Sebastian K T S Wärmländer | University of California, Los Angeles (original) (raw)

Papers by Sebastian K T S Wärmländer

biomolecules, 2024

Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyl... more Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy (FAP)) is an endemic amyloidosis involving the harmful aggregation of proteins, most commonly transthyretin (TTR) but sometimes also apolipoprotein A-1 or gelsolin. hATTR appears to be transmitted as an autosomal dominant trait. Over 100 point mutations have been identified, with the Val30Met substitution being the most common. Yet, the mechanism of pathogenesis and the overall origin of hATTR remain unclear. Here, we argue that hATTR could be related to harmful metal exposure. hATTR incidence is unevenly distributed globally, and the three largest defined clusters exist in Japan, Portugal, and Sweden. All three disease regions are also ancient mining districts with associated metal contamination of the local environment. There are two main mechanisms for how harmful metals, after uptake into tissues and body fluids, could induce hATTR. First, the metals could directly influence the expression, function, and/or aggregation of the proteins involved in hATTR pathology. Such metal–protein interactions might constitute molecular targets for anti-hATTR drug design. Second, metal exposure could induce hATTR -associated genetic mutations, which may have happened several generations ago. These two mechanisms can occur in parallel. In conclusion, the possibility that hATTR could be related to metal exposure in geochemically defined regions deserves further attention.

Research Square Preprint, 2023

Because silver is toxic to microbes, but not considered toxic to humans, the metal has been used ... more Because silver is toxic to microbes, but not considered toxic to humans, the metal has been used as an antimicrobial agent since ancient times. Today, silver nanoparticles and colloidal silver are used for antibacterial purposes, and silver-peptide and similar complexes are being developed as therapeutic agents. Yet, the health effects of silver exposure are not fully understood, nor are the molecular details of silver-protein interactions. In Alzheimer's disease (AD), the most common form of dementia worldwide, amyloid-β (Aβ) peptides aggregate to form soluble oligomers that are neurotoxic. Here, we report that monovalent silver ions (Ag +) bind wildtype Aβ 40 peptides with a binding a nity of 25 ± 12 µM in MES buffer at 20 °C. The N-terminal His residues are involved as binding ligands. Weaker Ag + binding is observed for the truncated Aβ(4-40) variant, for an Aβ 40 mutant without histidines, and for the wt Aβ 40 peptide at acidic pH. Because the Ag + ions do not induce any changes in the size or structure of Aβ 42 oligomers, we speculate that Ag + ions have a minor in uence on Aβ toxicity.

Journal of Trace Elements in Medicine and Biology, 2024

Background: Leaded fuel was banned in South Africa in 2006, in order to improve human health and ... more 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.

Preprints.org, 2023

In the 21st century, museums have come to realize that the human skeletons they display might hav... more In the 21st century, museums have come to realize that the human skeletons they display might have problematic origins. The older anthropological skeletal collections typically originate from anatomical dissection of the executed and the very poor, or from scavenged graves of indigenous people. Such collections are currently being re-evaluated in many countries, and reburying or repatriating museum skeletons have become viable options. A particularly difficult question is what to do with human remains of unknown origins. Here, we present and discuss one such case, where a human skeleton of unclear origin in the 1930’s was brought to a local museum in Bollnäs, Sweden, under likely unethical circumstances. Most of the bones have now been lost, except for the skull, the sacrum and one lumbar vertebra, which in 2007 were transferred to the Museum of Ethnography in Stockholm. The skull was there put on display as the “Bollnäs skull”, and was presented to the public to illustrate the dilemmas involved in handling human remains in the post-colonial era. The original gift letter from 1934 stated that the skeleton came from San Nicolas Island outside the California coast, but this letter contained numerous instances of incorrect information and was therefore deemed not trustworthy. However, our critical examination of the skull and its background information indicates that San Nicolas Island is a plausible origin, and we suggest that a bioarchaeological comparison should be made between the skull and living descendants of the San Nicolas Island population, and/or with archaeological human skeletons excavated from the island.

Zenodo preprint, 2023

Familial Amyloid Polyneuropathy (FAP) is an endemic amyloidosis involving harmful aggregation of ... more Familial Amyloid Polyneuropathy (FAP) is an endemic amyloidosis involving harmful aggregation of proteins, most commonly transthyretin (TTR) but sometimes also apolipoprotein A-1 or gelsolin. TTR FAP appears to be transmitted as an autosomal dominant trait. Over 100 point mutations have been identified, with the Val30Met substitution being the most common. Yet, the mechanism of pathogenesis and the overall origin of FAP remain unclear. Here, we argue that FAP could be related to harmful metal exposure. FAP incidence is unevenly distributed over the planet, and the three largest defined clusters exist in Japan, Portugal, and Sweden. All three disease regions are also ancient mining districts, with associated metal contamination of the local environment. There are two main mechanisms for how harmful metals, after uptake into tissues and body fluids, could induce FAP. First, the metals could directly influence the expression, function, and/or aggregation of the proteins involved in FAP pathology, and these particular metal-protein interactions might constitute molecular targets for anti-FAP drug design. Second, metal exposure could induce FAP-associated genetic mutations, which may have happened several generations ago. These two mechanisms can occur in parallel. In conclusion, the possibility that FAP could be related to metal exposure in geochemically defined regions deserves further attention.

Scientific Reports

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD brains display deposi... more Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-β (Aβ) peptides, and Aβ oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD plaques show elevated concentrations of metals such as Cu, Fe, and Zn. Yet, the metal chemistry in AD pathology remains unclear. Ni(II) ions are known to interact with Aβ peptides, but the nature and effects of such interactions are unknown. Here, we use numerous biophysical methods—mainly spectroscopy and imaging techniques—to characterize Aβ/Ni(II) interactions in vitro, for different Aβ variants: Aβ(1–40), Aβ(1–40)(H6A, H13A, H14A), Aβ(4–40), and Aβ(1–42). We show for the first time that Ni(II) ions display specific binding to the N-terminal segment of full-length Aβ monomers. Equimolar amounts of Ni(II) ions retard Aβ aggregation and direct it towards non-structured aggregates. The H...

Pharmaceutics

Cell-penetrating peptides (CPPs) with sequences derived originally from a prion protein (PrP) hav... more 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 t...

Zenodo preprint, 2023

Shears, being everyday objects, have received significantly less attention by archaeometallurgist... more Shears, being everyday objects, have received significantly less attention by archaeometallurgists than other edged tools or weapons. Yet, shear blades were forged with the same techniques as blades of e.g. knifes and swords. The most common shear type in ancient times was the bow shears, where the bow had to be flexible so it could be repeatedly bent without cracking or breaking. The shear-maker therefore faced the challenge of combining hard steel (the blades) with soft/flexible steel (the bow). In fact, bow shears are one of the first tools to be invented where metal acts as a spring. Thus, ancient bow shears can be used for investigating the history and development of spring steel technology, which currently is unclear. Here, we present the metallurgical characterization of two 11th – 12th c. single bow shears from Sigtuna, Sweden. Both the blades and the bows of the two shears were found to be of decent quality, and much better than in older shears from the Roman period. Although the steel qualities are not quite up to modern standards, this does not in itself prove that the Sigtuna blacksmiths lacked the technological knowledge to make ideal spring steel. Shears are relatively cheap everyday objects intended to be used until they break, at which point they are discarded. Therefore, it might not have been worth the Medieval blacksmiths’ time and effort to perfect the material properties of steel used in shears. The shears’ blades are on par with Medieval period knife blades, and future studies on ancient shear-making should preferably involve comparisons of shears and knives from the same origins.

The Anatomical Record, 2018

bioRxiv, 2021

Misfolding of the cellular prion protein (PrPC) is associated with the development of fatal neuro... more 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 the protein misfolding, and metal imbalance may be part of TSE pathologies. 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. Here, we used biophysical methods to characterize Cu(II) and Zn(II) binding to the isolated OR region. Circular dichroism (CD) spectroscopy data suggest that the OR domain binds up to four Cu(II) ions or two Zn(II) ions. Upon metal binding, the OR region seems to adopt a transient antiparallel β-sheet hairpin structure. Fluorescence spectroscopy data indicates that under neutral conditions, the OR region can bind both Cu(II) and Zn(II) ions, whereas under acidic conditions it binds only Cu(II) ions. Molecular dynamics simulations suggest that binding of both ...

Single-stranded DNA (ssDNA) is characterized by high conformational flexibility that allows these... more Single-stranded DNA (ssDNA) is characterized by high conformational flexibility that allows these molecules to adopt a variety of conformations. Here we used native polyacrylamide gel electrophoresis (PAGE), circular dichroism (CD) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy to show that cytosine methylation at CpG sites affects the conformational flexibility of short ssDNA molecules. The CpG containing 37-nucleotide PDYN (prodynorphin) fragments were used as model molecules. The presence of secondary DNA structures was evident from differences in oligonucleotide mobilities on PAGE, from CD spectra, and from formation of A-T, G-C, and non-canonical G-T base pairs observed by NMR spectroscopy. The oligonucleotides displayed secondary structures at 4uC, and some also at 37uC. Methylation at CpG sites prompted sequence-dependent formation of novel conformations, or shifted the equilibrium between different existing ssDNA conformations. The effects of methylation on g...

29 iron rings with diameters between 9 and 15 cm were excavated in 1989 at a Vendel Period settle... more 29 iron rings with diameters between 9 and 15 cm were excavated in 1989 at a Vendel Period settlement site with a longhouse, located at Åselby in Dalecarlia, Sweden. Most of the rings had between one and three smaller rings attached. Rings of this type and size are fairly common at Scandinavian Vendel and Viking Period sites – settlements, cemeteries and cult precincts – but their function remains debated. The rings from Åselby have been interpreted as iron/steel bars, to be used or traded as raw material for e.g. weapons production. Previous metallurgical analysis of one Åselby ring showed it to consist of somewhat uneven but still decentquality carbon steel. General conclusions should however not be drawn from a single observation. Here, we have sampled six Åselby rings for metallographic examination of the cross-sections. The material quality and carbon content of the sampled rings were found to be very uneven, and relatively large inclusions of unworked slag were common. We conc...

JBIC Journal of Biological Inorganic Chemistry, 2019

The amyloid-β (Aβ) peptides are key molecules in Alzheimer’s disease (AD) pathology. They interac... more The amyloid-β (Aβ) peptides are key molecules in Alzheimer’s disease (AD) pathology. They interact with cellular membranes, and can bind metal ions outside the membrane. Certain oligomeric Aβ aggregates are known to induce membrane perturbations and the structure of these oligomers—and their membrane-perturbing effects—can be modulated by metal ion binding. If the bound metal ions are redox active, as e.g., Cu and Fe ions are, they will generate harmful reactive oxygen species (ROS) just outside the membrane surface. Thus, the membrane damage incurred by toxic Aβ oligomers is likely aggravated when redox-active metal ions are present. The combined interactions between Aβ oligomers, metal ions, and biomembranes may be responsible for at least some of the neuronal death in AD patients.

Biophysical Journal, 2019

Biophysical Journal, 2018

Journal of neuroinflammation, Jan 4, 2018

Chronic neuroinflammation is a hallmark of Parkinson's disease (PD) pathophysiology, associat... more Chronic neuroinflammation is a hallmark of Parkinson's disease (PD) pathophysiology, associated with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer's disease. This is the first report on the co-aggregation of α-synuclein (α-syn) and S100A9 both in vitro and ex vivo in PD brain. Single and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and α-syn location and aggregation. In vitro studies revealing S100A9 and α-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods. Co-localized and co-aggregated S100A9 and α-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also o...

PloS one, 2017

Stone tools, often the sole remnant of prehistoric hunter-gatherer behavior, are frequently used ... more Stone tools, often the sole remnant of prehistoric hunter-gatherer behavior, are frequently used as evidence of ancient human mobility, resource use, and environmental adaptation. In North America, studies of morphological variation in projectile points have provided important insights into migration and interactions of human groups as early as 12-13 kya. Using new approaches to 3D imaging and morphometric analysis, we here quantify bifacial asymmetry among early North American projectile point styles to better understand changes in knapping technique and cultural transmission. Using a sample of 100 fluted bifaces of Clovis and post-Clovis styles in the eastern United States ca. 13,100-9,000 cal BP (i.e., Clovis, Debert-Vail, Bull Brook, Michaud-Neponset/Barnes, and Crowfield), we employed two different approaches for statistical shape analysis: our previously presented method for analysis of 2D flake scar contours, and a new approach for 3D surface analysis using spherical harmonic...

Environmental health : a global access science source, Jun 23, 2017

Polycyclic aromatic hydrocarbons (PAHs) are the main toxic compounds in natural bitumen, a fossil... more Polycyclic aromatic hydrocarbons (PAHs) are the main toxic compounds in natural bitumen, a fossil material used by modern and ancient societies around the world. The adverse health effects of PAHs on modern humans are well established, but their health impacts on past populations are unclear. It has previously been suggested that a prehistoric health decline among the native people living on the California Channel Islands may have been related to PAH exposure. Here, we assess the potential health risks of PAH exposure from the use and manufacture of bitumen-coated water bottles by ancient California Indian societies. We replicated prehistoric bitumen-coated water bottles with traditional materials and techniques of California Indians, based on ethnographic and archaeological evidence. In order to estimate PAH exposure related to water bottle manufacture and use, we conducted controlled experiments to measure PAH contamination 1) in air during the manufacturing process and 2) in wate...

The Journal of biological chemistry, Jan 20, 2016

Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. ... more Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many struxctural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer's disease amyloid-β(Aβ) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer's disease should...

Three-dimensional (3D) laser scanners are becoming increasingly more affordable and user-friendly... more Three-dimensional (3D) laser scanners are becoming increasingly more affordable and user-friendly, making 3D-modeling tools more widely available to researchers in various countries and disciplines. In archaeology, 3D-modeling has the particular advantages of facilitating the documentation and analysis of objects that are fragile, rare, and often difficult to access. We have previously shown that 3D-modeling is a highly useful tool for shape analysis of archaeological bone material, due to the high measurement accuracy inherent in the latest generation of 3D laser scanners (Sholts et al. 2010; 2011). In this work, we explore the utility of 3D-modeling as a tool for Viking Age artefact analysis. To test the usefulness of 3D-modeling when analyzing artefacts with a very complex morphology, we chose highly ornate Viking Age baroque shaped brooches as study objects. These baroque shaped brooches constitute a group of dress ornaments mainly encountered in eastern Viking Age Scandinavia. Due to their large cast and/or attached bosses they obtain an almost baroque appearance, hence their name (cf. Jansson 1984: p. 81). They appear in two major versions, i.e. circular or equal armed, and in two kinds of material, i.e. silver- and copper-based alloys. Because of the position of bronze brooches in burial contexts, it appears they were used to fasten the cape or shawl in the female dress (cf. Jansson 1984: p. 75ff., Aagard 1984: p. 96ff.; Neis 2006, figs. 3, 4; Capelle 1962: p. 106). For the present work a recently excavated brooch from Denmark was analyzed, together with three Russian brooches with nearly iconic status in the field of Viking Age studies. In the three case studies, we investigated possible uses of 3D-modeling for artefact analysis, artefact reconstruction, and tool mark and motif analysis. Exploring the usefulness of 3D-modeling for these purposes allowed us to draw conclusions regarding how 3D-analysis can be best incorporated into future artefact analysis. In addition, the case studies allowed us to gain new insights about the baroque shaped brooches and their uses.

biomolecules, 2024

Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyl... more Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy (FAP)) is an endemic amyloidosis involving the harmful aggregation of proteins, most commonly transthyretin (TTR) but sometimes also apolipoprotein A-1 or gelsolin. hATTR appears to be transmitted as an autosomal dominant trait. Over 100 point mutations have been identified, with the Val30Met substitution being the most common. Yet, the mechanism of pathogenesis and the overall origin of hATTR remain unclear. Here, we argue that hATTR could be related to harmful metal exposure. hATTR incidence is unevenly distributed globally, and the three largest defined clusters exist in Japan, Portugal, and Sweden. All three disease regions are also ancient mining districts with associated metal contamination of the local environment. There are two main mechanisms for how harmful metals, after uptake into tissues and body fluids, could induce hATTR. First, the metals could directly influence the expression, function, and/or aggregation of the proteins involved in hATTR pathology. Such metal–protein interactions might constitute molecular targets for anti-hATTR drug design. Second, metal exposure could induce hATTR -associated genetic mutations, which may have happened several generations ago. These two mechanisms can occur in parallel. In conclusion, the possibility that hATTR could be related to metal exposure in geochemically defined regions deserves further attention.

Research Square Preprint, 2023

Because silver is toxic to microbes, but not considered toxic to humans, the metal has been used ... more Because silver is toxic to microbes, but not considered toxic to humans, the metal has been used as an antimicrobial agent since ancient times. Today, silver nanoparticles and colloidal silver are used for antibacterial purposes, and silver-peptide and similar complexes are being developed as therapeutic agents. Yet, the health effects of silver exposure are not fully understood, nor are the molecular details of silver-protein interactions. In Alzheimer's disease (AD), the most common form of dementia worldwide, amyloid-β (Aβ) peptides aggregate to form soluble oligomers that are neurotoxic. Here, we report that monovalent silver ions (Ag +) bind wildtype Aβ 40 peptides with a binding a nity of 25 ± 12 µM in MES buffer at 20 °C. The N-terminal His residues are involved as binding ligands. Weaker Ag + binding is observed for the truncated Aβ(4-40) variant, for an Aβ 40 mutant without histidines, and for the wt Aβ 40 peptide at acidic pH. Because the Ag + ions do not induce any changes in the size or structure of Aβ 42 oligomers, we speculate that Ag + ions have a minor in uence on Aβ toxicity.

Journal of Trace Elements in Medicine and Biology, 2024

Background: Leaded fuel was banned in South Africa in 2006, in order to improve human health and ... more 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.

Preprints.org, 2023

In the 21st century, museums have come to realize that the human skeletons they display might hav... more In the 21st century, museums have come to realize that the human skeletons they display might have problematic origins. The older anthropological skeletal collections typically originate from anatomical dissection of the executed and the very poor, or from scavenged graves of indigenous people. Such collections are currently being re-evaluated in many countries, and reburying or repatriating museum skeletons have become viable options. A particularly difficult question is what to do with human remains of unknown origins. Here, we present and discuss one such case, where a human skeleton of unclear origin in the 1930’s was brought to a local museum in Bollnäs, Sweden, under likely unethical circumstances. Most of the bones have now been lost, except for the skull, the sacrum and one lumbar vertebra, which in 2007 were transferred to the Museum of Ethnography in Stockholm. The skull was there put on display as the “Bollnäs skull”, and was presented to the public to illustrate the dilemmas involved in handling human remains in the post-colonial era. The original gift letter from 1934 stated that the skeleton came from San Nicolas Island outside the California coast, but this letter contained numerous instances of incorrect information and was therefore deemed not trustworthy. However, our critical examination of the skull and its background information indicates that San Nicolas Island is a plausible origin, and we suggest that a bioarchaeological comparison should be made between the skull and living descendants of the San Nicolas Island population, and/or with archaeological human skeletons excavated from the island.

Zenodo preprint, 2023

Familial Amyloid Polyneuropathy (FAP) is an endemic amyloidosis involving harmful aggregation of ... more Familial Amyloid Polyneuropathy (FAP) is an endemic amyloidosis involving harmful aggregation of proteins, most commonly transthyretin (TTR) but sometimes also apolipoprotein A-1 or gelsolin. TTR FAP appears to be transmitted as an autosomal dominant trait. Over 100 point mutations have been identified, with the Val30Met substitution being the most common. Yet, the mechanism of pathogenesis and the overall origin of FAP remain unclear. Here, we argue that FAP could be related to harmful metal exposure. FAP incidence is unevenly distributed over the planet, and the three largest defined clusters exist in Japan, Portugal, and Sweden. All three disease regions are also ancient mining districts, with associated metal contamination of the local environment. There are two main mechanisms for how harmful metals, after uptake into tissues and body fluids, could induce FAP. First, the metals could directly influence the expression, function, and/or aggregation of the proteins involved in FAP pathology, and these particular metal-protein interactions might constitute molecular targets for anti-FAP drug design. Second, metal exposure could induce FAP-associated genetic mutations, which may have happened several generations ago. These two mechanisms can occur in parallel. In conclusion, the possibility that FAP could be related to metal exposure in geochemically defined regions deserves further attention.

Scientific Reports

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD brains display deposi... more Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-β (Aβ) peptides, and Aβ oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD plaques show elevated concentrations of metals such as Cu, Fe, and Zn. Yet, the metal chemistry in AD pathology remains unclear. Ni(II) ions are known to interact with Aβ peptides, but the nature and effects of such interactions are unknown. Here, we use numerous biophysical methods—mainly spectroscopy and imaging techniques—to characterize Aβ/Ni(II) interactions in vitro, for different Aβ variants: Aβ(1–40), Aβ(1–40)(H6A, H13A, H14A), Aβ(4–40), and Aβ(1–42). We show for the first time that Ni(II) ions display specific binding to the N-terminal segment of full-length Aβ monomers. Equimolar amounts of Ni(II) ions retard Aβ aggregation and direct it towards non-structured aggregates. The H...

Pharmaceutics

Cell-penetrating peptides (CPPs) with sequences derived originally from a prion protein (PrP) hav... more 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 t...

Zenodo preprint, 2023

Shears, being everyday objects, have received significantly less attention by archaeometallurgist... more Shears, being everyday objects, have received significantly less attention by archaeometallurgists than other edged tools or weapons. Yet, shear blades were forged with the same techniques as blades of e.g. knifes and swords. The most common shear type in ancient times was the bow shears, where the bow had to be flexible so it could be repeatedly bent without cracking or breaking. The shear-maker therefore faced the challenge of combining hard steel (the blades) with soft/flexible steel (the bow). In fact, bow shears are one of the first tools to be invented where metal acts as a spring. Thus, ancient bow shears can be used for investigating the history and development of spring steel technology, which currently is unclear. Here, we present the metallurgical characterization of two 11th – 12th c. single bow shears from Sigtuna, Sweden. Both the blades and the bows of the two shears were found to be of decent quality, and much better than in older shears from the Roman period. Although the steel qualities are not quite up to modern standards, this does not in itself prove that the Sigtuna blacksmiths lacked the technological knowledge to make ideal spring steel. Shears are relatively cheap everyday objects intended to be used until they break, at which point they are discarded. Therefore, it might not have been worth the Medieval blacksmiths’ time and effort to perfect the material properties of steel used in shears. The shears’ blades are on par with Medieval period knife blades, and future studies on ancient shear-making should preferably involve comparisons of shears and knives from the same origins.

The Anatomical Record, 2018

bioRxiv, 2021

Misfolding of the cellular prion protein (PrPC) is associated with the development of fatal neuro... more 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 the protein misfolding, and metal imbalance may be part of TSE pathologies. 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. Here, we used biophysical methods to characterize Cu(II) and Zn(II) binding to the isolated OR region. Circular dichroism (CD) spectroscopy data suggest that the OR domain binds up to four Cu(II) ions or two Zn(II) ions. Upon metal binding, the OR region seems to adopt a transient antiparallel β-sheet hairpin structure. Fluorescence spectroscopy data indicates that under neutral conditions, the OR region can bind both Cu(II) and Zn(II) ions, whereas under acidic conditions it binds only Cu(II) ions. Molecular dynamics simulations suggest that binding of both ...

Single-stranded DNA (ssDNA) is characterized by high conformational flexibility that allows these... more Single-stranded DNA (ssDNA) is characterized by high conformational flexibility that allows these molecules to adopt a variety of conformations. Here we used native polyacrylamide gel electrophoresis (PAGE), circular dichroism (CD) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy to show that cytosine methylation at CpG sites affects the conformational flexibility of short ssDNA molecules. The CpG containing 37-nucleotide PDYN (prodynorphin) fragments were used as model molecules. The presence of secondary DNA structures was evident from differences in oligonucleotide mobilities on PAGE, from CD spectra, and from formation of A-T, G-C, and non-canonical G-T base pairs observed by NMR spectroscopy. The oligonucleotides displayed secondary structures at 4uC, and some also at 37uC. Methylation at CpG sites prompted sequence-dependent formation of novel conformations, or shifted the equilibrium between different existing ssDNA conformations. The effects of methylation on g...

29 iron rings with diameters between 9 and 15 cm were excavated in 1989 at a Vendel Period settle... more 29 iron rings with diameters between 9 and 15 cm were excavated in 1989 at a Vendel Period settlement site with a longhouse, located at Åselby in Dalecarlia, Sweden. Most of the rings had between one and three smaller rings attached. Rings of this type and size are fairly common at Scandinavian Vendel and Viking Period sites – settlements, cemeteries and cult precincts – but their function remains debated. The rings from Åselby have been interpreted as iron/steel bars, to be used or traded as raw material for e.g. weapons production. Previous metallurgical analysis of one Åselby ring showed it to consist of somewhat uneven but still decentquality carbon steel. General conclusions should however not be drawn from a single observation. Here, we have sampled six Åselby rings for metallographic examination of the cross-sections. The material quality and carbon content of the sampled rings were found to be very uneven, and relatively large inclusions of unworked slag were common. We conc...

JBIC Journal of Biological Inorganic Chemistry, 2019

The amyloid-β (Aβ) peptides are key molecules in Alzheimer’s disease (AD) pathology. They interac... more The amyloid-β (Aβ) peptides are key molecules in Alzheimer’s disease (AD) pathology. They interact with cellular membranes, and can bind metal ions outside the membrane. Certain oligomeric Aβ aggregates are known to induce membrane perturbations and the structure of these oligomers—and their membrane-perturbing effects—can be modulated by metal ion binding. If the bound metal ions are redox active, as e.g., Cu and Fe ions are, they will generate harmful reactive oxygen species (ROS) just outside the membrane surface. Thus, the membrane damage incurred by toxic Aβ oligomers is likely aggravated when redox-active metal ions are present. The combined interactions between Aβ oligomers, metal ions, and biomembranes may be responsible for at least some of the neuronal death in AD patients.

Biophysical Journal, 2019

Biophysical Journal, 2018

Journal of neuroinflammation, Jan 4, 2018

Chronic neuroinflammation is a hallmark of Parkinson's disease (PD) pathophysiology, associat... more Chronic neuroinflammation is a hallmark of Parkinson's disease (PD) pathophysiology, associated with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer's disease. This is the first report on the co-aggregation of α-synuclein (α-syn) and S100A9 both in vitro and ex vivo in PD brain. Single and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and α-syn location and aggregation. In vitro studies revealing S100A9 and α-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods. Co-localized and co-aggregated S100A9 and α-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also o...

PloS one, 2017

Stone tools, often the sole remnant of prehistoric hunter-gatherer behavior, are frequently used ... more Stone tools, often the sole remnant of prehistoric hunter-gatherer behavior, are frequently used as evidence of ancient human mobility, resource use, and environmental adaptation. In North America, studies of morphological variation in projectile points have provided important insights into migration and interactions of human groups as early as 12-13 kya. Using new approaches to 3D imaging and morphometric analysis, we here quantify bifacial asymmetry among early North American projectile point styles to better understand changes in knapping technique and cultural transmission. Using a sample of 100 fluted bifaces of Clovis and post-Clovis styles in the eastern United States ca. 13,100-9,000 cal BP (i.e., Clovis, Debert-Vail, Bull Brook, Michaud-Neponset/Barnes, and Crowfield), we employed two different approaches for statistical shape analysis: our previously presented method for analysis of 2D flake scar contours, and a new approach for 3D surface analysis using spherical harmonic...

Environmental health : a global access science source, Jun 23, 2017

Polycyclic aromatic hydrocarbons (PAHs) are the main toxic compounds in natural bitumen, a fossil... more Polycyclic aromatic hydrocarbons (PAHs) are the main toxic compounds in natural bitumen, a fossil material used by modern and ancient societies around the world. The adverse health effects of PAHs on modern humans are well established, but their health impacts on past populations are unclear. It has previously been suggested that a prehistoric health decline among the native people living on the California Channel Islands may have been related to PAH exposure. Here, we assess the potential health risks of PAH exposure from the use and manufacture of bitumen-coated water bottles by ancient California Indian societies. We replicated prehistoric bitumen-coated water bottles with traditional materials and techniques of California Indians, based on ethnographic and archaeological evidence. In order to estimate PAH exposure related to water bottle manufacture and use, we conducted controlled experiments to measure PAH contamination 1) in air during the manufacturing process and 2) in wate...

The Journal of biological chemistry, Jan 20, 2016

Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. ... more Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many struxctural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer's disease amyloid-β(Aβ) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer's disease should...

Three-dimensional (3D) laser scanners are becoming increasingly more affordable and user-friendly... more Three-dimensional (3D) laser scanners are becoming increasingly more affordable and user-friendly, making 3D-modeling tools more widely available to researchers in various countries and disciplines. In archaeology, 3D-modeling has the particular advantages of facilitating the documentation and analysis of objects that are fragile, rare, and often difficult to access. We have previously shown that 3D-modeling is a highly useful tool for shape analysis of archaeological bone material, due to the high measurement accuracy inherent in the latest generation of 3D laser scanners (Sholts et al. 2010; 2011). In this work, we explore the utility of 3D-modeling as a tool for Viking Age artefact analysis. To test the usefulness of 3D-modeling when analyzing artefacts with a very complex morphology, we chose highly ornate Viking Age baroque shaped brooches as study objects. These baroque shaped brooches constitute a group of dress ornaments mainly encountered in eastern Viking Age Scandinavia. Due to their large cast and/or attached bosses they obtain an almost baroque appearance, hence their name (cf. Jansson 1984: p. 81). They appear in two major versions, i.e. circular or equal armed, and in two kinds of material, i.e. silver- and copper-based alloys. Because of the position of bronze brooches in burial contexts, it appears they were used to fasten the cape or shawl in the female dress (cf. Jansson 1984: p. 75ff., Aagard 1984: p. 96ff.; Neis 2006, figs. 3, 4; Capelle 1962: p. 106). For the present work a recently excavated brooch from Denmark was analyzed, together with three Russian brooches with nearly iconic status in the field of Viking Age studies. In the three case studies, we investigated possible uses of 3D-modeling for artefact analysis, artefact reconstruction, and tool mark and motif analysis. Exploring the usefulness of 3D-modeling for these purposes allowed us to draw conclusions regarding how 3D-analysis can be best incorporated into future artefact analysis. In addition, the case studies allowed us to gain new insights about the baroque shaped brooches and their uses.