Autocatalytic amplification of Alzheimer-associated Aβ42 peptide aggregation in human cerebrospinal fluid

Funder: Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation); doi: https://doi.org/10.13039/501100004063Funder: Alzheimerfonden; doi: https://doi.org/10.13039/501100008599Abstract: Alzheimer’s disease is linked to amyloid β (Aβ) peptide aggregation in the brain, and a detailed understanding of the molecular mechanism of Aβ aggregation may lead to improved diagnostics and therapeutics. While previous studies have been performed in pure buffer, we approach the mechanism in vivo using cerebrospinal fluid (CSF). We investigated the aggregation mechanism of Aβ42 in human CSF through kinetic experiments at several Aβ42 monomer concentrations (0.8–10 µM). The data were subjected to global kinetic analysis and found consistent with an aggregation mechanism involving secondary nucleation of monomers on the fibril surface. A mechanism only including primary nucleation was ruled out. We find that the aggregation process is composed of the same microscopic steps in CSF as in pure buffer, but the rate constant of secondary nucleation is decreased. Most importantly, the autocatalytic amplification of aggregate number through catalysis on the fibril surface is prevalent also in CSF

IgG and fibrinogen driven nanoparticle aggregation

A thorough understanding of how proteins induce nanoparticle (NP) aggregation is crucial when designing in vitro and in vivo assays and interpreting experimental results. This knowledge is also crucial when developing nano-applications and formulation for drug delivery systems. In this study, we found that extraction of immunoglobulin G (IgG) from cow serum results in lower polystyrene NPs aggregation. Moreover, addition of isolated IgG or fibrinogen to fetal cow serum enhanced this aggregation, thus demonstrating that these factors are major drivers of NP aggregation in serum. Counter-intuitively, NP aggregation was inversely dependent on protein concentration; i.e., low protein concentrations induced large aggregates, whereas high protein concentrations induced small aggregates. Protein-induced NP aggregation and aggregate size were monitored by absorbance at 400 nm and dynamic light scattering, respectively. Here, we propose a mechanism behind the protein concentration dependent aggregation; this mechanism involves the effects of multiple protein interactions on the NP surface, surface area limitations, aggregation kinetics, and the influence of other serum proteins.We thank Professor Sara Linse for scientific discussions and advice and Professor Patrik Brundin for enabling access to the light microscope. The project received financial support from Nanometer structure consortium at Lund University (nmC@LU), Lars Hierta Foundation, and the research school FLAK of Lund University

Emerging methods and tools for environmental risk assessment, decision-making, and policy for nanomaterials: summary of NATO Advanced Research Workshop

Nanomaterials and their associated technologies hold promising opportunities for the development of new materials and applications in a wide variety of disciplines, including medicine, environmental remediation, waste treatment, and energy conservation. However, current information regarding the environmental effects and health risks associated with nanomaterials is limited and sometimes contradictory. This article summarizes the conclusions of a 2008 NATO workshop designed to evaluate the wide-scale implications (e.g., benefits, risks, and costs) of the use of nanomaterials on human health and the environment. A unique feature of this workshop was its interdisciplinary nature and focus on the practical needs of policy decision makers. Workshop presentations and discussion panels were structured along four main themes: technology and benefits, human health risk, environmental risk, and policy implications. Four corresponding working groups (WGs) were formed to develop detailed summaries of the state-of-the-science in their respective areas and to discuss emerging gaps and research needs. The WGs identified gaps between the rapid advances in the types and applications of nanomaterials and the slower pace of human health and environmental risk science, along with strategies to reduce the uncertainties associated with calculating these risks

A Condensation-Ordering Mechanism in Nanoparticle-Catalyzed Peptide Aggregation

Nanoparticles introduced in living cells are capable of strongly promoting the aggregation of peptides and proteins. We use here molecular dynamics simulations to characterise in detail the process by which nanoparticle surfaces catalyse the self- assembly of peptides into fibrillar structures. The simulation of a system of hundreds of peptides over the millisecond timescale enables us to show that the mechanism of aggregation involves a first phase in which small structurally disordered oligomers assemble onto the nanoparticle and a second phase in which they evolve into highly ordered beta-sheets as their size increases

Inorganic hydrophobic coatings: Surfaces mimicking the nature

Added value products are being developed in ceramic industry. Different optical effects as bright metallic shine or new functionalities as hydrophobicity or bactericide characteristics are the new properties searched on the tiles. In this study, we prepare glassy coatings for tiles based on copper pigment by a conventional industrial process. The obtained coatings present different aesthetical aspects, including bright metallic aspect which confers a high decorative value to the tile. Furthermore, these metallic coatings present hydrophobic properties with contact angles with water as high as 115 degrees and also bactericide characteristics. Superficial microstructure and nanoparticles were found in the bactericide-hydrophobic samples, resembling the surface of hydrophobic leaf surfaces. This structure was formed by the crystallization of CuO nanoparticles as Tenorite due to the copper saturation of the glassy matrix at the surface of the coatings

Thermodynamic study of interactions between ZnO and ZnO binding peptides using isothermal titration calorimetry

Whilst material specific peptide binding sequences have been identified using a combination of combinato-rial methods and computational modelling tools, a deep molecular level understanding of the fundamental principles through which these interactions occur and in some instances modify the morphology of inorganic materials is far from being fully realized. Understanding the thermodynamic changes that occur during peptide-inorganic interactions and correlating these to structural modifications of the inorganic materials could be the key to achieving and mastering con-trol over material formation processes. This study is a detailed investigation applying isothermal titration calorimetry (ITC) to directly probe thermodynamic changes that occur during interaction of ZnO binding peptides (ZnO-BPs) and ZnO. The ZnO-BPs used are reported sequences G-12 (GLHVMHKVAPPR), GT-16 (GLHVMHKVAPPR-GGGC) and alanine mutants of G-12 (G-12A6, G-12A11 and G-12A12) whose interaction with ZnO during solution synthesis studies have been extensively investigated. The interactions of the ZnO-BPs with ZnO yielded biphasic isotherms comprising both an endo-thermic and an exothermic event. Qualitative differences were observed in the isothermal profiles of the different pep-tides and ZnO particles studied. Measured ΔG values were between -6 and -8.5 kcal/mol and high adsorption affinity val-ues indicated the occurrence of favourable ZnO-BP-ZnO interactions. ITC has great potential in its use to understand peptide-inorganic interactions and with continued development, the knowledge gained may be instrumental for simplifi-cation of selection processes of organic molecules for the advancement of material synthesis and design

Requirements of Business Judgment Rule and Their Effect on the Practical Use of the Rule

Pravilo poslovne presoje ima v Združenih državah Amerike že dolgo tradicijo, v evropskih državah s kontinentalnimi pravnimi sistemi pa so se ga sodišča pri presoji poslovnih odločitev članov organov vodenja in nadzora začela posluževati šele v zadnjih desetletjih. Slovenija je ena izmed vse manjše skupine držav, ki pravila poslovne presoje in njihovih kriterijev še ni prenesla iz sodne prakse v zakonodajo. Pravilo poslovne presoje omogoča sodiščem, da pri presoji, ali so člani organov vodenja in nadzora odškodninsko odgovorni za družbi škodljive odločitve, s pomočjo upoštevanja kriterijev pravila prilagodijo presojo specifičnemu položaju tožencev. Magistrska naloga z namenom iskanja bistva in praktičnega pomena kriterijev pravila poslovne presoje najprej pojasni pojem korporacijskega upravljanja in dinamiko akterjev v delovanju gospodarskih družb. Po kratki naslovitvi dolžnosti članov organov vodenja in nadzora tako v našem pravu kot v pravu tujih držav sledi pregled razvoja kriterijev pravila skozi sodno prakso v njegovem domicilu, Združenih državah Amerike. Kratko so predstavljene različne variacije pravila poslovne presoje v različnih zakonodajnih in kvazizakonodajnih aktih ter pojasnjeni razlogi za njegove pojavne oblike, ki jih v največji meri zaznamujejo različna razumevanja njegovega namena. Sledi podrobna obravnava posameznih kriterijev pravila od prve omembe do sodobne interpretacije, z ozirom na način njegove razlage v slovenski teoriji in praksi. Dilema (ne)pravilnosti slovenske percepcije pravila poslovne presoje se prevesi v zaključni sklep, ki predvsem poudarja pomen prostega polja presoje, ki ga sodiščem omogoča določena mera nedoločenosti kriterijev.Although business judgment rule has a long tradition in the United States of America, the courts in European countries with continental legal systems have only started to use it in the last decades for dealing with business decisions of management. Slovenia is one of the shrinking group of countries that has not yet transferred the rule from case law to law in books. Business judgment rule enables the courts to make use of requirements of the rule in order to properly adjust the judicial decision whether board members are liable for business decisions that resulted in losses for the company. In pursuit of finding the core purpose and practical contribution of requirements of the rule, this master\u27s thesis first explains the concept of corporate governance and dynamics among the different subjects in the company\u27s framework. After a brief mention of management\u27s duties in Slovenian law as well as the law in other countries, thesis continues with an overview of development of the rule\u27s requirements in the rule\u27s cradle, the United States of America. Following is the presentation of different varieties of business judgment rule in different legislative and quasi-legislative acts and the clarification of reasons for so many variations of the rule, which are shaped mostly by different understandings of its core purpose. Detailed explanation of each individual requirement is next, from its first mentions in case law to its modern interpretation with respect to the way each requirement is interpreted in Slovenian case law. The question of suitability of the Slovenian perception of business judgment rule is followed by final conclusion which emphasizes the importance of discretion field the rule\u27s requirements create if they are, to the certain extent, undetermined

Formation of Nano-Bio-Complex as Nanomaterials Dispersed in a Biological Solution for Understanding Nanobiological Interactions

Information on how cells interface with nanomaterials in biological environments has important implications for the practice of nanomedicine and safety consideration of nanomaterials. However, our current understanding of nanobiological interactions is still very limited. Here, we report the direct observation of nanomaterial bio-complex formation (other than protein corona) from nanomaterials dispersed in biologically relevant solutions. We observed highly selective binding of the components of cell culture medium and phosphate buffered saline to ZnO and CuO nanoparticles, independent of protein molecules. Our discoveries may provide new insights into the understanding of how cells interact with nanomaterials

The contrasting role of technology as both supportive and hindering in the everyday lives of people with mild cognitive deficits: a focus group study

Background: It is well known that people with mild cognitive deficits face challenges when performing complex everyday activities, and that the use of technology has become increasingly interwoven with everyday activities. However, less is known of how technology might be involved, either as a support or hindrance, in different areas of everyday life and of the environments where challenges appear. The aim of this study was to investigate the areas of concern where persons with cognitive deficits meet challenges in everyday life, in what environments these challenges appear and how technology might be involved as part of the challenge and/or the solution to the challenge. Methods: Data were gathered through four focus group interviews with participants that live with cognitive deficits or cohabit with a person with cognitive deficits, plus health professionals and researchers in the field. Data were transcribed, coded and categorized, and finally synthesized to trace out the involvement of technology. Results: Five areas of concern in everyday life were identified as offering challenges to persons with cognitive deficits: A) Managing personal finances, B) Getting around, C) Meeting family and friends, D) Engaging with culture and media and, E) Doing everyday chores. Findings showed that the involvement of technology in everyday activities was often contrastive. It could be hindering and evoke stress, or it could bring about feelings of control; that is, being a part of the solution. The involvement of technology was especially obvious in challenges linked to Managing personal finances, which is a crucial necessity in many everyday activities. In contrast, technology was least obviously involved in the area Socializing with family and friends. Conclusions: The findings imply that technology used for orientation and managing finances, often used outside home, would benefit from being further developed in order to be more supportive; i.e. accessible and usable. To make a positive change for many people, the ideas of inclusive design fit well for this purpose and would contribute to an age-friendly society