N-Octanoyl Dopamine,a Non-Hemodyanic Dopamine Derivative,for Cell Protection during Hypothermic Organ Preservation

Background

Although donor dopamine treatment reduces the requirement for post transplantation dialysis in renal transplant recipients, implementation of dopamine in donor management is hampered by its hemodynamic side-effects. Therefore novel dopamine derivatives lacking any hemodynamic actions and yet are more efficacious in protecting tissue from cold preservation injury are warranted. We hypothesized that variation of the molecular structure would yield more efficacious compounds avoid of any hemodynamic effects.

Methodology/Principal Findings

To this end, we assessed protection against cold preservation injury in HUVEC by the attenuation of lactate dehydrogenase (LDH) release. Modification of dopamine by an alkanoyl group increased cellular uptake and significantly improved efficacy of protection. Further variation revealed that only compounds bearing two hydroxy groups in ortho or para position at the benzene nucleus, i.e. strong reductants, were protective. However, other reducing agents like N-acetyl cysteine and ascorbate, or NADPH oxidase inhibition did not prevent cellular injury following cold storage. Unlike dopamine, a prototypic novel compound caused no hemodynamic side-effects.

Conclusions/Significance

In conclusion, we demonstrate that protection against cold preservation injury by catecholamines is exclusively governed by strong reducing capacity and sufficient lipophilicity. The novel dopamine derivatives might be of clinical relevance in donor pre-conditioning as they are completely devoid of hemodynamic action, their increased cellular uptake would reduce time of treatment and therefore also may have a potential use for non-heart beating donors.     

Tree mortality across biomes is promoted by drought intensity,lower wood density and higher specific leaf area

Drought events are increasing globally, and reports of consequent forest mortality are widespread. However, due to a lack of a quantitative global synthesis, it is still not clear whether drought‐induced mortality rates differ among global biomes and whether functional traits influence the risk of drought‐induced mortality. To address these uncertainties, we performed a global meta‐analysis of 58 studies of drought‐induced forest mortality. Mortality rates were modelled as a function of drought, temperature, biomes, phylogenetic and functional groups and functional traits. We identified a consistent global‐scale response, where mortality increased with drought severity [log mortality (trees trees^?1 year^?1) increased 0.46 (95% CI = 0.2–0.7) with one SPEI unit drought intensity]. We found no significant differences in the magnitude of the response depending on forest biomes or between angiosperms and gymnosperms or evergreen and deciduous tree species. Functional traits explained some of the variation in drought responses between species (i.e. increased from 30 to 37% when wood density and specific leaf area were included). Tree species with denser wood and lower specific leaf area showed lower mortality responses. Our results illustrate the value of functional traits for understanding patterns of drought‐induced tree mortality and suggest that mortality could become increasingly widespread in the future.     

Hypolithic Cyanobacteria Supported Mainly by Fog in the Coastal Range of the Atacama Desert

The Atacama Desert is one of the driest places on Earth, with an arid core highly adverse to the development of hypolithic cyanobacteria. Previous work has shown that when rain levels fall below ~1 mm per year, colonization of suitable quartz stones falls to virtually zero. Here, we report that along the coast in these arid regions, complex associations of cyanobacteria, archaea, and heterotrophic bacteria inhabit the undersides of translucent quartz stones. Colonization rates in these areas, which receive virtually no rain but mainly fog, are significantly higher than those reported inland in the hyperarid zone at the same latitude. Here, hypolithic colonization rates can be up to 80%, with all quartz rocks over 20 g being colonized. This finding strongly suggests that hypolithic microbial communities thriving in the seaward face of the Coastal Range can survive with fog as the main regular source of moisture. A model is advanced where the development of the hypolithic communities under quartz stones relies on a positive feedback between fog availability and the higher thermal conductivity of the quartz rocks, which results in lower daytime temperatures at the quartz–soil interface microenvironment.     

Carotenoid supplementation and sex-specific trade-offs between colouration and condition in common tern chicks

Carotenoids, as pigments with antioxidant and immunoregulatory properties, play a crucial role in developing chicks. Carotenoids must be acquired through diet and are relatively scarce, suggesting that their availability is a limiting factor leading to a trade-off between colour displays and physiological functions. However, potential differences in this trade-off between male and female chicks have been little studied. We manipulated carotenoid availability in 9 days old common tern Sterna hirundo chicks by supplementing their fish diet with four carotenoids during 9 days. Our aim was to examine sex-specific responses to the experimental increase of dietary carotenoids on plasma circulation, physiological and condition variables and successful fledging. Furthermore, to explore the functional and evolutionary basis of the trade-off, we studied the relationships among carotenoid concentration, mediated immune response and foot colouration. After treatment, control chicks showed decreasing plasma levels for most carotenoid types, whereas supplemented chicks had strong increases. Colour luminosity and saturation increased in both treatment groups, while hue only changed significantly towards redder feet in supplemented females. Supplemented chicks presented neither different T-cell-mediated immunity nor other differences compared to control chicks. Nevertheless, supplemented females showed tendencies towards decreased immune responses and increased δ¹⁵N signatures, and supplemented males towards greater body mass. Our results indicate colouration may have, in females, a signalling function as to compensate for immunological costs. In males, additional availability of carotenoids may contribute to improve the body condition. This study suggests that trade-off responses to carotenoid availability are sex-specific in tern chicks. Thus, parental carotenoid supply to chicks may be an unrecognised component in sex allocation.     

Genetic manipulation of butyrate formation pathways in Clostridium butyricum

Clostridium butyricum is one of the commonly used species for fermentative hydrogen production. While producing H₂, it can produce acids (lactic, acetic and butyric acids) and CO₂, as well as a small amount of ethanol. It has been proposed that elimination of competing pathways, such as the butyrate formation pathway, should increase H₂ yields in Clostridium species. However, the application of this strategy has been hindered by the unavailability of genetic tools for these organisms. In this study, we successfully transferred a plasmid (pMTL007) to C. butyricum by inter-specific conjugation with Escherichia coli and disrupted hbd, the gene encoding β-hydroxybutyryl-CoA dehydrogenase in C. butyricum. Fermentation data showed that inactivation of hbd in C. butyricum eliminated the butyrate formation pathway, resulting in a significant increase in ethanol production and an obvious decrease in H₂ yield compared with the wild type strain. However, under low partial pressure of H₂, the hbd-deficient strain showed increased H₂ production with the simultaneous decrease of ethanol production, indicating that H₂ production by C. butyricum may compete for NADH with the ethanol formation pathway. Together with the discovery of a potential bifurcating hydrogenase, this study extends our understanding of the mechanism of H₂ production by C. butyricum.     

Pilot clinical trial of type 1 dendritic cells loaded with autologous tumor lysates combined with GM-CSF, pegylated IFN, and cyclophosphamide for metastatic cancer patients

Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-α, TNF-α, and polyinosinic:polycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-γ-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing.     

Validity and Reproducibility of a Spanish Dietary History

Objective

To assess the validity and reproducibility of food and nutrient intake estimated with the electronic diet history of ENRICA (DH-E), which collects information on numerous aspects of the Spanish diet.

Methods

The validity of food and nutrient intake was estimated using Pearson correlation coefficients between the DH-E and the mean of seven 24-hour recalls collected every 2 months over the previous year. The reproducibility was estimated using intraclass correlation coefficients between two DH-E made one year apart.

Results

The correlations coefficients between the DH-E and the mean of seven 24-hour recalls for the main food groups were cereals (r = 0.66), meat (r = 0.66), fish (r = 0.42), vegetables (r = 0.62) and fruits (r = 0.44). The mean correlation coefficient for all 15 food groups considered was 0.53. The correlations for macronutrients were: energy (r = 0.76), proteins (r = 0.58), lipids (r = 0.73), saturated fat (r = 0.73), monounsaturated fat (r = 0.59), polyunsaturated fat (r = 0.57), and carbohydrates (r = 0.66). The mean correlation coefficient for all 41 nutrients studied was 0.55. The intraclass correlation coefficient between the two DH-E was greater than 0.40 for most foods and nutrients.

Conclusions

The DH-E shows good validity and reproducibility for estimating usual intake of foods and nutrients.