| 1. |
- Groenen, M. A., et al.
(författare)
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Analyses of pig genomes provide insight into porcine demography and evolution
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 491:7424, s. 393-398
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Tidskriftsartikel (refereegranskat)abstract
- For 10,000 years pigs and humans have shared a close and complex relationship. From domestication to modern breeding practices, humans have shaped the genomes of domestic pigs. Here we present the assembly and analysis of the genome sequence of a female domestic Duroc pig (Sus scrofa) and a comparison with the genomes of wild and domestic pigs from Europe and Asia. Wild pigs emerged in South East Asia and subsequently spread across Eurasia. Our results reveal a deep phylogenetic split between European and Asian wild boars approximately 1 million years ago, and a selective sweep analysis indicates selection on genes involved in RNA processing and regulation. Genes associated with immune response and olfaction exhibit fast evolution. Pigs have the largest repertoire of functional olfactory receptor genes, reflecting the importance of smell in this scavenging animal. The pig genome sequence provides an important resource for further improvements of this important livestock species, and our identification of many putative disease-causing variants extends the potential of the pig as a biomedical model.
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| 2. |
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| 3. |
- Stenler, S., et al.
(författare)
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Micro-minicircle gene therapy : Implications of size on fermentation, complexation, shearing resistance, and expression
- 2014
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Ingår i: Molecular Therapy Nucleic Acids. - : Elsevier BV. - 2162-2531. ; 3, s. e140-
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Tidskriftsartikel (refereegranskat)abstract
- The minicircle (MC), composed of eukaryotic sequences only, is an interesting approach to increase the safety and efficiency of plasmid-based vectors for gene therapy. In this paper, we investigate micro-MC (miMC) vectors encoding small regulatory RNA. We use a construct encoding a splice-correcting U7 small nuclear RNA, which results in a vector of 650 base pairs (bp), as compared to a conventional 3600 bp plasmid carrying the same expression cassette. Furthermore, we construct miMCs of varying sizes carrying different number of these cassettes. This allows us to evaluate how size influences production, supercoiling, stability and efficiency of the vector. We characterize coiling morphology by atomic force microscopy and measure the resistance to shearing forces caused by an injector device, the Biojector. We compare the behavior of miMCs and plasmids in vitro using lipofection and electroporation, as well as in vivo in mice. We here show that when the size of the miMC is reduced, the formation of dimers and trimers increases. There seems to be a lower size limit for efficient expression. We demonstrate that miMCs are more robust than plasmids when exposed to shearing forces, and that they show extended expression in vivo.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
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| 8. |
- Cherif, M. K., et al.
(författare)
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Fc gamma RIIa Polymorphism and Anti-Malaria-Specific IgG and IgG Subclass Responses in Populations Differing in Susceptibility to Malaria in Burkina Faso
- 2012
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 75:6, s. 606-613
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Tidskriftsartikel (refereegranskat)abstract
- Fc?RIIa is known to be polymorphic; and certain variants are associated with different susceptibilities to malaria. Studies involving the Fulani ethnic group reported an ethnic difference in Fc?RIIa-R131H genotype frequencies between the Fulani and other sympatric groups. No previous studies have addressed these questions in Burkina Faso. This study aimed to assess the influence of Fc?RIIa-R131H polymorphism on anti-falciparum malaria IgG and IgG subclass responses in the Fulani and the Mossi ethnic groups living in Burkina Faso. Healthy adults more than 20 years old belonging to the Mossi or the Fulani ethnic groups were enrolled for the assessment of selected parasitological, immunological and genetic variables in relation to their susceptibility to malaria. The prevalence of the Plasmodium falciparum infection frequency was relatively low in the Fulani ethnic group compared to the Mossi ethnic group. For all tested antigens, the Fulani had higher antibody levels than the Mossi group. In both ethnic groups, a similar distribution of Fc?RIIa R131H polymorphism was found. Individuals with the R allele of Fc?RIIa had higher antibody levels than those with the H allele. This study confirmed that malaria infection affected less the Fulani group than the Mossi group. Fc?RIIa-R131H allele distribution is similar in both ethnic groups, and higher antibody levels are associated with the Fc?RIIa R allele compared to the H allele.
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| 9. |
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| 10. |
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| 11. |
- Lucking, Andrew J, et al.
(författare)
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Particle traps prevent adverse vascular and prothrombotic effects of diesel engine exhaust inhalation in men
- 2011
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 123:16, s. 1721-1728
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In controlled human exposure studies, diesel engine exhaust inhalation impairs vascular function and enhances thrombus formation. The aim of the present study was to establish whether an exhaust particle trap could prevent these adverse cardiovascular effects in men. METHODS AND RESULTS: Nineteen healthy volunteers (mean age, 25±3 years) were exposed to filtered air and diesel exhaust in the presence or absence of a particle trap for 1 hour in a randomized, double-blind, 3-way crossover trial. Bilateral forearm blood flow and plasma fibrinolytic factors were assessed with venous occlusion plethysmography and blood sampling during intra-arterial infusion of acetylcholine, bradykinin, sodium nitroprusside, and verapamil. Ex vivo thrombus formation was determined with the use of the Badimon chamber. Compared with filtered air, diesel exhaust inhalation was associated with reduced vasodilatation and increased ex vivo thrombus formation under both low- and high-shear conditions. The particle trap markedly reduced diesel exhaust particulate number (from 150 000 to 300 000/cm(3) to 30 to 300/cm(3); P<0.001) and mass (320±10 to 7.2±2.0 μg/m(3); P<0.001), and was associated with increased vasodilatation, reduced thrombus formation, and an increase in tissue-type plasminogen activator release. CONCLUSIONS: Exhaust particle traps are a highly efficient method of reducing particle emissions from diesel engines. With a range of surrogate measures, the use of a particle trap prevents several adverse cardiovascular effects of exhaust inhalation in men. Given these beneficial effects on biomarkers of cardiovascular health, the widespread use of particle traps on diesel-powered vehicles may have substantial public health benefits and reduce the burden of cardiovascular disease.
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| 12. |
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| 13. |
- Mills, Nicholas L, et al.
(författare)
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Diesel exhaust inhalation does not affect heart rhythm or heart rate variability
- 2011
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 97:7, s. 544-550
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Tidskriftsartikel (refereegranskat)abstract
- Objective Exposure to air pollution is associated with increases in cardiovascular morbidity and mortality. This study was undertaken to determine the effect of diesel exhaust inhalation on heart rhythm and heart rate variability in healthy volunteers and patients with coronary heart disease.Design and setting Double-blind randomised crossover studies in a university teaching hospital.Patients 32 healthy non-smoking volunteers and 20 patients with prior myocardial infarction.Interventions All 52 subjects were exposed for 1 h to dilute diesel exhaust (particle concentration 300 μg/m(3)) or filtered air.Main outcome measures Heart rhythm and heart rate variability were monitored during and for 24 h after the exposure using continuous ambulatory electrocardiography and assessed using standard time and frequency domain analysis.Results No significant arrhythmias occurred during or following exposures. Patients with coronary heart disease had reduced autonomic function in comparison to healthy volunteers, with reduced standard deviations of the NN interval (SDNN, p<0.001) and triangular index (p<0.001). Diesel exhaust did not affect heart rate variability compared with filtered air (p>0.05 for all) in healthy volunteers (SDNN 101±6 vs 91±6, triangular index 20±1 vs 21±1) or patients with coronary heart disease (SDNN 47±5 vs 38±4, triangular index 8±1 vs 7±1).Conclusions Brief exposure to dilute diesel exhaust does not alter heart rhythm or heart rate variability in healthy volunteers or well-treated patients with stable coronary heart disease. Autonomic dysfunction does not appear to be a dominant mechanism that can explain the observed excess in cardiovascular events following exposure to combustion-derived air pollution.
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| 14. |
- Tengblad, O., et al.
(författare)
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Phoswich scintillator for proton and gamma radiation of high energy
- 2011
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Ingår i: AIP Conference Proceedings. - : AIP. - 1551-7616 .- 0094-243X. - 9780735409835 ; 1409, s. 141-144
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Konferensbidrag (refereegranskat)abstract
- We present here a Phoswich scintillator design to achieve both high resolution gamma ray detection, and good efficiency for high energy protons. There are recent developments of new high resolution scintillator materials. Especially the LaBr3(Ce) and LaCl3(Ce) crystals have very good energy resolution in the order of 3% for 662 keV gamma radiation. In addition, these materials exhibit a very good light output (63 and 32 photons/keV respectively). A demonstrator detector in the form of an Al cylinder of 24 mm diameter and a total length of 80 mm with 2 mm wall thickness, containing a LaBr3(Ce) crystal of 20 mm diameter and 30 mm length directly coupled to a LaCl3(Ce) crystal of 50 mm length, and closed with a glass window of 5 mm, was delivered by Saint Gobain. To the glass window a Hamamatsu R5380 Photomultiplier tube (PMT) was coupled using silicon optical grease. © 2011 American Institute of Physics.
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| 15. |
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| 16. |
- Amodu, O. K., et al.
(författare)
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Association of the sickle cell trait and the ABO blood group with clinical severity of malaria in southwest Nigeria
- 2012
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Ingår i: Acta Tropica. - : Elsevier BV. - 0001-706X .- 1873-6254. ; 123:2, s. 72-77
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Tidskriftsartikel (refereegranskat)abstract
- In regions of high Plasmodium falciparum malaria endemicity, certain erythrocyte polymorphisms confer resistance to severe disease. In this study, we evaluate the role of the sickle cell trait (HbS) and ABO blood groups in the clinical manifestations of childhood malaria in Southwest Nigeria. The subjects comprised 3100 children (53% males, median age 39 months), including 1400 children with uncomplicated malaria, 1000 children with asymptomatic malaria and 700 with severe malaria. Haemoglobin (Hb) types were determined using electrophoresis and serum agglutination techniques were used to determine ABO blood groups. Blood group O was the commonest ABO blood group (47.7%) in the study population, the others were A (22.5%), B (25.2%) and AB (4.6%). The frequencies of the HbAS and HbAC were 14.4% and 5.8%, respectively. In regression models adjusting for age, gender, parasite density and blood group, HbAS was associated with a reduced risk of severe malaria OR=0.46 (CI95%: 0.273-0.773). Among severe malaria subjects, HbAS was associated with significantly lower parasite densities. The protective effect of blood group 0 was demonstrated with a decreased risk of severe malaria OR=0.743 (CI95%: 0.566-0.976) after adjusting for age, gender and parasite density and Hb genotype. Blood group B was associated with increased risk of severe malaria OR=1.638 (CI95%: 1.128-2.380) after adjusting for age, gender, packed cell volume, parasite density and Hb genotype. We have confirmed from this large study of Nigerian children the major protective effective of the sickle cell heterozygous state against both cerebral malaria and severe malarial anaemia. We also show that the B blood group is associated with an increased risk of severe malaria. In conclusion, the sickle cell haemoglobin type and ABO groups modulate the risk of severe malaria in Nigerian children.
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| 17. |
- Ansorge, C, et al.
(författare)
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Diagnostic value of abdominal drainage in individual risk assessment of pancreatic fistula following pancreaticoduodenectomy
- 2014
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 101:2, s. 100-108
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe use of prophylactic abdominal drainage following pancreaticoduodenectomy (PD) is controversial as its therapeutic value is uncertain. However, the diagnosis of postoperative pancreatic fistula (POPF), the main cause of PD-associated morbidity, is often based on drain pancreatic amylase (DPA) levels. The aim of this study was to assess the predictive value of DPA, plasma pancreatic amylase (PPA) and serum C-reactive protein (CRP) for diagnosing POPF after PD.MethodsPatients undergoing PD with prophylactic drainage between 2008 and 2012 were studied prospectively. DPA, PPA and CRP levels were obtained daily. Differences between groups with clinically relevant POPF (International Study Group on Pancreatic Fistula (ISGPF) grade B/C) and without clinically relevant POPF (no POPF or ISGPF grade A) were evaluated. Receiver operating characteristic (ROC) analyses were performed to determine the value of DPA, PPA and CRP in prediction of POPF. Risk profiles for clinically relevant POPF were constructed and related to the intraoperative pancreatic risk assessment.ResultsFifty-nine (18·7 per cent) of 315 patients developed clinically relevant POPF. DPA, PPA and CRP levels on postoperative day (POD) 1–3 differed significantly between the study groups. In predicting POPF, the DPA level on POD 1 (cut-off at 1322 units/l; odds ratio (OR) 24·61, 95 per cent confidence interval 11·55 to 52·42) and POD 2 (cut-off at 314 units/l; OR 35·45, 14·07 to 89·33) was superior to that of PPA on POD 1 (cut-off at 177 units/l; OR 13·67, 6·46 to 28·94) and POD 2 (cut-off at 98 units/l; OR 16·97, 8·33 to 34·59). When DPA was combined with CRP (cut-off on POD 3 at 202 mg/l; OR 16·98, 8·43 to 34·21), 90·3 per cent of postoperative courses could be predicted correctly (OR 44·14, 16·89 to 115·38).ConclusionThe combination of serum CRP and DPA adequately predicted the development of clinically relevant pancreatic fistula following PD.
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| 18. |
- Arama, Charles, et al.
(författare)
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A recombinant Bacille Calmette-Guerin construct expressing the Plasmodium falciparum circumsporozoite protein enhances dendritic cell activation and primes for circumsporozoite-specific memory cells in BALB/c mice
- 2012
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Ingår i: Vaccine. - : Elsevier. - 0264-410X .- 1873-2518. ; 30:37, s. 5578-5584
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Tidskriftsartikel (refereegranskat)abstract
- A protective malaria vaccine may induce both high levels of neutralising antibodies and strong T-cell responses. The Plasmodium falciparum circumsporozoite protein (CSp) is a leading pre-erythrocytic vaccine candidate. CSp is a week immunogen per se, but Mycobacterium bovis Bacille Calmette-Guérin (BCG) has excellent adjuvant activity and has been utilized as a vector to deliver heterologous vaccine candidate antigens. It is safe in immunocompetent individuals and inexpensive to produce. We assessed in vitro and in vivo a recombinant BCG-expressing CSp (BCG-CS) as malaria vaccine candidate. Immunisation of BALB/c mice with BCG-CS augmented numbers of dendritic cells (DCs) in draining lymph nodes and in the spleen. The activation markers MHC-class-II, CD40, CD80 and CD86 on DCs were significantly upregulated by BCG-CS as compared to wild-type BCG (wt-BCG). In vitro stimulation of bone marrow-derived DCs and macrophages with BCG-CS induced IL-12 and TNF-α production. BCG-CS induced higher phagocytic activity in macrophages as compared to wt-BCG. Immunogenicity studies show that BCG-CS induced CS-specific antibodies and IFN-γ-producing memory cells. In conclusion, BCG-CS is highly efficient in activating antigen-presenting cells (APCs) for priming of adaptive immunity. Implications for the rational design of novel vaccines against malaria and TB, the two major devastating poverty-related diseases, are discussed.
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| 19. |
- Arama, Charles, et al.
(författare)
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Heterologous prime-boost regimen adenovector 35-circumsporozoite protein vaccine/recombinant Bacillus Calmette-Guerin expressing the Plasmodium falciparum circumsporozoite induces enhanced long-term memory immunity in BALB/c mice
- 2012
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 30:27, s. 4040-4045
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sustained antibody levels are a hallmark of immunity against many pathogens, and induction of long-term durable antibody titers is an essential feature of effective vaccines. Heterologous prime-boost approaches with vectors are optimal strategies to improve a broad and prolonged immunogenicity of malaria vaccines. Results: In this study, we demonstrate that the heterologous prime-boost regimen Ad35-CS/BCG-CS induces stronger immune responses by enhancing type 1 cellular producing-cells with high levels of CSp-specific IFN-gamma and cytophilic IgG2a antibodies as compared to a homologous BCG-CS and a heterologous BCG-CS/CSp prime-boost regimen. Moreover, the heterologous prime-boost regimen elicits the highest level of LLPC-mediated immune responses. Conclusion: The increased IFN-gamma-producing cell responses induced by the combination of Ad35-CS/BCG-CS and sustained type 1 antibody profile together with high levels of LLPCs may be essential for the development of long-term protective immunity against liver-stage parasites.
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| 20. |
- Awah, Nancy, 1976-, et al.
(författare)
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Antibodies to the Plasmodium falciparum rhoptry protein RAP-2/RSP-2 in relation to anaemia in Cameroonian children
- 2011
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Ingår i: Parasite immunology (Print). - : Wiley. - 0141-9838 .- 1365-3024. ; 33:2, s. 104-115
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have implicated reactive antibodies to the low molecular weight rhoptry-associated proteins (RAP-1, RAP-2/RSP-2 and RAP-3) in erythroid cell destruction during Plasmodium falciparum infection. In this pilot study, the frequency, specificity and functional capacity of naturally acquired anti-RAP-2/RSP-2 antibodies were investigated in the sera of anaemic and nonanaemic malaria-infected Cameroonian children. All sera recognized RAP-2/RSP-2 by FACS, irrespective of the clinical status of the subjects. However, the anaemic children showed higher levels of IgG antibodies than the nonanaemic group, while both groups showed similar levels of IgM antibodies. Only few individuals had detectable levels of RAP-2/RSP-2-specific IgG1 and IgG3 subclass antibodies, while no IgG2 and IgG4 subclass antibodies were detected in these subjects. By ELISA, the anaemic group tended to show higher levels of antibodies to RAP-2/RSP-2 regarding all antibody classes tested, except for IgG4 and IgE. Unexpectedly, sera from the nonanaemic group activated complement to a greater extent than those from the anaemic group. These results need to be confirmed in extended studies but indicate that the effector functions of the RAP-2/RSP-2-reactive antibodies may be more important than their amounts. Such antibodies could play a role in both immunity and pathogenesis during P. falciparum infection.
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| 21. |
- Balmes, Olivier, et al.
(författare)
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Reversible formation of a PdCx phase in Pd nanoparticles upon CO and O-2 exposure
- 2012
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Ingår i: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9084 .- 1463-9076. ; 14:14, s. 4796-4801
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Tidskriftsartikel (refereegranskat)abstract
- The structure and chemical composition of Pd nanoparticles exposed to pure CO and mixtures of CO and O-2 at elevated temperatures have been studied in situ by a combination of X-ray Diffraction and X-ray Photoelectron Spectroscopy in pressures ranging from ultra high vacuum to 10 mbar and from room temperature to a few hundred degrees celsius. Our investigation shows that under CO exposure, above a certain temperature, carbon dissolves into the Pd particles forming a carbide phase. Upon exposure to CO and O-2 mixtures, the carbide phase forms and disappears reversibly, switching at the stoichiometric ratio for CO oxidation. This finding opens new scenarios for the understanding of catalytic oxidation of C-based molecules.
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| 22. |
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| 23. |
- Barath, Stefan, et al.
(författare)
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Impaired vascular function after exposure to diesel exhaust generated at urban transient running conditions
- 2010
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Ingår i: Particle and Fibre Toxicology. - : BioMed Central. - 1743-8977. ; 7:1, s. 19-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Traffic emissions including diesel engine exhaust are associated with increased respiratory and cardiovascular morbidity and mortality. Controlled human exposure studies have demonstrated impaired vascular function after inhalation of exhaust generated by a diesel engine under idling conditions.OBJECTIVES: To assess the vascular and fibrinolytic effects of exposure to diesel exhaust generated during urban-cycle running conditions that mimic ambient 'real-world' exposures.METHODS: In a randomised double-blind crossover study, eighteen healthy male volunteers were exposed to diesel exhaust (approximately 250 mug/m3) or filtered air for one hour during intermittent exercise. Diesel exhaust was generated during the urban part of the standardized European Transient Cycle. Six hours post-exposure, vascular vasomotor and fibrinolytic function was assessed during venous occlusion plethysmography with intra-arterial agonist infusions.MEASUREMENTS AND MAIN RESULTS: Forearm blood flow increased in a dose-dependent manner with both endothelial-dependent (acetylcholine and bradykinin) and endothelial-independent (sodium nitroprusside and verapamil) vasodilators. Diesel exhaust exposure attenuated the vasodilatation to acetylcholine (P < 0.001), bradykinin (P < 0.05), sodium nitroprusside (P < 0.05) and verapamil (P < 0.001). In addition, the net release of tissue plasminogen activator during bradykinin infusion was impaired following diesel exhaust exposure (P < 0.05).CONCLUSION: Exposure to diesel exhaust generated under transient running conditions, as a relevant model of urban air pollution, impairs vasomotor function and endogenous fibrinolysis in a similar way as exposure to diesel exhaust generated at idling. This indicates that adverse vascular effects of diesel exhaust inhalation occur over different running conditions with varying exhaust composition and concentrations as well as physicochemical particle properties. Importantly, exposure to diesel exhaust under ETC conditions was also associated with a novel finding of impaired of calcium channel-dependent vasomotor function. This implies that certain cardiovascular endpoints seem to be related to general diesel exhaust properties, whereas the novel calcium flux-related effect may be associated with exhaust properties more specific for the ETC condition, for example a higher content of diesel soot particles along with their adsorbed organic compounds.
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| 24. |
- Barath, Stefan, 1963-
(författare)
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Respiratory and cardiovascular effects of exposure to oxidative air pollutants
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The negative effects of air pollution on morbidity and mortality have been known since the mid 20th century. The two most well known examples are the Meuse Valley disaster in the 1930’ies and the London black fog in December 1952. Whilst there are numerous epidemiological studies, in which associations between morbidity and mortality and high levels of pollutants have been reported, the underlying mechanisms are not clear. Two of the main air pollutants are particulate matter (PM) mostly emanating from diesel exhaust (DE), and ozone, both of which are highly oxidative. Exposure to DE has resulted in adverse effects both in the respiratory tract and in the cardiovascular system. High ozone levels have also been shown to be associated with increased admissions to hospital for respiratory as well as cardiovascular conditions. The main aim of this thesis was to investigate the respiratory and cardiovascular effects of a combination of exposures to ozone and DE. DE generated during the urban part of the standardized European Transient Cycle (ETC) was compared to DE generated by an idling engine. It was also evaluated whether an acute exposure to ozone would have any effects on the cardiovascular system as assessed by venous occlusion forearm plethysmography and heart rate variability (HRV). In addition, fraction of exhaled nitric oxide (FENO) was evaluated as a potential marker for acute exposure to ozone or DE. Methods: Four double-blind randomized cross-over exposure studies were conducted to investigate the effects of ozone and DE on both the respiratory tract and the vascular function in healthy volunteers. All of the exposures were performed in purposely built “walk-in” chambers with strictly controlled exposures. In the first study, the volunteers were exposed to DE (300µg/m3) generated by an idling engine or to air, for one hour in the morning and to ozone (200 ppb) for two hours in the afternoon. A bronchoscopy with bronchial wash (BW) and bronchoalveolar lavage (BAL) was performed 24 hours after the initial exposure. In study II and III, an assessment of vascular function using venous occlusion forearm plethysmography was performed after an exposure to DE (250 µg/m3) generated under transient running conditions, compared to air exposure (study II) and ozone and air exposure (study III). HRV was assessed under a 24 hour period starting before each exposure (study III). In study IV, FENO measurements were conducted after DE and ozone exposures to investigate whether the previously established airway inflammation would be detectable by this non-invasive method. Results: DE exposure enhanced the established ozone-induced airway inflammation in terms of a pronounced neutrophilia in BW. DE generated under transient running conditions, impaired vascular function in healthy volunteers, whereas exposure to ozone did not. HRV were not altered by exposure to ozone. Exposure to DE caused a significant increase in FENO at the 10 (FENO10) and 50 (FENO50) mL/s flow rates at 6 hours post-exposure, but ozone exposure did not affect FENO at any flow rate or time point. Conclusion: We have tried to mimic real-life exposure to air pollutants. In the first study, an exposure to DE followed by an exposure to ozone in the afternoon resulted in an enhanced airway inflammation, suggesting an additive or synergistic effect, supporting the epidemiological findings of unfavorable effects of the combination of these two air pollutants. DE generated by an engine running at the urban part of the standardized European Transient Cycle impaired two important and complementary aspects of vascular function, the regulation of vascular tone and endogenous fibrinolysis. This has previously been shown with DE generated at idling conditions. This suggests that the mechanisms behind the adverse effects can be found in the properties of the particles and not in the gaseous components. In these studies, exposure to ozone did not impair vascular function in healthy subjects, or cause any alterations in HRV. This suggests that the epidemiological evidence for an increased risk of cardiovascular mortality following acute exposure to ozone might not be totally accurate. Previous controlled exposure studies with ozone have not shown an airway inflammation affecting the endothelium, at least not in the same time-frame as following DE exposure. FENO could possibly be a useful tool for assessing airway inflammation caused by DE, whereas the powerful oxidant ozone did not affect FENO. This suggests that the airway inflammatory effects caused by these two pollutants are regulated via different mechanisms.
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| 25. |
- Barath, Stefan, 1963-, et al.
(författare)
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Short-Term Exposure to Ozone Does Not Impair Vascular Function or Affect Heart Rate Variability in Healthy Young Men
- 2013
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Ingår i: Toxicological Sciences. - : Oxford University Press. - 1096-6080 .- 1096-0929. ; 135:2, s. 292-299
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Tidskriftsartikel (refereegranskat)abstract
- Air pollution exposure is associated with cardiovascular morbidity and mortality, yet the role of individual pollutants remains unclear. In particular, there is uncertainty regarding the acute effect of ozone exposure on cardiovascular disease. In these studies, we aimed to determine the effect of ozone exposure on vascular function, fibrinolysis, and the autonomic regulation of the heart. Thirty-six healthy men were exposed to ozone (300 ppb) and filtered air for 75min on two occasions in randomized double-blind crossover studies. Bilateral forearm blood flow (FBF) was measured using forearm venous occlusion plethysmography before and during intra-arterial infusions of vasodilators 2–4 and 6–8h after each exposure. Heart rhythm and heart rate variability (HRV) were monitored during and 24h after exposure. Compared with filtered air, ozone exposure did not alter heart rate, blood pressure, or resting FBF at either 2 or 6h. There was a dose-dependent increase in FBF with all vasodilators that was similar after both exposures at 2–4h. Ozone exposure did not impair vasomotor or fibrinolytic function at 6–8h but rather increased vasodilatation to acetylcholine (p = .015) and sodium nitroprusside (p = .005). Ozone did not affect measures of HRV during or after the exposure. Our findings do not support a direct rapid effect of ozone on vascular function or cardiac autonomic control although we cannot exclude an effect of chronic exposure or an interaction between ozone and alternative air pollutants that may be responsible for the adverse cardiovascular health effects attributed to ozone.
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| 26. |
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| 27. |
- Bestas, Burcu, et al.
(författare)
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Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model
- 2014
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 124:9, s. 4067-4081
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Tidskriftsartikel (refereegranskat)abstract
- X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTKtranscripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.
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| 28. |
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| 29. |
- Blomberg, Margareta R. A., et al.
(författare)
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A quantum chemical study of the mechanism for proton-coupled electron transfer leading to proton pumping in cytochrome c oxidase
- 2010
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Ingår i: Molecular Physics. - : Informa UK Limited. - 0026-8976 .- 1362-3028. ; 108:19-20, s. 2733-2743
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Tidskriftsartikel (refereegranskat)abstract
- The proton pumping mechanism in cytochrome c oxidase, the terminal enzyme in the respiratory chain, has been investigated using hybrid DFT with large chemical models. In previous studies, a gating mechanism was suggested based on electrostatic interpretations of kinetic experiments. The predictions from that analysis are tested here. The main result is that the suggestion of a positively charged transition state for proton transfer is confirmed, while some other suggestions for the gating are not supported. It is shown that a few critical relative energy values from the earlier studies are reproduced with quite high accuracy using the present model calculations. Examples are the forward barrier for proton transfer from the N-side of the membrane to the pump-loading site when the heme a cofactor is reduced, and the corresponding back leakage barrier when heme a is oxidised. An interesting new finding is an unexpected double-well potential for proton transfer from the N-side to the pump-loading site. In the intermediate between the two transition states found, the proton is bound to PropD on heme a. A possible purpose of this type of potential surface is suggested here. The accuracy of the present values are discussed in terms of their sensitivity to the choice of dielectric constant. Only one energy value, which is not critical for the present mechanism, varies significantly with this choice and is therefore less certain.
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| 30. |
- Blomberg, Margareta R. A., et al.
(författare)
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Mechanism for N2O Generation in Bacterial Nitric Oxide Reductase : A Quantum Chemical Study
- 2012
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 51:25, s. 5173-5186
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Tidskriftsartikel (refereegranskat)abstract
- The catalytic mechanism of reduction of NO to N2O in the bacterial enzyme nitric oxide reductase has been investigated using hybrid density functional theory and a model of the binuclear center (BNC) based on the newly determined crystal structure. The calculations strongly suggest a so-called cis:b(3) mechanism, while the commonly suggested trans mechanism is found to be energetically unfavorable. The mechanism suggested here involves a stable cis-hyponitrite, and it is shown that from this intermediate one N-O bond can be cleaved without the transfer of a proton or an electron into the binuclear active site, in agreement with experimental observations. The fully oxidized intermediate in the catalytic cycle and the resting form of the enzyme are suggested to have an oxo-bridged BNC with two high-spin ferric irons antiferromagnetically coupled. Both steps of reduction of the BNC after N2O formation are found to be pH-dependent, also in agreement with experiment. Finally, it is found that the oxo bridge in the oxidized BNC can react with NO to give nitrite, which explains the experimental observations that the fully oxidized enzyme reacts with NO, and most likely also the observed substrate inhibition at higher NO concentrations.
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| 31. |
- Blomberg, Margareta R. A., et al.
(författare)
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Proton pumping in cytochrome c oxidase : Energetic requirements and the role of two proton channels
- 2014
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Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - : Elsevier BV. - 0005-2728 .- 1879-2650. ; 1837:7, s. 1165-1177
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Tidskriftsartikel (refereegranskat)abstract
- Cytochrome c oxidase is a superfamily of membrane bound enzymes catalyzing the exergonic reduction of molecular oxygen to water, producing an electrochemical gradient across the membrane. The gradient is formed both by the electrogenic chemistry, taking electrons and protons from opposite sides of the membrane, and by proton pumping across the entire membrane. In the most efficient subfamily, the A-family of oxidases, one proton is pumped in each reduction step, which is surprising considering the fact that two of the reduction steps most likely are only weakly exergonic. Based on a combination of quantum chemical calculations and experimental information, it is here shown that from both a thermodynamic and a kinetic point of view, it should be possible to pump one proton per electron also with such an uneven distribution of the free energy release over the reduction steps, at least up to half the maximum gradient. A previously suggested pumping mechanism is developed further to suggest a reason for the use of two proton transfer channels in the A-family. Since the rate of proton transfer to the binuclear center through the D-channel is redox dependent, it might become too slow for the steps with low exergonicity. Therefore, a second channel, the K-channel, where the rate is redox-independent is needed. A redox-dependent leakage possibility is also suggested, which might be important for efficient energy conservation at a high gradient. A mechanism for the variation in proton pumping stoichiometry over the different subfamilies of cytochrome oxidase is also suggested. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.
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| 32. |
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| 33. |
- Blomberg, Margareta R. A., et al.
(författare)
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Quantum chemistry as a tool in bioenergetics
- 2010
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Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - : Elsevier BV. - 0005-2728 .- 1879-2650. ; 1797:2, s. 129-142
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Forskningsöversikt (refereegranskat)abstract
- Recent developments of quantum chemical methods have made it possible to tackle crucial questions in bioenergetics. The most important systems, cytochrome c oxidase in cellular respiration and photosystem II (PSII) in photosynthesis will here be used as examples to illustrate the power of the quantum chemical tools. One main contribution from quantum chemistry is to put mechanistic suggestions onto an energy scale. Accordingly, free energy profiles can be constructed both for reduction of molecular oxygen in cytochrome c oxidase and water oxidation in PSII, including O-O bond cleavage and formation, and also proton pumping in cytochrome c oxidase. For the construction of the energy diagrams, the computational results sometimes have to be combined with experimental information, such as reduction potentials and rate constants for individual steps in the reactions.
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| 34. |
- Blomberg, Margareta R. A., et al.
(författare)
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The mechanism for proton pumping in cytochrome c oxidase from an electrostatic and quantum chemical perspective
- 2012
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Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - : Elsevier BV. - 0005-2728 .- 1879-2650. ; 1817:4, s. 495-505
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Forskningsöversikt (refereegranskat)abstract
- The mechanism for proton pumping in cytochrome c oxidase in the respiratory chain, has for decades been one of the main unsolved problems in biochemistry. However, even though several different suggested mechanisms exist, many of the steps in these mechanisms are quite similar and constitute a general consensus framework for discussing proton pumping. When these steps are analyzed, at least three critical gating situations are found, and these points are where the suggested mechanisms in general differ. The requirements for gating are reviewed and analyzed in detail, and a mechanism is suggested, where solutions for all the gating situations are formulated. This mechanism is based on an electrostatic analysis of a kinetic experiment for the O to E transition. The key component of the mechanism is a positively charged transition state. An electron on heme a opens the gate for proton transfer from the N-side to a pump loading site (PLS). When the negative charge of the electron is compensated by a chemical proton, the positive transition state prevents backflow from the PLS to the N-side at the most critical stage of the pumping process. The mechanism has now been tested by large model DFT calculations, and these calculations give strong support for the suggested mechanism. This article is part of a Special Issue entitled: Respiratory Oxidases.
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| 35. |
- Blomberg, Margareta R. A., et al.
(författare)
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Why is the reduction of NO in cytochrome c dependent nitric oxide reductase (cNOR) not electrogenic?
- 2013
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Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - : Elsevier BV. - 0005-2728 .- 1879-2650. ; 1827:7, s. 826-833
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Tidskriftsartikel (refereegranskat)abstract
- The membrane-bound enzyme cNOR (cytochrome c dependent nitric oxide reductase) catalyzes the reduction of NO in a non-electrogenic process. This is in contrast to the reduction of O-2 in cytochrome c oxidase (CcO), the other member of the heme-copper oxidase family, which stores energy by the generation of a membrane gradient. This difference between the two enzymes has not been understood, but it has been speculated to be of kinetic origin, since per electron the NO reduction is more exergonic than the O-2 reduction, and the energy should thus be enough for an electrogenic process. However, it has not been clear how and why electrogenicity, which mainly affects the thermodynamics, would slow down the very exergonic NO reduction. Quantum chemical calculations are used to construct a free energy profile for the catalytic reduction of NO in the active site of cNOR. The energy profile shows that the reduction of the NO molecules by the enzyme and the formation of N2O are very exergonic steps, making the rereduction of the enzyme endergonic and rate-limiting for the entire catalytic cycle. Therefore the NO reduction cannot be electrogenic, i.e. cannot take electrons and protons from the opposite sides of the membrane, since it would increase the endergonicity of the rereduction when the gradient is present, thereby increasing the rate-limiting barrier, and the reaction would become too slow. It also means that proton pumping coupled to electron transfer is not possible in cNOR In CcO the corresponding rereduction of the enzyme is very exergonic.
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| 36. |
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| 37. |
- Bohlin, Maria E, 1979-, et al.
(författare)
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Effects of ionic strength, temperature and conformation on affinity interactions of β2-glycoprotein I monitored by capillary electrophoresis
- 2011
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Ingår i: Electrophoresis. - : Wiley. - 0173-0835 .- 1522-2683. ; 32, s. 728-737
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Tidskriftsartikel (refereegranskat)abstract
- We have used CE to evaluate the interaction between β2-glycoprotein I (β2gpI) and heparin. β2gpI is a human plasma protein involved in the blood coagulation cascade. It is of interest to functionally characterize the interactions of β2gpI because the exact function is not entirely known and because circulating autoantibodies against β2gpI are associated with an increased risk of thrombotic events. The effect of the ionic strength, temperature, and conformation of the protein on the interaction between β2gpI and heparin has been studied. The CE procedure for this study is simple, fast and automatic. β2gpI and heparin were allowed to interact during electrophoresis at different ionic strength buffers and at different capillary temperatures. To mimic perturbation of the conformation of β2gpI, different denaturing agents (SDS, ACN and urea) were added to the background electrolyte. While simple 1:1 binding isotherms were obtained at 22 °C the data strongly suggests that at physiological temperature the binding stoichiometry is not 1:1 and/or that cooperative interactions begin to play a role. We found that (i) the KD values differed by a factor of 60 at the ionic strengths studied (ii) β2gpI was resistant to denaturation with SDS and ACN, but was partially denatured by urea and (iii) the KD for the β2gpI-heparin interaction in the presence of urea was 10 times higher than the KD determined at the same conditions without urea added. Therefore, we conclude that the interaction between β2gpI and heparin is dependent on electrostatic interactions and on the conformation of β2gpI.
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| 38. |
- Bohlin, Maria E., 1979-
(författare)
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Method development for affinity capillary electrophoresis of ß2-glycoprotein I and biological ligands
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The final goal of this study is to establish a microscale analysis method that allows solution phase characterization of interactions between β2-glycoprotein I (β2gpI) and some of its ligands. Human β2gpI is a phospholipid- and heparin-binding plasma glycoprotein. The physiological role of the protein in normal blood coagulation is not entirely known, nor is its role in autoimmune diseases characterized by blood clotting disturbances (thrombosis). Quantitative binding data of β2gpI interactions with some of its ligands may help elucidating the mechanisms behind these diseases and in the development of new approaches for diagnostics, prevention, and therapy.In this thesis, capillary electrophoresis (CE) was used as methodological platform for the interaction studies. The analysis of peptides and proteins by CE is desirable due to low sample consumption, possibilities for non-denaturing and highly effective separations. The first objective of this thesis was to find an approach to prevent charge dependent adsorption of β2gpI to the inner surface of the capillaries. Analyte adsorption at the negatively charged inner surface of fused silica capillaries is detrimental to interaction analyses. This phenomenon is especially pronounced in the analysis of basic proteins and proteins containing exposed positively charged domains, such as β2gpI. A new strategy to suppress these solute-wall interactions was devised, investigated and optimized. This strategy exploits the pH hysteresis behavior of fused silica surfaces, by simply performing an acidic pretreatment of the capillary. The results in this thesis show that the acidic pretreatment efficiently prevents protein adsorption.
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| 39. |
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| 40. |
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| 41. |
- Borowski, Tomasz, et al.
(författare)
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The alkenyl migration mechanism catalyzed by extradiol dioxygenases : a hybrid dft study
- 2012
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Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 17:6, s. 881-890
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Tidskriftsartikel (refereegranskat)abstract
- 6-Hydroxymethyl-6-methylcyclohexa-2,4-dienone is a mechanistic probe which when incubated with an extradiol dioxygenase yields a 2-tropolone product. This observation was originally interpreted as evidence supporting a direct heterolytic 1,2-alkenyl migration mechanism for a ring expansion reaction catalyzed by this class of Fe(II)-dependent nonheme enzymes (Xin and Bugg in J Am Chem Soc 130:10422-10430, 2008). In the work reported in this contribution we used quantum chemical methods to test whether such a mechanism is energetically possible and we found that it is not, neither for the mechanistic probe nor for the native catalytic cycle intermediate. Models of increasing complexity were used to calculate energy barriers to the heterolytic 1,2-alkenyl migration and alternative radical mechanisms. It was found that the former involves substantially higher barriers than the latter. A tentative radical mechanism that accounts for the transformation of the probe substrate to 2-tropolone was also proposed, and it involves acceptable barriers.
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| 42. |
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| 43. |
- Buckley, Yvonne M., et al.
(författare)
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Causes and consequences of variation in plant population growth rate : a synthesis of matrix population models in a phylogenetic context
- 2010
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Ingår i: Ecology Letters. - : Wiley. - 1461-023X .- 1461-0248. ; 13:9, s. 1182-1197
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Forskningsöversikt (refereegranskat)abstract
- Explaining variation in population growth rates is fundamental to predicting population dynamics and population responses to environmental change. In this study, we used matrix population models, which link birth, growth and survival to population growth rate, to examine how and why population growth rates vary within and among 50 terrestrial plant species. Population growth rates were more similar within species than among species; with phylogeny having a minimal influence on among-species variation. Most population growth rates decreased over the observation period and were negatively autocorrelated between years; that is, higher than average population growth rates tended to be followed by lower than average population growth rates. Population growth rates varied more through time than space; this temporal variation was due mostly to variation in post-seedling survival and for a subset of species was partly explained by response to environmental factors, such as fire and herbivory. Stochastic population growth rates departed from mean matrix population growth rate for temporally autocorrelated environments. Our findings indicate that demographic data and models of closely related plant species cannot necessarily be used to make recommendations for conservation or control, and that post-seedling survival and the sequence of environmental conditions are critical for determining plant population growth rate.
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| 44. |
- Burns, Jean H., et al.
(författare)
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Empirical tests of life-history evolution theory using phylogenetic analysis of plant demography
- 2010
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Ingår i: Journal of Ecology. - : Wiley. - 0022-0477 .- 1365-2745. ; 98:2, s. 334-344
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Tidskriftsartikel (refereegranskat)abstract
- 1. A primary goal of evolutionary ecology is to understand factors selecting for the diversity of life histories. Life-history components, such as time-to-reproduction, adult survivorship and fecundity, might differ among species because of variation in direct and indirect benefits of these life histories in different environments or might have lower-than-expected variability because of phylogenetic constraints. Here, we present a phylogenetic examination of demography and life histories using a data base of 204 terrestrial plant species. 2. Overall, statistical models without phylogeny were preferred to models with phylogeny for vital rates and elasticities, suggesting that they lacked phylogenetic signal and are evolutionarily labile. However, the effect of phylogeny was significant in models including sensitivities, suggesting that sensitivities exhibit greater phylogenetic signal than vital rates or elasticities. 3. Species with a greater age at first reproduction had lower fecundity, consistent with a cost of delayed reproduction, but only in some habitats (e.g. grassland). We found no evidence for an indirect benefit of delayed reproduction via a decrease in variation in fecundity with age to first reproduction. 4. The greater sensitivity and lower variation in survival than in fecundity was consistent with buffering of more important vital rates, as others have also found. This suggests that studies of life-history evolution should include survival, rather than only fecundity, for the majority of species. 5. Synthesis. Demographic matrix models can provide informative tests of life-history theory because of their shared construction and outputs and their widespread use among plant ecologists. Our comparative analysis suggested that there is a cost of delayed reproduction and that more important vital rates exhibit lower variability. The absolute importance of vital rates to population growth rates (sensitivities) exhibited phylogenetic signal, suggesting that a thorough understanding of life-history evolution might require an understanding of the importance of vital rates, not just their means, and the role of phylogenetic history.
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| 45. |
- Chen, Shi-Lu, et al.
(författare)
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An investigation of possible competing mechanisms for Ni-containing methyl-coenzyme M reductase
- 2014
-
Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 16:27, s. 14029-14035
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Tidskriftsartikel (refereegranskat)abstract
- Ni-containing methyl-coenzyme M reductase (MCR) is capable of catalyzing methane formation from methyl-coenzyme M (CH3-SCoM) and coenzyme B (CoB-SH), and also its reverse reaction (methane oxidation). Based on extensive experimental and theoretical investigations, it has turned out that a mechanism including an organometallic methyl-Ni(III)F-430 intermediate is inaccessible, while another mechanism involving a methyl radical and a Ni(II)-SCoM species currently appears to be the most acceptable one for MCR. In the present paper, using hybrid density functional theory and an active-site model based on the X-ray crystal structure, two other mechanisms were studied and finally also ruled out. One of them, involving proton binding on the CH3-SCoM substrate, which should facilitate methyl-Ni(III)F-430 formation, is demonstrated to be quite unfavorable since the substrate has a much smaller proton affinity than the F-430 cofactor. Another one (oxidative addition mechanism) is also shown to be unfavorable for the MCR reaction, due to the large endothermicity for the formation of the ternary intermediate with side-on C-S (for CH3-SCoM) or C-H (for methane) coordination to Ni.
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| 46. |
- Chen, Shi-Lu, et al.
(författare)
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How Is a Co-Methyl Intermediate Formed in the Reaction of Cobalamin-Dependent Methionine Synthase? : Theoretical Evidence for a Two-Step Methyl Cation Transfer Mechanism
- 2011
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 115:14, s. 4066-4077
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Tidskriftsartikel (refereegranskat)abstract
- A methyl-Co(cobalamin) species has been characterized to be a crucial intermediate in the last step of the de novo biosynthesis of methionine catalyzed by cobalamin-dependent methionine synthase (MetH). However, exactly how it is formed is still an open question. In the present article, the formation of the methyl-Co(cobalamin) species in MetH has been investigated with B3LYP* hybrid DFT including van der Waals (vdW) interactions (i.e., dispersion) and using a chemical model built on X-ray crystal structures. The methyl cation and radical transfer mechanisms have been examined in various protonation states. The calculations reveal that the CH(3)-Co(III)(cobalamin) formation in MetH proceeds along a stepwise pathway, where the first step is a methyl cation transfer from the protonated methyltetrahydrofolate (CH(3)-THF) substrate to the Co(I)cobalamin. The second step is a binding of His759 to the other side (a-face) of Co. The former methyl transfer is computed to be the rate-limiting step with a barrier of 18 kcal/mol, which is reduced to 13 kcal/mol when dispersion is included. For the first step, the protonation at the methyl-bound nitrogen of CH(3)-THF is very important. The methyl transfer is otherwise unreachable with a very high barrier of similar to 38 kcal/mol. The deprotonation of the alpha-face His759-Asp757-Ser810 triad is found to be much less significant but slightly facilitates the CH(3)-Co(III)Cbl formation. There has been a long-standing discrepancy of 10-20 kcal/mol between theory and experiment in previous B3LYP computations of the Co C bond dissociation energy for the methyl-Co(cobalamin) species. The calculations indicate that the lack of dispersion (similar to 11 kcal/mol) is the main origin of this puzzling problem. With these effects, B3LYP* gives a bond strength of 32 kcal/mol compared to the experimental value of 37 +/- 3 kcal/mol. Overall, the present calculations give many examples of dispersion that makes non-negligible contributions to the energetics of enzyme reactions, especially for systems involving at least one large reacting fragment approaching or departing.
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| 47. |
- Chen, Shi-Lu, et al.
(författare)
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How Is Methane Formed and Oxidized Reversibly When Catalyzed by Ni-Containing Methyl-Coenzyme M Reductase?
- 2012
-
Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 18:20, s. 6309-6315
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Tidskriftsartikel (refereegranskat)abstract
- Ni-containing methyl-coenzyme M reductase (MCR) is capable of catalyzing methane formation and has recently been observed to also be able to catalyze the reverse reaction, the anaerobic oxidation of methane. The forward reaction has been extensively studied theoretically before and was found to consist of two steps. The first step is rate-limiting and the second step was therefore treated at a lower level. For an accurate treatment of the reverse reaction, both steps have to be studied at the same level. In the present paper, the mechanisms for the reversible formation and oxidation of methane catalyzed by MCR have been investigated using hybrid density functional theory with recent developments, in particular including dispersion effects. An active-site model was constructed based on the X-ray crystal structure. The calculations indicate that the MCR reaction is indeed reversible and proceeds via a methyl radical and a Ni-S(CoM) intermediate with reasonable reaction barriers in both directions. In a competing mechanism, the formation of the crucial Ni-methyl intermediate, was found to be strongly endergonic by over 20 kcal?mol-1 (including a barrier) with dispersion and entropy effects considered, and thus would not be reachable in a reasonable time under natural conditions.
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| 48. |
- Currier, Russell W, et al.
(författare)
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The evolution of infectious agents in relation to sex in animals and humans: brief discussions of some individual organisms.
- 2011
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 1749-6632 .- 0077-8923. ; 1230, s. 74-107, s. 74-107
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Forskningsöversikt (refereegranskat)abstract
- The following series of concise summaries addresses the evolution of infectious agents in relation to sex in animals and humans from the perspective of three specific questions: (1) what have we learned about the likely origin and phylogeny, up to the establishment of the infectious agent in the genital econiche, including the relative frequency of its sexual transmission; (2) what further research is needed to provide additional knowledge on some of these evolutionary aspects; and (3) what evolutionary considerations might aid in providing novel approaches to the more practical clinical and public health issues facing us currently and in the future?
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| 49. |
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| 50. |
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