Adsorption of bio-organic eco-corona molecules reduces the toxic response to metallic nanoparticles in <i>Daphnia magna</i>

As the use of engineered nanomaterials increases, so does the risk of them spreading to natural ecosystems. Hitherto, knowledge regarding the toxic properties of nanoparticles (NP’s) and their potential interactions with natural bio-organic molecules adsorbed to them, and thereby forming surface coronas, is limited. However, we show here that the toxic effect of NPs of tungsten carbide cobalt (WC–Co) and cobalt (Co) on the crustacean Daphnia magna is postponed in the presence of natural biological degradation products (eco-corona biomolecules). For Daphnia exposed to WC–Co NPs the survival time increased with 20–25% and for Co NPs with 30–47% after mixing the particles with a solution of eco-corona biomolecules before exposure. This suggests that an eco-corona, composed of biomolecules always present in natural ecosystems, reduces the toxic potency of both studied NPs. Further, the eco-coronas did not affect the particle uptake, suggesting that the reduction in toxicity was related to the particle-organism interaction after eco-corona formation. In a broader context, this implies that although the increasing use and production of NPs may constitute a novel, global environmental threat, the acute toxicity and long-term effects of some NPs will, at least under certain conditions, be reduced as they enter natural ecosystems

Modeling the Time Evolution of the Nanoparticle-Protein Corona in a Body Fluid

Background: Nanoparticles in contact with biological fluids interact with proteins and other biomolecules, thus forming a dynamic corona whose composition varies over time due to continuous protein association and dissociation events. Eventually equilibrium is reached, at which point the continued exchange will not affect the composition of the corona. Results: We developed a simple and effective dynamic model of the nanoparticle protein corona in a body fluid, namely human plasma. The model predicts the time evolution and equilibrium composition of the corona based on affinities, stoichiometries and rate constants. An application to the interaction of human serum albumin, high density lipoprotein (HDL) and fibrinogen with 70 nm N-iso-propylacrylamide/N-tert-butylacrylamide copolymer nanoparticles is presented, including novel experimental data for HDL. Conclusions: The simple model presented here can easily be modified to mimic the interaction of the nanoparticle protein corona with a novel biological fluid or compartment once new data will be available, thus opening novel applications in nanotoxicity and nanomedicine

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

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

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

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

BRCA2-dependent homologous recombination is required for repair of Arsenite-induced replication lesions in mammalian cells

Arsenic exposure constitutes one of the most widespread environmental carcinogens, and is associated with increased risk of many different types of cancers. Here we report that arsenite (As[III]) can induce both replication-dependent DNA double-strand breaks (DSB) and homologous recombination (HR) at doses as low as 5 µM (0.65 mg/l), which are within the typical doses often found in drinking water in contaminated areas. We show that the production of DSBs is dependent on active replication and is likely to be the result of conversion of a DNA single-strand break (SSB) into a toxic DSB when encountered by a replication fork. We demonstrate that HR is required for the repair of these breaks and show that a functional HR pathway protects against As[III]-induced cytotoxicity. In addition, BRCA2-deficient cells are sensitive to As[III] and we suggest that As[III] could be exploited as a therapy for HR-deficient tumours such as BRCA1 and BRCA2 mutated breast and ovarian cancers