| 1. |
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| 2. |
- Wacker, A, et al.
(författare)
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Secondary structure determination of conserved SARS-CoV-2 RNA elements by NMR spectroscopy
- 2020
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Ingår i: Nucleic acids research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 48:22, s. 12415-12435
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Tidskriftsartikel (refereegranskat)abstract
- The current pandemic situation caused by the Betacoronavirus SARS-CoV-2 (SCoV2) highlights the need for coordinated research to combat COVID-19. A particularly important aspect is the development of medication. In addition to viral proteins, structured RNA elements represent a potent alternative as drug targets. The search for drugs that target RNA requires their high-resolution structural characterization. Using nuclear magnetic resonance (NMR) spectroscopy, a worldwide consortium of NMR researchers aims to characterize potential RNA drug targets of SCoV2. Here, we report the characterization of 15 conserved RNA elements located at the 5′ end, the ribosomal frameshift segment and the 3′-untranslated region (3′-UTR) of the SCoV2 genome, their large-scale production and NMR-based secondary structure determination. The NMR data are corroborated with secondary structure probing by DMS footprinting experiments. The close agreement of NMR secondary structure determination of isolated RNA elements with DMS footprinting and NMR performed on larger RNA regions shows that the secondary structure elements fold independently. The NMR data reported here provide the basis for NMR investigations of RNA function, RNA interactions with viral and host proteins and screening campaigns to identify potential RNA binders for pharmaceutical intervention.
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| 3. |
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| 4. |
- Martins, RM, et al.
(författare)
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An ApiAP2 member regulates expression of clonally variant genes of the human malaria parasite Plasmodium falciparum
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 14042-
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Tidskriftsartikel (refereegranskat)abstract
- Variegated surface antigen expression is key to chronic infection and pathogenesis of the human malaria parasite Plasmodium falciparum. This protozoan parasite expresses distinct surface molecules that are encoded by clonally variant gene families such as var, rif and stevor. The molecular mechanisms governing activation of individual members remain ill-defined. To investigate the molecular events of the initial transcriptional activation process we focused on a member of the apicomplexan ApiAP2 transcription factor family predicted to bind to the 5′ upstream regions of the var gene family, AP2-exp (PF3D7_1466400). Viable AP2-exp mutant parasites rely on expressing no less than a short truncated protein including the N-terminal AP2 DNA-binding domain. RNA-seq analysis in mutant parasites revealed transcriptional changes in a subset of exported proteins encoded by clonally variant gene families. Upregulation of RIFINs and STEVORs was validated at the protein levels. In addition, morphological alterations were observed on the surface of the host cells infected by the mutants. This work points to a complex regulatory network of clonally variant gene families in which transcription of a subset of members is regulated by the same transcription factor. In addition, we highlight the importance of the non-DNA binding AP2 domain in functional gene regulation.
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| 5. |
- Wurz, P., et al.
(författare)
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Particles and Photons as Drivers for Particle Release from the Surfaces of the Moon and Mercury
- 2022
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Ingår i: Space Science Reviews. - : Springer. - 0038-6308 .- 1572-9672. ; 218:3
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Forskningsöversikt (refereegranskat)abstract
- The Moon and Mercury are airless bodies, thus they are directly exposed to the ambient plasma (ions and electrons), to photons mostly from the Sun from infrared range all the way to X-rays, and to meteoroid fluxes. Direct exposure to these exogenic sources has important consequences for the formation and evolution of planetary surfaces, including altering their chemical makeup and optical properties, and generating neutral gas exosphere. The formation of a thin atmosphere, more specifically a surface bound exosphere, the relevant physical processes for the particle release, particle loss, and the drivers behind these processes are discussed in this review.
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| 6. |
- Burrows, Hugh D., et al.
(författare)
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Solubilization of poly{1,4-phenylene-[9,9-bis(4-phenoxy-butylsulfonate)]fluorene-2,7-diyl} in Water by Non-Ionic Amphiphiles
- 2009
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 25:10, s. 5545-5556
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Tidskriftsartikel (refereegranskat)abstract
- In the presence of the nonionic alkyloxyethylene surfactant n-dodecylpentaoxyethylene glycol ether (C12E5), the anionic conjugated polyelectrolyte (CPE) poly{1,4-phenylene-[9,9-bis(4-phenoxy-butylsulfonate)]fluorene-2,7-diyl} (PBS-PFP) dissolves in water, leading to a blue shift in fluorescence and dramatic increases in fluorescence quantum yields above the surfactant critical micelle concentration (cmc). No significant changes were seen with a poly(ethylene oxide) of similar size to the surfactant headgroup, confirming that specific surfactant-polyelectrolyte interactions are important. From UV-visible and fluorescence spectroscopy, dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), cryogenic transmission electron microscopy (cryo-TEM), and electrical conductivity, together with our published NMR and small-angle neutron scattering (SANS) results, we provide a coherent model for this behavior in terms of breakup of PBS-PFP clusters through polymer-surfactant association leading to cylindrical aggregates containing isolated polymer chains. This is supported by molecular dynamics simulations, which indicate stable polymer-surfactant structures and also provide indications of the tendency of C12E5 to break up polymer clusters to form these mixed polymer-surfactant aggregates. Radial electron density profiles of the cylindrical cross section obtained from SAXS results reveal the internal structure of such inhomogeneous species. DLS and cryo-TEM results show that at higher surfactant concentrations the micelles start to grow, possibly partially due to formation of long, threadlike species. Other alkyloxyethylene surfactants, together with poly(propylene glycol) and hydrophobically modified poly(ethylene glycol), also solubilize this polymer in water, and it is suggested that this results from a balance between electrostatic (or ion-dipole), hydrophilic, and hydrophobic interactions. There is a small, but significant, dependence of the emission maximum on the local environment.
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| 7. |
- Cheun, H., et al.
(författare)
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Polarized optical absorption spectroscopy, NEXAFS, and GIXRD measurements of chain alignment in polyfluorene thin films
- 2008
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Ingår i: Macromolecules. - : American Chemical Society (ACS). - 0024-9297 .- 1520-5835. ; 41:17, s. 6463-6472
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Tidskriftsartikel (refereegranskat)abstract
- The uniaxial chain alignment of low molecular weight poly(9,9-bis(ethylhexyl)fluorene-2,7-diyl) (PF2/6) in thin films cast atop rubbed polyimide templates is characterized by polarized optical absorption spectroscopy, carbon K near-edge X-ray absorption fine structure spectroscopy (NEXAFS), and grazing incidence X-ray diffraction (GIXRD) in response to thermal annealing and increasing film thickness (ca. 15-150 nm). The highest overall levels of uniaxial alignment are obtained in the thinnest PF2/6 films. However, the orientation of chains at the top surface after thermal annealing is nearly thickness independent despite a large drop in the maximum optical dichroic ratio as the film thickness increases. The kinetics of chain alignment on heating are strongly film thickness dependent and only weakly correlated with a crossover to a nematic liquid crystal state. All told these data support a structural model in which there is a graded morphology such that the top and bottom surfaces exhibit appreciable planar, uniaxial alignment while the film interior includes a greater proportion of nomplanar (i.e., tilted) chains after thermal cycling. These inhomogeneities are likely to influence technologically important optical and transport properties.
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| 8. |
- Fusai, T, et al.
(författare)
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Characterisation of the chondroitin sulphate of Saimiri brain microvascular endothelial cells involved in Plasmodium falciparum cytoadhesion
- 2000
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Ingår i: Molecular and biochemical parasitology (Print). - 0166-6851 .- 1872-9428. ; 108:1, s. 25-37
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Tidskriftsartikel (refereegranskat)abstract
- Cytoadhesion of Plasmodium falciparum-infected erythrocytes (IRBC) to chondroitin-4-sulphate (CSA) is inhibited by soluble CSA in vitro on Saimiri brain microvascular endothelial cells (SBEC) and in vivo in P. falciparum-infected Saimiri monkeys. We tested whether the SBEC model was appropriate for studying CSA-binding IRBC using four cell lines. All SBEC expressed a chondroitin sulphate (CS), with a composition of CSA. The mean sizes of these CSA were 20.5, 22, 23, 32.5 and 36 kDa for SBEC 3A and C2, CHO, SBEC 1D and 17, respectively. We found that cytoadhesion of the Palo-Alto (FUP)1 CSA-binding phenotype, selected by panning on SBEC 17, was specifically inhibited in a dose-dependent manner by all the purified CSA. The extent of inhibition depended on the cellular origin of the tested CSA. SBEC 17 CSA was 33 times more efficient than CHO-CSA and 21 times more efficient than the 50 kDa commercial bovine trachaea CSA. Dynabeads coated with a total extract of SBEC 1D CS-proteoglycans interacted with CSA- but not with CD36- or ICAM-1-binding IRBC. These Dynabeads also interacted specifically with the PfEMP1 DBL-3 domain, on the surface of CHO transfectants, but not with the CIDR-1 domain. Thrombomodulin was involved in IRBC adhesion to all SBEC whereas CD44 was only expressed by SBEC 1D and 17. These two CSA-proteoglycans have also been detected at the surface of human endothelial cells. Thus, the two homologous models, SBEC/Saimiri sciureus, are useful and reliable tools for the evaluation of new anti-CSA adhesion treatments and anti-disease vaccines for pregnant women.
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| 9. |
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| 10. |
- Justino, L. L. G., et al.
(författare)
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Structural and electronic properties of poly(9,9-dialkylfluorene)-based alternating copolymers in solution : An NMR spectroscopy and density functional theory study
- 2013
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Ingår i: The Journal of Physical Chemistry C. - : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 117:35, s. 17969-17982
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Tidskriftsartikel (refereegranskat)abstract
- The structural and electronic properties of three alternating poly(9,9-dialkylfluorene) copolymers, poly[2,7-(9,9-bis(octyl)-fluorene)-alt- benzothiadiazole] (F8BT), poly[2,7-(9,9-bis(2′-ethylhexyl)-fluorene)-alt- thiophene S,S-dioxide] (PFTSO2), and poly[2,7-(9,9-bis(2′-ethylhexyl)- fluorene)-alt-1,4-phenylene] (PFP), containing, respectively, benzothiadiazole (BT), thiophene S,S-dioxide, and phenylene groups, have been investigated and compared to those of the homopolymer poly[2,7-(9,9-bis(2′-ethylhexyl)- fluorene)] (PF2/6). The NMR spectra and corresponding shielding tensors of the 1H and 13C nuclei have been studied in solution and are interpreted by density functional theory (DFT) with complete geometry optimization using the B3LYP functional. Particular emphasis is placed on the conformational behavior and electronic properties in the electronic ground state. In addition, time-dependent DFT is applied to obtain detailed insight into the character of selected excited states. A new TDDFT interpretation is presented for optical absorption spectra of singlet and triplet states that have previously been reported for these fluorene-based conjugated copolymers using photoexcitation and pulse radiolysis-energy transfer studies. As well as providing detailed assignment of excited states, the results show that the triplet excitation is slightly more localized than S1 excitation, in agreement with experimental observations. The DFT analysis provides a link between structure and NMR, optical, electronic properties, allowing optimization of the potential of such polymers for photovoltaic and electroluminescence applications.
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| 11. |
- Knaapila, Matti, et al.
(författare)
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An effect of side chain length on the solution structure of poly(9,9-dialkylfluorene)s in toluene
- 2008
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Ingår i: Polymer. - : Elsevier BV. - 0032-3861. ; 49:8, s. 2033-2038
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Tidskriftsartikel (refereegranskat)abstract
- The effect of side chain length of pi-conjugated poly(9,9-dialkylfluorene)s has been studied in semi-dilute (10 mg/mL) toluene solutions using small-angle neutron scattering (SANS) and H-1 and H-2 NMR spectroscopies. Under these conditions, SANS data indicate that poly(9,9-dinonylfluorene) and poly(9,9-dioctylfluorene) are dissolved down to the molecule level and appear as elongated one-dimensional chains (length >20-30 nm). In contrast, the shorter side chain polymers exhibit a self-association so that poly(9,9-diheptylfluorene) forms thin sheet-like (similar to 1 nm) and poly(9,9-dihexylfluorene) thin (similar to 1 nm) and thick sheet-like (>6 nm) aggregates. H-1 NMR data, together with the density functional theory (DFT) calculations, however, show that this occurs without changes in the conformation of the polymer backbone.
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| 12. |
- Knaapila, Matti, et al.
(författare)
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Control over phase behavior and solution structure of hairy-rod polyfluorene by means of side-chain length and branching
- 2008
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Ingår i: Physical Review E (Statistical, Nonlinear, and Soft Matter Physics). - 1539-3755. ; 77:5
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Tidskriftsartikel (refereegranskat)abstract
- We present guidelines on how the solution structure of pi-conjugated hairy-rod polyfluorenes is controlled by the side-chain length and branching. First, the semiquantitative mean-field theory is formulated to predict the phase behavior of the system as a function of side-chain beads (N). The phase transition at N=N* separates a lyotropic phase with solvent coexistence (N < N*) and a metastable membrane phase (N > N*). The membrane phase transforms into the isotropic phase of dissolved rodlike polymers at the temperature T-mem*(N), which decreases both with N and with the degree of side-chain branching. This picture is complemented by polymer demixing with the transition temperature T-IN*(N), which decreases with N. For N < N*, the lyotropic phase turns isotropic with increasing T at T-IN*. For N > N*, stable membranes are predicted for T-IN*< T < T-mem* and metastable membranes with nematic coexistence for T < T-IN*. Second, in experiment, samples of poly(9,9-dialkylfluorene) with N=6-10 were mixed in methylcyclohexane. For N=8 the side-chain branching was controlled by (9,9-dioctylfluorene)/(9,9-bis(2-ethylhexyl)fluorene) (F8/F2/6) random copolymers. The proportion of F8 to F2/6 repeat units was 100:0, 95:5, 90:10, 50:50, and 0:100. In accordance with the theory, lyotropic, membrane, and isotropic phases with the corresponding phase transitions were observed. For N < N*similar to 6 only the lyotropic phase is present for attainable temperatures. The membrane and isotropic phases are present for N > N*. T-mem*(N) decreases from 340 K to 280 K for N >= 8. For copolymers, the membrane phase is found when the fraction of F8 units is at least 90%, T-mem* decreasing with this fraction. The membrane phase contains three material types: loose sheets of two polymer layers, a better packed beta phase, and dissolved polymer. For N >= 7 and T < T-mem* the tendency for membrane formation becomes stronger with increasing temperature.
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| 13. |
- Knaapila, M., et al.
(författare)
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Effect of side-chain asymmetry on the intermolecular structure and order-disorder transition in alkyl-substituted polyfluorenes
- 2016
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Ingår i: Physical Review E: covering statistical, nonlinear, biological, and soft matter physics. - 2470-0045. ; 93:4
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Tidskriftsartikel (refereegranskat)abstract
- We study relations among the side-chain asymmetry, structure, and order-disorder transition (ODT) in hairy-rod-type poly(9,9-dihexylfluorene) (PF6) with two identical side chains and atactic poly(9-octyl-9-methyl-fluorene) (PF1-8) with two different side chains per repeat. PF6 and PF1-8 organize into alternating side-chain and backbone layers that transform into an isotropic phase at TODT(PF6) and TbiODT(PF1-8). We interpret polymers in terms of monodisperse and bidisperse brushes and predict scenarios TODT
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| 14. |
- Knaapila, Matti, et al.
(författare)
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Influence of side chain length on the self-assembly of hairy-rod poly(9,9-dialkylfluorene)s in the poor solvent methylcyclohexane
- 2007
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Ingår i: Macromolecules. - : American Chemical Society (ACS). - 0024-9297 .- 1520-5835. ; 40:26, s. 9398-9405
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Tidskriftsartikel (refereegranskat)abstract
- We report on the phase behavior of poly(9,9-dihexylfluorene) (PF6), poly(9,9-diheptylfluorene) (PF7), poly(9,9-diocylfluorene) (PF8) poly(9,9-dinonylfluorene) (PF9), and poly(9,9-didecylfluorene) (PF10) in methylcyclohexane (MCH). After a heating-cooling cycle, in the 10-50 mg/mL. concentration range. PF6/ MCH. PF7/MCH. PF8/MCH, and PF9/MCH systems were found to be gel-like, while PF10/MCH appears less viscous. PF6/MCH, PF7/MCH, PF8/MCH, and PF9/MCH form large (10- 100 nm) sheetlike assemblies (thickness of 2-3 nm). The larger length scale Structures of these sheets show an odd-even dependence on the side chain (spacer) length: the PF6 and PF8 sheets are broader and thinner, whereas PF7 and PF9 sheets are thicker with a Putative double layer Structure. PF10 does not follow this sequence, and only part of the polymer is assembled into a sheetlike structure the rest remaining dissolved at the molecular level. PF8/MCH and PF9/MCH mixtures also have lower length scale crystalline structures with an internal period corresponding to the periodicity observed in the solid-state P phase of PF8. Vestiges of crystalline domains are found for PF6 and PF7 but not for PF10. PF7/MCH. PF8/MCH, and PF9/MCH systems contain the conformational isomer C, of those chains observed in the ss phase, while this is not observed with other polymer/MCH systems.
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| 15. |
- Zaitlen, Noah, et al.
(författare)
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Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies
- 2012
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low-BMI cases are larger than those estimated from high-BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-controlcovariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled falsepositive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1x10(-9)). The improvement varied across diseases with a 16% median increase in chi(2) test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci.
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