| 1. |
- Larsson, B-M, et al.
(författare)
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Road tunnel air pollution induces bronchoalveolar inflammation in healthy subjects
- 2007
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 29:4, s. 699-705
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Tidskriftsartikel (refereegranskat)abstract
- Traffic-related air pollution is associated with adverse respiratory effects. The aim of the present study was to investigate whether exposure to air pollution in a road tunnel causes airway inflammatory and blood coagulation responses. A total of 16 healthy subjects underwent bronchoscopy with bronchial mucosal biopsies and bronchoalveolar lavage (BAL) on two occasions, in random order: once at 14 h after a 2-h exposure to air pollution in a busy road tunnel, and once after a control day with subjects exposed to urban air during normal activities. Peripheral blood was sampled prior to bronchoscopy. The road tunnel exposures included particulate matter with a 50% cut-off aerodynamic diameter of 2.5 μm, particulate matter with a 50% cut-off aerodynamic diameter of 10 μm and nitrogen dioxide which had median concentrations of 64, 176 and 230 µg·m−3, respectively. Significantly higher numbers of BAL fluid total cell number, lymphocytes and alveolar macrophages were present after road tunnel exposure versus control. Significantly higher nuclear expression of the transcription factor component c-Jun was found in the bronchial epithelium after exposure. No upregulation of adhesion molecules or cellular infiltration was present and blood coagulation factors were unaffected. In conclusion, exposure of healthy subjects to traffic-related air pollution resulted in a lower airway inflammatory response with cell migration, together with signs of an initiated signal transduction in the bronchial epithelium.
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| 2. |
- Middleton, Steven J, et al.
(författare)
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Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.
- 2022
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 145:10, s. 3637-3653
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Tidskriftsartikel (refereegranskat)abstract
- Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial EMG (n = 3 CIP participants and n = 8 healthy controls) we have found that these patients also have abnormalities in the encoding of affective touch which is mediated by the specialised afferents; C-low threshold mechanoreceptors (C-LTMRs). In the mouse we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.
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| 3. |
- Behravan, G., et al.
(författare)
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THE INTERACTION OF ELLIPTICINE DERIVATIVES WITH NUCLEIC-ACIDS STUDIED BY OPTICAL AND H-1-NMR SPECTROSCOPY - EFFECT OF SIZE OF THE HETEROCYCLIC RING
- 1994
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Ingår i: Biopolymers. - : Wiley. - 0006-3525 .- 1097-0282. ; 34:5, s. 599-609
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Tidskriftsartikel (refereegranskat)abstract
- The DNA interaction of derivatives of ellipticine with heterocyclic ring systems with three, four, or five rings and a dimethylaminoethyl side chain was studied. Optical spectroscopy of drug complexes with calf thymus DNA, poly [(dA-dT).(dA-dT)], or poly [(dG-dC).(dG-dC)] showed a 10 nm bathochromic shift of the light absorption bands of the pentacyclic and tetracyclic compounds upon binding to the nucleic acids, which indicates binding by intercalation. For the tricyclic compound a smaller shift of 1-3 nm was observed upon binding to the nucleic acids. Flow linear dichroism studies show that the geometry of all complexes is consistent with intercalation of the ring system, except for the DNA and poly [(dG-dC).(dG-dC)] complexes of the tricyclic compound, where the average angle between the drug molecular plane and the DNA helix axis was found to be 65 degrees. One-dimensional H-1-nmr spectroscopy was used to study complexes between d(CGCGATCGCG)(2) and the tricyclic and pentacyclic compounds. The results on the pentacyclic compound show nonselective broadening due to intermediate chemical exchange of most oligonucleotide resonances upon drug binding. The imino proton resonances are in slow chemical exchange, and new resonances with upheld shifts approaching 1 ppm appear upon drug binding, which supports intercalative binding of the pentacyclic compound. The results on the tricyclic compound show more rapid binding kinetics and very selective broadening of resonances. The data suggest that the tricyclic compound is in an equilibrium between intercalation and minor groove binding, with a preference to bind close to the AT base pairs with the side chain residing in the minor groove. (C) 1994 John Wiley and Sons, Inc.
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| 4. |
- Pfeffer, Paul E., et al.
(författare)
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Urban particulate matter stimulation of human dendritic cells enhances priming of naive CD8 T lymphocytes
- 2018
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Ingår i: Immunology. - : John Wiley & Sons. - 0019-2805 .- 1365-2567. ; 153:4, s. 502-512
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies have consistently shown associations between elevated concentrations of urban particulate matter (UPM) air pollution and exacerbations of asthma and chronic obstructive pulmonary disease, which are both associated with viral respiratory infections. The effects of UPM on dendritic cell (DC) -stimulated CD4 T lymphocytes have been investigated previously, but little work has focused on CD8 T-lymphocyte responses despite their importance in anti-viral immunity. To address this, we examined the effects of UPM on DC-stimulated naive CD8 T-cell responses. Expression of the maturation/activation markers CD83, CCR7, CD40 and MHC class I on human myeloid DCs (mDCs) was characterized by flow cytometry after stimulation with UPM in vitro in the presence/absence of granulocyte-macrophage colony-stimulating factor (GM-CSF). The capacity of these mDCs to stimulate naive CD8 T-lymphocyte responses in allogeneic co-culture was then assessed by measuring T-cell cytokine secretion using cytometric bead array, and proliferation and frequency of interferon-γ (IFN-γ)-producing T lymphocytes by flow cytometry. Treatment of mDCs with UPM increased expression of CD83 and CCR7, but not MHC class I. In allogeneic co-cultures, UPM treatment of mDCs enhanced CD8 T-cell proliferation and the frequency of IFN-γ+ cells. The secretion of tumour necrosis factor-α, interleukin-13, Granzyme A and Granzyme B were also increased. GM-CSF alone, and in concert with UPM, enhanced many of these T-cell functions. The PM-induced increase in Granzyme A was confirmed in a human experimental diesel exposure study. These data demonstrate that UPM treatment of mDCs enhances priming of naive CD8 T lymphocytes and increases production of pro-inflammatory cytokines. Such UPM-induced stimulation of CD8 cells may potentiate T-lymphocyte cytotoxic responses upon concurrent airway infection, increasing bystander damage to the airways.
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| 5. |
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| 6. |
- Sehlstedt, Ulrica, 1969-
(författare)
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A biophysical study of nucleic acid interactions with analogues and drugs
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- work presented in this thesis concerns studies on the physicochemical nature of interactions between nucleic acids and small ligands. The outcome of such studies can yield insights at a molecular level into the physiological mechanisms of action of biologically active nucleic-acid binding molecules. The thesis work includes investigations of a number of such low molecular weight compounds designed for nucleic acid sequence probing or therapeutic use. The interactions have been characterised by means of various optical spectroscopic techniques - including linear dichroism, circular dichroism and fluorescence - as well as nuclear magnetic resonance spectroscopy.The fluorescent dye 4',6-diamidino-2-phenylindole (DAPI) is known to adopt different DNA binding modes in regions containing consecutive AT base-pairs as compared to those consisting of long sequences of GC base-pairs. In mixed sequence DNA, DAPI exhibits a pronounced preference to bind in the minor groove of AT rich regions. To verify whether the variation in ligand mode of binding could be attributed to the exocyclic N2 group of guanine, guanines in the polynucleotide [poly(dG-dC)]2 were substituted for the 2-desamino analogue inosine, denoted I. Comparison of the spectral characteristics of DAPI in complex with either of the polymeric nucleic acid host structures revealed a clear difference in binding geometries; the spectroscopic properties of the IC complex closely resemble those of the AT complex, in which DAPI is inserted edgewisely along the minor groove. These results are rationalised in terms of steric hindrance and decreased electronegative attraction caused by the amino group protruding into the minor groove of B-type GC tracts.Studies of complexes between DNA and a series of cobalt porphyrins and their unmetallated analogues revealed contact energy transfer from the DNA bases and binding orientation angles nearly parallel to the planes of the DNA base-pairs, indicative of intercalation, for the non-metal porphyrins. The metalloporphyrins, on the other hand, are suggested to bind in a partially melted region of DNA. This hypothesis is supported by cleavage reactions in which a break in one of the DNA strands is induced by a single activation event on the cobalt porphyrins.The DNA interaction properties for a series of quinoxaline derivatives with a positively charged side chain were examined with respect to variation of the size of the molecular heterocyclic ring system. Derivatives with three, four, and five rings were included in the investigations. All but the tricyclic compound are found to bind in an intercalative mode irrespective of DNA base sequence. For the tricyclic derivative it is suggested that the binding involves a competitive equilibrium between intercalation preferred by the ring system, and minor groove binding favoured by the side chain.The second part of this thesis focuses on the interactions between nucleic acids and two compounds with the potential of being used in the novel therapeutic antigene/antisense strategies, either by means of its own action (PNA, peptide nucleic acid) or as an antigene enhancer (9-OH-B220).The binding of the biologically active quinoxaline derivative 9-OH-B220 to double and triple helices of synthetic DNA and RNA was characterised. The drug is found to adopt an intercalative binding geometry in all complexes except when the RNA triplex serves as a host structure. In the latter case, the spectroscopic properties are indicative of a binding of the drug chromophore in the wide and shallow minor groove of the RNA triplex polymer. The drug is also found to enhance the thermal stability of each nucleic acid structure, with the DNA triplex stabilising capacity being extraordinary; when the DNA triplex is formed in a 0.1 M NaCl buffer, its triplex-to-duplex equilibrium is shifted towards higher temperature by 52.5oC upon drug association. The results indicate that 9-OH-B220 has the potential of being used both as a partner in an antigene strategy and as an antiretroviral agent.An NMR study of the base-pair breathing dynamics of hybrid duplexes formed between DNA and the nucleic acid analogue PNA revealed intriguing kinetic features of these complexes. PNA strand bases open and close with unusually high rates. The bases in the complementary DNA strands are influenced by this fast kinetics in different ways; while the DNA strand guanines are virtually unaffected, the thymine imino protons become hypersensitive to exchange catalysis. Hence, we conclude that base-pair opening is an asymmetric process in these hybrid duplexes. A model compatible with experimental data, in which a longitudinal breathing motion within the backbones is a pre-equilibrium state to that of lateral base opening, is presented and discussed. The results are of importance for efficient development of new DNA modulating drugs.
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| 7. |
- Tuite, Eimer, 1966, et al.
(författare)
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Effects of minor and major groove-binding drugs and intercalators on the DNA association of minor groove-binding proteins RecA and deoxyribonuclease I detected by flow linear dichroism
- 1997
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 243:1-2, s. 482-492
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Tidskriftsartikel (refereegranskat)abstract
- Linear and circular dichroic spectroscopies have been employed to investigate the effects of small DNA ligands on the interactions of two proteins which bind to the minor groove of DNA, viz. RecA protein from Escherichia coli and deoxyribonuclease I (bovine pancreas). Ligands representing three specific non-covalent binding modes were investigated: 4',6-diamidino-2-phenylindole and distamycin A (minor groove binders), methyl green (major groove binder), and methylene blue, ethidium bromide and ethidium dimer (intercalators). Linear dichroism was demonstrated to be an excellent detector, in real time, of DNA double-strand cleavage by deoxyribonuclease I. Ligands bound in all three modes interfered with the deoxyribonuclease I digestion of dsDNA, although the level of interference varied in a manner which could be related to the ligand binding site, the ligand charge appearing to be less important. In particular, the retardation of deoxyribonuclease I cleavage by the major groove binder methyl green demonstrates that accessibility to the minor groove can be affected by occupancy of the opposite groove. Binding of all three types of ligand also had marked effects on the interaction of RecA with dsDNA in the presence of non-hydrolyzable cofactor adenosine 5'-O-3-thiotriphosphate, decreasing the association rate to varying extents but with the strongest effects from ligands having some minor groove occupancy. Finally, each ligand was displaced from its DNA binding site upon completion of RecA association, again demonstrating that modification of either groove can affect the properties and behaviour of the other. The conclusions are discussed against the background of previous work on the use of small DNA ligands to probe DNA-protein interactions.
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| 8. |
- Tuulari, Jetro J., et al.
(författare)
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Neural correlates of gentle skin stroking in early infancy
- 2019
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Ingår i: Developmental Cognitive Neuroscience. - : Elsevier BV. - 1878-9293 .- 1878-9307. ; 35, s. 36-41
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Tidskriftsartikel (refereegranskat)abstract
- Physical expressions of affection play a foundational role in early brain development, but the neural correlates of affective touch processing in infancy remain unclear. We examined brain responses to gentle skin stroking, a type of tactile stimulus associated with affectionate touch, in young infants. Thirteen term-born infants aged 11-36. days, recruited through the FinnBrain Birth Cohort Study, were included in the study. Soft brush strokes, which activate brain regions linked to somatosensory as well as socio-affective processing in children and adults, were applied to the skin of the right leg during functional magnetic resonance imaging. We examined infant brain responses in two regions-of-interest (ROIs) known to process gentle skin stroking - the postcentral gyrus and posterior insular cortex - and found significant responses in both ROIs. These results suggest that the neonate brain is responsive to gentle skin stroking within the first weeks of age, and that regions linked to primary somatosensory as well as socio-affective processing are activated. Our findings support the notion that social touch may play an important role in early life sensory processing. Future research will elucidate the significance of these findings for human brain development.
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