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Supplementary Data from Targeting Melanoma with Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitors

The Insect Allies program of the Defense Advanced Research Projects Agency has already sparked scientific debate concerning technology assessment-related issues, among which the most prevalent is that of dual use. Apart from the issues concerning peaceful applications, the technology also provides the blueprint for a potential bioweapon. However, the combination of a virus-induced genetic modification of crop plants in the field using genetically modified insect vectors poses a greater risk than the hitherto existing use of genetically modified organisms. The technology's great depth of intervention allows a number of sources for hazard and a tendency towards high exposure, but it is also encumbered with notable deficits in knowledge. These issues call for a thorough technology assessment. This article aims to provide an initial characterization from a technology assessment perspective, focusing on potential sources of risk for this novel invasive environmental biotechnology at an early stage of research and development. Integr Environ Assess Manag 2022;18:1488-1499. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental ToxicologyChemistry (SETAC).

Biological redox reactions often use a set-up in which final redox partners are localized in different compartments and electron transfer (ET) among them is mediated by redox-active molecules. In enzymes, these ET processes occur over nm distances, whereas multi-protein filaments bridge μm ranges. Electrons are transported over cm ranges in cable bacteria, which are formed by thousands of cells. In this review, we describe molecular mechanisms that explain how respiration in a compartmentalized set-up ensures redox homeostasis. We highlight mechanistic studies on ET through metal-free peptides and proteins demonstrating that long-distance ET is possible because amino acids Tyr, Trp, Phe, and Met can act as relay stations. This cuts one long ET into several short reaction steps. The chances and challenges of long-distance ET for cellular redox reactions are then discussed.

Rolf Huisgen would have celebrated his 100th birthday this year. Three of his academic progeny look back on Huisgen as a person, teacher, and scientist. They underline his leading role in rebuilding the chemistry department in Munich after the Second World War and the enduring importance of the 1,3-dipolar cycloaddition (Huisgen reaction).

Contamination of the environment with nano-and microplastic particles (NMPs) and its putative adverse effects on organisms, ecosystems, and human health is gaining increasing scientific and public attention. Various studies show that NMPs occur abundantly within the environment, leading to a high likelihood of human exposure to NMPs. Here, different exposure scenarios can occur. The most notable exposure routes of NMPs into the human body are via the airways and gastrointestinal tract (GIT) through inhalation or ingestion, but also via the skin due to the use of personal care products (PCPs) containing NMPs. Once NMPs have entered the human body, it is possible that they are translocated from the exposed organ to other body compartments. In our review article, we combine the current knowledge on the (1) exposure routes of NMPs to humans with the basic understanding of the potential (2) translocation mechanisms into human tissues and, consequently, their (3) fate within the human body. Regarding the (1) exposure routes, we reviewed the current knowledge on the occurrence of NMPs in food, beverages, personal care products and the air (focusing on indoors and workplaces) and found that the studies suggest an abundant presence of MPs within the exposure scenarios. The overall abundance of MPs in exposure matrices relevant to humans highlights the importance of understanding whether NMPs have the potential for tissue translocation. Therefore, we describe the current knowledge on the potential (2) translocation pathways of NMPs from the skin, GIT and respiratory systems to other body compartments. Here, particular attention was paid to how likely NMPs can translocate from the primary exposed organs to secondary organs due to naturally occurring defence mechanisms against tissue translocation. Based on the current understanding, we conclude that a dermal translocation of NMPs is rather unlikely. In contrast, small MPs and NPs can generally translocate from the GIT and respiratory system to other tissues. Thus, we reviewed the existing literature on the (3) fate of NMPs within the human body. Based on the current knowledge of the contamination of human exposure routes and the potential translocation mechanisms, we critically discuss the size of the detected particles reported in the fate studies. In some cases, the particles detected in human tissue samples exceed the size of a particle to overcome biological barriers allowing particle translocation into tissues. Therefore, we emphasize the importance of critically reading and discussing the presented results of NMP in human tissue samples.

This article reviews the current status of nanotechnology with emphasis on application and related environmental considerations as well as legislation. Application and analysis of nanomaterials in infrastructure (construction, building coatings, and water treatment) is discussed, and in particular nanomaterial release during the lifecycle of these applications. Moreover, possible grouping approaches with regard to ecotoxicological and toxicological properties, and the fate of nanomaterials in the environment are evaluated. In terms of potential exposure, the opportunities that arise from leveraging advances in several key areas, such as water treatment and construction are addressed. Additionally, this review describes challenges with regard to the European Commission’s definition of ‘nanomaterial’. The revised REACH information requirements, intended to enable a comprehensive risk assessment of nanomaterials, are outlined.

New biotechnologies such as gene drives and engineered viruses herald a viral era that would give humans exceptional power over any organism at the level of the genotype.

Synthetic gene drives are transgenic constructs that aim to bias heredity and thereby influence the characteristics and fate of populations regarding abundance and evolution. Aside from irreversible effects in ecosystems that could be triggered by the release of a gene drive, research on confinable drives or even the reversibility of gene drives is underway and shows first success under laboratory conditions. However, their effectiveness under realistic conditions is not entirely clear unless first test releases have taken place. Since a potentially irreversible intervention into ecosystems is created, a prospective assessment is needed. We present an approach of prospective ecological vulnerability analysis for the proposed control of the invasive pest Drosophila suzukii by using gene drives. The analysis considers the accidental spread of the gene drive to the native habitat of Drosophila suzukii, with a focus on Japan. It contains a mapping of potential impacts as a consequence of the suppression of the insect. Multiple cascading effects were identified including the potential spread of the gene drive in geographic range or potential hybridization with non-target species. Determining the vulnerability of an ecosystem requires information regarding specific characteristics at different organizational levels. The vulnerability analysis of an affected ecosystem will initially serve to identify gaps in knowledge. Reducing complexity and breaking down the potential events that might arise from a gene drive population suppression enables to better understand endpoints i.e. concrete effects. Three potential effects have been selected for a specific analysis of the vulnerability of populations and species. A high vulnerability was obtained for the suppression of non-target (native) populations of Drosophila suzukii as well as for a decrease in specialized parasitoid abundance. The paper proposes the outline of a comprehensive prospective approach to understand the susceptibility of an ecosystem to unintended and irreversible harm.

Metal nanoparticles (NPs), chalcogenides, and carbon quantum dots can be easily synthesized from whole microorganisms (fungi and bacteria) and cell‐free sterile filtered spent medium. The particle size distribution and the biosynthesis time can be somewhat controlled through the biomass/metal solution ratio. The biosynthetic mechanism can be explained through the ion‐reduction theory and UV photoconversion theory. Formation of biosynthetic NPs is part of the detoxification strategy employed by microorganisms, either in planktonic or biofilm form, to reduce the chemical toxicity of metal ions. In fact, most reports on NP biosynthesis show extracellular metal ion reduction. This is important for environmental and industrial applications, particularly in biofilms, as it allows in principle high biosynthetic rates. The antimicrobial and antifungal effect on biosynthetic NPs can be explained in terms of reactive oxygen species and can be enhanced by the capping agents attached to the NP during the biosynthesis process. Industrial applications of NP biosynthesis are still lagging, due to the difficulty of controlling NP size and low titer. Further, the environmental assessment of biosynthetic NPs has not yet been carried out. It is expected that further advancements in biosynthetic NP research will lead to applications, particularly in environmental biotechnology.

Vulnerability analysis can be seen as the counterpart to technology characterization. Technology characterisation scrutinises the intervening technology. Vulnerability analyses potentially affected systems. That may be socio-ecological, socio-technical, socio-economic or other systems. In this chapter ecological systems are in focus.

Besides great expectations in terms of public health and nature protection gene drives (GD) have raised serious concerns because of their inherent functionality to spread and invade natural populations. Not only does this novel technology pose a paradigm shift for the release of genetically engineered organisms (GMOs) as GDs are intended to spread within wild populations. A released GD thus represents an unprecedented intervention into the molecular foundation of natural populations, transforming them into GMOs themselves. Once released, it can hardly be retrieved at the current stage of development. The investigations of the potential impacts of GD-applications are complex and still at the very beginning. Up to now, consequences are not foreseeable in the case of malfunction. Thus, precautionary risk management has to find ways to adequately deal with lacking knowledge up to complete ignorance about potential adverse effects. Three main options are available for risk management, first, a reduction of exposure by strategies of containment, second, a substitution by socio-technical alternatives that fulfil comparable functions combined with lower exposure- and hazard potentials and third an integration of responsible research and innovation in the technological development by choosing potential low risk development paths from the very beginning. In this chapter, we analyse and compare different types of gene drives as well as promising alternative approaches that may provide a reduced risk potential.

The effects of toxic Microcystis aeruginosa on the liver of Nile tilapia, Oreochromis niloticus were investigated in the laboratory. Four treatments were setup into aquariums for 15 days to investigate the histopathological changes exposed to Microcystis aeruginosa bloom. Fishes of treatment A1 were treated as a control group and given artificial feed. In the three treatments (A 2 , A 3 and A 4 ), the M. aeruginosa cell concentration were 35 × 10 2 , 72 × 10 2 , 149 × 10 2 colony/ml, respectively. In the control group, no histopathological change was observed. In exposed fish, histopathological alterations were characterized by swollen and granular cytoplasm, vascular proliferation, bile stasis, fatty change and focal necrosis. Histopathological changes were observed within five days of exposure when fish exposed to moderate (72 × 10 2 colony/ml) to high (149 × 10 2 colony/ml) bloom concentration, whereas it took 15 days in lower concentration (35 × 10 2 colony/ml). Histopathological changes proved that intake of toxic M. aeruginosa bloom by aquatic animals, particularly Nile tilapia has significant effects on its internal organs that may cause of massive mortality. Accordingly, cyanotoxin accumulation in fish tissue my pose a risk to human health through the food chain. Bangladesh J. Zool. 45 (1): 1-10, 2017

Die Reduktion von Ag+-Ionen zu Ag0-Atomen ist ein stark endergonischer Schritt, und erst die Aggregation zu Agn-Clustern fuhrt zu einem exergonischen Prozess. Diese elementaren Reaktionen spielen eine entscheidende Rolle, wenn Ag-Nanopartikel (AgNPs) durch Elektronentransfer(ET)-Reaktionen aus Ag+-Ionen erzeugt werden. Wir haben sowohl die Bildung von AgNPs durch photoinduzierten ET in Peptiden, als auch durch ET in c-Cytochromen uber deren Fe2+-Hame untersucht. Unsere fruheren photoinduzierten ET-Experimente in Peptiden hatten gezeigt, dass Histidin die Bildung von AgNPs hemmt. Nun konnten wir zeigen, dass AgNPs gebildet werden konnen, wenn Aminosauren verwendet werden, die Ag+-Ionen schwacher binden als Histidin, und zwar mit steigender Bildungsrate von Lysin

The reduction of Ag+ ions to Ag0 atoms is a highly endergonic reaction step, only the aggregation to Agn clusters leads to an exergonic process. These elementary chemical reactions play a decisive role if Ag nanoparticles (AgNPs) are generated by electron transfer (ET) reactions to Ag+ ions. We studied the formation of AgNPs in peptides by photoinduced ET, and in c-cytochromes by ET from their Fe2+ /hemes. Our earlier photoinduced experiments in peptides had demonstrated that histidine prevents AgNP formation. We have now observed that AgNPs can be easily synthesized with less-efficient Ag+ -binding amino acids, and the rate increases in the order lysine

Anaerobic microorganisms of the Geobacter genus are effective electron sources for the synthesis of nanoparticles, for bioremediation of polluted water, and for the production of electricity in fuel cells. In multistep reactions, electrons are transferred via iron/heme cofactors of c‐type cytochromes from the inner cell membrane to extracellular metal ions, which are bound to outer membrane cytochromes. We measured electron production and electron flux rates to 5×105 e s−1 per G. sulfurreducens. Remarkably, these rates are independent of the oxidants, and follow zero order kinetics. It turned out that the microorganisms regulate electron flux rates by increasing their Fe2+/Fe3+ ratios in the multiheme cytochromes whenever the activity of the extracellular metal oxidants is diminished. By this mechanism the respiration remains constant even when oxidizing conditions are changing. This homeostasis is a vital condition for living systems, and makes G. sulfurreducens a versatile electron source.

International audience; Gene Drives are regarded as future tools with a high potential for population control. Due to their inherent ability to overcome the rules of Mendelian inheritance, gene drives (GD) may spread genes rapidly through populations of sexually reproducing organisms. A release of organisms carrying a GD would constitute a paradigm shift in the handling of genetically modified organisms because gene drive organisms (GDO) are designed to drive their transgenes into wild populations and thereby increase the number of GDOs. The rapid development in this field and its focus on wild populations demand a prospective risk assessment with a focus on exposure related aspects. Presently, it is unclear how adequate risk management could be guaranteed to limit the spread of GDs in time and space, in order to avoid potential adverse effects in socio-ecological systems. The recent workshop on the “Evaluation of Spatial and Temporal Control of Gene Drives” hosted by the Institute of Safety/Security and Risk Sciences (ISR) in Vienna aimed at gaining some insight into the potential population dynamic behavior of GDs and appropriate measures of control. Scientists from France, Germany, England, and the USA discussed both topics in this meeting on April 4–5, 2019. This article summarizes results of the workshop.

Food analysis has been gaining interest throughout recent decades for different reasons: the detection of hazardous substances in food and routine investigations of food composition and vitamin/nutrient contents. Regardless of the targeted component, food analysis raises a few challenges regarding the complexity of the matrix and detecting trace amounts of substances. We report herein the results obtained regarding the simultaneous detection of two B vitamins (riboflavin, vitamin B2 and cyanocobalamin, vitamin B12) by means of SERS. SERS provides molecular fingerprint identification and high analytical sensitivity together with a low processing time and cost. All these make SERS a promising tool for the development of food analytical methods.

The Saturnian satellite Tethys exhibits geological and spectral properties, whose appearance, nature and spatial distribution partly mirror those identified on the neighboring satellites Dione and Rhea or fit to the picture how spectral surface properties are expected to change from one satellite to the other within the inner Saturnian system. However, we also identified spectral variations that are unique in the Saturnian system. Whereas geologically young surface features are characterized by pure H2O-ice composition with relatively large particles, which match the particle sizes measured for fresh surface features also on Dione and Rhea, geologically old weathered regions are dominated by submicron-sized ice particles. Our investigations confirm that the Odysseus impact event did not cause the formation of Tethys' extended graben system Ithaca Chasma. On the contrary, Odysseus might be responsible for the N-S trending 'icy' bands that mark Tethys' surface in the center of its leading and trailing hemisphere.

In nature, proteins serve as media for long-distance electron transfer (ET) to carry out redox reactions in distant compartments. This ET occurs either by a single-step superexchange or through a multi-step charge hopping process, which uses side chains of amino acids as stepping stones. In this study we demonstrate that Phe can act as a relay amino acid for long-distance electron hole transfer through peptides. The considerably increased susceptibility of the aromatic ring to oxidation is caused by the lone pairs of neighbouring amide carbonyl groups, which stabilise the Phe radical cation. This neighbouring-amide-group effect helps improve understanding of the mechanism of extracellular electron transfer through conductive protein filaments (pili) of anaerobic bacteria during mineral respiration.

Long distance electron transfer in proteins requires relay stations that can be transitorily oxidized or reduced. Although individual prolines cannot assume this function, because of their high ionization energy, it has been shown that polyprolines have the ability to transfer charges. In order to determine the role of the proline in the hole distribution and transport within a PheProPhe tripeptide, the radical cation of a model compound where the phenylalanines carry two or three methoxy groups, respectively, was generated by flash photolysis. Surprisingly, after equilibration, about two thirds of the holes were found to reside on the phen(OMe)2 instead of the more easily oxidizable phen(OMe)3 moiety. DFT calculations showed that, in most of the accessible conformations, the phen(OMe)2• +-moiety profits more from stabilization by N- and/or O-lone pairs of neighboring amide groups than the phen(OMe)3• + moiety can, which explains the apparently counterthermodynamic hole distribution. Similar calculations showed that, in several conformers of the natural PheProPhe radical cation, the unpaired electron is delocalized over two amide groups, by residing in a σ MO which links the N-lone pair of the central proline unit with the O-lone pair of a proximate amino acid, through hyperconjugation via the intervening C―Cα σ-bond. The same pattern is found in a model compound, N-acetylproline dimethylamide. It seems that prolines favor conformers which foster hyperconjugation of two amide groups, which lowers the ionization energy of peptides. One should thus consider such interacting amide groups as potential relay stations in the course of electron transfer in polyprolines. Copyright © 2015 John Wiley & Sons, Ltd.

We have mapped the locations of over 100,000 ice blocks across the south polar region of Saturn’s moon Enceladus, thus generating the first quantitative estimates of ice-block number density distribution in relation to major geological features. Ice blocks were manually identified and mapped from twenty of the highest resolution (4–25 m per pixel) Cassini Imaging Science Subsystem (ISS) narrow-angle images using ArcGIS software. The 10–100 m-diameter positive-relief features are marginally visible at the resolution of the images, making ice-block identifications difficult but not impossible. Our preliminary results reveal that ice blocks in the southern hemisphere are systematically most concentrated within the geologically active South Polar Terrain (SPT) and exhibit peak concentrations within 20 km of the tiger-stripe fractures as well as close to the south pole. We find that ice blocks are concentrated just as heavily between tiger-stripe fractures as on the directly adjacent margins; although significant local fluctuations in ice-block number density do occur, we observe no clear pattern with respect to the tiger stripes or jet sources. We examine possible roles of several mechanisms for ice-block origin, emplacement, and evolution: impact cratering, ejection from fissures during cryovolcanic eruptions, tectonic disruption of lithospheric ice, mass wasting, seismic disturbance, and vapor condensation around icy fumeroles. We conclude that impact cratering as well as mass wasting, perhaps triggered by seismic events, cannot account for a majority of ice-block features within the inner SPT. The pervasiveness of fracturing at many size scales, the ubiquity of ice blocks in the inner SPT, as well as the occurrence of linear block arrangements that parallel through-cutting crack networks along the flanks of tiger stripes indicate that tectonic deformation is an important source of blocky-ice features in the SPT. Ejection during catastrophic cryovolcanic eruptions and condensation around surface vents, however, cannot be ruled out. Further, sublimation processes likely erode and disaggregate ice blocks from solid exposures of ice, especially near the warm tiger-stripe fractures. The relative paucity of blocks beyond the bounds of the SPT, particularly on stratigraphically old cratered terrains, may be explained in part by mantling of the surface by fine particulate ice grains that accumulate over time.

We used 126 Voyager-1 and -2 as well as 87 Galileo images of Ganymede and searched for stereo images suitable for digital 3D stereo analysis. Specifically, we consider image resolutions, stereo angles, as well as matching illumination conditions of respective stereo pairs. Lists of regions and local areas with stereo coverage are compiled. We present anaglyphs and we selected areas, not previously discussed, for which we constructed Digital Elevation Models and associated visualizations. The terrain characteristics in the models are in agreement with our previous notion of Ganymede morphology, represented by families of lineaments and craters of various sizes and degradation stages. The identified areas of stereo coverage may serve as important reference targets for the Ganymede Laser Altimeter (GALA) experiment on the future JUICE (Jupiter Icy Moons Explorer) mission.

For frequently used engineered nanomaterials (ENMs) CeO2-, SiO2-, and Ag, past, current, and future use and environmental release are investigated. Considering an extended period (1950 to 2050), we assess ENMs released through commercial activity as well as found in natural and technical settings. Temporal dynamics, including shifts in release due to ENM product application, stock (delayed use), and subsequent end-of-life product treatment were taken into account. We distinguish predicted concentrations originating in ENM use phase and those originating from end-of-life release. Furthermore, we compare Ag- and CeO2-ENM predictions with existing measurements. The correlations and limitations of the model, and the analytic validity of our approach are discussed in the context of massive use of assumptive model data and high uncertainty on the colloidal material captured by the measurements. Predictions for freshwater CeO2-ENMs range from 1 pg/l (2017) to a few hundred ng/l (2050). Relative to CeO2, the SiO2-ENMs estimates are approximately 1,000 times higher, and those for Ag-ENMs 10 times lower. For most environmental compartments, ENM pose relatively low risk; however, organisms residing near ENM ‘point sources’ (e.g., production plant outfalls and waste treatment plants), which are not considered in the present work, may be at increased risk.

Long-distance transfer of a positive charge through DNA can be described by a hopping model. In double strands where the (A:T)n bridges between the guanines are short (n 3), the charge hops only between guanines, and each hopping step depends strongly upon the guanine to guanine distances. In strands where the (A:T)n sequences between the guanines are rather long (n 4), also the adenines act as charge carriers. To predict the yields of the H2O-trapping products one has to take into account not only the charge-transfer rates but also the rates of H2O-trapping reactions.

The small (approximately 500 km in diameter) satellite Enceladus is moving near the equatorial plane and deep in the gravity field of its parent planet Saturn. Owing to tidal interaction with its parent, Enceladus has adopted a pronounced 3-axial ellipsoidal shape and is tidally locked, with rotational and orbital periods of about 1.37 days. As the equator of Saturn is inclined to the planet’s orbital plane, Enceladus, like most of the other satellites of Saturn, undergoes pronounced seasons. This paper gives a summary of the current status as well as shortcomings of our current knowledge regarding Enceladus’ geodetic and dynamic parameters.