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There is growing interest in developing spatially resolved methane (CH4) isotopic source signatures to aid in geographic source attribution of CH4 emissions. CH4 hydrogen isotope measurements (δ2H–CH4) have the potential to be a powerful tool for geographic differentiation of CH4 emissions from freshwater environments, as well as other microbial sources. This is because microbial δ2H–CH4 values are partially dependent on the δ2H of environmental water (δ2H–H2O), which exhibits large and well-characterized spatial variability globally. We have refined the existing global relationship between δ2H–CH4 and δ2H–H2O by compiling a more extensive global dataset of δ2H–CH4 from freshwater environments, including wetlands, inland waters, and rice paddies, comprising a total of 129 different sites, and compared these with measurements and estimates of δ2H–H2O, as well as δ13C-CH4 and δ13C–CO2 measurements. We found that estimates of δ2H–H2O explain approximately 42 % of the observed variation in δ2H–CH4, with a flatter slope than observed in previous studies. The inferred global δ2H–CH4 vs. δ2H–H2O regression relationship is not sensitive to using either modelled precipitation δ2H or measured δ2H–H2O as the predictor variable. The slope of the global freshwater relationship between δ2H–CH4 and δ2H–H2O is similar to observations from incubation experiments but is different from pure culture experiments. This result is consistent with previous suggestions that variation in the δ2H of acetate, controlled by environmental δ2H–H2O, is important in determining variation in δ2H–CH4. The relationship between δ2H–CH4 and δ2H–H2O leads to significant differences in the distribution of freshwater δ2H–CH4 between the northern high latitudes (60–90∘ N), relative to other global regions. We estimate a flux-weighted global freshwater δ2H–CH4 of −310 ± 15 ‰, which is higher than most previous estimates. Comparison with δ13C measurements of both CH4 and CO2 implies that residual δ2H–CH4 variation is the result of complex interactions between CH4 oxidation, variation in the dominant pathway of methanogenesis, and potentially other biogeochemical variables. We observe a significantly greater distribution of δ2H–CH4 values, corrected for δ2H–H2O, in inland waters relative to wetlands, and suggest this difference is caused by more prevalent CH4 oxidation in inland waters. We used the expanded freshwater CH4 isotopic dataset to calculate a bottom-up estimate of global source δ2H–CH4 and δ13C-CH4 that includes spatially resolved isotopic signatures for freshwater CH4 sources. Our bottom-up global source δ2H–CH4 estimate (−278 ± 15 ‰) is higher than a previous estimate using a similar approach, as a result of the more enriched global freshwater δ2H–CH4 signature derived from our dataset. However, it is in agreement with top-down estimates of global source δ2H–CH4 based on atmospheric measurements and estimated atmospheric sink fractionations. In contrast our bottom-up global source δ13C-CH4 estimate is lower than top-down estimates, partly as a result of a lack of δ13C-CH4 data from C4-plant-dominated ecosystems. In general, we find there is a particular need for more data to constrain isotopic signatures for low-latitude microbial CH4 sources.

Cancer cells are under oxidative stress due to a large production of reactive oxygen species (ROS), which involve in cell proliferation and cancer promotion and progression. On the other hand, ROS promotes cell death, depending on the rate of ROS production and the activity of antioxidant systems. Recently, "oxidation therapy" has arisen as a promising anticancer strategy, which can be achieved by inducing the generation of cytotoxic level of ROS or inhibiting the antioxidant systems in tumor cells. Here, we report oxidative stress amplifying nanoplatforms as novel anticancer therapeutics, which are able not only to suppress antioxidant but also to generate ROS simultaneously in acidic tumor microenvironments. The oxidative stress amplifying nanoplatforms are composed of dual pH-sensitive PBCAE copolymer, polymeric prodrug of BCA (benzoyloxycinnamaldehyde) and heme oxygenase-1 (HO-1) inhibiting zinc protoporphyrin (ZnPP). PBCAE was designed to incorporate ROS-generating BCA in its backbone via acid-cleavable acetal linkages and self-assemble to form micelles that encapsulate ZnPP. In vitro proof-of-concept studies revealed that ZnPP encapsulated in PBCAE micelles suppressed HO-1 to make cancer cells more vulnerable to BCA-induced ROS, leading to enhanced apoptotic cell death. In addition, ZnPP-loaded PBCAE micelles significantly suppressed the tumor growth in human cancer xenograft mouse models. We believe that oxidative stress amplifying micellar nanoparticles have a great potential as novel redox anticancer therapeutics.

Gábor Raffai,1 Byungkuk Kim,1 Sanga Park,1 Gilson Khang,1 Dongwon Lee,1 Paul M Vanhoutte1,21World Class University, Department of BIN Fusion Technology, Chonbuk National University, Jeonju, Jeonbuk, South Korea; 2Department of Pharmacology and Pharmacy and State Key Laboratory for Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, ChinaBackground and purpose: Cinnamaldehyde, a major component of cinnamon, induces the generation of reactive oxygen species and exerts vasodilator and anticancer effects, but its short half-life limits its clinical use. The present experiments were designed to compare the acute relaxing properties of cinnamaldehyde with those of self-assembling polymer micelles either loaded with cinnamaldehyde or consisting of a polymeric prodrug [poly(cinnamaldehyde)] that incorporates the compound in its backbone.Methods: Rings of porcine coronary arteries were contracted with the thromboxane A2 receptor agonist U46619 or 40 mM KCl, and changes in isometric tension were recorded.Results: Cinnamaldehyde induced concentration-dependent but endothelium-independent, nitric oxide synthase (NOS)-independent, cyclooxygenase-independent, soluble guanylyl cyclase (sGC)-independent, calcium-activated potassium-independent, and TRPA1 channel-independent relaxations. Cinnamaldehyde also inhibited the contractions induced by 40 mM KCl Ca2+ reintroduction in 40 mM KCl Ca2+-free solution or by the Ca2+ channel opener Bay K8644. Cinnamaldehyde-loaded control micelles induced complete, partly endothelium-dependent relaxations sensitive to catalase and inhibitors of NOS or sGC, but not cyclooxygenase or TRPA1, channels. Cinnamaldehyde-loaded micelles also inhibited contractions induced by 40 mM KCl Ca2+ reintroduction or Bay K8644. Poly(cinnamaldehyde) micelles induced only partial, endothelium-dependent relaxations that were reduced by inhibitors of NOS or sGC and by catalase and the antioxidant tiron, but not by indomethacin or TRPA1 channel blockers.Conclusion: The present findings demonstrate that cinnamaldehyde-loaded and poly(cinnamaldehyde) micelles possess vasodilator properties, but that the mechanism underlying the relaxation that they cause differs from that of cinnamaldehyde, and thus could be used both to relieve coronary vasospasm and for therapeutic drug delivery.Keywords: calcium sensitivity, cinnamaldehyde, L-type Ca2+ channel, NO synthase, micelle-forming polymeric prodrug, porcine coronary artery

Acetaminophen (APAP) is the most widely used analgesic and its overdose, intentional or unintentional, is known to cause massive oxidative stress and liver tissue damages characterized by hepatocellular apoptosis and hemorrhagic necrosis, leading to acute liver failure (ALF). There has been great interest in the use of antioxidant and anti-inflammatory drugs for the effective treatment of ALF. Manganese porphyrin (MnP), a nonpeptidyl mimic of superoxide dismutase is a promising compound with antioxidant activity, but its application is curtailed by a short half-life in blood. We have recently developed a new family of biodegradable and antioxidant polymeric prodrug, poly(vanillyl alcohol-co-oxalate) (PVAX), which is able to scavenge H2O2 and release antioxidant and anti-inflammatory vanillyl alcohol. In this work, we developed MnP-loaded PVAX particles and evaluated their potential as antioxidant and anti-inflammatory therapeutic agents for APAP-induced ALF. PVAX particles and MnP showed synergistic antioxidant and anti-inflammatory activities in macrophages stimulated with LPS (lipopolysaccharide). Animal studies using a mouse model of APAP-induced ALF revealed that MnP-loaded PVAX particles significantly reduced the serum ALT level and protected liver damages. We anticipated that MnP-loaded PVAX particles have great potential as a therapeutic agent for oxidative stress-associated diseases such as APAP-induced ALF.

Cinnamaldehyde, a major active compound of cinnamon, is known to induce apoptotic cell death in numerous human cancer cells. Here, dual acid-responsive polymeric micelle-forming cinnamaldehyde prodrugs, poly[(3-phenylprop-2-ene-1,1-diyl)bis(oxy)bis(ethane-2,1-diyl)diacrylate]-co-4,4’(trimethylene dipiperidine)-co-poly(ethylene glycol), termed PCAE copolymers, are reported. PCAE is designed to incorporate cinnamaldehyde via acid-cleavable acetal linkages in its pH-sensitive hydrophobic backbone and self assemble to form stable micelles which can encapsulate camptothecin (CPT). PCAE self assembles to form micelles which release CPT and cinnamaldehyde in pH-dependent manners. PCAE micelles induce apoptotic cell death through the generation of intracellular reactive oxygen species (ROS) and exert synergistic anticancer effects with a payload of CPT in vitro and in vivo model of SW620 human colon tumor-bearing mice. It is anticipated that dual acid-sensitive micelle-forming PCAE with intrinsic anticancer activities has enormous potential as novel anticancer therapeutics.

This paper presents to develop a multi-degree of freedom motion platform utilizing spherical wheels for unmanned systems. Recently, as rapidly developing unmanned robotic systems, it increases demands to control the systems by operators remotely and precisely, in particular for unmanned vehicles. Various multi-degree of freedoms (DOFs) motion control platforms have been utilized to transfer realistic motion to remote operators as they are on board by providing virtual reality. However, existing motion platforms have limits in motion realization and the number of DOFs due to mechanical linkages and actuating mechanism. In this paper, a new concept and design of 6 DOFs motion platform, capable of controlling 3 DOFs rotation and 3 DOFs translation motion is developed and feasibility and performance of motion control are practically demonstrated using an open-loop control. The performance shows the design of the motion platform sucessfully control rotation and translation motion independently and thus effectively control the unmanned systems.