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Wärmländer, SebastianORCID iD iconorcid.org/0000-0001-6836-5610
Alternative names
Publications (10 of 74) Show all publications
Olowoyo, J. O., Tshoni, U. A., Kobyana, A. S., Lion, G. N., Mugivhisa, L. L., Koski, L., . . . Roos, P. M. (2024). Blood lead concentrations in exposed forecourt attendants and taxi drivers in parts of South Africa. Journal of Trace Elements in Medicine and Biology, 81, Article ID 127348.
Open this publication in new window or tab >>Blood lead concentrations in exposed forecourt attendants and taxi drivers in parts of South Africa
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2024 (English)In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 81, article id 127348Article in journal (Refereed) Published
Abstract [en]

Background: Leaded fuel was banned in South Africa in 2006, in order to improve human health and reduce environmental pollution. Lead (Pb) has been suggested to contribute to the development of neurodegenerative disorders, and the role of respiratory exposure to Pb from petrol fumes should not be neglected in this context. In addition to Pb, petrol contains various harmful chemicals including other neurotoxic metals and hydrocarbons.

Objectives and Methods: Here, we investigated concentrations of Pb and other metals in blood from petrol station forecourt attendants (n = 38), taxi drivers (n = 21), and unexposed controls (n = 36). Taxi drivers and forecourt attendants were divided into three groups each, based on number of years worked. A questionnaire was designed to investigate the health status of the participants. Blood samples were collected by medical professionals and analyzed for metal concentrations by ICP-MS.

Results: A positive correlation between number of years worked and Pb blood concentrations was found. The highest Pb concentration (60.2 µg/L) was observed in a forecourt attendant who had worked 11–20 years, and the average Pb concentration in this group (24.5 µg/L) was significantly (p < 0.05) higher than in forecourt attendants who had worked 2–5 years (10.4 µg/L). Some individuals had elevated concentrations of manganese, arsenic, cadmium, chromium and cobalt, yet not significantly elevated at the group level. The blood levels of arsenic appeared to be related to smoking. Mood swings, dizziness, headaches and tiredness were reported by the workers.

Conclusion: Blood Pb concentrations in petrol station forecourt attendants and taxi drivers exposed to leaded petrol are elevated and correlate to exposure time. A health monitoring program should be erected for all individuals working in these industries, and preventive measures should be implemented to eliminate metal exposure from petrol.

Keywords
Occupational exposure, Petrol, Arsenic, Cadmium, Chromium, Cobalt, Lead, Manganese
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:su:diva-225773 (URN)10.1016/j.jtemb.2023.127348 (DOI)001128105500001 ()38016357 (PubMedID)2-s2.0-85178339413 (Scopus ID)
Available from: 2024-01-22 Created: 2024-01-22 Last updated: 2024-01-22Bibliographically approved
Wärmländer, S. K. T., Ljungkvist, J., Jahrehorn, M. & Hennius, A. (2023). A 6th-8th c. wire-drawing iron plate with silver residue from a Vendel Period workshop in Old Uppsala, Sweden. Journal of Archaeological Science: Reports, 51, Article ID 104193.
Open this publication in new window or tab >>A 6th-8th c. wire-drawing iron plate with silver residue from a Vendel Period workshop in Old Uppsala, Sweden
2023 (English)In: Journal of Archaeological Science: Reports, ISSN 2352-409X, E-ISSN 2352-4103, Vol. 51, article id 104193Article in journal (Refereed) Published
Abstract [en]

Metal wire is in modern society manufactured by drawing metal rods through dies with conical holes of decreasing diameters, until the desired thickness is obtained. The history and origin of this technique remains unclear, although it was likely developed from earlier wire-making techniques such as strip-drawing and roll-drawing. Proper wire-drawing was an established technology in Europe during the High Middle Ages, and numerous draw-plates have been found at Scandinavian Viking Age trading centers. Here, we report the technical examination of an iron draw-plate found in Uppsala in central Sweden. The draw-plate was excavated in a Vendel Period fine metals workshop, located immediately next to the royal hall in Old Uppsala, the central building of the royal estate in the 6th −8th c. X-ray and scanning electron microscopy (SEM) analysis of the draw-plate revealed silver particles in the plate’s holes, indicating drawing of silver wire. The plate is dated to the 6th – 8th c., which makes it one of the oldest confirmed tools for wire-drawing so far encountered. The presence of this tool in the workshop indicates that some high-quality jewelry in this region was locally produced. Thus, the finding of this draw-plate increases our understanding of Vendel Period jewelry production, and of the social organization of this craft.

Keywords
Archaeometallurgy, Wire drawing, SEM-EDS analysis, Scandinavian Archaeology, Early Medieval Period
National Category
Archaeology
Identifiers
urn:nbn:se:su:diva-223430 (URN)10.1016/j.jasrep.2023.104193 (DOI)001081817500001 ()2-s2.0-85171686024 (Scopus ID)
Available from: 2023-11-01 Created: 2023-11-01 Last updated: 2023-11-01Bibliographically approved
Rajkovic, A., Kanchugal, S., Abdurakhmanov, E., Howard, R., Wärmländer, S., Erwin, J., . . . Coulbourn Flores, S. (2023). Amino acid substitutions in human growth hormone affect coiled-coil content and receptor binding. PLOS ONE, 18(3), Article ID e0282741.
Open this publication in new window or tab >>Amino acid substitutions in human growth hormone affect coiled-coil content and receptor binding
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2023 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 18, no 3, article id e0282741Article in journal (Refereed) Published
Abstract [en]

The interaction between human Growth Hormone (hGH) and hGH Receptor (hGHR) has basic relevance to cancer and growth disorders, and hGH is the scaffold for Pegvisomant, an anti-acromegaly therapeutic. For the latter reason, hGH has been extensively engineered by early workers to improve binding and other properties. We are particularly interested in E174 which belongs to the hGH zinc-binding triad; the substitution E174A is known to significantly increase binding, but to now no explanation has been offered. We generated this and several computationally-selected single-residue substitutions at the hGHR-binding site of hGH. We find that, while many successfully slow down dissociation of the hGH-hGHR complex once bound, they also slow down the association of hGH to hGHR. The E174A substitution induces a change in the Circular Dichroism spectrum that suggests the appearance of coiled-coiling. Here we show that E174A increases affinity of hGH against hGHR because the off-rate is slowed down more than the on-rate. For E174Y (and certain mutations at other sites) the slowdown in on-rate was greater than that of the off-rate, leading to decreased affinity. The results point to a link between structure, zinc binding, and hGHR-binding affinity in hGH.

National Category
Biophysics
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-202694 (URN)10.1371/journal.pone.0282741 (DOI)000984103600028 ()36952491 (PubMedID)2-s2.0-85150746917 (Scopus ID)
Available from: 2022-03-09 Created: 2022-03-09 Last updated: 2023-06-07Bibliographically approved
Berntsson, E., Vosough, F., Noormagi, A., Padari, K., Asplund, F., Gielnik, M., . . . Wärmländer, S. (2023). Characterization of Uranyl (UO22+) Ion Binding to Amyloid Beta (Aβ) Peptides: Effects on Aβ Structure and Aggregation. ACS Chemical Neuroscience, 14(15), 2618-2633
Open this publication in new window or tab >>Characterization of Uranyl (UO22+) Ion Binding to Amyloid Beta (Aβ) Peptides: Effects on Aβ Structure and Aggregation
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2023 (English)In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 14, no 15, p. 2618-2633Article in journal (Refereed) Published
Abstract [en]

Uranium (U) is naturally present in ambient air, water, and soil, and depleted uranium (DU) is released into the environment via industrial and military activities. While the radiological damage from U is rather well understood, less is known about the chemical damage mechanisms, which dominate in DU. Heavy metal exposure is associated with numerous health conditions, including Alzheimer’s disease (AD), the most prevalent age-related cause of dementia. The pathological hallmark of AD is the deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils in the brain. However, the toxic species in AD are likely oligomeric Aβ aggregates. Exposure to heavy metals such as Cd, Hg, Mn, and Pb is known to increase Aβ production, and these metals bind to Aβ peptides and modulate their aggregation. The possible effects of U in AD pathology have been sparsely studied. Here, we use biophysical techniques to study in vitro interactions between Aβ peptides and uranyl ions, UO22+, of DU. We show for the first time that uranyl ions bind to Aβ peptides with affinities in the micromolar range, induce structural changes in Aβ monomers and oligomers, and inhibit Aβ fibrillization. This suggests a possible link between AD and U exposure, which could be further explored by cell, animal, and epidemiological studies. General toxic mechanisms of uranyl ions could be modulation of protein folding, misfolding, and aggregation. 

Keywords
Alzheimer's disease, amyloid aggregation, metal-protein binding, neurodegeneration, heavy metal toxicity
National Category
Neurosciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-221233 (URN)10.1021/acschemneuro.3c00130 (DOI)001035034000001 ()37487115 (PubMedID)2-s2.0-85166386170 (Scopus ID)
Available from: 2023-09-19 Created: 2023-09-19 Last updated: 2023-09-19Bibliographically approved
Biswas, A., Maloverjan, M., Padari, K., Abroi, A., Rätsep, M., Wärmländer, S. K. T., . . . Pooga, M. (2023). Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery. Pharmaceutics, 15(2), Article ID 396.
Open this publication in new window or tab >>Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery
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2023 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 15, no 2, article id 396Article in journal (Refereed) Published
Abstract [en]

Cell-penetrating peptides (CPPs) are highly promising transfection agents that can deliver various compounds into living cells, including nucleic acids (NAs). Positively charged CPPs can form non-covalent complexes with negatively charged NAs, enabling simple and time-efficient nanoparticle preparation. However, as CPPs have substantially different chemical and physical properties, their complexation with the cargo and characteristics of the resulting nanoparticles largely depends on the properties of the surrounding environment, i.e., solution. Here, we show that the solvent used for the initial dissolving of a CPP determines the properties of the resulting CPP particles formed in an aqueous solution, including the activity and toxicity of the CPP–NA complexes. Using different biophysical methods such as dynamic light scattering (DLS), atomic force microscopy (AFM), transmission and scanning electron microscopy (TEM and SEM), we show that PepFect14 (PF14), a cationic amphipathic CPP, forms spherical particles of uniform size when dissolved in organic solvents, such as ethanol and DMSO. Water-dissolved PF14, however, tends to form micelles and non-uniform aggregates. When dissolved in organic solvents, PF14 retains its α-helical conformation and biological activity in cell culture conditions without any increase in cytotoxicity. Altogether, our results indicate that by using a solvent that matches the chemical nature of the CPP, the properties of the peptide–cargo particles can be tuned in the desired way. This can be of critical importance for in vivo applications, where CPP particles that are too large, non-uniform, or prone to aggregation may induce severe consequences.

Keywords
cell-penetrating peptides, solvent, nanoparticle formation, nucleic acid delivery
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-215998 (URN)10.3390/pharmaceutics15020396 (DOI)000940877200001 ()36839718 (PubMedID)2-s2.0-85149152654 (Scopus ID)
Available from: 2023-03-31 Created: 2023-03-31 Last updated: 2023-03-31Bibliographically approved
Noormägi, A., Golubeva, T., Berntsson, E., Wärmländer, S. K. T., Tõugu, V. & Palumaa, P. (2023). Direct Competition of ATCUN Peptides with Human Serum Albumin for Copper(II) Ions Determined by LC-ICP MS. ACS Omega, 8(37), 33912-33919
Open this publication in new window or tab >>Direct Competition of ATCUN Peptides with Human Serum Albumin for Copper(II) Ions Determined by LC-ICP MS
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2023 (English)In: ACS Omega, E-ISSN 2470-1343, Vol. 8, no 37, p. 33912-33919Article in journal (Refereed) Published
Abstract [en]

Copper is an indispensable biometal, primarily serving as a redox-competent cofactor in numerous proteins. Apart from preformed copper-binding sites within the protein structures, small peptide motifs exist called ATCUN, which are composed of an N-terminal tripeptide XZH, able to bind Cu(II) ions in exchangeable form. These motifs are common for serum albumin, but they are also present in a wide range of proteins and peptides. These proteins and peptides can be involved in copper metabolism, and copper ions can affect their biological role. The distribution of copper between the ATCUN peptides, including truncated amyloid-β (Aβ) peptides Aβ4–42 and Aβ11–42, which may be involved in Alzheimer’s disease pathogenesis, is mainly determined by their concentrations and relative Cu(II)-binding affinities. The Cu(II)-binding affinity (log Kd) of several ATCUN peptides, determined by different methods and authors, varies by more than three orders of magnitude. This variation may be attributed to the chemical properties of peptides but can also be influenced by the differences in methods and experimental conditions used for the determination of Kd. In the current study, we performed direct competition experiments between selected ATCUN peptides and HSA by using an LC-ICP MS-based approach. We demonstrated that ATCUN and truncated Aβ peptides Aβ4–16 and Aβ11–15 bind Cu(II) ions with an affinity similar to that for HSA. Our results demonstrate that ATCUN motifs cannot compete with excess HSA for the binding of Cu(II) ions in the blood and cerebrospinal fluid. 

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-223038 (URN)10.1021/acsomega.3c04649 (DOI)001066027700001 ()2-s2.0-85173171732 (Scopus ID)
Available from: 2023-10-18 Created: 2023-10-18 Last updated: 2023-11-29Bibliographically approved
Koski, L., Berntsson, E., Vikström, M., Wärmländer, S. K. T. & Roos, P. M. (2023). Metal ratios as possible biomarkers for amyotrophic lateral sclerosis. Journal of Trace Elements in Medicine and Biology, 78, Article ID 127163.
Open this publication in new window or tab >>Metal ratios as possible biomarkers for amyotrophic lateral sclerosis
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2023 (English)In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 78, article id 127163Article in journal (Refereed) Published
Abstract [en]

Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown aetiology. Metals have been suspected to contribute to ALS pathogenesis since mid-19th century, yet studies on measured metal concentrations in ALS patients have often yielded conflicting results, with large individual variation in measured values. Calculating metal concentration ratios can unveil possible synergistic effects of neurotoxic metals in ALS pathogenesis. The aim of this study was to investigate if ratios of different metal concentrations in cerebrospinal fluid (CSF) and blood plasma, respectively, differ between ALS patients and healthy controls.

Methods: Cerebrospinal fluid and blood plasma were collected from 17 ALS patients and 10 controls. Samples were analysed for 22 metals by high-resolution inductively coupled plasma mass spectrometry (HR-ICP-MS), and all possible 231 metal ratios calculated in each body fluid.

Results: Fifty-three metal ratios were significantly elevated in ALS cases as compared to controls (p < 0.05); five in blood plasma, and 48 in CSF. The finding of fewer elevated ratios in blood plasma may indicate specific transport of metals into the central nervous system. The elevated metal ratios in CSF include Cd/Se (p = 0.031), and 16 ratios with magnesium, such as Mn/Mg (p = 0.005) and Al/Mg (p = 0.014).

Conclusion: Metal ratios may be used as biomarkers in ALS diagnosis and as guidelines for preventive measures.

Keywords
Neurodegeneration, Neurotoxicity, Neuroprotection, Ratio, Metal exposure
National Category
Neurology Chemical Sciences
Identifiers
urn:nbn:se:su:diva-217137 (URN)10.1016/j.jtemb.2023.127163 (DOI)000972390800001 ()37004478 (PubMedID)2-s2.0-85151351858 (Scopus ID)
Available from: 2023-05-17 Created: 2023-05-17 Last updated: 2023-05-17Bibliographically approved
Gielnik, M., Szymańska, A., Dong, X., Jarvet, J., Svedružić, Ž. M., Gräslund, A., . . . Wärmländer, S. . T. (2023). Prion Protein Octarepeat Domain Forms Transient β-Sheet Structures upon Residue-Specific Binding to Cu(II) and Zn(II) Ions. Biochemistry, 62(11), 1689-1705
Open this publication in new window or tab >>Prion Protein Octarepeat Domain Forms Transient β-Sheet Structures upon Residue-Specific Binding to Cu(II) and Zn(II) Ions
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2023 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 62, no 11, p. 1689-1705Article in journal (Refereed) Published
Abstract [en]

Misfolding of the cellular prion protein (PrPC) is associated with the development of fatal neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). Metal ions appear to play a crucial role in PrPC misfolding. PrPC is a combined Cu(II) and Zn(II) metal-binding protein, where the main metal-binding site is located in the octarepeat (OR) region. Thus, the biological function of PrPC may involve the transport of divalent metal ions across membranes or buffering concentrations of divalent metal ions in the synaptic cleft. Recent studies have shown that an excess of Cu(II) ions can result in PrPC instability, oligomerization, and/or neuroinflammation. Here, we have used biophysical methods to characterize Cu(II) and Zn(II) binding to the isolated OR region of PrPC. Circular dichroism (CD) spectroscopy data suggest that the OR domain binds up to four Cu(II) ions or two Zn(II) ions. Binding of the first metal ion results in a structural transition from the polyproline II helix to the β-turn structure, while the binding of additional metal ions induces the formation of β-sheet structures. Fluorescence spectroscopy data indicate that the OR region can bind both Cu(II) and Zn(II) ions at neutral pH, but under acidic conditions, it binds only Cu(II) ions. Molecular dynamics simulations suggest that binding of either metal ion to the OR region results in the formation of β-hairpin structures. As the formation of β-sheet structures can be a first step toward amyloid formation, we propose that high concentrations of either Cu(II) or Zn(II) ions may have a pro-amyloid effect in TSE diseases.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-218066 (URN)10.1021/acs.biochem.3c00129 (DOI)000988877300001 ()37163663 (PubMedID)2-s2.0-85160591106 (Scopus ID)
Available from: 2023-07-25 Created: 2023-07-25 Last updated: 2023-10-12Bibliographically approved
Österlund, N., Wärmländer, S. K. T. & Gräslund, A. (2022). Cell-Penetrating Peptides with Unexpected Anti-Amyloid Properties. Pharmaceutics, 14(4), Article ID 823.
Open this publication in new window or tab >>Cell-Penetrating Peptides with Unexpected Anti-Amyloid Properties
2022 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 14, no 4, article id 823Article, review/survey (Refereed) Published
Abstract [en]

Cell-penetrating peptides (CPPs) with sequences derived originally from a prion protein (PrP) have been shown to exhibit both anti-prion and anti-amyloid properties particularly against prion proteins and the amyloid-β (Aβ) peptide active in Alzheimer’s disease. These disease-modifying properties are so far observed in cell cultures and in vitro. The CPP sequences are composed of a hydrophobic signal sequence followed by a highly positively charged hexapeptide segment. The original signal sequence of the prion protein can be changed to the signal sequence of the NCAM1 protein without losing the anti-prion activity. Although the detailed molecular mechanisms of these CPP peptides are not fully understood, they do form amyloid aggregates by themselves, and molecular interactions between the CPPs and PrP/Aβ can be observed in vitro using various spectroscopic techniques. These initial intermolecular interactions appear to re-direct the aggregation pathways for prion/amyloid formation to less cell-toxic molecular structures (i.e., co-aggregates), which likely is why the disease-inducing PrP/Aβ aggregation is counteracted in vivo.

Keywords
protein aggregation, secretion signal peptide, peptide engineering, drug design
National Category
Neurosciences Biological Sciences
Identifiers
urn:nbn:se:su:diva-204559 (URN)10.3390/pharmaceutics14040823 (DOI)000785290300001 ()35456657 (PubMedID)2-s2.0-85128454673 (Scopus ID)
Available from: 2022-05-10 Created: 2022-05-10 Last updated: 2022-05-10Bibliographically approved
Berntsson, E., Sardis, M., Noormägi, A., Jarvet, J., Roos, P. M., Töugu, V., . . . Wärmländer, S. K. .. (2022). Mercury Ion Binding to Apolipoprotein E Variants ApoE2, ApoE3, and ApoE4: Similar Binding Affinities but Different Structure Induction Effects. ACS Omega, 7(33), 28924-28931
Open this publication in new window or tab >>Mercury Ion Binding to Apolipoprotein E Variants ApoE2, ApoE3, and ApoE4: Similar Binding Affinities but Different Structure Induction Effects
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2022 (English)In: ACS Omega, E-ISSN 2470-1343, Vol. 7, no 33, p. 28924-28931Article in journal (Refereed) Published
Abstract [en]

Mercury intoxication typically produces more severe outcomes in people with the APOE-ε4 gene, which codes for the ApoE4 variant of apolipoprotein E, compared to individuals with the APOE-ε2 and APOE-ε3 genes. Why the APOE-ε4 allele is a risk factor in mercury exposure remains unknown. One proposed possibility is that the ApoE protein could be involved in clearing of heavy metals, where the ApoE4 protein might perform this task worse than the ApoE2 and ApoE3 variants. Here, we used fluorescence and circular dichroism spectroscopies to characterize the in vitro interactions of the three different ApoE variants with Hg(I) and Hg(II) ions. Hg(I) ions displayed weak binding to all ApoE variants and induced virtually no structural changes. Thus, Hg(I) ions appear to have no biologically relevant interactions with the ApoE protein. Hg(II) ions displayed stronger and very similar binding affinities for all three ApoE isoforms, with KD values of 4.6 μM for ApoE2, 4.9 μM for ApoE3, and 4.3 μM for ApoE4. Binding of Hg(II) ions also induced changes in ApoE superhelicity, that is, altered coil–coil interactions, which might modify the protein function. As these structural changes were most pronounced in the ApoE4 protein, they could be related to the APOE-ε4 gene being a risk factor in mercury toxicity.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-209191 (URN)10.1021/acsomega.2c02254 (DOI)000846759000001 ()36033665 (PubMedID)
Available from: 2022-09-19 Created: 2022-09-19 Last updated: 2022-09-19Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-6836-5610

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