Magnetic iron oxide nanoparticles as MRI contrast agents - a comprehensive physical and theoretical study

Magnetite nanoparticles, especially superparamagnetic iron oxide nanoparticles, are established contrast agents for magnetic resonance imaging. Magnetosomes, which are magnetite nanoparticles of biological origin, have been shown to have better contrast properties than current formulations possibly because of their larger size and high monodispersity. Here, we present an integrated study of magnetosomes and synthetic magnetite nanoparticles of varying size, hence, magnetic properties. We investigate not only the relaxation times as a measure for the contrast properties of these particles, but also their cytotoxicity and demonstrate the higher contrast of the larger particles. A theoretical model is presented that enables us to simulate the R2=R1 ratio of a contrast agent and con�rm that larger particles offer higher contrast. The results from this study illustrate the possibility to obtain colloidal stability of large magnetic nanoparticles for magnetic resonance imaging applications and serve as an impetus for a more quantitative description of the contrast effect as a function of the size

Genomic Expansion of Magnetotactic Bacteria Reveals an Early Common Origin of Magnetotaxis with Lineage-specific Evolution

The origin and evolution of magnetoreception, which in diverse prokaryotes and protozoa is known as magnetotaxis and enables these microorganisms to detect Earth’s magnetic field for orientation and navigation, is not well understood in evolutionary biology. The only known prokaryotes capable of sensing the geomagnetic field are magnetotactic bacteria (MTB), motile microorganisms that biomineralize intracellular, membrane-bounded magnetic single-domain crystals of either magnetite (Fe3O4) or greigite (Fe3S4) called magnetosomes. Magnetosomes are responsible for magnetotaxis in MTB. Here we report the first large-scale metagenomic survey of MTB from both northern and southern hemispheres combined with 28 genomes from uncultivated MTB. These genomes expand greatly the coverage of MTB in the Proteobacteria, Nitrospirae, and Omnitrophica phyla, and provide the first genomic evidence of MTB belonging to the Zetaproteobacteria and “Candidatus Lambdaproteobacteria” classes. The gene content and organization of magnetosome gene clusters, which are physically grouped genes that encode proteins for magnetosome biosynthesis and organization, are more conserved within phylogenetically similar groups than between different taxonomic lineages. Moreover, the phylogenies of core magnetosome proteins form monophyletic clades. Together, these results suggest a common ancient origin of iron-based (Fe3O4 and Fe3S4) magnetotaxis in the domain Bacteria that underwent lineage-specific evolution, shedding new light on the origin and evolution of biomineralization and magnetotaxis, and expanding significantly the phylogenomic representation of MTB

Flow cytometry as a rapid analytical tool to determine physiological responses to changing O2 and iron concentration by Magnetospirillum gryphiswaldense strain MSR-1

Magnetotactic bacteria (MTB) are a diverse group of bacteria that synthesise magnetosomes, magnetic membrane-bound nanoparticles that have a variety of diagnostic, clinical and biotechnological applications. We present the development of rapid methods using flow cytometry to characterize several aspects of the physiology of the commonly-used MTB Magnetospirillum gryphiswaldense MSR-1. Flow cytometry is an optical technique that rapidly measures characteristics of individual bacteria within a culture, thereby allowing determination of population heterogeneity and also permitting direct analysis of bacteria. Scatter measurements were used to measure and compare bacterial size, shape and morphology. Membrane permeability and polarization were measured using the dyes propidium iodide and bis-(1,3-dibutylbarbituric acid) trimethine oxonol to determine the viability and ‘health’ of bacteria. Dyes were also used to determine changes in concentration of intracellular free iron and polyhydroxylakanoate (PHA), a bacterial energy storage polymer. These tools were then used to characterize the responses of MTB to different O2 concentrations and iron-sufficient or iron-limited growth. Rapid analysis of MTB physiology will allow development of bioprocesses for the production of magnetosomes, and will increase understanding of this fascinating and useful group of bacteria

Fur in Magnetospirillum gryphiswaldense Influences Magnetosomes Formation and Directly Regulates the Genes Involved in Iron and Oxygen Metabolism

Magnetospirillum gryphiswaldense strain MSR-1 has the unique capability of taking up large amounts of iron and synthesizing magnetosomes (intracellular magnetic particles composed of Fe3O4). The unusual high iron content of MSR-1 makes it a useful model for studying biological mechanisms of iron uptake and homeostasis. The ferric uptake regulator (Fur) protein plays a key role in maintaining iron homeostasis in many bacteria. We identified and characterized a fur-homologous gene (MGR_1314) in MSR-1. MGR_1314 was able to complement a fur mutant of E. coli in iron-responsive manner in vivo. We constructed a fur mutant strain of MSR-1. In comparison to wild-type MSR-1, the mutant strain had lower magnetosome formation, and was more sensitive to hydrogen peroxide and streptonigrin, indicating higher intracellular free iron content. Quantitative real-time RT-PCR and chromatin immunoprecipitation analyses indicated that Fur protein directly regulates expression of several key genes involved in iron transport and oxygen metabolism, in addition it also functions in magnetosome formation in M. gryphiswaldense

Avaliaçao Clínica da Estimulaçao em Malha Fechada usando Estimulaçao Ventricular e Eventos de Sensibilidade: um Estudo Multicêntrico

Introduçao: O conceito de Estimulaçao em Malha Fechada usa medidas da impedância intracardíaca, obtidas no ventrículo direito, para detectar mudanças na contratilidade miocárdica e assim adaptar a freqüência de estimulaçao. Objetivo: Avaliar um método estimulaçao em malha fechada que supera a limitaçao dos sistemas anteriores. Métodos: Participaram do estudo 27 portadores de marcapasso Protos DR/CLS. O protocolo incluiu teste ergométrico em esteira e teste ortostático, bem como registro das tendências da freqüência cardíaca no período de 24 horas. As freqüências obtidas durante o exercício em esteira foram correlacionadas com o modelo linear de Wilkoff. Resultados: A média da curva de regressao foi de 0,851, com intervalo de confiança de 95% de [0,705; 0,996] (N = 14). O aumento da freqüência média correlacionada com a mudança da posiçao supina para em pé foi de 12,9 bpm (N = 8). O aumento médio da freqüência máxima observada na transiçao da posiçao supina esquerda/direita para supina direita/esquerda foi 3,2 bpm (N = 15). A diferença da freqüência circadiana média foi 9,3 bpm (N = 35). A diferença de freqüência para cada paciente foi obtida a partir média das freqüências cardíacas diurna e noturna. Conclusao: O método mostrou-se seguro e efetivo e comportou-se de forma fisiológica no contexto das mudanças avaliadas

Interplay of Magnetic Interactions and Active Movements in the Formation of Magnetosome Chains

Magnetotactic bacteria assemble chains of magnetosomes, organelles that contain magnetic nano-crystals. A number of genetic factors involved in the controlled biomineralization of these crystals and the assembly of magnetosome chains have been identified in recent years, but how the specific biological regulation is coordinated with general physical processes such as diffusion and magnetic interactions remains unresolved. Here, these questions are addressed by simulations of different scenarios for magnetosome chain formation, in which various physical processes and interactions are either switched on or off. The simulation results indicate that purely physical processes of magnetosome diffusion, guided by their magnetic interactions, are not sufficient for the robust chain formation observed experimentally and suggest that biologically encoded active movements of magnetosomes may be required. Not surprisingly, the chain pattern is most resembling experimental results when both magnetic interactions and active movement are coordinated. We estimate that the force such active transport has to generate is compatible with forces generated by the polymerization or depolymerization of cytoskeletal filaments. The simulations suggest that the pleiotropic phenotypes of mamK deletion strains may be due to a defect in active motility of magnetosomes and that crystal formation in magneteosome vesicles is coupled to the activation of their active motility in M. gryphiswaldense, but not in M. magneticum

Avaliaçao Clínica da Estimulaçao em Malha Fechada usando Estimulaçao Ventricular e Eventos de Sensibilidade: um Estudo Multicêntrico

Introduçao: O conceito de Estimulaçao em Malha Fechada usa medidas da impedância intracardíaca, obtidas no ventrículo direito, para detectar mudanças na contratilidade miocárdica e assim adaptar a freqüência de estimulaçao. Objetivo: Avaliar um método estimulaçao em malha fechada que supera a limitaçao dos sistemas anteriores. Métodos: Participaram do estudo 27 portadores de marcapasso Protos DR/CLS. O protocolo incluiu teste ergométrico em esteira e teste ortostático, bem como registro das tendências da freqüência cardíaca no período de 24 horas. As freqüências obtidas durante o exercício em esteira foram correlacionadas com o modelo linear de Wilkoff. Resultados: A média da curva de regressao foi de 0,851, com intervalo de confiança de 95% de [0,705; 0,996] (N = 14). O aumento da freqüência média correlacionada com a mudança da posiçao supina para em pé foi de 12,9 bpm (N = 8). O aumento médio da freqüência máxima observada na transiçao da posiçao supina esquerda/direita para supina direita/esquerda foi 3,2 bpm (N = 15). A diferença da freqüência circadiana média foi 9,3 bpm (N = 35). A diferença de freqüência para cada paciente foi obtida a partir média das freqüências cardíacas diurna e noturna. Conclusao: O método mostrou-se seguro e efetivo e comportou-se de forma fisiológica no contexto das mudanças avaliadas

Jahrbuch Wirtschaftsrecht Schweiz - EU - Überblick und Kommentar 2022/23

Der vorliegende 18. Band der Jahrbuchreihe „Wirtschaftsrecht Schweiz – EU“ dokumentiert die aktuellen Entwicklungen in zentralen Bereichen des EU-Wirtschaftsrechts und deren Bedeutung für die Schweiz. Berücksichtigt werden diverse wirtschaftsrelevante Rechtsgebiete, u.a. Kapitalmarktrecht, Immaterialgüterrecht, Arbeitsrecht, Steuerrecht und Wettbewerbsrecht. Das Jahrbuch richtet sich an Unternehmens-, Wirtschafts- und VerwaltungsjuristInnen sowie an RichterInnen und RechtsanwältInnen und bietet ihnen einen kompakten Überblick über die wichtigsten Gesetzgebungsvorstösse, neue Rechtsakte und ergangene Urteile im vergangenen Jahr 2022

P2RX7 gene variants associate with altered inflammasome assembly and reduced pyroptosis in chronic nonbacterial osteomyelitis (CNO).

Chronic nonbacterial osteomyelitis (CNO), an autoinflammatory bone disease primarily affecting children, can cause pain, hyperostosis and fractures, affecting quality-of-life and psychomotor development. This study investigated CNO-associated variants in P2RX7, encoding for the ATP-dependent trans-membrane K+ channel P2X7, and their effects on NLRP3 inflammasome assembly. Whole exome sequencing in two related transgenerational CNO patients, and target sequencing of P2RX7 in a large CNO cohort (N = 190) were conducted. Results were compared with publicly available datasets and regional controls (N = 1873). Findings were integrated with demographic and clinical data. Patient-derived monocytes and genetically modified THP-1 cells were used to investigate potassium flux, inflammasome assembly, pyroptosis, and cytokine release. Rare presumably damaging P2RX7 variants were identified in two related CNO patients. Targeted P2RX7 sequencing identified 62 CNO patients with rare variants (32.4%), 11 of which (5.8%) carried presumably damaging variants (MAF 20). This compared to 83 of 1873 controls (4.4%), 36 with rare and presumably damaging variants (1.9%). Across the CNO cohort, rare variants unique to one (Median: 42 versus 3.7) or more (≤11 patients) participants were over-represented when compared to 190 randomly selected controls. Patients with rare damaging variants more frequently experienced gastrointestinal symptoms and lymphadenopathy while having less spinal, joint and skin involvement (psoriasis). Monocyte-derived macrophages from patients, and genetically modified THP-1-derived macrophages reconstituted with CNO-associated P2RX7 variants exhibited altered potassium flux, inflammasome assembly, IL-1β and IL-18 release, and pyroptosis. Damaging P2RX7 variants occur in a small subset of CNO patients, and rare P2RX7 variants may represent a CNO risk factor. Observations argue for inflammasome inhibition and/or cytokine blockade and may allow future patient stratification and individualized care