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  • 1.
    Abelein, Axel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, Juri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. National Institute of Chemical Physics and Biophysics, Estonia.
    Luo, Jinghui
    Tiiman, Ann
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    The hairpin conformation of the amyloid beta peptide is an important structural motif along the aggregation pathway2014In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 19, no 4-5, p. 623-634Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 2. Bartelink, Eric J.
    et al.
    Sholts, Sabrina B.
    Milligan, Colleen F.
    Van Deest, Traci L.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Linköping University, Sweden.
    A Case of Contested Cremains Analyzed Through Metric and Chemical Comparison2015In: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 60, no 4, p. 1068-1073Article in journal (Refereed)
    Abstract [en]

    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.

  • 3. Bulut, Ozgur
    et al.
    Petaros, Anja
    Hizliol, Ismail
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Linköping University, Sweden; University of California in Los Angeles, USA.
    Hekimoglu, Baki
    Sexual dimorphism in frontal bone roundness quantified by a novel 3D-based and landmark-free method2016In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 261, p. 162.e1-162.e5Article in journal (Refereed)
    Abstract [en]

    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.

  • 4. Carvalho, Alexandra T. P.
    et al.
    Gouveia, Leonor
    Kanna, Charan Raju
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Platts, Jamie A.
    Kamerlin, Shina Caroline Lynn
    Understanding the structural and dynamic consequences of DNA epigenetic modifications: Computational insights into cytosine methylation and hydroxymethylation2014In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 9, no 12, p. 1604-1612Article in journal (Refereed)
    Abstract [en]

    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.

  • 5. Chemerovski-Glikman, Marina
    et al.
    Rozentur-Shkop, Eva
    Richman, Michal
    Grupi, Asaf
    Getler, Asaf
    Cohen, Haim Y.
    Shaked, Hadassa
    Wallin, Cecilia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Haas, Elisha
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Chill, Jordan H.
    Rahimipour, Shai
    Self-Assembled Cyclic D,L-alpha-Peptides as Generic Conformational Inhibitors of the alpha-Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies2016In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 40, p. 14236-14246Article in journal (Refereed)
    Abstract [en]

    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.

  • 6. Frković, Vedran
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Linköping University, Sweden.
    Petaros, Anja
    Španjol-Pandelo, Iva
    Ažman, Josip
    Finger width as a measure of femoral block puncture site: an ultrasonographic anatomical-anthropometric study2015In: Journal of clinical anesthesia, ISSN 0952-8180, E-ISSN 1873-4529, Vol. 27, no 7, p. 553-557Article in journal (Refereed)
    Abstract [en]

    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.

  • 7.
    Ghalebani, Leila
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wahlström, Anna
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    pH-dependence of the specific binding of Cu(II) and Zn(II) ions to the amyloid-beta peptide2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 421, no 3, p. 554-560Article in journal (Refereed)
    Abstract [en]

    Metal ions like Cu(II) and Zn(II) are accumulated in Alzheimer's disease amyloid plaques. The amyloid-beta (A beta) peptide involved in the disease interacts with these metal ions at neutral pH via ligands provided by the N-terminal histidines and the N-terminus. The present study uses high-resolution NMR spectroscopy to monitor the residue-specific interactions of Cu(II) and Zn(II) with N-15- and C-13,N-15-labeled A beta(1-40) peptides at varying pH levels. At pH 7.4 both ions bind to the specific ligands, competing with one another. At pH 5.5 Cu(II) retains its specific histidine ligands, while Zn(II) seems to lack residue-specific interactions. The low pH mimics acidosis which is linked to inflammatory processes in vivo. The results suggest that the cell toxic effects of redox active Cu(II) binding to AD may be reversed by the protective activity of non-redox active Zn(II) binding to the same major binding site under non-acidic conditions. Under acidic conditions, the protective effect of Zn(II) may be decreased or changed, since Zn(II) is less able to compete with Cu(II) for the specific binding site on the AD peptide under these conditions.

  • 8. Gingerich, Joseph A. M.
    et al.
    Sholts, Sabrina B.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Stanford, Dennis
    Fluted point manufacture in eastern North America: an assessment of form and technology using traditional metrics and 3D digital morphometrics2014In: World archaeology, ISSN 0043-8243, E-ISSN 1470-1375, Vol. 46, no 1, p. 101-122Article in journal (Refereed)
    Abstract [en]

    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.

  • 9. Horvath, Istvan
    et al.
    Iashchishyn, Igor A.
    Moskalenko, Roman A.
    Wang, Chao
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wallin, Cecilia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kovacs, Gabor G.
    Morozova-Roche, Ludmilla A.
    Co-aggregation of pro-inflammatory S100A9 with alpha-synuclein in Parkinson's disease: ex vivo and in vitro studies2018In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 172Article in journal (Refereed)
    Abstract [en]

    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.

  • 10. Lindgren, Joel
    et al.
    Segerfeldt, Patrik
    Sholts, Sabrina B.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Karlström, Amelie Eriksson
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    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 affinity2013In: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 120, p. 18-23Article in journal (Refereed)
    Abstract [en]

    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.

  • 11. Luo, Jinghui
    et al.
    Mohammed, Inayathulla
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hiruma, Yoshitaka
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    Endogenous Polyamines Reduce the Toxicity of Soluble A beta Peptide Aggregates Associated with Alzheimer's Disease2014In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, no 6, p. 1985-1991Article in journal (Refereed)
    Abstract [en]

    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.

  • 12. Luo, Jinghui
    et al.
    Otero, José M
    Yu, Chien-Hung
    Wärmländer, Sebastian K T S
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Overhand, Mark
    Abrahams, Jan Pieter
    Inhibiting and Reversing Amyloid-β Peptide (1-40) Fibril Formation with Gramicidin S and Engineered Analogues2013In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 51, p. 17338-17348Article in journal (Refereed)
    Abstract [en]

    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.

  • 13. Luo, Jinghui
    et al.
    Wärmlander, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    Alzheimer Peptides Aggregate into Transient Nanoglobules That Nucleate Fibrils2014In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 53, no 40, p. 6302-6308Article in journal (Refereed)
    Abstract [en]

    Protein/peptide oligomerization, cross-beta strand fibrillation, and amyloid deposition play a critical role in many diseases, but despite extensive biophysical characterization, the structural and dynamic details of oligomerization and fibrillation of amyloidic peptides/proteins remain to be fully clarified. Here, we simultaneously monitored the atomic, molecular, and mesoscopic states of aggregating Alzheimer's amyloid beta (A beta) peptides over time, using a slow aggregation protocol and a fast aggregation protocol, and determined the cytotoxicity of the intermediate states. We show that in the early stage of fast fibrillation (the lag phase) the A beta peptides coalesced into apparently unstructured globules (15-200 nm in diameter), which slowly grew larger. Then a sharp transition occurred, characterized by the first appearance of single fibrillar structures of approximately >= 100 nm. These fibrils emerged from the globules. Simultaneously, an increase was observed for the cross-beta strand conformation that is characteristic of the fibrils that constitute mature amyloid. The number and size of single fibrils rapidly increased. Eventually, the fibrils coalesced into mature amyloid. Samples from the early lag phase of slow fibrillation conditions were especially toxic to cells, and this toxicity sharply decreased when fibrils formed and matured into amyloid. Our results suggest that the formation of fibrils may protect cells by reducing the toxic structures that appear in the early lag phase of fibrillation.

  • 14. Luo, Jinghui
    et al.
    Wärmlander, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Yu, Chien-Hung
    Muhammad, Kamran
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    The A beta peptide forms non-amyloid fibrils in the presence of carbon nanotubes2014In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 6, no 12, p. 6720-6726Article in journal (Refereed)
    Abstract [en]

    Carbon nanotubes have specific properties that make them potentially useful in biomedicine and biotechnology. However, carbon nanotubes may themselves be toxic, making it imperative to understand how carbon nanotubes interact with biomolecules such as proteins. Here, we used NMR, CD, and ThT/fluorescence spectroscopy together with AFM imaging to study pH-dependent molecular interactions between single walled carbon nanotubes (SWNTs) and the amyloid-beta (A beta) peptide. The aggregation of the A beta peptide, first into oligomers and later into amyloid fibrils, is considered to be the toxic mechanism behind Alzheimer's disease. We found that SWNTs direct the A beta peptides to form a new class of beta-sheet-rich yet non-amyloid fibrils.

  • 15. Luo, Jinghui
    et al.
    Wärmländer, Sebastian
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    Human lysozyme inhibits the in vitro aggregation of A beta peptides, which in vivo are associated with Alzheimer's disease2013In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 49, no 58, p. 6507-6509Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease is a neurodegenerative disorder characterized by accumulation of A beta peptide aggregates in the brain. Using ThT fluorescence assays, AFM imaging, NMR and CD spectroscopy, and MD modeling we show that lysozyme - a hydrolytic enzyme abundant in human secretions - completely inhibits the aggregation of A beta peptides at equimolar lysozyme : A beta peptide ratios.

  • 16. Luo, Jinghui
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    Cross-interactions between the Alzheimer Disease Amyloid-beta Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis2016In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 32, p. 16485-16493Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 17. Luo, Jinghui
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    Non-chaperone Proteins Can Inhibit Aggregation and Cytotoxicity of Alzheimer Amyloid beta Peptide2014In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, no 40, p. 27766-27775Article in journal (Refereed)
    Abstract [en]

    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.

  • 18. Luo, Jinghui
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    Reciprocal Molecular Interactions between the A beta Peptide Linked to Alzheimer's Disease and Insulin Linked to Diabetes Mellitus Type II2016In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 7, no 3, p. 269-274Article in journal (Refereed)
    Abstract [en]

    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.

  • 19. Luo, Jinghui
    et al.
    Yu, Chien-Hung
    Yu, Huixin
    Borstnar, Rok
    Kamerlin, Shina C. L.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cellular Polyamines Promote Amyloid-Beta (A beta) Peptide Fibrillation and Modulate the Aggregation Pathways2013In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 4, no 3, p. 454-462Article in journal (Refereed)
    Abstract [en]

    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.

  • 20. Neiss, Michael
    et al.
    Sholts, Sabrina B.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of California, USA.
    New applications of 3D modeling in artefact analysis: three case studies of Viking Age brooches2016In: Archaeological and Anthropological Sciences, ISSN 1866-9557, E-ISSN 1866-9565, Vol. 8, no 4, p. 651-662Article in journal (Refereed)
    Abstract [en]

    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.

  • 21. Petaros, Anja
    et al.
    Garvi, Heather M.
    Sholts, Sabrina B.
    Schlager, Stefan
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. UCLA, USA; Linköping University, Sweden.
    Sexual dimorphism and regional variation in human frontal bone inclination measured via digital 3D models2017In: Legal Medicine, ISSN 1344-6223, E-ISSN 1873-4162, Vol. 29, p. 53-61Article in journal (Refereed)
    Abstract [en]

    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.

  • 22. Petaros, Anja
    et al.
    Sholts, Sabrina B.
    Slaus, Mario
    Bosnar, Alan
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Linköping University, Sweden; University of California in Los Angeles, USA.
    Evaluating sexual dimorphism in the human mastoid process: A viewpoint on the methodology2015In: Clinical anatomy (New York, N.Y. Print), ISSN 0897-3806, E-ISSN 1098-2353, Vol. 28, no 5, p. 593-601Article in journal (Refereed)
    Abstract [en]

    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.

  • 23. Richman, Michal
    et al.
    Wilk, Sarah
    Chemerovski, Marina
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wahlström, Anna
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Rahimipour, Shai
    In Vitro and Mechanistic Studies of an Antiamyloidogenic Self-Assembled Cyclic D,L-alpha-Peptide Architecture2013In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 135, no 9, p. 3474-3484Article in journal (Refereed)
    Abstract [en]

    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.

  • 24. Shearer, Brian M.
    et al.
    Sholts, Sabrina B.
    Garvin, Heather M.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sexual dimorphism in human browridge volume measured from 3D models of dry crania: A new digital morphometrics approach2012In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 222, no 1-3, p. 400.e1-Article in journal (Refereed)
    Abstract [en]

    Sex estimation from the human skull is often a necessary step when constructing a biological profile from unidentified human remains. Traditional methods for determining the sex of a skull require observers to rank the expression of sexually dimorphic skeletal traits by subjectively assessing their qualitative differences. One of these traits is the prominence of the glabellar region above the browridge. In this paper, the volume of the browridge region was measured from digital 3D models of 128 dry crania ( 65 female, 63 male). The 3D models were created with a desktop laser scanner, and the browridge region of each 3D model was isolated using geometric planes defined by cranial landmarks. Statistical analysis of browridge-to-cranium volume ratios revealed significant differences between male and female crania. Differences were also observed between geographically distinct populations, and between temporally distinct populations from the same locale. The results suggest that in the future, sex determination of human crania may be assisted by quantitative computer-based volume calculations from 3D models, which can provide increased objectivity and repeatability when compared to traditional forensic techniques. The method presented in this paper can easily be extended to other volumetric regions of the human cranium.

  • 25. Sholts, Sabrina B.
    et al.
    Gingerich, Joseph A. M.
    Schlager, Stefan
    Stanford, Dennis J.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of California Los Angeles, California.
    Tracing social interactions in Pleistocene North America via 3D model analysis of stone tool asymmetry2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 7, article id e0179933Article in journal (Refereed)
    Abstract [en]

    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.

  • 26. Sholts, Sabrina B.
    et al.
    Smith, Kevin
    Wallin, Cecilia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ahmed, Trifa M.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Wärmlander, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. UCLA, USA.
    Ancient water bottle use and polycyclic aromatic hydrocarbon (PAH) exposure among California Indians: a prehistoric health risk assessment2017In: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 16, article id 61Article in journal (Refereed)
    Abstract [en]

    Background: 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. Methods: 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 water and olive oil stored in a completed bottle for varying periods of time. Samples were analyzed with gas chromatography/mass spectrometry (GC/MS) for concentrations of the 16 PAHs identified by the US Environmental Protection Agency (EPA) as priority pollutants. Results: Eight PAHs were detected in concentrations of 1-10 mu g/m(3) in air during bottle production and 50-900 ng/L in water after 2 months of storage, ranging from two-ring (naphthalene and methylnaphthalene) to four-ring (fluoranthene) molecules. All 16 PAHs analyzed were detected in olive oil after 2 days (2 to 35 mu g/kg), 2 weeks (3 to 66 mu g/kg), and 2 months (5 to 140 mu g/kg) of storage. Conclusions: For ancient California Indians, water stored in bitumen-coated water bottles was not a significant source of PAH exposure, but production of such bottles could have resulted in harmful airborne PAH exposure.

  • 27. Sholts, Sabrina B.
    et al.
    Stanford, Dennis J.
    Flores, Louise M.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Flake scar patterns of Clovis points analyzed with a new digital morphometrics approach: evidence for direct transmission of technological knowledge across early North America2012In: Journal of Archaeological Science, ISSN 0305-4403, E-ISSN 1095-9238, Vol. 39, no 9, p. 3018-3026Article in journal (Refereed)
    Abstract [en]

    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.

  • 28. Sholts, Sabrina B.
    et al.
    Wärmländer, Sebastian
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    zygomaticomaxillary suture shape analyzed with digital morphometrics: reassessing patterns of variation in american indian and european populations2012In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 217, no 1-3Article in journal (Refereed)
    Abstract [en]

    Typological classification of human zygomaticomaxillary suture (ZMS) shape is often used in forensic assessment of ancestry, following earlier studies reporting higher frequencies of angled sutures among American Indians and higher frequencies of curved sutures among Caucasians. In this paper we present a new method of digital morphometrics to quantify and compare ZMS shape in 60 American Indian and 60 European crania. Suture outlines were recorded as three-dimensional (3D) contours on digital models of adult male and female crania created with a portable 3D laser scanner. Each contour was represented by about four hundred point coordinates, which were transformed via Fourier analysis into amplitude coefficients suitable for use in linear discriminant analysis. Discriminant functions were created that accurately predicted group membership for 83% of the crania in the sample, after leave-one-out cross-validation. The results were compared with traditional typological classifications based on visual evaluation of ZMS shape, and the contour-based method was found to be more effective than the typological approach. However, the distribution of ZMS types within the two sample groups did not conform to previously reported patterns. This discrepancy indicates that ZMS shape may reflect not only genetic factors, but also environmental factors such as diet and stress. In addition, some evidence for sexual dimorphism in the zygomaticomaxillary complex was observed. Based on these findings, we recommend caution when using ZMS shape analysis in forensic ancestry determination.

  • 29. Smith, Kevin N.
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Vellanoweth, Rene L.
    Smith, Chelsea M.
    Kendig, William E.
    Residue analysis links sandstone abraders to on San Nicolas Island, California shell fishhook production2015In: Journal of Archaeological Science, ISSN 0305-4403, E-ISSN 1095-9238, Vol. 54, p. 287-293Article in journal (Refereed)
    Abstract [en]

    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.

  • 30. Taqi, Malik Mumtaz
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Yamskova, Olga
    Madani, Fatemeh
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bazov, Igor
    Luo, Jinghui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Zubarev, Roman
    Verbeek, Dineke
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bakalkin, Georgy
    Conformation Effects of CpG Methylation on Single-Stranded DNA Oligonucleotides: Analysis of the Opioid Peptide Dynorphin-Coding Sequences2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e39605-Article in journal (Refereed)
    Abstract [en]

    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 4 degrees C, and some also at 37 degrees C. 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 gel mobility and base pairing were comparable in strength to the effects induced by point mutations in the DNA sequences. The conformational effects of methylation may be relevant for epigenetic regulatory events in a chromatin context, including DNA-protein or DNA-DNA recognition in the course of gene transcription, and DNA replication and recombination when double-stranded DNA is unwinded to ssDNA.

  • 31.
    Teixeira, Pedro F.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Masuyer, Geoffrey
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Pinho, Catarina M.
    Branca, Rui M. M.
    Kmiec, Beata
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wallin, Cecilia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Berntsson, Ronnie P. -A.
    Ankarcrona, Maria
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lehtiö, Janne
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin2018In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 3, p. 348-362Article in journal (Refereed)
    Abstract [en]

    Proteolysis plays an important role in mitochondria! biogenesis, from the processing of newly imported precursor proteins to the degradation of mitochondrial targeting peptides. Disruption of peptide degradation activity in yeast, plant and mammalian mitochondria is known to have deleterious consequences for organism physiology, highlighting the important role of mitochondrial peptidases. In the present work, we show that the human mitochondrial peptidase neurolysin (hNLN) can degrade mitochondrial presequence peptides as well as other fragments up to 19 amino acids long. The crystal structure of hNLN(E475Q) in complex with the products of neurotensin cleavage at 2.7 angstrom revealed a closed conformation with an internal cavity that restricts substrate length and highlighted the mechanism of enzyme opening/closing that is necessary for substrate binding and catalytic activity. Analysis of peptide degradation in vitro showed that hNLN cooperates with presequence protease (PreP or PITRM1) in the degradation of long targeting peptides and amyloid-beta peptide, A beta 1-40, associated with Alzheimer disease, particularly cleaving the hydrophobic fragment A beta 35-40. These findings suggest that a network of proteases may be required for complete degradation of peptides localized in mitochondria.

  • 32.
    Tiiman, Ann
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luo, Jinghui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Oxford, UK.
    Wallin, Cecilia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Olsson, Lisa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindgren, Joel
    Jarvet, Jϋri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Roose, Per
    Sholts, Sabrina B.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. National Museum of Natural History, USA.
    Rahimipour, Shai
    Abrahams, Jan Pieter
    Eriksson Karlström, Amelie
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Specific Binding of Cu(II) Ions to Amyloid-Beta Peptides Bound to Aggregation-Inhibiting Molecules or SDS Micelles Creates Complexes that Generate Radical Oxygen Species2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 54, no 3, p. 971-982Article in journal (Refereed)
    Abstract [en]

    Aggregation of the amyloid-beta (A beta) peptide into insoluble plaques is a major factor in Alzheimer's disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate A beta aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo, A beta is found in various cellular locations including membranes. So far, Cu(II)/A beta interactions and ROS generation have not been investigated in a membrane environment. Here, we study Cu(II) and Zn(II) interactions with A beta bound to SDS micelles or to engineered aggregation-inhibiting molecules (the cyclic peptide CP-2 and the Z(A beta 3)(12-58) Y18L Affibody molecule). In all studied systems the A beta N-terminal segment was found to be unbound, unstructured, and free to bind metal ions. In SDS micelles, A beta was found to bind Cu(II) and Zn(II) with the same ligands and the same K-D as in aqueous solution. ROS was generated in all Cu(II)/A beta complexes. These results indicate that binding of A beta to membranes, drugs, and other entities that do not interact with the A beta N-terminal part, appears not to compromise the N-terminal segment's ability to bind metal ions, nor impede the capacity of N-terminally bound Cu(II) to generate ROS.

  • 33.
    Wallin, Cecilia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kulkarni, Yashraj S.
    Abelein, Axel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Karolinska Institutet, Sweden.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Liao, Qinghua
    Strodel, Birgit
    Olsson, Lisa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luo, Jinghui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Oxford, UK.
    Abrahams, Jan Pieter
    Sholts, Sabrina B.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. National Museum of Natural History, USA.
    Roos, Per M.
    Kamerlin, Shina C. L.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Characterization of Mn(II) ion binding to the amyloid-beta peptide in Alzheimer's disease2016In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 38, p. 183-193Article in journal (Refereed)
    Abstract [en]

    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.

  • 34.
    Wallin, Cecilia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luo, Jinghui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Oxford, UK.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The Amyloid-beta Peptide in Amyloid Formation Processes: Interactions with Blood Proteins and Naturally Occurring Metal Ions2017In: Israel Journal of Chemistry, ISSN 0021-2148, Vol. 57, no 7-8, p. 674-685Article, review/survey (Refereed)
    Abstract [en]

    This review describes interactions between the amyloid- peptide (A) involved in Alzheimer's disease (AD) and endogenous metal ions and proteins, with an emphasis on future potential drug therapies and targets. AD is characterised by loss of neurons, memory, and cognitive functions, and by formation of cerebral senile plaque deposits. These plaques consist mainly of aggregated A peptides. AD pathology includes a) on the molecular level imbalanced concentrations of A peptides and metal ions, and formation of amyloid structures, and b) on the physiological level a combination of inflammatory responses and oxidative stress effects causing neuronal death. Interestingly, certain blood proteins and metal ions can affect the A amyloid aggregation process. These interactions are the topics of the present review. A deeper understanding of these interactions could facilitate new therapeutic strategies against AD. Previous therapeutic approaches and trials are also briefly described.

  • 35.
    Wallin, Cecilia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sholts, Sabrina B.
    Österlund, Nicklas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Luo, Jinghui
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Roos, Per M.
    Ilag, Leopold
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Alzheimer's disease and cigarette smoke components: effects of nicotine, PAHs, and Cd(II), Cr(III), Pb(II), Pb(IV) ions on amyloid-beta peptide aggregation2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 14423Article in journal (Refereed)
    Abstract [en]

    Cigarette smoking is a significant risk factor for Alzheimer’s disease (AD), which is associated with extracellular brain deposits of amyloid plaques containing aggregated amyloid-β (Aβ) peptides. Aβ aggregation occurs via multiple pathways that can be influenced by various compounds. Here, we used AFM imaging and NMR, fluorescence, and mass spectrometry to monitor in vitro how Aβ aggregation is affected by the cigarette-related compounds nicotine, polycyclic aromatic hydrocarbons (PAHs) with one to five aromatic rings, and the metal ions Cd(II), Cr(III), Pb(II), and Pb(IV). All PAHs and metal ions modulated the Aβ aggregation process. Cd(II), Cr(III), and Pb(II) ions displayed general electrostatic interactions with Aβ, whereas Pb(IV) ions showed specific transient binding coordination to the N-terminal Aβ segment. Thus, Pb(IV) ions are especially prone to interact with Aβ and affect its aggregation. While Pb(IV) ions affected mainly Aβ dimer and trimer formation, hydrophobic toluene mainly affected formation of larger aggregates such as tetramers. The uncharged and hydrophilic nicotine molecule showed no direct interactions with Aβ, nor did it affect Aβ aggregation. Our Aβ interaction results suggest a molecular rationale for the higher AD prevalence among smokers, and indicate that certain forms of lead in particular may constitute an environmental risk factor for AD.

  • 36. Wang, Chao
    et al.
    Klechikov, Alexey G.
    Gharibyan, Anna L.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. National Institute of Chemical Physics & Biophysics (NICPB), Estonia.
    Zhao, Lina
    Jia, Xueen
    Shankar, S. K.
    Olofsson, Anders
    Brännström, Thomas
    Mu, Yuguang
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Morozova-Roche, Ludmilla A.
    The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade2014In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 127, no 4, p. 507-522Article in journal (Refereed)
    Abstract [en]

    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.

  • 37.
    Wärmländer, Sebastian K. T. S.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of California, Los Angeles, USA.
    Wåhlander, Linda
    Saage, Ragnar
    Rezakhani, Khodadad
    Hassan, Saied A. Hamid
    Neiss, Michael
    Analysis and Interpretation of a Unique Arabic Finger Ring from the Viking Age Town of Birka, Sweden2015In: Scanning, ISSN 0161-0457, E-ISSN 1932-8745, Vol. 37, no 2, p. 131-137Article in journal (Refereed)
    Abstract [en]

    In this work we used non-destructive SEM imaging and EDS analysis to characterize the material composition of an Arabic finger ring, which was found in a 9(th) c. woman's grave at the Viking Age (A.D. 793-1066) trading center of Birka, Sweden. The ring is set with a violet stone inscribed with Arabic Kufic writing, here interpreted as reading il-la-lah, i.e. For/to Allah. The stone was previously thought to be an amethyst, but the current results show it to be coloured glass. The ring has been cast in a high-grade silver alloy (94.5/5.5 Ag/Cu) and retains the post-casting marks from the filing done to remove flash and mold lines. Thus, the ring has rarely been worn, and likely passed from the silversmith to the woman buried at Birka with few owners in between. The ring may therefore constitute material evidence for direct interactions between Viking Age Scandinavia and the Islamic world. Being the only ring with an Arabic inscription found at a Scandinavian archaeological site, it is a unique object among Swedish Viking Age material. The technical analysis presented here provides a better understanding of the properties and background of this intriguing piece of jewelry.

  • 38.
    Wärmländer, Sebastian
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Tiiman, Ann
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Tallinn Technical University, Estonia.
    Abelein, Axel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luo, Jinghui
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Leiden University, Netherlands.
    Söderberg, Kajsa L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Biophysical Studies of the Amyloid beta-Peptide: Interactions with Metal Ions and Small Molecules2013In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 14, no 14, p. 1692-1704Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease is the most common of the protein misfolding (amyloid) diseases. The deposits in the brains of afflicted patients contain as a major fraction an aggregated insoluble form of the so-called amyloid beta-peptides (A beta peptides): fragments of the amyloid precursor protein of 39-43 residues in length. This review focuses on biophysical studies of the A beta peptides: that is, of the aggregation pathways and intermediates observed during aggregation, of the molecular structures observed along these pathways, and of the interactions of A beta with Cu and Zn ions and with small molecules that modify the aggregation pathways. Particular emphasis is placed on studies based on high-resolution and solid-state NMR methods. Theoretical studies relating to the interactions are also included. An emerging picture is that of A beta peptides in aqueous solution undergoing hydrophobic collapse together with identical partners. There then follows a relatively slow process leading to more ordered secondary and tertiary (quaternary) structures in the growing aggregates. These aggregates eventually assemble into elongated fibrils visible by electron microscopy. Small molecules or metal ions that interfere with the aggregation processes give rise to a variety of aggregation products that may be studied in vitro and considered in relation to observations in cell cultures or in vivo. Although the heterogeneous nature of the processes makes detailed structural studies difficult, knowledge and understanding of the underlying physical chemistry might provide a basis for future therapeutic strategies against the disease. A final part of the review deals with the interactions that may occur between the A beta peptides and the prion protein, where the latter is involved in other protein misfolding diseases.

  • 39. Zarina, Gunita
    et al.
    Sholts, Sabrina B.
    Tichinin, Alina
    Rudovica, Vita
    Viksna, Arturs
    Engizere, Austra
    Muiznieks, Vitolds
    Bartelink, Eric J.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. UCLA/Getty Conservation Programme, UCLA, United States.
    Cribra orbitalia as a potential indicator of childhood stress: Evidence from paleopathology, stable C, N, and O isotopes, and trace element concentrations in children from a 17th-18th century cemetery in Jekabpils, Latvia2016In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 38, p. 131-137Article in journal (Refereed)
    Abstract [en]

    Cribra orbitalia (CO), or porotic hyperostosis (PH) of the orbital roof, is one of the most common pathological conditions found in archaeological subadult skeletal remains. Reaching frequencies higher than 50% in many prehistoric samples, CO has been generally attributed to a variety of factors including malnutrition (e.g., megaloblastic anemia) and parasitism. In this study, we tested the relationship between CO, trace element concentrations, and stable isotope values (delta C-13, delta N-15, delta O-18) in subadult skeletons from a 17th to 18th century cemetery in the historic town of Jekabpils, Latvia. A total of 28 subadults were examined, seven of which (25%) showed evidence of CO. Bioarchaeological evidence indicated high mortality for children in this cemetery: half of the burials were subadults under the age of 14, while a third were under the age of four. Life expectancy at birth was estimated to have been only 21.6 years. Trace element concentrations measured by Inductively Coupled Plasma - Mass Spectrometry (ICP-MS) showed no relationship between presence or absence of CO and levels of manganese, zinc, strontium, barium, copper, cadmium, or lead in the bones (p>0.05). However, a significant correlation (p<0.05) was found between the presence of CO and decreased levels of iron. The correlations between CO and decreased levels of copper and lead approached significance (p=0.056 for both elements). Individuals with CO furthermore displayed significantly lower delta N-15 isotope values, suggesting greater consumption of lower trophic level food resources than those unaffected by CO; delta C-13 and delta O-18 values, in contrast, showed no significant differences. These results suggest that the prevalence of CO may be related to dietary deficiencies. In this case, low iron levels may also signify a diet low in other key vitamins (e.g., B-g and B-12), which are known to cause megaloblastic anemia.

1 - 39 of 39
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