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Background and Objective Astaxanthin is a naturally occurring carotenoid with high anti-oxidant properties, but it is a very lipophilic compound with low oral bioavailability. This study was conducted to compare the pharmacokinetic parameters of a novel astaxanthin preparation based on micellar solubilization technology, NovaSOL ® 400-mg capsules (Test product), and those of astaxanthin 400-mg capsules (reference product), after single oral dose administration to healthy male adults. Methods A single oral dose (400 mg equivalent to 8 mg astaxanthin) of test and reference astaxanthin were administered with 240 mL of water to 12 volunteers according to crossover design, in two phases, with a washout period of 1 week in between. Blood samples were collected at hourly intervals for the first 12 h, then at 24.0, 48.0, and 72.0 h after administration. Aliquots of plasma were centrifuged and the clear supernatant was injected into the high performance liquid chromatography–diode array detection (HPLC-DAD) system. Plasma concentration of astaxanthin versus time profiles were constructed, and the primary pharmacokinetic parameters, maximum concentration ( C max ), area under concentration time curve from time of administration (0) to time (t) [AUC 0-t ] or to infinity ∞, [AUC 0-∞ ],  half-life ( T ½ ) and time to reach C max ( T max ) were calculated. Results The test micellar astaxanthin reached a C max of 7.21 µg/ml after 3.67 h compared to only 3.86 µg/ml after 8.5 h for the reference native astaxanthin. Conclusion Micellar formulation of astaxanthin is capable of producing a high concentration of astaxanthin in plasma in a shorter time, thereby expected to provide faster potential therapeutic efficacy.

Mitigation pathways exploring end-of-century temperature targets often entail temperature overshoot. Little is known about the additional climate risks generated by overshooting temperature. Here we assessed the benefits of limiting overshoot. We computed the probabilistic impacts for different warming targets and overshoot levels on the basis of an ensemble of integrated assessment models. We explored both physical and macroeconomic impacts, including persistent and non-persistent climate impacts. We found that temperature overshooting affects the likelihood of many critical physical impacts, such as those associated with heat extremes. Limiting overshoot reduces risk in the right tail of the distribution, in particular for low-temperature targets where larger overshoots arise as a way to lower short-term mitigation costs. We also showed how, after mid-century, overshoot leads to both higher mitigation costs and economic losses from the additional impacts. The study highlights the need to include climate risk analysis in low-carbon pathways.Mitigation pathways allowing for temperature overshoot often ignore the related climate and macroeconomic impacts. Net-zero pathways with limited overshoot could reduce low-probability high-consequence risks and economic loss.

Understanding the drivers of yield levels under climate change is required to support adaptation planning and respond to changing production risks. This study uses an ensemble of crop models applied on a spatial grid to quantify the contributions of various climatic drivers to past yield variability in grain maize and winter wheat of European cropping systems (1984-2009) and drivers of climate change impacts to 2050. Results reveal that for the current genotypes and mix of irrigated and rainfed production, climate change would lead to yield losses for grain maize and gains for winter wheat. Across Europe, on average heat stress does not increase for either crop in rainfed systems, while drought stress intensifies for maize only. In low-yielding years, drought stress persists as the main driver of losses for both crops, with elevated CO2 offering no yield benefit in these years.

Global emissions scenarios play a critical role in the assessment of strategies to mitigate climate change. The current scenarios, however, are criticized because they feature strategies with pronounced overshoot of the global temperature goal, requiring a long-term repair phase to draw temperatures down again through net-negative emissions. Some impacts might not be reversible. Hence, we explore a new set of net-zero CO2 emissions scenarios with limited overshoot. We show that upfront investments are needed in the near term for limiting temperature overshoot but that these would bring long-term economic gains. Our study further identifies alternative configurations of net-zero CO2 emissions systems and the roles of different sectors and regions for balancing sources and sinks. Even without net-negative emissions, CO2 removal is important for accelerating near-term reductions and for providing an anthropogenic sink that can offset the residual emissions in sectors that are hard to abate.Current emissions scenarios include pathways that overshoot the temperature goals set out in the Paris Agreement and rely on future net negative emissions. Limiting overshoot would require near-term investment but would result in longer-term economic benefit.

•Micellar curcumin is much more active than the native extract in inhibiting paw edema induced by adjuvant inoculation.•Reduction in paw volume is associated with a decrease in inflammatory cytokines, C-reactive protein (CRP), and myeloperoxidase (MPO).•Micellar curcumin shows potent antioxidant activity by reducing the thiobarbituric acid reactive substances (TBARS) level and raising the total antioxidant activity.•Combining micellar curcumin with micellar boswellia markedly enhances its antiinflammatory and antioxidant activity. [Display omitted] Using advanced micellation technology, stable solubilisates of curcumin and boswellia extracts with markedly enhanced bioavailability were prepared. The drugs were given daily for 3 weeks, starting from the day of Freund complete adjuvant innoculation. Solubilized curcumin showed a reduction in paw volume, tumor necrosis factor-α, interleukin-6 and C-reactive protein, myloperoxidase and lipid peroxidation markers as well as an increase in total antioxidant capacity, an effect which wass equivalent to diclofenac. The native forms showed no significant effect compared to control untreated groups. Native extracts of curcumin and boswellia are known to exert antiinflammatory properties but have poor bioavailability when given orally. Using advanced micellation technology, it has been possible to produce stable solubilisates of these extracts with markedly enhanced bioavailability. In the present study, we compared the chronic antiinflammatory activities of native and micellar curcumin in the rat adjuvant arthritis model, using diclofenac as a reference drug. Adjuvant arthritis was induced by injecting Freund's complete adjuvant (FCA) into the right hind paw of rats and monitoring paw volume over 3 wk. The drugs were given daily for 3 wk, starting from the day of adjuvant inoculation. The serum was collected at end of the experiment for the assay of inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test. Solubilized curcumin showed better antiinflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), myeloperoxidase (MPO), and lipid peroxidation markers. The combination of curcumin and boswellia solubilisates synergistically produced an even more potent therapeutic effect. The findings confirm that micellar solubilisation of curcumin and boswellia not only increases their bioavailability, but also enhances their biological activity. Micellar curcumin, in particular in combination with micellar boswellia, may thus represent a promising concomitant tool for antiinflammatory treatment and a potential antiinflammatory alternative to synthetic drugs.

In this paper, we provide an overview of how Safe-by-Design is conceived and applied in practice in a large number of engineering disciplines. We discuss the differences, commonalities, and possibilities for mutual learning found in those practices and identify several ways of putting those disciplinary outlooks in perspective. The considered engineering disciplines in the order of historically grown technologies are construction engineering, chemical engineering, aerospace engineering, urban engineering, software engineering, bio-engineering, nano-engineering, and finally cyber space engineering. Each discipline is briefly introduced, the technology at issue is described, the relevant or dominant hazards are examined, the social challenge(s) are observed, and the relevant developments in the field are described. Within each discipline the risk management strategies, the design principles promoting safety or safety awareness, and associated methods or tools are discussed. Possible dilemmas that the designers in the discipline face are highlighted. Each discipline is concluded by discussing the opportunities and bottlenecks in addressing safety. Commonalities and differences between the engineering disciplines are investigated, specifically on the design strategies for which empirical data have been collected. We argue that Safe-by-Design is best considered as a specific elaboration of Responsible Research and Innovation, with an explicit focus on safety in relation to other important values in engineering such as well-being, sustainability, equity, and affordability. Safe-by-Design provides for an intellectual venue where social science and the humanities (SSH) collaborate on technological developments and innovation by helping to proactively incorporate safety considerations into engineering practices, while navigating between the extremes of technological optimism and disproportionate precaution. As such, Safe-by-Design is also a practical tool for policymakers and risk assessors that helps shape governance arrangements for accommodating and incentivizing safety, while fully acknowledging uncertainty.

Concentrations of total suspended particulate matter, particulate matter with aerodynamic diameter <2.5 μm (PM2.5), particulate matter <10 μm (PM10), and fallout dust were measured at the Iranian Gol-E-Gohar Mining and Industrial Facility. Samples were characterized in terms of mineralogy, morphology, and oxidative potential. Results show that indoor samples exceeded the 24-h PM2.5 and PM10 mass concentration limits (35 and 150 µg m−3, respectively) set by the US National Ambient Air Quality Standards. Calcite, magnetite, tremolite, pyrite, talc, and clay minerals such as kaolinite, vermiculite, and illite are the major phases of the iron ore PM. Accessory minerals are quartz, dolomite, hematite, actinolite, biotite, albite, nimite, laumontite, diopside, and muscovite. The scanning electron microscope structure of fibrous-elongated minerals revealed individual fibers in the range of 1.5 nm to 71.65 µm in length and 0.2 nm to 3.7 µm in diameter. The presence of minerals related to respiratory diseases, such as talc, crystalline silica, and needle-shaped minerals like amphibole asbestos (tremolite and actinolite), strongly suggests the need for detailed health-based studies in the region. The particulate samples show low to medium oxidative potential per unit of mass, in relation to an urban road side control, being more reactive with ascorbate than with glutathione or urate. However, the PM oxidative potential per volume of air is exceptionally high, confirming that the workers are exposed to a considerable oxidative environment. PM released by iron ore mining and processing activities should be considered a potential health risk to the mine workers and nearby employees, and strategies to combat the issue are suggested.

Purpose Evaluation of dose escalated salvage radiotherapy (SRT) in patients after radical prostatectomy (RP) who had never received antihormonal therapy. To investigate prognostic factors of the outcome of SRT and to analyze which patient subsets benefit most from dose escalation. Materials and methods Between 2002 and 2008, 76 patients were treated in three different dose-groups: an earlier cohort treated with 66 Gy irrespective of pre-RT-characteristics and two later cohorts treated with 70 Gy or 75 Gy depending on pre-RT-characteristics. Biochemical-relapse-free-survival (bRFS), clinical-relapse-free-survival (cRFS) and late toxicity were evaluated. Results Four-year bRFS and cRFS were 62.5% and 85%. Gleason score <8, positive surgical resection margin (PSRM) and low PSA (≤0.5 ng/ml) before SRT resulted in higher bRFS. Analysis of the whole group showed no clear dose-outcome relationship. Patients with PSRM, however, had improved bRFS when escalating >66 Gy. While > 70 Gy did not improve the overall results, 4-year bRFS for patients with manifest local recurrence in the high-dose group was still comparable to those without manifest local recurrences. No grade 4 and minimal grade 3 gastrointestinal and urinary toxicity were observed. Conclusions Dose-escalated SRT achieves high biochemical control. The data strongly support the application of at least 70 Gy rather than 66 Gy. They do not prove positive effects of doses >70 Gy but do not disprove them as these doses were only applied to an unfavorable patients selection.

Xanthohumol (XN), a prenylated chalcone from hops, has been reported to exhibit a variety of health-beneficial effects. However, poor bioavailability may limit its application in the prevention and therapy of diseases. The objective of this study was to determine whether a micellar solubilization of xanthohumol could enhance the bioavailability and biological efficacy of xanthohumol in a Western-type diet (WTD) induced model of obesity, diabetes and non-alcoholic fatty liver disease (NAFLD). After 3 weeks feeding with WTD, XN was additionally applied per oral gavage as micellar solubilizate (s-XN) or native extract (n-XN) at a daily dose of 2.5 mg/kg body weight for a further 8 weeks. Control mice received vehicle only in addition to the WTD. WTD-induced body weight-gain and glucose intolerance were significantly inhibited by s-XN application. Furthermore, WTD-induced hepatic steatosis, pro-inflammatory gene expression (MCP-1 and CXCL1) and immune cell infiltration as well as activation of hepatic stellate cells (HSC) and expression of collagen alpha I were significantly reduced in the livers of s-XN-treated mice compared to WTD controls. In contrast, application of n-XN had no or only slight effects on the WTD-induced pathological effects. In line with this, plasma XN concentration ranged between 100–330 nmol/L in the s-XN group while XN was not detectable in the serum samples of n-XN-treated mice. In conclusion, micellar solubilization enhanced the bioavailability and beneficial effects of xanthohumol on different components of the metabolic syndrome including all pathological steps of NAFLD. Notably, this was achieved in a dose more than 10-fold lower than effective beneficial doses of native xanthohumol reported in previous in vivo studies.

Interposers with through-silicon vias (TSVs) play a key role in the three-dimensional integration and packaging of integrated circuits and microelectromechanical systems. In the current practice of fabricating interposers, solder balls are placed next to the vias; however, this approach requires a large foot print for the input/output (I/O) connections. Therefore, in this study, we investigate the possibility of placing the solder balls directly on top of the vias, thereby enabling a smaller pitch between the solder balls and an increased density of the I/O connections. To reach this goal, inkjet printing (that is, piezo and super inkjet) was used to successfully fill and planarize hollow metal TSVs with a dielectric polymer. The under bump metallization (UBM) pads were also successfully printed with inkjet technology on top of the polymer-filled vias, using either Ag or Au inks. The reliability of the TSV interposers was investigated by a temperature cycling stress test (−40 °C to +125 °C). The stress test showed no impact on DC resistance of the TSVs; however, shrinkage and delamination of the polymer was observed, along with some micro-cracks in the UBM pads. For proof of concept, SnAgCu-based solder balls were jetted on the UBM pads. Three-dimensional circuits by jetting droplets Inkjet printers that disperse extremely tiny droplets of functional material with high positioning accuracy can help to quadruple the input/output densities of 3D circuit packages. Stacking chips vertically packs more computing power into a device, but making reliable connections between circuit boards with different thermal expansion properties is tricky. Behnam Khorramdel at Tampere University of Technology, Finland, and his co-workers turned to inkjet printing to improve the fabrication of through-silicon vias (TSVs) that link 3D circuits through hollow, copper-plated pathways. The team discovered that filling TSVs droplet-by-droplet with an ultraviolet-light-curable polymer insulates against detrimental thermal expansion for dramatically improved connection densities. Precision jetprinted depositions of metal solder directly on top of the TSVs for chip stacking also reduced typical connection footprints. Stress tests on high-density prototype chips demonstrated that the polymer-infused TSVs remained stable over thousands of temperature cycling experiments.