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This article presents an automated image-processing workflow for quantitative assessment of SPION accumulation in tissue sections stained with Prussian blue for iron detection. We utilized supervised machine learning with manually labeled features used for training the classifier. Performance of the classifier was validated by 10-fold cross-validation of obtained data and by measuring Dice and Jaccard Similarity Coefficients between manually segmented image and automated segmentation. The proposed approach provides time and cost-effective solution for quantitative imaging analysis of SPION in tissue with a precision similar to that obtained via thresholding method for stain quantification. Furthermore, we exploited the classifiers to generate segmented 3D volumes from histological slides. This enabled visualization of particles which were obscured in original 3D histology stacks. Our approach offers a powerful tool for preclinical assessment of the precise tissue-specific SPION biodistribution, which could affect both their toxicity and their efficacy as nanocarriers for medicines.

With the development and simplification of The article describes the application of European norms in the domestic practice for the design of reinforced concrete structures using European norms Eurocode-2. For Eurocode-2, the number of nationally defined parameters is more than a hundred. These are different coefficients, shrinkage, creep of concrete, thickness of protective layers of concrete for steel fittings depending on the type, environment of operation, etc. Differ in the SNIP on the design of designs and individual Eurocodes, the size and shape of the samples tested to determine the strength (regulatory) characteristics of building materials, making it impossible to apply many of the calculation formulas directly. Addressing these issues is a rather capacious task. Many series of prototypes will be required only to determine statistically reliable transitional coefficients for the strength of the materials used in SNIP and Eurocodes.

Spadavecchia J, Movia D, Moore C, et al. Int J Nanomedicine. 2016;11:791–822. Page 815, Figure S6, the following copyright notice should have been included in the figure caption. Copyright ©2016. Elsevier. Reproduced from Spadavecchia J, Perumal R, Casale S, Krafft JM, Methivier C, Pradier CM. Polyethylene glycol gold-nanoparticles: Facile nanostructuration of doxorubicin and its complex with DNA molecules for SERS detection. Chem Phys Lett. 2016;648:182–188.1 Page 822, the following reference should have been included in a new reference list for the supplementary materials. 1. Spadavecchia J, Perumal R, Casale S, Krafft JM, Methivier C, Pradier CM. Polyethylene glycol gold-nanoparticles: Facile nanostructuration of doxorubicin and its complex with DNA molecules for SERS detection. Chem Phys Lett. 2016;648:182–188. doi 10.2147/IJN.S97476 The authors apologize for this error.

The article addresses the problem of the genesis of the beauty principle in scientific cognition from the standpoint of the gnoseological approach supplemented by some conceptual generalizations from the fields of social epistemology and sociology of thinking. The relevance of this approach is due to the critical attitude to gnoseology as a general theory and methodology of science on the part of non-classical epistemology, the history of science and scientific theories of the middle range. An external factor that actualizes the current internal scientific situation is the prolongation of integration processes typical for postmodern culture associated with the search for points of contact between science and art. The article shows that despite the addition of the principle of beauty to the heuristic tools of modern exemplary science, there is an unresolved problem of the genetic relationship between aesthetics and science. This connection was best demonstrated in detail by the example of the similarity and difference between mathematics and music initiated in antique culture and reflecting the love of symmetry and harmony inherent in the Greek worldview. On the other hand, the differences in the perception of works of science and art which are obvious to ordinary consciousness required ancient thinkers to introduce concepts and principles that synthesize different aspects of the manifestations of the useful, true, and beautiful. In this connection, the binary mythopoetic cosmos-chaos opposition, which is found in its direct form in archaic and natural-philosophical cosmologies, is proposed as the historically first form that integrates the complex and contradictory content of the beauty principle. The results of the study lead to the conclusion that only natural philosophical models of the cosmos make a fundamental distinction between the “chaos” of opinions about phenomena and the “cosmos” of the true knowledge about their speculative entities. It is this worldview scheme of a single, conceptually ordered, and therefore truly beautiful world that served as an ideal model for classical European science.

Nanotechnology in medicine-nanomedicine-is extensively employed to diagnose, treat, and prevent pulmonary diseases. Over the last few years, this brave new world has made remarkable progress, offering opportunities to address historical clinical challenges in pulmonary diseases including multidrug resistance, adverse side effects of conventional therapeutic agents, novel imaging, and earlier disease detection. Nanomedicine is also being applied to tackle the new emerging infectious diseases, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), influenza A virus subtype H1N1 (A/H1N1), and more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review we provide both a historical overview of the application of nanomedicine to respiratory diseases and more recent cutting-edge approaches such as nanoparticle-mediated combination therapies, novel double-targeted nondrug delivery system for targeting, stimuli-responsive nanoparticles, and theranostic imaging in the diagnosis and treatment of pulmonary diseases.

В нормах по проектированию железобетонных конструкций зданий и сооружений (начиная с 1962 г. и по настоящее время) содержится методика расчета на выносливость, которая была составлена с учетом обобщения и анализа данных многочисленных экспериментально-теоретических исследований. Последующее использование данной методики в практике проектирования железобетонных конструкций показало, что при эксплуатации конструкций, рассчитанных с учетом требований по выносливости, разрушений не происходило. Вместе с тем, анализ показал отличие отечественной методики от подходов иностранных норм в части расчета по растянутой арматуре. Дальнейшие исследования показали некоторые неcовершенства нормативной методики расчета по растянутой арматуре (как ненапрягаемой, так и предварительно напряженной). С учетом данных проведенных расчет-но-теоретических исследований, а также в целях гармонизации с основными положениями расчета на усталость, принятого в нормах проектирования ряда ведущих стран, представляется полезным в расчете на усталость по растянутой арматуре наряду с максимальным напряжением в пределах цикла нагрузки учитывать и предельную амплитуду напряжений. В этой связи предполагается проведение актуализации существующей методики расчета на выносливость, которая будет дополнена новыми положениями расчета по растянутой арматуре. При актуализации методики наиболее правильным будет максимально учесть другие положения существующей методики. В частности, будет сохранен прежний подход к определению действующих напряжений в бетоне и арматуре, а также расчет на усталость по сжатому бетону.

The influence of the parameters of a pulsed power supply of a glow discharge and the substrate temperature on the growth kinetics of CVD polycrystalline diamond films have been studied. It was found that an increase in the pulse frequency from 13 to 50 kHz and a decrease in the pulse duty cycle from 90 to 80% promotes an increase in the films growth rate by 1.5 – 2 times. The non-monotonous character of the dependence of the film growth rate on the deposition temperature upon pulsed excitation of a glow discharge is similar to that characteristic by direct current. In the optimal pulse mode the maximum film growth rate is near a temperature of 1050°C. With an increase in the deposition time, an increase in the average growth rate of the diamond film is observed. When the synthesis process lasts more than 6 hours, the deposition rate reaches 11 μm / hour. The power consumption in the pulsed mode of diamond films synthesis is 0.3 kW / μm, which is 3 times lower than when using a DC power source.

The final section of A. S. Zapesotsky's monograph «Formation of global culture and conflicts of civilizations (based on the materials of international Likhachev scientific readings)» in the genre of replica is reviewed. The main purpose of the presented recall is the analysis of opposite in its ideological orientation philosophical and ideological positions of the participants of the Readings in their comparison with the general concept and methodology of the monograph. At the same time, all the critically analyzed ideological attitudes of the authors of the reports are considered from the point of view of their compliance with the anti-metaphysical methodology of building the book which sets the task of finding common in the ideological oppositions. It is suggested that the book under review uses two variants of the dialectical method ‒ «Socratic» which aimed at finding the initially unknown essence of real contradictions and «Hegelian» which designed to synthesize the selected logical way the final result. It is shown that the second kind of dialectics is more relief presented in subsection 7.3. «Sense-forming dominants of the Russian civilization» where the some main ideological orientations of the globalisation national culture are considered. Among them is the opposition of two ideological projects of man: classical and neo-pagan, the idea of dialogue between science and religion, existential and cultural understanding of the nature of sense. It is noted that the worldview guidelines of the Russian idea presented in the book which can act as a building material for the state ideology and geopolitical strategies first of al, take into account its national specifics. In this regard the book indicates the general principles of national and at the same time global ethics of the future most prominently formulated in the creation of F. M. Dostoevsky. The general conclusion of the remark: in the combination of different worldview and stylistic positions, but with the mandatory preservation of the with the remaining ideological orientation of the overall design of the project it is one of the distinctive features of the reviewed section of the book which managed to convey a special creative world of Likhachev's scientific readings.

In connection with the use of built-in on-board diagnostics on cars, the development of satellite navigation systems and mobile communications, modern information technologies, it became possible to carry out remote monitoring with an assessment of the level of technical condition of the vehicle. This, in turn, allows us to switch to an adaptive system of technical maintenance and repair of cars, the key point of which is the development of an information and communication system and information software systems that provide, by monitoring remotely, the technical parameters of a vehicle in operating conditions, and assess the technical parameters of vehicles in operation and development of corrective actions. The purpose of the work is to generalize and develop existing modern information technologies in road transport in the conditions of intelligent transport systems (ITS). It is shown that in the formation of the information software complex in the conditions of ITS, for the formalization of the main processes, the methodology of structural analysis and design of SADT was applied. The source data for monitoring the technical condition of the vehicle, in accordance with the provisions of the IDEF0 methodology, the design features of the vehicle and the particular operating conditions, there is information on the technical condition of the vehicle. In this case, the general software of the manufacturing enterprise for the operation of automobile transport has been supplemented with respect to the algorithms of the software when performing: vehicle identification; identification of operating conditions; checking the conformity of the vehicle condition to operating conditions. To determine the subject area of ​​the information system for assessing the technical condition of a vehicle under operating conditions during its monitoring, a data flow diagram was used, which represents the highest descriptive level of a vehicle monitoring system.

Aim: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine, which has been shown to promote disease severity in cystic fibrosis. Methods: In this study, aerosolized drug-loaded nanoparticles containing SCD-19, an inhibitor of MIF's tautomerase enzymatic activity, were developed and characterized. Results: The aerosolized nanoparticles had an optimal droplet size distribution for deep lung deposition, with a high degree of biocompatibility and significant cellular uptake. Conclusion: For the first time, we have developed an aerosolized nano-formulation against MIF's enzymatic activity that achieved a significant reduction in the inflammatory response of macrophages, and inhibited Pseudomonas aeruginosa biofilm formation on airway epithelial cells. This represents a potential novel adjunctive therapy for the treatment of P. aeruginosa infection in cystic fibrosis.

Carbon-based nanomaterials (C-BNM) have recently attracted an increased attention as the materials with potential applications in industry and medicine. Bioresistance and proinflammatory potential of C-BNM is the main obstacle for their medicinal application which was documented in vivo and in vitro. However, there are still limited data especially on graphene derivatives such as graphene platelets (GP). In this work, we compared multi-walled carbon nanotubes (MWCNT) and two different types of pristine GP in their potential to activate inflammasome NLRP3 (The nod-like receptor family pyrin domain containing 3) in vitro. Our study is focused on exposure of THP-1/THP1-null cells and peripheral blood monocytes to C-BNM as representative models of canonical and alternative pathways, respectively. Although all nanomaterials were extensively accumulated in the cytoplasm, increasing doses of all C-BNM did not lead to cell death. We observed direct activation of NLRP3 via destabilization of lysosomes and release of cathepsin B into cytoplasm only in the case of MWCNTs. Direct activation of NLRP3 by both GP was statistically insignificant but could be induced by synergic action with muramyl dipeptide (MDP), as a representative molecule of the family of pathogen-associated molecular patterns (PAMPs). This study demonstrates a possible proinflammatory potential of GP and MWCNT acting through NLRP3 activation.

Anthropogenic activity causes the introduction of zinc compounds into the biological cycle in mining and processing sites and its accumulation in organs and tissues, causing systemic toxicity. A cumulative effect of zinc is predominantly neurotoxic and it also affects the respiratory, cardiovascular and digestive systems. This study evaluates the effects of single-dose intragastric administration of 100 mg/kg zinc succinate on the structure and function of organs and tissues in male Wistar rats 1 month after treatment. The presented morphofunctional approach for the toxicity evaluation included the study of behavioral responses using the automated Laboras® complex, fluorescent spectral analysis of the NADH and FAD activity and histological evaluation of animal organs and tissues. The results of the behavioral activity assessment showed a significant decrease in animals’ motor activity, whereas the fluorescence spectra analysis demonstrated a decrease in coenzyme NADH without the reduction of FAD levels. We detected toxic and dystrophic changes in the cerebral cortex, heart, lungs and liver tissues. Our original multiparametric approach enables a comprehensive assessment of the long-term toxic effects of the metal salts such as zinc succinate, especially in the cerebral cortex at the doses much lower than the acute LD50 reported for the common zinc salts., Zinc succinate; Tissue and organ toxicity; Morphofunctional approach; Behavioral activity; Endogenous fluorescence; Experimental rats; Health Sciences; Neuroscience; Psychiatry; Toxicology.

Magnetic hyperthermia involves the use of iron oxide nanoparticles to generate heat in tumours following stimulation with alternating magnetic fields. In recent times, this treatment has undergone numerous clinical trials in various solid malignancies and subsequently achieved clinical approval to treat glioblastoma and prostate cancer in 2011 and 2018, respectively. However, despite recent clinical advances, many questions remain with regard to the underlying mechanisms involved in this therapy. One such query is whether intracellular or extracellular nanoparticles are necessary for treatment efficacy. Herein, we compare the effects of intracellular and extracellular magnetic hyperthermia in BxPC-3 cells to determine the differences in efficacy between both. Extracellular magnetic hyperthermia at temperatures between 40&ndash, 42.5 &deg, C could induce significant levels of necrosis in these cells, whereas intracellular magnetic hyperthermia resulted in no change in viability. This led to a discussion on the overall relevance of intracellular nanoparticles to the efficacy of magnetic hyperthermia therapy.

Evidence supports the advantages of inhalation over other drug-administration routes in the treatment of lung diseases, including cancer. Although data obtained from animal models and conventional in vitro cultures are informative, testing the efficacy of inhaled chemotherapeutic agents requires human-relevant preclinical tools. Such tools are currently unavailable. Here, we developed and characterized in vitro models for the efficacy testing of inhaled chemotherapeutic agents against non-small-cell lung cancer (NSCLC). These models recapitulated key elements of both the lung epithelium and the tumour tissue, namely the direct contact with the gas phase and the three-dimensional (3D) architecture. Our in vitro models were formed by growing, for the first time, human adenocarcinoma (A549) cells as multilayered mono-cultures at the Air-Liquid Interface (ALI). The in vitro models were tested for their response to four benchmarking chemotherapeutics, currently in use in clinics, demonstrating an increased resistance to these drugs as compared to sub-confluent monolayered 2D cell cultures. Chemoresistance was comparable to that detected in 3D hypoxic tumour spheroids. Being cultured in ALI conditions, the multilayered monocultures demonstrated to be compatible with testing drugs administered as a liquid aerosol by a clinical nebulizer, offering an advantage over 3D tumour spheroids. In conclusion, we demonstrated that our in vitro models provide new human-relevant tools allowing for the efficacy screening of inhaled anti-cancer drugs.

The size-dependent optical properties of quantum dots (QDs) are frequently exploited for use in medical imaging and labelling applications. Similarly, presented here, they also elicit profound size-dependent anticoagulant properties. Cadmium telluride quantum dot (QDs) (3.2 nm) were shown to have a dramatic anticoagulant effect centred on around the intrinsic coagulation pathway, compared to their 3.6 nm counterparts. Several clinically relevant diagnostic tests were carried out over a concentration range of the QDs and demonstrated that the 3.2 nm QDs elicited their response on the intrinsic pathway as a whole, yet the activity of the individual intrinsic coagulation factors was not affected. The mechanism appears also to be strongly influenced by the concentration of calcium ions and not cadmium ions leached from the QDs. Static and shear-based primary haemostasis assays were also carried out, demonstrating a profound anticoagulant effect which was independent of platelets and phospholipids. The data presented here suggest that the physical-chemical properties of the QDs may have a role in the modulation of haemostasis and the coagulation cascade, in a yet not fully understood mechanism. This study has implications for the use of similar QDs as diagnostic or therapeutic tools in vivo, and for the occupational health and safety of those working with such materials.

Alternative models such as three-dimensional (3D) cell cultures represent a distinct milestone towards capturing the realities of cancer biology in vitro and reduce animal experimentation in the preclinical stage of drug discovery. Significant work remains to be done to understand how substrates used in in vitro alternatives influence cancer cells phenotype and drug efficacy responses, so that to accurately link such models to specific in vivo disease scenarios. Our study describes how the morphological, mechanical and biochemical properties of adenocarcinoma (A549) cells change in response to a 3D environment and varying substrates. Confocal Laser Scanning (LSCM), He-Ion (HIM) and Atomic Force (AFM) microscopies, supported by ELISA and Western blotting, were used. These techniques enabled us to evaluate the shape, cytoskeletal organization, roughness, stiffness and biochemical signatures of cells grown within soft 3D matrices (PuraMatrix™ and Matrigel™), and to compare them to those of cells cultured on two-dimensional glass substrates. Cell cultures are also characterized for their biological response to docetaxel, a taxane-type drug used in Non-Small-Cell Lung Cancer (NSCLC) treatment. Our results offer an advanced biophysical insight into the properties and potential application of 3D cultures of A549 cells as in vitro alternatives in lung cancer research.

David Hutchinson,1,2 Judith Müller,3 Joseph E McCarthy,4 Yurii K Gun’ko,4,5 Navin Kumar Verma,6 Xuezhi Bi,7 Luisana Di Cristo,8 Laura Kickham,8 Dania Movia,8 Adriele Prina-Mello,5,8 Yuri Volkov5,8,9 1Royal Cornwall Hospital NHS Trust, Treliske, 2University of Exeter Medical School Cornwall, UK; 3University of Basel, Basel, Switzerland; 4School of Chemistry, 5Advanced Materials for BioEngineering Research Centre (AMBER), Trinity College Dublin, Dublin, Ireland; 6Lee Kong Chian School of Medicine, Nanyang Technological University, 7Bioprocessing Technology Institute, A*STAR Graduate Academy, Singapore; 8Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland; 9International Laboratory of Magnetically Controlled Nanosystems for Theranostics of Oncological and Cardiovascular Diseases, ITMO University, St. Petersburg, Russia Objective: The objective of the study was to determine whether the cadmium-derived materials induce intracellular protein citrullination. Methods: Human A549 lung epithelial cells were exposed to cadmium in soluble and nanoparticulate forms represented by cadmium chloride (CdCl2) and cadmium oxide (CdO), respectively, and their combinations with ultrafine carbon black (ufCB) produced by high temperature combustion, imitating cigarette burning. Protein citrullination in cell lysates was analyzed by Western immunoblotting and verified by immunofluorescent confocal microscopy. Target citrullinated proteins were identified by proteomic analysis. Results: CdO, ufCB and its combination with CdCl2 and CdO after high temperature combustion induced protein citrullination in cultured human lung epithelial cells, as detected by immunoblotting with anti-citrullinated protein antibody. Cytokeratins of type II (1, 2, 5, 6A, 6B and 77) and type I (9, 10) were identified as major intracellular citrullination targets. Immunofluorescent staining confirmed the localization of citrullinated proteins both in the cytoplasm and cell nuclei. Conclusion: Cadmium oxide nanoparticle exposure facilitated post-translational citrullination of proteins. Keywords: cadmium, COPD, nanoparticles, cytokeratins, citrullination, autoimmunity, proteomics

Citrullination, or the post-translational deimination of polypeptide-bound arginine, is involved in several pathological processes in the body, including autoimmunity and tumorigenesis. Recent studies have shown that nanomaterials can trigger protein citrullination, which might constitute a common pathogenic link to disease development. Here we demonstrated auto-antibody production in serum of nanomaterials-treated mice. Citrullination-associated phenomena and PAD levels were found to be elevated in nanomaterials -treated cell lines as well as in the spleen, kidneys and lymph nodes of mice, suggesting a systemic response to nanomaterials injection, and validated in human pleural and pericardial malignant mesothelioma (MM) samples. The observed systemic responses in mice exposed to nanomaterials support the evidence linking exposure to environmental factors with the development of autoimmunity responses and reinforces the need for comprehensive safety screening of nanomaterials. Furthermore, these nanomaterials induce pathological processes that mimic those observed in Pleural MM, and therefore require further investigations into their carcinogenicity.

Environmental and biomedical nanoparticles can pose potential health risks to the human respiratory system by inducing severe lung inflammation. The aim of this case study is to present a comparison of the inflammatory response in four in vitro models of the human lung epithelium, differing by composition and/or culturing substrates, when exposed to gold nanoparticles (AuNPs). Three in vitro models of lung adenocarcinoma (A549) cells and a commercially available three-dimensional (3D) culture (MucilAir™) were tested. The models were exposed to AuNPs for 3, 6, and 24 h. AuNPs internalisation was investigated by confocal, electron microscopy, and Raman spectroscopy. Enzyme-Linked Immuno-Sorbent Assay (ELISA) was used for quantifying the secretion of the inflammatory mediator Interleukin-6 (IL-6) following exposure to AuNPs. Finally, a microfluidic approach was developed in-house to investigate whether pro-inflammatory mediators present in supernatants harvested from the AuNPs-treated cell cultures could trigger monocyte activation. Our results demonstrated that AuNPs were internalised only in submerged cultures grown on glass substrates. Nevertheless, AuNPs internalisation did not trigger a significant IL-6 secretion. Significant amounts of IL-6 were secreted by AuNPs-treated mono-cultures grown on Transwell™ inserts, triggering monocyte activation in dynamic microfluidic experiments. AuNPs did not induce IL-6 secretion in co-cultures and MucilAir™ models, although supernatants harvested from co-cultures triggered monocyte activation. Our case study demonstrates that in vitro complexity, as well as culturing substrates, deeply influence the detectable cellular responses to nanoparticles, and advocate for the adoption of more advanced tissue-mimetic cultures of the human respiratory system for nanomaterials testing.

The physical properties of substrates can have profound effects on the structure and function of cultured cells. In this study, we aimed to examine the viability, adherence, and morphological and functional variations between SH-SY5Y human neuroblastoma cells cultured on SU-8 surfaces compared with control surfaces composed of borosilicate glass, which are routinely used for cell culture. The SU-8 polymer has been extensively studied for its biocompatibility, but there has been little investigation into the characteristic differences between cells cultured on SU-8 when compared with glass. SH-SY5Y cells were cultured within polydimethylsiloxane wells on both SU-8 and glass substrates for up to 72 h after which flow cytometry and enzyme-linked immunosorbent assay analysis was performed to examine cell viability and neurotoxicity. Immunocytochemistry was also performed to analyze the morphological and functional characteristics of the cells. Atomic force microscopy was performed to measure surface roughness and to map cell-substrate interactions. Nanoindentation testing was used to characterize the mechanical properties of polymer surface. Results showed that SH-SY5Y cells grown on SU-8 have significantly improved viability and increased morphological and functional characteristics of neurodevelopment. The results from this study suggest that the mechanical properties of the polymer are optimal for the study of cultured cell lines, which could account for the increased viability, adherence, and morphological and functional characteristics of neurodevelopment. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2129-2138, 2017.

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International audience; In this paper we show that conjugation of magnetic nanoparticles (MNPs) with Gemcitabine and/or NucAnt (N6L) fostered their internalization into pancreatic tumor cells and that the coupling procedure did not alter the cytotoxic potential of the drugs. By treating tumor cells (BxPC3 and PANC-1) with the conjugated MNPs and magnetic hyperthermia (43°C, 60 min), cell death was observed. The two pancreatic tumor cell lines showed different reactions against the combined therapy according to their intrinsic sensitivity against Gemcitabine (cell death, ROS production, ability to activate ERK 1/2 and JNK). Finally, tumors (e.g. 3 mL) could be effectively treated by using almost 4.2 × 10 5 times lower Gemcitabine doses compared to conventional therapies. Our data show that this combinatorial therapy might well play an important role in certain cell phenotypes with low readiness of ROS production. This would be of great significance in distinctly optimizing local pancreatic tumor treatments.

Nuclear power industry could be truly sustainable only under the condition of the Treaty on the Non- Proliferation of Nuclear Weapons. Thus, the issue of nuclear materials illicit diversion is crucial. One possible way to increase the resistance of the nuclear system to proliferation could be the increase of inherent security of nuclear materials used. One of the practical steps here could be the creation of intrinsic barriers in low-enriched uranium (LEU) fuel that is used in light water reactors worldwide. By the way, not only natural uranium could be used as raw material for such LEU, but also reprocessed uranium produced from spent nuclear fuel. In this study, proliferation resistance of enriched reprocessed uranium (in other words, commercial LEU made of reprocessed uranium) in the case of its covert diversion was analyzed. The conditions, under which this material could be turned into a direct use material in terms of IAEA was outlined. The scale of enrichment facility required to produce a significant quantity (SQ) of highly enriched uranium (HEU) throughout the duration of three months to two years, having the predetermined amount of diverted material (one SQ of LEU stolen from fresh fuel) was also assessed. Then, it was shown that such a feature of fuel made of reprocessed uranium as 232U presence makes the detection of potential diversion possible even for much smaller quantities of LEU than in the case of fuel made of natural uranium.

Manufactured nanomaterials have a variety of medical applications, including diagnosis and targeted treatment of cancer. A series of experiments were conducted to determine the pharmacokinetic, biodistribution and biocompatibility of two novel magnetic nanoparticles (MNPs) in the anaesthetized pig. Dimercaptosuccinic acid (DMSA) coated superparamagnetic iron oxide nanoparticles (MF66-labelled 12 nm, core nominal diameter and OD15 15 nm); at 0.5, or 2.0 mg/kg) were injected intravenously. Particles induced a dose-dependent decrease in blood pressure following administration which recovered to control levels several minutes after injection. Blood samples were collected for a 5-h period and stored for determination of particle concentration using particle electron paramagnetic resonance (pEPR). Organs were harvested post-mortem for magnetic resonance imaging (MRI at 1.5 T field strength) and histology. OD15 (2.0 mg/kg) MNP had a plasma half-life of approximately 15 min. Both doses of the MF66 (0.5 and 2.0 mg/kg) MNP were below detection limits. MNP accumulation was observed primarily in the liver and spleen with MRI scans which was confirmed by histology. MRI also showed that both MNPs were present in the lungs. The results show that further modifications may be required to improve the biocompatibility of these particles for use as diagnostic and therapeutic agents.

Understanding the correlation between the physico-chemical properties of carbonaceous nanomaterials and how these properties impact on cells and subcellular mechanisms is critical to their risk assessment and safe translation into newly engineered devices. Here the toxicity, uptake and catabolic response of primary human macrophages to pristine graphene (PG) and pristine single walled carbon nanotubes (pSWCNT) are explored, compared and contrasted. The nanomaterial toxicity was assessed using three complementary techniques (live–dead assay, real time impedance technique and confocal microscopic analysis), all of which indicated no signs of acute cytotoxicity in response to PG or pSWCNT. Transmission electron microscopy (TEM) demonstrated that PG was phagocytosed by the cells into single membrane lysosomal vesicles, whereas the primary macrophages exposed to pSWCNT contained many double membrane vesicles indicative of an autophagic response. These distinct catabolic pathways were further verified by biochemical and microscopic techniques. Raman spectroscopic mapping was used to explore the nanomaterial uptake and distribution. Based on the G-band, significant uptake and accumulation of the PG in discrete vesicles was recorded, whereas the pSWCNT were not taken up to the same extent. Thermogravimetric analysis (TGA) of the cells treated with PG revealed that ∼20–30% of the remaining dry mass was made up of PG. No detectable amount of pSWCNT was recorded using TGA. TEM analysis confirmed that PG was still graphitic even after 24 hours of accumulation in the lysosomal compartments. In conclusion, these two nanomaterials, with similar surface chemistries but unique geometries, differ significantly in their uptake mechanisms and subsequently induced lysosomal and autophagic catabolic pathways in human primary macrophages.

The review addresses the current state of progress in the use of ultra-small nanoparticles from the category of quantum dots (QDs), which presently embraces a widening range of nanomaterials of different nature, including "classical" semiconductor groups III-V and II-VI nanocrystals, along with more recently emerged carbon, silicon, gold and other types of nanoparticles falling into this class of nanomaterials due to their similar physical characteristics such as small size and associated quantum confinement effects. A diverse range of QDs applications in nanomedicine has been extensively summarised previously in numerous publications. Therefore, this review is not intended to provide an all-embracing survey of the well documented QDs uses, but is rather focused on the most recent emerging developments, concepts and outstanding unresolved problematic and sometimes controversial issues. Over 125 publications are overviewed and discussed here in the context of major nanomedicine domains, i.e. medical imaging, diagnostics, therapeutic applications and combination of them in multifunctional theranostic systems.

The size-dependent optical properties of quantum dots (QDs) are frequently exploited for use in medical imaging and labelling applications. Similarly, presented here, they also elicit profound size-dependent anticoagulant properties. Cadmium telluride quantum dot (QDs) (3.2 nm) were shown to have a dramatic anticoagulant effect centred on around the intrinsic coagulation pathway, compared to their 3.6 nm counterparts. Several clinically relevant diagnostic tests were carried out over a concentration range of the QDs and demonstrated that the 3.2 nm QDs elicited their response on the intrinsic pathway as a whole, yet the activity of the individual intrinsic coagulation factors was not affected. The mechanism appears also to be strongly influenced by the concentration of calcium ions and not cadmium ions leached from the QDs. Static and shear-based primary haemostasis assays were also carried out, demonstrating a profound anticoagulant effect which was independent of platelets and phospholipids. The data presented here suggest that the physical-chemical properties of the QDs may have a role in the modulation of haemostasis and the coagulation cascade, in a yet not fully understood mechanism. This study has implications for the use of similar QDs as diagnostic or therapeutic tools in vivo, and for the occupational health and safety of those working with such materials.

We present two new synthetic routes for bismuth ferrite harmonic nanoparticles (BiFeO3 HNPs). Both phase-pure and mixed phase BiFeO3 materials were produced after improvement of the solvent evaporation and sol-gel combustion routes. Metal nitrates with a series of dicarboxylic acids (tartronic, tartaric and mucic) were used to promote crystallization. We found that the longer the carbon backbone with a hydroxyl group attached to each carbon, the lower the annealing temperature. We also demonstrate that nanocrystals more readily formed at a given temperature by adding glycerol but to the detriment of phase purity, whereas addition of NaCl in excess with mucic acid promotes the formation of phase-pure, monocrystalline nanoparticles. This effect was possibly associated with a better dispersion of the primary amorphous precursors and formation of intermediate complexes. The nanoparticles have been characterized by XRD, TEM, ζ-potential, photon correlation spectroscopy, two-photon microscopy and Hyper-Rayleigh Scattering measurements. The improved crystallization leads to BiFeO3 HNPs without defect-induced luminescence and with a very high averaged second harmonic efficiency (220 pm/V), almost triple the efficiency previously reported. This development of simple, scalable synthesis routes which yield phase-pure and, crucially, monocrystalline BiFeO3 HNPs demonstrates a significant advance in engineering the properties of nanocrystals for bio-imaging and diagnostics applications.

Aim: Superparamagnetic iron oxide nanoparticles (SPIONs) may play an important role in nanomedicine by serving as drug carriers and imaging agents. In this study, we present the biodistribution and pharmacokinetic properties of SPIONs using a new detection method, particle electron paramagnetic resonance (pEPR). Materials & methods: The pEPR technique is based on a low-field and low-frequency electron paramagnetic resonance. pEPR was compared with inductively coupled plasma mass spectrometry and MRI, in in vitro and in vivo. Results: The pEPR, inductively coupled plasma mass spectrometry and MRI results showed a good correlation between the techniques. Conclusion: The results indicate that pEPR can be used to detect SPIONs in both preclinical and clinical studies.

The impact of central nervous system (CNS) disorders on the human population is significant, contributing almost €800 billion in annual European healthcare costs. These disorders not only have a disabling social impact but also a crippling economic drain on resources. Developing novel therapeutic strategies for these disorders requires a better understanding of events that underlie mechanisms of neural circuit physiology. Studying the relationship between genetic expression, synapse development and circuit physiology in CNS function is a challenging task, involving simultaneous analysis of multiple parameters and the convergence of several disciplines and technological approaches. However, current gold-standard techniques used to study the CNS have limitations that pose unique challenges to furthering our understanding of functional CNS development. The recent advancement in nanotechnologies for biomedical applications has seen the emergence of nanoscience as a key enabling technology for delivering a translational bridge between basic and clinical research. In particular, the development of neuroimaging and electrophysiology tools to identify the aetiology and progression of CNS disorders have led to new insights in our understanding of CNS physiology and the development of novel diagnostic modalities for therapeutic intervention. This review focuses on the latest applications of these nanotechnologies for investigating CNS function and the improved diagnosis of CNS disorders.

The recent surge in graphene research, since its liquid phase monolayer isolation and characterization in 2004, has led to advancements which are accelerating the exploration of alternative 2D materials such as molybdenum disulphide (MoS2), whose unique physico-chemical properties can be exploited in applications ranging from cutting edge electronic devices to nanomedicine. However, to assess any potential impact on human health and the environment, the need to understand the bio-interaction of MoS2 at a cellular and sub-cellular level is critical. Notably, it is important to assess such potential impacts of materials which are produced by large scale production techniques, rather than research grade materials. The aim of this study was to explore cytotoxicity, cellular uptake and inflammatory responses in established cell-lines that mimic different potential exposure routes (inhalation, A549; ingestion, AGS; monocyte, THP-1) following incubation with MoS2 flakes of varying sizes (50 nm, 117 nm and 177 nm), produced by liquid phase exfoliation. Using high content screening (HCS) and live/dead assays, it was established that 1 μg/ml (for the three different MoS2 sizes) did not induce toxic effects on any of the cell-lines. Confocal microscopy images revealed a normal cellular morphology in all cases. Transmission electron microscopy (TEM) confirmed the uptake of all MoS2 nanomaterials in all the cell-lines, the MoS2 ultimately locating in single membrane vesicles. At such sub-lethal doses, inflammatory responses are observed, however, associated, at least partially, with the presence of lipopolysaccharide endotoxin in nanomaterial suspensions and surfactant samples. Therefore, the inflammatory response of the cells to the MoS2 or endotoxin contamination was interrogated using a 10-plex ELISA which illustrates cytokine production. The experiments carried out using wild-type and endotoxin hyporesponsive bone marrow derived dendritic cells confirmed that the inflammatory responses result from a combination of endotoxin contamination, the MoS2 nanomaterials themselves, and the stabilizing surfactant.

Background Smoking has emerged as a consistent risk factor for ACPA positive RA, although the specific constituents of cigarette smoke that induce citrullination are unknown. It has been hypothesised that cadmium triggers RA as its inhalation links various well established risk factors for RA such as smoking (the most important environmental source of cadmium) and numerous working class occupations [1]. Objectives To determine whether the cadmium-derived materials induce intracellular citrullination. Methods Human A549 lung epithelial cells were exposed to cadmium in ionic and particulate form represented by cadmium chloride and cadmium oxide, respectively, and their combinations with ultrafine carbon black (ufCB) nanoparticles produced following high temperature combustion, imitating cigarette burning. Protein citrullination in cell lysates was analysed by SDS-PAGE electrophoresis with western blotting and verified by immunofluorescence staining and confocal microscopy. Target citrullinated proteins were identified by proteomic analysis. Results Cytotoxicity studies demonstrated that cadmium compounds were toxic to the cells. Based on the results of cytotoxicity measurements, all the materials utilised in the experiments were subsequently applied to the cells in sub-toxic concentrations. Cadmium oxide, ufCB and its combination with cadmium chloride and cadmium oxide after high temperature combustion induced citrullination of multiple proteins in cultured human lung epithelial cells of A549 cell line, as demonstrated by SDS-SDS-PAGE electrophoresis and western blotting. This phenomenon develops via a peptidylargininedeiminase-dependent mechanism, as demonstrated in our previous studies [2]. The majority of citrullinated proteins were represented by the bands corresponding to the molecular weights between 55 and 72 kDa, and several less abundant bands at the level of ∼25kDa and over 130 kDa. Acidic cytokeratins of type I (9, 10) and basic/neutral cytokeratins type II (1, 2, 5, 6A, 6B and 77) were identified as major intracellular citrullination targets. Immunofluorescent staining demonstrated that the citrullinated proteins were localised both in the cytoplasm and nuclei of cells exposed to cadmium particles, similar to the distribution patterns observed in cells exposed to ufCB. Conclusions Cadmium nanoparticle exposure facilitates post-translational citrullination of proteins. References Hutchinson D. Cadmium, one of the villains behind the curtain:has exposure to cadmium helped to pull the strings of seropositive rheumatoid arthritis pathogenesis all along? International journal of rheumatic diseases 2015;18:570–3. Mohamed BM, Verma NK, Davies AM, McGowan A, Crosbie-staunton K, Prina-Mello A, et al. Citrullination of proteins:a common post-translational modification pathway induced by different nanoparticles in vitro and in vivo. Nanomedicine 2012;7:1181–95. Acknowledgements This work has been supported by the Higher Education Authority of Ireland, Science Foundation of Ireland through the Advanced Materials and BioEngineering Research (AMBER) project (Grant #SFI/12/RC/2278) and the Cornwall Arthritis Trust. Disclosure of Interest None declared

Surface protein labeling followed by immunoprecipitation

Gold nanomaterials are currently raising a significant interest for human welfare in the field of clinical diagnosis, therapeutics for chronic pathologies, as well as of many other biomedical applications. In particular, gold nanomaterials are becoming a promising technology for developing novel approaches and treatments against widespread societal diseases such as cancer. In this study, we investigated the potential of proprietary gold nanoboxes (AuNBs) as carriers for their perspective translation into multifunctional, pre-clinical nano-enabled systems for personalized medicine approaches against lung cancer. A safe-by-design, tiered approach, with systematic tests conducted in the early phases on uncoated AuNBs and more focused testing on the coated, drug-loaded nanomaterial toward the end, was adopted. Our results showed that uncoated AuNBs could effectively penetrate into human lung adenocarcinoma (A549) cells when in simple (mono-cultures) or complex (co- and three-dimensional-cultures) in vitro microenvironments mimicking the alveolar region of human lungs. Uncoated AuNBs were biologically inert in A549 cells and demonstrated signs of biodegradability. Concurrently, preliminary data revealed that coated, drug-loaded AuNBs could efficiently deliver a chemotherapeutic agent to A549 cells, corroborating the hypothesis that AuNBs could be used in the future for the development of personalized nano-enabled systems for lung cancer treatment.

Clinically, overexpression of human epidermal growth factor receptor 2 (ErbB2) is considered to be an important hallmark for a number of solitary and metastatic cancers, and has been approved as a drug treatment target for ErbB2-positive cancers. Additionally, the soluble cleaved form of ErbB2 protein (sErbB2), found in blood, has been shown to be a valuable marker for tumour diagnosis in ErbB2-positive breast cancer. Although a variety of clinical diagnostic approaches have been developed to establish ErbB2 load, they each have their own pitfalls. Nanotechnology has offered some promising breakthrough solutions towards imaging and quantifying ErbB2 at the molecular level and holds the possibility of improving the sensitivity and reliability of ErbB2 detection for clinical purposes. Here we review the currently available methods of ErbB2 detection and quantification in biological samples, followed by analysis and evaluation of those nanotechnological approaches which have demonstrated most potential to improve clinical diagnostic practises.

Chirality strongly influences many biological properties of materials, such as cell accumulation, enzymatic activity, and toxicity. In the past decade, it has been shown that quantum dots (QDs), fluorescent semiconductor nanoparticles with unique optical properties, can demonstrate optical activity due to chiral ligands bound on their surface. Optically active QDs could find potential applications in biomedical research, therapy, and diagnostics. Consequently, it is very important to investigate the interaction of QDs capped with chiral ligands with living cells. The aim of our study was to investigate the influence of the induced chirality of Mn-doped ZnS QDs on the viability of A549 cells. These QDs were stabilized with D- and L-cysteine using a ligand exchange technique. The optical properties of QDs were studied using UV-Vis, photoluminescence (PL), and circular dichroism (CD) spectroscopy. The cytotoxicity of QDs was investigated by high content screening analysis. It was found that QDs stabilized by opposite ligand enantiomers, had identical PL and UV-Vis spectra and mirror-imaged CD spectra, but displayed different cytotoxicity: QDs capped with D-cysteine had greater cytotoxicity than L-cysteine capped QDs.