein kinetics in vivo and furthering our understanding of the pathogenesis of dyslipoproteinemia.

  • 9. Adori, Csaba
    et al.
    Barde, Swapnali
    Bogdanovic, Nenad
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Karolinska Institutet, Sweden.
    Reinscheid, Rainer R.
    Kovacs, Gabor G.
    Hokfelt, Tomas
    Neuropeptide S- and Neuropeptide S receptor-expressing neuron populations in the human pons2015Ingår i: Frontiers in Neuroanatomy, ISSN 1662-5129, E-ISSN 1662-5129, Vol. 9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuropeptide S (NPS) is a regulatory peptide with potent pharmacological effects. In rodents, NPS is expressed in a few pontine cell clusters. Its receptor (NPSR1) is, however, widely distributed in the brain. The anxiolytic and arousal promoting effects of NPS make the NPS NPSR1 system an interesting potential drug target in mood-related disorders. However, so far possible disease-related mechanisms involving NPS have only been studied in rodents. To validate the relevance of these animal studies for i.a. drug development, we have explored the distribution of NPS-expressing neurons in the human pons using in situ hybridization and stereological methods and we compared the distribution of NPS mRNA expressing neurons in the human and rat brain. The calculation revealed a total number of 22,317 +/- 2411 NPS mRNA-positive neurons in human, bilaterally. The majority of cells (84%) were located in the parabrachial area in human: in the extension of the medial and lateral parabrachial nuclei, in the Kolliker-Fuse nucleus and around the adjacent lateral lemniscus. In human, in sharp contrast to the rodents, only very few NPS-positive cells (5%) were found close to the locus coeruleus. In addition, we identified a smaller cell cluster (11% of all NPS cells) in the pontine central gray matter both in human and rat, which has not been described previously even in rodents. We also examined the distribution of NPSR1 mRNA-expressing neurons in the human pons. These cells were mainly located in the rostral laterodorsal tegmental nucleus, the cuneiform nucleus, the microcellular tegmental nucleus region and in the periaqueductal gray. Our results show that both NPS and NPSR1 in the human pons are preferentially localized in regions of importance for integration of visceral autonomic information and emotional behavior. The reported interspecies differences must, however, be considered when looking for targets for new pharmacotherapeutical interventions.

  • 10. Adori, Csaba
    et al.
    Barde, Swapnali
    Vas, Szilvia
    Ebner, Karl
    Su, Jie
    Svensson, Camilla
    Mathé, Aleksander A.
    Singewald, Nicolas
    Reinscheid, Rainer R.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kultima, Kim
    Bagdy, Gyorgy
    Hökfelt, Tomas
    Exploring the role of neuropeptide S in the regulation of arousal: a functional anatomical study2016Ingår i: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 221, nr 7, s. 3521-3546Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuropeptide S (NPS) is a regulatory peptide expressed by limited number of neurons in the brainstem. The simultaneous anxiolytic and arousal-promoting effect of NPS suggests an involvement in mood control and vigilance, making the NPS-NPS receptor system an interesting potential drug target. Here we examined, in detail, the distribution of NPS-immunoreactive (IR) fiber arborizations in brain regions of rat known to be involved in the regulation of sleep and arousal. Such nerve terminals were frequently apposed to GABAergic/galaninergic neurons in the ventro-lateral preoptic area (VLPO) and to tyrosine hydroxylase-IR neurons in all hypothalamic/thalamic dopamine cell groups. Then we applied the single platform-on-water (mainly REM) sleep deprivation method to study the functional role of NPS in the regulation of arousal. Of the three pontine NPS cell clusters, the NPS transcript levels were increased only in the peri-coerulear group in sleep-deprived animals, but not in stress controls. The density of NPS-IR fibers was significantly decreased in the median preoptic nucleus-VLPO region after the sleep deprivation, while radioimmunoassay and mass spectrometry measurements showed a parallel increase of NPS in the anterior hypothalamus. The expression of the NPS receptor was, however, not altered in the VLPO-region. The present results suggest a selective activation of one of the three NPS-expressing neuron clusters as well as release of NPS in distinct forebrain regions after sleep deprivation. Taken together, our results emphasize a role of the peri-coerulear cluster in the modulation of arousal, and the importance of preoptic area for the action of NPS on arousal and sleep.

  • 11. Adori, Csaba
    et al.
    Glueck, Laura
    Barde, Swapnali
    Yoshitake, Takashi
    Kovacs, Gabor G.
    Mulder, Jan
    Magloczky, Zsofia
    Havas, Laszlo
    Boelcskei, Kata
    Mitsios, Nicholas
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Szolcsanyi, Janos
    Kehr, Jan
    Ronnback, Annica
    Schwartz, Thue
    Rehfeld, Jens F.
    Harkany, Tibor
    Palkovits, Miklos
    Schulz, Stefan
    Hokfelt, Tomas
    Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer's disease2015Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, nr 4, s. 541-563Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alzheimer's disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is noteworthy since cortical and hypothalamic somatostatin content is reduced in neurodegenerative pathologies. Yet a possible role of a somatostatin signal deficit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometry and mRNA profiling in a cohort of Alzheimer's and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer's disease, we found significantly reduced somatostatin protein expression in the temporal cortex, with aberrant clustering and bulging of tyrosine hydroxylase-immunoreactive afferents. As such, somatostatin receptor 2 (SSTR2) mRNA was highly expressed in the human LC, with its levels significantly decreasing from Braak stages III/IV and onwards, i.e., a process preceding advanced Alzheimer's pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine beta-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2 (-/-) mice and, unlike in Sstr1 (-/-) or Sstr4 (-/-) genotypes, they showed selective, global and progressive degeneration of their central noradrenergic projections. However, neuronal perikarya in the LC were found intact until late adulthood (< 8 months) in Sstr2 (-/-) mice. In contrast, the noradrenergic neurons in the superior cervical ganglion lacked SSTR2 and, as expected, the sympathetic innervation of the head region did not show any signs of degeneration. Our results indicate that SSTR2-mediated signaling is integral to the maintenance of central noradrenergic projections at the system level, and that early loss of somatostatin receptor 2 function may be associated with the selective vulnerability of the noradrenergic system in Alzheimer's disease.

  • 12. Aebersold, Ruedi
    et al.
    Agar, Jeffrey N.
    Amster, I. Jonathan
    Baker, Mark S.
    Bertozzi, Carolyn R.
    Boja, Emily S.
    Costello, Catherine E.
    Cravatt, Benjamin F.
    Fenselau, Catherine
    Garcia, Benjamin A.
    Ge, Ying
    Gunawardena, Jeremy
    Hendrickson, Ronald C.
    Hergenrother, Paul J.
    Huber, Christian G.
    Ivanov, Alexander R.
    Jensen, Ole N.
    Jewett, Michael C.
    Kelleher, Neil L.
    Kiessling, Laura L.
    Krogan, Nevan J.
    Larsen, Martin R.
    Loo, Joseph A.
    Loo, Rachel R. Ogorzalek
    Lundberg, Emma
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
    MacCoss, Michael J.
    Mallick, Parag
    Mootha, Vamsi K.
    Mrksich, Milan
    Muir, Tom W.
    Patrie, Steven M.
    Pesavento, James J.
    Pitteri, Sharon J.
    Rodriguez, Henry
    Saghatelian, Alan
    Sandoval, Wendy
    Schluter, Hartmut
    Sechi, Salvatore
    Slavoff, Sarah A.
    Smith, Lloyd M.
    Snyder, Michael P.
    Thomas, Paul M.
    Uhlen, Mathias
    Van Eyk, Jennifer E.
    Vidal, Marc
    Walt, David R.
    White, Forest M.
    Williams, Evan R.
    Wohlschlager, Therese
    Wysocki, Vicki H.
    Yates, Nathan A.
    Young, Nicolas L.
    Zhang, Bing
    How many human proteoforms are there?2018Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 14, nr 3, s. 206-214Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite decades of accumulated knowledge about proteins and their post-translational modifications (PTMs), numerous questions remain regarding their molecular composition and biological function. One of the most fundamental queries is the extent to which the combinations of DNA-, RNA-and PTM-level variations explode the complexity of the human proteome. Here, we outline what we know from current databases and measurement strategies including mass spectrometry-based proteomics. In doing so, we examine prevailing notions about the number of modifications displayed on human proteins and how they combine to generate the protein diversity underlying health and disease. We frame central issues regarding determination of protein-level variation and PTMs, including some paradoxes present in the field today. We use this framework to assess existing data and to ask the question, "How many distinct primary structures of proteins (proteoforms) are created from the 20,300 human genes?" We also explore prospects for improving measurements to better regularize protein-level biology and efficiently associate PTMs to function and phenotype.

  • 13.
    Afkham, Heydar Maboudi
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC).
    Qiu, Xuanbin
    KTH, Skolan för datavetenskap och kommunikation (CSC).
    The, Matthew
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Käll, Lukas
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uncertainty estimation of predictions of peptides' chromatographic retention times in shotgun proteomics2017Ingår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 33, nr 4, s. 508-513Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Motivation: Liquid chromatography is frequently used as a means to reduce the complexity of peptide-mixtures in shotgun proteomics. For such systems, the time when a peptide is released from a chromatography column and registered in the mass spectrometer is referred to as the peptide's retention time. Using heuristics or machine learning techniques, previous studies have demonstrated that it is possible to predict the retention time of a peptide from its amino acid sequence. In this paper, we are applying Gaussian Process Regression to the feature representation of a previously described predictor ELUDE. Using this framework, we demonstrate that it is possible to estimate the uncertainty of the prediction made by the model. Here we show how this uncertainty relates to the actual error of the prediction. Results: In our experiments, we observe a strong correlation between the estimated uncertainty provided by Gaussian Process Regression and the actual prediction error. This relation provides us with new means for assessment of the predictions. We demonstrate how a subset of the peptides can be selected with lower prediction error compared to the whole set. We also demonstrate how such predicted standard deviations can be used for designing adaptive windowing strategies.

  • 14. Agostinho, A.
    et al.
    Kouznetsova, A.
    Hernández-Hernández, A.
    Bernhem, Kristoffer
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Blom, Hans
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Brismar, Hjalmar
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Höög, C.
    Sexual dimorphism in the width of the mouse synaptonemal complex2018Ingår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 131, nr 5, artikel-id jcs212548Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sexual dimorphism has been used to describe morphological differences between the sexes, but can be extended to any biologically related process that varies between males and females. The synaptonemal complex (SC) is a tripartite structure that connects homologous chromosomes in meiosis. Here, aided by superresolution microscopy techniques, we show that the SC is subject to sexual dimorphism, in mouse germ cells. We have identified a significantly narrower SC in oocytes and have established that this difference does not arise from a different organization of the lateral elements nor from a different isoform of transverse filament protein SYCP1. Instead, we provide evidence for the existence of a narrower central element and a different integration site for the C-termini of SYCP1, in females. In addition to these female-specific features, we speculate that post-translation modifications affecting the SYCP1 coiled-coil region could render a more compact conformation, thus contributing to the narrower SC observed in females.

  • 15. Agostinho, Ana
    et al.
    Manneberg, Otto
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    van Schendel, Robin
    Hernandez-Hernandez, Abrahan
    Kouznetsova, Anna
    Blom, Hans
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Cellens fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Brismar, Hjalmar
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Cellens fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Höög, Christer
    High density of REC8 constrains sister chromatid axes and prevents illegitimate synaptonemal complex formation2016Ingår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 17, nr 6, s. 901-913Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During meiosis, cohesin complexes mediate sister chromatid cohesion (SCC), synaptonemal complex (SC) assembly and synapsis. Here, using super-resolution microscopy, we imaged sister chromatid axes in mouse meiocytes that have normal or reduced levels of cohesin complexes, assessing the relationship between localization of cohesin complexes, SCC and SC formation. We show that REC8 foci are separated from each other by a distance smaller than 15% of the total chromosome axis length in wild-type meiocytes. Reduced levels of cohesin complexes result in a local separation of sister chromatid axial elements (LSAEs), as well as illegitimate SC formation at these sites. REC8 but not RAD21 or RAD21L cohesin complexes flank sites of LSAEs, whereas RAD21 and RAD21L appear predominantly along the separated sister-chromatid axes. Based on these observations and a quantitative distribution analysis of REC8 along sister chromatid axes, we propose that the high density of randomly distributed REC8 cohesin complexes promotes SCC and prevents illegitimate SC formation.

  • 16. Ahmad, Yasmeen
    et al.
    Boisvert, Francois-Michel
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lamond, Angus I.
    Systematic Analysis of Protein Pools, Isoforms, and Modifications Affecting Turnover and Subcellular Localization2012Ingår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 11, nr 3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 17.
    Ahmadian, Afshin
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    AnderssonSvahn, Helene
    KTH, Skolan för bioteknologi (BIO), Nanobioteknologi (stängd 20130101). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Massively parallel sequencing platforms using lab on a chip technologies2011Ingår i: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 11, nr 16, s. 2653-2655Artikel i tidskrift (Refereegranskat)
  • 18. Ahmadinejad, F.
    et al.
    Møller, S. G.
    Hashemzadeh-Chaleshtori, M.
    Bidkhori, Gholamreza
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Jami, M. -S
    Molecular mechanisms behind free radical scavengers function against oxidative stress2017Ingår i: Antioxidants, ISSN 2076-3921, Vol. 6, nr 3, artikel-id 51Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Accumulating evidence shows that oxidative stress is involved in a wide variety of human diseases: rheumatoid arthritis, Alzheimers disease, Parkinsons disease, cancers, etc. Here, we discuss the significance of oxidative conditions in different disease, with the focus on neurodegenerative disease including Parkinsons disease, which is mainly caused by oxidative stress. Reactive oxygen and nitrogen species (ROS and RNS, respectively), collectively known as RONS, are produced by cellular enzymes such as myeloperoxidase, NADPH-oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) and nitric oxide synthase (NOS). Natural antioxidant systems are categorized into enzymatic and non-enzymatic antioxidant groups. The former includes a number of enzymes such as catalase and glutathione peroxidase, while the latter contains a number of antioxidants acquired from dietary sources including vitamin C, carotenoids, flavonoids and polyphenols. There are also scavengers used for therapeutic purposes, such as 3,4-dihydroxyphenylalanine (L-DOPA) used routinely in the treatment of Parkinsons disease (not as a free radical scavenger), and 3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) that acts as a free radical detoxifier frequently used in acute ischemic stroke. The cell surviving properties of L-DOPA and Edaravone against oxidative stress conditions rely on the alteration of a number of stress proteins such as Annexin A1, Peroxiredoxin-6 and PARK7/DJ-1 (Parkinson disease protein 7, also known as Protein deglycase DJ-1). Although they share the targets in reversing the cytotoxic effects of H2O2, they seem to have distinct mechanism of function. Exposure to L-DOPA may result in hypoxia condition and further induction of ORP150 (150-kDa oxygen-regulated protein) with its concomitant cytoprotective effects but Edaravone seems to protect cells via direct induction of Peroxiredoxin-2 and inhibition of apoptosis.

  • 19. Ahmed, Engy
    et al.
    Hugerth, Luisa W.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Logue, Jürg Brendan
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bruchert, Volker
    Andersson, Anders F.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Holmström, Sara J. M.
    Mineral Type Structures Soil Microbial Communities2017Ingår i: Geomicrobiology Journal, ISSN 0149-0451, E-ISSN 1521-0529, Vol. 34, nr 6, s. 538-545Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Soil microorganisms living in close contact with minerals play key roles in the biogeochemical cycling of elements, soil formation, and plant nutrition. Yet, the composition of microbial communities inhabiting the mineralosphere (i.e., the soil surrounding minerals) is poorly understood. Here, we explored the composition of soil microbial communities associated with different types of minerals in various soil horizons. To this effect, a field experiment was set up in which mineral specimens of apatite, biotite, and oligoclase were buried in the organic, eluvial, and upper illuvial horizons of a podzol soil. After an incubation period of two years, the soil attached to the mineral surfaces was collected, and microbial communities were analyzed by means of Illumina MiSeq sequencing of the 16S (prokaryotic) and 18S (eukaryotic) ribosomal RNA genes. We found that both composition and diversity of bacterial, archaeal, and fungal communities varied across the different mineral surfaces, and that mineral type had a greater influence on structuring microbial assemblages than soil horizon. Thus, our findings emphasize the importance of mineral surfaces as ecological niches in soils.

  • 20.
    Ahmed, Mona
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Ctr Mol Med, S-17176 Stockholm, Sweden..
    Gustafsson, Björn
    Karolinska Inst, Dept Mol Med & Surg, Ctr Mol Med, S-17176 Stockholm, Sweden..
    Aldi, Silvia
    Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Dusart, Philip
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Cellulär och klinisk proteomik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Egri, Gabriella
    Surflay Nanotec GmbH, Max Planck Str 3, D-12489 Berlin, Germany..
    Butler, Lynn M.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Cellulär och klinisk proteomik.
    Bone, Dianna
    Karolinska Inst, Dept Mol Med & Surg, Ctr Mol Med, S-17176 Stockholm, Sweden..
    Dahne, Lars
    Surflay Nanotec GmbH, Max Planck Str 3, D-12489 Berlin, Germany..
    Hedin, Ulf
    Karolinska Inst, Dept Mol Med & Surg, Ctr Mol Med, S-17176 Stockholm, Sweden..
    Caidahl, Kenneth
    Karolinska Inst, Dept Mol Med & Surg, Ctr Mol Med, S-17176 Stockholm, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, S-41345 Gothenburg, Sweden..
    Molecular Imaging of a New Multimodal Microbubble for Adhesion Molecule Targeting2019Ingår i: Cellular and Molecular Bioengineering, ISSN 1865-5025, E-ISSN 1865-5033, Vol. 12, nr 1, s. 15-32Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Inflammation is an important risk-associated component of many diseases and can be diagnosed by molecular imaging of specific molecules. The aim of this study was to evaluate the possibility of targeting adhesion molecules on inflammation-activated endothelial cells and macrophages using an innovative multimodal polyvinyl alcohol-based microbubble (MB) contrast agent developed for diagnostic use in ultrasound, magnetic resonance, and nuclear imaging. Methods: We assessed the binding efficiency of antibody-conjugated multimodal contrast to inflamed murine or human endothelial cells (ECs), and to peritoneal macrophages isolated from rats with peritonitis, utilizing the fluorescence characteristics of the MBs. Single-photon emission tomography (SPECT) was used to illustrate 99m Tc-labeled MB targeting and distribution in an experimental in vivo model of inflammation. Results: Flow cytometry and confocal microscopy showed that binding of antibody-targeted MBs to the adhesion molecules ICAM-1, VCAM-1, or E-selectin, expressed on cytokine-stimulated ECs, was up to sixfold higher for human and 12-fold higher for mouse ECs, compared with that of non-targeted MBs. Under flow conditions, both VCAM-1- and E-selectin-targeted MBs adhered more firmly to stimulated human ECs than to untreated cells, while VCAM-1-targeted MBs adhered best to stimulated murine ECs. SPECT imaging showed an approximate doubling of signal intensity from the abdomen of rats with peritonitis, compared with healthy controls, after injection of anti-ICAM-1-MBs. Conclusions: This novel multilayer contrast agent can specifically target adhesion molecules expressed as a result of inflammatory stimuli in vitro, and has potential for use in disease-specific multimodal diagnostics in vivo using antibodies against targets of interest.

  • 21.
    Akan, Pelin
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Alexeyenko, Andrey
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Costea, Paul Igor
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Hedberg, Lilia
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Werne Solnestam, Beata
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lundin, Sverker
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Hallman, Jimmie
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Comprehensive analysis of the genome transcriptome and proteome landscapes of three tumor cell lines2012Ingår i: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 4, s. 86-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We here present a comparative genome, transcriptome and functional network analysis of three human cancer cell lines (A431, U251MG and U2OS), and investigate their relation to protein expression. Gene copy numbers significantly influenced corresponding transcript levels; their effect on protein levels was less pronounced. We focused on genes with altered mRNA and/or protein levels to identify those active in tumor maintenance. We provide comprehensive information for the three genomes and demonstrate the advantage of integrative analysis for identifying tumor-related genes amidst numerous background mutations by relating genomic variation to expression/protein abundance data and use gene networks to reveal implicated pathways.

  • 22.
    Akan, Pelin
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO).
    Stranneheim, Henrik
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO).
    Lexow, Preben
    LingVitae, Oslo.
    Lundeberg, Joakim
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO).
    Design and assessment of binary DNA for nanopore sequencing2010Ingår i: Genome biology, ISSN 1474-760X, Vol. 11, s. P4-Artikel i tidskrift (Övrigt vetenskapligt)
  • 23.
    Akhter, Shirin
    et al.
    Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala Bioctr, Dept Plant Biol, Uppsala, Sweden..
    Kretzschmar, Warren W.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nordal, Veronika
    Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala Bioctr, Dept Plant Biol, Uppsala, Sweden..
    Delhomme, Nicolas
    Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, Umea Plant Sci Ctr, Umea, Sweden..
    Street, Nathaniel R.
    Umea Sweden, Dept Plant Physiol, Umea Plant Sci Ctr, Umea, Sweden..
    Nilsson, Ove
    Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, Umea Plant Sci Ctr, Umea, Sweden..
    Emanuelsson, Olof
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sundström, Jens F.
    Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala Bioctr, Dept Plant Biol, Uppsala, Sweden..
    Integrative Analysis of Three RNA Sequencing Methods Identifies Mutually Exclusive Exons of MADS-Box Isoforms During Early Bud Development in Picea abies2018Ingår i: Frontiers in Plant Science, ISSN 1664-462X, E-ISSN 1664-462X, Vol. 9, artikel-id 1625Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent efforts to sequence the genomes and transcriptomes of several gymnosperm species have revealed an increased complexity in certain gene families in gymnosperms as compared to angiosperms. One example of this is the gymnosperm sister Glade to angiosperm TM3-like MADS-box genes, which at least in the conifer lineage has expanded in number of genes. We have previously identified a member of this subclade, the conifer gene DEFICIENS AGAMOUS LIKE 19 (DAL19), as being specifically upregulated in cone-setting shoots. Here, we show through Sanger sequencing of mRNA-derived cDNA and mapping to assembled conifer genomic sequences that DAL19 produces six mature mRNA splice variants in Picea abies. These splice variants use alternate first and last exons, while their four central exons constitute a core region present in all six transcripts. Thus, they are likely to be transcript isoforms. Quantitative Real-Time PCR revealed that two mutually exclusive first DAL19 exons are differentially expressed across meristems that will form either male or female cones, or vegetative shoots. Furthermore, mRNA in situ hybridization revealed that two mutually exclusive last DAL19 exons were expressed in a cell-specific pattern within bud meristems. Based on these findings in DAL19, we developed a sensitive approach to transcript isoform assembly from short-read sequencing of mRNA. We applied this method to 42 putative MADS-box core regions in P abies, from which we assembled 1084 putative transcripts. We manually curated these transcripts to arrive at 933 assembled transcript isoforms of 38 putative MADS-box genes. 152 of these isoforms, which we assign to 28 putative MADS-box genes, were differentially expressed across eight female, male, and vegetative buds. We further provide evidence of the expression of 16 out of the 38 putative MADS-box genes by mapping PacBio Iso-Seq circular consensus reads derived from pooled sample sequencing to assembled transcripts. In summary, our analyses reveal the use of mutually exclusive exons of MADS-box gene isoforms during early bud development in P. abies, and we find that the large number of identified MADS-box transcripts in P. abies results not only from expansion of the gene family through gene duplication events but also from the generation of numerous splice variants.

  • 24.
    Akkuratov, Evgeny E.
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab. St Petersburg State Univ, Inst Translat Biomed, St Petersburg, Russia.
    Gelfand, Mikhail S.
    Skolkovo Inst Sci & Technol, Ctr Data Intens Biomed & Biotechnol, Moscow, Russia.;Russian Acad Sci, Inst Informat Transmiss Problems, Moscow, Russia.;Natl Res Univ, Higher Sch Econ, Fac Comp Sci, Moscow, Russia.;MM Lomonosov Moscow State Univ, Dept Bioengn & Bioinformat, Moscow, Russia..
    Khrameeva, Ekaterina E.
    Skolkovo Inst Sci & Technol, Ctr Data Intens Biomed & Biotechnol, Moscow, Russia.;Russian Acad Sci, Inst Informat Transmiss Problems, Moscow, Russia..
    Neanderthal and Denisovan ancestry in Papuans: A functional study2018Ingår i: Journal of Bioinformatics and Computational Biology, ISSN 0219-7200, E-ISSN 1757-6334, Vol. 16, nr 2, artikel-id 1840011Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sequencing of complete nuclear genomes of Neanderthal and Denisovan stimulated studies about their relationship with modern humans demonstrating, in particular, that DNA alleles from both Neanderthal and Denisovan genomes are present in genomes of modern humans. The Papuan genome is a unique object because it contains both Neanderthal and Denisovan alleles. Here, we have shown that the Papuan genomes contain different gene functional groups inherited from each of the ancient people. The Papuan genomes demonstrate a relative prevalence of Neanderthal alleles in genes responsible for the regulation of transcription and neurogenesis. The enrichment of specific functional groups with Denisovan alleles is less pronounced; these groups are responsible for bone and tissue remodeling. This analysis shows that introgression of alleles from Neanderthals and Denisovans to Papuans occurred independently and retention of these alleles may carry specific adaptive advantages.

  • 25.
    Alagaratnam, S.
    et al.
    DNV GL, Grp Technol & Res, Precis Med Programme, Hovik, Norway..
    Pedersen, G. Meldre
    DNV GL, Grp Technol & Res, Precis Med Programme, Hovik, Norway..
    McAdam, S.
    DNV GL, Digital Hlth Incubator, Digital Solut, Hovik, Norway..
    Wirta, Valtteri
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Sci Life Lab, Stockholm, Sweden..
    Lundeberg, Joakim
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Duno, M.
    Copenhagen Univ Hosp, Dept Clin Genet, Copenhagen, Denmark..
    Wadt, K. A. W.
    Copenhagen Univ Hosp, Dept Clin Genet, Copenhagen, Denmark..
    Rossing, M.
    Copenhagen Univ Hosp, Ctr Genom Med, Copenhagen, Denmark..
    Jonsson, J. J.
    Univ Iceland, Dept Genet & Mol Med, Landspitali Natl Univ Hosp, Reykjavik, Iceland.;Univ Iceland, Dept Biochem & Mol Biol, Fac Med, Reykjavik, Iceland..
    Saarela, J.
    Ctr Mol Med Norway, Oslo, Norway.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland..
    Undlien, D.
    Oslo Univ Hosp, Dept Med Genet, Oslo, Norway..
    Quality improvement in clinical NGS through a peer-driven Nordic collaboration2019Ingår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, s. 1622-1623Artikel i tidskrift (Övrigt vetenskapligt)
  • 26.
    Alexeyenko, Andrey
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lee, Woojoo
    Pernemalm, Maria
    Guegan, Justin
    Dessen, Philippe
    Lazar, Vladimir
    Lehtio, Janne
    Pawitan, Yudi
    Network enrichment analysis: extension of gene-set enrichment analysis to gene networks2012Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 13, s. 226-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Gene-set enrichment analyses (GEA or GSEA) are commonly used for biological characterization of an experimental gene-set. This is done by finding known functional categories, such as pathways or Gene Ontology terms, that are over-represented in the experimental set; the assessment is based on an overlap statistic. Rich biological information in terms of gene interaction network is now widely available, but this topological information is not used by GEA, so there is a need for methods that exploit this type of information in high-throughput data analysis. Results: We developed a method of network enrichment analysis (NEA) that extends the overlap statistic in GEA to network links between genes in the experimental set and those in the functional categories. For the crucial step in statistical inference, we developed a fast network randomization algorithm in order to obtain the distribution of any network statistic under the null hypothesis of no association between an experimental gene-set and a functional category. We illustrate the NEA method using gene and protein expression data from a lung cancer study. Conclusions: The results indicate that the NEA method is more powerful than the traditional GEA, primarily because the relationships between gene sets were more strongly captured by network connectivity rather than by simple overlaps.

  • 27.
    Alexeyenko, Andrey
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nystedt, Björn
    Vezzi, Francesco
    Sherwood, Ellen
    Ye, Rosa
    Knudsen, Bjarne
    Simonsen, Martin
    Turner, Benjamin
    de Jong, Pieter
    Wu, Cheng-Cang
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Efficient de novo assembly of large and complex genomes by massively parallel sequencing of Fosmid pools2014Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, nr 1, s. 439-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Sampling genomes with Fosmid vectors and sequencing of pooled Fosmid libraries on the Illumina platform for massive parallel sequencing is a novel and promising approach to optimizing the trade-off between sequencing costs and assembly quality. Results: In order to sequence the genome of Norway spruce, which is of great size and complexity, we developed and applied a new technology based on the massive production, sequencing, and assembly of Fosmid pools (FP). The spruce chromosomes were sampled with similar to 40,000 bp Fosmid inserts to obtain around two-fold genome coverage, in parallel with traditional whole genome shotgun sequencing (WGS) of haploid and diploid genomes. Compared to the WGS results, the contiguity and quality of the FP assemblies were high, and they allowed us to fill WGS gaps resulting from repeats, low coverage, and allelic differences. The FP contig sets were further merged with WGS data using a novel software package GAM-NGS. Conclusions: By exploiting FP technology, the first published assembly of a conifer genome was sequenced entirely with massively parallel sequencing. Here we provide a comprehensive report on the different features of the approach and the optimization of the process. We have made public the input data (FASTQ format) for the set of pools used in this study: ftp://congenie.org/congenie/Nystedt_2013/Assembly/ProcessedData/FosmidPools/.(alternatively accessible via http://congenie.org/downloads).The software used for running the assembly process is available at http://research.scilifelab.se/andrej_alexeyenko/downloads/fpools/.

  • 28.
    Alexeyenko, Andrey
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Schmitt, Thomas
    Tjärnberg, Andreas
    Stockholm University, Science for Life Laboratory.
    Guala, Dmitri
    Stockholm University, Science for Life Laboratory.
    Frings, Oliver
    Stockholm University, Science for Life Laboratory.
    Sonnhammer, Erik L. L.
    Stockholm University, Science for Life Laboratory.
    Comparative interactomics with Funcoup 2.02012Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, nr D1, s. D821-D828Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    FunCoup (http://FunCoup.sbc.su.se) is a database that maintains and visualizes global gene/protein networks of functional coupling that have been constructed by Bayesian integration of diverse high-throughput data. FunCoup achieves high coverage by orthology-based integration of data sources from different model organisms and from different platforms. We here present release 2.0 in which the data sources have been updated and the methodology has been refined. It contains a new data type Genetic Interaction, and three new species: chicken, dog and zebra fish. As FunCoup extensively transfers functional coupling information between species, the new input datasets have considerably improved both coverage and quality of the networks. The number of high-confidence network links has increased dramatically. For instance, the human network has more than eight times as many links above confidence 0.5 as the previous release. FunCoup provides facilities for analysing the conservation of subnetworks in multiple species. We here explain how to do comparative interactomics on the FunCoup website.

  • 29. Ali, E. S.
    et al.
    Rajapaksha, H.
    Lundborg, Magnus
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Carr, J. M.
    Petrovsky, N.
    Norovirus drug candidates that inhibit viral capsid attachment to human histo-blood group antigens2016Ingår i: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 133, s. 14-22Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Human noroviruses are the leading causative agents of epidemic and sporadic viral gastroenteritis and childhood diarrhoea worldwide. Human histo-blood group antigens (HBGA) serve as receptors for norovirus capsid protein attachment and play a critical role in infection. This makes HBGA-norovirus binding a promising target for drug development. Recently solved crystal structures of norovirus bound to HBGA have provided a structural basis for identification of potential anti-norovirus drugs and subsequently performed in silico and in vitro drug screens have identified compounds that block norovirus binding and may thereby serve as structural templates for design of therapeutic norovirus inhibitors. This review explores norovirus therapeutic options based on the strategy of blocking norovirus-HBGA binding.

  • 30.
    Ali, Raja Hashim
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsvetenskap och beräkningsteknik (CST). KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Bark, Mikael
    KTH, Skolan för informations- och kommunikationsteknik (ICT).
    Miró, Jorge
    KTH, Skolan för informations- och kommunikationsteknik (ICT).
    Muhammad, Sayyed Auwn
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsvetenskap och beräkningsteknik (CST). KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Sjöstrand, J.
    Zubair, Syed M.
    KTH, Skolan för elektro- och systemteknik (EES), Kommunikationsnät. University of Balochistan, Pakistan.
    Abbas, R. M.
    Arvestad, L.
    VMCMC: A graphical and statistical analysis tool for Markov chain Monte Carlo traces2017Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 18, nr 1, artikel-id 97Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: MCMC-based methods are important for Bayesian inference of phylogeny and related parameters. Although being computationally expensive, MCMC yields estimates of posterior distributions that are useful for estimating parameter values and are easy to use in subsequent analysis. There are, however, sometimes practical difficulties with MCMC, relating to convergence assessment and determining burn-in, especially in large-scale analyses. Currently, multiple software are required to perform, e.g., convergence, mixing and interactive exploration of both continuous and tree parameters. Results: We have written a software called VMCMC to simplify post-processing of MCMC traces with, for example, automatic burn-in estimation. VMCMC can also be used both as a GUI-based application, supporting interactive exploration, and as a command-line tool suitable for automated pipelines. Conclusions: VMCMC is a free software available under the New BSD License. Executable jar files, tutorial manual and source code can be downloaded from https://bitbucket.org/rhali/visualmcmc/.

  • 31.
    Ali, Raja Hashim
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Khan, Ammad Aslam
    Tracing the evolution of FERM domain of Kindlins2014Ingår i: Molecular Phylogenetics and Evolution, ISSN 1055-7903, E-ISSN 1095-9513, Vol. 80, s. 193-204Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Kindlin proteins represent a novel family of evolutionarily conserved FERM domain containing proteins (FDCPs) and are members of B4.1 superfamily. Kindlins consist of three conserved protein homologs in vertebrates: Kindlin-1, Kindlin-2 and Kindlin-3. All three homologs are associated with focal adhesions and are involved in Integrin activation. FERM domain of each Kindlin is bipartite and plays a key role in Integrin activation. A single ancestral Kindlin protein can be traced back to earliest metazoans, e.g., to Parazoa. This protein underwent multiple rounds of duplication in vertebrates, leading to the present Kindlin family. In this study, we trace phylogenetic and evolutionary history of Kindlin FERM domain with respect to FERM domain of other FDCPs. We show that FERM domain in Kindlin homologs is conserved among Kindlins but amount of conservation is less in comparison with FERM domain of other members in B4.1 superfamily. Furthermore, insertion of Pleckstrin Homology like domain in Kindlin FERM domain has important evolutionary and functional consequences. Important residues in Kindlins are traced and ranked according to their evolutionary significance. The structural and functional significance of high ranked residues is highlighted and validated by their known involvement in Kindlin associated diseases. In light of these findings, we hypothesize that FERM domain originated from a proto-Talin protein in unicellular or proto-multicellular organism and advent of multi-cellularity was accompanied by burst of FDCPs, which supported multi-cellularity functions required for complex organisms. This study helps in developing a better understanding of evolutionary history of FERM domain of FDCPs and the role of FERM domain in metazoan evolution.

  • 32.
    Ali, Raja Hashim
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Muhammad, Sayyed Auwn
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Khan, Mehmodd Alam
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Arvestad, Lars
    Stockholms universitet.
    Quantitative synteny scoring improves homology inference and partitioning of gene families2013Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 14, s. S12-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Clustering sequences into families has long been an important step in characterization of genes and proteins. There are many algorithms developed for this purpose, most of which are based on either direct similarity between gene pairs or some sort of network structure, where weights on edges of constructed graphs are based on similarity. However, conserved synteny is an important signal that can help distinguish homology and it has not been utilized to its fullest potential. Results: Here, we present GenFamClust, a pipeline that combines the network properties of sequence similarity and synteny to assess homology relationship and merge known homologs into groups of gene families. GenFamClust identifies homologs in a more informed and accurate manner as compared to similarity based approaches. We tested our method against the Neighborhood Correlation method on two diverse datasets consisting of fully sequenced genomes of eukaryotes and synthetic data. Conclusions: The results obtained from both datasets confirm that synteny helps determine homology and GenFamClust improves on Neighborhood Correlation method. The accuracy as well as the definition of synteny scores is the most valuable contribution of GenFamClust.

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  • 33.
    Aljadi, Zenib
    et al.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden.
    Kalm, Frida
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden;Sachs´ Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden.
    Nilsson, Caroline
    Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden.;Soder Sjukhuset, Sachs Children & Youth Hosp, Stockholm, Sweden..
    Winqvist, Ola
    Karolinska Univ Hosp, Dept Clin Immunol, Stockholm, Sweden..
    Russom, Aman
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Nanobioteknologi.
    Lundahl, Joachim
    Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden.;Soder Sjukhuset, Sachs Children & Youth Hosp, Stockholm, Sweden..
    Nopp, Anna
    Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden.;Soder Sjukhuset, Sachs Children & Youth Hosp, Stockholm, Sweden..
    A novel tool for clinical diagnosis of allergy operating a microfluidic immunoaffinity basophil activation test technique2019Ingår i: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 209, artikel-id UNSP 108268Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Basophil Activation Test (BAT) is a valuable allergy diagnostic tool but is time-consuming and requires skilled personnel and cumbersome processing, which has limited its clinical use. We therefore investigated if a microfluidic immunoaffinity BAT (miBAT) technique can be a reliable diagnostic method. Blood was collected from allergic patients and healthy controls. Basophils were challenged with negative control, positive control (anti-FccRI), and two concentrations of a relevant and non-relevant allergen. CD203c and CD63 expression was detected by fluorescent microscopy and flow cytometry. In basophils from allergic patients the CD63% was significantly higher after allergen activation as compared to the negative control (p < .0001-p = .0004). Activation with non-relevant allergen showed equivalent CD63% expression as the negative control. Further, the miBAT data were comparable to flow cytometry. Our results demonstrate the capacity of the miBAT technology to measure different degrees of basophil allergen activation by quantifying the CD63% expression on captured basophils.

  • 34.
    Aljadi, Zenib
    et al.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden; Soder Sjukhuset, Stockholm, Sweden .
    Kalm, Frida
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden; Soder Sjukhuset, Stockholm, Sweden.
    Ramachandraiah, Harisha
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nopp, Anna
    Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden.;Soder Sjukhuset, Stockholm, Sweden..
    Lundahl, Joachim
    Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden.;Soder Sjukhuset, Stockholm, Sweden..
    Russom, Aman
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Microfluidic Immunoaffinity Basophil Activation Test for Point-of-Care Allergy Diagnosis2019Ingår i: Journal of Applied Laboratory Medicine (JALM), ISSN 2475-7241, Vol. 4, nr 2, s. 152-163Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The flow cytometry-based basophil activation test (BAT) is used for the diagnosis of allergic response. However, flow cytometry is time-consuming, requiring skilled personnel and cumbersome processing, which has limited its use in the clinic. Here, we introduce a novel microfluidic-based immunoaffinity BAT (miBAT) method. Methods: The microfluidic device, coated with anti-CD203c, was designed to capture basophils directly from whole blood. The captured basophils are activated by anti-FceRI antibody followed by optical detection of CD63 expression (degranulation marker). The device was first characterized using a basophil cell line followed by whole blood experiments. Weevaluated the device with ex vivo stimulation of basophils in whole blood from healthy controls and patients with allergies and compared it with flow cytometry. Results: The microfluidic device was capable of capturing basophils directly from whole blood followed by in vitro activation and quantification of CD63 expression. CD63 expression was significantly higher (P = 0.0002) in on-chip activated basophils compared with nonactivated cells. The difference in CD63 expression on anti-FceRI-activated captured basophils in microfluidic chip was significantly higher (P = 0.03) in patients with allergies compared with healthy controls, and the results were comparable with flow cytometry analysis (P = 0.04). Furthermore, there was no significant difference of CD63% expression in anti-FceRI-activated captured basophils in microfluidic chip compared with flow cytometry. Conclusions: We report on the miBAT. This device is capable of isolating basophils directly from whole blood for on-chip activation and detection. The new miBAT method awaits validation in larger patient populations to assess performance in diagnosis and monitoring of patients with allergies at the point of care.

  • 35. Alkasalias, Twana
    et al.
    Alexeyenko, Andrey
    Hennig, Katharina
    Danielsson, Frida
    Lebbink, Robert Jan
    Fielden, Matthew
    Turunen, S. Pauliina
    Lehti, Kaisa
    Kashuba, Vladimir
    Madapura, Harsha S.
    Bozoky, Benedek
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Balland, Martial
    Guven, Hayrettin
    Klein, George
    Gad, Annica K. B.
    Pavlova, Tatiana
    RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 8, s. E1413-E1421Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fibroblasts are a main player in the tumor-inhibitory microenvironment. Upon tumor initiation and progression, fibroblasts can lose their tumor-inhibitory capacity and promote tumor growth. The molecular mechanisms that underlie this switch have not been defined completely. Previously, we identified four proteins over-expressed in cancer-associated fibroblasts and linked to Rho GTPase signaling. Here, we show that knocking out the Ras homolog family member A (RhoA) gene in normal fibroblasts decreased their tumor-inhibitory capacity, as judged by neighbor suppression in vitro and accompanied by promotion of tumor growth in vivo. This also induced PC3 cancer cell motility and increased colony size in 2D cultures. RhoA knockout in fibroblasts induced vimentin intermediate filament reorganization, accompanied by reduced contractile force and increased stiffness of cells. There was also loss of wide F-actin stress fibers and large focal adhesions. In addition, we observed a significant loss of a-smooth muscle actin, which indicates a difference between RhoA knockout fibroblasts and classic cancer-associated fibroblasts. In 3D collagen matrix, RhoA knockout reduced fibroblast branching and meshwork formation and resulted in more compactly clustered tumor-cell colonies in coculture with PC3 cells, which might boost tumor stem-like properties. Coculturing RhoA knockout fibroblasts and PC3 cells induced expression of proinflammatory genes in both. Inflammatory mediators may induce tumor cell stemness. Network enrichment analysis of transcriptomic changes, however, revealed that the Rho signaling pathway per se was significantly triggered only after coculturing with tumor cells. Taken together, our findings in vivo and in vitro indicate that Rho signaling governs the inhibitory effects by fibroblasts on tumor-cell growth.

  • 36.
    Alm, Tove
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Introducing the Affinity Binder Knockdown Initiative-A public-private partnership for validation of affinity reagents2016Ingår i: EuPA Open Proteomics, ISSN 0014-2328, E-ISSN 2212-9685, Vol. 10, s. 56-58Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The newly launched Affinity Binder Knockdown Initiative encourages antibody suppliers and users to join this public-private partnership, which uses crowdsourcing to collect characterization data on antibodies. Researchers are asked to share validation data from experiments where gene-editing techniques (such as siRNA or CRISPR) have been used to verify antibody binding. The initiative is launched under the aegis of Antibodypedia, a database designed to allow comparisons and scoring of publicly available antibodies towards human protein targets. What is known about an antibody is the foundation of the scoring and ranking system in Antibodypedia.

  • 37.
    Alm, Tove
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    von Feilitzen, Kalle
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sivertsson, Åsa
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    A Chromosome-Centric Analysis of Antibodies Directed toward the Human Proteome Using Antibodypedia2014Ingår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, nr 3, s. 1669-1676Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Antibodies are crucial for the study of human proteins and have been defined as one of the three pillars in the human chromosome-centric Human Proteome Project (CHPP). In this article the chromosome-centric structure has been used to analyze the availability of antibodies as judged by the presence within the portal Antibodypedia, a database designed to allow comparisons and scoring of publicly available antibodies toward human protein targets. This public database displays antibody data from more than one million antibodies toward human protein targets. A summary of the content in this knowledge resource reveals that there exist more than 10 antibodies to over 70% of all the putative human genes, evenly distributed over the 24 human chromosomes. The analysis also shows that at present, less than 10% of the putative human protein-coding genes (n = 1882) predicted from the genome sequence lack antibodies, suggesting that focused efforts from the antibody-based and mass spectrometry-based proteomic communities should be encouraged to pursue the analysis of these missing proteins. We show that Antibodypedia may be used to track the development of available and validated antibodies to the individual chromosomes, and thus the database is an attractive tool to identify proteins with no or few antibodies yet generated.

  • 38.
    Alneberg, Johannes
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bioinformatic Methods in Metagenomics2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Mikrobiella organismer är en vital del av vårt globala ekosystem. Trots detta är vår kunskap om dessa fortfarande begränsad. Sekvensering direkt applicerad på mikrobiella samhällen, så kallad metagenomik, har möjliggjort detaljerade studier av dessa mikroskopiska organismer genom deras DNA-sekvenser. Utvecklingen av modern sekvenseringsteknik har vidare gjort denna strategi både mer kraftfull och mer kostnadseffektiv. Sammantaget har detta förändrat mikrobiologi-fältet, från att ha varit centrerat kring mikroskopi, till att till stor del bero på dataintensiva analyser av DNA-sekvenser. En sådan analys, som är det huvudsakliga fokuset för den här avhandlingen, syftar till att återskapa den kompletta DNA-sekvensen för en organism, dvs. dess genom, direkt från korta metagenom-sekvenser.

    Den här avhandlingen består av en introduktion till ämnet, följt av fem artiklar. Artikel I beskriver en omfattande databas för metagenomik över Östersjöns mikrobiella samhällen. Till denna databas hör också en webbsida som ger forskare möjlighet att lätt extrahera och visualisera detaljerad information. Artikel II introducerar en bioinformatisk metod som kan återskapa genom från metagenom. Denna metod, som kallas CONCOCT, används för data från Östersjön i artikel III och Artikel V. Detta möjliggjorde återskapandet av ett stort antal genom. Analys av dessa genom presenterad i Artikel III ledde till hypotesen om, och belägg för, ett globalt brackvattenmikrobiom. Artikel IV innehåller en jämförelse mellan genom återskapade från metagenom och individuellt sekvenserade genom. Detta validerade metoden som presenterades i Artikel II ytterligare då denna metod visade sig producera större och mer kompletta genom än sekvensering av individuella celler.

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  • 39.
    Alneberg, Johannes
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Bennke, Christin
    Leibniz Inst Balt Sea Res, Warnemunde, Germany..
    Beier, Sara
    Leibniz Inst Balt Sea Res, Warnemunde, Germany.;Sorbonne Univ, CNRS, Lab Oceanog Microbienne, LOMIC, Banyuls Sur Mer, France..
    Bunse, Carina
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden.;Carl von Ossietzky Univ Oldenburg, HIFMB, Oldenburg, Germany.;Helmholtz Zentrum Polar & Meeresforsch, Alfred Wegener Inst, Bremerhaven, Germany..
    Quince, Christopher
    Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England..
    Ininbergs, Karolina
    Stockholm Univ, Dept Ecol Environm & Plant Sci, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Stockholm, Sweden..
    Riemann, Lasse
    Univ Copenhagen, Marine Biol Sect, Dept Biol, Helsingor, Denmark..
    Ekman, Martin
    Stockholm Univ, Dept Ecol Environm & Plant Sci, Stockholm, Sweden..
    Juergens, Klaus
    Leibniz Inst Balt Sea Res, Warnemunde, Germany..
    Labrenz, Matthias
    Leibniz Inst Balt Sea Res, Warnemunde, Germany..
    Pinhassi, Jarone
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden..
    Andersson, Anders F.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Ecosystem-wide metagenomic binning enables prediction of ecological niches from genomes2020Ingår i: COMMUNICATIONS BIOLOGY, ISSN 2399-3642, Vol. 3, nr 1, artikel-id 119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alneberg et al. conduct metagenomics binning of water samples collected over major environmental gradients in the Baltic Sea. They use machine-learning to predict the placement of genome clusters along niche gradients based on the content of functional genes. The genome encodes the metabolic and functional capabilities of an organism and should be a major determinant of its ecological niche. Yet, it is unknown if the niche can be predicted directly from the genome. Here, we conduct metagenomic binning on 123 water samples spanning major environmental gradients of the Baltic Sea. The resulting 1961 metagenome-assembled genomes represent 352 species-level clusters that correspond to 1/3 of the metagenome sequences of the prokaryotic size-fraction. By using machine-learning, the placement of a genome cluster along various niche gradients (salinity level, depth, size-fraction) could be predicted based solely on its functional genes. The same approach predicted the genomes' placement in a virtual niche-space that captures the highest variation in distribution patterns. The predictions generally outperformed those inferred from phylogenetic information. Our study demonstrates a strong link between genome and ecological niche and provides a conceptual framework for predictive ecology based on genomic data.

  • 40.
    Alneberg, Johannes
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Bennke, Christin
    Leibniz Institute for Baltic Sea Research, Warnemünde, Germany.
    Beier, Sara
    Leibniz Institute for Baltic Sea Research, Warnemünde, Germany.
    Pinhassi, Jarone
    Centre for Ecology and Evolution in Microbial Model Systems, Linnaeus University, Kalmar, Sweden.
    Jürgens, Klaus
    Leibniz Institute for Baltic Sea Research, Warnemünde, Germany.
    Ekman, Martin
    Department of Ecology, Environment and Plant Sciences, Stockholm University Science for Life Laboratory, Solna, Sweden.
    Ininbergs, Karolina
    Department of Ecology, Environment and Plant Sciences, Stockholm University Science for Life Laboratory, Solna, Sweden.
    Labrenz, Matthias
    Leibniz Institute for Baltic Sea Research, Warnemünde, Germany.
    Andersson, Anders F.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Recovering 2,032 Baltic Sea microbial genomes by optimized metagenomic binningManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Aquatic microorganism are key drivers of global biogeochemical cycles and form the basis of aquatic food webs. However, there is still much left to be learned about these organisms and their interaction within specific environments, such as the Baltic Sea. Crucial information for such an understanding can be found within the genome sequences of organisms within the microbial community.

    In this study, the previous set of Baltic Sea clusters, constructed by Hugert et al., is greatly expanded using a large set of metagenomic samples, spanning the environmental gradients of the Baltic Sea. In total, 124 samples were individually assembled and binned to obtain 2,032 Metagenome Assembled Genomes (MAGs), clustered into 353 prokaryotic and 14 eukaryotic species- level clusters. The prokaryotic genomes were widely distributed over the prokaryotic tree of life, representing 20 different phyla, while the eukaryotic genomes were mostly limited to the division of Chlorophyta. The large number of reconstructed genomes allowed us to identify key factors determining the quality of the genome reconstructions.

    The Baltic Sea is heavily influenced of human activities of which we might not see the full implications. The genomes reported within this study will greatly aid further studies in our strive for an understanding of the Baltic Sea microbial ecosystem.

  • 41.
    Alneberg, Johannes
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bjarnason, Brynjar Smári
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    de Bruijn, Ino
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Bioinformatics Infrastructure for Life Sciences (BILS), Sweden.
    Schirmer, Melanie
    Quick, Joshua
    Ijaz, Umer Z.
    Lahti, Leo
    Loman, Nicholas J.
    Andersson, Anders F.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Quince, Christopher
    Binning metagenomic contigs by coverage and composition2014Ingår i: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 11, nr 11, s. 1144-1146Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Shotgun sequencing enables the reconstruction of genomes from complex microbial communities, but because assembly does not reconstruct entire genomes, it is necessary to bin genome fragments. Here we present CONCOCT, a new algorithm that combines sequence composition and coverage across multiple samples, to automatically cluster contigs into genomes. We demonstrate high recall and precision on artificial as well as real human gut metagenome data sets.

  • 42.
    Alneberg, Johannes
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Garcia, M. U.
    Karolinska Inst, Dept Oncol, Solna, Sweden..
    Peltzer, A.
    Univ Tubingen, Quantitat Biol Ctr QBiC, Tubingen, Germany..
    Koch, T.
    Univ Tubingen, Quantitat Biol Ctr QBiC, Tubingen, Germany..
    Proks, M.
    Univ Southern Denmark, Odense, Denmark..
    Wilm, A.
    ASTAR, Genome Inst Singapore, Bioinformat Core Unit, Singapore, Singapore..
    Ewels, P. A.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Natl Genom Infrastruct Stockholm, Stockholm, Sweden..
    Analysis of genome sequencing data with a minimal investment IT-infrastructure2019Ingår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, s. 1706-1706Artikel i tidskrift (Övrigt vetenskapligt)
  • 43.
    Alneberg, Johannes
    et al.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Karlsson, Christofer M. G.
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, EEMiS, Kalmar, Sweden..
    Divne, Anna-Maria
    Uppsala Univ, Dept Cell & Mol Biol, SciLifeLab, Uppsala, Sweden..
    Bergin, Claudia
    Uppsala Univ, Dept Cell & Mol Biol, SciLifeLab, Uppsala, Sweden..
    Homa, Felix
    Uppsala Univ, Dept Cell & Mol Biol, SciLifeLab, Uppsala, Sweden..
    Lindh, Markus V.
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, EEMiS, Kalmar, Sweden.;Lund Univ, Dept Biol, Lund, Sweden..
    Hugerth, Luisa
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Ettema, Thijs J. G.
    Uppsala Univ, Dept Cell & Mol Biol, SciLifeLab, Uppsala, Sweden..
    Bertilsson, Stefan
    Uppsala Univ, Dept Ecol & Genet, Sci Life Lab, Limnol, Uppsala, Sweden..
    Andersson, Anders F.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Pinhassi, Jarone
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, EEMiS, Kalmar, Sweden..
    Genomes from uncultivated prokaryotes: a comparison of metagenome-assembled and single-amplified genomes2018Ingår i: Microbiome, ISSN 0026-2633, E-ISSN 2049-2618, Vol. 6, artikel-id 173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Prokaryotes dominate the biosphere and regulate biogeochemical processes essential to all life. Yet, our knowledge about their biology is for the most part limited to the minority that has been successfully cultured. Molecular techniques now allow for obtaining genome sequences of uncultivated prokaryotic taxa, facilitating in-depth analyses that may ultimately improve our understanding of these key organisms. Results: We compared results from two culture-independent strategies for recovering bacterial genomes: single-amplified genomes and metagenome-assembled genomes. Single-amplified genomes were obtained from samples collected at an offshore station in the Baltic Sea Proper and compared to previously obtained metagenome-assembled genomes from a time series at the same station. Among 16 single-amplified genomes analyzed, seven were found to match metagenome-assembled genomes, affiliated with a diverse set of taxa. Notably, genome pairs between the two approaches were nearly identical (average 99.51% sequence identity; range 98.77-99.84%) across overlapping regions (30-80% of each genome). Within matching pairs, the single-amplified genomes were consistently smaller and less complete, whereas the genetic functional profiles were maintained. For the metagenome-assembled genomes, only on average 3.6% of the bases were estimated to be missing from the genomes due to wrongly binned contigs. Conclusions: The strong agreement between the single-amplified and metagenome-assembled genomes emphasizes that both methods generate accurate genome information from uncultivated bacteria. Importantly, this implies that the research questions and the available resources are allowed to determine the selection of genomics approach for microbiome studies.

  • 44.
    Alneberg, Johannes
    et al.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Karlsson, Christofer M.G.
    Centre for Ecology and Evolution in Microbial Model Systems, EEMiS, Linnaeus University, Barlastgatan 11, 391 82 Kalmar, Sweden.
    Divne, Anna-Maria
    Department of Cell and Molecular Biology, SciLifeLab, Uppsala University, Uppsala, Sweden .
    Bergin, Claudia
    Department of Cell and Molecular Biology, SciLifeLab, Uppsala University, Uppsala, Sweden .
    Homa, Felix
    Department of Cell and Molecular Biology, SciLifeLab, Uppsala University, Uppsala, Sweden .
    Lindh, Markus V.
    Centre for Ecology and Evolution in Microbial Model Systems, EEMiS, Linnaeus University, Barlastgatan 11, 391 82 Kalmar, Sweden.
    Hugerth, Luisa W.
    Karolinska Institutet, Science for Life Laboratory, Department of Molecular, Tumour and Cell Biology, Centre for Translational Microbiome Research, Solna, Sweden.
    Ettema, Thijs JG
    Department of Cell and Molecular Biology, SciLifeLab, Uppsala University, Uppsala, Sweden.
    Bertilsson, Stefan
    Department of Ecology and Genetics, Limnology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Andersson, Anders F.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Pinhassi, Jarone
    Centre for Ecology and Evolution in Microbial Model Systems, EEMiS, Linnaeus University, Barlastgatan 11, 391 82 Kalmar, Sweden.
    Genomes from uncultivated prokaryotes: a comparison of metagenome-assembled and single-amplified genomesManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: Prokaryotes dominate the biosphere and regulate biogeochemical processes essential to all life. Yet, our knowledge about their biology is for the most part limited to the minority that has been successfully cultured. Molecular techniques now allow for obtaining genome sequences of uncultivated prokaryotic taxa, facilitating in-depth analyses that may ultimately improve our understanding of these key organisms.

    Results: We compared results from two culture-independent strategies for recovering bacterial genomes: single-amplified genomes and metagenome-assembled genomes. Single-amplified genomes were obtained from samples collected at an offshore station in the Baltic Sea Proper and compared to previously obtained metagenome-assembled genomes from a time series at the same station. Among 16 single-amplified genomes analyzed, seven were found to match metagenome-assembled genomes, affiliated with a diverse set of taxa. Notably, genome pairs between the two approaches were nearly identical (>98.7% identity) across overlapping regions (30-80% of each genome). Within matching pairs, the single-amplified genomes were consistently smaller and less complete, whereas the genetic functional profiles were maintained. For the metagenome-assembled genomes, only on average 3.6% of the bases were estimated to be missing from the genomes due to wrongly binned contigs; the metagenome assembly was found to cause incompleteness to a higher degree than the binning procedure.

    Conclusions: The strong agreement between the single-amplified and metagenome-assembled genomes emphasizes that both methods generate accurate genome information from uncultivated bacteria. Importantly, this implies that the research questions and the available resources are allowed to determine the selection of genomics approach for microbiome studies.

    Ladda ner fulltext (pdf)
    fulltext
  • 45.
    Alneberg, Johannes
    et al.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sundh, John
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
    Bennke, Christin
    Leibniz Institute for Baltic Sea Research, Warnemünde, Germany.
    Beier, Sara
    Leibniz Institute for Baltic Sea Research, Warnemünde, Germany.
    Lundin, Daniel
    Centre for Ecology and Evolution in Microbial Model Systems, Linnaeus University, Kalmar, Sweden.
    Hugerth, Luisa
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO).
    Pinhassi, Jarone
    Centre for Ecology and Evolution in Microbial Model Systems, Linnaeus University, Kalmar, Sweden.
    Kisand, Veljo
    University of Tartu, Institute of Technology, Tartu, Estonia.
    Riemann, Lasse
    Section for Marine Biological Section, Department of Biology, University of Copenhagen, Helsingør, Denmark.
    Jürgens, Klaus
    Leibniz Institute for Baltic Sea Research, Warnemünde, Germany.
    Labrenz, Matthias
    Leibniz Institute for Baltic Sea Research, Warnemünde, Germany.
    Andersson, Anders F.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    BARM and BalticMicrobeDB, a reference metagenome and interface to meta-omic data for the Baltic SeaManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The Baltic Sea is one of the world’s largest brackish water bodies and is characterised by pronounced physicochemical gradients where microbes are the main biogeochemical catalysts. Meta-omic methods provide rich information on the composition of, and activities within microbial ecosystems, but are computationally heavy to perform. We here present the BAltic Sea Reference Metagenome (BARM), complete with annotated genes to facilitate further studies with much less computational effort. The assembly is constructed using 2.6 billion metagenomic reads from 81 water samples, spanning both spatial and temporal dimensions, and contains 6.8 million genes that have been annotated for function and taxonomy. The assembly is useful as a reference, facilitating taxonomic and functional annotation of additional samples by simply mapping their reads against the assembly. This capability is demonstrated by the successful mapping and annotation of 24 external samples. In addition, we present a public web interface, BalticMicrobeDB, for interactive exploratory analysis of the dataset.

    Ladda ner fulltext (pdf)
    fulltext
  • 46.
    Alneberg, Johannes
    et al.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sundh, John
    Stockholm Univ, Sci Life Lab, Dept Biochem & Biophys, S-17165 Solna, Sweden..
    Bennke, Christin
    Leibniz Inst Balt Sea Res Warnemunde, D-18119 Rostock, Germany..
    Beier, Sara
    Leibniz Inst Balt Sea Res Warnemunde, D-18119 Rostock, Germany..
    Lundin, Daniel
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, S-39182 Kalmar, Sweden..
    Hugerth, Luisa W.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Mol Tumor & Cell Biol, Ctr Translat Microbiome Res, Sci Life Lab, S-17165 Solna, Sweden..
    Pinhassi, Jarone
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, S-39182 Kalmar, Sweden..
    Kisand, Veljo
    Univ Tartu, Inst Technol, EE-50411 Tartu, Estonia..
    Riemann, Lasse
    Univ Copenhagen, Sect Marine Biol Sect, Dept Biol, DK-3000 Helsingor, Denmark..
    Juergens, Klaus
    Leibniz Inst Balt Sea Res Warnemunde, D-18119 Rostock, Germany..
    Labrenz, Matthias
    Leibniz Inst Balt Sea Res Warnemunde, D-18119 Rostock, Germany..
    Andersson, Anders F.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    BARM and BalticMicrobeDB, a reference metagenome and interface to meta-omic data for the Baltic Sea2018Ingår i: Scientific Data, E-ISSN 2052-4463, Vol. 5, artikel-id 180146Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Baltic Sea is one of the world's largest brackish water bodies and is characterised by pronounced physicochemical gradients where microbes are the main biogeochemical catalysts. Meta-omic methods provide rich information on the composition of, and activities within, microbial ecosystems, but are computationally heavy to perform. We here present the Baltic Sea Reference Metagenome (BARM), complete with annotated genes to facilitate further studies with much less computational effort. The assembly is constructed using 2.6 billion metagenomic reads from 81 water samples, spanning both spatial and temporal dimensions, and contains 6.8 million genes that have been annotated for function and taxonomy. The assembly is useful as a reference, facilitating taxonomic and functional annotation of additional samples by simply mapping their reads against the assembly. This capability is demonstrated by the successful mapping and annotation of 24 external samples. In addition, we present a public web interface, BalticMicrobeDB, for interactive exploratory analysis of the dataset.

  • 47.
    Altay, Özlem
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Mol & Clin Med, Gothenburg, Sweden..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Systems biology perspective for studying the gut microbiota in human physiology and liver diseases2019Ingår i: EBioMedicine, E-ISSN 2352-3964, Vol. 49, s. 364-373Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The advancement in high-throughput sequencing technologies and systems biology approaches have revolutionized our understanding of biological systems and opened a new path to investigate unacknowledged biological phenomena. In parallel, the field of human microbiome research has greatly evolved and the relative contribution of the gut microbiome to health and disease have been systematically explored. This review provides an overview of the network-based and translational systems biology-based studies focusing on the function and composition of gut microbiota. We also discussed the association between the gut microbiome and the overall human physiology, as well as hepatic diseases and other metabolic disorders.

  • 48.
    Alvelid, Jonatan
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Testa, Ilaria
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Fluorescence microscopy at the molecular scale2019Ingår i: Current Opinion in Biomedical Engineering, ISSN 2468-4511, Vol. 12, s. 34-42Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The diffraction limit is no longer a concept that stands as a true constant in imaging, with fluorescence switching–based methods having made the breakthrough to circumvent this limit. Multiple ingenious solutions have been presented over the last decades and continue to be explored. The techniques used today have undergone constant development both conceptually and technically, which has enabled an increased number of biological studies at the molecular scale. Here we review recent developments to stimulated emission depletion microscopy, reversible saturable optical fluorescence transitions microscopy, single-molecule localization microscopy, and MINFLUX and mention key applications of these methods. Finally, we present our view on what the future holds for super-resolution imaging, especially in terms of even more challenging live-cell imaging in different biological model systems.

  • 49.
    Alvelid, Jonatan
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Testa, Ilaria
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Stable stimulated emission depletion imaging of extended sample regions2020Ingår i: Journal of Physics D: Applied Physics, ISSN 0022-3727, E-ISSN 1361-6463, Vol. 53, nr 2, artikel-id 024001Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Stimulated emission depletion (STED) nanoscopy has become one of the most used nanoscopy techniques over the last decade. However, most recordings are done in specimen regions no larger than 10–30  ×  10–30 μm2 due to aberrations, instability and manual mechanical stages. Here, we demonstrate automated 2D and 3D STED nanoscopy of extended sample regions up to 0.5  ×  0.5 mm2 by using a scanning system that maintains stationary beams in the back focal plane. The setup allows up to 80–100  ×  80–100 μm2 field of view (FOV) with uniform spatial resolution, a mechanical stage allowing sequential tiling to record larger sample areas, and a feedback system keeping the sample in focus at all times. Taken together, this allows automated recording of theoretically unlimited-sized sample areas and volumes, without compromising the achievable spatial resolution and image quality.

  • 50. Amarouch, Mohamed-Yassine
    et al.
    Kurt, Han
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik.
    Delemotte, Lucie
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Abriel, Hugues
    Biophysical Characterization of Epigallocatechin-3-Gallate Effect on the Cardiac Sodium Channel Na(v)1.52020Ingår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 25, nr 4, artikel-id 902Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Epigallocatechin-3-Gallate (EGCG) has been extensively studied for its protective effect against cardiovascular disorders. This effect has been attributed to its action on multiple molecular pathways and transmembrane proteins, including the cardiac Na(v)1.5 channels, which are inhibited in a dose-dependent manner. However, the molecular mechanism underlying this effect remains to be unveiled. To this aim, we have characterized the EGCG effect on Na(v)1.5 using electrophysiology and molecular dynamics (MD) simulations. EGCG superfusion induced a dose-dependent inhibition of Na(v)1.5 expressed in tsA201 cells, negatively shifted the steady-state inactivation curve, slowed the inactivation kinetics, and delayed the recovery from fast inactivation. However, EGCG had no effect on the voltage-dependence of activation and showed little use-dependent block on Na(v)1.5. Finally, MD simulations suggested that EGCG does not preferentially stay in the center of the bilayer, but that it spontaneously relocates to the membrane headgroup region. Moreover, no sign of spontaneous crossing from one leaflet to the other was observed, indicating a relatively large free energy barrier associated with EGCG transport across the membrane. These results indicate that EGCG may exert its biophysical effect via access to its binding site through the cell membrane or via a bilayer-mediated mechanism.

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