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Träfflista för sökning "WFRF:(Wärmländer Sebastian K. T. S.) "

Sökning: WFRF:(Wärmländer Sebastian K. T. S.)

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1.
  • Wang, Chao, et al. (författare)
  • The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade
  • 2014
  • Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 127:4, s. 507-522
  • Tidskriftsartikel (refereegranskat)abstract
    • Pro-inflammatory S100A9 protein is increasingly recognized as an important contributor to inflammation-related neurodegeneration. Here, we provide insights into S100A9 specific mechanisms of action in Alzheimer's disease (AD). Due to its inherent amyloidogenicity S100A9 contributes to amyloid plaque formation together with A beta. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with A beta and amyloid fibrillar antibodies. They may serve as precursor-plaques for AD, implicating TBI as an AD risk factor. S100A9 was observed in some hippocampal and cortical neurons in TBI, AD and non-demented aging. In vitro S100A9 forms neurotoxic linear and annular amyloids resembling A beta protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with A beta, which results in a variety of micron-scale amyloid complexes. NMR and molecular docking demonstrated transient interactions between native S100A9 and A beta. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate A beta aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target.
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2.
  • Carvalho, Alexandra T. P., et al. (författare)
  • Understanding the structural and dynamic consequences of DNA epigenetic modifications : Computational insights into cytosine methylation and hydroxymethylation
  • 2014
  • Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 9:12, s. 1604-1612
  • Tidskriftsartikel (refereegranskat)abstract
    • We report a series of molecular dynamics (MD) simulations of up to a microsecond combined simulation time designed to probe epigenetically modified DNA sequences. More specifically, by monitoring the effects of methylation and hydroxymethylation of cytosine in different DNA sequences, we show, for the first time, that DNA epigenetic modifications change the molecule's dynamical landscape, increasing the propensity of DNA toward different values of twist and/or roll/tilt angles (in relation to the unmodified DNA) at the modification sites. Moreover, both the extent and position of different modifications have significant effects on the amount of structural variation observed. We propose that these conformational differences, which are dependent on the sequence environment, can provide specificity for protein binding.
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3.
  • Olowoyo, J. O., et al. (författare)
  • Blood lead concentrations in exposed forecourt attendants and taxi drivers in parts of South Africa
  • 2024
  • Ingår i: Journal of Trace Elements in Medicine and Biology. - 0946-672X .- 1878-3252. ; 81
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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4.
  • Wallin, Cecilia, et al. (författare)
  • Characterization of Mn(II) ion binding to the amyloid-beta peptide in Alzheimer's disease
  • 2016
  • Ingår i: Journal of Trace Elements in Medicine and Biology. - : Elsevier BV. - 0946-672X .- 1878-3252. ; 38, s. 183-193
  • Tidskriftsartikel (refereegranskat)abstract
    • Growing evidence links neurodegenerative diseases to metal exposure. Aberrant metal ion concentrations have been noted in Alzheimer's disease (AD) brains, yet the role of metals in AD pathogenesis remains unresolved. A major factor in AD pathogenesis is considered to be aggregation of and amyloid formation by amyloid-beta (A beta) peptides. Previous studies have shown that A beta displays specific binding to Cu(II) and Zn(II) ions, and such binding has been shown to modulate A beta aggregation. Here, we use nuclear magnetic resonance (NMR) spectroscopy to show that Mn(II) ions also bind to the N-terminal part of the A beta(1-40) peptide, with a weak binding affinity in the milli- to micromolar range. Circular dichroism (CD) spectroscopy, solid state atomic force microscopy (AFM), fluorescence spectroscopy, and molecular modeling suggest that the weak binding of Mn(II) to A beta may not have a large effect on the peptide's aggregation into amyloid fibrils. However, identification of an additional metal ion displaying A beta binding reveals more complex AD metal chemistry than has been previously considered in the literature.
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5.
  • Österlund, Nicklas, et al. (författare)
  • Amyloid-beta Peptide Interactions with Amphiphilic Surfactants : Electrostatic and Hydrophobic Effects
  • 2018
  • Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 9:7, s. 1680-1692
  • Tidskriftsartikel (refereegranskat)abstract
    • The amphiphilic nature of the amyloid-beta (A beta) peptide associated with Alzheimer's disease facilitates various interactions with biomolecules such as lipids and proteins, with effects on both structure and toxicity of the peptide. Here, we investigate these peptide-amphiphile interactions by experimental and computational studies of A beta(1-40) in the presence of surfactants with varying physicochemical properties. Our findings indicate that electrostatic peptide-surfactant interactions are required for coclustering and structure induction in the peptide and that the strength of the interaction depends on the surfactant net charge. Both aggregation-prone peptide-rich coclusters and stable surfactant-rich coclusters can form. Only A beta(1-40) monomers, but not oligomers, are inserted into surfactant micelles in this surfactant-rich state. Surfactant headgroup charge is suggested to be important as electrostatic peptide-surfactant interactions on the micellar surface seems to be an initiating step toward insertion. Thus, no peptide insertion or change in peptide secondary structure is observed using a nonionic surfactant. The hydrophobic peptide-surfactant interactions instead stabilize the A beta monomer, possibly by preventing self-interaction between the peptide core and C terminus, thereby effectively inhibiting the peptide aggregation process. These findings give increased understanding regarding the molecular driving forces for A beta aggregation and the peptide interaction with amphiphilic biomolecules.
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6.
  • Abelein, Axel, et al. (författare)
  • The hairpin conformation of the amyloid beta peptide is an important structural motif along the aggregation pathway
  • 2014
  • Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 19:4-5, s. 623-634
  • Forskningsöversikt (refereegranskat)abstract
    • The amyloid beta (A beta) peptides are 39-42 residue-long peptides found in the senile plaques in the brains of Alzheimer's disease (AD) patients. These peptides self-aggregate in aqueous solution, going from soluble and mainly unstructured monomers to insoluble ordered fibrils. The aggregation process(es) are strongly influenced by environmental conditions. Several lines of evidence indicate that the neurotoxic species are the intermediate oligomeric states appearing along the aggregation pathways. This minireview summarizes recent findings, mainly based on solution and solid-state NMR experiments and electron microscopy, which investigate the molecular structures and characteristics of the A beta peptides at different stages along the aggregation pathways. We conclude that a hairpin-like conformation constitutes a common motif for the A beta peptides in most of the described structures. There are certain variations in different hairpin conformations, for example regarding H-bonding partners, which could be one reason for the molecular heterogeneity observed in the aggregated systems. Interacting hairpins are the building blocks of the insoluble fibrils, again with variations in how hairpins are organized in the cross-section of the fibril, perpendicular to the fibril axis. The secondary structure propensities can be seen already in peptide monomers in solution. Unfortunately, detailed structural information about the intermediate oligomeric states is presently not available. In the review, special attention is given to metal ion interactions, particularly the binding constants and ligand structures of A beta complexes with Cu(II) and Zn(II), since these ions affect the aggregation process(es) and are considered to be involved in the molecular mechanisms underlying AD pathology.
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7.
  • Bartelink, Eric J., et al. (författare)
  • A Case of Contested Cremains Analyzed Through Metric and Chemical Comparison
  • 2015
  • Ingår i: Journal of Forensic Sciences. - : Wiley. - 0022-1198 .- 1556-4029. ; 60:4, s. 1068-1073
  • Tidskriftsartikel (refereegranskat)abstract
    • Since the 1980s, cremation has become the fastest growing area of the U.S. funeral industry. At the same time, the number of litigations against funeral homes and cremation facilities has increased. Forensic anthropologists are often asked to determine whether the contents of an urn are actually cremated bone, and to address questions regarding the identity of the remains. This study uses both metric and chemical analyses for resolving a case of contested cremains. A cremains weight of 2021.8 g was predicted based on the decedent's reported stature and weight. However, the urn contents weighed 4173.5 g. The urn contents also contained material inconsistent with cremains (e.g., moist sediment, stones, ferrous metal). Analysis using XRD and SEM demonstrated that the urn contained thermally altered bone as well as inorganic material consistent with glass fiber cement. Although forensically challenging, cremains cases such as this one can be resolved using a multidisciplinary approach.
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8.
  • Berntsson, Elina, et al. (författare)
  • Mercury Ion Binding to Apolipoprotein E Variants ApoE2, ApoE3, and ApoE4 : Similar Binding Affinities but Different Structure Induction Effects
  • 2022
  • Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 7:33, s. 28924-28931
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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9.
  • Berntsson, Elina, et al. (författare)
  • Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides
  • 2023
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 His6, His13, and His14 residues are implicated as binding ligands, and the Ni(II)·Aβ binding affinity is in the low µM range. The redox-active Ni(II) ions induce formation of dityrosine cross-links via redox chemistry, thereby creating covalent Aβ dimers. In aqueous buffer Ni(II) ions promote formation of beta sheet structure in Aβ monomers, while in a membrane-mimicking environment (SDS micelles) coil-coil helix interactions appear to be induced. For SDS-stabilized Aβ oligomers, Ni(II) ions direct the oligomers towards larger sizes and more diverse (heterogeneous) populations. All of these structural rearrangements may be relevant for the Aβ aggregation processes that are involved in AD brain pathology.
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10.
  • Biswas, Abhijit, et al. (författare)
  • Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery
  • 2023
  • Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 15:2
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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11.
  • Bulut, Ozgur, et al. (författare)
  • Sexual dimorphism in frontal bone roundness quantified by a novel 3D-based and landmark-free method
  • 2016
  • Ingår i: Forensic Science International. - : Elsevier BV. - 0379-0738 .- 1872-6283. ; 261, s. 162.e1-162.e5
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study we present a novel and landmark-free method for quantifying shape differences between male and female frontal bones. CT scans were recorded for 80 male and 80 female Turkish hospital patients, age 25-40. The frontal bones were first isolated from the 3D models by digital cutting along the bordering sutures, and then aligned to a CAD-based sphere. This allowed us to quantify the amount of frontal bone overlapping with the sphere (on average 43.2 +/- 6.5% for males and 33.9 +/- 6.6% for females, the difference is significant at p < 0.0001), and to identify areas of shape difference and deviation from the sphere surface in male and female bones. The larger proportion of spherical frontal bone surface in males challenges the common description of the female forehead as rounder''. Based on the overlap data, we developed discriminant functions able to correctly classify 77.5% of the frontal bone models as male/female. This demonstrates that 3D-based and landmark-free approaches to statistical shape analysis may become a viable alternative to the currently dominating landmark-based approaches for shape investigation.
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12.
  • Chemerovski-Glikman, Marina, et al. (författare)
  • Self-Assembled Cyclic D,L-alpha-Peptides as Generic Conformational Inhibitors of the alpha-Synuclein Aggregation and Toxicity : In Vitro and Mechanistic Studies
  • 2016
  • Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 22:40, s. 14236-14246
  • Tidskriftsartikel (refereegranskat)abstract
    • Many peptides and proteins with large sequences and structural differences self-assemble into disease-causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross-interaction. Here, we demonstrate how the self-assembled, cyclic D,L-alpha-peptide CP-2, which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson's disease associated alpha-synuclein (alpha-syn) aggregation to toxic oligomers by an, off-pathway mechanism. We show that CP-2 interacts with the N-terminal and the non-amyloid-beta component region of alpha-syn, which are responsible for alpha-syn's membrane intercalation and self-assembly, thus changing the overall conformation of alpha-syn. CP-2 also remodels alpha-syn fibrils to nontoxic amorphous species and permeates cells through endosomes/lysosomes to reduce the accumulation and toxicity of intracellular alpha-syn in neuronal cells overexpressing alpha-syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases.
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13.
  • Dong, Xiaolin, et al. (författare)
  • Copper ions induce dityrosine-linked dimers in human but not in murine islet amyloid polypeptide (IAPP/amylin)
  • 2019
  • Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 510:4, s. 520-524
  • Tidskriftsartikel (refereegranskat)abstract
    • Dysregulation and aggregation of the peptide hormone IAPP (islet amyloid polypeptide, a.k.a. amylin) into soluble oligomers that appear to be cell-toxic is a known aspect of diabetes mellitus (DM) Type 2 pathology. IAPP aggregation is influenced by several factors including interactions with metal ions such as Cu(II). Because Cu(II) ions are redox-active they may contribute to metal-catalyzed formation of oxidative tyrosyl radicals, which can generate dityrosine cross-links. Here, we show that such a process, which involves Cu(II) ions bound to the IAPP peptide together with H2O2, can induce formation of large amounts of IAPP dimers connected by covalent dityrosine cross-links. This cross-linking is less pronounced at low pH and for murine IAPP, likely due to less efficient Cu(II) binding. Whether IAPP can carry out its hormonal function as a cross-linked dimer is unknown. As dityrosine concentrations are higher in blood plasma of DM Type 2 patients - arguably due to disease-related oxidative stress - and as dimer formation is the first step in protein aggregation, generation of dityrosine-linked dimers may be an important factor in IAPP aggregation and thus relevant for DM Type 2 progression.
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14.
  • Frković, Vedran, et al. (författare)
  • Finger width as a measure of femoral block puncture site : an ultrasonographic anatomical-anthropometric study
  • 2015
  • Ingår i: Journal of clinical anesthesia. - : Elsevier BV. - 0952-8180 .- 1873-4529. ; 27:7, s. 553-557
  • Tidskriftsartikel (refereegranskat)abstract
    • Study objective: Femoral nerve blockade is a regional anesthetic procedure that may be used in prehospital and emergency settings in cases of femoral trauma. Its speed and performance depend on how well the puncture site can be accurately located, something that usually is achieved via visible landmarks and/or by combining various universal preestablished measurements. Most of these methods have been derived from cadaver studies, which often suffer limitations in clinical settings. To facilitate a quick and easy determination of the puncture site, we here attempt to find an in vivo anthropometric measure that closely corresponds to the distance between the femoral artery and femoral nerve.Design: This is a prospective observational study.Patients: The study includes 67 patients presenting for elective surgery.Measurements: The distance from the femoral nerve to the femoral artery, projected to the skin, was measured by a 13-MHz ultrasonographic linear probe. Anthropometric measurements of the width of the hand fingers were carried out at the distal interphalangeal joints.Results: The distance from the femoral artery to the femoral nerve projected to the skin was found to closely correspond to the width of the fifth finger of the dominant hand measured at the distal interphalangeal joint.Conclusion: Because it relies on individual anthropometric information, this finding offers an individualized approach to determining the puncture site in a given patient. We believe that such an approach can improve and simplify femoral nerve blockade procedures in prehospital and emergency settings.
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15.
  • Gielnik, Maciej, et al. (författare)
  • Prion Protein Octarepeat Domain Forms Transient β-Sheet Structures upon Residue-Specific Binding to Cu(II) and Zn(II) Ions
  • 2023
  • Ingår i: Biochemistry. - 0006-2960 .- 1520-4995. ; 62:11, s. 1689-1705
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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16.
  • Gielnik, Maciej, et al. (författare)
  • The engineered peptide construct NCAM1-Aβ inhibits fibrillization of the human prion protein (PrP)
  • 2022
  • Ingår i: Acta Biochimica Polonica. - : Polskie Towarzystwo Biochemiczne (Polish Biochemical Society). - 0001-527X .- 1734-154X. ; 69:1, s. 257-261
  • Tidskriftsartikel (refereegranskat)abstract
    • In prion diseases, the prion protein (PrP) becomes misfolded and forms fibrillar aggregates that are responsible for prion infectivity and pathology. So far, no drug or treatment procedures have been approved for prion disease treatment. We have previously shown that engineered cell-penetrating peptide constructs can reduce the amount of prion aggregates in infected cells. However, the molecular mechanism underlying this effect is unknown. Here, we use atomic force microscopy (AFM) imaging to show that the amyloid aggregation and fibrillization of the human PrP protein can be inhibited by equimolar amounts of the 25 residues long engineered peptide construct NCAM1-Aβ. 
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17.
  • Gielnik, Maciej, et al. (författare)
  • Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein
  • 2021
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The cellular prion protein (PrP(C)) is a mainly alpha-helical 208-residue protein located in the pre- and postsynaptic membranes. For unknown reasons, PrP(C) can undergo a structural transition into a toxic, beta-sheet rich scrapie isoform (PrPSc) that is responsible for transmissible spongiform encephalopathies (TSEs). Metal ions seem to play an important role in the structural conversion. PrP(C) binds Zn(II) ions and may be involved in metal ion transport and zinc homeostasis. Here, we use multiple biophysical techniques including optical and NMR spectroscopy, molecular dynamics simulations, and small angle X-ray scattering to characterize interactions between human PrP(C) and Zn(II) ions. Binding of a single Zn(II) ion to the PrP(C) N-terminal domain via four His residues from the octarepeat region induces a structural transition in the C-terminal alpha-helices 2 and 3, promotes interaction between the N-terminal and C-terminal domains, reduces the folded protein size, and modifies the internal structural dynamics. As our results suggest that PrP(C) can bind Zn(II) under physiological conditions, these effects could be important for the physiological function of PrP(C).
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18.
  • Gingerich, Joseph A. M., et al. (författare)
  • Fluted point manufacture in eastern North America : an assessment of form and technology using traditional metrics and 3D digital morphometrics
  • 2014
  • Ingår i: World archaeology. - : Informa UK Limited. - 0043-8243 .- 1470-1375. ; 46:1, s. 101-122
  • Tidskriftsartikel (refereegranskat)abstract
    • Differences in Paleoindian projectile point morphology have previously been used to define technologies, infer colonization patterns, propose chronological and regional boundaries. In this study, we evaluate the effectiveness of traditional linear measurements and ratios, flake scar angles, and 3D model-based flake contours for the statistical differentiation of projectile point type(s) and reduction technique. Sixty-three fluted bifaces from eastern North America and fourteen replicate Clovis points are analyzed. Discriminant analysis shows that 3D model-based Fourier descriptors of flake scar contours are less successful than traditional metrics in correctly differentiating styles, but more successful in identifying individual knappers. Changes in the symmetry of front and back flake scars between Clovis and later fluted point styles indicate a possible shift in reduction techniques. These findings demonstrate the usefulness of both traditional and modern morphometric variables to quantify biface morphology, and address questions about social interaction and technological change in Pleistocene North America.
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19.
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20.
  • Henning-Knechtel, Anja, et al. (författare)
  • Designed Cell-Penetrating Peptide Inhibitors of Amyloid-beta Aggregation and Cytotoxicity
  • 2020
  • Ingår i: Cell Reports Physical Science. - : Elsevier BV. - 2666-3864. ; 1:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyloid proteins and peptides are a major contributing factor to the development of various neurodegenerative disorders, including Alzheimer’s and prion diseases. Previously, a designed cell-penetrating peptide (CPP) comprising a hydrophobic signal sequence followed by a prion protein (PrP)-derived polycationic sequence (PrP23–28: KKRPKP) was shown to have potent anti-prion properties. Here, we extend this approach toward the amyloid-beta (Aβ) peptide amyloid formation, which is associated with Alzheimer’s disease. We characterized the interactions of the CPP with Aβ using complementary in vitro and in silico experiments. We report that the CPP stabilizes Aβ in a non-amyloid state and inhibits Aβ-induced neurotoxicity. Moreover, replacing PrP23–28 with a corresponding segment from Aβ results in a construct with similar CPP functionality and antagonism of Aβ aggregation and neurotoxicity. Our findings reveal a general underlying principle for inhibition of pathogenic protein aggregation that may facilitate the design of CPP-based therapeutics for amyloid diseases.
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21.
  • Horvath, Istvan, et al. (författare)
  • Co-aggregation of pro-inflammatory S100A9 with alpha-synuclein in Parkinson's disease : ex vivo and in vitro studies
  • 2018
  • Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 15
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: 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 alpha-synuclein (alpha-syn) and S100A9 both in vitro and ex vivo in PD brain. Methods: 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 alpha-syn location and aggregation. In vitro studies revealing S100A9 and alpha-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods. Results: Co-localized and co-aggregated S100A9 and alpha-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also observed in Lewy bodies in PD frontal lobe (Braak stages 4-6). Lewy bodies were characterized by ca. 10-23 mu m outer diameter, with S100A9 and alpha-syn being co-localized in the same lamellar structures. S100A9 was also detected in neurons and blood vessels of the aged patients without PD, but in much lesser extent. In vitro S100A9 and alpha-syn were shown to interact with each other via the alpha-syn C-terminus with an apparent dissociation constant of ca. 5 mu M. Their co-aggregation occurred significantly faster and led to formation of larger amyloid aggregates than the self-assembly of individual proteins. S100A9 amyloid oligomers were more toxic than those of alpha-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers. Conclusions: We suggest that sustained neuroinflammation promoting the spread of amyloidogenic S100A9 in the brain tissues may trigger the amyloid cascade involving alpha-syn and S100A9 and leading to PD, similar to the effect of S100A9 and A beta co-aggregation in Alzheimer's disease. The finding of S100A9 involvement in PD may open a new avenue for therapeutic interventions targeting S100A9 and preventing its amyloid self-assembly in affected brain tissues.
  •  
22.
  • Koski, Lassi, et al. (författare)
  • Metal ratios as possible biomarkers for amyotrophic lateral sclerosis
  • 2023
  • Ingår i: Journal of Trace Elements in Medicine and Biology. - : Elsevier BV. - 0946-672X .- 1878-3252. ; 78
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
  •  
23.
  • Koski, Lassi, et al. (författare)
  • Metals in ALS TDP-43 Pathology
  • 2021
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:22
  • Forskningsöversikt (refereegranskat)abstract
    • Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology.
  •  
24.
  • Leshem, Guy, et al. (författare)
  • Photoactive chlorin e6 is a multifunctional modulator of amyloid-β aggregation and toxicity via specific interactions with its histidine residues
  • 2019
  • Ingår i: Chemical Science. - : Royal Society of Chemistry (RSC). - 2041-6520 .- 2041-6539. ; 10:1, s. 208-217
  • Tidskriftsartikel (refereegranskat)abstract
    • The self-assembly of A to -sheet-rich neurotoxic oligomers is a main pathological event leading to Alzheimer's disease (AD). Selective targeting of A oligomers without affecting other functional proteins is therefore an attractive approach to prevent the disease and its progression. In this study, we report that photodynamic treatment of A in the presence of catalytic amounts of chlorin e6 can selectively damage A and inhibit its aggregation and toxicity. Chlorin e6 also reversed the amyloid aggregation process in the dark by binding its soluble and low molecular weight oligomers, as shown by thioflavin T (ThT) fluorescence and photoinduced cross-linking of unmodified protein (PICUP) methods. Using HSQC NMR spectroscopy, ThT assays, amino acid analysis, SDS/PAGE, and EPR spectroscopy, we show that catalytic amounts of photoexcited chlorin e6 selectively damage the A histidine residues H6, H13, and H14, and induce A cross-linking by generating singlet oxygen. In contrast, photoexcited chlorin e6 was unable to cross-link ubiquitin and -synuclein, demonstrating its high selectivity for A. By binding to the A histidine residues, catalytic amounts of chlorin e6 can also inhibit the Cu2+-induced aggregation and toxicity in darkness, while at stoichiometric amounts it acts as a chelator to reduce the amount of free Cu2+. This study demonstrates the great potential of chlorin e6 as a multifunctional agent for treatment of AD, and shows that the three N-terminal A histidine residues are a suitable target for A-specific drugs.
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25.
  • Lindgren, Joel, et al. (författare)
  • Engineered non-fluorescent Affibody molecules facilitate studies of the amyloid-beta (A beta) peptide in monomeric form : Low pH was found to reduce A beta/Cu(II) binding affinity
  • 2013
  • Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 120, s. 18-23
  • Tidskriftsartikel (refereegranskat)abstract
    • Aggregation of amyloid-beta (A beta) peptides into oligomers and amyloid plaques in the human brain is considered a causative factor in Alzheimer's disease (AD). As metal ions are over-represented in AD patient brains, and as distinct A beta aggregation pathways in presence of Cu(II) have been demonstrated, metal binding to A beta likely affects AD progression. A beta aggregation is moreover pH-dependent, and AD appears to involve inflammatory conditions leading to physiological acidosis. Although metal binding specificity to A beta varies at different pH's, metal binding affinity to A beta has so far not been quantitatively investigated at sub-neutral pH levels. This may be explained by the difficulties involved in studying monomeric peptide properties under aggregation-promoting conditions. We have recently devised a modified Affibody molecule, Z(A beta 3)(12-58), that binds A beta with sub-nanomolar affinity, thereby locking the peptide in monomeric form without affecting the N-terminal region where metal ions bind. Here, we introduce non-fluorescent A beta-binding Affibody variants that keep A beta monomeric while only slightly affecting the A beta peptide's metal binding properties. Using fluorescence spectroscopy, we demonstrate that Cu(II)/A beta(1-40) binding is almost two orders of magnitude weaker at pH 5.0 (apparent K-D = 51 mu M) than at pH 7.3 (apparent K-D = 0.86 mu M). This effect is arguably caused by protonation of the histidines involved in the metal ligandation. Our results indicate that engineered variants of Affibody molecules are useful for studying metal-binding and other properties of monomeric A beta under various physiological conditions, which will improve our understanding of the molecular mechanisms involved in AD.
  •  
26.
  • Luo, Jinghui, et al. (författare)
  • Cellular Polyamines Promote Amyloid-Beta (A beta) Peptide Fibrillation and Modulate the Aggregation Pathways
  • 2013
  • Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 4:3, s. 454-462
  • Tidskriftsartikel (refereegranskat)abstract
    • The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer's disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (A beta) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric A beta(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 mu M spermine (normal intracellular concentration is similar to 1 mM) significantly decreased the lag and transition times of the aggregation process. Spermidine and putrescine additions yielded similar but weaker effects. CD measurements demonstrated that the three polyamines induce different aggregation pathways, involving different forms of induced secondary structure. This is supported by AFM images showing that the three polyamines induce A beta(1-40) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of A beta peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer's disease.
  •  
27.
  • Luo, Jinghui, et al. (författare)
  • Cross-interactions between the Alzheimer Disease Amyloid-beta Peptide and Other Amyloid Proteins : A Further Aspect of the Amyloid Cascade Hypothesis
  • 2016
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 291:32, s. 16485-16493
  • Forskningsöversikt (refereegranskat)abstract
    • Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural 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 disease amyloid-beta (A beta) 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 disease should be expanded to include cross-interactions between A beta and other amyloid proteins.
  •  
28.
  • Luo, Jinghui, et al. (författare)
  • Endogenous Polyamines Reduce the Toxicity of Soluble A beta Peptide Aggregates Associated with Alzheimer's Disease
  • 2014
  • Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1525-7797 .- 1526-4602. ; 15:6, s. 1985-1991
  • Tidskriftsartikel (refereegranskat)abstract
    • Polyamines promote the formation of the A beta peptide amyloid fibers that are a hallmark of Alzheimer's disease. Here we show that polyamines interact with nonaggregated A beta peptides, thereby reducing the peptide's hydrophobic surface. We characterized the associated conformational change through NMR titrations and molecular dynamics simulations. We found that even low concentrations of spermine, sperimidine, and putrescine fully protected SH-SY5Y (a neuronal cell model) against the most toxic conformational species of AA even at an A beta oligomer concentration that would otherwise kill half of the cells or even more. These observations lead us to conclude that polyamines interfere with the more toxic prefibrillar conformations and might protect cells by promoting the structural transition of A beta toward its less toxic fibrillar state that we reported previously. Since polyamines are present in brain fluid at the concentrations where we observed all these effects, their activity needs to be taken into account in understanding the molecular processes related to the development of Alzheimer's disease.
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29.
  • Luo, Jinghui, et al. (författare)
  • Inhibiting and Reversing Amyloid-β Peptide (1-40) Fibril Formation with Gramicidin S and Engineered Analogues
  • 2013
  • Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 19:51, s. 17338-17348
  • Tidskriftsartikel (refereegranskat)abstract
    • In Alzheimer's disease, amyloid-β (Aβ) peptides aggregate into extracellular fibrillar deposits. Although these deposits may not be the prime cause of the neurodegeneration that characterizes this disease, inhibition or dissolution of amyloid fibril formation by Aβ peptides is likely to affect its development. ThT fluorescence measurements and AFM images showed that the natural antibiotic gramicidin S significantly inhibited Aβ amyloid formation in vitro and could dissolve amyloids that had formed in the absence of the antibiotic. In silico docking suggested that gramicidin S, a cyclic decapeptide that adopts a β-sheet conformation, binds to the Aβ peptide hairpin-stacked fibril through β-sheet interactions. This may explain why gramicidin S reduces fibril formation. Analogues of gramicidin S were also tested. An analogue with a potency that was four-times higher than that of the natural product was identified.
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30.
  • Luo, Jinghui, et al. (författare)
  • Non-chaperone Proteins Can Inhibit Aggregation and Cytotoxicity of Alzheimer Amyloid beta Peptide
  • 2014
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 289:40, s. 27766-27775
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: A amyloid formation is associated with Alzheimer disease. Results: Non-chaperone proteins prevent amyloid formation and reduce the cytotoxicity of the A peptide. Conclusion: Non-chaperone proteins may affect the onset and development of Alzheimer disease by interfering with A peptide aggregation. Significance: Non-chaperone proteins can function as a chaperone protein to regulate the pathway of the A fibrillation in proteostasis providing a new strategy in the treatment of Alzheimer disease. Many factors are known to influence the oligomerization, fibrillation, and amyloid formation of the A peptide that is associated with Alzheimer disease. Other proteins that are present when A peptides deposit in vivo are likely to have an effect on these aggregation processes. To separate specific versus broad spectrum effects of proteins on A aggregation, we tested a series of proteins not reported to have chaperone activity: catalase, pyruvate kinase, albumin, lysozyme, -lactalbumin, and -lactoglobulin. All tested proteins suppressed the fibrillation of Alzheimer A(1-40) peptide at substoichiometric ratios, albeit some more effectively than others. All proteins bound non-specifically to A, stabilized its random coils, and reduced its cytotoxicity. Surprisingly, pyruvate kinase and catalase were at least as effective as known chaperones in inhibiting A aggregation. We propose general mechanisms for the broad-spectrum inhibition A fibrillation by proteins. The mechanisms we discuss are significant for prognostics and perhaps even for prevention and treatment of Alzheimer disease.
  •  
31.
  • Luo, Jinghui, et al. (författare)
  • Reciprocal Molecular Interactions between the A beta Peptide Linked to Alzheimer's Disease and Insulin Linked to Diabetes Mellitus Type II
  • 2016
  • Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 7:3, s. 269-274
  • Tidskriftsartikel (refereegranskat)abstract
    • Clinical studies indicate diabetes mellitus type II (DM) doubles the risk that a patient will also develop Alzheimer's disease (AD). DM is caused by insulin resistance and a relative lack of active insulin. AD is characterized by the deposition of amyloid beta (A beta) peptide fibrils. Prior to fibrillating, A beta forms intermediate, prefibrillar oligomers, which are more cytotoxic than the mature A beta fibrils. Insulin can also form amyloid fibrils. In vivo studies have revealed that insulin promotes the production of A beta, and that soluble A beta competes with insulin for the insulin receptor. Here, we report that monomeric insulin interacted with soluble A beta and that both molecules reciprocally slowed down the aggregation kinetics of the other. Prefibrillar oligomers of A beta that eventually formed in the presence of insulin were less cytotoxic than A beta oligomers formed in the absence of insulin. Mature A beta fibrils induced fibrillation of soluble insulin, but insulin aggregates did not promote A beta fibrillation. Our study indicates that direct molecular interactions between insulin and A beta may contribute to the strong link between DM and AD.
  •  
32.
  • Neiß (Neiss), Michael, 1977-, et al. (författare)
  • 3D laser scanning as a tool for Viking Age studies
  • 2013
  • Ingår i: Virtual archaeology: nondestructive methods of prospections, modeling, reconstructions: Proceedings of the First International Conference held at the State Hermitage Museum 4–6 June 2012 St. Petersburg, Russia. - St. Petersburg : The State Hermitage Publishers. - 9785935725167 ; , s. 170-184
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • 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., Aagård 1984: p. 96ff.; Neiß 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.
  •  
33.
  • Neiß (Neiss), Michael, 1977-, et al. (författare)
  • New applications of 3D modeling in artefact analysis : three case studies in Viking Age brooches
  • 2016
  • Ingår i: Archaeological and Anthropological Sciences. - Springer : Berlin. - 1866-9557 .- 1866-9565. ; 8:4, s. 651-662
  • Tidskriftsartikel (refereegranskat)abstract
    • Three-dimensional (3D) laser scanning is a nondestructive and versatile technique that provides archaeologists with 3D models of archaeological and ethnographic objects. We have previously shown that 3D models facilitate shape analysis of archaeological bones and stone tools, due to the high measurement accuracy inherent in the latest generation of 3D laser scanners. Here, we explore the utility of 3D modeling as a tool for analyzing Viking Age metal artefacts with complex morphologies. Four highly ornate Viking Age brooches from Scandinavia and Russia were digitized with a portable laser scanner, and the resulting 3D models were used in three case studies of (a) artefact reconstruction, (b) tool mark analysis, and (c) motif documentation. The results revealed both strengths and limitations of the employed techniques. 3D modeling proved to be very well suited for artefact reconstruction and was helpful also in the stylistic and motif analysis. The tool mark analysis was only partially successful, due to the resolution limits of the laser scanner used. 3D-based motif analysis of a grandiose Scandinavian-style brooch from Yelets, Russia, identified an anthropomorphic figure with a bird-like body that previously has been overlooked. This figure may be a Rurikid coat of arms, possibly linking the object to a princely household and providing further evidence for a connection between Scandinavia and the Rurikids. As 3D technology keeps improving, we expect that additional applications for 3D modeling in archaeology will be developed, likely leading to many new findings when old objects are re-analyzed with modern techniques. However, our results indicate that 3D modeling cannot completely replace traditional artefact analysis—instead, we argue that the two approaches are best used in combination.
  •  
34.
  • Noormägi, Andra, et al. (författare)
  • Direct Competition of ATCUN Peptides with Human Serum Albumin for Copper(II) Ions Determined by LC-ICP MS
  • 2023
  • Ingår i: ACS Omega. - 2470-1343. ; 8:37, s. 33912-33919
  • Tidskriftsartikel (refereegranskat)abstract
    • 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. 
  •  
35.
  • Owen, Michael C., et al. (författare)
  • Effects of in vivo conditions on amyloid aggregation
  • 2019
  • Ingår i: Chemical Society Reviews. - : Royal Society of Chemistry (RSC). - 0306-0012 .- 1460-4744. ; 48:14, s. 3946-3996
  • Forskningsöversikt (refereegranskat)abstract
    • One of the grand challenges of biophysical chemistry is to understand the principles that govern protein misfolding and aggregation, which is a highly complex process that is sensitive to initial conditions, operates on a huge range of length- and timescales, and has products that range from protein dimers to macroscopic amyloid fibrils. Aberrant aggregation is associated with more than 25 diseases, which include Alzheimer's, Parkinson's, Huntington's, and type II diabetes. Amyloid aggregation has been extensively studied in the test tube, therefore under conditions that are far from physiological relevance. Hence, there is dire need to extend these investigations to in vivo conditions where amyloid formation is affected by a myriad of biochemical interactions. As a hallmark of neurodegenerative diseases, these interactions need to be understood in detail to develop novel therapeutic interventions, as millions of people globally suffer from neurodegenerative disorders and type II diabetes. The aim of this review is to document the progress in the research on amyloid formation from a physicochemical perspective with a special focus on the physiological factors influencing the aggregation of the amyloid-beta peptide, the islet amyloid polypeptide, alpha-synuclein, and the hungingtin protein.
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36.
  • Pansieri, Jonathan, et al. (författare)
  • Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs
  • 2019
  • Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 14:7, s. 1410-1417
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyloid cascade and neuroinflammation are hallmarks of neurodegenerative diseases, and pro-inflammatory S100A9 protein is central to both of them. Here, we have shown that NCAM1 peptide constructs carrying polycationic sequences derived from A beta peptide (KKLVFF) and PrP protein (KKRPKP) significantly promote the S100A9 amyloid self-assembly in a concentration-dependent manner by making transient interactions with individual S100A9 molecules, perturbing its native structure and acting as catalysts. Since the individual molecule misfolding is a rate-limiting step in S100A9 amyloid aggregation, the effects of the NCAM1 construct on the native S100A9 are so critical for its amyloid self-assembly. S100A9 rapid self assembly into large aggregated clumps may prevent its amyloid tissue propagation, and by modulating S100A9 aggregation as a part of the amyloid cascade, the whole process may be effectively tuned.
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37.
  • Paul, Suman, et al. (författare)
  • 13C- and 15N-labeling of amyloid-β and inhibitory peptides to study their interaction via nanoscale infrared spectroscopy
  • 2023
  • Ingår i: Communications Chemistry. - 2399-3669. ; 6:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Interactions between molecules are fundamental in biology. They occur also between amyloidogenic peptides or proteins that are associated with different amyloid diseases, which makes it important to study the mutual influence of two polypeptides on each other's properties in mixed samples. However, addressing this research question with imaging techniques faces the challenge to distinguish different polypeptides without adding artificial probes for detection. Here, we show that nanoscale infrared spectroscopy in combination with C-13, N-15-labeling solves this problem. We studied aggregated amyloid-& beta; peptide (A & beta;) and its interaction with an inhibitory peptide (NCAM1-PrP) using scattering-type scanning near-field optical microscopy. Although having similar secondary structure, labeled and unlabeled peptides could be distinguished by comparing optical phase images taken at wavenumbers characteristic for either the labeled or the unlabeled peptide. NCAM1-PrP seems to be able to associate with or to dissolve existing A & beta; fibrils because pure A & beta; fibrils were not detected after mixing. Interactions of proteins or polypeptides with different secondary structures can be studied in a mixture by nanoscale infrared spectroscopy, however, this technique remains challenging for polypeptides with similar secondary structures. Here, the authors demonstrate clear discrimination of two polypeptides from a mixture by scattering-type scanning near-field optical microscopy when one of the components is labeled with C-13- and N-15-isotopes.
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38.
  • Petaros, Anja, et al. (författare)
  • Evaluating sexual dimorphism in the human mastoid process : A viewpoint on the methodology
  • 2015
  • Ingår i: Clinical anatomy (New York, N.Y. Print). - : Wiley. - 0897-3806 .- 1098-2353. ; 28:5, s. 593-601
  • Tidskriftsartikel (refereegranskat)abstract
    • The mastoid process is one of the most sexually dimorphic features in the human skull, and is therefore often used to identify the sex of skeletons. Numerous techniques for assessing variation in the size and shape of the mastoid process have been proposed and implemented in osteological research, but its complex form still presents difficulties for consistent and effective analysis. In this article, we compare the different techniques and variables that have been used to define, measure, and visually score sexual dimorphism in the mastoid process. We argue that the current protocols fail to capture the full morphological range of this bony projection, and suggest ways of improving and standardizing them, regarding both traditional and 3D-based approaches. Clin. Anat. 28:593-601, 2015.
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39.
  • Petaros, Anja, et al. (författare)
  • Sexual dimorphism and regional variation in human frontal bone inclination measured via digital 3D models
  • 2017
  • Ingår i: Legal Medicine. - : Elsevier BV. - 1344-6223 .- 1873-4162. ; 29, s. 53-61
  • Tidskriftsartikel (refereegranskat)abstract
    • The frontal bone is one of the most sexually dimorphic elements of the human skull, due to features such as the glabella, frontal eminences, and frontal inclination. While glabella is frequently evaluated in procedures to estimate sex in unknown human skeletal remains, frontal inclination has received less attention. In this study we present a straightforward, quick, and reproducible method for measuring frontal inclination angles from glabella and supraglabella. Using a sample of 413 human crania from four different populations (U.S. Whites, U.S. Blacks, Portuguese, and Chinese), we test the usefulness of the inclination angles for sex estimation and compare their performance to traditional methods of frontal inclination assessment. Accuracy rates in the range 75-81% were achieved for the U.S. White, U.S. Black, and Portuguese groups. For Chinese the overall accuracy was lower, i.e. 66%. Although some regional variation was observed, a cut-off value of 78.2 for glabellar inclination angles separates female and male crania from all studied populations with good accuracy. As inclination angles measured from glabella captures two sexually dimorphic features (i.e. glabellar prominence and frontal inclination) in a single measure, the observed clear male/female difference is not unexpected. Being continuous variables, inclination angles are suitable for use in statistical methods for sex estimations.
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40.
  • Petaros, Anja, et al. (författare)
  • Sexual dimorphism in mastoid process volumes measured from 3D models of dry crania from mediaeval Croatia
  • 2021
  • Ingår i: Homo (Stuttgart). - : Schweizerbart. - 0018-442X .- 1618-1301. ; 72:2, s. 113-127
  • Tidskriftsartikel (refereegranskat)abstract
    • 3D analysis of skeletal volumes has become an important field in digital anthropology studies. The volume of the mastoid process has been proposed to display significant sexual dimorphism, but it has a complex shape and to date no study has quantified the full mastoid volume for sex estimation purposes. In this study we compared three different ways to isolate the volume of the mastoid process from digital 3D models of dry crania, and then evaluated the performance of the three different volume definitions for sex estimation purposes. A total of 170 crania (86 male, 84 females) excavated from five medieval Croatian sites were CT-scanned and used to produce 3D stereolitographic models. The three different isolation techniques were based on various anatomical landmarks and planes, as well as the anatomy of the mastoid process itself. Measurements of the three different mastoid volumes yielded different accuracies and precisions. Interestingly, anatomical structures were sometimes more useful than classical landmarks as demarcators of mastoid volume. For all three volume definitions, male mastoid volumes were significantly larger than female volumes, in both relative and absolute numbers. Sex estimation based on mastoid volume showed a slightly higher precision and better accuracy (71% correct classifications) than visual scoring techniques (67%) and linear distance measurements (69%) of the mastoid process. Sex estimation based on cranial size performed even better (78%), and multifactorial analysis (cranium size + mastoid volume) reached up to 81% accuracy. These results show that measurements of the mastoid volume represent a promising metric to be used in multifactorial approaches for sex estimation of human remains.
  •  
41.
  • Richman, Michal, et al. (författare)
  • In Vitro and Mechanistic Studies of an Antiamyloidogenic Self-Assembled Cyclic D,L-alpha-Peptide Architecture
  • 2013
  • Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 135:9, s. 3474-3484
  • Tidskriftsartikel (refereegranskat)abstract
    • Misfolding of the A beta protein and its subsequent aggregation into toxic oligomers are related to Alzheimer's disease. Although peptides of various sequences can self-assemble into amyloid structures, these structures share common three-dimensional features that may promote their cross-reaction. Given the significant similarities between amyloids and the architecture of self-assembled cyclic D,L-alpha-peptide, we hypothesized that the latter may bind and stabilize a nontoxic form of A beta thereby preventing its aggregation into toxic forms. By screening a focused library of six-residue cyclic D,L-alpha-peptides and optimizing the activity of a lead peptide, we found one cyclic D,L-alpha-peptide (CP-2) that interacts strongly with A beta and inhibits its aggregation. In transmission electron microscopy, optimized thioflavin T and cell survival assays, CP-2 inhibits the formation of A beta aggregates, entirely disassembles preformed aggregated and fibrillar A beta, and protects rat pheochromocytoma PC12 cells from A beta toxicity, without inducing any toxicity by itself. Using various immunoassays, circular dichroism spectroscopy, photoinduced cross-linking of unmodified proteins (PICUP) combined with SDS/PAGE, and NMR, we probed the mechanisms underlying CP-2's antiamyloidogenic activity. NMR spectroscopy indicates that CP-2 interacts with A beta through its self-assembled conformation and induces weak secondary structure in A beta. Upon coincubation, CP-2 changes the aggregation pathway of A beta and alters its oligomer distribution by stabilizing small oligomers (1-3 mers). Our results support studies suggesting that toxic early oligomeric states of A beta may be composed of antiparallel beta-peptide structures and that the interaction of A beta with CP-2 promotes formation of more benign parallel beta-structures. Further studies will show whether these kinds of abiotic cyclic D,L-alpha-peptides are also beneficial as an intervention in related in vivo models.
  •  
42.
  • Roos, Elin, et al. (författare)
  • Amyotrophic Lateral Sclerosis After Exposure to Manganese from Traditional Medicine Procedures in Kenya
  • 2021
  • Ingår i: Biological Trace Element Research. - : Springer Science and Business Media LLC. - 0163-4984 .- 1559-0720. ; 199, s. 3618-3624
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss and widespread muscular atrophy. Despite intensive investigations on genetic and environmental factors, the cause of ALS remains unknown. Recent data suggest a role for metal exposures in ALS causation. In this study we present a patient who developed ALS after a traditional medical procedure in Kenya. The procedure involved insertion of a black metal powder into several subcutaneous cuts in the lower back. Four months later, general muscle weakness developed. Clinical and electrophysiological examinations detected widespread denervation consistent with ALS. The patient died from respiratory failure less than a year after the procedure. Scanning electron microscopy and X-ray diffraction analyses identified the black powder as potassium permanganate (KMnO4). A causative relationship between the systemic exposure to KMnO4 and ALS development can be suspected, especially as manganese is a well-known neurotoxicant previously found to be elevated in cerebrospinal fluid from ALS patients. Manganese neurotoxicity and exposure routes conveying this toxicity deserve further attention.
  •  
43.
  • Saage, Ragnar, et al. (författare)
  • Metal residues in 5th c. BCE-13th c. CE Estonian tools for non-ferrous metal casting
  • 2018
  • Ingår i: Journal of Archaeological Science. - : Elsevier BV. - 2352-409X .- 2352-4103. ; 19, s. 35-51
  • Tidskriftsartikel (refereegranskat)abstract
    • This paper investigates Estonian tools for non-ferrous metal casting in the form of crucibles, moulds, and casting ladles dating to the Estonian Iron Age (500 BCE-1227 CE), adding elemental analysis and 3D modelling to the traditional typological comparison. In contrast to the neighbouring countries of Russia, Latvia, and Sweden, no comprehensive study has previously been published on this subject for Estonian material. The typological analysis sets Iron Age Estonia in the same metalworking tradition as that of other eastern Baltic countries and Northwestern Russia. However, some classes of casting tools present in Scandinavian and Slavonic areas have so far not been encountered in the Estonian archaeological record. The elemental analysis included qualitative pXRF analysis of 175 artefacts and detailed residue analysis using SEM-EDS of thirteen selected artefacts. This analysis identified for the first time Estonian Iron Age casting tools - crucibles - used for casting gold and silver. Most of the investigated crucibles were used for casting various copper alloys, while the casting ladles and most of the stone moulds were used for casting pewter. Casting of pewter and precious metals only occurred in regional centres such as hill forts and strongholds, while copper alloys were cast in all parts of Estonia. In addition to clarifying fundamental questions about Estonian Iron Age metal casting, this study also lays a foundation for using modern analytical techniques in future investigations of Estonian metalworking traditions.
  •  
44.
  • Sholts, Sabrina B., et al. (författare)
  • Brief Communication : Additional Cases of Maxillary Canine-First Premolar Transposition in Several Prehistoric Skeletal Assemblages From the Santa Barbara Channel Islands of California
  • 2010
  • Ingår i: American Journal of Physical Anthropology. - : Wiley. - 0002-9483 .- 1096-8644. ; 143:1, s. 155-160
  • Tidskriftsartikel (refereegranskat)abstract
    • This article identifies and discusses seven new cases of complete maxillary canine-premolar transposition in ancient populations from the Santa Barbara Channel region of California. A high frequency of this tooth transposition has been previously documented within a single prehistoric cemetery on one of the Channel Islands. A total of 966 crania representing 30 local sites and about 7,000 years of human occupation were examined, revealing an abnormally high prevalence of this transposition trait among islanders during the Early period of southern California prehistory (-,5500-600 B.C.). One of the affected crania is from a cemetery more than 7,000-years-old and constitutes the earliest case of tooth transposition in humans so far reported. The results are consistent with findings by other studies that have indicated inbreeding among the early Channel Islands groups. Together with the normal transposition rates among mainland populations, the decreasing prevalence of maxillary canine-first premolar transposition among island populations across the Holocene suggests that inbreeding on the northern Channel Islands had all but ceased by the end of the first millennium B.C., most likely as a result of increased cross-channel migration and interaction. Am J Phys Anthropol 143:155-160, 2010.
  •  
45.
  • Sholts, Sabrina B., et al. (författare)
  • Flake scar patterns of Clovis points analyzed with a new digital morphometrics approach : evidence for direct transmission of technological knowledge across early North America
  • 2012
  • Ingår i: Journal of Archaeological Science. - : Elsevier BV. - 0305-4403 .- 1095-9238. ; 39:9, s. 3018-3026
  • Tidskriftsartikel (refereegranskat)abstract
    • Clovis points are the principal diagnostic artifacts of a Clovis complex that spread across North America between ca. 11,050-10,800 radiocarbon years before present. Clovis may be the best documented Paleoamerican culture in North America, but much remains to be learned about the movement and interactions of Clovis peoples. Similarities among Clovis points from geographically diverse locations have led some researchers to suggest that a uniform projectile point technology existed across North America during Clovis times. Others have rejected this idea, proposing local and independent technological adaptations to different regional environments. To investigate these ideas, we used digital morphometrics to analyze 50 Clovis points from nine different contexts. First, 3D surface models of the points were created with a portable laser scanner. Next, these models were digitally cross-sectioned through both faces, yielding two-dimensional isoheight contours of flake scar patterns that reflect the original reduction techniques used to shape the projectile points. In the final step, the contours were transformed with elliptic Fourier analysis into Fourier coefficient series, and patterns of variation and symmetry were explored with principal components analysis. When compared to modern Clovis point replicas made by an expert knapper, the flake scar contours of the ancient Clovis points showed little morphological variation and a large degree of bifacial symmetry. Our results support the existence of a widespread standardized Clovis knapping technique, most likely transmitted through direct interaction between knappers from different groups.
  •  
46.
  • Sholts, Sabrina B., et al. (författare)
  • Identification of Group Affinity from Cross-sectional Contours of the Human Midfacial Skeleton Using Digital Morphometrics and 3D Laser Scanning Technology
  • 2011
  • Ingår i: Journal of Forensic Sciences. - : Wiley. - 0022-1198 .- 1556-4029. ; 56:2, s. 333-338
  • Tidskriftsartikel (refereegranskat)abstract
    • Identifying group affinity from human crania is a long-standing problem in forensic and physical anthropology. Many craniofacial differences used in forensic skeletal identification are difficult to quantify, although certain measurements of the midfacial skeleton have shown high predictive value for group classifications. This study presents a new method for analyzing midfacial shape variation between different geographic groups. Three-dimensional laser scan models of 90 crania from three populations were used to obtain cross-sectional midfacial contours defined by three standard craniometric landmarks. Elliptic Fourier transforms of the contours were used to extract Fourier coefficients for statistical analysis. After cross-validation, discriminant functions based on the Fourier coefficients provided an average of 86% correct classifications for crania from the three groups. The high rate of accuracy of this method indicates its usefulness for identifying group affinities among human skeletal remains and demonstrates the advantages of digital 3D model-based analysis in forensic research.
  •  
47.
  • Sholts, Sabrina B., et al. (författare)
  • Tracing social interactions in Pleistocene North America via 3D model analysis of stone tool asymmetry
  • 2017
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:7
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 harmonics (SPHARM). Whereas bifacial asymmetry in point shape does not vary significantly across this stylistic sequence, our measure of asymmetric flake scar patterning shows temporal variation that may signify the beginning of regionalization among early New World colonists.
  •  
48.
  • Sholts, Sabrina B., et al. (författare)
  • Variation in the Measurement of Cranial Volume and Surface Area Using 3D Laser Scanning Technology
  • 2010
  • Ingår i: Journal of Forensic Sciences. - : Wiley. - 0022-1198 .- 1556-4029. ; 55:4, s. 871-876
  • Tidskriftsartikel (refereegranskat)abstract
    • Three-dimensional (3D) laser scanner models of human crania can be used for forensic facial reconstruction, and for obtaining craniometric data useful for estimating age, sex, and population affinity of unidentified human remains. However, the use of computer-generated measurements in a casework setting requires the measurement precision to be known. Here, we assess the repeatability and precision of cranial volume and surface area measurements using 3D laser scanner models created by different operators using different protocols for collecting and processing data. We report intraobserver measurement errors of 0.2% and interobserver errors of 2% of the total area and volume values, suggesting that observer-related errors do not pose major obstacles for sharing, combining, or comparing such measurements. Nevertheless, as no standardized procedure exists for area or volume measurements from 3D models, it is imperative to report the scanning and postscanning protocols employed when such measurements are conducted in a forensic setting.
  •  
49.
  • Smith, Kevin N., et al. (författare)
  • Residue analysis links sandstone abraders to on San Nicolas Island, California shell fishhook production
  • 2015
  • Ingår i: Journal of Archaeological Science. - : Elsevier BV. - 0305-4403 .- 1095-9238. ; 54, s. 287-293
  • Tidskriftsartikel (refereegranskat)abstract
    • Excavations at the upper component of the Tule Creek site (CA-SNI-25), dating between approximately 600-350 cal BP, yielded numerous well-preserved sandstone abraders referred to as saws. Many of these tools show heavy use-wear and abundant white residue still adhering to the surface. We used X-ray diffraction (XRD) analysis to characterize the residue from two of the abraders, which identified the mineral phases calcite and aragonite (both CaCO3), albite (NaAlSi3O8), and quartz (SiO2). A scanning electron microscope (SEM) equipped for Energy Dispersive X-Ray (EDS) analysis identified the elements C, Ca, S, Na, and Al in the samples, confirming the XRD results. Albite, quartz, and calcite in the scrapings are consistent with the mineralogy of sandstone, though the presence of calcium carbonate in the form of calcite and aragonite suggests marine shell is also present in the residue samples. XRD and SEM analysis of a modern red abalone (Haliotis rufescens) shell indicates that the inner-layer (nacre) consists mostly of aragonite phase calcium carbonate, whereas the outer layer (epidermis) is made up mostly of calcite phase. SEM images revealed that calcite and aragonite from the archaeological residues display similar morphologies as the material from a modern abalone sample, and a greater presence of aragonite over calcite suggests the abraders were primarily used to work the inner layer of the abalone shell. These results provide a functional linkage between sandstone saws and shell fishhook production at CA-SNI-25.
  •  
50.
  • Smith, Kevin N., et al. (författare)
  • Residue analysis, use-wear patterns, and replicative studies indicate that sandstone tools were used as reamers when producing shell fishhooks on San Nicolas Island, California
  • 2018
  • Ingår i: Journal of Archaeological Science. - : Elsevier BV. - 2352-409X .- 2352-4103. ; 20, s. 502-505
  • Tidskriftsartikel (refereegranskat)abstract
    • Elucidating the tools and production steps involved in manufacturing the characteristic circular shell fishhooks found on the California Channel Islands has been a long-standing problem in California archaeology. A prehistoric production site for shell fishhooks excavated on the most remote island, San Nicolas Island, has provided a rare opportunity to examine manufacturing sequences. We have previously employed a multidisciplinary research approach to demonstrate that fishhook production at this site involved using sandstone slabs as abraders, or saws. Here, we use chemical residue analysis, replicative experiments, and microwear patterns to show that fishhook production also involved the use of small pointed pieces of sandstone as reamers. These results bring us one step closer to understanding the complete prehistoric toolkit used for production of circular shell fishhooks.
  •  
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