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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.
    Björling, Sten-Erik
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    Integration of knowledge management systems and end-user interfaces for MPMM2011In: MPMM 2011: Maintenance Performance Measurement & Management: Conference Proceedings / [ed] Diego Galar; Aditya Parida; Håkan Schunnesson; Uday Kumar, Lulleå: Luleå tekniska universitet, 2011, p. 209-212Conference paper (Refereed)
    Abstract [en]

    Maintenance can be considered as a combined information and knowledge processing and management system. Effective knowledge, practices and experiences management is growing in importance, especially in advanced processes and management of advanced and expensive assets. Efforts of integrating maintenance knowledge management (MKM) processes with MKMM will be increasingly more important due to the increasing complexities of these overall systems – the context in which the performance measurements has been performed is also important input in the performance analysis. Integration of MKM in MPMM can result in higher quality of the decisions and actions in the maintenance processes and in the overall work to increase efficiency and decreasing costs in the organizations.Integration of MKM (Maintenance Knowledge Management – knowledge, experiences and practices management) with collaborative structures and interfacing abilities with qualified services for simulation, modeling and computations can be regarded as Intelligence-based Maintenance (iMaintenance).These infrastructures present in iMaintenance can further improve MPMM efforts due to possible utilization of more accurate property and context information and services – changes in installations, environmental factors etc. not easily integrated in current MPMM implementations.Integration of MPMM with iMaintenance solutions can also improve the interaction between management and the maintenance operators and also allow improved interaction and integration with production operators in the organization. MPMM can with this approach be integrated as a natural component in the overall ICT-based maintenance and collaboration solutions – the performance status reporting will be seen as a natural extension to the normal routines. In this context the usability of the end-user environments will be very important – especially when designing systems for mobile use by maintenance operators in the field.

  • 4.
    Björling, Sten-Erik
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    Modular tool concepts for sustainable product development environments2009In: Proceedings of the 2nd International Conference on Advanced Design and Manufacture / [ed] Daizhong Su; Quingbin Zhiang; Shifan Zhu, Trans Tech Publications Inc., 2009, p. 55-59Conference paper (Refereed)
    Abstract [en]

    An existing demonstrator for E-maintenance solutions for advanced aviation maintenance staff was extended to incorporate abilities as a collaborative environment for developers of sustain­able products. Most of the existing core concepts and functions in the demonstrator were found to be viable: work context management, modularisation, information and web services access. This paper pres­en­ts more in detail the modularization concept used in the demonstrator and its potential use in collaborative environments for sustainable prod­ucts developers. This concept if implemented allow faster integration of external web services and information sources into the sustainable product design work­flows and processes.

  • 5.
    Björling, Sten-Erik
    et al.
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    Baglee, David
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    Galar, Diego
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    Singh, Sarbjeet
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    Kumar, Uday
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    Maintenance knowledge management with fusion of CMMS and CM2013In: DMIN 2013 International Conference on Data Mining: 22nd -25th July 2013, Las Vegas, Nevada, USA, 2013Conference paper (Refereed)
    Abstract [en]

    Maintenance can be considered as an information, knowledge processing and management system. The management of knowledge resources in maintenance is a relatively new issue compared to Computerized Maintenance Management Systems (CMMS) and Condition Monitoring (CM) approaches and systems. Information Communication technologies (ICT) systems including CMMS, CM and enterprise administrative systems amongst others are effective in supplying data and in some cases information. In order to be effective the availability of high-quality knowledge, skills and expertise are needed for effective analysis and decision-making based on the supplied information and data. Information and data are not by themselves enough, knowledge, experience and skills are the key factors when maximizing the usability of the collected data and information. Thus, effective knowledge management (KM) is growing in importance, especially in advanced processes and management of advanced and expensive assets. Therefore efforts to successfully integrate maintenance knowledge management processes with accurate information from CMMSs and CM systems will be vital due to the increasing complexities of the overall systems.Low maintenance effectiveness costs money and resources since normal and stable production cannot be upheld and maintained over time, lowered maintenance effectiveness can have a substantial impact on the organizations ability to obtain stable flows of income and control costs in the overall process. Ineffective maintenance is often dependent on faulty decisions, mistakes due to lack of experience and lack of functional systems for effective information exchange [10]. Thus, access to knowledge, experience and skills resources in combination with functional collaboration structures can be regarded as vital components for a high maintenance effectiveness solution.Maintenance effectiveness depends in part on the quality, timeliness, accuracy and completeness of information related to machine degradation state, based on which decisions are made. Maintenance effectiveness, to a large extent, also depends on the quality of the knowledge of the managers and maintenance operators and the effectiveness of the internal & external collaborative environments. With emergence of intelligent sensors to measure and monitor the health state of the component and gradual implementation of ICT) in organizations, the conceptualization and implementation of E-Maintenance is turning into a reality. Unfortunately, even though knowledge management aspects are important in maintenance, the integration of KM aspects has still to find its place in E-Maintenance and in the overall information flows of larger-scale maintenance solutions. Nowadays, two main systems are implemented in most maintenance departments: Firstly, Computer Maintenance Management Systems (CMMS), the core of traditional maintenance record-keeping practices that often facilitate the usage of textual descriptions of faults and actions performed on an asset. Secondly, condition monitoring systems (CMS). Recently developed (CMS) are capable of directly monitoring asset components parameters; however, attempts to link observed CMMS events to CM sensor measurements have been limited in their approach and scalability. In this article we present one approach for addressing this challenge. We argue that understanding the requirements and constraints in conjunction - from maintenance, knowledge management and ICT perspectives - is necessary. We identify the issues that need be addressed for achieving successful integration of such disparate data types and processes (also integrating knowledge management into the “data types” and processes).

  • 6. Björling, Sten-Erik
    et al.
    Kumar, Uday
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    ICT concepts for managing future challenges in e-maintenance2009In: 22nd International Congress on Condition Monitoring and Diagnostic Engineering Management: COMADEM 2009 ; June 9 - 11, 2009, San Sebastian, Spain, Miramar Palace / [ed] Aitor Arnaiz, Eibar: Fundaci n Tekniker , 2009Conference paper (Refereed)
    Abstract [en]

    The maintenance & operations fields are & will increasingly be dominated by information fragmentation, product & process complexities, increasingly important needs to access relevant knowledge in an ever faster pace, increased need for accurate analysis & implementation of the analysis results & need for more effective & accurate management.In addition to this the created solutions & processes also has to be effectively used in different work contexts including mobile work contexts & supporting interoperability with external ICT systems & processes. ICT-based frameworks should according to the factors & challenges described above be structured to be flexible enough to over time integrate new types of information & services, be usable both internally in the industrial facilities & in the field (mobile) & effectively act as a bridge between older & future ICT-systems. An example of such an integration approach is the PROTEUS project aiming at developing an "integrating" platform for maintenance management. The frameworks described during this presentation also will include modularised integration of not only data in existing maintenance systems and knowledge resources but also integration with web services (SOA), access & management of external computational services (analysis). These different modules will be accessible more dynamically than earlier web-based solutions. This in an environment that support several parallel work contexts & use not only in fixed networks but also in mobile / nomadic settings allowing a high degree of flexibility for the maintenance & operations staff.

  • 7. 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.

  • 8. 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.

  • 9. 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.

  • 10. Dong, Xiaolin
    et al.
    Svantesson, Teodor
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sholts, Sabrina B.
    Wallin, Cecilia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    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.
    Copper ions induce dityrosine-linked dimers in human but not in murine islet amyloid polypeptide (IAPP/amylin)2019In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 510, no 4, p. 520-524Article in journal (Refereed)
    Abstract [en]

    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.

  • 11. 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.

  • 12.
    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.

  • 13. 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.

  • 14. 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.

  • 15. Leshem, Guy
    et al.
    Richman, Michal
    Lisniansky, Elvira
    Antman-Passig, Merav
    Habashi, Maram
    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.
    Rahimipour, Shai
    Photoactive chlorin e6 is a multifunctional modulator of amyloid-β aggregation and toxicity via specific interactions with its histidine residues2019In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 10, no 1, p. 208-217Article in journal (Refereed)
    Abstract [en]

    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.

  • 16. 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.

  • 17. 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.

  • 18. 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.

  • 19. 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.

  • 20. 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.

  • 21. 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.

  • 22. 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.

  • 23. 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.

  • 24. 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.

  • 25. 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.

  • 26. 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.

  • 27. Owen, Michael C.
    et al.
    Gnutt, David
    Gao, Mimi
    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.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Winter, Roland
    Ebbinghaus, Simon
    Strodel, Birgit
    Effects of in vivo conditions on amyloid aggregation2019In: Chemical Society Reviews, ISSN 0306-0012, E-ISSN 1460-4744, Vol. 48, no 14, p. 3946-3996Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 28. Pansieri, Jonathan
    et al.
    Ostojic, Lucija
    Iashchishyn, Igor A.
    Magzoub, Mazin
    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.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mai, Nguyen
    Smirnovas, Vytautas
    Svedruzic, Zeljko
    Morozova-Roche, Ludmilla A.
    Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs2019In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 14, no 7, p. 1410-1417Article in journal (Refereed)
    Abstract [en]

    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.

  • 29. 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.

  • 30. 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.

  • 31. 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.

  • 32. Saage, Ragnar
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Cotsen Institute of Archaeology, UCLA, USA.
    Metal residues in 5th c. BCE-13th c. CE Estonian tools for non-ferrous metal casting2018In: Journal of Archaeological Science: Reports, ISSN 2352-409X, E-ISSN 2001-1199, Vol. 19, p. 35-51Article in journal (Refereed)
    Abstract [en]

    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.

  • 33.
    Selghed, Bengt
    Kristianstad University, School of Education and Environment.
    Betygen i skolan: kunskapssyn, bedömningsprinciper och lärarpraxis2011 (ed. 2)Book (Other academic)
    Abstract [sv]

    Boken är en reviderad upplaga som uppdaterats enligt de nya läroplanerna för grundskolan och gymnasieskolan och den beskriver och analyserar den betygsskala och de kunskapskrav som började gälla hösten 2011. Ambitionen med revisionen från statens sida är att skapa förutsättningar för en rättvis och likvärdig bedömning och betygsättning i landet. Men vad kommer revisionen att innebära för lärare och elever? Kommer lärares bedömningar och betygsättning att bli rättvisa och likvärdiga genom revisionen av kursplaner och en ny, mer differentierad betygsskala? Detta är centrala frågor i boken.

    Boken är viktig för blivande och yrkesverksamma lärare, rektorer, föräldrar och andra med anknytning till och intresse för en väl fungerande och rättssäker svensk skola.

  • 34.
    Selghed, Bengt
    Kristianstad University, Department of Behavioural Sciences.
    Betygen i skolan: kunskapssyn, bedömningsprinciper och lärarpraxis2006Book (Other academic)
  • 35.
    Selghed, Bengt
    Kristianstad University, Department of Behavioural Sciences.
    Betygssystemet som fenomen ur ett lärarperspektiv2004In: Studies in Educational Policy and Educational Philosophy, ISSN 1652-2729, no 2, p. 1-18Article in journal (Other academic)
    Abstract [en]

    This article focus on how teachers’ experience the criterion-referenced grading system as a phenomenon and consists of one of three themes from a thesis titled Not yet passed: How teachers’ experience a criterion-referenced grading system and what they say about its use in Swedish secondary schools. The empirical study was carried out as semi-structured audiotaped interviews with thirty qualified teachers, in the subjects English, Maths and Swedish, who all had experiences of assessing and grading according to the new grading system. Teachers in just these subjects are the only ones that have national tests as a support for grading their students. This theme has a phenomenographic approach. The results are described in four hierarchically arranged categories. The results show that the new criterionreferenced grading system in secondary schools in Sweden seems to function unsatisfactorily. Teachers seem not to have grasped the assumptions underlying the grading system. The change from grading based on quantitative aspects of knowledge to qualitative ones, was evidently too big a step. Instead teachers’ assessments and gradings follow ingrained habits.

  • 36.
    Selghed, Bengt
    Kristianstad University, School of Education and Environment.
    Dagens betygssystem är inte mättekniskt uppbyggt2006In: Sydsvenskan, ISSN 1652-814X, no 3 juniArticle in journal (Refereed)
  • 37.
    Selghed, Bengt
    Kristianstad University, Department of Behavioural Sciences.
    Ett orimligt uppdrag?: några reflektioner kring betygssystemet2007In: Svenskläraren, ISSN 0346-2412, Vol. 50, no 1, p. 19-20Article in journal (Other (popular science, discussion, etc.))
    Abstract [sv]

    Få frågor inom svensk skolpolitik har blivit så grundligt utredda och diskuterade som betygen. En förklaring kan vara att betygsättning är en viktig men svår uppgift för lärare. Lärare är skyldiga att sätta betyg på sina elever från skolår 8. Betygen är dessutom betydelsefulla för elevens fortsatta studiemöjligheter och framtida studie- och yrkesval. Kring mitten av 1990-talet infördes dagens betygssystem, som fick beteckningen mål- och kunskapsrelaterat.

  • 38.
    Selghed, Bengt
    et al.
    Kristianstad University, School of Education and Environment.
    Nordström, Åke
    Kristianstad University, School of Education and Environment.
    Att bedöma lärande2011In: Skolan och läraruppdraget: att bli och vara lärare / [ed] Mona Holmqvist, Lund: Studentlitteratur , 2011, p. 83-98Chapter in book (Other academic)
  • 39. 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. University of California, USA; Linköping University, Sweden.
    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.e1-400.e5Article 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.

  • 40. 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.

  • 41. 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.

  • 42. 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.

  • 43. 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.

  • 44.
    Singh, Sarbjeet
    et al.
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    Galar, Diego
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    Baglee, David
    Department of Computing, Engineering and Technology, Institute for Automotive and Manufacturing Advanced Practise, University of Sunderland.
    Björling, Sten-Erik
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    Self-maintenance techniques: a smart approach towards self-maintenance system2014In: International Journal of Systems Assurance Engineering and Management, ISSN 0975-6809, E-ISSN 0976-4348, Vol. 5, no 1, p. 75-83Article in journal (Refereed)
    Abstract [en]

    The modern systems operating at varying conditions brought a new paradigm shift to in-machine renovation and repair. These systems often encounter an infinite collection of clumsy diagnostic tools and applications that decrease agility, increase time-to-repair, and increase management overheads. One approach is to remove the human and potential costly and time consuming human errors, from the diagnosis of faults and implementation of a maintenance strategy. In order to achieve this it is necessary to develop systems that support advanced intelligent maintenance systems or smart maintenance technologies. Self-maintenance machines can be a better option with the capabilities of condition monitoring, diagnosing, repair planning and executing in order to extend the life and performance of equipment. The objective of this paper is to discuss the concept of self-maintenance, need of self-maintenance, potential scenarios where self-maintenance can be successfully implemented and issues related to self-maintenance machines. It has been concluded that the aim is to have self-maintenance system in order to make a machine capable of reconfiguration, compensation, and self-maintenance.

  • 45. Smith, Kevin N.
    et al.
    Vellanoweth, Rene L.
    Sholts, Sabrina B.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. UCLA, USA.
    Residue analysis, use-wear patterns, and replicative studies indicate that sandstone tools were used as reamers when producing shell fishhooks on San Nicolas Island, California2018In: Journal of Archaeological Science: Reports, ISSN 2352-409X, E-ISSN 2001-1199, Vol. 20, p. 502-505Article in journal (Refereed)
    Abstract [en]

    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.

  • 46. 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.

  • 47. 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.

  • 48.
    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.

  • 49.
    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.

  • 50.
    Wallin, Cecilia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hiruma, Yoshitaka
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Huvent, Isabelle
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lippens, Guy
    Luo, Jinghui
    The Neuronal Tau Protein Blocks in Vitro Fibrillation of the Amyloid-beta (A beta) Peptide at the Oligomeric Stage2018In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 26, p. 8138-8146Article in journal (Refereed)
    Abstract [en]

    In Alzheimer's disease, amyloid-beta (A beta) plaques and tau neurofibrillary tangles are the two pathological hallmarks. The co-occurrence and combined reciprocal pathological effects of A beta and tau protein aggregation have been observed in animal models of the disease. However, the molecular mechanism of their interaction remain unknown. Using a variety of biophysical measurements, we here show that the native full-length tau protein solubilizes the A beta(40) peptide and prevents its fibrillation. The tau protein delays the amyloid fibrillation of the A beta(40) peptide at substoichiometric ratios, showing different binding affinities toward the different stages of the aggregated A beta(40) peptides. The A beta monomer structure remains random coil in the presence of tau, as observed by nuclear magnetic resonance (NMR), circular dichroism (CD) spectroscopy and photoinduced cross-linking methods. We propose a potential interaction mechanism for the influence of tau on A beta fibrillation.

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