| 1. |
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| 2. |
- Bellavia, Andrea, et al.
(author)
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Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia
- 2023
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In: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 216:Part 1
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Journal article (peer-reviewed)abstract
- Objective: Women of reproductive age are exposed to ubiquitous chemicals such as phthalates, parabens, and per -and polyfluoroalkyl substances (PFAS), which have potential endocrine disrupting properties and might affect fertility. Our objective was to investigate associations between potential endocrine-disrupting chemicals (EDCs) and female fertility in two cohorts of women attending fertility clinics.Methods: In a total population of 333 women in Sweden and Estonia, we studied the associations between chemicals and female fertility, evaluating ovarian sensitivity index (OSI) as an indicator of ovarian response, as well as clinical pregnancy and live birth from fresh and frozen embryo transfers. We measured 59 chemicals in follicular fluid samples and detected 3 phthalate metabolites, di-2-ethylhexyl phthalate (DEHP) metabolites, 1 paraben, and 6 PFAS in > 90% of the women. Associations were evaluated using multivariable-adjusted linear or logistic regression, categorizing EDCs into quartiles of their distributions, as well as with Bayesian Kernel Ma-chine Regression.Results: We observed statistically significant lower OSI at higher concentrations of the sum of DEHP metabolites in the Swedish cohort (Q4 vs Q1, beta =-0.21, 95% CI:-0.38,-0.05) and methylparaben in the Estonian cohort (Q3 vs Q1, beta =-0.22, 95% CI:-0.44,-0.01). Signals of potential associations were also observed at higher concentrations of PFUnDA in both the combined population (Q2 vs. Q1,beta =-0.16, 95% CI-0.31,-0.02) and the Estonian population (Q2 vs. Q1,beta =-0.27, 95% CI-0.45,-0.08), and for PFOA in the Estonian population (Q4 vs. Q1, beta =-0.31, 95% CI-0.61,-0.01). Associations of chemicals with clinical pregnancy and live birth presented wide confidence intervals.Conclusions: Within a large chemical mixture, we observed significant inverse associations levels of DEHP me-tabolites and methylparaben, and possibly PFUnDA and PFOA, with OSI, suggesting that these chemicals may contribute to altered ovarian function and infertility in women.
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| 3. |
- De Kerpel, Jan O A, et al.
(author)
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Theoretical study of the structural and spectroscopic properties of stellacyanin
- 1998
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In: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 102:23, s. 4638-4647
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Journal article (peer-reviewed)abstract
- The electronic spectrum of the azurin Met121Gln mutant, a model of the blue copper protein stellacyanin, has been studied by ab initio multiconfigurational second-order perturbation theory (the CASPT2 method), including the effect of the protein and solvent by point charges. The six lowest electronic transitions have been calculated and assigned with an error of less than 2400 cm-1. The ground-state singly occupied orbital is found to be a predominantly π antibonding orbital involving Cu3d and Scys3pπ. However, it also contains a significant amount (18%) of Cu-Scys σ antibonding character. This σ interaction is responsible for the appearance in the absorption spectrum of a band at 460 nm, with a significantly higher intensity than observed for other, axial, type 1 copper proteins (i.e., plastocyanin or azurin). The π-σ mixing is caused by the axial glutamine ligand binding at a much shorter distance to copper than the corresponding methionine ligand in the normal blue copper proteins. This explains why, based on its spectral properties, stellacyanin is classified among the rhombic type 1 copper proteins, although its structure is clearly trigonal, as it is for the axial proteins. Calculations have also been performed on structures where the glutamine model coordinates to the copper ion via the deprotonated N∈ atom instead of the O∈ atom. However, the resulting transition energies do not resemble the experimental spectrum obtained at normal or elevated pH. Thus, the results do not confirm the suggestion that the coordinating atom of glutamine changes at high pH.
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| 4. |
- Halbritter, Aud H., et al.
(author)
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Plant trait and vegetation data along a 1314 m elevation gradient with fire history in Puna grasslands, Perú
- 2024
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In: SCIENTIFIC DATA. - 2052-4463. ; 11:1
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Journal article (peer-reviewed)abstract
- Alpine grassland vegetation supports globally important biodiversity and ecosystems that are increasingly threatened by climate warming and other environmental changes. Trait-based approaches can support understanding of vegetation responses to global change drivers and consequences for ecosystem functioning. In six sites along a 1314 m elevational gradient in Puna grasslands in the Peruvian Andes, we collected datasets on vascular plant composition, plant functional traits, biomass, ecosystem fluxes, and climate data over three years. The data were collected in the wet and dry season and from plots with different fire histories. We selected traits associated with plant resource use, growth, and life history strategies (leaf area, leaf dry/wet mass, leaf thickness, specific leaf area, leaf dry matter content, leaf C, N, P content, C and N isotopes). The trait dataset contains 3,665 plant records from 145 taxa, 54,036 trait measurements (increasing the trait data coverage of the regional flora by 420%) covering 14 traits and 121 plant taxa (ca. 40% of which have no previous publicly available trait data) across 33 families.
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| 5. |
- Kalincik, Tomas, et al.
(author)
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Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis
- 2023
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In: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 80:7, s. 702-713
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Journal article (peer-reviewed)abstract
- Importance Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS).Objective To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials.Design, Setting, and Participants This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics.Exposure AHSCT vs fingolimod, natalizumab, or ocrelizumab.Main outcomes Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement.Results Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%).Conclusion In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.
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| 6. |
- Olsson, Mats H M, et al.
(author)
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On the relative stability of tetragonal and trigonal Cu(II) complexes with relevance to the blue copper proteins
- 1998
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In: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 3:2, s. 109-125
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Journal article (peer-reviewed)abstract
- The role of the cysteine thiolate ligand for the unusual copper coordination geometry in the blue copper proteins has been studied by comparing the electronic structure, geometry, and energetics of a number of small Cu(II) complexes. The geometries have been optimised with the density functional B3LYP method, and energies have been calculated by multi- configurational second-order perturbation theory (the CASPT2 method). Most small inorganic Cu(II) complexes assume a tetragonal geometry, where four ligands make σ bonds to a Cu 3d orbital. If a ligand lone-pair orbital instead forms a π bond to the copper ion, it formally occupies two ligand positions in a square coordination, and the structure becomes trigonal. Large, soft, and polarisable ligands, such as SH- and SeH-, give rise to covalent copper-ligand bonds and structures close to a tetrahedron, which might be trigonal or tetragonal with approximately the same stability. On the other hand, small and hard ligands, such as NH3, OH2, and OH-, give ionic bonds and flattened tetragonal structures. It is shown that axial type 1 (blue) copper proteins have a trigonal structure with a π bond to the cysteine sulphur atom, whereas rhombic type 1 and type 2 proteins have a tetragonal structure with σ bonds to all strong ligands. The soft cysteine ligand is essential for the stabilisation of a structure that is close to a tetrahedron (either trigonal or tetragonal), which ensures a low reorganisation energy during electron transfer.
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| 7. |
- Pierloot, Kristine, et al.
(author)
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Relation between the structure and spectroscopic properties of blue copper proteins
- 1998
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 120:50, s. 13156-13166
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Journal article (peer-reviewed)abstract
- The electronic spectra of three rhombic type 1 blue copper proteins, nitrite reductase, pseudoazurin, and cucumber basic protein, have been studied by ab initio multiconfigurational second-order perturbation theory (the CASPT2 method). The six lowest excitations have been calculated and assigned with an error of less than 1800 cm-1. The singly occupied orbital in the ground-state forms a strongly covalent antibond between the copper ion and the thiolate group of the cysteine ligand with a mixture of σ and π character. This is in contrast to the axial type 1 copper protein plastocyanin which has an almost pure Cu-S(Cys) π interaction. The two brightest lines in the absorption spectrum originate from transitions to the corresponding σ (~460 nm) and π (~600 mm) bonding orbitals. The relative intensity of these two lines is determined by the character of the ground- state orbital. It is possible to obtain a structure closely similar to the one found in nitrite reductase by geometry optimizations with the hybrid density functional B3LYP method in vacuum. It is a tetragonal structure with bonds of mainly σ character to the four ligands like normal square-planar Cu(II) complexes, but the cysteine thiolate group donates much charge to the copper ion and thereby makes the structure strongly distorted toward a tetrahedron. Both this structure and a trigonal π-bonded structure, which also can be obtained for all complexes and is an excellent model of plastocyanin, are equilibrium structures (although usually not with the same ligand models). They have virtually the same energy (within ~7 kJ/mol), and the barrier between them is low. Therefore, small differences in the structure and electrostatics of different proteins may lead to stabilization of one or the other of the structures. The results indicate that axial type 1 proteins have a trigonal structure with an almost pure Cu-S(Cys) π bond, whereas rhombic type 1 proteins have tetragonal structures with a significant σ character in this bond. Type 1.5 and 2 copper-cysteinate proteins arise when the tetragonal structure becomes more flattened than in nitrite reductase, probably by the inclusion of stronger (type 1.5) and more (type 2) ligands.
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| 8. |
- Pierloot, Kristine, et al.
(author)
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Theoretical study of the electronic spectrum of plastocyanin
- 1997
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 119:1, s. 218-226
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Journal article (peer-reviewed)abstract
- The electronic spectrum of the blue copper protein plastocyanin has been studied by ab initio multiconfigurational second-order perturbation theory (the CASPT2 method). The six lowest electronic transitions have been calculated and assigned with an error of less than 2000 cm-1. The singly occupied orbital in the ground state is Cu 3d-S(Cys) 3pπ antibonding with some N(His) 2pσ character. The bright blue color originates from an electron transfer to this orbital from the corresponding Cu 3d-S(Cys)3pπ bonding orbital. The influence of different ligand models on the spectrum has been thoroughly studied; Cu(imidazole)2(SCH3)(S(CH3)2)+ as a model of CuHis2CysMet is the smallest system that gives converged results.The spectrum is surprisingly sensitive to changes in the geometry, especially in the Cu-S bond distances; a 5 pm change in the Cu-S(Cys) bond length may change the excitation energies by as much as 2000 cm-1. The effect of the surrounding protein and solvent on the transition energies has been modeled by point charges and is found to be significant for some of the transitions (up to 2000 cm-1).
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| 9. |
- Ryde, Ulf, et al.
(author)
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On the role of strain in blue copper proteins
- 2000
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In: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 5:5, s. 565-574
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Journal article (peer-reviewed)abstract
- Theoretical investigations of the structure and function of the blue copper proteins are described. We have studied the optimum vacuum geometry of oxidised and reduced copper sites, the relative stability of trigonal and tetragonal Cu(II) structures, the relation between the structure and electronic spectra, the reorganisation energy, and reduction potentials. Our calculations give no support to the suggestion that strain plays a significant role in the function of these proteins; on the contrary, our results show that the structures encountered in the proteins are close to their optimal vacuum geometries (within 7 kJ/mol). We stress the importance of defining what is meant by strain and of quantifying strain energies or forces in order to make strain hypotheses testable.
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| 10. |
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| 11. |
- Ryde, Ulf, et al.
(author)
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The cupric geometry of blue copper proteins is not strained
- 1996
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In: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836. ; 261:4, s. 586-596
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Journal article (peer-reviewed)abstract
- The geometry of several realistic models of the metal coordination sphere in the blue copper proteins has been optimised using high-level quantum chemical methods. The results show that the optimal vacuum structure of the Cu(II) models is virtually identical to the crystal structure of oxidised blue copper proteins. For the reduced forms, the optimised structure seems to be more tetrahedral than the one found in the proteins, but the energy difference between the two geometries is less than 5 kJ/mol, i.e. within the error limits of the method. Thus, the results raise strong doubts against hypotheses (entatic state and the induced-rack theory) suggesting that blue copper proteins force the oxidised metal coordination sphere into a structure similar to that preferred by Cu(I) in order to minimise the reorganisation energy of the electron transfer reaction. Instead, a small reorganisation energy seems to be reached by an appropriate choice of metal ligands. In particular, the cysteine thiolate ligand appears to be crucial, changing the preferred geometry of the oxidised complexes from square-planar to a more trigonal geometry.
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| 12. |
- Tarvainen, Ilari, et al.
(author)
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Identification of phthalate mixture exposure targets in the human and mouse ovary in vitro
- 2023
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In: Reproductive Toxicology. - : Elsevier. - 0890-6238 .- 1873-1708. ; 119
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Journal article (peer-reviewed)abstract
- Chemical health risk assessment is based on single chemicals, but humans and wildlife are exposed to extensive mixtures of industrial substances and pharmaceuticals. Such exposures are life-long and correlate with multiple morbidities, including infertility. How combinatorial effects of chemicals should be handled in hazard charac-terization and risk assessment are open questions. Further, test systems are missing for several relevant health outcomes including reproductive health and fertility in women. Here, our aim was to screen multiple ovarian cell models for phthalate induced effects to identify biomarkers of exposure. We used an epidemiological cohort study to define different phthalate mixtures for in vitro testing. The mixtures were then tested in five cell models representing ovarian granulosa or stromal cells, namely COV434, KGN, primary human granulosa cells, primary mouse granulosa cells, and primary human ovarian stromal cells. Exposures at epidemiologically relevant levels did not markedly elicit cytotoxicity or affect steroidogenesis in short 24-hour exposure. However, significant effects on gene expression were identified by RNA-sequencing. Altogether, the exposures changed the expression of 124 genes on the average (9-479 genes per exposure) in human cell models, without obvious concentration or mixture-dependent effects on gene numbers. The mixtures stimulated distinct changes in different cell models. Despite differences, our analyses suggest commonalities in responses towards phthalates, which forms a starting point for follow-up studies on identification and validation of candidate biomarkers that could be developed to novel assays for regulatory testing or even into clinical tests.
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