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Helsingin yliopiston tutkijoiden julkaisemia artikkeleja.

Helsingin yliopiston tutkijat voivat rinnakkaistallentaa tutkimusjulkaisujansa HELDAan liittämällä kokotekstin julkaisuun TUHAT-tutkimustietojärjestelmässä. (Toimintaohje tutkijalle)

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  • Hallamies, Sanna; Pelttari, Liisa M.; Poikonen-Saksela, Paula; Jekunen, Antti; Jukkola-Vuorinen, Arja; Auvinen, Paivi; Blomqvist, Carl; Aittomaki, Kristiina; Mattson, Johanna; Nevanlinna, Heli (BioMed Central Ltd, 2017)
    Background: Several susceptibility genes have been established for female breast cancer, of which mutations in BRCA1 and especially in BRCA2 are also known risk factors for male breast cancer (MBC). The role of other breast cancer genes in MBC is less well understood. Methods: In this study, we have genotyped 68 MBC patients for the known breast or ovarian cancer associated mutations in the Finnish population in CHEK2, PALB2, RAD51C, RAD51D, and FANCM genes. Results: CHEK2 c.1100delC mutation was found in 4 patients (5.9%), which is significantly more frequent than in the control population (OR: 4.47, 95% CI 1.51-13.18, p = 0.019). Four CHEK2 I157T variants were also detected, but the frequency did not significantly differ from population controls (p = 0.781). No RAD51C, RAD51D, PALB2, or FANCM mutations were found. Conclusions: These data suggest that the CHEK2 c.1100delC mutation is associated with an increased risk for MBC in the Finnish population.
  • Saurus, Pauliina; Tolvanen, Tuomas A.; Lindfors, Sonja; Kuusela, Sara; Holthofer, Harry; Lehtonen, Eero; Lehtonen, Sanna (Nature Publishing Group, 2017)
    Lack of CD2-associated protein (CD2AP) in mice increases podocyte apoptosis and leads to glomerulosclerosis and renal failure. We showed previously that SHIP2, a negative regulator of the PI3K/AKT signalling pathway, interacts with CD2AP. Here, we found that the expression level and activity of SHIP2 and production of reactive oxygen species (ROS) are increased in cultured CD2AP knockout (CD2AP-/-) mouse podocytes. Oxidative stress was also increased in CD2AP-/- mouse glomeruli in vivo. We found that puromycin aminonucleoside (PA), known to increase ROS production and apoptosis, increases SHIP2 activity and reduces CD2AP expression in cultured human podocytes. PDK1 and CDK2, central regulators of AKT, were downregulated in CD2AP-/- or PA-treated podocytes. Downregulation of PDK1 and CDK2, ROS generation and apoptosis were prevented by CD2AP overexpression in both models. Notably, inhibition of SHIP2 activity with a small molecule inhibitor AS1949490 ameliorated ROS production in CD2AP-/- podocytes, but, surprisingly, further reduced PDK1 expression and aggravated apoptosis. AKT-and ERK-mediated signalling was diminished and remained reduced after AS1949490 treatment in the absence of CD2AP. The data suggest that inhibition of the catalytic activity of SHIP2 is beneficial in reducing oxidative stress, but leads to deleterious increase in apoptosis in podocytes with reduced expression of CD2AP.
  • Bilkova, Eva; Pleskot, Roman; Rissanen, Sami; Sun, Simou; Czogalla, Aleksander; Cwiklik, Lukasz; Rog, Tomasz; Vattulainen, Ilpo; Cremer, Paul S.; Jungwirth, Pavel; Coskun, Uenal (American Chemical Society, 2017)
    The orchestrated recognition of phosphoinositides and concomitant intracellular release of Ca2+ is pivotal to almost every aspect of cellular processes, including membrane homeostasis, cell division and growth, vesicle trafficking, as well as secretion. Although Ca2+ is known to directly impact phosphoinositide clustering, little is known about the molecular basis for this or its significance in cellular signaling. Here, we study the direct interaction of Ca2+ with phosphatidylinositol sphosphate (PI(4,5)P-2), the main lipid marker of the plasma membrane. Electrokinetic potential measurements of PI(4,5)P-2 containing liposomes reveal that Ca2+ as well as Mg2+ reduce the zeta potential of liposomes to nearly background levels of pure phosphatidylcholine membranes. Strikingly, lipid recognition by the default PI(4,5)P-2 lipid sensor, phospholipase C delta 1 pleckstrin homology domain (PLC delta 1-PH), is completely inhibited in the presence of Ca2+, while Mg2+ has no effect with 100 nm liposomes and modest effect with giant unilamellar vesicles. Consistent with biochemical data, vibrational sum frequency spectroscopy and atomistic molecular dynamics simulations reveal how Ca2+ binding to the PI(4,5)P-2 headgroup and carbonyl regions leads to confined lipid headgroup tilting and conformational rearrangements. We rationalize these findings by the ability of calcium to block a highly specific interaction between PLC delta 1-PH and PI(4,5)P-2, encoded within the conformational properties of the lipid itself. Our studies demonstrate the possibility that switchable phosphoinositide conformational states can serve as lipid recognition and controlled cell signaling mechanisms.
  • Polley, Anirban; Orlowski, Adam; Danne, Reinis; Gurtovenko, Andrey A.; de la Serna, Jorge Bernardino; Eggeling, Christian; Davis, Simon J.; Rog, Tomasz; Vattulainen, Ilpo (American Chemical Society, 2017)
    Proteins embedded in the plasma membrane mediate interactions with the cell environment and play decisive roles in many signaling events. For cell-cell recognition molecules, it is highly likely that their structures and behavior have been optimized in ways that overcome the limitations of membrane tethering. In particular, the ligand binding regions of these proteins likely need to be maximally exposed. Here we show by means of atomistic simulations of membrane-bound CD2, a small cell adhesion receptor expressed by human T-cells and natural killer cells, that the presentation of its ectodomain is highly dependent on membrane lipids and receptor glycosylation acting in apparent unison. Detailed analysis shows that the underlying mechanism is based on electrostatic interactions complemented by steric interactions between glycans in the protein and the membrane surface. The findings are significant for understanding the factors that render membrane receptors accessible for binding and signaling.
  • Rong, Mark K.; van Duin, Koen; van Dijk, Tom; de Pater, Jeroen J. M.; Deelman, Berth-Jan; Nieger, Martin; Ehlers, A. W.; Slootweg, J. Chris; Lammertsma, Koop (American Chemical Society, 2017)
    Highly stable iminophosphanes, obtained from alkylating nitriles and reaction of the resulting nitrilium ions with secondary phosphanes, were explored as tunable P-monodentate and 1,3-P,N bidentate ligands in rhodium complexes. X-ray crystal structures are reported for both k1 and k2 complexes with the counterion in one of them being an unusual anionic coordination polymer of silver triflate. The iminophosphane-based ruthenium(II)-catalyzed hydration of benzonitrile in 1,2-dimethoxyethane (180 degrees C, 3 h) and water (100 degrees C, 24 h) and under solvent free conditions (180 degrees C, 3 h) results in all cases in the selective formation of benzamide with yields of up to 96%, thereby outperforming by far the reactions in which the common 2-pyridyldiphenylphosphane is used as the 1,3-P,N ligand.
  • Mendizabal, Fernando; Mera-Adasme, Raul; Xu, Wen-Hua; Sundholm, Dage (The Royal Society of Chemistry, 2017)
    Dye-sensitized solar-cell (DSSC) systems have been investigated by calculating light-absorption and electron-injection processes of the LD13 ([5,15-bis(2,6-(1,1-dimethylethyl)-phenyl)-10-4-dimethylaminophenylethynyl-20-4-carboxy phenylethynyl porphyrinato]zinc-(II)) and YD2-o-C8 ([5,15bis( 2,6-dioctoxyphenyl)-10-(bis(4-hexylphenyl)amino-20-4-carboxyphenylethynyl)porphyrinato]zinc-(II)) dyes adsorbed on a TiO2 cluster simulating the semiconductor. The binding energy of the dyes with the TiO2 clusters has been calculated at the density functional theory (DFT) level using the B3LYP and CAM-B3LYP functionals. The electronic excitation energies have been calculated at the time-dependent DFT (TDDFT) level for the dyes in the gas and solvent phase employing the B3LYP, CAM-B3LYP and BHLYP functionals. The calculated excitation energies have been compared to values obtained at the algebraic diagrammatic construction through second order (ADC(2)) level of theory. The TDDFT calculations with the B3LYP in tetrahydrofuran solvent with the dye and dye-TiO2 models yield excitation energies that agree well with the transitions in the experimental absorption spectra. Changes in the free energy for electron injection support the better performance of the dyes on the TiO2 clusters.
  • Tessier, Laurence; Cote, Olivier; Clark, Mary Ellen; Viel, Laurent; Diaz-Mendez, Andres; Anders, Simon; Bienzle, Dorothee (BioMed Central Ltd, 2017)
    Background: Severe equine asthma is a naturally occurring lung inflammatory disease of mature animals characterized by neutrophilic inflammation, bronchoconstriction, mucus hypersecretion and airway remodeling. Exacerbations are triggered by inhalation of dust and microbial components. Affected animals eventually are unable of aerobic performance. In this study transcriptomic differences between asthmatic and non-asthmatic animals in the response of the bronchial epithelium to an inhaled challenge were determined. Results: Paired endobronchial biopsies were obtained pre- and post-challenge from asthmatic and non-asthmatic animals. The transcriptome, determined by RNA-seq and analyzed with edgeR, contained 111 genes differentially expressed (DE) after challenge between horses with and without asthma, and 81 of these were upregulated. Genes involved in neutrophil migration and activation were in central location in interaction networks, and related gene ontology terms were significantly overrepresented. Relative abundance of specific gene products as determined by immunohistochemistry was correlated with differential gene expression. Gene sets involved in neutrophil chemotaxis, immune and inflammatory response, secretion, blood coagulation and apoptosis were overrepresented among up-regulated genes, while the rhythmic process gene set was overrepresented among down-regulated genes. MMP1, IL8, TLR4 and MMP9 appeared to be the most important proteins in connecting the STRING protein network of DE genes. Conclusions: Several differentially expressed genes and networks in horses with asthma also contribute to human asthma, highlighting similarities between severe human adult and equine asthma. Neutrophil activation by the bronchial epithelium is suggested as the trigger of the inflammatory cascade in equine asthma, followed by epithelial injury and impaired repair and differentiation. Circadian rhythm dysregulation and the sonic Hedgehog pathway were identified as potential novel contributory factors in equine asthma.
  • Gu, Yufei; Lensu, Anssi; Perämäki, Siiri; Ojala, Anne Kristiina; Vähätalo, Anssi Vesa (American Chemical Society Journals, 2017)
  • Laukkanen, S.; Gronroos, T.; Polonen, P.; Kuusanmaki, H.; Mehtonen, J.; Cloos, J.; Ossenkoppele, G.; Gjertsen, B.; Oystein, B.; Heckman, C.; Heinaniemi, M.; Kontro, M.; Lohi, O. (Nature Publishing Group, 2017)
  • Kurten, Theo; Moller, Kristian H.; Nguyen, Tran B.; Schwantes, Rebecca H.; Misztal, Pawel K.; Su, Luping; Wennberg, Paul O.; Fry, Juliane L.; Kjaergaard, Henrik G. (American Chemical Society, 2017)
    Oxidation of monoterpenes (C10H16) by nitrate radicals (NO3) constitutes an important source of atmospheric secondary organic aerosol (SOA) and organonitrates. However, knowledge of the mechanisms of their formation is incomplete and differences in yields between similar monoterpenes are poorly understood. In particular, yields of SOA and organonitrates from alpha-pinene + NO3 are low, while those from Delta(3)-carene + NO3 are high. Using computational methods, we suggest that bond scission of the nitrooxy alkoxy radicals from Delta(3)-carene lead to the formation of reactive keto-nitrooxy-alkyl radicals, which retain the nitrooxy moiety and can undergo further reactions to form SOA. By contrast, bond scissions of the nitrooxy alkoxy radicals from alpha-pinene lead almost exclusively to the formation of the relatively unreactive and volatile product pinonaldehyde (C10H16O2), thereby limiting organonitrate and SOA formation. This hypothesis is supported by laboratory experiments that quantify products of the reaction of alpha-pinene + NO3 under atmospherically relevant conditions.
  • Ahlberg, Erik; Falk, John; Eriksson, Axel; Holst, Thomas; Brune, William H.; Kristensson, Adam; Roldin, Pontus; Svenningsson, Birgitta (Elsevier Scientific Publ. Co, 2017)
    The atmospheric organic aerosol is a tremendously complex system in terms of chemical content. Models generally treat the mixtures as ideal, something which has been questioned owing to model-measurement discrepancies. We used an oxidation flow reactor to produce secondary organic aerosol (SOA) mixtures containing oxidation products of biogenic (alpha-pinene, myrcene and isoprene) and anthropogenic (m-xylene) volatile organic compounds (VOCs). The resulting volume concentration and chemical composition was measured using a scanning mobility particle sizer (SMPS) and a high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS), respectively. The SOA mass yield of the mixtures was compared to a partitioning model constructed from single VOC experiments. The single VOC SOA mass yields with no wall-loss correction applied are comparable to previous experiments. In the mixtures containing myrcene a higher yield than expected was produced. We attribute this to an increased condensation sink, arising from myrcene producing a significantly higher number of nucleation particles compared to the other precursors. Isoprene did not produce much mass in single VOC experiments but contributed to the mass of the mixtures. The effect of high concentrations of isoprene on the OH exposure was found to be small, even at OH reactivities that previously have been reported to significantly suppress OH exposures in oxidation flow reactors. Furthermore, isoprene shifted the particle size distribution of mixtures towards larger sizes, which could be due to a change in oxidant dynamics inside the reactor. (C) 2017 The Authors. Published by Elsevier Ltd.
  • Hilmarsson, Hrannar Smari; Hytonen, Timo; Isobe, Sachiko; Goransson, Magnus; Toivainen, Tuomas; Hallsson, Jon Hallsteinn (PUBLIC LIBRARY OF SCIENCE, 2017)
    The woodland strawberry, Fragaria vesca, holds great promise as a model organism. It not only represents the important Rosaceae family that includes economically important species such as apples, pears, peaches and roses, but it also complements the well-known model organism Arabidopsis thaliana in key areas such as perennial life cycle and the development of fleshy fruit. Analysis of wild populations of A. thaliana has shed light on several important developmental pathways controlling, for example, flowering time and plant growth, suggesting that a similar approach using F. vesca might add to our understanding on the development of rosaceous species and perennials in general. As a first step, 298 F. vesca plants were analyzed using microsatellite markers with the primary aim of analyzing population structure and distribution of genetic diversity. Of the 68 markers tested, 56 were polymorphic, with an average of 4.46 alleles per locus. Our analysis partly confirms previous classification of F. vesca subspecies in North America and suggests two groups within the subsp. bracteata. In addition, F. vesca subsp. vesca forms a single global population with evidence that the Icelandic group is a separate cluster from the main Eurasian population.
  • Nichman, Leonid; Järvinen, Emma; Dorsey, James; Connolly, Paul; Duplissy, Jonathan; Fuchs, Claudia; Ignatius, Karoliina; Sengupta, Kamalika; Stratmann, Frank; Möhler, Ottmar; Schnaiter, Martin; Gallagher, Martin (COPERNICUS GESELLSCHAFT MBH, 2017)
    Optical probes are frequently used for the detection of microphysical cloud particle properties such as liquid and ice phase, size and morphology. These properties can eventually influence the angular light scattering properties of cirrus clouds as well as the growth and accretion mechanisms of single cloud particles. In this study we compare four commonly used optical probes to examine their response to small cloud particles of different phase and as-phericity. Cloud simulation experiments were conducted at the Cosmics Leaving OUtdoor Droplets (CLOUD) chamber at European Organisation for Nuclear Research (CERN). The chamber was operated in a series of multi-step adiabatic expansions to produce growth and sublimation of ice particles at super-and subsaturated ice conditions and for initial temperatures of -30, -40 and -50 degrees C. The experiments were performed for ice cloud formation via homogeneous ice nucleation. We report the optical observations of small ice particles in deep convection and in situ cirrus simulations. Ice crystal asphericity deduced from measurements of spatially resolved single particle light scattering patterns by the Particle Phase Discriminator mark 2 (PPD-2K, Karlsruhe edition) were compared with Cloud and Aerosol Spectrometer with Polarisation (CASPOL) measurements and image roundness captured by the 3View Cloud Particle Imager (3V-CPI). Averaged path light scattering properties of the simulated ice clouds were measured using the Scattering Intensity Measurements for the Optical detectioN of icE (SIMONE) and single particle scattering properties were measured by the CASPOL. We show the ambiguity of several optical measurements in ice fraction determination of homogeneously frozen ice in the case where sublimating quasi-spherical ice particles are present. Moreover, most of the instruments have difficulties of producing reliable ice fraction if small aspherical ice particles are present, and all of the instruments cannot separate perfectly spherical ice particles from supercooled droplets. Correlation analysis of bulk averaged path depolarisation measurements and single particle measurements of these clouds showed higher R-2 values at high concentrations and small diameters, but these results require further confirmation. We find that none of these instruments were able to determine unambiguously the phase of the small particles. These results have implications for the interpretation of atmospheric measurements and parametrisations for modelling, particularly for low particle number concentration clouds.
  • Väisänen, Petri; Reunanen, Juha; Kotilainen, Jari; Mattila, Seppo; Johansson, Peter H.; Ramphul, Rajin; Romero-Canizales, Cristina; Kuncarayakti, Hanindyo (Oxford University Press, 2017)
    We present new SINFONI near-infrared (NIR) integral field unit (IFU) spectroscopy and Southern African Large Telescope (SALT) optical long-slit spectroscopy characterizing the history of a nearby merging luminous infrared galaxy, dubbed the Bird (IRAS19115-2124). TheNIR line-ratio maps of the IFU data cubes and stellar population fitting of the SALT spectra now allow dating of the star formation (SF) over the triple system uncovered from our previous adaptive optics data. The distinct components separate clearly in line-ratio diagnostic diagrams, both thermal and non-thermal excitation is present. An off-nuclear starburst dominates the current SF of the Bird with 60-70 per cent of the total, with a 4-7 Myr age. The most massive nucleus, in contrast, is quenched with a starburst age of >40 Myr and shows hints of budding active galactic nucleus (AGN) activity. The secondary massive nucleus is at an intermediate stage. The two major components have signs of an older stellar population, consistent with a starburst triggered 1 Gyr ago in a first encounter. The simplest explanation of the history is that of a triple merger, where the strongly star-forming component has joined later. We detect multiple gas flows. The Bird offers an opportunity to witness multiple stages of galaxy evolution in the same system; triggering as well as very recent quenching of SF, and, perhaps, an early appearance of AGN activity. It also serves as a cautionary note on interpretations of observations with lower spatial resolution and/or without infrared data. At high redshift the system would look like a clumpy starburst with crucial pieces of its puzzle hidden in danger of misinterpretations.
  • Kiamehr, Mostafa; Viiri, Leena E.; Vihervaara, Terhi; Koistinen, Kaisa M.; Hilvo, Mika; Ekroos, Kim; Kakela, Reijo; Aalto-Setala, Katriina (Company of Biologists Ltd, 2017)
    Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem cells (iPSCs) offer an alternative model to primary human hepatocytes to study lipid aberrations. However, the detailed lipid profile of HLCs is yet unknown. In the current study, functional HLCs were differentiated from iPSCs generated from dermal fibroblasts of three individuals by a three-step protocol through the definitive endoderm (DE) stage. In parallel, detailed lipidomic analyses as well as gene expression profiling of a set of lipid-metabolism-related genes were performed during the entire differentiation process from iPSCs to HLCs. Additionally, fatty acid (FA) composition of the cell culture media at different stages was determined. Our results show that major alterations in the molecular species of lipids occurring during DE and early hepatic differentiation stages mainly mirror the quality and quantity of the FAs supplied in culture medium at each stage. Polyunsaturated phospholipids and sphingolipids with a very long FA were produced in the cells at a later stage of differentiation. This work uncovers the previously unknown lipid composition of iPSC-HLCs and its alterations during the differentiation in conjunction with the expression of key lipid-associated genes. Together with biochemical, functional and gene expression measurements, the lipidomic analyses allowed us to improve our understanding of the concerted influence of the exogenous metabolite supply and cellular biosynthesis essential for iPSC-HLC differentiation and function. Importantly, the study describes in detail a cell model that can be applied in exploring, for example, the lipid metabolism involved in the development of fatty liver disease or atherosclerosis.